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A. Overview of Antiretroviral Therapy (ART) [1,2] navigator

  1. ART goal is suppression of HIV to allow restoration of effective immune response
  2. ART has reduced risk of death by >50%
  3. Updates posted by HIV/AIDS Treatment Information Service (ATIS) at www.hivatis.org
  4. Thorough patient understanding of issues concerning ART is critical [1]
    1. Patients MUST understand importance of drug compliance in preventing resistance [8]
    2. Drug "holiday" in patients with incomplete viral suppression may reduce resistance [9]
    3. Early drug failures are usually due to poor compliance and missed clinic visits [6]
    4. Drug compliance also affects prognosis and mortality risk [6]
    5. Increased use and duration of ART substantially reduce mortality and morbidity [26]
  5. Initiate Treatment Before Immunodeficiency Occurs [1,2]
    1. Any patient with evidence of immunodeficiency should receive ART
    2. Any patient with CD4 <350/µL and prior to CD4<200/µL [2,5]
    3. Any patient with viral load >50,000 (50K)/mL
    4. Any patient with acute HIV infection (within weeks) or within 6 months of infection
    5. Initiating ART with CD4 >200µL has much better prognosis than initiating when CD4 <200/µL [2,5,6]
    6. Post-ART initiation CD4 count >200/µL and viral load <10K/mL associated with good prognosis; pre-ART levels have no prognostic value in setting of post-HAART levels [7]
  6. Over 21 Antiretroviral Drugs in 5 Classes
    1. Nucleoside and Nucleotide reverse transcriptase inhibitors (NRTI)
    2. Non-nucleoside reverse transcriptase inhibitors (NNRTI)
    3. Protease inhibitors (PI)
    4. HIV-1 Fusion Inhibitors
    5. Integrase Inhibitors (experimental)
  7. Initiate Therapy with Three Drugs [1,2,4,11]
    1. Two NRTIs plus either efavirenz (EFA, an NNRTI) or lopinovir/ritonovir (PI) for first line [2,27,56]
    2. Virologic failure is less likely with efavirenz than with lopinovir/ritonovir in first line [27]
    3. EFA + lopinovir/ritonovir first line is discouraged for initial therapy [23,27]
    4. ART including 3-drug/two class (NRTI+NNRTI) including EFA is superior to PI-containing 3- or 4-drug therapy [11,19,56]
    5. Initial NRTI usually lamivudine (LAM) with either zidovudine or stavudine
    6. Initial NNRTI usually EFA or nevirapine
    7. Initial PI usually nelfinavir or indinavir
    8. Alternating different 3-drug ART can improve virologic outcomes [10] but no clinical benefits [15,16]
    9. Maintenance therapy with 2 drugs usually leads to early failure, but atazanavir-ritonavir has shown promise in 36 patients over 24 weeks [36]
    10. Initiating 4 drug ART not superior to 3 drugs [11,16,19,23]
  8. Reduce plasma viral load as much as possible for as long as possible
    1. Goal is reduction of viral load to <50 copies/mL [2]
    2. Viral load should fall 1.5-2 logs within 1 month of therapy
    3. Viral load nadir <50 /mL is associated with excellent durable control
    4. Viral load nadir 50-500 /mL have rapid rebound viral replication
    5. Interrupted ART with reinitiated therapy when viral load increases to ~10,000/mL or CD4+ decreases to <250/µL leads to more rapid progression than continued therapy [12,13]
  9. Monitor Plasma Viral Load and CD4 Counts [3]
    1. Viral load increases precede CD4 count reductions, which lead to clinical disease
    2. HIV RNA level and CD4 cell count after 8 weeks is good prognostic indicator [77]
    3. HIV RNA level 1 week after ART predicts longer term efficacy [78]
    4. CD4 count and viral load after 6 months is best prognosis for disease progression [14]
    5. Viral load >100,000 copies/mL has slow rate of viral suppression with ART [79]
    6. Change to new regimen if plasma viral load increases >5000-30,000 / mL for >8 weeks
    7. Triple ART induces HIV RNA <50/mL ~75% of persons at 3 years [19]
  10. Frequency of Monitoring CD4 Counts and HIV RNA Levels [2]
    1. In general, two baseline CD4 and HIV RNA level counts should be obtained
    2. q6 months for CD4>500/µL
    3. q4 months for CD4 200-500/µL
    4. q3 months for CD4 <200/µL
    5. Delay CD4 counts to >3-4 weeks after an illness
    6. HIV RNA levels should also be determined initially q2-3 months to follow therapy
  11. HIV-1 Drug Resistance Testing prior to initiating ART [21]
    1. Consider testing prior to treatment naive patients, which appears cost-effective [21]
    2. Also use resistance testing in patients temporarily taken off ART [9]
    3. Resistance testing prior to initiating treatment predicts outcomes [87]
    4. Resistance testing should be used in ANY treatment failure and for all pregnant women
  12. Immune Recovery and OI's
    1. Considerable immune recovery occurs with ART, with CD4 increases to normal levels possible with complete viral suppression [61]
    2. ART substantially reduces OI's even in very severe AIDS (CD4<10-15/µL) [22,73]
  13. HIV Associated Mortality [26]
    1. ART reduces morbidity and mortality even in very severe AIDS (CD4<10-15/µL) [73]
    2. ART reduces risk of death in HIV+ children by 70-90% [76]
    3. CD4 counts at initiation of ART best overall prognostic marker [85]
    4. Average lifespan (HIV+, HCV-) ~9 years in 2005 (Denmark Study) [35]
  14. Major Adverse Effects of ART [24]
    1. Mitochondrial toxicity - lactic acidosis, pancreatitis, myopathy, neuropathy, steatosis
    2. Hypersensitivity - usually rash with or without fever, myalgias, fatigue
    3. Lipodystrophy - multifactorial, particularly PI therapy [25,40]
    4. Drug interactions - between ART and other agents [69]
    5. Probable 26% per year increased risk of myocardial infarction [48,49]
  15. Potentially Life-Threatening Side Effects of ART [38]
    1. Abacavir: systemic hypersensitivity
    2. Nevirapine: Stevens-Johnson Sydrome or toxic epidermal necrolysis
    3. Hepatotoxicity: all agents, especially nevirapine
    4. Pancreatitis: didanosine, stavudine
    5. NRTIs: lactic acidosis syndrome, hepatotoxicity, hepatitic steatosis
    6. Indinavir and Tenofovir: nephrotoxicity, acute renal failure

