ANTIRETROVIRAL THERAPY

See current guidelines from the International AIDS Society

Note--In a multi-center prostpective trial of 24,000 pts with HIV with median 1.6y f/u, use of combination antiretroviral therapy was an independent risk factor for MI (RR 1.26) (NEJM 349:1993, 2003--JW)

I. Nucleoside reverse transcriptase inhibitors--Side f/x of AZT, DDI, and D4T include a syndrome of hepatic steatosis and lactic acidosis.

1. Zidovudine (AZT; Retrovir)*
2. Didanosine (ddI; Videx)
3. Lamivudine (3TC; Epivir)*-Also active against Hepatitis B
4. Stavudine (d4T; Zerit)
5. Zalcitabine (ddC; Hivid)
6. Abacavir (ABC; Ziagen)
   1. 3% of pts get a hypersensitivity reaction, with fever, GI sx, malaise, and sometimes, rash. Occurs after mean 11d tx and resolves after drug is stopped; if rechallenged with abacavir, severe reactions and death can occur
7. Entecavir (Baraclude)
   1. Note that although this is a nucleoside analogue, as of 2005 it has not been studied (as far as I know) for treatment of HIV disease, but rather for Hepatitis B

*--Available in combination (Combivir)

II. Nucleotide reverse transcriptase inhibitors

1. Adefovir (Preveon)
   1. Must take with L-carnitine supplements
   2. Can cause mild-moderate nephrotoxicity--us. dose-related prox. renal tubular dysfunction or "Fanconi-like" syndrome; occurs in > 30% of pts, us. > 20wks after starting; resolves slowly (median 11wks) after reducing or d/c'ing the drug.
   3. Also may cause nausea, diarrhea, fatigue, and transaminase elevation
2. Tenofovir (TDF;Viread) 300mg QD
3. Emtricitabine (Emtriva)-Also active against Hepatitis B

III. Non-nucleoside reverse transcriptase inhibitors

1. Nevirapine (Viramune)

1. Acts synergistically with nucleosides against some HIV strains; if used alone or with only one nucleoside, HIV resistance develops rapidly.
2. Nevirapine + AZT + DDI x 1y caused greater increases in CD4 and greater decreases in HIV RNA levels than AZT + DDI alone in pts with "moderately advanced HIV disease" and no prior therapy (AIDS 10 suppl 2:S15, 1996-Med Lett.)
3. Nevirapine + AZT + DDI more effective than AZT + DDI alone in pts with "extensive prior HIV treatment" at lowering HIV RNA levels and mainaining CD4 counts, but rates of disease progression and mortality were similar.
4. Causes rash which can be severe or life-threatening; also fever, nausea, headache

2. Efavirenz (EFV; Sustiva)
   1. Can cause dizziness, HA, insomnia, inability to concentrate, and rash. CNS f/x occur us. 1-3h after each dose and stop within a few days or weeks of starting the meds. MAY BE TERATOGENIC
   2. Must increase indinavir dose from 800-1000mg Q8h when using Efavirenz
   3. Don't combine w/Saquinavir per Med. Lett.
   4. May be as effective as protease inhibitors
      1. 450 HIV-positive adults (mean CD4 345/mm3, mean HIV RNA 60K/ml; 80% had received no previous antiretrobirals) randomized to AZT, lamivudine, and either Efavirenz or Indinavir; at 48wks; the 90% Efavirenz group had HIV RNA < 50/ml vs. 75% of the Indinavir group (NEJM 341:1865, 1999--JW)

3. Delavirdine (Rescriptor)
4. Etravirine

IV. Protease inhibitors-n.b. can't use as monotherapy because rapidly induce viral resistance; may cause significant Dyslipidemias, esp. Saquinavir and Ritonavir; also hyperglycemia and AST elevation and occasionally, pancreatitis

1. Saquinavir (Invirase, Fortovase)
2. Ritonavir (Norvir)--Ass'd with 30% incidence of severe elevations in transaminases in a cohort of pts with HIV followed for median 5mos, unlike other protease inhibitors (JAMA 283:74, 2000--abst)
3. Indinavir (Crixivan)
4. Nelfinavir (Viracept)
5. Amprenavir (Agenerase)--can cause n/v, diarrhea, oral paresthesias, and rash (including, in some cases, Stevens-Johnson Sd.)
6. Atazanavir (Reyataz)--Can cause jaundice and prolonged PR interval; may cause less hyperlipidemia than other PPIs
7. Fosamprenavir (Lexiva)
8. Tipranavir (Aptivus) (for co-administration with ritonavir)
9. Lopinavir/Ritonavir combination (Kaletra)
   1. Both are protease-inhibitors; Lopinavir is only available in this formulation as of 2001
   2. Ritonavir inhibits hepatic P450 CYP3A4, which metabolizes Lopinavir, allowing Lopinavir levels to rise very high
   3. Effective for some HIV strains resistant to multiple protease inhibitors
10. Darunavir (TMC114)-Effective against some protease-inhibitor-resistant strains of HIV.  Can be given with low-dose ritonavir to boost blood levels.

