Antiretroviral Agents General Statement

[Section Outline]

Laboratory Monitoring
Adverse Effects
Drug Interactions
Initial Antiretroviral Therapy in Antiretroviral-naive Adults and Adolescents
Antiretroviral Therapy in Antiretroviral-experienced Adults and Adolescents
Antiretroviral Therapy in Pediatric Patients
Antiretroviral Therapy During Pregnancy
Antiretrovirals for Prevention of Perinatal HIV Transmission
Antiretrovirals for Prevention of Sexual Transmission of HIV (TasP)
Antiretrovirals for Preexposure Prophylaxis for Prevention of HIV-1 Infection (PrEP)
Antiretrovirals for Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)
Antiretrovirals for Postexposure Prophylaxis following Sexual, Injection Drug Use, or other Nonoccupational Exposures to HIV (nPEP)
Clinical Experience and Trials of HIV Protease Inhibitors in Patients with COVID-19

Classification of Antiretroviral Agents

Antiretroviral agents are synthetic antiviral agents that have antiviral activity against human immunodeficiency virus (HIV) and are used in the management of HIV infection.7,65,71,200,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,235 Six different classes of antiretroviral agents are commercially available in the US: HIV nucleoside reverse transcriptase inhibitors (NRTIs), HIV protease inhibitors (PIs), HIV nonnucleoside reverse transcriptase inhibitors (NNRTIs), HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors (INSTIs), and HIV entry and fusion inhibitors.200,203,204,205,206,207,208,209,210,211,212,213,214,215,216,217,218,219,220,221,222,223,224,225,226,235 These 6 different antiretroviral classes include over 30 different antiretroviral agents and the majority of these drugs are commercially available as single-entity preparations and in various fixed-combination preparations, including some formulations that provide a single-tablet antiretroviral regimen.200

HIV NUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NRTIs)

abacavir sulfate (ABC)
didanosine (ddI)
emtricitabine (FTC)
lamivudine (3TC)
stavudine (d4T)
zidovudine (ZDV, AZT)

HIV NRTIs are synthetic analogs of naturally occurring nucleosides.65,71,109,120,216,217,218,219,220,222,222,433,434,438,439

All 6 HIV NRTIs currently available in the US are available as single-entity preparations216,217,218,219,220,222 and most also are available in various 2- or 3-drug fixed combinations.227,228,229,230,232,233,235,240,243,244,245,248,250,251,254,256 Abacavir, lamivudine, and zidovudine are available in fixed combinations that contain only other NRTIs (dual NRTIs, triple NRTIs).227,228,229 In addition, emtricitabine and lamivudine are available in 2-drug fixed combinations with an HIV nucleotide reverse transcriptase inhibitor (tenofovir alafenamide fumarate [TAF] or tenofovir disoproxil fumarate [TDF])230,245 and abacavir, emtricitabine, and lamivudine are available in various 3-drug fixed combinations that include an HIV INSTI, NNRTI, or PI.232,233,235,240,243,244,248,250,251,254

Fixed Combinations Containing Only NRTIs

abacavir/lamivudine
abacavir/lamivudine/zidovudine
lamivudine/zidovudine

NRTIs generally are active in vitro against human retroviruses, including HIV type 1 (HIV-1)65,109,120,216,217,218,219,220,222,428,437,439,440,441,442 and HIV type 2 (HIV-2).16,17,65,200,216,218,219,222,433,437,440,441,442 Lamivudine and emtricitabine also are active against hepatitis B virus (HBV);200 however, abacavir,311 didanosine,435 and zidovudine109,433,435 have only limited activity against HBV. Abacavir, didanosine, and zidovudine are active against many animal retroviruses, including feline leukemia virus, Friend leukemia virus, Harvey murine sarcoma virus, murine leukemia virus, and simian T lymphotropic virus.311,429 HIV NRTIs generally have been inactive against other human or animal viruses tested, including herpes simplex virus (HSV) types 1 and 2, influenza virus, adenovirus, cytomegalovirus (CMV), respiratory syncytial virus (RSV), varicella zoster virus (VZV), and vaccinia virus.109,429,431,440,441

NRTIs are prodrugs that are inactive until phosphorylated by cellular enzymes and converted into active triphosphate metabolites.65,71,109,120,216,217,218,219,220,222,311,312,428,432,433,438,439,444 The pharmacologically active triphosphate metabolites then compete with naturally occurring deoxynucleoside triphosphates for the active binding site on viral reverse transcriptase, an enzyme essential for viral replication.65,120,216,217,218,219,220,222,311,428,432,434,438,439,444 Once the triphosphate metabolites become incorporated into viral DNA, synthesis of the viral DNA chain is terminated since the metabolites lack a functional 3'-hydroxyl group preventing further 5' to 3' phosphodiester linkages.71,109,120,216,311,428,433,434,438,439

HIV NUCLEOTIDE REVERSE TRANSCRIPTASE INHIBITORS

tenofovir alafenamide fumarate (TAF)
tenofovir disoproxil fumarate (TDF; tenofovir DF)

HIV nucleotide reverse transcriptase inhibitors are a group of synthetic acyclic nucleoside phosphonates that have a similar mechanism of action.383 Tenofovir is the only nucleotide reverse transcriptase inhibitor commercially available in the US and, for purposes of therapeutic decisions, is grouped with the NRTI class of antiretrovirals.200 Tenofovir is commercially available as tenofovir alafenamide fumarate (TAF)243,244,245,248,250 and tenofovir disoproxil fumarate (TDF).221,230,232,233,235,251,254,258,259

For the treatment of HIV infection, TAF is commercially available in the US only in fixed-combination preparations.243,244,245,248,250

TDF is commercially available in the US as a single-entity preparation221 and also is commercially available in fixed-combination preparations.230,232,233,235,251,254,258,259

Fixed Combinations Containing TAF

bictegravir/emtricitabine/TAF
darunavir/cobicistat/emtricitabine/TAF
elvitegravir/cobicistat/emtricitabine/TAF
emtricitabine/rilpivirine/TAF
emtricitabine/TAF

Fixed Combinations Containing TDF

doravirine/lamivudine/TDF
efavirenz/emtricitabine/TDF
efavirenz/lamivudine/TDF
elvitegravir/cobicistat/emtricitabine/TDF
emtricitabine/rilpivirine/TDF
emtricitabine/TDF
lamivudine/TDF

TAF200,482,483,484 and TDF200,221,383 are both tenofovir prodrugs that are inactive until hydrolyzed in plasma to tenofovir and then converted intracellularly to the active metabolite tenofovir diphosphate. Tenofovir diphosphate competes with naturally occurring deoxyadenosine triphosphate and, after incorporation into viral DNA, synthesis of the viral DNA chain is terminated.221,383 TAF is more stable in blood and plasma and more efficiently converted intracellularly to tenofovir diphosphate than TDF, resulting in lower circulating levels of tenofovir and higher concentrations of the active metabolite within HIV target cells than those reported with TDF.200,482,483,484

Tenofovir is active against HIV-1,200,221 has some activity against HIV-2,221 and also has activity against HBV.200,407

HIV INTEGRASE INHIBITORS (INSTIs)

bictegravir (BIC)
dolutegravir sodium (DTG)
elvitegravir (EVG)
raltegravir potassium (RAL)

HIV integrase inhibitors inhibit an HIV enzyme that integrates viral DNA into the infected cell's DNA.415 All 4 HIV integrase inhibitors currently available in the US are HIV integrase strand transfer inhibitors (INSTIs).225,235,236,248,420

Bictegravir is commercially available in the US only in fixed combination with emtricitabine and TAF.248 Elvitegravir is commercially available in the US only in fixed-combination preparations that contain cobicistat (a pharmacokinetic enhancer), emtricitabine, and either TAF (EVG/c/FTC/TAF)243 or TDF (EVG/c/FTC/TDF).235 Dolutegravir is commercially available in the US as a single-entity preparation236 and also is commercially available in various fixed-combination preparations.240,247,256 Raltegravir is commercially available in the US only as a single-entity preparation.225

Fixed Combinations Containing INSTIs

abacavir/dolutegravir/lamivudine
bictegravir/emtricitabine/TAF
dolutegravir/lamivudine
dolutegravir/rilpivirine
elvitegravir/cobicistat/emtricitabine/TAF
elvitegravir/cobicistat/emtricitabine/TDF

INSTIs inhibit the activity of HIV-1 integrase, an enzyme that integrates HIV DNA into the host cell genome.225,235,248,420 Integration is required for maintenance of the viral genome and for efficient viral gene expression and replication.225,235,248,420 Inhibition of integration prevents propagation of viral infection.225,235,248,420 Bictegravir, dolutegravir, elvitegravir, and raltegravir also have potent in vitro activity against HIV-2.6,16,17,200,236,248

HIV NONNUCLEOSIDE REVERSE TRANSCRIPTASE INHIBITORS (NNRTIs)

doravirine (DOR)
efavirenz (EFV)
etravirine (ETV)
nevirapine (NVP)
rilpivirine (RPV)

HIV NNRTIs are a group of structurally diverse synthetic antiretrovirals that have a similar mechanism of action.62

All 5 HIV NNRTIs currently available in the US are available as single-entity preparations.212,213,214,226,255 In addition, doravirine, efavirenz, and rilpivirine are available in fixed combinations.232,233,244,247,251,254

Fixed Combinations Containing NNRTIs

dolutegravir/rilpivirine
doravirine/lamivudine/TDF
efavirenz/emtricitabine/TDF
efavirenz/lamivudine/TDF
emtricitabine/rilpivirine/TAF
emtricitabine/rilpivirine/TDF

NNRTIs have a very specific spectrum of antiviral activity.62,212,215,447 NNRTIs are active against HIV-1,212,213,214,215,226,255,446,447 but HIV-2 are intrinsically resistant to NNRTIs.16,17,200,212,213,215,226,446,447 NNRTIs also have been inactive against other human or animal viruses tested to date.300,447

NNRTIs inhibit replication of HIV-1 by interfering with viral RNA- and DNA-directed polymerase activities of reverse transcriptase.84,212,214,215,226,445,446,447,449 The mechanism of action of NNRTIs differs from that of NRTIs.84,445 While NRTIs interfere with reverse transcriptase activity by becoming incorporated into the growing viral DNA chain, NNRTIs interfere with the function of reverse transcriptase by binding directly to the enzyme in a noncompetitive fashion.62,212,214,215,255,445,449 Unlike the NRTIs, the antiretroviral activity of NNRTIs does not depend on intracellular conversion to an active metabolite.84,445

HIV PROTEASE INHIBITORS (PIs)

atazanavir sulfate (ATV)
darunavir (DRV)
fosamprenavir calcium (FPV)
indinavir sulfate (IDV)
lopinavir and ritonavir (LPV/r)
nelfinavir mesylate (NFV)
ritonavir (RTV)
saquinavir mesylate (SQV)
tipranavir (TPV)

HIV PIs are synthetic antiviral agents that were specifically designed based on the structure of HIV protease, an enzyme that plays an essential role in the HIV replication cycle.7,9,15,74,193,205,206,208,209,210,261,302,303,472,473 Using computer models of the enzyme and binding sites on the enzyme, a wide variety of compounds have been identified as potential inhibitors of HIV protease activity.7,15,74,193,261,302,303,472,473,476 There currently are 9 HIV PIs available in the US.203,206,207,208,209,210,211 Amprenavir was discontinued in late 2007 and is no longer commercially available in the US;419 commercially available fosamprenavir calcium is a prodrug that is hydrolyzed in vivo to amprenavir.205

Lopinavir is commercially available in the US only in fixed combination with low-dose ritonavir (lopinavir/ritonavir).207 Atazanavir and darunavir are commercially available in the US as single-entity preparations203,204 and in fixed combination with cobicistat, a pharmacokinetic enhancer.237,238 Other HIV PIs (fosamprenavir, indinavir, nelfinavir, ritonavir, saquinavir, tipranavir) are commercially available in the US only as single-entity preparations.203,204,205,206,208,209,210,211 HIV PIs usually are used in conjunction with a pharmacokinetic enhancer (either cobicistat or low-dose ritonavir).200 (See Pharmacokinetic Enhancers under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Drug Interactions.)

Fixed Combinations Containing PIs

atazanavir/cobicistat
darunavir/cobicistat
darunavir/cobicistat/emtricitabine/TAF
lopinavir/ritonavir

PIs have a limited spectrum of antiviral activity.7,193,206,261,303,472,474,475 These drugs are active against HIV-1,7,193,203,204,205,206,207,208,209,210,211,261,303,472,474,475 but have variable activity against HIV-2.16,17,200 Darunavir, lopinavir, and saquinavir are more active against HIV-2 than other currently available HIV PIs.16,17,200

HIV PIs have similar mechanisms of action.7,9,193,261,302,303,310,472,474,475 These drugs inhibit replication of HIV-1 and HIV-2 by directly interfering with HIV protease activity.7,9,15,193,203,204,205,206,207,208,209,210,211,261,303,310,472,474,475 This prevents the formation of mature virions.9,203,204,205,206,207,208,209,210,211,303,472,475 Most of the drugs function as selective, competitive, reversible inhibitors of the enzyme.7,9,15,193,261,302,472 Although fosamprenavir calcium is a prodrug and has little or no antiviral activity until hydrolyzed in vivo to amprenavir,205 the antiretroviral activity of other HIV PIs does not depend on intracellular conversion to an active metabolite.203,204,206,207,208,209,210,303,474,475

HIV ENTRY AND FUSION INHIBITORS

enfuvirtide (T-20)
fostemsavir tromethamine
ibalizumab-uiyk (IBA)
maraviroc (MVC)

HIV entry and fusion inhibitors are a group of antiretrovirals that have mechanisms of action that involve blocking HIV from entering human cells.223,224,249,385,386,415,492,257 These antiretrovirals are commercially available in the US only as single-entity preparations.223,224,249,257

Enfuvirtide is an HIV fusion inhibitor that interferes with entry of HIV-1 into host cells by inhibiting fusion of viral and cellular membranes.223,385,386,492 The drug binds to the first heptad-repeat (HR1) in the gp41 subunit of the viral envelope glycoprotein and prevents the conformational changes that are required for fusion of the virus to the membrane of the host CD4⁺ T-cell.223,385 Enfuvirtide is active against HIV-1, but inactive against HIV-2.223

Fostemsavir tromethamine is a prodrug that is inactive until hydrolyzed in vivo to temsavir, an HIV-1 attachment inhibitor.257 Temsavir binds to the gp120 subunit of the HIV-1 envelope glycoprotein gp160 and selectively inhibits the interaction between the virus and cellular CD4 receptors, thereby preventing attachment.257 In addition, temsavir can inhibit gp120-dependent post-attachment steps required for viral entry into host cells.257

Ibalizumab-uiyk is a CD4-directed post-attachment HIV-1 inhibitor.249,492 The drug is a recombinant humanized monoclonal antibody that blocks HIV-1 from infecting CD4⁺ T-cells by binding to domain 2 of CD4, thereby interfering with post-attachment steps required for HIV-1 entry into host cells and prevents viral transmission that occurs via cell-cell fusion.249,492 The binding of ibalizumab-uiyk to domain 2 of CD4 is specific and blocks HIV-1 entry into host cells without causing immunosuppression.249,492 The drug is active in vitro against CCR5- and CXCR4-tropic HIV-1 strains.249

Maraviroc is a CC chemokine receptor 5 (CCR5) antagonist.224,416,417,492 The drug is active against HIV-1;224 activity of CCR5 antagonists against HIV-2 needs further study.16,17 HIV can enter host cells by attaching to the CD4⁺ T-cell receptor using 1 of 2 chemokine co-receptors, CCR5 or CXCR4.415,417 Maraviroc selectively binds to CCR5 on the cell membrane and prevents the interaction of HIV-1 glycoprotein 120 and CCR5 necessary for CCR5-tropic HIV-1 to enter cells.224,415

Guidelines for Use of Antiretroviral Agents for Management of HIV Infection

Therapeutic options for the treatment and prevention of HIV infection and recommendations concerning the use of antiretrovirals are continuously evolving as the result of expanded knowledge concerning the immunopathogenesis of HIV, availability of several different classes of antiretrovirals (HIV nucleoside reverse transcriptase inhibitors [NRTIs], HIV nucleotide reverse transcriptase inhibitors, HIV integrase inhibitors [INSTIs], HIV nonnucleoside reverse transcriptase inhibitors [NNRTIs], HIV protease inhibitors (PIs), HIV entry and fusion inhibitors), and improvements in laboratory methods used to evaluate the rate of disease progression and response to antiretroviral therapy.1,4,8,12,13,27,28,30,31,32,34,36,37,46,47,49,50,51,52,53,54,56,57,58,59,60,70,200,201,202 Effective management of HIV infection must be based on up-to-date information about the biology and pathogenesis of HIV infection and currently available antiretrovirals.1,4,200,201,202

The primary goals of antiretroviral therapy in the management of HIV infection are maximal and durable suppression of HIV viral load (as measured by plasma HIV-1 RNA levels), restoration and/or preservation of immunologic function, prevention or reduction of HIV-related morbidity and mortality, improvements in the duration and quality of life, and prevention of secondary transmission of HIV.1,4,200,201 These goals can best be met by the use of potent multiple-drug antiretroviral regimens that suppress HIV replication to undetectable levels, limit the potential for selection of resistant HIV strains, delay disease progression, and minimize drug-related toxicities and drug interactions.1,4,200,201,202 In addition, strategies that facilitate decisions regarding modification of antiretroviral regimens (e.g., clinical and laboratory monitoring), address comorbidities that can complicate antiretroviral therapy (e.g., coinfection with hepatitis B virus [HBV], hepatitis C virus [HCV], mycobacterial infections), maximize patient adherence to antiretroviral therapy, and minimize the risk of HIV transmission (e.g., through perinatal transmission, blood exposures, high-risk sexual and drug abuse behaviors) also are integral parts of management of HIV infection.1,4,200,201,202

Antiretroviral regimens that were considered treatments of choice for the initial management of HIV infection in the past (e.g., monotherapy or 2-drug regimens that include only NRTIs) are suboptimal since clinical benefits associated with such therapy (i.e., delay in disease progression, decrease in incidence of opportunistic infections, improved survival) are not sustained over the long term.1,4,12,13,27,28,31,32,70,200,201,289,291,316,376,486,487,488 Potent antiretroviral regimens that usually include 3 antiretroviral agents currently are recommended for the management of HIV infection in most adults, adolescents, and children.200,201 These treatment regimens usually are referred to as antiretroviral therapy (ART), combination antiretroviral therapy (combination ART or cART), or multiple-drug antiretroviral therapy,200,201,202 and also have been referred to as highly active antiretroviral therapy (HAART) to differentiate them from the less potent regimens previously used for management of HIV infection.4

Most individuals who receive an appropriate multiple-drug antiretroviral regimen for initial antiretroviral therapy will achieve viral suppression in 8-24 weeks if they are adherent and do not harbor HIV with resistance mutations to the drugs included in the regimen.200 However, experience with various antiretroviral regimens has shown that the duration of clinical benefit from any one regimen may be limited and that optimal antiretroviral therapy involves continuous evaluation of the patient's response to the current regimen and appropriate modification of the regimen whenever the need for a change is indicated by increases in viral load (plasma HIV-1 RNA levels), disease progression, or drug toxicity or intolerance.1,4,200,201 While potent multiple-drug antiretroviral regimens may effectively decrease plasma HIV-1 RNA to undetectable levels for prolonged periods and provide substantial benefits in terms of immunologic, virologic, and clinical responses,1,4,50,51,52,53,55,200,252,274 discontinuing or briefly interrupting antiretroviral therapy in patients with viremia may be associated with rapid increases in plasma HIV-1 RNA levels, decreased CD4⁺ T-cell counts, and increased risk of clinical progression.1,53,200,274

Since information on and experience with available multiple-drug regimens are changing rapidly, experts in the management of patients with HIV infection should be consulted regarding the potential advantages and limitations of available therapeutic options.1,4,200,201,202 The choice of antiretrovirals to include in initial treatment regimens in HIV-infected individuals who are antiretroviral naive (have not previously received antiretroviral therapy) and the most appropriate agents to use in subsequent regimens in antiretroviral-experienced (previously treated) individuals must be individualized based on the advantages and disadvantages of the drugs and on virologic, immunologic, and clinical characteristics of the individual patient.1,4,200,201,202 Some factors that should be considered when selecting antiretrovirals to use in multiple-drug regimens include the antiretroviral potency of the agents, availability and cost of the agents, potential rate of development of resistance, potential pharmacokinetic interactions among the drugs and with other drugs that the patient may be receiving, dosing convenience, adverse effects profile, patient's pretreatment HIV-1 viral load and CD4⁺ T-cell count, gender, pregnancy potential, results of drug-resistance testing, and the patient's ability to adhere to the dosage regimens involved.1,4,200,201

While the most appropriate antiretroviral regimen cannot be defined for each clinical scenario, the US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents,200 HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV,201 and HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission202 have developed comprehensive guidelines that provide information on selection and use of antiretrovirals for the treatment or prevention of HIV infection. These guidelines are based on current knowledge regarding the pathogenesis of HIV, results of clinical studies, and expert opinion and are available at [Web].200,201,202

For information on results of controlled clinical studies evaluating the safety and efficacy of currently available antiretroviral agents and experience to date regarding various antiretroviral regimens, see the Uses sections in the individual drug monographs in 8:18.08.

Laboratory Monitoring

Diagnostic HIV Testing

Early detection of HIV infection facilitates early initiation of antiretroviral treatment and can lead to improved health outcomes, including slower clinical progression and reduced mortality.200,201 The US Centers for Disease Control and Prevention (CDC) recommends routine HIV testing and screening for all adults and adolescents 13-64 years of age in all health-care settings, unless the patient declines (opt-out HIV screening).200,408 This strategy of providing routine HIV testing and screening, regardless of the perceived risk of infection, is considered essential for optimal management of the disease.200 In addition, HIV testing and screening is recommended as a standard of care for all pregnant women and for neonates born to women whose HIV status is unknown.201,202 (See HIV Testing During Pregnancy under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy During Pregnancy.)