B. Nucleoside Reverse Transcriptase Inhibitors (NRTI) [28]navigator

  1. Mechanism
    1. DNA chain terminators
    2. Activation to triphosphate form by cellular kinases
    3. Preferential incorporation into retroviral DNA by RT
    4. Reduction 0.5-0.8 logs in HIV RNA
    5. May increase risk of developing lipodystrophy syndrome (see below)
  2. Azidothymidine (zidovudine, ZDV, Retrovir®)
    1. Single amino acid changes can lead to ZDV resistance which occurs in 6-12 months
    2. Severe Side Effects: anemia (MCV usually >103 fL), neutropenia, gastrointestinal distress
    3. Minor side effects: headache, dizziness, insomnia, anorexia, nausea / vomiting, malaise, myalgia, hepatitis, macrocytosis
    4. Dose: 300mg bid po
    5. May be used with any other RTI except stavudine
    6. Fixed dose combination with lamuvidine (Combivir®)
    7. Fixed dose combination with abacavir (Ziagen®) and abacavir/lamuvidine (Trizivir®)
    8. Anemia may be treated with erythropoietin [70]
  3. Lamivudine (Lam, 3TC, Epivir®)
    1. 3'-thiacytidine (-)enantiomer
    2. Very well tolerated RTI
    3. Dose is 150mg po bid; should always be used in combination
    4. Combivir® is 3TC+ZDV 1 tablet po bid (300mg ZDV + 150mg 3TC)
    5. Combination with abacavir (Ziagen®) and ZDV available (Trizivir®)
    6. Active against hepatitis B virus (HBV) so should be considered in HIV/HBV coinfection
  4. Abacavir (Ziagen®) [28]
    1. Guanosine nucleoside RTI
    2. Combination with Lam is Epzicom® [97]
    3. Trizivir® is combination of abacavir, Lam, and ZDV
    4. Abacavir + ZDV + Lam reduced HIV levels to undetectable in ~75% similar to ZDV + Lam + indinavir [34]
    5. Abacavir + Lam more effective than abacavir + ZDV or ZDV + Lam in children [82]
    6. Reasonable first line treatment with Trizivir® for HIV viral load <100,000/mL
    7. Not optimal substitute for PI to maintain virologic suppression [30]
    8. Hypersensitivity reaction occurs in ~9% of patients, 9-11 days after beginning drug
    9. This reaction includes gastrointestinal symptoms, malaise, occasional rash
    10. Hypersensitivity resolves when drug is stopped
    11. Hypersensitivity mainly in patients with HLA-B*5701, -DR7, and -DQ3 [83]
    12. Withholding abacarvir from these patients should reduce risk of hypersensitivty >70%
    13. Abacavir should not be retried as rechallenge may be fatal
  5. Emtricitabine (Emtriva®) [94]
    1. Fluorinated derivative of lamivudine
    2. Active against HIV and HBV
    3. Dose is 200mg qd
    4. Tenofovir+emtricitabine+EFA (Atripla®) superior to ZDV+Lam+EFA for initial therapy [29]
    5. No anti-HIV activity over LAM
    6. Combination with tenofovir as Truvada® [97]
  6. Tenofovir (Viread®) [28,33]
    1. Approved for combination therapy in resistant HIV infections
    2. Tenofovir+emtricitabine+EFA (Atrpla®) superior to ZDV+Lam+EFA for initial therapy [29]
    3. Once daily 300mg with food
    4. Nausea, vomiting, diarrhea are most common adverse events
    5. Activity against HBV as well
  7. Dideoxyinosine (DDI; didanosine, Videx®)
    1. Side effects: anemia, painful peripheral neuropathy, pancreatitis, other GI complaints
    2. Dose: 200mg po bid or 400mg qd on empty stomach
    3. Resistance to DDI develops less rapidly than to ZDV
    4. Ethyl alcohol and iv pentamidine interaction: increased risk of pancreatitis and hepatitis
    5. Decreases absorption of itraconazole, ketoconazole, and possibly dapsone
  8. Stavudine (d4T, Zerit®)
    1. Reduction of 0.5-0.8 logs HIV RNA
    2. Active against most ZDV resistant (and sensitive) strains
    3. Combination with Lam is very effective; resistance develops slowly
    4. Good combination with DDI and EFA [19]; should not be combined with ZDV
    5. Side Effects: Painful peripheral neuropathy (~12%); no hematologic or GI problems
    6. Transaminase elevations uncommon; rare cases of pancreatitis
  9. Adefovir (Preveon®) [17]
    1. Generally for HIV resistant to 2 NRTIs and one PI
    2. FDA has not approved adefovir for HIV due to its nephrotoxicity at high doses used in HIV
    3. Approved as Hepsera® at lower doses for HBV
    4. Active against Lam resistant HBV in HIV+ patients [75]
    5. Nephrotoxicity occurs in ~30% of patients within 20 weeks of starting drug
    6. May cause nausea, asthenia, diarrhea, and/or increase in transaminases
    7. Dose 60mg once daily is safer than 120mg qd and is recommended dose
    8. Only available for HIV through expanded access program (800-445-3235)
  10. Dideoxycytosine (Zalcitabine, Hivid®)
    1. Low potency chain terminator; rarely used
    2. Side Effects: Rash, aphthous stomatitis, painful peripheral neuropathy
    3. Dose: 0.75mg po tid
  11. Entecavir (Baraclude®) [51]
    1. 2'-deoxyguanosine analog approved only for chronic HBV infection
    2. Also active against HIV reverse transcriptase
    3. Can reduce HIV levels in coinfected patients
    4. Induces high levels of M184V mutation, resistance to Lam and entecavir
    5. Caution when used in HIV unless full ART is used

