Note: Rapidly changing field; identify local consultants and resources

Cause:Human immunodeficiency virus (HIV) type 1 (Nejm 1991;324:308); rarely in US but commonly in Africa, HIV-2 (Ann IM 1993;118:211); a retrovirus

Pathophys:

AIDS defined by HIV infection and T4 count <200

Increased suppressor T8 and decreased helper T4 cells (CD4) (Nejm 1985;313:79); deficient production of interferon- (Nejm 1985;313:1504)

Billions of virons produced daily from infection w high viral RNA mutation rate, which allows rapid selection of resistant organisms in face of rx (Ann IM 1996;124:984)

Spread via sex (3% infection rate w HIV-pos semen—JAMA 1995;273:854), but no heterosexual transmission when viral loads <1500/cc (Nejm 2000;342:921); contaminated needles; blood products, eg, screened blood transfusion 1996 risk = 1/500 000 (Nejm 1996;334:1685), factor VIII concentrates (Nejm 1993;329:1835), and breast milk (Jama 2000;283:1167; 1999;282:744); rarely by casual or nonsexual familial contact (Nejm 1987;317:1125), percutaneous inoculation in healthcare workers, 0.3%/incident, incr w incr volume and probably HIV titer (Nejm 1997;337:1485)

Prevalence in wives of infected hemophiliacs 12% (Ann IM 1991;115:764); 0.2% of Massachusetts women positive at delivery (Nejm 1988;318:525) and NY State but NY City rate = 14% (Am J Pub Hlth 1991;81:[May suppl]); 5% Baltimore ER patients (Nejm 1988;318:1645)

Transmission enhanced by the presence of chancroid or other genital ulcers (Ann IM 1993;119:1150)

Prevalence increased in gay males (67% in San Francisco 1984—Ann IM 1985;103:210), drug abusers, hemophiliacs (Nejm 1983;308:79), female partners of infected males (Nejm 1983;308:1181)

90% of persons transfused with HIV-positive blood convert to positive themselves (Ann IM 1990;113:733); but only 0.3% become positive after a needlestick from an HIV-positive patient; <0.5% of exposed healthcare workers convert over 1 yr (Nejm 1988;319:1118); 30% untreated babies of HIV-pos mothers are pos at 16 mo (Nejm 1992;327:1192)

Incidence of AIDS in 1990s decr in US as are AIDS deaths, probably from preventive maneuvers, drug rx of HIV infection, and prophylaxis and rx of opportunistic infections (Mmwr 1997;46:861). In US, 50k new cases yearly from 2003-6 (Jama 2008;300:520)

Sx:

Primary HIV infection (Nejm 1998;339:33; Ann IM 1996;125:259) consists of a mono-like syndrome 5-30 d after exposure lasting ~2 wk, rarely seek care; w fever (95%), sore throat (70%), wgt loss (70%), myalgias (60%), headache (60%), cervical adenopathy (50%), maculopapular or other rash involving trunk (40-80%)

AIDS: diarrhea (60%—Nejm 1993;329:14), malaise, weight loss, fever, adenopathy, dyspnea (pneumocystis pneumonia)

Si:

Early: lymphadenopathy; oral monilia/thrush (exudative, chelosis or erythematous diffuse rash types) precedes overt disease often (Nejm 1984;311:354), and multiple other oral manifestations (Ann IM 1996;125:487); dermatoses including warts and shingles; chronic fatigue syndrome

Later: wasting syndromes, chronic diarrhea, dementias/seizures, FUO, thrombocytopenia, cervical dysplasia, KS, hairy leukoplakia corrugations on sides of tongue due to reactivation of EB virus (Nejm 1985;313:1564)

FIG 9.1 HIV Course

Reproduced with permission from Pantaleo G, et al. Mechanisms of disease: the immunopathogenesis of human immunodeficiency virus infection, New Eng J Med 1993;328:327-335. Copyright 1993 Mass. Medical Society, all rights reserved.

of HIV infection: variable RNA viral loads in 1st 4 mos but worse/faster crs predicted by levels at 5-18 mos from infection and by severity of primary infection sx (Ann IM 1998;128:613; Jama 1996;276:105); evolution to AIDS 10 yr post-seroconversion varies from 0-72%

of AIDS: mortality figures markedly improving w aggressive multidrug rx based on viral loads (Jama 2008;300:51), approaching survivals of uninfected populations for all age groups (Europe). Survival worse w increasing age of pt and some HLA MHC types (Nejm 2001;344;1668), but not associated w pre-rx CD4 and viral load values (Ann IM 2004;140:256), gender, iv drug use, race, or socioeconomic status (Nejm 1995;333:751). Survival improved when coinfection w GB virus C, a hepatitis C-like virus (Nejm 2004;350:981)