Plasma HIV-1 RNA Levels and CD4+ T-cell Counts

Decisions regarding initial antiretroviral therapy and subsequent modification of antiretroviral therapy are guided by plasma HIV-1 RNA levels (viral load), CD4⁺ T-cell counts, and the clinical condition of the patient.200 Although various other surrogate markers and laboratory parameters were used in the past to assess the risk of progression of HIV infection and evaluate efficacy of antiretrovirals (e.g., peripheral blood mononuclear cell [PBMC] HIV-1 titers, plasma concentrations or levels of HIV p24 core antigen [p24 gag protein], β₂-microglobulin, neopterin),12,18,27,34,39,40,41,46,47,49,70,75,78,79,80,87,344 considerable experience showed that the most important surrogate markers are plasma HIV-1 RNA levels and CD4⁺ T-cell counts and these have been used for several decades to manage and monitor HIV infection.18,38,40,43,68,70,78,200,344 Monitoring of lymphocyte subsets other than CD4⁺ T-cells (e.g., CD8, CD19) has not proven clinically useful, adds to costs, and is not routinely recommended.200

Although plasma HIV-1 RNA levels are the most important indicator of response to antiretroviral therapy and are useful in predicting clinical progression,200 CD4⁺ T-cell counts are the major laboratory indicator of immune function in HIV-infected patients and the strongest predictor of subsequent disease progression and survival.200 Measurement of CD4⁺ T-cell count is particularly useful before initiating antiretroviral therapy and plasma HIV-1 RNA levels are particularly useful for monitoring effectiveness of antiretroviral therapy after it has been initiated.200

Updated CDC surveillance case definitions for HIV infection include information regarding age-specific CD4⁺ T-cell counts; therefore, absolute CD4⁺ T-cell counts are recommended for monitoring immune status in children of all ages, with CD4⁺ T-cell percentages used as an alternative in those younger than 5 years of age.201

Recommended Frequency of Plasma HIV-1 RNA Level and CD4+ T-cell Count Testing

Baseline CD4⁺ T-cell counts and plasma HIV-1 RNA levels should be measured in all newly diagnosed HIV-infected patients to provide information on the immunologic and virologic status of the patient and the risk of disease progression.200,201 If initiation of antiretroviral therapy is delayed in HIV-infected adults or adolescents (see Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Initial Antiretroviral Therapy in Antiretroviral-naive Adults and Adolescents), CD4⁺ T-cell counts should be measured every 3-6 months.200 If a decision is made not to initiate antiretroviral therapy in HIV-infected children (see Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy in Pediatric Patients), CD4⁺ T-cell counts/CD4⁺ T-cell percentages and plasma HIV-1 RNA levels should be measured every 3-4 months.201

The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents recommends that plasma HIV-1 RNA levels be measured at the time antiretroviral therapy is initiated and within 2-4 weeks (but not later than 8 weeks) after initiation of treatment.200 If plasma HIV-1 RNA is still detectable 2-8 weeks after initiation of therapy, levels should be measured every 4-8 weeks until they decline to less than 200 copies/mL and then every 3-6 months thereafter.200 For patients receiving stable, suppressive antiretroviral therapy, plasma HIV-1 RNA levels are typically measured every 3-4 months; however, in adherent patients with consistent viral suppression who have had stable immunologic status for longer than 2 years, the interval for plasma HIV-1 RNA testing can be extended to every 6 months.200 Whenever a modification is made to the antiretroviral regimen (e.g., for regimen simplification or because of drug toxicity or intolerance), plasma HIV-1 RNA levels should be measured at the time the change is made and 2-8 weeks after the modification to confirm potency of the new regimen.200

The HHS panel recommends that CD4⁺ T-cell counts be measured at the time antiretroviral therapy is initiated or modified and every 3-6 months during the first 2 years of antiretroviral therapy and whenever viremia (plasma HIV-1 RNA levels consistently greater than 200 copies/mL) develops or CD4⁺ T-cell counts decrease to less than 300 cells/mm³ while the patient is receiving antiretroviral therapy.200 After the patient has received 2 years of antiretroviral therapy and has consistent viral suppression, CD4⁺ T-cell counts can be measured every 12 months in those with counts of 300-500 cells/mm³; CD4⁺ T-cell monitoring is considered optional in those with counts exceeding 500 cells/mm³.200 If antiretroviral therapy is not initiated for any reason in an HIV-infected individual, the panel recommends that CD4⁺ T-cell counts be measured every 3-6 months to assess the urgency for initiation of treatment and assess the need for prophylaxis against opportunistic infections reported in HIV-infected individuals.200

Interpretation of Plasma HIV-1 RNA Levels and CD4+ T-cell Counts

When evaluating response to an antiretroviral regimen, a threefold (0.5 log₁₀) decrease or increase in plasma HIV-1 RNA levels generally is accepted as the minimally significant change in viral load.200 Optimal viral suppression generally is defined as a viral load persistently below the level of detection (plasma HIV-1 RNA level less than 20 to 75 copies/mL, depending on the assay used).200 Transient increases (“blips”) in viral load (i.e., detectable low viral loads typically less than 400 copies/mL that return to undetectable) may occur in successfully treated patients and may not represent viral replication or virologic failure.200 Individuals who adhere to their antiretroviral regimen and do not have HIV-1 resistant to the drugs in the treatment regimen generally achieve viral suppression 8-24 weeks after initiation of antiretroviral therapy.200 Although data on the association between persistently low level but quantifiable viremia (plasma HIV-1 RNA level less than 200 copies/mL) and virologic failure are conflicting, viral load persistently 200 copies/mL or greater should be considered virologic failure.200 (See Virologic Failure under Antiretroviral Therapy in Antiretroviral-experienced Adults and Adolescents: Management of Treatment Regimen Failure, in Guidelines for Use of Antiretroviral Agents for Management of HIV Infection.)

An adequate CD4⁺ T-cell response for most patients on antiretroviral therapy is defined as an increase in CD4⁺ T-cell count that averages 50-150 cells/mm³ per year, generally with an accelerated response during the first 3 months.200 Subsequent increases with good virologic control show an average increase of approximately 50-100 cells/mm³ per year for the subsequent few years until a plateau level is reached.200 A blunted increase in CD4⁺ T-cell counts may occur despite virologic suppression if antiretroviral therapy was initiated in patients with low baseline CD4⁺ T-cell counts or advanced age.200 A poor or suboptimal CD4⁺ T-cell response in a patient with viral suspension is not necessarily an indication to modify a virologically suppressive antiretroviral regimen.200 (See Suboptimal Immunologic Response under Antiretroviral Therapy in Antiretroviral-experienced Adults and Adolescents: Management of Treatment Regimen Failure, in Guidelines for Use of Antiretroviral Agents for Management of HIV Infection.)

In Vitro Resistance Testing

Drug resistance testing is performed using genotypic assays (detect drug resistance mutations present in the viral genes) or phenotypic assays (measure the virus's ability to replicate in the presence of different concentrations of antiretrovirals).200,201 Most genotypic assays involve sequencing the reverse transcriptase, protease, and integrase genes to detect mutations known to confer resistance to HIV NRTIs, INSTIs, NNRTIs, and PIs;200,201 assays to detect mutations on the gp41 (envelope) gene also are available to provide information on resistance to HIV fusion inhibitors.200,201 Phenotypic assays can be used to detect resistance to HIV NRTIs, INSTIs, NNRTIs, and PIs.200,201 Viral coreceptor (tropism) assay, a type of phenotypic assay, also is available to detect the presence of HIV with tropism that will not respond to CCR5 antagonists (see Coreceptor Tropism Assay under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Laboratory Monitoring).200,201

Genotypic assays can be performed rapidly, and results may be available within 1-2 weeks of collection of the sample.200 Phenotypic assays are more expensive to perform than genotypic assays, and results may be available within 2-3 weeks.200,201 Interpretation of results of genotypic assays requires knowledge of the mutations that the various antiretrovirals select for and knowledge regarding cross-resistance that may be conferred by certain mutations.200,201 Interpretation of results of phenotypic assays is complicated since data regarding the specific resistance level that is associated with drug failure may not be available.200,201 Although some resources are available to provide guidance regarding interpretation of genotypic drug-resistance testing (e.g., [Web], [Web]), consultation with a specialist in HIV drug resistance is recommended to facilitate interpretation of genotypic and/or phenotypic assay results.200,201

Although genotypic or phenotypic evidence of in vitro resistance to an antiretroviral suggests that the drug may not be effective in suppressing viral replication in vivo, such testing should not be used as the sole indicator that modifications need to be made to an antiretroviral regimen since factors other than viral resistance (e.g., poor adherence, pharmacokinetic interactions, drug potency) also affect virologic response to therapy and/or may contribute to disease progression.200,201,320,321,349 Some antiretroviral regimens can provide sustained viral suppression in vivo despite the presence of HIV-1 strains resistant to one of the components of the regimen.200,201,320,321,349 In addition, the absence of genotypic or phenotypic evidence of resistance does not necessarily predict a good response to a drug since minor variants may not be detected by current assays or resistance may be evolving at the time the assay is performed.200,201,320,321,340,349

Recommendations Regarding In Vitro Resistance Testing

Baseline HIV drug-resistance testing is recommended for all newly diagnosed (antiretroviral-naive) HIV-infected adults, adolescents, and children.200,201 If antiretroviral therapy is deferred, drug-resistance testing should be repeated at the time initiation of therapy is being considered.200,201 Drug-resistance testing also is recommended whenever decisions are being made regarding modification of an antiretroviral regimen.200,201

The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents states that genotypic resistance testing is the preferred assay to guide selection of initial antiretroviral regimens in antiretroviral-naive patients and also may be the preferred assay to guide regimen modification in patients who have suboptimal virologic responses or virologic failure.200 Although definitive prospective data are not available to support use of genotypic over phenotypic assays in different clinical situations, genotypic testing usually is preferred because of faster turnaround time, lower cost, and enhanced sensitivity for detecting mixtures of wild-type and resistant virus.200 However, for patients with a complex treatment history and known or suspected complex drug resistance mutations (especially to PIs), results of both genotypic and phenotypic assays might provide critical and complementary information to guide selection of the most appropriate antiretroviral regimens.200

Standard genotypic drug-resistance testing in antiretroviral-naive patients involves testing for mutations in the reverse transcriptase (RT) and protease (PR) genes.200 If transmitted INSTI resistance is a concern, additional testing with an INSTI genotype test may be indicated.200

Drug-resistance testing should be performed to guide drug selection when modifications are being made in patients with virologic failure and plasma HIV-1 RNA levels exceeding 1000 copies/mL.200 In individuals with virologic failure who have plasma HIV-1 RNA levels greater than 500 but less than 1000 copies/mL, drug-resistance testing should be considered, but may be unsuccessful.200 Drug-resistance testing in the setting of virologic failure should be performed while the patient is receiving the failing regimen or, if not possible, within 4 weeks of discontinuance of the failing regimen.200,201 If it has been longer than 4 weeks since antiretrovirals were discontinued, drug-resistance testing may still provide useful information to guide therapy, although previously selected resistance mutations may be missed.200

In vitro drug-resistance testing (i.e., genotypic resistance testing) is recommended for all pregnant women prior to initiation of antiretroviral therapy and for antiretroviral-experienced women entering pregnancy with detectable plasma HIV-1 RNA levels.200 Initiation of antiretroviral therapy before results of resistance testing are available may be necessary for optimal prevention of perinatal HIV transmission.200 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Prevention of Perinatal HIV Transmission.)

Drug-resistance testing is not usually recommended in patients with plasma HIV-1 RNA levels less than 500 copies/mL because the assays cannot be consistently performed with low HIV-1 RNA levels.200,340

Coreceptor Tropism Assay

A coreceptor tropism assay should be performed whenever use of a CC chemokine receptor 5 (CCR5) antagonist (e.g., maraviroc) is being considered.200,224 Some experts also recommend that this test be considered in patients who exhibit virologic failure while receiving a CCR5 antagonist.200,201

Human Leukocyte Antigen (HLA)-B*5701 Screening

Prior to initiation of abacavir or a fixed-combination preparation containing abacavir (abacavir/lamivudine, abacavir/lamivudine/zidovudine, abacavir/dolutegravir/lamivudine), screening for the HLA-B*5701 allele is recommended.200,201,216,228,229,240 Screening also is recommended prior to reinitiating an abacavir-containing preparation in patients who previously tolerated the drug and whose HLA-B*5701 status is unknown.216,240 Individuals who carry this allele are at high risk for abacavir hypersensitivity reactions.200,216,240 Abacavir or abacavir-containing preparations should not be used in individuals who test positive for HLA-B*5701.200,201,216,228,229,240 If HLA-B*5701 screening is not readily available, some experts suggest that it is reasonable to initiate abacavir with appropriate clinical counseling and monitoring for signs of hypersensitivity reactions.200 (See Cautions: Hypersensitivity Reactions, in Abacavir Sulfate 8:18.08.20.)

Therapeutic Drug Monitoring

Therapeutic drug monitoring of antiretrovirals is not recommended routinely in the management of HIV infection.200 However, information on plasma concentrations of antiretrovirals may be useful for patient management in certain situations, including when pharmacokinetic drug-drug or drug-food interactions are suspected, the patient has pathophysiologic states that result in impaired GI, hepatic, or renal function and altered drug pharmacokinetics, there are concerns regarding concentration-dependent toxicities, or expected virologic responses have not been attained in adherent patients.200 Consultation with a clinical pharmacist or pharmacologist with HIV expertise is recommended in such cases.200

Adverse Effects

Although most patients receiving antiretroviral therapy do not experience treatment-limiting adverse effects, modification of the antiretroviral regimen may be necessary in some patients because of serious and/or potentially life-threatening adverse effects.200 Non-life-threatening toxicities usually can be handled by substituting another antiretroviral for the presumed causative drug without interrupting antiretroviral therapy.200 Acute, life-threatening toxicities (e.g., acute hypersensitivity reaction, lactic acidosis, liver and/or severe cutaneous toxicities) usually require immediate discontinuance of all antiretrovirals and reinitiation of an alternative regimen that is not associated with the same toxicities.200 A switch from an effective antiretroviral regimen to a new regimen must be done carefully and only when potential benefits of the change outweigh the potential complications of altering treatment.200 When a change in the regimen is indicated, the management strategy must be individualized to ensure that viral suppression is maintained.200 Expert consultation may be necessary.200

Some adverse effects appear to be common to specific drug classes of commercially available antiretrovirals (e.g., HIV NRTIs, INSTIs, NNRTIs, PIs).200 These adverse effects should be considered when selecting alternative agents.200 In some cases, adverse effects were initially reported to be strongly associated with one class of antiretroviral agents and then found to occur in patients receiving various antiretroviral regimens that may or may not have included these agents (e.g., adipogenic effects).200

For specific information on adverse effects reported with the individual antiretroviral agents and precautions and contraindications associated with the drugs, see the Cautions sections in the individual monographs in 8:18.08.

Drug Interactions

Drug Interactions Among the Antiretroviral Agents

Considerable data are available regarding pharmacokinetic interactions among the various antiretrovirals.200,206,208,209,210,212,213,215,216,217,219,220,222,227 Some pharmacokinetic interactions between antiretrovirals can be used for therapeutic advantage, such as use of low-dose ritonavir to boost plasma concentrations of some other PIs (see Pharmacokinetic Enhancers under Guidelines for Use of Antiretroviral Agents for Management of HIV: Drug Interactions).200 Other pharmacokinetic interactions among antiretrovirals result in decreased or suboptimal antiretroviral concentrations and reduced therapeutic effects or increased antiretroviral concentrations and increased toxicity.200 In some cases, dosage adjustment of one or more of the antiretrovirals is indicated because of a pharmacokinetic interaction; however, in other cases, concomitant use is contraindicated or should be avoided.200 Potential drug interactions among the antiretrovirals must be considered whenever selecting or changing drugs used in multiple-drug regimens.200

For information on drug interactions involving the antiretrovirals and recommendations regarding these interactions, see the Drug Interactions sections in the individual monographs in 8:18.08.

Pharmacokinetic Enhancers

Concomitant use of a pharmacokinetic enhancer (pharmacokinetic booster) is necessary to improve the pharmacokinetic profile of most HIV PIs.200,201,203,204,205,207,210,211,237,238,239 HIV PIs usually are used in conjunction with low-dose ritonavir ( ritonavir-boosted PI) or in conjunction with cobicistat ( cobicistat-boosted PI).200,201,203,204,205,207,210,211,237,238,239 Ritonavir and cobicistat are both potent inhibitors of cytochrome P-450 (CYP) 3A4 and increase plasma concentrations of concomitantly administered drugs that are metabolized by this pathway.200 Unboosted HIV PIs (i.e., without low-dose ritonavir or cobicistat) are not recommended for initial antiretroviral therapy and unboosted darunavir, saquinavir, or tipranavir are not recommended at any time.200

Low-dose ritonavir (100-400 mg daily) inhibits metabolism of HIV PIs and increases plasma concentrations and prolongs the plasma half-lives of the drugs.200 The antiretroviral activity of these regimens is due to the other PI since the dosage of ritonavir used (100-400 mg daily) is not considered a therapeutic dosage.200 A fixed-combination preparation of lopinavir and low-dose ritonavir is commercially available (lopinavir/ritonavir).207 Other ritonavir-boosted regimens involve administration of specified low doses of single-entity ritonavir at the same time as a single-entity preparation of the HIV PI (e.g., atazanavir, darunavir, fosamprenavir, saquinavir, tipranavir).200,203,204,205,210,211

Atazanavir and darunavir can be used with low-dose ritonavir ( ritonavir-boosted ) or with cobicistat ( cobicistat-boosted ).200,203,204,237,238,239 Although concomitant use of low-dose ritonavir or cobicistat increases peak plasma concentrations and area under the plasma concentration-time curve (AUC) of these HIV PIs, these pharmacokinetic enhancers are not interchangeable in antiretroviral regimens since low-dose ritonavir and cobicistat have different dosage and administration requirements and are associated with different adverse effects, precautions, contraindications, and drug interactions.200,237,238,239 When cobicistat-boosted atazanavir or cobicistat-boosted darunavir is included in an antiretroviral regimen, fixed-combination preparations containing the HIV PI and cobicistat (atazanavir/cobicistat, darunavir/cobicistat) are commercially available200,237,238 or, alternatively, single-entity atazanavir or single-entity darunavir can be administered at the same time as single-entity cobicistat.200,203,204,239 Cobicistat-boosted darunavir also is commercially available in a fixed combination containing darunavir, cobicistat, emtricitabine, and TAF.250

Elvitegravir (an HIV INSTI) also must be used in conjunction with a pharmacokinetic enhancer; the drug is administered in conjunction with cobicistat in the fixed combination EVG/c/FTC/TAF or the fixed combination EVG/c/FTC/TDF.200,235,243

HCV Antivirals

Concurrent treatment of HIV and HCV infection is recommended for most coinfected patients.119,200 However, the possibility of drug interactions and overlapping toxicities between antiretrovirals and HCV direct-acting antivirals (DAAs), including HCV NS3/4A protease inhibitors (e.g., glecaprevir, paritaprevir, voxilaprevir),119,200 HCV NS5B polymerase inhibitors (e.g., grazoprevir, sofosbuvir),119,176,181,188,200 and HCV NS5A replication complex inhibitors (e.g., elbasvir, ledipasvir, pibrentasvir, velpatasvir),119,176,177,181,200 should be considered.119,200 In addition, possible drug interactions between certain HIV NRTIs (i.e., didanosine, zidovudine) and ribavirin also should be considered.119,200,217,222

Concomitant use of some HCV DAAs and some HIV NRTIs (e.g., TDF), HIV INSTIs (e.g., dolutegravir, EVG/c/FTC/TDF, EVG/c/FTC/TAF), HIV NNRTIs (e.g., efavirenz, etravirine, nevirapine), or HIV PIs can affect plasma concentrations of one or both drugs.119,176,177,181,188,200,204 Therefore, concomitant use of certain HCV DAAs and certain antiretrovirals is not recommended or requires close monitoring for HIV and HCV treatment responses; in some cases, dosage adjustments may be needed.119,176,177,181,188,200 Concomitant use of ribavirin and didanosine or zidovudine may increase the risk of NRTI-associated adverse effects (e.g., hepatotoxicity, pancreatitis, anemia) and is contraindicated or not recommended.119,217,222

When a decision is made to treat HCV infection in an HIV-infected patient already receiving antiretroviral therapy, the antiretroviral regimen may need to be modified before HCV treatment is initiated (e.g., because of possible drug interactions).200 If an antiretroviral regimen is modified to accommodate HCV treatment, initiation of the HCV antiviral regimen should be delayed for at least 2 weeks and effectiveness of the modified HIV regimen should be confirmed by measuring plasma HIV-1 RNA levels within 2-8 weeks after the regimen chan in addition, after HCV treatment is completed, resumption of the original antiretroviral regimen should be delayed for at least 2 weeks.200 The prolonged half-lives of some antiretrovirals and HCV DAAs pose a potential risk of drug interactions if the HCV antiviral regimen is initiated too soon after antiretroviral modification or if the original antiretroviral regimen is resumed too soon after completion of HCV treatment.200 Because the management of patients with HIV and HCV coinfection is complex and must be individualized, experts in the management of HCV infection in HIV-infected patients should be consulted.119

For information on drug interactions between antiretroviral agents and HCV DAAs and recommendations regarding these interactions, see the Drug Interactions sections in the individual antiretroviral monographs in 8:18.08 and in the individual HCV antiviral monographs in 8:18.40.

Antimycobacterial Agents

Concurrent treatment of HIV and tuberculosis is recommended for most coinfected patients.200 However, the fact that pharmacokinetic interactions between some antimycobacterial agents (e.g., rifamycins; rifabutin, rifampin, rifapentine) and some antiretrovirals (e.g., HIV INSTIs, NNRTIs, PIs) have been reported or are expected to occur must be considered when antimycobacterial therapy is indicated for the treatment of active tuberculosis or latent tuberculosis infection or for the prophylaxis or treatment of Mycobacterium avium complex (MAC) infections in HIV-infected patients who are receiving or being considered for antiretroviral therapy.200,346,379,392 Antiretroviral therapy should be continued when tuberculosis is diagnosed in a patient already receiving such therapy, but the antiretroviral regimen should be assessed with particular attention to potential drug interactions between antiretroviral agents and antimycobacterial agents and the regimen may need to be modified to permit use of an optimal tuberculosis treatment regimen.200 If tuberculosis is diagnosed in a patient not yet receiving antiretroviral therapy, initiation of an antiretroviral regimen should not be delayed until tuberculosis treatment is completed.200 Because the management of these patients is complex and must be individualized, experts in the management of mycobacterial infections in HIV-infected patients should be consulted.346,392

For information on drug interactions between antiretroviral agents and antimycobacterial agents (e.g., rifamycins) and recommendations regarding these interactions, see the Drug Interactions sections in the individual antiretroviral monographs in 8:18.08.

Illicit Drugs and Drugs Used to Treat Opioid Addiction

The potential exists for interactions between antiretrovirals that affect CYP isoenzymes and many classes of recreational (illicit) drugs that are metabolized by these enzymes.200,394,395,396 Life-threatening reactions and at least one fatality have been reported secondary to interactions between methylenedioxymethamphetamine (MDMA, ecstasy) or γ-hydroxybutyrate (GHB, liquid ecstasy) and HIV PIs.394,395,396 (See Drug Interactions: CNS Agents, in Ritonavir 8:18.08.08.) MDMA undergoes demethylenation principally by CYP2D6 but also is metabolized by CYP1A2, CYP2B6, and CYP3A4; concomitant use with inhibitors of these enzymes (e.g., HIV PIs, efavirenz) can result in substantial increases in MDMA exposure.394,395,396 Other amphetamines (e.g., methamphetamine; crystal meth, speed) also are metabolized by CYP2D6.394,395 In addition, metabolism of ketamine (special K) appears to be mediated principally by CYP2B6 and to a lesser extent by CYP3A4 and CYP2C9 and metabolism of PCP (angel dust, rocket fuel, killer weed) appears to be mediated by CYP3A4 and possibly by CYP2C11.394 Although metabolism of GHB has not been characterized, the drug may undergo first-pass metabolism mediated by the CYP isoenzyme system.394

CYP3A4 appears to play only a small role in metabolism of cocaine and interactions between antiretrovirals and cocaine have not been described.394 However, further study is needed to more fully evaluate possible interactions between cocaine and antiretrovirals.394

Limited data suggest that CYP3A and CYP2C9 isoenzymes are involved in microsomal oxidation of tetrahydrocannabinol (THC), but the effects of THC are unlikely to be substantially attenuated by drugs that inhibit these enzymes.394 There is evidence that THC can decrease plasma concentrations of indinavir and concentrations of the active metabolite of nelfinavir (M8), but these effects are not likely to have a clinically important effect on efficacy of the antiretrovirals.394

Because the margin of safety for many illicit drugs is narrow or poorly defined and the known or potential interactions between some of these drugs and antiretrovirals is complex and potentially life-threatening, patients should be advised of the risk of serious consequences if they use these drugs while receiving antiretroviral therapy.394,395,396 In addition, in HIV-infected patients being treated for opioid addiction with buprenorphine or methadone, the possibility of pharmacokinetic interactions between these drugs and antiretrovirals should be considered since dosage modifications or use of alternative antiretrovirals may be necessary.32,200,209,208,211,212,213,215,216,394

For information on drug interactions between antiretroviral agents and drugs used to treat opioid addiction and recommendations regarding these interactions, see the Drug Interactions sections in the individual antiretroviral monographs in 8:18.08.

Initial Antiretroviral Therapy in Antiretroviral-naive Adults and Adolescents

The US Department of Health and Human Services (HHS) Panel on Antiretroviral Guidelines for Adults and Adolescents recommends that antiretroviral therapy be initiated in all HIV-infected adults and adolescents, regardless of the patient's viral load or CD4⁺ T-cell count.200 Without antiretroviral therapy, most individuals with HIV infection will eventually develop progressive immunodeficiency marked by CD4⁺ T-cell depletion and AIDS-defining illnesses and premature death.200

Results of studies that addressed the optimal time to initiate antiretroviral therapy demonstrated a 50% reduction in morbidity and mortality among HIV-infected adults with CD4⁺ T-cell counts exceeding 500/mm³ who were randomized to receive immediate antiretroviral therapy compared with those randomized to receive deferred initiation of antiretroviral therapy.200 The magnitude of CD4⁺ T-cell count recovery appears to be directly correlated with counts at the time of initiation of antiretroviral therapy and many individuals who begin treatment when CD4⁺ T-cell counts are less than 350/mm³ never achieve counts greater than 500/mm³ despite long-term antiretroviral therapy.200 In addition, there is evidence that early initiation of effective antiretroviral therapy can reduce secondary transmission of HIV to sexual partners.200 Therefore, the HHS panel recommends prompt initiation of antiretroviral therapy in all patients diagnosed with HIV infection, including pregnant women not currently receiving antiretroviral therapy.200 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy During Pregnancy.)