C. Non-Nucleoside RTI (NNRTI) [28]navigator

  1. Appear as effective as PI with reduced side effects
  2. EFA or nevirapine (but not abacavir) likely superior to PI as initial therapy [19,30]
  3. Resistance to NNRTI is increasing [87]
  4. Efavirenz (EFA; Sustiva®) [1]
    1. EFA + ZDV + Lam is more effective than 3- or 4- drug PI-containing ART [11,15,16]
    2. EFA + DDI + Stav is more effective than PI-containing triple ART [19]
    3. Tenofovir+emtricitabine+EFA (Atripla®) superior to ZDV+Lam+EFA for initial therapy [29]
    4. EFA + 2 non-PI drugs better tolerated than PI regimens
    5. EFA + nelfinavir + RTI is effective in children with HIV infection
    6. Adverse effects: dizziness, headache, insomnia, rash, difficulty concentrating, vivid dreams, hallucinations, nightmares
    7. Neurologic symptoms, mainly subjective, in up to 50%, but most resolve within 4 weeks [99]
    8. Induces CYP 3A4 and therefore increases metabolism of other drugs
    9. Dose 600mg po qd
  5. Nevirapine (Nev; Viramune®) [37]
    1. Nev +Stav+Lam similar efficacy to EFA with Stav+Lam, similar to PI containing regimen
    2. Nev 200mg po x 1 for mothers prior to delivery and infant 2mg/kg x 1 within 72 hours of birth cuts transmission rate ~50% compared with ZDV [77]
    3. Nev single dose to mother added to standard oral ZDV prophylaxis beginning at 28 weeks reduced transmission from 6.3% to 2.8% [95]
    4. Nev of limited utility women already receiving ART and where elective Cesarean section available [88]
    5. Intrapartum exposure to Nev reduces subsequent maternal responses to it [96]
    6. Rash (may be severe with combination therapy) is common side effect
    7. Hepatitis or fulminant hepatic failure is rare but may occur
    8. Dose 200mg qd initially x 14 days; then 200mg po qd or bid (if no rash develops)
  6. Delavirdine (Rescriptor®)
    1. Modestly effective in combination with other agents
    2. Dose 400mg po tid
    3. Increases serum concentrations of PI levels
    4. Rash is less severe and less common compared with other NNRTIs
  7. Etravirine (Intelence®) [80,81]
    1. NNRTI with activity against most NNRTI-resistant HIV strains
    2. FDA approved (fast track) for combination therapy in HIV patients with NNRTI and other ART resistance []
    3. Good activity in treatment-experienced HIV patients with >2 protease inhibitor mutations
    4. Combines well with other agents; rash in ~20% (versus10% on placebo)
    5. Dose is 200mg bid