• Infections with common bacterial pathogens (Nejm 1995;333:845) as well as opportunistic organisms, esp when CD4 <50 (Ann IM 1996;124:333), including:
• Pneumocystis (in 1980s was presenting sx in 75%, much rarer w prophylaxis—Nejm 1993;329:1822)
• Atypical tbc (Ann IM 1986;105:184), esp M. avium/intracellulare, rarely M. haemophilum
• Herpes infections including tongue fissures (Nejm 1993;329:1859); CMV; candida; aspergillosis; strongyloides
• Nocardia
• Mucor
• Cryptococcus, esp meningitis
• Toxoplasma
• Legionella
• Chlamydia
• Monilia, torulopsi
• Penicillium marneffei, a SE Asian dimorphic fungus (Nejm 1998;339:1739)
• Cryptosporidiosis (Cryptosporidium Diarrhea), Isospora belli(Cryptosporidium Diarrhea)
• Cat scratch Bartonella(Rochalimaea) henselaeor quintanacausing bacillary angiomatosis (r/o Kaposi's by bx) and peliosis hepatitis (Cat Scratch Fever)
• Syphilis w rapid (<4 yr) appearance of neurosyphilis that manifest by strokes, meningitis, and cranial nerve palsies and which is only transiently suppressed by penicillin regimens (Nejm 1994;331:1469, 1488, 1516)
• Tumors including:
• Kaposi's sarcoma (Kaposi's Sarcoma)
• Non-Hodgkin's lymphoma, in 15% after 3 yr of AZT rx (Ann IM 1990;113:276)
• Burkitt's (Nejm 1986;314:874), EB virus associated, in adults
• Leiomyosarcomas (Nejm 1986;314:874), EB virus associated, in children (Nejm 1995;332:12)
• Cervical cancer due to higher prevalence of HPV infection (Nejm 1997;337:1343); get q 1 yr after 2 q 6 mo Paps (Ann IM 1999;130:97)
• Hematologic including ITP (Nejm 1985;313:1375) and aplastic anemias from parvovirus infections (Ann IM 1990;113:926); and from diminished half-life and megakaryocyte infection (Nejm 1992;327:1779)
• Myocardiopathy, dilated type (Nejm 1998;339:1093; 1992;327:1260)
• Neurologic (Ann IM 1994;121:769) including early subtle CNS degeneration (Nejm 1990;323:864) leading to dementia (Nejm 1995;332:934); progressive multifocal leukoencephalopathy (p?) associated w JC polyoma virus, also seen in transplant pts and those getting natalizumab for Crohn's and MS (Nejm 2009;361:1067; 2005;353:362, 369, 375, 414); cord lesions; aseptic meningitis; peripheral neuropathy (Nejm 1985;313:1538); cerebral toxoplasmosis; cerebral lymphomas
• Nephropathy (Nejm 1989;321:625)
• Rheumatologic including Reiter's without conjunctivitis; and psoriasis with arthritis (Bull Rheum Dis 1990;39:5); aseptic necrosis of femoral head 4.5% prevalence (Ann IM 2002;137:17)
• Suicide (Jama 1996;276:1743)
• Diabetes and hyperlipidemia (Nejm 2003;348:702) due to both the HIV infection and its drug rx

r/o HTLV I and II infections, former associated w paraparesis, latter w no disease (Ann IM 1993;118:448); rare idiopathic CD4 cell lymphopenia syndrome (Nejm 1993;328:429)

Lab:

Immunol:

• Standard tests, negative for 4+-mo incubation period (Nejm 1989;321:941):
• Viral load, most important test, positive at >50 000/cc in acute primary disease (Nejm 1998;339:33); RNA by PCR, peripheral mononuclear cell viral mRNA levels predict prognosis (Ann IM 1995;123:641) and treatment success (Nejm 1996;335:1091; 1996;334:426; Ann IM 1996;124:984); indicates rapidity of disease progression (Jama 1997;278:983); <10 000/cc good, 10 000-100 000/cc moderately ok, >100 000/cc bad
• T4 (CD4) <200/cc defines AIDS and predicts opportunistic pneumonias, 200-500 = intermediate risk
• ELISA w Western blot test, only 1.5% false positive in low-risk military population (Nejm 1988;319:961); if indeterminant, repeat in 1 mo and should become pos if really HIV; if persistently equivocal, get viral load and culture (R Smith 4/95)
• P24 nuclear antigen detection either of free antigen or dissociated from IgG antibody-antigen complex (Nejm 1993;328:297); pos usually in early disease including the primary disease syndrome when ELISA still neg in 50% (Nejm 1998;339:33)
• Rapid tests (Med Let 2003;45:54); all require confirmatory Western blot if positive:
• Ora-Sure HIV-1 test from 2-min swab btwn cheek and gum, as specif as serum by ELISA/Western blot (Jama 1997;277:254)
• OraQuick, whole blood finger stick 20-min test; 99.6% sens, 100% specif; $15
• Reveal rapid HIV-1 test, serum 3-min test; 99.8% sens, 99.1% specif; $15

Path:Bronchoscopic brushings and lavage are 85% specif and sens for specific infections (Ann IM 1985;102:747)

Urine:Proteinuria >0.5 gm/d in 50%, nephrotic syndrome in 10% (Ann IM 1984;101:429)

Rx:

Preventive maneuvers:

• Screening
• Consistent condom use prevents disease; 0/124 conversions in HIV-neg partners over 2 yr, otherwise 5/100 pt/yr convert (Nejm 1994;331:341)
• In pregnancy (USPSTF—Ann IM 2005;143:38; Nejm 1995;333:298), avoid peripartum scalp electrodes, rupture of membranes >4 h (Nejm 1996;334:1617), and episiotomies. Pre- and peripartum AZT no matter what the maternal viral load or CD4 count (Nejm 1996;335:1621) reduces maternal–fetal transmission from 25% to 8% (Jama 1995;273:977; Nejm 1994;331:1173) and decr to a lesser extent w peri or postpartum rx w/i 1st 6 mo of age (Nejm 1998;339:1409); so rx mother beginning at 28-wk gestation through delivery and infant for 1st 6 wk of life (Nejm 2004;351:217, 229; 2000;343:982). Rx of prepartum mother viral load to <20 000 (Jama 1996;275:599) or <1000 (Nejm 1999;341:394) or <500 (Nejm 1999;341:385) yields infant infection rate = 0, and is safe for infant (Jama 1999;281:151). Elective C/S reduces infant infection to <1% (Jama 1998;280:55) and w postpartum antibiotics reduces infant infection to 2% (Nejm 1999;340:977). Avoid breastfeeding, which has a 6-10+% transmission rate over 1-1.5 yr (Jama 2001;285:2413; 2000;283:1167). All these efforts have decr neonatal AIDS in US by 67% (Jama 1999;282:531)

Prophylaxis immediately (<24-48 h) (CDC prophylaxis/exposure guideline—Mmwr 1998;47[#RR-7]:1) postexposure × 1 mo w AZT (Nejm 1997;337:1485) 300 mg bid + lamivudine (3TC) (Ann IM 1998;128:306; Jama 1998;280:1769) 150 mg bid; may add indinavir 800 mg q 8 h or nelfinavir 750 mg tid if exposure substantial, or perhaps daily prophylaxis w retrovirals (Nejm 2010;363:2587, 2663) decr risk in gay men w constant exposure from 69% to 39%/year (MMWR 2011;60:65), or Tenofovir + emtricitabine (Truvada) w or w/o Kaletra (Nejm 2009;361:1768)

of pregnant women or breast feeding or of newborn, nevirapine po for 28 wk (Nejm 2010;362:2271, 2282, 2316)

Prevention of AIDS associated infections (Ann IM 2002;137:239; Nejm 2000;342:1416); can stop when CD4 counts >200 for >6 mo:

• Pneumocystis prophylaxis (Nejm 1995;332:693) w CD4 counts <200. Can stop after rx persistently raises CD4 counts >200 (Nejm 2001;344:159, 168, 222; 1999;340:1301)
• 1st: Tm/S SS qd or DS tiw, qd-bid; also helps toxoplasmosis
• 2nd: pentamidine aerosol 150-300 mg monthly if CD4 <200 (Nejm 1991;324:1079; 1990;323:769), least toxic; or
• atovaquone (Nejm 1998;339:1895) 1500 mg po qd
• 3rd: dapsone 50 mg po bid or qd w pyrimethamine, also helps prevent toxoplasmosis
• M. avium(MAI) prophylaxis (Atypical Tuberculosis) if CD4 counts <50 w clarithromycin, azithromycin 1200 mg po q 1 wk, or rifabutin; can stop after rx persistently raises CD4 counts >100-200 (Nejm 2000;342:1085)
• Toxoplasmosis after encephalitis, w sulfadiazine + pyrimethamine folate po qd (Ann IM 1995;123:175); or if pos IgG titer and CD4 <100, w Tm/S DS qd or dapsone + pyrimethamine
• CMV infections w ganciclovir 1 gm po tid, if CD4 <50-100, decr rates by 1/2 (Nejm 1996;334:1491)
• Pneumovax immunization helps in DBRT (Nejm 2010;362:812)
• Chickenpox: vaccination + VZIG if exposed
• Tuberculosis prophylaxis if ppd pos w INH, or rifampin + pyrazinamide, or rifabutin + pyrazinamide (Nejm 1999;340:371)
• HPV w pap smears q 6-12 mo, esp if CD4 500 (Jama 2005;293:1471)

of questionable benefit:

• Cryptococcus, histo and cocci w chronic fluconazole, but no prolongation of survival (Nejm 1995;332:700)
• Candidal local mucosal and systemic infections w fluconazole 200 mg po q 1 wk (Ann IM 1997;126:689) but no prolongation of survival (Nejm 1995;332:700) and resistance a problem
• Cryptosproidiosis w careful exposure prevention (see list—Ann IM 1999;131:879)
• Human herpesvirus 8 (Kaposi virus) perhaps (Ann IM 1999;131:891)
• Influenza w vaccine (Ann IM 1999;131:430)

of acute primary infection: triple-drug rx (Nejm 2005;353:1702)

of disease (Jama 2006;296:769, 827; 2004;292:251); rapidly changing field, should check most recent Med Let and other journal issues

Drug therapy (Antiviral Antibiotics) triplet+ for adults and children (Nejm 2001;345:1522) when CD4 count drops <350, at least by <200 or a little higher. Most start at 300^± or if viral load >100 000 to get RNA load levels <50; both survival and other measures of disease severity are improved (Jama 2001;286:2560, 2568; 1998;280:1497) but must start at CD4 counts of <200 and adhere to rx (Ann IM 2003;139:810), starting w CD4 <350 is better. Women run lower viral loads, but prognosis same so maybe use CD4 <500 even if viral loads higher (Nejm 2001;344:720). Simultaneous initiation of triple rx results in >80% still adequately suppressed whereas w sequential initiation <40% suppressed at 2+ yr (Jama 1998;280:35); tapering to 1-2 drugs after 3-6 mos not as good as cont'd 3-drug rx (Nejm 2006;355:2283). Multiple-drug-resistant organisms appearing, >12% in US (Nejm 2002;347:385; Jama 1999;282:1135, 1142, 1177), so sensitivity testing necessary. Avoid combinations of d4T + AZT; or ddC w ddI, d4T, 3TC, and others (table—Jama 2004;292:259)

Triple-drug rx (table 4—Nejm 2005;353:1702) w:

• 2 nRTIs + a PI or a nnRTI; or
• 2 nRTIs + ritonavir + another PI like lopinavir (Nejm 2002;346:2039)

Most common triple-drug combos:

1. Zidovudine (AZT) bid + lamivudine (3TC) bid + efavirenz (Sustiva) qd (Nejm 2003;349:2293, 2304, 2351) or indinavir; or
2. Tenofovir DF qd + emtricitabine qd, + efavirenz qd, perhaps best (Nejm 2006;354:251)

of aphthous stomatitis (Aphthous Stomatitis)

of lipodystrophy: perhaps rosiglitazone 4 mg po qd (Ann IM 2004;140:786), or metformin 2 gm po qd (Ann IM 2005;143:337)

of wasting syndrome (Palliative Care)

of diarrhea: rx primary cause if can be found; octreotide 50 mg sc q 8 h (Ann IM 1991;115:705), opiates, loperamide (Imodium), or diphenoxylate-atropine (Lomotil)

• Overall AIDS Primary Care Strategies