The decision to initiate antiretroviral therapy should always include consideration of a patient's comorbid conditions and their willingness and readiness to initiate treatment.200 On a case-by-case basis, there may be some situations when antiretroviral therapy is deferred because of clinical and/or psychosocial factors; however, the HHS panel recommends that antiretroviral therapy be initiated as soon as possible.200

Recommended Regimens for Initial Antiretroviral Therapy in Adults and Adolescents

Antiretroviral therapy in HIV-infected adults and adolescents who are antiretroviral naive (have not previously received antiretroviral therapy) should be initiated with a potent multiple-drug regimen.200 Treatment should be aggressive with the goal of maximal suppression of viral load to undetectable levels.200

Based on clinical trial data and expert opinion, the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents recommends that antiretroviral therapy in most antiretroviral-naive adults and adolescents be initiated with one of several recommended 3-drug INSTI-based regimens that include an INSTI with 2 NRTIs (dual NRTIs);200 a 2-drug INSTI-based regimen of dolutegravir and lamivudine also is a recommended regimen for initial treatment in antiretroviral-naive adults.200 In certain clinical situations, the HHS panel recommends that antiretroviral therapy be initiated with one of several recommended INSTI-, NNRTI-, or PI-based regimens that include an INSTI, NNRTI, or PI (and a pharmacokinetic enhancer) with 2 NRTIs (dual NRTIs).200 Selection of a specific regimen for initial treatment should be individualized based on virologic efficacy, potential adverse effects, pill burden, dosing frequency, potential for drug interactions, results of drug-resistance testing, comorbid conditions, and access to and cost of the drugs.200

Table 1 provides the recommended INSTI-based antiretroviral regimens for initial treatment in most antiretroviral-naive adults and adolescents (i.e., regimens with demonstrated durable virologic efficacy, favorable tolerability and toxicity profiles, and ease of use).200

Table 1. Recommended Antiretroviral Regimens for Initial Therapy in Most Antiretroviral-naive Adults and Adolescents200

INSTI-based Regimens (2 NRTIs)	Bictegravir, emtricitabine, and TAF (fixed combination BIC/FTC/TAF)
	or
	Dolutegravirwith abacavir^a and lamivudine
	or
	Dolutegravirwith (TAF or TDF)^b and (emtricitabine or lamivudine)
	or
	Raltegravirwith (TAF or TDF)^b and (emtricitabine or lamivudine)
	or
INSTI-based Regimens (1 NRTI)	Dolutegravirwith lamivudine^c

^aUse regimens containing abacavir only in those who are HLA-B*5701 negative.

^bTenofovir alafenamide fumarate (TAF) and tenofovir disoproxil fumarate (TDF) are both tenofovir prodrugs. When choosing between TAF and TDF, consider adverse effects and access to and cost of the drugs. Adverse bone and renal effects are reported less frequently with TAF than with TDF; dyslipidemia is reported less frequently with TDF than with TAF.

^c Do not use this 2-drug regimen in those with plasma HIV-1 RNA levels greater than 500,000 copies/mL or with HBV coinfection and do not use if results of HIV genotypic resistance testing for reverse transcriptase or results of HBV testing are not available.

Adapted from Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents with HIV (December 18, 2019). Updates may be available at the US Department of Health and Human Services (HHS) AIDS Information (AIDSinfo) website ([Web]).

Table 2 provides the recommended INSTI- PI-, or NNRTI-based antiretroviral regimens for initial treatment in antiretroviral-naive adults and adolescents in certain clinical circumstances (i.e., regimens that are effective and tolerable, but have some disadvantages compared with regimens recommended for most individuals, including less supporting data from randomized clinical trials).200 In certain clinical situations, one of these regimens may be the preferred regimen based on individual patient characteristics.200

Table 2. Recommended Antiretroviral Regimens for Initial Therapy in Antiretroviral-naive Adults and Adolescents in Certain Clinical Situations200

INSTI-based Regimens (2 NRTIs)	Elvitegravir, cobicistat, emtricitabine, and TAF^a (fixed combination EVG/c/FTC/TAF)
	or
	Elvitegravir, cobicistat, emtricitabine, and TDF^a (fixed combination EVG/c/FTC/TDF)
PI-based Regimens (2 NRTIs)	Cobicistat-boosted or ritonavir-boosted Darunavir^bwith (TAF or TDF)^a and (emtricitabine or lamivudine)
	or
	Cobicistat-boosted or ritonavir-boosted Atazanavir^bwith (TAF or TDF)^a and (emtricitabine or lamivudine)
	or
	Cobicistat-boosted or ritonavir-boosted Darunavirwith abacavir^c and lamivudine
NNRTI-based Regimens (2 NRTIs)	Doravirinewith TAF and emtricitabine
	or
	Doravirinewith TDF and lamivudine
	or
	Efavirenzwith (TAF or TDF)^a and (emtricitabine or lamivudine)
	or
	Rilpivirine^dwith (TAF or TDF)^a and emtricitabine
Regimens to Consider when Abacavir, TAF, and TDF Cannot be Used	Dolutegravirwith lamivudine^e
	or
	Ritonavir-boosted Darunavirwith Raltegravir (twice daily)^d
	or
	Ritonavir-boosted Darunavir (once daily) with lamivudine

^aTenofovir alafenamide fumarate (TAF) and tenofovir disoproxil fumarate (TDF) are both tenofovir prodrugs. When choosing between TAF and TDF, consider adverse effects and access to and cost of the drugs. Adverse bone and renal effects are reported less frequently with TAF than with TDF; dyslipidemia is reported less frequently with TDF than with TAF.

^bIn general, cobicistat-boosted or ritonavir-boosted darunavir is preferred over cobicistat-boosted or ritonavir-boosted atazanavir.

^cUse regimens containing abacavir only in those who are HLA-B*5701 negative.

^dUse this regimen only in those with plasma HIV-1 RNA levels less than 100,000 copies/mL and CD4⁺ T-cell counts greater than 200 cells/mm³.

^eDo not use this regimen in those with plasma HIV-1 RNA levels greater than 500,000 copies/mL or HBV coinfection and do not use if results of HIV genotypic resistance testing for reverse transcriptase or results of HBV testing are not available.

Recommended Dual NRTI Options

Most INSTI-, NNRTI-, and PI-based regimens recommended for initial treatment of antiretroviral-naive adults and adolescents include 2 NRTIs (dual NRTIs).200 These dual NRTI options are commonly referred to as the “backbone” of antiretroviral regimens.200 There are 6 commercially available NRTIs;200 in addition, TAF and TDF (nucleotide reverse transcriptase inhibitors) are grouped with the NRTIs for purposes of therapeutic decisions.200 The choice of the specific dual NRTI option is based on virologic potency and durability, short- and long-term toxicity, and dosing convenience.200

The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents states that the dual NRTI options used in initial treatment regimens recommended for antiretroviral-naive adults and adolescents are TAF and (emtricitabine or lamivudine), TDF and (emtricitabine or lamivudine), and abacavir and lamivudine.200 (See Table 1 and see Table 2.)

TAF and Emtricitabine:Advantages of this dual NRTI option include less potential for adverse bone and kidney effects compared with the dual option of TDF and emtricitabine, substantially higher intracellular concentrations of the active tenofovir metabolite than those reported with TDF, activity against HBV, and availability of fixed-combination preparations.200 A fixed-combination preparation containing TAF and emtricitabine (emtricitabine/TAF) is commercially available for use in adults and pediatric patients weighing 35 kg or more.245 In addition, the dual NRTI option of TAF and emtricitabine is commercially available in fixed combination with bictegravir, rilpivirine, or cobicistat-boosted elvitegravir; each of these fixed-combination preparations provides a complete single-tablet antiretroviral regimen.200,243,244,248 Disadvantages of the dual option of TAF and emtricitabine include greater increases in triglycerides and cholesterol than those reported with TDF, possibility of greater weight gain when TAF is initiated compared with initiation of TDF, the need to monitor renal function, urine glucose, and urine protein in all patients, and the precaution that TAF should not be used in patients with creatinine clearances less than 30 mL/minute.200

TDF and (Emtricitabine or Lamivudine): Advantages include a better virologic response than that reported with the dual NRTI option of abacavir and lamivudine when used in conjunction with ritonavir-boosted atazanavir or efavirenz in patients with baseline viral load of 100,000 copies/mL or greater, activity against HBV, a once-daily dosing regimen that can be administered without regard to meals, and availability of fixed-combination preparations.200 Fixed-combination preparations containing TDF and emtricitabine (emtricitabine/TDF)230 or TDF and lamivudine (lamivudine/TDF)258 are commercially available and may be preferred to decrease pill burden and improve adherence when this dual NRTI option is used.200 In addition, the dual NRTI option of TDF and emtricitabine is commercially available in fixed combination with efavirenz, rilpivirine, or cobicistat-boosted elvitegravir and each of these fixed-combination preparations provides a complete single-tablet antiretroviral regimen.200,232,233,235 Disadvantages of the dual NRTI option of TDF and emtricitabine include potential adverse effects reported with TDF (e.g., bone effects, nephrotoxicity), the need to monitor renal function, urine glucose, and urine protein in all patients, and the precaution that TDF should be used with caution or avoided in patients with renal disease and osteoporosis.200

Abacavir and Lamivudine: This dual NRTI option should be used only in those who are negative for HLA-B*5701.200 Advantages include a once-daily dosing regimen that can be administered without regard to meals, no reported nephrotoxicity, and availability of fixed-combination preparations.200 A fixed-combination preparation containing abacavir and lamivudine (abacavir/lamivudine) is commercially available and may be preferred to decrease pill burden and improve adherence when this dual NRTI option is used.200 In addition, the dual NRTI option of abacavir and lamivudine is commercially available in fixed combination with dolutegravir (abacavir/dolutegravir/lamivudine) and can be used to provide a complete single-tablet antiretroviral regimen.200,240 Disadvantages include the need to test for the HLA-B*5701 allele before initiation of abacavir (see Human Leukocyte Antigen [HLA]-B*5701 Screening under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Laboratory Monitoring), inferior virologic response compared with that reported with the dual NRTI option of TDF and emtricitabine when used in conjunction with ritonavir-boosted atazanavir or efavirenz in patients with baseline viral load of 100,000 copies/mL or greater (difference in efficacy not evident in those with baseline viral load less than 100,000 copies/mL and no difference in efficacy when abacavir and lamivudine was used with dolutegravir), and potential adverse effects reported with abacavir, such as hypersensitivity reactions and adverse cardiovascular effects.200

For HIV-infected adults and adolescents coinfected with HBV, the dual NRTI option of TAF and (emtricitabine or lamivudine) and the dual NRTI option of TDF and (emtricitabine or lamivudine) are preferred since these antiretrovirals all have some activity against HBV.200

NRTI Pairings Not Recommended for Initial Therapy

Zidovudine and Lamivudine: Not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents because of greater toxicities (e.g., bone marrow suppression, GI toxicities, skeletal muscle myopathy, cardiomyopathy, mitochondrial toxicities such as lipoatrophy, lactic acidosis, and hepatic steatosis) than that reported with the recommended dual NRTI options.200 (See Recommended Dual NRTI Options under Initial Antiretroviral Therapy in Antiretroviral-naive Adults and Adolescents: Recommended Regimens for Initial Antiretroviral Therapy in Adults and Adolescents, in Guidelines for Use of Antiretroviral Agents for Management of HIV Infection.) However, the dual NRTI option of zidovudine and lamivudine is recommended as an alternative dual NRTI option for initial treatment regimens in antiretroviral-naive pregnant women (see Safety and Choice of Antiretrovirals During Pregnancy under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy During Pregnancy).202 In addition, zidovudine and (lamivudine or emtricitabine) is a preferred dual NRTI option for initial treatment regimens in pediatric patients from birth to less than 6 years of age and an alternative option in pediatric patients 6 years of age or older (see Initial Antiretroviral Therapy in Antiretroviral-naive Pediatric Patients under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy in Pediatric Patients).201

Didanosine and (Emtricitabine or Lamivudine): Not recommended for initial treatment regimens in antiretroviral-naive HIV-infected adults and adolescents because of inferior virologic efficacy, limited clinical trial experience in antiretroviral-naive patients, and didanosine toxicities (e.g., pancreatitis, peripheral neuropathy).200 In addition, didanosine is no longer recommended at any time.200

Didanosine and TDF: Not recommended because of a high rate of early virologic failure, rapid selection of resistance mutations, potential for immunologic nonresponse and CD4⁺ T-cell decline, and increased didanosine concentrations and toxicities.200 In addition, didanosine is no longer recommended at any time.200

Stavudine and Lamivudine: Not recommended because of reported toxicities (e.g., lipoatrophy, peripheral neuropathy, hyperlactatemia including symptomatic and life-threatening lactic acidosis, hepatic steatosis, pancreatitis).200 In addition, stavudine is no longer recommended at any time.200

Antiretrovirals Not Recommended for Initial Therapy

Etravirine: Not recommended for use in NNRTI-based regimens for initial antiretroviral therapy200 since safety and efficacy have not been established in such patients.200,214

Nevirapine: Not recommended for initial treatment regimens in antiretroviral-naive adults and adolescents because this NNRTI has been associated with serious and potentially fatal toxicity (hepatic events, severe rash, Stevens-Johnson syndrome, toxic epidermal necrolysis) and did not meet noninferiority criteria when compared to efavirenz.200

Unboosted Atazanavir (i.e., without low-dose ritonavir or cobicistat): Not recommended for initial treatment regimens because it is less potent than ritonavir-boosted or cobicistat-boosted atazanavir.200

Unboosted Darunavir (i.e., without low-dose ritonavir or cobicistat): Not recommended for initial treatment regimens because of inadequate bioavailability and because it has not been studied.200

Fosamprenavir (with or without low-dose ritonavir): Not recommended for initial treatment regimens.200 Regimens that include unboosted fosamprenavir may be associated with virologic failure and result in emergence of resistance, and clinical trial data regarding use of ritonavir-boosted fosamprenavir are more limited compared with clinical trial data available for other ritonavir-boosted PIs.200

Lopinavir/ritonavir: Not recommended for initial treatment regimens because of GI intolerance and because of higher ritonavir dose and higher pill burden than other ritonavir-boosted PIs.200

Ritonavir as the sole PI: Not recommended because of high pill burden, GI intolerance, and metabolic toxicity.200 However, low-dose ritonavir is used concomitantly with certain other PIs for therapeutic advantage ( ritonavir-boosted PIs), and some recommended and alternative PI-based regimens for initial therapy include low-dose ritonavir.200

Saquinavir (with or without low-dose ritonavir): Not recommended for initial treatment regimens.200 Unboosted saquinavir has inadequate bioavailability and inferior virologic efficacy;200 ritonavir-boosted saquinavir has a high pill burden and potential for adverse cardiovascular effects, including QT and PR prolongation.200

Ritonavir-boosted Tipranavir: Not recommended for initial therapy because of inferior virologic efficacy and because of higher ritonavir dose and higher rate of adverse effects than other ritonavir-boosted PIs.200

Enfuvirtide: Has not been evaluated for use in antiretroviral-naive patients, requires twice-daily subcutaneous injections, and is associated with a high rate of injection site reactions.200,223

Ibalizumab: Has not been evaluated for use in antiretroviral-naive patients, requires IV administration, and has a high cost.200

Maraviroc: Not recommended for initial treatment regimens because a coreceptor tropism assay (see Coreceptor Tropism Assay under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Laboratory Monitoring) should be performed before the drug is initiated, there is no virologic benefit compared with other recommended regimens, and a twice-daily dosing regimen is required.200

Antiretrovirals and Regimens Not Recommended at Any Time

Didanosine, Indinavir, Nelfinavir, Stavudine: The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents states that these antiretrovirals are no longer recommended for the treatment of HIV infection at any time in adults and adolescents because of suboptimal antiviral potency, unacceptable toxicities, high pill burden, or pharmacologic concerns.200 Delavirdine (no longer commercially available in the US) also is not recommended for the treatment of HIV infection at any time.200

Monotherapy: Use of an NRTI alone is not recommended at any time because it is inferior to dual NRTIs.12,13,27,28,31,32,200,316,376,486,487,488 Use of an INSTI alone has resulted in virologic rebound and INSTI resistance.200 Use of a PI (boosted or unboosted) alone is inferior to combination antiretroviral therapy.200

All NRTI Regimens: Use of 2 NRTIs alone (without a third antiretroviral) is suboptimal and not recommended at any time.200 Although 2-drug regimens that included 2 NRTIs were used in the past for initial antiretroviral therapy in antiretroviral-naive individuals,316,486,487,488,489 these regimens may be associated with initial declines in plasma HIV-1 RNA levels,316,486,487,488,489 are associated with rapid development of resistance, and are less effective in providing durable suppression of HIV replication than regimens that include 3 or more drugs and include at least 1 antiretroviral from another class.200 Use of 3 or 4 NRTIs (without any drugs from another class) is not recommended because such regimens have inferior virologic efficacy.200 A triple NRTI regimen that includes abacavir, lamivudine, and zidovudine has been used and a fixed combination containing these 3 NRTIs is commercially available (abacavir/lamivudine/zidovudine).229 However, the HHS panel states that all-NRTI regimens of abacavir, lamivudine, and zidovudine with or without TDF are not recommended since such regimens have inferior virologic efficacy.200

TAF with TDF: These tenofovir prodrugs should not be used concomitantly.200 Care should be taken to avoid inadvertent concomitant use of TAF and TDF, especially during transition from one drug to the other.200 Data are not available regarding potential additive toxicity if these tenofovir prodrugs are inadvertently used concomitantly.200

Unboosted Darunavir, Saquinavir, Tipranavir: These HIV PIs should not be used at any time without a pharmacokinetic enhancer because of inadequate bioavailability and because virologic benefit has been demonstrated only when used with a pharmacokinetic enhancer.200,204,210,211

Cobicistat with Ritonavir: These pharmacokinetic enhancers should not be used concomitantly.200 Inadvertent concomitant use of both of these drugs may result in additive CYP3A4 inhibition and further increases in concentrations of the antiretrovirals or other drugs that the patient is receiving.200 (See Pharmacokinetic Enhancers under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Drug Interactions.)

Multiple NNRTIs: Use of 2 NNRTIs is not recommended at any time because regimens that include multiple NNRTIs have been associated with a high incidence of adverse effects.200 In addition, efavirenz and nevirapine are enzyme inducers, and both of these drugs can decrease concentrations of etravirine and rilpivirine.200

Etravirine with PIs: This NNRTI should not be used concomitantly with an unboosted PI or with ritonavir-boosted fosamprenavir at any time since etravirine may alter plasma concentrations of the PI and appropriate dosages for such regimens have not been established.200 In addition, etravirine should not be used concomitantly with ritonavir-boosted tipranavir at any time because of substantially decreased etravirine concentrations.200

Antiretroviral Therapy in Antiretroviral-experienced Adults and Adolescents

Optimal antiretroviral therapy involves continuous evaluation of the patient's tolerance and virologic and immunologic response to their current regimen.200 Regimen modification is indicated in individuals experiencing toxicity or intolerance to their current regimen and whenever there is evidence of treatment failure.200 In addition, consideration can be given to modifying an effective antiretroviral regimen in patients who are virologically suppressed if the change results in regimen simplification, promotes long-term adherence, enhances tolerability and decreases short- or long-term toxicity, prevents or mitigates drug interactions, eliminates food or fluid requirements, reduces the risk of virologic failure, or reduces costs.200

Whenever a change in antiretroviral therapy is considered in antiretroviral-experienced patients, a review of the agents that the patient already has received is essential.200 Viral mutants will emerge in all HIV-infected patients over time; however, use of potent regimens that provide durable suppression of HIV replication are less likely to result in rapid emergence of resistant strains.200 The new regimen should include antiretrovirals that are predicted to provide maximal suppression of HIV replication while avoiding use of those that might be ineffective.200

Management of Treatment Regimen Failure

Failure of an antiretroviral treatment regimen may be the result of poor patient adherence, poor tolerability, pharmacokinetic issues (including drug-food or drug-drug interactions), suboptimal virologic potency, and resistance factors.200 Failure of a regimen can be associated with virologic failure or suboptimal immunologic response.200

Virologic Failure

Virologic suppression is defined as a confirmed plasma HIV-1 RNA level below the limits of detection.200 Virologic failure is defined as the inability of an antiretroviral regimen to achieve or maintain suppression of viral replication to plasma HIV-1 RNA levels less than 200 copies/mL.200 An incomplete virologic response is defined as 2 consecutive plasma HIV-1 RNA levels of 200 copies/mL or greater after 24 weeks of an antiretroviral regimen.200 Virologic rebound refers to confirmed plasma HIV-1 RNA levels of 200 copies/mL or greater after prior suppression of viremia.200 After virologic suppression, transient increases (“blips”) in viral load may occasionally occur and may not represent virologic failure.200 Baseline plasma HIV-1 RNA levels may affect the time course of response and some regimens may take longer than others to suppress viremia.200

Virologic failure can occur as the result of viral resistance or suboptimal adherence to the treatment regimen (e.g., because of intolerance/toxicity or complex dosage regimens).200 Other factors include suboptimal pharmacokinetics of the drugs, drug or food interactions, higher pretreatment or baseline plasma HIV-1 RNA levels, lower pretreatment or nadir CD4⁺ T-cell counts, prior AIDS diagnosis, or prior treatment failure.200 Although it is not always possible to identify the cause of virologic failure, identifying the cause is beneficial since it can provide valuable information to use when modifying the treatment regimen.200

Evaluation of virologic failure should include assessment of HIV disease severity, antiretroviral treatment history, plasma HIV-1 RNA level and CD4⁺ T-cell count trends over time, results of prior drug-resistance testing, concomitant therapy (including prescription and nonprescription drugs and dietary or herbal supplements), comorbidities (including substance abuse), and the patient's adherence to the treatment regimen (including dose, dosing frequency, and administration with or without food).200 When currently recommended antiretroviral regimens are used for initial treatment, HIV-infected patients have a high likelihood of achieving and maintaining plasma HIV-1 RNA levels below the lower limits of detection.200 If this does not occur or if virologic rebound occurs, resistance mutations to one or more components of the regimen may have developed.200 However, many patients with detectable viral loads are nonadherent to treatment; some of these patients may have minimal or no drug resistance while others may have extensive resistance.200 Management of patients with extensive resistance is complex and usually requires consultation with an HIV expert.200

In patients experiencing virologic failure who have plasma HIV-1 RNA levels greater than 1000 copies/mL with identified drug resistance, the antiretroviral regimen should be modified with the goal of maximal suppression of plasma HIV-1 RNA levels (i.e., below the lower limits of detection) and prevention of further selection of resistance mutations.200 This usually involves a change to a new regimen with at least 2 (preferably 3) fully active antiretrovirals.200

In those with plasma HIV-1 RNA levels greater than 1000 copies/mL without identified drug resistance, virologic failure is almost always related to nonadherence and management usually involves a thorough assessment to determine the level of adherence and identify any food or drug interactions.200

Because there is evidence that emergence of drug-resistance mutations often occurs when plasma HIV-1 RNA levels are 200 copies/mL or higher, especially when levels exceed 500 copies/mL, patients with plasma HIV-1 RNA levels persistently in the range of 200-1000 copies/mL should be considered as virologic failures, drug-resistance testing should be performed in those with levels greater than 500 copies/mL, and regimen modification considered if there are sufficient therapeutic options.200

The clinical implications of plasma HIV-1 RNA levels above the lower limits of detection but less than 200 copies/mL are controversial; there is no consensus on how to manage such patients, but the risk of emerging resistance is believed to be relatively low.200 Therefore, such patients may continue their current regimen and plasma HIV-1 RNA levels should be measured at least every 3 months to assess the need for a regimen change in the future.200

Suboptimal Immunologic Response

Suboptimal immunologic response refers to failure to achieve and maintain an adequate CD4⁺ T-cell response despite virologic suppression.200

In antiretroviral-naive patients, the increase in CD4⁺ T-cell counts in response to initial antiretroviral therapy usually is about 150 cells/mm³ over the first year of treatment.200 After 4-6 years on a suppressive regimen, the CD4⁺ T-cell count may plateau.200 Although there is no clear definition of suboptimal immunologic response, some studies describe it as a failure to increase CD4⁺ T-cell count above a certain threshold (e.g., greater than 350 or 500 cells/mm³) over a specified time period (e.g., 4-7 years).200 Alternatively, others have focused on an inability to increase CD4⁺ T-cell counts by a certain threshold (e.g., greater than 50 or 100 cells/mm³) over a given time period.200