D. Protease Inhibitors (PI) [50]navigator

  1. HIV protease cleaves viral Gag-Pol polypeptide into gag, integrase, and protease
  2. PI Block HIV Protease
    1. Failure to cleave the Gag-Pol polypeptide leads to formation of noninfectious particles
    2. HIV grown in presence of PI leads to noninfectious, immature particles
    3. Resistance to one PI often leads to cross resistance
    4. Indinivir is generally considered the most potent
  3. Activity
    1. PI single agent HIV RNA reductions of 1-2.2 logs
    2. Always used in combination with one or two RTIs or NNRTIs
    3. Should be used at highest tolerated doses; reduced doses may lead to rapid resistance
    4. Regimens with 2 PIs more effective than single PI regimens in drug resistant HIV infection [86]
  4. PI Associated Lipodystrophy [40]
    1. PI's cause hyperglycemia; frank diabetes occurs in ~5%
    2. PI's are associated with lipodistrophy (~80%), hyperlipidemia, diabetes
    3. PI's associated with 1.16X increased risk of heart attack per year of use [65]
    4. Central adiposity also occurs; likely related to insulin resistance
    5. Diagnosis by observation and measurement of elevated insulin C-peptide
    6. Demonstration of glucose intolerance with oral glucose loading can also be done
    7. Likely that RTI's contribute to development of lipodystrophy in HIV infected persons
    8. Inhibition of mitochondrial DNA polymerase gamma contributes to lipodistrophy
    9. May also represent an autonomic neuropathy controlled by central nervous system [63]
    10. Rosiglitazone (Avandia®) appears to have beneficial effects in HIV associated lipodystrophy [55]
  5. Indinavir (Ind; Crixivan®)
    1. About 2.3 log HIV reduction as monotherapy
    2. Combination ZDV+Lam+Ind: undetectable serum HIV in >90% of patients at 3 months
    3. ZDV + Lam + Ind maintained viral load <50 copies/mL for >3 years in ~65% of patients [41]
    4. ZDV + Lam + Ind equivalent to ZDV + Lam + Abacavir in first line HIV [34]
    5. Ind crystals in urine seen in most patients
    6. Symptomatic nephrolithiasis occurs only <10% per year (36% in three years [49])
    7. Nephrolithiasis is associated with stones, flank pain, and dysuria
    8. Symptomatic nephrolithiasis is reduced by drinking >48 ounces of water daily [43]
    9. Mild indirect hyperbilirubinemia also reported; no reduction in drug needed
    10. Dose is 800mg po tid 1 hour before or 2 hours after meals (thus, on empty stomach)
    11. Resistant strains usually show >3 mutations in protease, usually cross resistant [44]
  6. Saquinavir (Fortovase®; formerly Invirase®) [1]
    1. Highly active against HIV, including ZDV resistant strains
    2. Fotovase® is newer soft gel formulation with improved absorption over Invirase®
    3. Generally well tolerated; some nausea, diarrhea and abdominal pain, fatigue common
    4. May be best tolerated of current PI's
    5. Begin dosing at 300mg po bid to reduce fatigue, increase to ~1200mg po tid
    6. Ritonavir (see below) can substantially increase saquinivir levels
    7. Rifampin and rifabutin may lower saquinavir serum levels to ineffective range
    8. Should be taken with food
  7. Ritonavir (Norvir®) [1,50]
    1. Single agent ~2 log reduction in HIV RNA levels