Factors associated with poor CD4⁺ T-cell response include baseline CD4⁺ T-cell counts less than 200/mm³, older age, coinfection (e.g., HCV, HIV-2, human T-cell leukemia virus type 1 or 2 [HTLV-1, HTLV-2]), certain antiretrovirals, persistent immune activation, loss of regenerative potential of the immune system, comorbidities).200

In the setting of virologic suppression, there is no consensus regarding how to manage suboptimal immunologic response.200 Although there is some evidence that persistently low CD4⁺ T-cell counts in individuals receiving a suppressive antiretroviral regimen are associated with a small, but appreciable, risk of AIDS-related or non-AIDS-related morbidity and mortality, it is not clear whether suboptimal immunologic response in the setting of virologic suppression should prompt a modification of the antiretroviral regimen.200

Considerations When Modifying an Antiretroviral Regimen

If a change in the antiretroviral regimen is being made because of problems with adherence, use of commercially available fixed-combination preparations should be considered to reduce pill burden and simplify the regimen.200 Other conditions that may reduce adherence (e.g., depression, substance abuse) should be addressed.200

If a change is being made because of pharmacokinetic issues, food/fasting requirements should be reviewed, the possibility of malabsorption assessed, and concomitant drugs and dietary supplements reviewed for possible drug-drug interactions and changes in the antiretroviral regimen and/or concomitant therapy should be made if possible.200

Evaluation and management of antiretroviral-experienced patients experiencing virologic failure, especially those with extensive resistance, is complex, and consultation with an expert is recommended and considered critical.200

Drug-resistance testing should be performed while the patient is taking the failing antiretroviral regimen or, if not possible, within 4 weeks of discontinuance of the failing regimen.200 If it has been longer than 4 weeks since antiretrovirals were discontinued, drug-resistance testing may still provide useful information to guide therapy, although previously selected resistance mutations may not be detected.200

If a change is being made because of virologic failure, the goal of therapy is to reestablish virologic suppression (e.g., plasma HIV-1 RNA levels below the lower limits of detection).200 However, in some highly antiretroviral-experienced patients, maximal virologic suppression is not possible.200 In these cases, antiretroviral therapy should be continued with regimens designed to minimize toxicity, preserve CD4⁺ T-cell counts, and delay clinical progression.200

To design a new regimen for patients with virologic failure, the patient's treatment history and past and current resistance testing should be used to identify at least 2 (preferably 3) fully active drugs (i.e., drugs likely to have antiretroviral activity based on treatment history, drug-resistance testing, and/or a novel mechanism of action) that can be used in conjunction with an optimized background antiretroviral regimen.200

In general, adding a single, fully active antiretroviral is not recommended because of the risk of rapid development of resistance to all drugs in the regimen.200

When no viable suppressive regimen can be constructed for a patient with extensive drug resistance, consideration can be given to enrolling the patient in a clinical trial of investigational antiretrovirals or contacting pharmaceutical sponsors that may have investigational agents available.200

Discontinuing or briefly interrupting antiretroviral therapy is not recommended since such a strategy in patients with viremia may result in rapid increases in plasma HIV-1 RNA, decreased CD4⁺ T-cell counts, and increased risk of clinical progression.200 Planned long-term interruptions of antiretroviral therapy are not recommended outside of controlled clinical trials.200

Optimizing Antiretroviral Therapy in the Setting of Virologic Suppression

With currently recommended antiretroviral regimens, most patients living with HIV can achieve and maintain HIV viral suppression.200 In some virologically suppressed patients, it may be desirable to switch to a simplified or better tolerated regimen, provided the change maintains viral suppression without jeopardizing future treatment options.200 Regimen modification in the setting of viral suppression may be considered to reduce pill burden and dosing frequency, enhance tolerability and decrease short- or long-term toxicity, prevent or mitigate drug interactions, eliminate food or fluid requirements, or reduce costs.200

Although 3-drug antiretroviral regimens are generally recommended when modifying an existing regimen in antiretroviral-experienced adults and adolescents who are virologically suppressed, there is growing evidence that certain 2-drug regimens can maintain virologic suppression in patients who initiated therapy and achieved virologic suppression with a 3-drug regimen and have infections caused by HIV susceptible to both antiretrovirals in the new regimen.200

If a 2-drug antiretroviral regimen is being considered in antiretroviral-experienced patients who are virologically suppressed, the HHS Panel on Antiretroviral Guidelines for Adults and Adolescents states that a ritonavir-boosted PI (i.e., ritonavir-boosted atazanavir, ritonavir-boosted darunavir, lopinavir/ritonavir) in conjunction with lamivudine may be a reasonable option when use of TAF, TDF, or abacavir is contraindicated or not desirable.200

The HHS panel states that a switch to a 2-drug antiretroviral regimen of dolutegravir and lamivudine is a good option, provided there is no evidence of resistance to either drug and the patient does not have HBV coinfection.200 A fixed-combination preparation containing dolutegravir and lamivudine (dolutegravir/lamivudine) is commercially available and is labeled by FDA for use in antiretroviral-experienced adults to replace the current antiretroviral regimen in those who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) on a stable antiretroviral regimen, have no history of treatment failure, and are infected with HIV-1 with no known substitutions associated with resistance to dolutegravir or lamivudine.156

The HHS panel also states that a 2-drug regimen of dolutegravir and rilpivirine is a reasonable option when use of an NRTI is not desirable, provided there is no evidence of resistance to either drug, the patient does not have HBV coinfection, and interactions with other drugs the patient is receiving are not expected.200 A fixed-combination preparation containing dolutegravir and rilpivirine (dolutegravir/rilpivirine) is commercially available and is labeled by FDA for use in antiretroviral-experienced adults to replace the current antiretroviral regimen in those who are virologically suppressed (i.e., plasma HIV-1 RNA levels less than 50 copies/mL) on a stable antiretroviral regimen for at least 6 months, have no known history of treatment failure, and are infected with HIV-1 with no known substitutions associated with resistance to dolutegravir or rilpivirine.247

Strategies Not Recommended in the Setting of Virologic Suppression

Monotherapy is not recommended as a switching strategy in the setting of virologic suppression.200 Based on results of preliminary studies indicating that low-level viremia is more common in antiretroviral-experienced patients receiving monotherapy with a ritonavir-boosted HIV PI than in those receiving regimens that include a ritonavir-boosted HIV PI with HIV NRTIs, the HHS panel states that such monotherapy regimens generally should be avoided.200 These experts also state that dolutegravir monotherapy cannot be recommended in the setting of virologic suppression based on results of uncontrolled trials and cohorts indicating an unacceptable risk of virologic failure and subsequent development of resistance.200

The HHS panel states that a 2-drug regimen of ritonavir-boosted atazanavir and raltegravir cannot be recommended because results of a randomized study in virologically suppressed patients indicated that a switch to such a regimen was associated with higher rates of virologic failure and treatment discontinuance than switching to a regimen of ritonavir-boosted atazanavir in conjunction with emtricitabine and TDF.200

The HHS panel states that a 2-drug regimen of maraviroc and an HIV PI (with a pharmacologic enhancer) is not recommended based on results of a randomized, controlled trial in virologically suppressed patients.200 These experts also state that a 2-drug regimen of maraviroc and raltegravir is not recommended because of the rate of virologic relapse reported in a nonrandomized pilot study in virologically suppressed patients who were switched to such a regimen.200

Antiretroviral Therapy in Pediatric Patients

The pathogenesis of HIV infection and the general virologic and immunologic principles of antiretroviral therapy that apply to HIV-infected adults also apply to HIV-infected pediatric patients; however, the treatment of HIV-infected neonates, children, and adolescents involves some unique pharmacologic, virologic, and immunologic considerations.201 The goals of antiretroviral therapy in treatment-naive pediatric patients are to prevent disease progression, preserve or restore immune function as reflected by CD4⁺ T-cell count, maximally suppress viral replication for as long as possible, prevent emergence of antiretroviral drug-resistance mutations, minimize drug toxicity, maintain normal physical growth and neurocognitive development, and improve quality of life.201 Because recommendations for the management of HIV infection in neonates, children, and adolescents are rapidly evolving and increasingly complex, management of HIV-infected pediatric patients should be directed by a clinician with expertise in the treatment of pediatric and adolescent HIV infection, whenever possible, or such a specialist should be consulted regularly throughout the course of treatment to obtain the most up-to-date information.201

The HHS Panel on Antiviral Therapy and Medical Management of Children Living with HIV states that antiretroviral therapy should be initiated in all HIV-infected infants and children as soon as possible after the infection is confirmed.201 The HHS panel guidelines should be consulted for information on diagnosis of HIV infection in pediatric patients, including infants with perinatal HIV exposure.201

There is clear evidence that early initiation of antiretroviral therapy in children younger than 1 year of age is associated with health benefits and reduced mortality.201 Treatment of young infants during the early stages of HIV infection is more effective in controlling viral replication and maintaining sustained viral control after achieving viral suppression and provides neurodevelopmental and immunologic benefits compared with deferral of initiation of antiretroviral therapy.201 In situations when antiretroviral therapy has not been initiated in a child diagnosed with HIV, the HHS panel recommends that virologic, immunologic, and clinical status should be monitored at least every 3-4 months.201

The majority of pediatric HIV infections are acquired perinatally, and early identification of HIV-exposed neonates is important in providing effective treatment of these infants.201 HIV testing is recommended as a standard of care in all pregnant women in the US and is an important tool for identifying neonates at risk for HIV infection.201 (See HIV Testing During Pregnancy under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy During Pregnancy.) If maternal HIV status was not determined during the prenatal or immediate postpartum period, diagnostic testing of the neonate is recommended as soon as possible after birth.201

All neonates born to HIV-infected woman should receive antiretroviral prophylaxis or presumptive treatment beginning as soon as possible after delivery (preferably within 6-12 hours) to reduce the risk of perinatal HIV transmission.201,202,222 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Prevention of Perinatal HIV Transmission.) If subsequent diagnostic testing indicates that the neonate is HIV infected, a 3-drug antiretroviral regimen for treatment of pediatric HIV infection should be initiated.201 (See Initial Antiretroviral Therapy in Antiretroviral-naive Pediatric Patients Under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy in Pediatric Patients.)

All adolescents living with HIV should receive maximally suppressive antiretroviral therapy, especially those who are sexually active, considering pregnancy, or pregnant.201 Antiretroviral regimens in adolescents must be individualized since HIV-infected adolescents are a heterogeneous group in terms of mode of HIV infection.200,201 Many adolescents acquired HIV through perinatal transmission and may already have a history of extensive antiretroviral treatment that possibly included initial treatment with suboptimal antiretroviral regimens (e.g., monotherapy).201 Some adolescents may have become infected with HIV through sexual exposure or IV drug use and these individuals may experience a clinical course that is similar to that of adults and are most appropriately treated using the guidelines recommended for adults.200,201 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Initial Antiretroviral Therapy in Antiretroviral-naive Adults and Adolescents.) Dosage of antiretrovirals in adolescents generally is based on the stage of puberty, rather than strictly on the basis of age, since physiologic changes may affect pharmacokinetics of some drugs.200,201 Using the adolescent sexual maturity rating (SMR), adolescents in early puberty (SMR 1-3) are most appropriately treated using pediatric guidelines and dosages and those in late puberty (SMR 4 or 5) are most appropriately treated using adult guidelines and dosages.200,201 However, SMR and age are not necessarily directly predictive of the pharmacokinetics of some drugs and there may be some discrepancies between puberty stage-based dosing and age-based dosing since puberty may be delayed in children who acquired HIV perinatally.200

Safety of Antiretrovirals In Pediatric Patients

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Considerable information is available regarding use of NRTIs in pediatric patients.91,92,93,96,97,98,99,100,113,120,201,217,219,222

Zidovudine is labeled by FDA for the treatment of HIV-1 infection in pediatric patients 4 weeks of age or older and for use in neonates for prevention of perinatal HIV transmission.222 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Prevention of Perinatal HIV Transmission.)

Safety and efficacy of emtricitabine have been established in pediatric patients 3 months of age or older and labeling for the drug also includes dosage recommendations for use in infants 0-3 months of age.218

Didanosine is labeled by FDA for the treatment of HIV-1 infection in pediatric patients 2 weeks of age or older.217,390 However, the HHS Panel on Antiviral Therapy and Medical Management of Children Living with HIV states that didanosine is no longer recommended for use in pediatric patients.201 (See Antiretrovirals and Regimens Not Recommended in Pediatric Patients under Antiretroviral Therapy in Pediatric Patients: Initial Antiretroviral Therapy in Antiretroviral-naive Pediatric Patients, in Guidelines for Use of Antiretroviral Agents for Management of HIV Infection.)

Abacavir216 and lamivudine219 are labeled for the treatment of HIV-1 infection in pediatric patients 3 months of age or older. Stavudine is labeled for the treatment of HIV-1 infection in pediatric patients, including neonates;220 however, the HHS panel states that stavudine is no longer recommended for use in pediatric patients.201

Although single-entity TDF is labeled for use in pediatric patients 2 years of age or older weighing 10 kg or more,221 the fixed combination containing emtricitabine and TDF (emtricitabine/TDF) is labeled for the treatment of HIV-1 infection in pediatric patients weighing at least 17 kg.230 The fixed combination EVG/c/FTC/TDF is labeled by FDA for use in pediatric patients 12 years of age or older weighing 35 kg or more,235 the fixed combination emtricitabine/rilpivirine/TDF is labeled for use in those weighing 35 kg or more,233 and the fixed combinations efavirenz/emtricitabine/TDF and efavirenz/lamivudine/TDF are labeled for use in pediatric patients weighing 40 kg or more,232,251

Regarding fixed combinations containing TAF, EVG/c/FTC/TAF is labeled by FDA for use in pediatric patients weighing 25 kg or more,243 emtricitabine/TAF is labeled for use in pediatric patients weighing 35 kg or more,245 and emtricitabine/rilpivirine/TAF is labeled for use in pediatric patients 12 years of age or older weighing 35 kg or more.244

HIV Integrase Inhibitors (INSTIs)

Single-entity raltegravir (twice-daily regimen) is labeled by FDA for use in pediatric patients weighing 2 kg or more225 and single-entity dolutegravir is labeled for use in pediatric patients at least 4 weeks of age weighing at least 3 kg.236

The fixed combination BIC/FTC/TAF is labeled for use in pediatric patients weighing 25 kg or more.248

Although the fixed combination EVG/c/FTC/TAF is labeled for use in pediatric patients weighing 25 kg or more,243 the fixed combination EVG/c/FTC/TDF is labeled for use in pediatric patients 12 years of age or older weighing 35 kg or more.235

The fixed combination abacavir/dolutegravir/lamivudine is labeled for use in pediatric patients weighing 40 kg or more.240

Safety and efficacy of the fixed combination of dolutegravir and lamivudine and fixed combination of dolutegravir and rilpivirine have not been established in pediatric patients.247,256

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

Nevirapine is labeled by FDA for use in pediatric patients 15 days of age or older.215

Single-entity efavirenz is labeled for use in children 3 months of age or older weighing 3.5 kg or more213 and the fixed combinations of efavirenz/emtricitabine/TDF and efavirenz/lamivudine/TDF are labeled for use in pediatric patients weighing 40 kg or more.232,251

Etravirine is labeled for use in pediatric patients 2 years of age or older.214

Single-entity rilpivirine is labeled for use in pediatric patients 12 years of age or older weighing 35 kg or more226 and the fixed combination emtricitabine/rilpivirine/TDF is labeled for use in pediatric patients weighing 35 kg or more.233

Safety and efficacy of doravirine have not been established in pediatric patients.255

HIV Protease Inhibitors (PIs)

Data are available regarding the safety and efficacy of most PIs in pediatric patients.101,102,103,108,110,201,290

Lopinavir/ritonavir is labeled by FDA for the treatment of HIV-1 infection in children 14 days of age or older, but should not be used in those with postmenstrual age less than 42 weeks (i.e., time elapsed since first day of the mother's last menstrual period to birth plus time elapsed after birth).207

Ritonavir is labeled for use in children 1 month of age or older209 and fosamprenavir is labeled for use in those 4 weeks of age or older.205

Nelfinavir208 and ritonavir-boosted tipranavir211 are labeled for use in children 2 years of age or older.208,211 However, the HHS panel states that nelfinavir is not recommended in pediatric patients.201

Atazanavir (unboosted or ritonavir-boosted ) is labeled for use in children 3 months of age or older weighing 5 kg or more;203 because of the risk of kernicterus, atazanavir should not be used in neonates and infants younger than 3 months of age.201,203 Ritonavir-boosted darunavir is labeled for use in children 3 years of age or older;204 because of toxicity and mortality observed in animal studies, darunavir should not be used in pediatric patients younger than 3 years of age.204 Safety and efficacy of the fixed combinations containing atazanavir or darunavir with cobicistat (atazanavir/cobicistat, darunavir/cobicistat) have not been established in patients younger than 18 years of age.237,238

Only limited information is available regarding use of indinavir in pediatric patients and the manufacturer states that optimal dosage has not been identified.206 Safety and efficacy of saquinavir have not been established in pediatric patients younger than 16 years of age.210 The HHS panel states that indinavir and saquinavir are not recommended in pediatric patients.201

HIV Entry and Fusion Inhibitors

Only limited information is available regarding use of HIV entry and fusion inhibitors in pediatric patients.201

Although enfuvirtide is labeled by FDA for the treatment of HIV-1 infection in pediatric patients weighing 11 kg or more,223 the HHS panel states that the drug is not recommended in pediatric patients.201

Maraviroc is labeled for use in pediatric patients 2 years of age or older weighing at least 10 kg.224

Safety and efficacy of ibalizumab-uiyk249 and fostemsavir257 have not been established in pediatric patients.249,257

Initial Antiretroviral Therapy in Antiretroviral-naive Pediatric Patients

For initial treatment of HIV-infected pediatric patients, the HHS Panel on Antiviral Therapy and Medical Management of Children Living with HIV recommends antiretroviral therapy with a 3-drug regimen that includes an HIV NNRTI, INSTI, or PI ( ritonavir-boosted or cobicistat-boosted ) with 2 NRTIs (dual NRTIs).201 The choice of antiretroviral regimen should be individualized based on patient characteristics (age, weight, SMR), efficacy, potential adverse effects, results of drug-resistance testing, family preferences, and advantages and disadvantages of the specific regimen.201

Based on data from clinical studies (preferably in children) demonstrating durable viral suppression with immunologic and clinical improvement, extent of pediatric experience, information regarding incidence and types of short- and long-term toxicity, availability and acceptability of pediatric drug formulations (including palatability, ease of preparation, volume of liquid dose required, pill size, and pill burden), dosing frequency, food and fluid requirements, and potential for drug interactions, the HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV recommends that antiretroviral therapy in antiretroviral-naive children be initiated with certain preferred or alternative NNRTI-, INSTI-, or PI-based regimens.201 Regimens are designated as preferred based on efficacy, ease of administration, and acceptable toxicity.201 Regimens designated as alternative also have demonstrated efficacy, but clinical experience with these regimens is limited or they are more difficult to administer than preferred regimens.201 Table 3 includes these preferred and alternative antiretroviral regimens for initial treatment in antiretroviral-naive pediatric patients.201

Table 3. Preferred and Alternative Antiretroviral Regimens for Initial Therapy in Antiretroviral-naive Pediatric Patients201

Age	Weight	NNRTI, INSTI , or PI with Dual NRTIs^a
Preferred Regimens:
Birth to <14 days^b	Any	Nevirapinewith 2 NRTIs
Birth to <14 days^b	≥2 kg	Raltegravirwith 2 NRTIs
14 days to <3 years	Any	Lopinavir/ritonavir^cwith 2 NRTIs
14 days to <3 years	≥2 kg	Raltegravirwith 2 NRTIs
≥3 years	<25 kg	Ritonavir-boosted Atazanavirwith 2 NRTIs
		or
		Ritonavir-boosted Darunavir^d (twice daily) with 2 NRTIs
		or
		Raltegravirwith 2 NRTIs
≥3 years	≥25 kg	Dolutegravir^ewith 2 NRTIs
		or
		Cobicistat-boosted Elvitegravirwith 2 NRTIs (fixed combination EVG/c/FTC/TAF)
≥12 years (SMR 1-3)	≥25 kg	Bictegravirwith 2 NRTIs (fixed combination BIC/FTC/TAF)
≥12 years (SMR 4 or 5)	Any	See Table 1 and see Table 2

Alternative Regimens:
14 days to <3 years	Any	Nevirapinewith 2 NRTIs
3 months to <3 years	Any	Ritonavir-boosted Atazanavirwith 2 NRTIs
≥3 years	20 to <25 kg	Dolutegravir^ewith 2 NRTIs
≥3 years	≥25 kg	Ritonavir-boosted Atazanavirwith 2 NRTIs
	≥25 kg	or
		Ritonavir-boosted Darunavir^dwith 2 NRTIs
		or
		Raltegravirwith 2 NRTIs
≥3 years	Any	Efavirenzwith 2 NRTIs
		or
		Lopinavir/ritonavir^cwith 2 NRTIs
6 to <12 years	≥25 kg	Bictegravirwith 2 NRTIs (fixed combination BIC/FTC/TAF)
≥12 years (SMR 1-3)	≥35 kg	Rilpivirine^fwith 2 NRTIs
		or
		Cobicistat-boosted Atazanavirwith 2 NRTIs
≥12 years (SMR 1-3)	≥40 kg	Cobicistat-boosted Darunavirwith 2 NRTIs
≥12 years (SMR 4 or 5)	Any	See Table 1 and see Table 2

^a See Table 4 for information on dual NRTI options for use in pediatric patients.

^b If treatment is initiated before 14 days of age, nevirapine or raltegravir are preferred because dosage information is available for this age group. Consultation with an expert in pediatric HIV infection is recommended since clinical trial data are not available suggesting that initiation of antiretroviral treatment within the first 14 days of life improves outcome compared with initiation after 14 days of age. Consider changing from nevirapine to lopinavir/ritonavir when the infant reaches 14 days of age with postmenstrual age 42 weeks or more.

^c Lopinavir/ritonavir should not be used in neonates unless they are at least 14 days of age with postmenstrual age 42 weeks or more.

^d Darunavir (once daily) should not be used in children younger than 12 years of age or weighing less than 40 kg or in patients who have HIV-1 with substitutions associated with darunavir resistance (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V).

^e Dolutegravir is recommended as a preferred antiretroviral in children and adolescents 3 years of age or older weighing at least 25 kg and is an alternative antiretroviral in those 3 years of age or older weighing 20 to less than 25 kg.

^f Rilpivirine should only be used in adolescents 12 years of age or older weighing at least 35 kg who have pretreatment plasma HIV-1 RNA levels of 100,000 copies/mL or lower.

Adapted from Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection (April 14, 2020). Updates may be available at the US Department of Health and Human Services HIV/AIDS Information Services (AIDSinfo) website ([Web]).

Recommended Dual NRTI Options in Pediatric Patients

Use of 2 NRTIs (dual NRTIs) is recommended in all preferred and alternative NNRTI-, INSTI-, or PI-based regimens in pediatric patients.201 Table 4 includes recommendations of the HHS Panel on Antiretroviral Therapy and Medical Management of Children Living with HIV regarding preferred and alternative dual NRTIs for use in initial treatment regimens in pediatric patients.201

Table 4. Dual NRTI Options for Use in Initial NNRTI-, INSTI-, or PI-based Regimens in Pediatric Patients201

Age	Dual NRTI Option
Preferred Dual NRTI Options:
Birth to <3 months	zidovudine and (lamivudine or emtricitabine)
3 months to <6 years	abacavir and (lamivudine or emtricitabine)
	or
	zidovudine and (lamivudine or emtricitabine)
≥6 years (SMR 1-3)	abacavir and (lamivudine or emtricitabine)
	or
	TAF and emtricitabine^a
≥12 years of age (SMR 4 or 5)	See Table 1 and see Table 2
Alternative Dual NRTI Options:
≥3 months	abacavir and zidovudine
2-12 years	TDF and (lamivudine or emtricitabine)
≥6 years (SMR 1-3)	zidovudine and (lamivudine or emtricitabine)

^a Dual NRTI option of TAF and emtricitabine may be used in those weighing at least 25 kg who have creatinine clearances of 30 mL/minute or greater and are receiving an INSTI- or NNRTI-based regimen.

Antiretrovirals and Regimens Not Recommended in Pediatric Patients

Didanosine, Enfuvirtide, Fosamprenavir, Indinavir, Nelfinavir, Saquinavir, Stavudine, Tipranavir: The HHS Panel on Antiviral Therapy and Medical Management of Children Living with HIV states that these antiretrovirals are not recommended for management of HIV infection in children because of unacceptable toxicities, inferior virologic efficacy, high pill burden, pharmacologic concerns, and/or limited amount of pediatric data.201

Monotherapy: Use of any antiretroviral agent alone is considered a suboptimal regimen for the treatment of HIV-infected children and is not recommended because of inferior antiviral activity and rapid development of resistance.201 Use of zidovudine monotherapy is appropriate only in HIV-exposed infants younger than 6 weeks of age when the drug is being used for prevention of perinatal transmission of HIV.201 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Prevention of Perinatal HIV Transmission.)

All NRTI Regimens: Use of dual NRTIs alone (2 NRTIs without any other antiretroviral) is considered suboptimal for the treatment of HIV-infected children and is not recommended.201 Use of 2 NRTIs alone is unlikely to result in sustained viral suppression and leads to the development of viral resistance.201 For children previously initiated on a dual NRTI regimen who have achieved viral suppression, some clinicians may opt to continue the regimen.201 Triple NRTI regimens that include 3 NRTIs (without any drugs from another class) have been used but are not recommended for initial treatment in antiretroviral-naive children because of inferior virologic potency.201 In addition, a triple NRTI regimen of abacavir, TDF, and lamivudine or emtricitabine is not recommended at any time in children because a high rate of early virologic failure was reported when these regimens were used in adults.201

Regimens with agents from 3 different drug classes: Concomitant use of an NRTI, NNRTI, and PI or use of an INSTI, NRTI, and PI or NNRTI is not recommended because of insufficient data and potential to induce resistance to 3 classes of antiretrovirals.201

Lamivudine with Emtricitabine: These NRTIs should not be used concomitantly at any time because the drugs have similar resistance profiles and concomitant use offers no additional benefit.201

TDF: Use in pediatric patients younger than 2 years of age is not recommended because of potential bone toxicity and because appropriate dosages have not been determined.201

Unboosted Atazanavir: PI-based regimens that include atazanavir without a pharmacokinetic enhancer are not recommended at any time in pediatric patients because of poor bioavailability and inferior virologic activity compared with other PI-based regimens.201

Darunavir (once daily): PI-based regimens that include once-daily darunavir are not recommended for initial treatment in children younger than 12 years of age because of insufficient data.201 Ritonavir-boosted darunavir (twice daily) is a preferred regimen in pediatric patients 3 years to less than 12 years of age.201

Lopinavir/ritonavir (once daily): PI-based regimens that include lopinavir/ritonavir (once daily) are not recommended in children because of reduced exposures.201 Lopinavir/ritonavir (twice daily) is used in pediatric patients 14 days or age or older with postmenstrual age 42 weeks or more.201

Doravirine or Etravirine: These NNRTIs are not recommended in pediatric patients because of insufficient data.201

Efavirenz: This NNRTI is not recommended for use in children younger than 3 years of age pending further accumulation of data;201 although the drug is labeled for use in pediatric patients 3 months of age or older,213 variable pharmacokinetics have been reported in young children.201

Nevirapine: This NNRTI should not be used in adolescent girls with CD4⁺ T-cell counts exceeding 250/mm³ or adolescent boys with CD4⁺ T-cell counts exceeding 400/mm³ unless benefits clearly outweigh risks since use of the drug in such patients is associated with an increased risk of symptomatic (including serious and potentially fatal) hepatic effects.201

Enfuvirtide or Maraviroc: These drugs are not recommended for initial treatment in children because of insufficient data.201

Antiretroviral Therapy in Previously Treated Pediatric Patients

Consideration should be given to altering the initial antiretroviral regimen in HIV-infected pediatric patients if there is clinical, immunologic, or virologic evidence of disease progression or if there are signs of toxicity or intolerance or problems with adherence.201 Children who are receiving effective and tolerable antiretroviral regimens can continue receiving such regimens as they age, even if the regimen is no longer a preferred regimen for their age group.201

Consultation with a specialist who has extensive experience in the care of HIV-infected children is strongly advised when a change in antiretroviral therapy is being considered.201

Antiretroviral Therapy During Pregnancy

Recommendations for use of antiretrovirals for the treatment of HIV infection in pregnant HIV-infected women generally are the same as those for nonpregnant HIV-infected adults, and women should receive optimal antiretroviral therapy regardless of pregnancy status.202,427,478,481 Multiple-drug antiretroviral therapy with at least 3 drugs is considered the standard of care for the treatment of HIV infection in pregnant women and for prevention of perinatal HIV transmission, and multiple-drug therapy should be discussed with and offered to all HIV-infected pregnant women.202

Decisions regarding the most appropriate drugs to include in antiretroviral regimens during pregnancy should be made on an individual basis and should involve collaboration between the pregnant woman, her obstetrician, and an HIV specialist.202 The clinical, virologic, and immunologic status of the woman, results of drug-resistance testing, presence of comorbidities, and the potential for teratogenicity and known and unknown benefits and risks of the drugs to the woman and her fetus should be considered.202 The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that antiretrovirals with known benefit to the HIV-infected woman should not be withheld during pregnancy, unless there are known adverse effects to the mother, fetus, or infant and these adverse effects outweigh the benefits to the woman.202 (See Safety and Choice of Antiretrovirals During Pregnancy under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy During Pregnancy.)

In most cases, HIV-infected women who become pregnant while receiving a multiple-drug antiretroviral regimen that is fully suppressive and well tolerated should continue that regimen during the intrapartum and postpartum period.202 Discontinuance or interruption of antiretroviral therapy during pregnancy can lead to an increase in viral load, decline in immune status, and disease progression and may increase the risk of perinatal HIV transmission.202 Women who are currently receiving an antiretroviral regimen that is not fully suppressive should be carefully evaluated for adherence and genotypic resistance and every effort should be made to achieve full virologic suppression through adherence interventions or changes in the regimen.202 Clinicians should consider that there are certain antiretrovirals that should not be continued in pregnant women because of toxicity risks (e.g., didanosine, stavudine, full-dose ritonavir) and that pharmacokinetics of some drugs are affected by pregnancy and may result in decreased drug exposures during pregnancy and the potential for virologic failure and that modification of the antiretroviral regimen may be indicated.202 (See Safety and Choice of Antiretrovirals During Pregnancy under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy During Pregnancy.) HIV-infected women receiving antiretroviral therapy who present for antenatal care during the first trimester of pregnancy should be advised about the benefits and risks of antiretroviral drugs during this period and that continuation of antiretroviral therapy is recommended.202

If an HIV-infected pregnant woman is treatment-naive or treatment-experienced but not currently receiving antiretroviral therapy, the HHS panel states that a multiple-drug antiretroviral regimen should be initiated as early in the pregnancy as possible (regardless of plasma HIV-1 RNA levels or CD4⁺ T-cell counts) and should be continued to maintain viral load below the limits of detection throughout the pregnancy (antepartum and intrapartum) and after delivery.202 Early initiation of antiretroviral treatment may be more effective in reducing perinatal HIV transmission, but the benefits of first trimester antiretroviral therapy should be weighed against first trimester fetal exposure and potential fetal effects of certain antiretroviral agents.202

If an HIV-infected pregnant women has plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown plasma HIV-1 RNA levels) near the time of delivery, she should receive an intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor (or 3 hours before scheduled cesarean delivery) and continued until delivery (unless contraindicated because of hypersensitivity) since this may further decrease the risk of perinatal HIV transmission.202 In addition, all neonates born to HIV-infected women (HIV-exposed neonates) should receive an antiretroviral regimen (either prophylaxis or presumptive HIV therapy) initiated as soon as possible after birth (preferably within 6-12 hours) and continued for 4-6 weeks.202 (See Guidelines for Use of Antiretrovirals Agents for Management of HIV Infection: Antiretrovirals for Prevention of Perinatal HIV Transmission.)

To monitor maternal-fetal outcomes of pregnant women who receive antiretroviral agents during their pregnancy, an antiretroviral pregnancy registry has been established, and physicians are strongly encouraged to contact the registry at 800-258-4263 or [Web] to enroll such women.202 Long-term follow-up of all infants born to women who received antiretroviral therapy during pregnancy is recommended to determine whether there are any late effects of such exposure.202

HIV Testing During Pregnancy

Universal HIV counseling and HIV testing (with consent) is a standard of care for all pregnant women in the US.202 This recommendation facilitates optimal antiretroviral treatment of HIV-infected pregnant women, provides an opportunity for appropriate and timely interventions to decrease the risk of maternal-fetal transmission of the virus (antiretroviral therapy, scheduled cesarean delivery, avoidance of breast-feeding), and facilitates early identification and optimal treatment of perinatally infected children.202

HIV testing is recommended as a standard of care for all sexually active women and should be a routine component of preconception care, since this allows women to know their HIV status before conception, and also should be included in the routine panel of prenatal screening tests for all pregnant women.202 Patients should be informed that HIV screening is recommended for all pregnant women and that the test will be performed unless they decline (opt-out screening).202

To promote informed and timely therapeutic decisions, women should be tested for HIV as early as possible during each pregnancy.202 Women who decline the test early in prenatal care should be encouraged to be tested at a subsequent visit.202

Repeat HIV testing is recommended during the third trimester of pregnancy in women who had initial negative tests if they are known to be at risk of acquiring HIV, are receiving care in facilities that have an HIV incidence in pregnant women of at least 1 per 1000 per year, or reside in jurisdictions with elevated HIV incidence.202

Expedited HIV testing (i.e., results available within 1 hour) should be performed at the time of labor or delivery in any woman with undocumented HIV status.202 Appropriate intrapartum and neonatal antiretroviral regimens for prevention of perinatal HIV transmission (see Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Prevention of Perinatal HIV Transmission) should be initiated immediately based on results of the expedited test without waiting for confirmatory tests.202 The mother should not breast-feed unless supplemental HIV testing is negative.202

Women who were not tested for HIV before or during labor should undergo expedited HIV testing during the immediate postpartum period (or their infants should undergo expedited HIV testing).202 If results in the mother or infant are positive, an appropriate neonatal antiretroviral regimen should be initiated immediately and the mother should not breast-feed unless supplemental HIV test are negative.202

Safety and Choice of Antiretrovirals During Pregnancy

Data from human and/or animal studies indicate that almost all the commercially available antiretroviral agents (or their active metabolites) cross the placenta.202 This includes abacavir, atazanavir, darunavir, didanosine, dolutegravir, doravirine, efavirenz, elvitegravir, emtricitabine, enfuvirtide, etravirine, fosamprenavir, fostemsavir, indinavir, lamivudine, lopinavir/ritonavir, maraviroc, nelfinavir, nevirapine, raltegravir, rilpivirine, ritonavir, saquinavir, stavudine, tenofovir, tipranavir, and zidovudine.202,203,206,208,213,215,216,217,218,219,220,221,222,223,227,236,257 Because ibalizumab-uiyk is a monoclonal antibody, the drug has the potential to cross the human placenta.249 Data are not available to date regarding whether bictegravir crosses the human placenta.248

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that data from the antiretroviral pregnancy registry of prospective cases of exposure to antiretroviral agents during pregnancy indicate that the prevalence of birth defects was 2.8 per 100 live births among women with first-trimester exposures to any antiretrovirals and was not significantly different from that reported in live births among women with second and/or third trimester exposures.202 However, data on the risks of birth defects for many antiretrovirals are limited.202

Data from the antiretroviral pregnancy registry regarding first-trimester exposures are sufficient to detect at least a twofold increase in the risk of overall birth defects for cobicistat, darunavir, didanosine, elvitegravir, indinavir, raltegravir, rilpivirine, and stavudine; however, no such increases have been detected to date.202 For abacavir, atazanavir, efavirenz, emtricitabine, lamivudine, lopinavir, nelfinavir, nevirapine, ritonavir, TDF, and zidovudine, sufficient numbers of first-trimester exposures have been monitored to detect at least a 1.5-fold increase in risk of overall birth defects and a twofold increase in risk of birth defects in cardiovascular and genitourinary systems; however, no such increases have been detected to date.202 The HHS panel states that data for bictegravir, doravirine, etravirine, fosamprenavir, ibalizumab, maraviroc, saquinavir, TAF, and tipranavir are insufficient to date to assess the risk of teratogenicity in humans, but there was no evidence of teratogenicity in animals.202

Although animal studies evaluating dolutegravir (an INSTI) did not reveal evidence of teratogenicity or adverse fetal or developmental outcomes,202,236 neural tube defects have been reported rarely in infants born to women who received dolutegravir at the time of conception or during early pregnancy.202,236

CNS malformations (including neural tube defects) and cleft palate have been reported in offspring of cynomolgus monkeys that received efavirenz (NNRTI) during the first trimester and there have been a few reports of CNS defects (neural tube defects, microencephaly) and facial clefts in infants born to women who received efavirenz-containing regimens during the first trimester of pregnancy.202,213

HIV Nucleoside Reverse Transcriptase Inhibitors (NRTIs) and Dual NRTI Options

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that the preferred dual NRTI options for use in multiple-drug antiretroviral treatment regimens in HIV-infected pregnant women are abacavir and lamivudine (should be used only in those negative for HLA-B*5701, may be administered as the fixed combination abacavir/lamivudine) and TDF and either emtricitabine or lamivudine (should be used with caution in patients with renal insufficiency).202

The dual NRTI option of zidovudine and lamivudine (may be administered as the fixed combination zidovudine/lamivudine) is considered an alternative option.202 Although zidovudine and lamivudine was previously considered a preferred dual NRTI option, it requires twice-daily dosing and is associated with higher rates of mild to moderate adverse effects (e.g., nausea, headache, reversible maternal and neonatal anemia and neutropenia) than the preferred options.202

The HHS panel states that safety and pharmacokinetic data regarding use of TAF during pregnancy are insufficient to date to recommend the drug for dual NRTIs used in pregnant women; however, it may be appropriate to continue TAF in some pregnant women who are virologically suppressed.202

Didanosine and stavudine are not recommended for use in pregnant women because of reported toxicity.202 The dual NRTI option of didanosine and stavudine should not be used at any time, including during pregnancy.200,202 Pregnant women receiving these drugs should be switched to a preferred or alternative dual NRTI option.202

HIV Integrase Inhibitors (INSTIs)

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that dolutegravir and raltegravir are preferred antiretrovirals for use in conjunction with NRTIs for initial treatment in antiretroviral-naive pregnant women and treatment in antiretroviral-experienced pregnant women.202 These experts state that raltegravir also is a preferred antiretroviral in women of childbearing potential trying to conceive, but dolutegravir is considered an alternative antiretroviral in such women.202

Data from an observational birth outcome surveillance study in Botswana showed that a small, but significant, increase in the risk of neural tube defects was associated with use of dolutegravir-containing regimens at the time of conception and during early pregnancy compared with use of antiretroviral regimens that did not contain dolutegravir (prevalence rate of 0.3 or 0.1%, respectively).202,236 Data to date from the Botswana study and postmarketing sources including more than 1000 pregnancy outcomes have not shown evidence of an increased risk of adverse birth outcomes from dolutegravir exposures occurring during the second and third trimesters of pregnancy.236 The manufacturer of dolutegravir states that the drug should not be used during the first trimester of pregnancy, may be considered during the second and third trimesters of pregnancy if expected benefits justify potential risks to the pregnant woman and fetus, and is not recommended in those actively trying to become pregnant unless there is no suitable alternative.236 Based on preliminary information, the HHS panel previously stated that dolutegravir should be avoided during the first trimester of pregnancy; however, after evaluating additional data and assessing the risk of neural tube defects, these experts now state that dolutegravir is a preferred antiretroviral for use in pregnant women,202 although some panel members prefer avoiding use of dolutegravir in antiretroviral-naive women who are initiating antiretroviral therapy before 6 weeks of gestation.202 The HHS panel states that the small increased risk of neural tube defects associated with dolutegravir exposure around the time of conception that was reported in Botswana (a country where food is not routinely fortified with folic acid, a substance known to prevent neural tube defects in the general population) should be weighed against the advantages of dolutegravir in the treatment of HIV-1 infection (e.g., once-daily dosing, generally well tolerated, associated with high rates of rapid and durable virologic suppression [important for prevention of perinatal transmission of HIV], high barrier to drug resistance) and also should be weighed against what is known (or not known) about the risk of neural tube defects associated with use of other antiretrovirals during pregnancy.202 The panel strongly emphasizes the importance of patient counseling to ensure informed decision-making before initiating dolutegravir in pregnant women and women who are trying to conceive.202 Clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for additional guidance regarding the use of dolutegravir in such women.202

Raltegravir is recommend by the HHS panel as a preferred antiretroviral for antiretroviral-naive and antiretroviral-experienced pregnant women and those trying to conceive based on pharmacokinetic, safety, and efficacy data available regarding use of the drug during pregnancy.202 One disadvantage is that a twice-daily regimen of raltegravir is recommended in pregnant women because data to date are insufficient regarding use of the once-daily raltegravir regimen in pregnant women.202

The HHS panel states that EVG/c/FTC/TAF and EVG/c/FTC/TDF are not recommended for initial treatment in antiretroviral-naive pregnant women and are not recommended for treatment in antiretroviral-experienced pregnant women or those trying to conceive.202 Only limited data are available on use of cobicistat-boosted elvitegravir during pregnancy and there is some evidence that concomitant use of elvitegravir and cobicistat results in clinically important decreases in concentrations of both drugs during the second and third trimester of pregnancy and these concentrations are lower than those expected to lead to virologic suppression.202 For women already receiving EVG/c/FTC/TAF or EVG/c/FTC/TDF at the time of pregnancy, the HHS panel suggests switching to a more effective recommended regimen.202 If the fixed combination is continued during pregnancy, viral load should be monitored frequently (e.g., every 1-2 months).202

Data are not available regarding the pharmacokinetics of bictegravir during pregnancy and only limited data are available regarding use of the fixed combination BIC/FTC/TAF during pregnancy.202,248 The HHS panel states that data are insufficient to recommend use of BIC/FTC/TAF for initial treatment in antiretroviral-naive pregnant women or for treatment in antiretroviral-experienced women or those trying to conceive.202

HIV Nonnucleoside Reverse Transcriptase Inhibitors (NNRTIs)

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that none of the currently available NNRTIs are preferred antiretrovirals for initial antiretroviral therapy in antiretroviral-naive pregnant women; however, efavirenz and rilpivirine are recommended as alternative antiretrovirals for use in pregnant women.202

Efavirenz is an alternative antiretroviral for use in conjunction with NRTIs for initial treatment in antiretroviral-naive pregnant women and treatment in antiretroviral-experienced pregnant women and those trying to conceive.202 Although efavirenz is associated with adverse CNS and psychiatric symptoms (e.g., dizziness, fatigue, vivid dreams and/or nightmares, increased suicidality risk), it may be a suitable choice when a once-daily regimen is desired provided that the drug is tolerated.202 Because of the potential risk of neural tube defects, the manufacturer states that efavirenz should not be used during the first trimester of pregnancy.213 However, based on data indicating that efavirenz is not associated with an increased risk of neural tube defects, the HHS panel states that the drug can be used as an alternative antiretroviral in antiretroviral-naive and antiretroviral-experienced pregnant women and in those trying to conceive.202 If a woman becomes pregnant while receiving an efavirenz-based regimen, the HHS panel states that the regimen can be continued if it is well tolerated and providing adequate virologic suppression.202 Although data from an observational birth outcome surveillance study in Botswana reported 3 cases of neural tube defects among infants born to women who received efavirenz-containing regimens at the time of conception, the incidence of neural tube defects was not higher than that reported in infants born to women without HIV infection.202 Data from a surveillance monitoring study detected an increased rate of microcephaly in infants born to women who received efavirenz compared to woman receiving other antiretroviral agents; however, the HHS panel states that additional evaluation of the association between microcephaly and in utero exposure to efavirenz is needed.202

Rilpivirine also is an alternative antiretroviral recommended by the HHS panel for use in conjunction with NRTIs in antiretroviral-naive or antiretroviral-experienced pregnant women and in those trying to conceive.202 Rilpivirine is not recommended in patients with pretreatment viral loads greater than 100,000 copies/mL or CD4⁺ T-cell counts less than 200 cells/mm³.202 Although pharmacokinetic data indicate that rilpivirine concentrations are decreased during the second and third trimesters, the HHS panel states that data are insufficient to recommend dosage adjustments during pregnancy.202 However, more frequent monitoring of viral load (e.g., every 1-2 months) should be considered if rilpivirine is used during pregnancy.202

Nevirapine is not recommended for initial treatment in antiretroviral-naive pregnant women because of the potential for adverse effects (e.g., hypersensitivity reactions, hepatotoxicity), a complex lead-in dosage regimen, and a low barrier for resistance.202 The HHS panel states that nevirapine should be initiated in pregnant women with pretreatment CD4⁺ T-cell counts of 250/mm³ or greater only if potential benefits clearly outweigh risks;202 there is an increased risk of life-threatening hepatotoxicity if the drug is initiated in women with high CD4⁺ T-cell counts.202 Nevirapine also is not recommended in antiretroviral-experienced pregnant women or those trying to conceive, except in special circumstances.202 However, if a woman becomes pregnant while receiving a nevirapine-containing regimen, the HHS panel suggests that the regimen can be continued (regardless of CD4⁺ T-cell count) if it is well tolerated and providing adequate virologic suppression.202

The HHS panel states that data regarding doravirine are insufficient to date to recommend use of the drug during pregnancy.202

Etravirine is not recommended for initial treatment in antiretroviral-naive pregnant women because of insufficient pharmacokinetic and safety data on use during pregnancy.202 The drug also is not recommended in antiretroviral-experienced pregnant women or those trying to conceive, except in special circumstances.202

HIV Protease Inhibitors (PIs)

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that ritonavir-boosted atazanavir and ritonavir-boosted darunavir are preferred antiretrovirals for use in conjunction with NRTIs for initial treatment in antiretroviral-naive pregnant women and treatment in antiretroviral-experienced pregnant women and those trying to conceive.202 Because of insufficient pharmacokinetic and safety data, the HHS panel states that cobicistat-boosted atazanavir and cobicistat-boosted darunavir are not recommended during pregnancy or in women trying to conceive.202

When ritonavir-boosted atazanavir is used in pregnant women, some experts suggest that an increased dosage of atazanavir should be used during the second and third trimester.202 Atazanavir without low-dose ritonavir (unboosted atazanavir) should not be used in pregnant women.202

When ritonavir-boosted darunavir is used in pregnant women, a twice-daily regimen should be used;202 once-daily regimens of ritonavir-boosted darunavir are not recommended during pregnancy.202

Lopinavir/ritonavir is an alternative antiretroviral recommended by the HHS panel for use in conjunction with NRTIs for initial treatment in antiretroviral-naive pregnant women and for treatment in antiretroviral-experienced pregnant women and those trying to conceive.202 When lopinavir/ritonavir is used in pregnant women, a twice-daily regimen should be used;202 once-daily lopinavir/ritonavir regimens are not recommended during pregnancy.202 Some experts suggest that dosage of twice-daily lopinavir/ritonavir should be increased during the second and third trimesters of pregnancy (especially in antiretroviral-experienced pregnant women and women who start treatment during pregnancy with baseline plasma HIV-1 RNA levels exceeding 50 copies/mL) and that, if the usual twice-daily lopinavir/ritonavir dosage is used, virologic response and lopinavir plasma concentrations should be monitored.202

Fosamprenavir, indinavir, nelfinavir, saquinavir, and tipranavir (including ritonavir-boosted regimens) are not recommended in pregnant women.202 The HHS panel states that these HIV PIs may have unacceptable toxicities, inferior virologic efficacy, or high pill burden, or there may be pharmacologic concerns or only limited data on use during pregnancy.202

HIV Entry and Fusion Inhibitors

Enfuvirtide and maraviroc are not recommended for initial treatment in antiretroviral-naive pregnant women because these drugs are not recommended for initial treatment in nonpregnant adults and safety and pharmacokinetic data are insufficient regarding use during pregnancy.202 The HHS panel also states that enfuvirtide and maraviroc are not recommended in antiretroviral-experienced pregnant women or those trying to conceive, except in special circumstances.202 However, if a woman becomes pregnant while receiving one of these drugs, the HHS panel suggests that the regimen can be continued if it is well tolerated and providing adequate virologic suppression.202

The HHS panel states that data regarding ibalizumab-uiyk are insufficient to date to recommend use of the drug during pregnancy.202