    2. Ritonavir liquid 600mg bid reduced HIV RNA >1 log, increased CD4+ >50cells/µL
    3. Safe and very effective in children with HIV [45]
    4. Severe hepatitis occurs in ~12%, often in setting of chronic hepatitis virus infections [46]
    5. Diarrhea, nausea and headache were fairly common, particularly when starting drug
    6. Extremely potent cytochrome P450 inhibitor causing numerous drug interactions
    7. May be used to reduce drug doses of other ART
    8. Avoid use with erythromycin, opiates, clonazepam, carbamazepine, others
    9. Begin 300mg po bid; increase in 100mg increments weekly to maximum 600mg po bid
    10. Should be taken with food
  8. Nelfinavir (Viracept®)
    1. FDA approved for CD4<100/µL; recommended in combination therapy
    2. Dose is 750mg po tid with food for adults
    3. Potency greater than saquinavir; similar to ritonavir and indinavir
    4. Combination with Stav led to undetectable HIV RNA in 75% of patients
    5. Good activity when added to EFA in nucleoside analogue resistant patients [74]
  9. Amprenavir (Agenerase®) [47]
    1. Approved for use with other agents in persons at least 4 years of age
    2. Dose is 1200mg po bid for persons >50kg; 20mg/kg bid or 15mg/kg tid for <50kg
    3. May be taken with food, but avoid taking with high fat meals
    4. Probably not as effective as Ind
    5. Inhibits CYP3A4; other drug levels may be altered
    6. May be effective against HIV strains resistant to other proteases
    7. Note: formulation contains high doses of vitamin E (do not use additional vitamin E)
    8. Nausea, vomiting, diarrhea, perioral rashes fairly common
    9. Patients can restart drug after rash resolves
    10. ~1% of patients develop Stevens-Johnson Syndrome
  10. Lopinavir with Ritonavir (Kaletra®) [50]
    1. New combo PI with good activity against PI-resistant HIV
    2. Kaletra dose is 3 capsules bid
    3. Kaletra is more effective than nelfinavir and reduces resistant HIV development in patients off of ART for >2 weeks [85]
    4. Kaletra + Lam + Stav reduced HIV load to <50/mL in 78% of patients [85]
    5. Mild diarrhea, nausea, headaches and asthenia
  11. Atazanavir (Reyataz®) [94]
    1. Azapeptide PI different than other PIs
    2. Dose is 400mg qd
    3. Common indirect hyperbilirubinemia; 11% develop jaundice, reversible with discontinuation
    4. Less likely to cause lipodystrophy than other PIs
  12. Fosamprenavir (Lexiva®)
    1. Superior to nelfinavir when combined with abacavir and LAM
    2. Dose 1400mg bid
    3. Diarrhea, nause, vomiting, headache, rash
  13. Tipranavir (Aptivus®) [98]
    1. Given with ritonavir
    2. Compared against other ritonavir boosted PI with optimized background therapy
    3. Provided superior HIV RNA reductions, CD4 elevations
    4. Appears very effective when combined with enfuviritide
    5. Dose is 500mg bid (with 200mg ritonavir bid boost)
    6. Liver function testing required (may cause hepatitis)
    7. Rash, diarrhea, nausea, elevated lipid levels
  14. Darunavir (Prezista®) [32,39]
    1. Approved for previously treated HIV
    2. Likely more effective than lopinavir in lopinavir naive, treatment experienced patients [62]
    3. Dose 600mg (+ 100mg ritonavir) bid, with food
    4. Similar side effects to other PI