Antiretrovirals for Prevention of Perinatal HIV Transmission

In the US, multiple-drug antiretroviral regimens are considered the standard of care for the treatment of HIV-1 infection in pregnant women and for the prevention of perinatal HIV transmission.202 The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that all pregnant HIV-infected women in the US should receive multiple-drug antiretroviral therapy, regardless of the woman's plasma HIV-1 RNA level or CD4⁺ T-cell count.202

In addition, to further decrease the risk of perinatal HIV transmission, the HHS panel states that all pregnant HIV-infected women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown plasma HIV-1 RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor (or 3 hours before scheduled cesarean delivery) and continued until delivery (unless contraindicated because of hypersensitivity), regardless of their antepartum antiretroviral regimen and all neonates born to HIV-infected women (HIV-exposed neonates) should receive an antiretroviral regimen (either prophylaxis or presumptive HIV therapy) initiated as soon as possible after birth (preferably within 6-12 hours) and continued for 4-6 weeks.202 This strategy of combined antepartum, intrapartum, and neonatal antiretrovirals reduces perinatal HIV transmission by several mechanisms, including lowering maternal antepartum viral load and providing pre- and postexposure prophylaxis in the infant.202 Ideally, decisions regarding management of HIV infection and prevention of perinatal HIV infection during pregnancy should involve collaboration between an HIV specialist, the pregnant woman, and her obstetrician.202

Maternal and neonatal regimens recommended for prevention of perinatal HIV transmission in the US may differ from those used in other countries.202 A variety of simple or short-course antiretroviral regimens (e.g., single-dose intrapartum and neonatal nevirapine alone or in conjunction with short-course zidovudine with or without lamivudine,200,202,313,314,315 intrapartum zidovudine and lamivudine with neonatal zidovudine,202,336,337 intrapartum/neonatal zidovudine alone,202 neonatal zidovudine alone202 ) have been used for prevention of perinatal HIV transmission in other countries or resource-limited settings (e.g., sub-Saharan Africa).202,307,308,317,318,319,377

The current guidelines published by the HHS panel available at [Web] should be consulted for more specific information regarding prevention of perinatal transmission of HIV.202 In addition, clinicians can consult the National Perinatal HIV Hotline at 888-448-8765 for information regarding antiretroviral treatment of pregnant HIV-infected women and their infants and prevention of perinatal HIV transmission.202

Risk of Perinatal HIV Transmission

The rate of transmission of HIV infection from infected mothers (who have not received antiretroviral therapy) to their fetuses has been estimated to range from 7-65%,10,22,111,126,173,174,194,423,425,426,253,284,477,478,479,481 and appears to depend on a variety of factors, including the health status of the mother.35,284,425 With the implementation of universal prenatal HIV counseling and testing, antiretroviral prophylaxis, scheduled cesarean delivery, and avoidance of breast-feeding, the rate of perinatal HIV transmission has decreased to 2% or lower in the US.202

Maternal-fetal transmission of HIV can occur in utero, intrapartum, or postpartum via breast-feeding.20,126,202,284,322,323,423,424,427 HIV has been detected in fetal tissue as early as 8-15 weeks of gestation.22,173,284,481 Based on presence or absence of HIV in cord blood or peripheral blood lymphocytes at birth, it has been estimated that HIV infection is acquired late in gestation or around the time of delivery in 50-70% of cases and earlier in the pregnancy in 30-50% of cases.20,21,424 HIV is distributed in milk, and postpartum transmission of HIV infection to infants can occur through breast-feeding, which is thought to be an important route of transmission in certain patient populations (e.g., in Africa, Haiti).126,173,202,322,323,477,481 Results of several studies in Africa indicate that the risk of HIV transmission through milk is continuous throughout the period of postpartum breast-feeding, but is greatest during the first 6 months postpartum.322,323

A variety of clinical or biologic factors in the mother appear to influence the risk of maternal-fetal HIV transmission during pregnancy or delivery.111,126,173,174,202,284,423,425,478,481 The risk of perinatal HIV transmission in untreated women is greater in those with advanced symptomatic disease, high viral load, or low CD4⁺ T-cell counts than in those with less advanced disease.23,126,173,195,284,423,424,425,426,334,477,481 In pregnant women receiving antiretroviral therapy, viral load and CD4⁺ T-cell counts may affect the risk of HIV transmission.202,333,334 In one study of pregnant women, plasma HIV-1 RNA levels were significantly higher in those who transmitted the infection to their infants than in those who did not, and the risk of transmission generally increased with increasing maternal viral load.334 Results of another study indicated that maternal plasma HIV-1 RNA levels at the time of delivery were the strongest predictor of the risk of maternal-fetal transmission of the virus.333 However, a threshold for viral load below which there is no risk of HIV transmission has not been identified.202,333,335 The risk for perinatal HIV transmission appears to be low in women with plasma HIV-1 RNA levels that are undetectable or less than 1000 copies/mL; however, there have been reports of perinatal transmission of the virus in women with all levels of plasma HIV-1 RNA, including those with levels below the limits of detection.202,333,334 Therefore, use of antiretrovirals during pregnancy for prevention of perinatal HIV transmission is recommended in all HIV-infected pregnant women, regardless of plasma HIV-1 RNA levels.202

Certain conditions that expose the neonate to large amounts of HIV-infected maternal blood and/or cervicovaginal secretions during labor and delivery (e.g., premature membrane rupture, abruptio placentae, invasive monitoring procedures) may increase the risk of transmission of the virus, even in women with low viral load.202 There is some evidence that mode of delivery (elective cesarean section, vaginal delivery) may affect the rate of perinatal HIV transmission. 202,306,424 A scheduled cesarean delivery at 38 weeks of gestation is recommended for prevention of perinatal transmission of HIV in women with plasma HIV RNA levels exceeding 1000 copies/mL near the time of delivery and for HIV-infected women with unknown plasma HIV RNA levels.202 The current guidelines published by the HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission available at [Web] should be consulted for specific information on maternal risks and current recommendations regarding when a scheduled cesarean section should be considered in HIV-infected women.202

Intrapartum Zidovudine for Prevention of Perinatal HIV Transmission

In addition to their current antiretroviral treatment regimen, the HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that all HIV-infected pregnant women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown HIV-1 RNA levels) near the time of delivery should receive an intrapartum IV zidovudine prophylaxis regimen initiated at the onset of labor (or 3 hours before scheduled cesarean delivery) and continued until delivery (unless contraindicated because of hypersensitivity).202 These experts state that the intrapartum IV zidovudine prophylaxis regimen also may be considered in pregnant HIV-infected women with plasma HIV-1 RNA levels of 50-999 copies/mL near the time of delivery.202 Although data are inadequate to determine whether the intrapartum IV zidovudine prophylaxis regimen provides any additional protection against perinatal transmission of HIV in women with plasma HIV-1 RNA levels between 50 and 999 copies/mL, some experts would administer the IV zidovudine prophylaxis regimen to such women since the risk of HIV transmission is slightly higher (approximately 1-2% higher) when viral loads are 50-999 copies/mL compared to when viral loads are less than 50 copies/mL.202 The intrapartum IV zidovudine prophylaxis regimen is not necessary in HIV-infected women receiving an antiretroviral treatment regimen if they have plasma HIV-1 RNA levels of 50 copies/mL or less during late pregnancy and near delivery, provided there are no concerns related to maternal adherence to the treatment regimen.202

If the intrapartum IV zidovudine prophylaxis regimen is indicated and the woman's current antiretroviral regimen includes oral zidovudine, IV zidovudine should be substituted for oral zidovudine until after delivery;202 other antiretrovirals included in the woman's treatment regimen can be continued orally during labor.202

If zidovudine was not included in the antenatal antiretroviral treatment regimen because of known or suspected zidovudine resistance, the HHS panel states that the intrapartum IV zidovudine prophylaxis regimen is still recommended in women with plasma HIV-1 RNA levels exceeding 1000 copies/mL (or unknown HIV-1 RNA levels) near the time of delivery, unless the woman has a documented history of zidovudine hypersensitivity.202

Antiretrovirals in HIV-exposed Neonates

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission recommends that all neonates born to HIV-infected women (HIV-exposed neonates) receive an antiretroviral regimen (either prophylaxis or presumptive HIV therapy) initiated as soon as possible after birth (preferably within 6-12 hours) and continued for up to 6 weeks.202 The choice of a neonatal antiretroviral prophylaxis regimen or a neonatal presumptive HIV therapy regimen should be based on an assessment of the likelihood of perinatal HIV transmission.202

In HIV-exposed neonates at low risk of perinatal HIV transmission (i.e., infants born to women who were receiving a recommended multiple-drug antiretroviral regimen during pregnancy with sustained viral suppression [plasma HIV-1 RNA levels less than 50 copies/mL] near delivery and no concerns related to maternal adherence to the treatment regimen), the HHS panel states that a 4-week zidovudine prophylaxis regimen can be used alone.202

The HHS panel states that HIV-exposed neonates at higher risk of HIV acquisition (e.g., those born to HIV-infected women who did not receive antepartum or intrapartum antiretrovirals, received only intrapartum antiretrovirals, or received antepartum and intrapartum antiretrovirals with suboptimal viral suppression near delivery) should receive presumptive HIV therapy with a 3-drug regimen of zidovudine, lamivudine, and nevirapine or zidovudine, emtricitabine, and raltegravir from birth to up to 6 weeks.202 The 3-drug presumptive HIV therapy regimen serves as antiretroviral prophylaxis to prevent acquisition of HIV and also serves as early treatment for neonates who are later confirmed to have acquired HIV.202 The optimal duration of presumptive HIV therapy in neonates at higher risk of HIV acquisition is unknown.202 Some experts opt to discontinue the 3-drug presumptive treatment regimen if results of the neonate's HIV nucleic acid amplification test (NAAT) are negative; others continue the 3-drug regimen for 2-6 weeks depending on the risk of HIV transmission.202 However, in all cases, zidovudine should be continued for 6 weeks even if the other drugs are discontinued.202

Although a 2-drug prophylaxis regimen (6-week zidovudine prophylaxis regimen and a 3-dose nevirapine prophylaxis regimen) has been used and is an option for HIV-exposed neonates at higher risk of HIV acquisition, there are no randomized trials comparing efficacy and safety of the 2-drug prophylaxis regimen and 3-drug presumptive treatment regimen in such neonates.202 While most of the HHS panel experts recommend use of the 3-drug presumptive treatment regimen in all neonates at higher risk, others opt to use the 2-drug prophylaxis regimen if maternal viral load is less than 200-400 copies/mL.202

Neonates with documented HIV infection should receive treatment with a 3-drug antiretroviral treatment regimen.202 (See Initial Antiretroviral Therapy in Antiretroviral-Naive Pediatric Patients under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretroviral Therapy in Pediatric Patients.)

Because safety and dosage data are not available, the HHS panel states that use of antiretrovirals other than zidovudine, lamivudine, and nevirapine cannot be recommended for premature HIV-exposed neonates (gestational age less than 37 weeks).202

Antiretrovirals for Prevention of Sexual Transmission of HIV (TasP)

Effective antiretroviral therapy that consistently suppresses plasma HIV-1 RNA levels to less than 200 copies/mL or below the lower limit of quantification has been shown to prevent transmission of HIV-1 to non-HIV-1-infected sexual partners and use of this strategy is considered treatment as prevention (TasP).200 Data from a clinical trial in mixed HIV status heterosexual couples indicated that the risk of HIV transmission to an uninfected sexual partner is substantially decreased when the HIV-infected individual has sustained plasma HIV-1 RNA levels less than 400 copies/mL for at least 6 months.200 Data from additional observational studies that included a more diverse population of mixed HIV status couples, including men who have sex with men (MSM), indicated that sexual transmission of the virus did not occur when the HIV-infected partner had plasma HIV-1 levels less than 200 copies/mL.200

The HHS Panel on Antiretroviral Guidelines for Adults and Adolescents recommends that all individuals with HIV infection be informed that transmission of the virus to sexual partners can be prevented if plasma HIV-1 RNA levels are maintained at less than 200 copies/mL.200 When antiretroviral therapy is initiated in antiretroviral-naive HIV-infected individuals, they should be counseled to use another method to prevent transmission of the virus to sexual partners (e.g., condoms, preexposure prophylaxis [PrEP] in the HIV-negative sexual partner, sexual abstinence) at least during the first 6 months of treatment and until plasma HIV-1 RNA levels less than 200 copies/mL have been documented.200 Many experts recommend confirming sustained viral suppression before assuming that there is no risk of sexual transmission of HIV.200 The HHS panel states that current data are insufficient to determine the optimal schedule for monitoring viral load for the purpose of preventing sexual transmission of HIV.200

Individuals who intend to rely on TasP for prevention of sexual transmission of HIV-1 need to maintain high levels of adherence to their antiretroviral regimen;200 such individuals should be informed that sexual transmission of HIV is possible during periods of poor adherence or treatment interruption and that additional methods to prevent sexual transmission of the virus are necessary whenever viral load is 200 copies/mL or greater.200 If antiretroviral therapy is interrupted or discontinued, viral rebound typically occurs within days to weeks and has been observed as soon as 3-6 days after treatment has been stopped.200 Intermittent or transient increases (“blips”) in viral load followed by return to viral loads less than 200 copies/mL may occur even in HIV-infected individuals who are highly adherent to their antiretroviral regimen.200 Most virologic blips likely represent normal biologic fluctuation (i.e., variation around a mean undetectable viral load) or laboratory artifact and do not necessarily indicate inadequate adherence.200 However, persistent viremia with plasma HIV-1 RNA levels of 200 copies/mL or greater has been associated with increasing risk of virologic failure that, in the context of TasP, can lead to increased risk of sexual transmission of HIV.200

Effectiveness of TasP for prevention of HIV transmission from blood exposures (e.g., through nonsterile drug injection) has not been determined.200 In addition, while suppression of maternal viral load substantially reduces the risk of perinatal transmission and transmission through breast-feeding, it does not eliminate these risks, and transmission has occurred via breast-feeding despite continuous viral suppression.200

Antiretrovirals for Preexposure Prophylaxis for Prevention of HIV-1 Infection (PrEP)

The fixed combination containing emtricitabine and TDF (emtricitabine/TDF) and the fixed combination containing emtricitabine and TAF (emtricitabine/TAF) are used for preexposure prophylaxis (PrEP) in non-HIV-1-infected individuals to reduce the risk of sexually acquired HIV-1 in those at high risk.196,197,230,245,450,452,453,454,457,458,459,463,466,468,469,470,493 Other antiretroviral regimens also have been used or are being investigated for PrEP in high-risk non-HIV-1-infected individuals in an attempt to prevent acquisition of the virus, including oral TDF alone and/or topical antiretrovirals or microbicides (e.g., intravaginal tenofovir gel [not commercially available in the US]).196,197,450,453,454,466

The principal interventions used for HIV prevention are screening, education, and counseling regarding high-risk behaviors (e.g., condom use, number of sex partners, risky sexual practices, substance abuse, sexually transmitted diseases), HIV testing and linkage to care, and early initiation of antiretroviral treatment in HIV-infected individuals.196,200,450,462 In addition, effective antiretroviral therapy in HIV-infected individuals that consistently decreases viral load to less than 200 copies/mL and strict adherence to such regimens are important for prevention of secondary HIV transmission through sexual contact.200,453,460,464 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Prevention of Sexual Transmission of HIV [TasP].) However, the risk of HIV transmission is not completely eliminated and can be affected by factors such as persistence of HIV in genital secretions, nonadherence to antiretroviral treatment regimens, presence of other sexually transmitted diseases, or increased high-risk behaviors (i.e., risk compensation).200,453,460,464

Data are accumulating regarding the safety and efficacy of PrEP in non-HIV-infected individuals and PrEP appears to be an important strategy for HIV prevention in high-risk individuals in conjunction with adherence counseling and risk-reduction measures.196,230,450,455,457,458,459,461,463,466,468,469,470,493 However, use of PrEP has been controversial since it requires certain important considerations and precautions in the non-HIV-infected individual (e.g., selection criteria, strict adherence to the PrEP regimen, use of PrEP in conjunction with other prevention strategies, close clinical and laboratory monitoring).196,450,452,453,454,455,456,457,461,468,469,470 In addition, further study is needed to more fully evaluate efficacy in specific populations at risk (US populations, low resource settings, MSM, discordant heterosexual couples, adolescents, pregnant and breast-feeding women, injection drug abusers) and to evaluate adverse effects associated with long-term use of antiretrovirals in non-HIV-infected individuals.196,450,452,453,454,455,456,457,461,468,469,470 There also are cost considerations and concerns that use of PrEP may increase the incidence of HIV resistance (especially in nonadherent individuals) and complicate future treatment of HIV infection and that the benefits of PrEP may be offset by increases in high-risk behaviors (i.e., risk compensation).196,450,452,453,454,455,456,461

Emtricitabine/TDF and Emtricitabine/TAF Preexposure Prophylaxis for Prevention of HIV-1 Infection (PrEP)

The fixed combination emtricitabine/TDF230 and the fixed combination emtricitabine/TAF245 are both labeled by FDA for PrEP in conjunction with safer sex practices to reduce the risk of sexually acquired HIV-1 infection in at-risk HIV-1-negative adults and adolescents weighing 35 kg or more.

Efficacy and safety of a once-daily regimen of emtricitabine/TDF for HIV-1 PrEP were evaluated in a multinational, randomized, double-blind, placebo-controlled, phase 3 trial (Preexposure Prophylaxis Initiative [iPrEx trial]) that included 2499 HIV-seronegative men or transgender women (male at birth) who have sex with men and have evidence of high-risk behavior for HIV-1 infection.230,450 Study participants were randomized to receive emtricitabine/TDF (single tablet containing 200 mg of emtricitabine and 300 mg of TDF once daily) or placebo in conjunction with usual prevention strategies (i.e., monthly HIV-1 testing, risk-reduction counseling, condoms, diagnosis and management of sexually transmitted infections) and were followed for 4237 person-years.230,450 The primary outcome measure was the incidence of documented HIV seroconversion.230 There was a 42% reduction in the risk of HIV-1 seroconversion in the group receiving emtricitabine/TDF (48 individuals receiving emtricitabine/TDF and 83 individuals receiving placebo seroconverted).230 Results of a post-hoc case-control study of plasma and intracellular drug concentrations in about 10% of study participants indicated that efficacy of emtricitabine/TDF PrEP is strongly correlated with adherence since risk reduction appeared to be greatest in those with detectable intracellular tenofovir.230

Efficacy and safety of a once-daily regimen of emtricitabine/TDF for HIV-1 PrEP in HIV-1-seronegative partners of serodiscordant heterosexual couples were evaluated in a randomized, double-blind, placebo-controlled, 3-arm trial (Partners Preexposure Prophylaxis [PrEP] trial) that included 4758 serodiscordant couples in Kenya and Uganda.230,463 The uninfected partners were randomized to receive emtricitabine/TDF (single tablet containing 200 mg of emtricitabine and 300 mg of TDF once daily), TDF alone (300 mg of TDF once daily), or placebo (once daily).230,463 Study participants received monthly HIV-1 testing, adherence evaluations, sexual behavior assessments, and safety evaluations.230,463 Women received monthly pregnancy tests; if pregnancy occurred, the study drug was interrupted during pregnancy and breast-feeding.230,463 After 7827 person-years of follow-up, there were a total of 82 emergent HIV-1 seroconversions (overall observed seroincidence rate of 1.05 per 100 person-years).230,463 The risk reduction for the emtricitabine/TDF group relative to the placebo group was 75%.230,463 There were 13 seroconversions in partners randomized to emtricitabine/TDF and 52 seroconversions in partners randomized to placebo (2 and 3 seroconversions, respectively, occurred during interruption of PrEP for pregnancy).230 Results of a post-hoc case-control study of plasma and drug concentrations in about 10% of study participants indicated that efficacy of emtricitabine/TDF PrEP is strongly correlated with adherence since risk reduction appeared to be greatest in those with detectable plasma tenofovir.230

The comparative efficacy and safety of a once-daily regimen of emtricitabine/TAF (single tablet containing 200 mg of emtricitabine and 25 mg of TAF once daily) and a once-daily regimen of emtricitabine/TDF (single tablet containing 200 mg of emtricitabine and 300 mg of TDF once daily) for HIV-1 PrEP were evaluated in a multinational, randomized, double-blind, noninferiority trial (DISCOVER) that included 5262 HIV-seronegative men and 73 HIV-seronegative transgender women who have sex with men and have evidence of high-risk behavior for HIV-1 infection.245,493 The primary outcome was the incidence of documented HIV-1 infection per 100 person-years in individuals randomized to emtricitabine/TAF and emtricitabine/TDF (with a minimum follow-up of 48 weeks and at least 50% of participants having 96 weeks of follow-up).245,493 Results indicate that emtricitabine/TAF is noninferior to emtricitabine/TDF in reducing the risk of acquiring HIV-1 infection.245,493 The rate of HIV-1 infection per 100 person-years was 0.16 in those receiving emtricitabine/TAF (4370 person-years of follow-up) and 0.34 in those receiving emtricitabine/TDF (4386 person-years of follow-up).245,493 Results were similar across the subgroups of age, race, and gender identity and efficacy for both regimens was strongly correlated with adherence.245,493

Recommendations for Preexposure Prophylaxis for Prevention of HIV-1 Infection (PrEP)

CDC first issued comprehensive guidelines for clinicians in the US regarding the use of PrEP for prevention of HIV-1 infection in heterosexually active adults and MSM at substantial risk for sexual acquisition of the virus in 2014 and updated these guidelines in 2017.197 These CDC guidelines provide information on the safety and efficacy of PrEP and include recommendations regarding eligibility prescreening and testing, risk behavior assessment, counseling prior to and during PrEP, and clinical and laboratory follow-up during and after discontinuance of PrEP.197

CDC states that PrEP is recommended as one prevention option for sexually active adult MSM in the US at substantial risk for acquiring HIV infection (i.e., those with an HIV-infected sexual partner, recent sexually transmitted bacterial infection, high number of sex partners, history of inconsistent or no condom use, commercial sex work).197 CDC also states that PrEP is recommended as one prevention option for adult heterosexually active men or women in the US who are at substantial risk for sexual acquisition of HIV infection (i.e., those with an HIV-infected sexual partner, recent sexually transmitted bacterial infection, high number of sex partners, history of inconsistent or no condom use, commercial sex work, in high-prevalence area or network).197 In addition, CDC states that PrEP is recommended as one prevention option for adult injection drug users in the US at substantial risk of HIV acquisition (i.e., those with an HIV-infected injecting partner and those sharing injection equipment or who recently received drug treatment but are currently injecting).197 CDC states that the risks and benefits of PrEP for adolescents should be weighed carefully in the context of local laws and regulations about autonomy in health-care decision-making by minors.197

The 2017 CDC guidelines recommended use of emtricitabine/TDF once daily (single fixed-combination tablet containing 200 mg of emtricitabine and 300 mg of TDF once daily) if PrEP is used in MSM, heterosexually active men and women, and injection drug users in the US.197 To date, the CDC guidelines have not been updated to address use of PrEP in adolescents or use of emtricitabine/TAF for PrEP.

Because there is some evidence that use of oral TDF alone may be effective in heterosexually active men and women and in injection drug users, CDC stated that TDF monotherapy (300 mg once daily) can be considered an alternative regimen for PrEP only in these specific populations; TDF alone is not recommended for PrEP in MSM.197 CDC stated that other antiretrovirals (e.g., emtricitabine, TAF) should not be used alone for PrEP and should not be used in addition to the recommended emtricitabine/TDF or TDF regimens.197 CDC also stated that other dosage regimens of emtricitabine/TDF or TDF (e.g., intermittent, episodic) should not be used for PrEP.197

The HHS Panel on Treatment of Pregnant Women with HIV Infection and Prevention of Perinatal Transmission states that PreP in non-HIV-1-infected sexual partners of HIV-infected individuals is recommended to reduce the risk of sexual transmission of HIV, especially if the HIV-infected partner has not achieved viral suppression or when viral suppression status is not known.202

The US Preventive Services Task Force (USPSTF) recommends that clinicians offer PrEP to individuals who are at high risk of HIV acquisition because there is convincing evidence that this strategy provides substantial benefit for decreasing the risk of HIV infection in individuals who are at high risk through sexual exposures as the result of certain risk factors or behaviors.196

Acute and chronic HIV infection must be excluded by symptom history and HIV testing immediately before PrEP is initiated.196,197,230,245 In addition, individuals receiving PrEP must be screened for HIV-1 infection at least once every 3 months.196,197,230,245 The emtricitabine/TDF and emtricitabine/TAF PrEP regimens are inadequate for the treatment of HIV-1 infection.196,197,230,245

Guidelines and other information regarding PrEP are available at [Web] and [Web] and should be consulted for additional information.196,197

Antiretrovirals for Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Antiretrovirals are used for postexposure prophylaxis of HIV infection following occupational exposure† (PEP) in health-care personnel and other individuals exposed via percutaneous injury (e.g., needlestick, cut with sharp object) or mucous membrane or nonintact skin (e.g., chapped, abraded, dermatitis) contact with blood, tissue, or other body fluids that might contain HIV.19,123,124,125,128,129,133,134,135,136,137,138,139,140,147,161,162,199

The principal means of preventing occupationally acquired HIV infection is avoidance of blood and body fluid exposures through the use of safety and isolation practices and strategies outlined in guidelines from the Health Care Infection Control Practices Advisory Committee (HICPAC) and CDC regarding standard precautions for prevention of transmission of infectious agents in health-care settings.149,150,151,152,153,199,471 While adherence to these and other precautions decreases the incidence of occupational exposure to HIV, accidental exposures that put health-care personnel and others at risk of infection can still occur.149,199 There is direct and indirect evidence from animal and human studies that antiretroviral PEP can reduce the risk of HIV transmission and infection.147,153,157,161,162,165,199 Therefore, use of antiretroviral PEP is important in the management of occupational exposures to HIV.147,153,157,161,162,165,199

In 2013, the US Public Health Service (USPHS) issued updated guidelines for management of occupational exposures to HIV and use of PEP following occupational exposures.199 Although the prior PEP guidelines required an assessment of the level of risk of HIV transmission and infection for each individual exposure incident and recommended either a 2- or 3-drug regimen based on the assessment of risk, the 2013 USPHS guidelines state that a PEP regimen that includes 3 (or more) antiretrovirals should be used for all occupational exposures associated with a risk of HIV transmission.199 These guidelines also include recommendations regarding preferred and alternative PEP regimens selected based on optimal tolerability and a convenient dosing schedule that encourages completion of the PEP regimen.199

Occupational Exposures Associated with Risk of HIV Infection

The risk of acquiring HIV following occupational exposure varies depending on the type and severity of exposure.149,150,151,152,163,199

Types of exposures that place health-care personnel at risk for HIV infection include percutaneous injuries (e.g., needlestick, cut with a sharp object) or contact of mucous membrane or nonintact skin (e.g., when the exposed skin is chapped, abraded, or afflicted with dermatitis) with blood, tissue, or other potentially infectious body fluids from an HIV-infected individual.150,151,152,163,199 In addition to blood and body fluids contaminated with visible blood, potentially infectious body fluids include semen and vaginal secretions (these fluids have been implicated in sexual transmission of HIV infection, but have not been implicated in occupational transmission) and CSF and synovial, pleural, peritoneal, pericardial, or amniotic fluids (the risk of transmission of HIV from these fluids has not yet been determined).151,199 Other body fluids (e.g., urine, saliva, sputum, nasal secretions, feces, vomitus, sweat, tears) are not considered potentially infectious unless they are visibly bloody.151,163,199 There has been at least one case of documented HIV seroconversion in an individual unintentionally bitten by a patient with advanced HIV infection who, at the time of the bite, was having a tonic-clonic (grand mal) seizure and had saliva contaminated with visible blood.159 Although transmission of HIV by this route is rare, clinical evaluation must include the possibility that both the person bitten and the person who inflicted the bite were potentially exposed to HIV.199 Any direct contact (i.e., without barrier protection) to concentrated HIV in a research laboratory or production facility is considered an exposure that requires clinical evaluation and consideration of the need for PEP.199

While the true incidence of HIV transmission following occupational exposure to HIV-positive material is unknown, the risk of transmission of the virus is greater following percutaneous exposures than following mucous membrane or skin exposures.147,148,149,150,151,152,163,199 The risk of transmission of HIV after occupational exposure to body fluids or tissues other than HIV-infected blood is unknown, but probably is considerably lower than for blood exposures.199

Although the risk of HIV transmission associated with an occupational exposure from an HIV-positive individual with plasma HIV-1 RNA levels that are undetectable is thought to be very low, the possibility of transmission cannot be ruled out since HIV transmission has been reported from source individuals with undetectable viral load following sexual exposure and via perinatal transmission.199

Percutaneous Exposure

The risk of HIV transmission following a percutaneous injury that results in exposure to HIV-positive blood has been estimated to be approximately 0.3%.126,140,147,148,149,150,151,152,163,199 The risk appears to be greatest for percutaneous exposures involving a large blood volume (indicated by a needle or other device visibly contaminated with the patient's blood, a procedure that involved a needle being placed directly in a vein or artery, or a deep injury) and/or a source patient with advanced HIV infection.147,148,150,151,152,154,199 There is evidence that more blood is transferred by deeper injuries and hollow-bore needles.199

Mucous-membrane Exposure

The risk of HIV transmission for each episode of mucous membrane exposure to HIV-positive blood is probably too low to measure accurately, but has been estimated to be about 0.09%.126,148,151,155,163,199 In documented cases of HIV transmission following mucous membrane exposure, factors that appeared to contribute to transmission of the virus included a large volume of blood and prolonged duration of contact.148,151

Skin Exposure

The risk of transmission following nonintact skin exposures to HIV-positive blood has not been precisely quantified, but is estimated to be less than that following mucous membrane exposures.199 There have been documented episodes of HIV transmission from nonintact skin exposures.199 Compared with exposures that involve intact skin, the risk of HIV transmission presumably would be increased for skin exposures involving an area where skin integrity is visibly compromised.199

Choice of Antiretroviral Agents for Postexposure Prophylaxis following Occupational Exposure to HIV (PEP)

Although recommendations for PEP initially involved zidovudine monotherapy and subsequently involved selection of a 2- or 3-drug regimen based on the level of risk,125,134,137,139,141,143,144,145,157,161,162,165,199 multiple-drug antiretroviral regimens that include 3 (or more) antiretroviral agents have been recommended since 2013 for all occupational exposures associated with a risk of HIV transmission.199 Although the optimal number of antiretrovirals necessary for PEP remains unknown, the recommendation for use of 3 (or more) drugs is based on evidence that regimens that include 3 or more antiretrovirals agents are more effective than monotherapy and 2-drug regimens for the treatment of HIV infection and the fact that it is highly likely that occupational exposures to HIV-positive materials will involve resistant strains of HIV.138,141,143,144,145,153,162,165,199

The 2013 USPHS nPEP guidelines state that the preferred regimen for PEP following an occupational exposure associated with a risk of HIV transmission is raltegravir in conjunction with emtricitabine and TDF (may be administered as the fixed combination emtricitabine/TDF).199 This regimen has a convenient dosing schedule and is potent, tolerable, and associated with minimal potential for drug interactions.199 These experts also recommend various alternative PEP regimens containing antiretrovirals selected based on known adverse effects and tolerability of the drugs, potential for drug interactions with other antiretrovirals in the regimen or other drugs the exposed individual may be taking, and convenient dosing schedules.199 (See USPHS Recommendations Regarding PEP under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Postexposure Prophylaxis following Occupational Exposure to HIV [PEP].)

Because strains of HIV resistant to each of the currently available antiretrovirals have been reported and horizontal or vertical transmission of resistant strains can occur, consideration can be given to whether the HIV source is known or suspected to be infected with resistant HIV.199 If the source person's virus is known or suspected to be resistant to 1 or more antiretrovirals, drugs that the source person's virus is unlikely to be resistant to should be selected for the PEP regimen.199 Initiation of PEP should not be delayed while waiting results of resistance testing of the source person's virus; the regimen can be modified, if necessary, if results become available.199

Consultation with an expert regarding the most appropriate antiretroviral regimen for PEP is recommended whenever possible.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199 (See Situations for Which Expert Consultation Regarding PEP is Advised under Choice of Antiretroviral Agents for Postexposure Prophylaxis following Occupational Exposure to HIV [PEP]: Management of Occupational Exposures to HIV, in Guidelines for Use of Antiretroviral Agents for Management of HIV Infection.)

Safety and Efficacy of HIV Postexposure Prophylaxis (PEP)

Efficacy of PEP has been difficult to determine because of the low incidence of occupational exposures to HIV and the low seroconversion rate following such exposure.138,140,147,150,153,199 Results of a retrospective case-control study suggest that the risk for HIV infection in health-care personnel who received zidovudine monotherapy for PEP following percutaneous exposure to HIV-positive blood was reduced by approximately 81%.147 This study included data reported to national surveillance systems in the US, France, and United Kingdom on health-care personnel who had documented occupational percutaneous exposure to HIV-infected blood (i.e., needlestick injury or cut with a sharp object such as a scalpel or lancet) and no other concurrent exposure to HIV.147

Prophylaxis Failures

There have been documented cases where PEP with zidovudine monotherapy failed to prevent transmission of HIV in health-care personnel or others exposed to the virus.127,128,129,130,131,137,138,140,141,142,148,155,164,166 Although zidovudine prophylaxis was initiated within 0.5-12 hours in most of these individuals, most experienced an acute retroviral illness 13-75 days (median: 22 days) after exposure and seroconverted within 6 months.128,131,136,138,140,142,164,166

There has been at least one report of prophylaxis failure in a health-care personnel who received a 6-week multiple-drug PEP regimen (zidovudine, lamivudine, indinavir, and didanosine) initiated within 40 minutes following a needle-stick injury that occurred while drawing blood from a parenteral drug abuser who was infected with HIV and hepatitis C virus (HCV).332 The health-care worker became HIV-positive and HCV-positive about 6 weeks after PEP was finished; HIV isolated from the health-care worker had a mutation associated with low-level zidovudine resistance and HIV isolated from the source patient had a mutation associated with lamivudine resistance but not the one associated with low-level zidovudine resistance.332 There have been 2 other reports of health-care workers allegedly seroconverting despite PEP with a multiple-drug regimen after occupational exposure to HIV; however, epidemiologic investigations and viral sequence comparisons indicated that HIV transmission in these 2 cases did not occur as a result of the reported occupational exposure.330

Adverse Effects of PEP Regimens

A substantial proportion of health-care personnel receiving previously recommended PEP regimens after occupational exposures to HIV experienced adverse effects and many were unable to complete a full 4-week prophylaxis regimen because of inability to tolerate the drugs.199

Although there is no evidence to date that any unusual adverse effects occur when antiretrovirals are used in healthy individuals for PEP, multiple-drug PEP regimens can be associated with adverse effects and these effects may impact adherence to and/or completion of the regimen.327,328,329,199 Serious adverse effects (e.g., nephrolithiasis, hepatitis, pancytopenia) have been reported rarely in health-care personnel receiving antiretroviral regimens for PEP.327,328

Information regarding tolerability of multiple-drug regimens previously used for PEP in health-care workers following occupational exposure to HIV is available from the Human Immunodeficiency Virus Postexposure Prophylaxis (HIV PEP) Registry, a prospective surveillance project that collected data from October 17, 1996 through March 31, 1999 and was sponsored by the CDC and 2 antiretroviral agent manufacturers.327 The registry (now closed) included data on 492 US health-care workers (71% female, median age: 37 years) who received PEP following an occupational exposure to HIV (63% received a regimen containing 3 or more antiretroviral agents).327 Overall, 76% of health-care workers for whom 4- to 6-week follow-up was available reported some symptom or adverse effect.327 The most frequent adverse effects were nausea (57%), fatigue/malaise (38%), headache (18%), vomiting (16%), and diarrhea (14%) and these effects generally were evident within 3-4 days after initiation of the PEP regimen.327 Of those who discontinued all drugs before completion of the PEP regimen, 50% did so because of adverse effects.327 A variety of PEP regimens were used (e.g., zidovudine monotherapy; zidovudine and lamivudine with or without indinavir; zidovudine, lamivudine, and saquinavir), and it was not possible to correlate toxicity with any particular drug.327 Although there were no reports of unusual adverse effects, serious adverse effects requiring dosage reduction or discontinuance of the PEP regimen (high fever and rash; adverse renal effects such as renal calculi, flank pain, and hematuria; adverse GI effects such as intractable vomiting or nausea; involuntary muscle movements or adverse ophthalmic effects) were reported in 6 health-care workers.327 All reported adverse effects resolved following completion or discontinuance of PEP.327

Additional information regarding adverse effects reported in health-care workers who received multiple-drug regimens for PEP is available from individual case reports or small prospective and retrospective studies in individual health-care facilities.328,329 In one facility, 68 health-care workers received PEP (zidovudine and lamivudine with or without indinavir) and 75% reported at least one adverse effect; adverse effects were more frequent in those receiving the 3-drug regimen and many failed to complete the 28-day regimen because of adverse effects.329 In a small retrospective study, most individuals who discontinued or modified their PEP regimens did so because of intolerable adverse effects that appeared to be related to indinavir (e.g., uncontrollable vomiting, nausea, or reflux; urticaria; galactorrhea with hyperprolactinemia).328 In a prospective study in France that evaluated adverse effects reported with a PEP regimen of zidovudine, lamivudine, and nelfinavir, 85% experienced at least one adverse effect (diarrhea, nausea, and vomiting were reported most frequently) and 25% discontinued nelfinavir from the regimen because of adverse effects.279

Because serious adverse effects, including hepatotoxicity (e.g., end-stage liver failure requiring transplantation, clinical hepatitis, and elevated serum ALT and AST concentrations without clinical hepatitis), skin reaction, and/or rhabdomyolysis, were reported in individuals who received multiple-drug PEP regimens that included nevirapine,215,381 nevirapine is contraindicated for and should not be used for PEP.199,215,381

Health-care personnel receiving PEP following an occupational exposure to HIV should be advised of the potential adverse effects and drug interactions associated with the regimen.199 Careful counseling about such effects may be necessary to improve adherence.199,327 In some cases, preemptive prescribing of antiemetic and antispasmodic agents may be useful to ameliorate adverse effects and may improve adherence to the PEP regimen.199

Health-care personnel receiving PEP should be monitored for toxicity by testing at baseline and 2 weeks after initiation of the regimen.199 The scope of testing should be based on medical conditions in the exposed individual and the known and anticipated toxicities of the drugs included in the regimen.199 At a minimum, complete blood counts (CBCs) and renal and hepatic function should be monitored.199 Depending on the clinical situation, further diagnostic studies may be indicated (e.g., monitoring for hyperglycemia in a diabetic if the PEP regimen includes a PI).199

If toxicity occurs, modification of the PEP regimen should be considered with expert consultation.199

Management of Occupational Exposures to HIV

Each health-care facility should develop institutional policies and protocols for management of occupational exposures that put health-care personnel and others at risk of HIV infection.125,149,150,151,152,199 These policies should include appropriate procedures for documenting and reporting such exposures, determining the HIV status of the source person, acquiring expert consultation from in-house infectious disease experts or outside experts, and appropriate immediate and follow-up postexposure testing, care, and counseling for the exposed individual.125,149,150,151,152,153,156,199

Since the great majority of occupational exposures to HIV do not result in transmission of the virus, the potential benefits and risks of PEP (including the potential for severe toxicity and/or drug interactions) must be considered carefully and, whenever possible, decisions regarding PEP should be made in consultation with experts.199

Assessment of the Type of Occupational Exposure and Associated Risk

An assessment of the likelihood of HIV transmission from the exposure should be made, taking into consideration information about the HIV source and the type of exposure.151,152 The exposure should be evaluated for potential to transmit HIV based on the type of body substance involved and the route and severity of the exposure.199

Exposure to blood, tissue, other body fluid containing visible blood, or other potentially infectious fluid (e.g., semen, vaginal secretions, CSF, and synovial, pleural, peritoneal, pericardial, amniotic fluids) or tissue resulting from a percutaneous injury (i.e., needlestick or cut with a sharp object) or through contact of mucous membrane or nonintact skin (e.g., exposed skin that is chapped, abraded, or affected by dermatitis) are situations that pose a risk for HIV transmission and require further evaluation.199 Feces, nasal secretions, saliva, sputum, sweat, tears, urine, and vomitus are not considered potentially infectious unless they are visibly bloody.199

Any direct contact (i.e., contact without barrier protection) with concentrated HIV in a research laboratory or production facility is considered an exposure that requires clinical evaluation to assess the need for PEP.199

For human bites, the clinical evaluation must consider possible exposure of both the bite recipient and the person who inflicted the bite.199 While HIV transmission only rarely has been reported by this route, postexposure follow-up (including consideration of PEP) may be indicated if a bite results in blood exposure to either person involved.199

Evaluation and Testing of the Source

The individual whose blood or body fluids are the source of an occupational exposure should be immediately evaluated for HIV infection and HIV antibody testing performed if indicated.199

If the source individual is known to be HIV seropositive, information regarding their viral load, current and previous antiretroviral therapy, and genotypic or phenotypic viral resistance testing should be collected and may be considered when selecting the PEP regimen for the exposed individual.199 Initiation of PEP should not be delayed while acquiring this information.199

If the exposure involved an HIV-infected source, information regarding whether or not the individual harbors drug-resistant HIV may or may not be available.199 Resistance testing of the source at the time of exposure will not provide results soon enough to influence selection of the PEP regimen.199 If the exposure involved an HIV-infected source known or suspected to harbor drug-resistant HIV, expert consultation is recommended regarding selection of an optimal PEP regimen.199 However, initiation of PEP should not be delayed while waiting for expert consultation.199 If drug resistance information about the source becomes available later in the course of PEP, additional expert consultation is recommended regarding possible modification of the PEP regimen.199

If the exposure involved an HIV-infected source who had undetectable plasma HIV-1 RNA at the time of the exposure, this does not eliminate the possibility of HIV transmission and does not eliminate the need for PEP and follow-up testing in the exposed individual.199

If the exposure involved a source individual who is HIV seronegative and has no clinical evidence of AIDS or symptoms of HIV infection, no further testing of the source is indicated.199 The likelihood of the source individual being in the window period of HIV infection before seroconversion (i.e., period between initial HIV infection and development of detectable HIV antibodies) is extremely small.199

If the HIV status of the source individual is unknown, availability of rapid HIV testing facilitates timely decisions regarding the need for PEP in the exposed individual.199 Results of some HIV tests may be available within 30-60 minutes; however, initiation of PEP should not be delayed while waiting for test results.199 If the source individual is determined to be HIV negative, PEP should be discontinued and testing of the exposed individual is not necessary.199

If the exposure source is unknown or cannot be tested (e.g., needle in disposal container or laundry), decisions regarding PEP should be made on an individual basis with expert consultation.199 Important considerations in these cases are the severity of the exposure and the epidemiologic likelihood of HIV exposure.199

HIV testing of needles or other sharp instruments involved in an exposure (regardless of whether the source is known) is not recommended.199

Initial Evaluation and Testing of Exposed Health-care Personnel

Following an occupational exposure, the exposed individual should be evaluated immediately and should be tested to establish HIV serostatus at the time of exposure.199 The exposed individual should be questioned regarding other drugs they may currently be taking and any current or underlying medical conditions or circumstances (e.g., pregnancy, breast-feeding, renal or hepatic disease) that may influence choice of antiretrovirals for a PEP regimen.199 A pregnancy test should be offered to all nonpregnant women of childbearing age whose pregnancy status is unknown.199

If the source individual is found to be HIV seronegative, baseline HIV testing and further follow-up testing of the exposed individual normally is not necessary.199

Regardless of whether PEP is initiated, follow-up reevaluation and counseling of the exposed individual is strongly recommended within 72 hours after the exposure to reassess the risks and benefits of PEP.199

Initiation and Duration of PEP

If PEP is appropriate for the exposure and the exposed health-care worker elects to receive PEP, it should be initiated as soon as possible (preferably within hours) following the exposure.148,151,153,199 To ensure timely access to PEP, an occupational exposure should be regarded as an urgent medical concern.199 When the most appropriate regimen to administer is unclear, it probably is preferable to immediately initiate a PEP regimen while waiting for expert consultation.199

Although there is some evidence from animal studies suggesting that prophylaxis is likely to be less effective when initiated more than 72 hours after exposure, the interval after which there is no benefit from PEP has not been defined in humans.199 If initiation of PEP is delayed, there is an increased likelihood that benefits might not outweigh risks.199 However, initiating PEP after a longer interval (e.g., 1 week) might still be considered for exposures associated with an extremely high risk of transmission.199

The optimal duration of PEP is unknown.199 In animal models, the duration of PEP has been shown to influence success.199 Based on evidence that 4 weeks of PEP appeared protective in vitro and in animal and occupational studies, PEP should be administered for 4 weeks, if tolerated.199

Follow-up and Counseling of Exposed Health-care Personnel

Health-care personnel with occupational exposure to HIV should receive postexposure testing, medical evaluation, and counseling regardless of whether they receive PEP.199

Follow-up HIV testing should be performed at baseline and at 6 weeks, 12 weeks, and 6 months after the exposure to determine whether transmission of HIV occurred.148,152,199 Extended follow-up (e.g., for 12 months) is recommended for health-care personnel who become infected with HCV following exposure to a source coinfected with both HIV and HCV; however, it is unclear whether extended follow-up is necessary in other circumstances.199 Although rare cases of delayed HIV seroconversion have been reported, this probably does not warrant increasing the exposed individual's anxiety by routinely extending the duration of postexposure follow-up.199 However, this does not preclude a decision to extend follow-up in an individual situation based on the clinical judgment of the health-care provider.199 HIV testing should be performed in any health-care worker who has an illness that is compatible with an acute retroviral syndrome, regardless of the interval since exposure.199

Exposed health-care workers should be advised to use measures to prevent secondary transmission of HIV during the follow-up period, especially during the first 6-12 weeks following the exposure.199 These individuals should be counseled to avoid donating blood or tissue, to use barrier contraception and avoid pregnancy, and to avoid breast-feeding if possible.199

Exposed individuals should be advised of the potential adverse effects of the PEP regimen and that evaluation of certain symptoms should not be delayed (e.g., rash, fever, back or abdominal pain, pain on urination, blood in the urine, dark urine, yellowing of skin or whites of the eyes, symptoms of hyperglycemia such as increased thirst or frequent urination).199

Individuals receiving PEP should be advised of the importance of adhering to and completing the recommended regimen.199

Situations for Which Expert Consultation Regarding PEP Is Advised

Because evaluation and management of occupational exposures to HIV can be complex, clinicians should consult local experts and/or the National Clinicians' Postexposure Prophylaxis Hotline (PEPline) at 888-448-4911 or [Web] whenever possible.199 At a minimum, the USPHS recommends expert consultation in the following situations:199

Occupational exposure report is delayed (i.e., more than 72 hours after the exposure):199 The interval after which there is no benefit from PEP is undefined.199
Source is unknown (e.g., needle in sharps disposal container or laundry):199 The use of PEP is decided on a case-by-case basis, taking into consideration the severity of the exposure and epidemiologic likelihood of HIV exposure.199 Needles or other sharp instruments should not be tested for HIV.199
Exposed individual is known or suspected to be pregnant or is breast-feeding:199 Initiation of PEP should not be delayed while waiting for expert consultation.199
Source virus is known or likely to be resistant to antiretroviral agents:199 If the source individual's virus is known or suspected to be resistant to at least 1 of the drugs being considered for the PEP regimen, a regimen should be selected that includes antiretrovirals to which the source individual's virus is unlikely to be resistant.199 Initiation of PEP should not be delayed while waiting for results of resistance testing of the source individual's virus.199
Toxicity occurs with the initial PEP regimen:199 Symptoms (e.g., GI and others) often can be managed by prescribing antimotility and/or antiemetic agents without changing the PEP regimen.199 Counseling and support for management of adverse effects are important since symptoms are often exacerbated by anxiety.199
Exposed individual has serious medical illness:199 The risk of drug toxicity and drug interactions may be increased if the exposed individual has significant underlying illness (e.g., renal disease) or is already taking multiple medications.199

USPHS Recommendations Regarding PEP

USPHS guidelines for management of occupational exposures to HIV and use of PEP include the following recommendations.199