E. Fusion Inhibitors [64,90,91,92]navigator

  1. Enfuvirtide (Fuzeon®, formerly T-20) is a 36-amino acid peptide fusion inhibitor
  2. Block fusion of virus (through gp120) with cell as well as cell to cell fusion
  3. T20 90mg sc bid reduces viral load in patients with resistant HIV ~0.8 log over placebo
  4. Increases CD4 count 30-40/µL in patients with resistant HIV
  5. Injection site reactions in 98%
  6. Eosinophilia and hypersensitivity in 10%
  7. Mutations in gp41 may cause resistance

F. Integrase Inhibitors [100]navigator

  1. Raltegravir (Isentress®) blocks HIV1 integrase
  2. Single agent ~1.0 log HIV RNA reductions versus optimized background therapy
  3. Well tolerated, approved for patients with HIV strains resistant to multiple ART
  4. Dose is 400mg po bid without adjustments for other drugs

G. Coreceptor Antagonists [64,100]navigator

  1. Most initial HIV infections use chemokine receptor 5 (CCR5) as coreceptor with CD4
  2. Maraviroc (Celsentri®) is a CCR5 antagonist approved for patients with CCR5 tropic HIV1
  3. Commercial assay available for CCR5 tropism
  4. Viral load reductions ~1.0 log in heavily pretreated patients taking 100mg bid
  5. Side effects not substantially different from placebo
  6. Dose is 150mg bid with strong CYP3A4 inhibitors; 300mg bid is standard dose

H. Use of ART in HIV [1,2,4]navigator

  1. An overview of treatment considerations is presented in Part A above
  2. Optimal strategies are continuously evolving and experts should be consulted
  3. Recent Recommendations [1,2,4]
    1. NNRTI containing initial regimen is recommended
    2. EFA is preferred NNRTI; nevirapine is second choice
    3. ZDV+Lam+EFA was superior to most other 3 and 4 drug combinations [11,15,16]
    4. Tenofovir+emtricitabine+EFA (Atripla®) superior to ZDV+Lam+EFA for initial therapy [29]
    5. For PI containing regimen, ritonavir boosting recommended
    6. Lopinavir/ritonavir, atazanavir/ritonavir, or indinavir/ritonavir recommended
    7. If ritonavir cannot be used, nelfinavir or atazanavir can be used
    8. 2 RTI regimens are ZDV or tenofovir AND Lam or emtricitabine
    9. In HIV patients previously treated with nucleoside analogs, treatment with nelfinavir + EFA + a new nucleoside analogue is recommended over two-drugs [74]
  4. Chronic therapy superior to structured interruption of therapy [13]
  5. Prognosis [3]
    1. Depends mainly on CD4 count and viral load after 6-12 months of therapy [7,14]
    2. Viral load <10K/mL and CD4 >200/µL associated with good prognosis [7]
    3. Changes in HIV RNA levels >2.5X are considered biologically important [54]
    4. HIV RNA levels should be monitored before and ~8 weeks after changing therapy [54]
    5. After 3 drug induction, maintain at least 3 drugs to suppress HIV levels [4]
    6. HAART is effective in advanced AIDS and can lead to immune response recovery to CMV and tuberculosis antigens [57]
    7. Anti-CMV agents can be stopped in patients with stable CMV disease and CD4 counts >150/µL [57]
  6. Persistence of HIV Replication
    1. Infectious HIV is found in the semen even on triple therapy with very low plasma HIV RNA
    2. Latent, replication competent HIV is present in resting CD4 cells with triple therapy and no detectable plasma HIV RNA [59]
    3. HIV replication persists in peripheral mononuclear cells in patients with no detectable plasma HIV RNA and with stable CD4 lymphocyte counts [60]