A PEP regimen containing 3 (or more) antiretroviral agents is recommended for all occupational exposures associated with risk of HIV infection.199 These exposures include percutaneous injury or contact of mucous membrane or nonintact skin with blood, tissue, or other body fluids from a source person known or suspected to be infected with HIV.199
The preferred PEP regimen is raltegravir in conjunction with emtricitabine and TDF (may be administered as the fixed combination emtricitabine/TDF).199 This regimen has a convenient dosing schedule and is potent, tolerable, and associated with minimal drug interactions.199
Alternative PEP regimens include certain PIs (ritonavir-boosted darunavir, ritonavir-boosted atazanavir, lopinavir/ritonavir) or certain NNRTIs (etravirine, rilpivirine) in conjunction with 2 NRTIs (dual NRTIs).199The fixed combination containing elvitegravir (EVG/c/FTC/TDF) used alone is another recommended alternative PEP regimen.199 Although alternative regimens that contain certain other antiretrovirals (i.e., efavirenz, enfuvirtide, fosamprenavir, maraviroc, saquinavir) in conjunction with 2 NRTIs can be used for PEP, these regimens should be used only with expert consultation.199
The preferred dual NRTI option for use in PEP regimens is emtricitabine and TDF (may be administered as the fixed combination emtricitabine/TDF); alternative dual NRTI options are TDF and lamivudine, zidovudine and lamivudine (may be administered as the fixed combination lamivudine/zidovudine), or zidovudine and emtricitabine.199 Abacavir should be used for PEP only with expert consultation since HLA-B*5701 testing is required (see Human Leukocyte Antigen [HLA]-B*5701 Screening under Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Laboratory Monitoring) and such testing may not be available or practical prior to initiating PEP.199
PEP should be initiated as soon as possible (preferably within hours) following an occupational exposure associated with risk of HIV infection.199 To ensure timely access to PEP, an occupational exposure should be regarded as an urgent medical concern and treated immediately.199
PEP should be administered for 4 weeks, if tolerated.199 Although optimal duration of PEP is unknown, 4 weeks has been protective in vitro and in animal and occupational studies.199
Whenever possible, the HIV status of the source person should be determined to guide appropriate use of PEP.199 Depending on the type of test used, results may be available within 30-60 minutes; however, initiation of PEP should not be delayed while waiting for HIV test results.199 If the source person is found to be HIV negative, PEP should be discontinued and follow-up HIV testing is not necessary in the exposed individual.199
If the source person is known to harbor drug-resistant HIV, expert consultation is recommended to identify an optimal PEP regimen.199 Initiation of PEP should not be delayed while waiting for expert consultation.199
When PEP is prescribed, the exposed individual should be advised of the importance of adhering to and completing the regimen and advised about possible drug toxicities and drug interactions associated with the regimen.199 To monitor for adverse effects, CBCs and renal and hepatic function tests should be performed at baseline and 2 weeks after initiation of PEP; additional testing may be indicated if abnormalities are detected or adverse effects occur.199
Regardless of whether PEP is prescribed, the exposed individual should be reevaluated within 72 hours after the exposure.199 This provides an opportunity to reassess the risks and benefits of PEP, helps ensure adherence and follow-up, and is especially important if additional information becomes available about the exposure incident or source individual.199
Health-care personnel with occupational exposure to HIV should receive counseling at the time of exposure and at follow-up appointments.199 These individuals should be advised to use precautions to prevent possible secondary transmission (e.g., avoidance of blood or tissue donations, use of barrier contraception and avoidance of pregnancy and breast-feeding), especially during the first 6-12 weeks after the exposure.199
HIV testing should be used to monitor for seroconversion after occupational exposure to HIV.199 HIV testing should be performed at baseline and at 6 weeks, 12 weeks, and 6 months after the exposure.199 Use of a fourth-generation combination HIV p24 antigen-HIV antibody test allows earlier detection of HIV infection; if a fourth generation test is used, HIV testing could be performed at baseline and at 6 weeks and 4 months after the exposure.199
If HIV infection is identified in the exposed individual, the person should be referred to a specialist with expertise in HIV treatment.199
Clinicians seeking information and guidance regarding the management of an occupational exposure to HIV and additional information on PEP can consult the National Clinicians' Postexposure Prophylaxis Hotline (PEPline) at 888-448-4911 or [Web].199
Any unusual or severe toxicity associated with PEP should be reported to the manufacturer and/or the FDA MedWatch program at 800-332-1088 or [Web].199
Cases of occupationally acquired HIV or failures of PEP should be reported to the CDC at 404-639-2050.199

Adapted from Updated US Public Health Service Guidelines for the Management of Occupational Exposures to Human Immunodeficiency Virus and Recommendations for Postexposure Prophylaxis. Infect Control Hosp Epidemiol. 2013; 34: 875-92 (may be available at [Web]).

Antiretrovirals for Postexposure Prophylaxis following Sexual, Injection Drug Use, or other Nonoccupational Exposures to HIV (nPEP)

Antiretrovirals are used for postexposure prophylaxis of HIV infection following nonoccupational exposure† (nPEP) in individuals exposed to blood, genital secretions, or other potentially infectious body fluids that might contain HIV when that exposure represents a substantial risk for HIV transmission.198

The most effective means for preventing HIV infection are methods that protect against exposure.198 Antiretroviral agents given after HIV exposure cannot replace behaviors that help avoid such exposure (e.g., sexual abstinence, sex in a mutually monogamous relationship with a noninfected partner, consistent and correct condom use, abstinence from injection drug use, consistent use of sterile equipment by those unable to cease injection drug use).198 However, data from animal transmission models, clinical studies evaluating antiretroviral prophylaxis for prevention of perinatal HIV transmission, observational studies evaluating use of PEP in health-care personnel following occupational exposures, and observational and case studies of antiretroviral prophylaxis following sexual exposures (e.g., sexual assault, inadvertent artificial insemination from an HIV-positive donor) or other nonoccupational exposures (e.g., needlestick injection, piercing, cutting with a sharp object) indicate that nPEP can reduce the risk of HIV infection following nonoccupational exposures.198,326

In 2016, CDC issued updated guidelines for management of nonoccupational exposures to HIV and recommendations regarding use of nPEP following nonoccupational exposures.198 These guidelines include new evidence on efficacy and safety of nPEP, updated information on laboratory evaluation of the source and exposed individuals, recommendations regarding preferred and alternative 3-drug nPEP regimens, information on follow-up evaluations, and suggestions for transitioning between nPEP and PrEP when appropriate for certain individuals at risk for frequent, recurring HIV exposures.198

Nonoccupational Exposures Associated with Risk of HIV Infection

Nonoccupational exposures that place an individual at risk for HIV infection include direct mucosal (vagina, rectum, eye, mouth, other mucosal membranes), nonintact skin, percutaneous, or IV contact with potentially infectious body fluids that occur outside of health-care settings and do not involve perinatal exposures.198 Potentially infectious body fluids from HIV-infected individuals that are considered to be associated with a substantial risk for HIV transmission include blood, semen, vaginal secretions, rectal secretions, breast milk, or any body fluid visibly contaminated with blood.198 Regardless of the known or suspected HIV status of the source individual, other body fluids (e.g., urine, saliva, nasal secretions, sweat, tears) are considered negligible risks for HIV transmission following nonoccupational exposures unless they are visibly contaminated with blood.198

Individuals who have had nonoccupational exposure to potentially infectious fluids of an HIV-infected individual are at highest risk for HIV infection, especially if the HIV-infected individual is not receiving antiretroviral therapy.198 Individuals who have had nonoccupational exposure to potentially infectious fluids of a person of unknown HIV status are at unknown risk for acquiring HIV infection.198 If the source is known to be from a group with a high prevalence of HIV infection (e.g., MSM, needle-sharing injection drug user), the risk for unrecognized HIV infection in the source is increased.198 If the source individual recently acquired HIV infection, the risk for HIV transmission may be particularly high since the viral burden in the blood and semen of such individuals may be particularly high.198

Nonoccupational exposures to potentially infectious body fluids from an HIV-infected individual are associated with different levels of risk for HIV transmission depending on the route.198 The highest levels of risk are associated with blood transfusions, needle-sharing injection drug use, receptive anal intercourse, and percutaneous needle stick.198 Other types of sexual exposures are associated with a lower level of risk;198 biting, spitting, and thrown body fluids (e.g., semen, saliva) are associated with a negligible level of risk.198

Management of Nonoccupational Exposure to HIV

The decision to initiate nPEP should be individualized based on the HIV status of the potentially exposed individual, HIV status of the source of the body fluids, timing regarding when the most recent sexual, injection drug use, or other nonoccupational exposure occurred, frequency of HIV exposures, and the transmission risk associated with the exposure (i.e., whether the potentially infected body fluids and exposure routes are associated with a substantial risk of HIV transmission).198 The likelihood of exposure to and need for prophylaxis or treatment of other transmissible infections (e.g., gonorrhea, chlamydial infection, trichomoniasis, HBV, HCV) or other health consequences of the exposure event (i.e., pregnancy) also should be considered.198

Following a nonoccupational exposure to HIV, initiation of nPEP usually is recommended when the exposed individual is HIV-negative, the source of the potentially infected body fluids is HIV-positive, the most recent exposure occurred within the last 72 hours, and the reported exposure represents a substantial risk for HIV transmission.198

Because exposed individuals might not know whether they are already infected with HIV, baseline HIV testing should be performed on all individuals seeking evaluation for potential nonoccupational HIV exposure, preferably using rapid antigen/antibody (Ag/Ab) combination HIV tests.198 If the HIV status of the source individual is unknown and the reported exposure would represent a substantial risk for HIV transmission if the source was HIV-positive, the decision to administer nPEP should be determined on a case-by-case basis.198 If the source individual is available and consents, the individual should be evaluated clinically and undergo HIV testing, preferably using rapid Ag/Ab combination HIV tests.198 If the risk for HIV transmission associated with the exposure is high, nPEP can be initiated in the exposed individual and then continued or discontinued if the HIV status of the source individual can be determined.198

Available data indicate that nPEP is most effective when initiated as soon as possible after exposure and is unlikely to be effective if initiated more than 72 hours after exposure.198 Therefore, nPEP is not recommended if an individual seeks care more than 72 hours after a potential nonoccupational exposure to HIV.198

If the reported exposure represents no substantial risk of HIV transmission, nPEP is not recommended.198 In addition, nPEP should be used only for infrequent exposures.198 Individuals who engage in behaviors that result in frequent, recurrent exposures (e.g., HIV discordant sex partners who inconsistently use condoms, injection drug users who often share injection equipment) should not receive frequent, repeated courses of nPEP.198 Such individuals need risk-reduction interventions and, in some cases, consideration can be given to transitioning the patient to PrEP after completion of nPEP.198 (See Guidelines for Use of Antiretroviral Agents for Management of HIV Infection: Antiretrovirals for Preexposure Prophylaxis for Prevention of HIV-1 Infection [PrEP].)

CDC Recommendations Regarding nPEP

CDC guidelines for management of nonoccupational exposures to HIV and use of nPEP include the following recommendations.198

When an individual seeks care within 72 hours after a sexual, injection drug use, or other nonoccupational exposure to HIV, the HIV status of the exposed individual should be determined, the HIV status of the source individual should be determined (if possible), and the type of exposure (i.e., type of potentially infectious body fluids, exposure route) should be evaluated to determine whether the exposure represents with a substantial risk of HIV transmission.198 HIV status should be determined using rapid Ag/Ab combined HIV tests whenever possible.198 If rapid HIV tests are unavailable, nPEP should be initiated in the exposed individual without delay if the source is known to have HIV infection and the reported exposure represents a substantial risk for HIV transmission;198 if the exposed individual is later determined to already be infected with HIV, nPEP can be changed to an appropriate antiretroviral treatment regimen.198
nPEP is not indicated if the exposed individual is HIV-positive, if the source individual is HIV-negative, if it has been more than 72 hours since the most recent nonoccupational exposure to HIV, or if the exposure is determined to be associated with a negligible risk for HIV transmission.198
When indicated, nPEP should be initiated as soon as possible (within 72 hours) following nonoccupational exposure associated with a substantial risk of HIV transmission and should be continued for 28 days.198
An nPEP regimen containing 3 antiretroviral agents is recommended for all nonoccupational exposures associated with a substantial risk of HIV transmission.198 Baseline serum creatinine and estimated creatinine clearance should be determined to aid in selection of the most appropriate nPEP regimen.198
For adults and adolescents 13 years of age or older with normal renal function (creatinine clearance of 60 mL/minute or greater), the preferred nPEP regimen is raltegravir or dolutegravir in conjunction with emtricitabine and TDF (administered as the fixed combination emtricitabine/TDF).198 The alternative nPEP regimen recommended for such individuals is ritonavir-boosted darunavir in conjunction with the fixed combination emtricitabine/TDF.198
For adults and adolescents 13 years of age or older with renal impairment (creatinine clearance of 59 mL/minute or lower), the preferred nPEP regimen is raltegravir or dolutegravir in conjunction with zidovudine and lamivudine (dosage adjusted based on the degree of renal impairment).198 The alternative nPEP regimen recommended for such individuals is ritonavir-boosted darunavir in conjunction with zidovudine and lamivudine (dosage adjusted based on the degree of renal impairment).198
For children 2-12 years of age, the preferred nPEP regimen is raltegravir in conjunction with emtricitabine and TDF.198 Alternative nPEP regimens recommended for such children are raltegravir or lopinavir/ritonavir in conjunction with zidovudine and lamivudine or lopinavir/ritonavir in conjunction with emtricitabine and TDF.198 A regimen of ritonavir-boosted darunavir in conjunction with emtricitabine and TDF is another alternative in children 3-12 years of age.198
For infants 4 weeks to less than 2 years of age, the preferred nPEP regimen is raltegravir or lopinavir/ritonavir in conjunction with zidovudine and lamivudine.198 The alternative nPEP regimen recommended for such infants is raltegravir or lopinavir/ritonavir in conjunction with zidovudine and emtricitabine.198
When nPEP is prescribed, the exposed individual should be advised of the importance of adhering to and completing the regimen and advised about possible drug toxicities and drug interactions associated with the regimen.198 Hematologic parameters and renal and hepatic function should be monitored as needed based on the antiretrovirals included in the nPEP regimen.198
HIV testing should be used to monitor for seroconversion after nonoccupational exposure to HIV.198 HIV testing should be repeated 4-6 weeks and 3 months after the exposure.198 Because HIV seroconversion may be delayed in individuals who acquire HIV and HCV simultaneously, exposed individuals who tested negative for HCV at baseline and positive for HCV at 4-6 weeks should be retested for HIV again 6 months after the exposure.
If HIV infection is identified in the exposed individual at baseline during initial evaluation or if there is laboratory evidence of HIV infection after initiation of nPEP, the individual should be referred to a specialist with expertise in HIV treatment.198 If the individual is taking a 3-drug antiretroviral regimen for nPEP at the time of HIV infection diagnosis, the 3-drug regimen should be continued until the patient has been evaluated by an HIV specialist and an HIV treatment plan is initiated.198
Expert consultation is advised when nPEP is indicated in certain exposed individuals (e.g., those with medical conditions such as renal impairment, pregnant women, children), when an antiretroviral regimen not included in the CDC guidelines is being considered, when the source virus is known or likely to be resistant to antiretroviral agents, or the healthcare provider is inexperienced in prescribing antiretrovirals.198 Initiation of nPEP should not be delayed while waiting for expert consultation.198
Clinicians seeking information and guidance regarding the management of a nonoccupational exposure to HIV and additional information on nPEP can consult the National Clinicians' Postexposure Prophylaxis Hotline (PEPline) at 888-448-4911 or [Web].198
Any unusual or severe toxicity associated with nPEP should be reported to the manufacturer and/or the FDA MedWatch program at 800-332-1088 or [Web].198

Adapted from US Centers from Disease Control and Prevention, US Department of Health and Human Services. Updated Guidelines for Antiretroviral Postexposure Prophylaxis after Sexual, Injection Drug Use, or Other Nonoccupational Exposure to HIV-United States, 2016 (may be available at [Web]).

Antiretrovirals in the Management of Coronavirus Disease 2019 (COVID-19)

Lopinavir/ritonavir and some other HIV PIs have been investigated for the treatment of coronavirus disease 2019† (COVID-19).494,495,496,497,498,499,500,502,504,505,506 However, efficacy and safety of lopinavir/ritonavir and other HIV PIs for the treatment of COVID-19 have not been established.502,503

Based on evidence of in vitro activity against coronaviruses, including SARS-CoV-2 (causative agent of COVID-19), various clinical trials were initiated worldwide to evaluate use of lopinavir/ritonavir in conjunction with other antivirals and other drugs (e.g., interferon) in patients with COVID-19.494,495,496,497,498,499,500,502,503,504,505 Although studies are ongoing,499 results of clinical trials to date have not demonstrated clinical benefits (e.g., reduced viral load, shorter time to clinical improvement, shorter duration of hospitalization, decreased mortality) when lopinavir/ritonavir was used in patients with COVID-19.494,496,502,503,504,505

The National Institutes of Health (NIH) COVID-19 Treatment Guidelines Panel recommends against the use of lopinavir/ritonavir or other HIV PIs for the treatment of COVID-19, except in the context of a clinical trial.502 The NIH panel states that, based on the pharmacodynamics of HIV PIs, there is concern that drug concentrations achieved with typical oral doses of the drugs are not adequate to inhibit SARS-CoV-2 protease.502 In addition, results of randomized clinical trials to date using lopinavir/ritonavir have not demonstrated a virologic or clinical benefit in patients with COVID-19.502

The Infectious Diseases Society of America (IDSA) recommends use of lopinavir/ritonavir for the treatment of COVID-19 only in the context of a clinical trial.503

The manufacturer of darunavir states that they have no clinical or pharmacologic evidence to support the use of cobicistat-boosted darunavir for the treatment of COVID-19.503 In vitro, darunavir did not show activity against SARS-CoV-2 at clinically relevant concentrations. 503 In addition, results of a clinical trial evaluating cobicistat-boosted darunavir in patients with COVID-19 did not demonstrate clinical benefits and there are no published clinical studies that have evaluated the efficacy and safety of ritonavir-boosted darunavir or the fixed combination darunavir/cobicistat/emtricitabine/TAF for the treatment of COVID-19.503

Clinical Experience and Trials of HIV Protease Inhibitors in Patients with COVID-19

In a randomized, open-label trial in China in hospitalized adults with severe COVID-19, patients were randomized 1:1 to receive lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 14 days) in conjunction with standard care (99 patients) or standard care alone (100 patients).494 The median age of patients was 58 years, the median time from symptom onset to randomization was 13 days, and 33% of patients in the lopinavir/ritonavir group and 36% of those in the standard care alone group also received systemic corticosteroids.494 The primary end point was time to clinical improvement (time from randomization to improvement of 2 points on a 7-category ordinal scale or hospital discharge, whichever came first).494 In the intention-to-treat (ITT) population, time to clinical improvement was not shorter with lopinavir/ritonavir compared with standard care (median time to clinical improvement was 16 days in both groups);494 in the modified ITT population, median time to clinical improvement was 15 days in the lopinavir/ritonavir group and 16 days in the standard care only group.494 The 28-day mortality rate was numerically lower in the lopinavir/ritonavir group (19 versus 25% in the ITT population; 17 versus 25% in the modified ITT population), but the difference was not statistically significant.494 There were no significant differences in reduction of viral RNA load, duration of viral RNA detectability, duration of oxygen therapy, duration of hospitalization, or time from randomization to death in patients treated with lopinavir/ritonavir.494 The drug was stopped early in 13 patients because of adverse effects.494

In a small, randomized study in hospitalized adults with COVID-19 in China, lopinavir/ritonavir was compared with chloroquine.504 A total of 12 patients (7 with moderate and 5 with severe COVID-19) received lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 10 days) and 10 patients (7 with moderate and 3 with severe COVID-19) received chloroquine (500 mg twice daily for 10 days).504 At baseline, patients had peripheral capillary oxygen saturation (SpO₂) ranging from 96-98% and a few patients had comorbidities.504 The primary end point was negative SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT-PCR) at days 10 and 14.504 At day 10, 90% of patients in the chloroquine group and 75% of those in the lopinavir/ritonavir group had negative RT-PCR results for SARS-CoV-2.504 At day 14, all 10 patients treated with chloroquine had negative RT-PCR results and were discharged from the hospital; 11/12 patients (92%) treated with lopinavir/ritonavir had negative RT-PCR results, but only 6/12 (50%) were discharged from the hospital.504 These results suggest that chloroquine was associated with a shorter time to RT-PCR conversion and quicker recovery than lopinavir/ritonavir; however, this study included only a limited number of patients and the median time from onset of symptoms to initiation of treatment was shorter in those treated with chloroquine than in those treated with lopinavir/ritonavir (2.5 versus 6.5 days, respectively).504

Efficacy of lopinavir/ritonavir used in conjunction with ribavirin and interferon beta-1b was compared with lopinavir/ritonavir alone in an open-label, randomized trial in hospitalized adults with mild to moderate COVID-19 in Hong Kong.505 A total of 127 patients were randomized 2:1 to receive lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily for 14 days) with ribavirin (400 mg twice daily) and interferon beta-1b (8 million IU subcutaneously on alternate days for up to 3 doses depending on how soon treatment was initiated after onset of COVID-19 symptoms; interferon beta-1b was not used in patients enrolled 7 or more days after symptom onset) or a 14-day regimen of lopinavir/ritonavir alone.505 The median time from symptom onset to enrollment was 5 days; 13% of patients were receiving supplemental oxygen and 1 patient was mechanically ventilated.505 Compared with use of lopinavir/ritonavir alone, the combination regimen was associated with shorter median time from treatment initiation to negative RT-PCR results for SARS-CoV-2 in nasopharyngeal samples (7 versus 12 days), earlier resolution of symptoms (4 versus 8 days), and shorter median duration of hospitalization (9 versus 14.5 days).505 In the subset of patients initiating treatment 7 or more days after symptom onset (i.e., those not treated with interferon beta-1b), there was no significant difference in time to negative RT-PCR result, time to resolution of symptoms, or duration of hospitalization between the combination regimen (lopinavir/ritonavir and ribavirin) and lopinavir/ritonavir alone.505 It is unclear whether lopinavir/ritonavir contributed to the response in patients treated with the combination regimen.502

Efficacy of lopinavir/ritonavir (lopinavir 400 mg/ritonavir 100 mg twice daily) with or without umifenovir (Arbidol^®; antiviral not commercially available in the US) for the treatment of COVID-19 in adults was evaluated in a retrospective cohort study in China.496 Some patients also received treatment with corticosteroids (24%) and/or immune globulin (73%).496 The primary efficacy end point was negative SARS-Co-V conversion in nasopharyngeal samples and progression or improvement of COVID-19 pneumonia.496 At day 7, SARS-CoV-2 was undetectable in nasopharyngeal specimens in 6/17 (35%) of patients who received lopinavir/ritonavir alone compared with 12/16 (75%) of those who received both drugs; chest CT scans were improving in only 29% of patients treated with lopinavir/ritonavir alone compared with 69% of patients treated with both drugs.496 At day 14, 53% of patient who received lopinavir/ritonavir alone and 94% of those who received lopinavir/ritonavir with umifenovir had undetectable SARS-CoV-2 in nasopharyngeal specimens.496

Efficacy of cobicistat-boosted darunavir for the treatment of COVID-19 in adults was evaluated in a randomized, open-label trial in China.506 A total of 30 adults with mild, laboratory-confirmed COVID-19 were randomized 1:1 to receive cobicistat-boosted darunavir (single tablet containing 800 mg of darunavir and 150 mg of cobicistat once daily for 5 days) or no cobicistat-boosted darunavir (control group); all patients received interferon alfa-2b and standard of care.506 The primary end point was viral clearance rate at day 7 (defined as negative RT-PCR results for SARS-CoV-2 in at least 2 consecutive oropharyngeal swabs collected at least 1-2 days apart).506 At day 7, the viral clearance rate in the ITT population was 47% in those treated with cobicistat-boosted darunavir and 60% in the control group.506 In the per-protocol (PP) population, the viral clearance rate at day 7 was 50% in those treated with cobicistat-boosted darunavir and 60% in the control group.506 The median time from randomization to negative RT-PCR results was 8 and 7 days, respectively.506 This study indicated that a 5-day regimen of cobicistat-boosted darunavir in patients with mild COVID-19 did not provide any clinical benefits compared with use of standard care alone.506

There are no data from clinical trials to support use of other HIV PIs (i.e., atazanavir, nelfinavir, saquinavir, tipranavir) for the treatment of COVID-19.502

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245. Gilead Sciences. Descovy^® (emtricitabine and tenofovir alafenamide) tablets prescribing information. Foster City, CA. 2020 Jan.

246. Gilead Sciences. Vemlidy^® (tenofovir alafenamide fumarate) tablets prescribing information. Foster City, CA. 2020 Feb

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Introduction ⬇

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