I. HIV Drug Resistance [21,42]navigator

  1. Mutations and ART
    1. Drug noncompliance is main risk factor (<80% compliance increase resistance risk)
    2. Patients reducing the number of ART drugs taken and poor compliance may be more important than mutations for developing resistance [44]
    3. ART resistance is now ~10-22% in newly diagnosed HIV in USA [42,89]
    4. Initial use of sequential ART strongly selects for resistance
    5. Pre-existing mutant virus in reservoirs may not lead to ART failures in patients with low levels of viremia on HAART therapy [72]
    6. Alternating triple therapy regimens leads to reduced genotypic resistance mutations [10]
  2. Biological Contributors
    1. Reservoirs of HIV form in treated patients and may lead to long term relapses
    2. Reservoirs include resting CD4+ T cells, marcrophages, follicular dendritic cells
    3. Reservoirs of mutant resistant virus may exist in untreated patients
    4. Low level viremia (<50 copies/mL) probably does not allow generation of resistance [72]
    5. Drug resistance mutations did not accumulate over 20 months in patients receiving triple therapy with low level HIV replication in peripheral mononuclear cells [60]
  3. Detecting HIV Resistance
    1. Diagnostic tests for specific HIV mutations should help guide selection of therapies [52]
    2. Concordance between genotype and phenotype is ~80-90%
    3. HIV mutation (genotyping) testing will help guide therapy in relapsing patients
    4. HIV-1 genotyping is often useful in relapsed HIV
    5. Phenotypic HIV drug resistance assays are also available (increased cost)
    6. Drug resistance testing is cost effective in all drug-failures, in relapse, and possibly in primary HIV infection [21]
  4. HIV-Resistance by Phenotyping (PhenoSense HIV®) [66]
    1. Resistance >10 fold was found in 2% of 140 primary HIV infected patients
    2. Resistance of 2.5-10 fold was found in 36% of 140 patients
    3. Moderate resistance (<10 fold) is of unclear clinical significance
    4. In addition, moderate resistance did not correlate with genotyping data
    5. Therefore, significant HIV resistance is likely to be low in primary infection

J. Anti-Retroviral Prophylaxis in Persons Exposed to HIV [1,67] navigator

  1. Four week prophylactic regimen is generally recommended
  2. New Recommendations for Non-Occupational Exposure [87]
    1. EFAvirenz + LAM OR
    2. Emtricitabine + ZDV or tenofovir OR
    3. Lopinavir/ritonavir with either Lam or ZDV/emtricitabine
  3. Combinations of 2 or 3 drugs are recommended for occupational exposure
    1. ZDV + Lam (or as single pill Combivir®)
    2. Lam + Stavudine
    3. DDI alone or in combination
    4. Basic regimen may be appropriate for very low risk of HIV exposure
    5. Higher risk exposures should include NNRTI and/or protease inibitors
  4. Prophylaxis for Perinatal Transmission of HIV [68,93]
    1. ZDV given antepartum + intrapartum lowered transmission to fetus by ~70%
    2. Nevirapine single dose to mother intrapartum and to neonate within 72 hours leads to
  5. 7% overall transmission rates at 18 months, compared with 25.8% for ZDV [93]
    1. Nevirapine single dose 200mg at labor then 2-4mg/kg to infant age up to 3 days more effective, less costly, and easier to administer than ZDV
    2. Peripartum Transmission rates without antiretorvirals ~26%
    3. Starting ZDV even 3 days after delivery reduces transmission rate >30%
    4. Lam added to ZDV reduces risk of transmission an additional 50%
  6. ART is not associated with increased pregnancy complications [84]

References navigator

  1. Yeni PG, Hammer SM, Hirsch MS, et al. 2004. JAMA. 292(2):251 abstract
  2. Hammer SM, Saag MS, Schechter M, et al. 2006. JAMA. 296(7):827 abstract
  3. CASCADE Collaboration. 2003. Lancet. 362(9392):1267 abstract
  4. Hammer SM. 2005. NEJM. 353(16):1702 abstract
  5. Palella FJ Jr, Deloria-Knoll M, Chmiel JS, et al. 2003. Ann Intern Med. 138(8):620 abstract
  6. Wood E, Hogg RS, Yip B, et al. 2003. Ann Intern Med. 139(10):810 abstract
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