V. Fusion inhibitors

1. Enfuvirtide (Fuzeon) 90mg BID
   1. Acts by bunding to gp41 on the HIV viral envelope and preventing the conformational change that is a required step in fusion of the viral and host cell membranes and entry of the virus into the cell
   2. In addition to a "standard" antiretroviral regimen, Enfuvirtide is ass'd with sig. greater reduction in mean HIV viral load compared with the standard regimen alone (Med. Lett. 45:49, 2003)

VI. Integrase inhibitors

1. Raltegravir
   1. Initially studied for use for "salvage therapy" added to a background antiretroviral regimen
   2. In a study in 566 treatment-naive HIV-positive adults with HIV viral load > 5000 copies/mL, all of whom were started on (tenofovir + emtricitabine), randomized to also receive either raltegravir 400mg BID vs. efavirenz 600mg QD, at 48wks, there was no sig. diff. in the % of pts achieving viral loads of < 50 copies/mL or mean 48-wk increases in CD4 counts.  Raltegravir recipients had sig. fewer drug-related adverse events (16% vs. 32%) (Lancet 374:796, 2009-JW)

VII. Interleukin-2 has been used to treat HIV infection (see below)

VIII. Some clinical trials of antiretroviral Rx

1. NEJM 333:401,1995

1. 1650 pts (90% white men) were randomized to AZT 500mg/d, or AZT 1500mg/d, or placebo
2. Starting 2 years into study, those with CD4 < 500 were offered open-label AZT 500mg/d, so the authors consider the trial to have compared immediate with deferred (until CD4 < 500) AZT therapy
3. Median f/u 4.8y
4. Outcome:

1. Overall survival and AIDS-free survival comparable among all groups
2. Slower decline in CD4 counts for both immediate-treatment groups: placebo had 1.0yr median time to CD4 <500; tx groups combined had 1.5yr median time
3. Severe anemia & granulocytopenia were more frequent in 1500/d than 500/d group

2. Switching from AZT to DDI (Ann. Int. Med. 123:561, 1995)

1. Multicenter trial randomized 245 pts who had been on AZT x >6mos and had CD4 counts 200-500 to continued AZT (600mg/d in divided doses) or DDI (weight-adjusted dose)
2. At start, 66% were asymptomatic, 30% had ARC, 4% had AIDS
3. After 48wks, 1 new AIDS-defining illness among DDI pts vs. 8 with AZT
4. Also less high-level drug resistance and sig. higher CD4 counts among DDI group

3. AZT monotherapy vs. combination regimens

1. 2493 HIV + adults with CD4 200-500 assigned (randomly?) to AZT, DDI, AZT + DDI, AZT + DDC; mean f/u 3y/ Higher (sig?) rate of decline in CD4, higher risk of progression to AIDS or death with AZT monotherapy than with other regimens (NEJM 335:1081, 1996-JW)
2. 3200 pts with CD4 50-350 randomized to AZT 600mg/d plus either DDC 2.25mg/d, DDI 400mg/d, or placebo over median f/u of 2.5u. Analyzed subgroups of AZT-naïve and AZT-exposed pts. Mortality lower for either combination group than group that got AZT alone, more for AZT-naïve group (42% and 32% reduction for DDI and DDC, respectively) than for AZT-exposed group (23% and 9%, the latter a nonsig. reduction). No sig. increase in toxicity with combination Rx. (The "Delta Trial" Lancet 348:283, 1996-JW)
3. 1102 with AIDS or CD4 < 200 randomized to AZT, AZT + DDI, or AZT + DDC. Combination Rx ass'd with nonsig. trend toward improved survival and less dis. progression. Improved prognosis was sig. among those pts who had had AZT previously (NEJM 335:1091, 1996-JW)

4. Adding protease inhibitors to other antiretrovirals

1. 297 HIV + pts with "advanced-stage illness". Median baseline CD4 of 156; 63% with symptomatic disease or AIDS. All got open-label AZT. Randomized to DDC, saquinavir, or both. Followup for 24-48wks. CD4 and viral load were improved to a greater degree and longer period with all 3 drugs than either of the 2-drug combinations; advantage in all-3-drug-group persisted through end of f/u period; too short to assess clinical end points. No greater incidence of sx or lab abnormalities attributable to study drugs in all-3-drug group (NEJM 334:1011, 1996-JW)

5. Adding nevirapine to other antiretrovirals (Ann. Int. Med. 124:1019, 1996-JW)

1. 398 adults with HIV-1 and CD4 < 350 with previous nucleoside Rx x > 6mos
2. All got AZT and DDI; randomized to nevirapine (200mg QD x 2wks then 400mg QD) or placebo; f/u x 48wks
3. At end of study nevirapine pts had higher mean CD4, lower mean HIV-1 titers and lower mean HIV-1 RNA levels; 9% developed severe rashes vs. 2% on placebo

6. 2-drug vs. 3-drug NEJM 337:734, 1997-JW

1. 1000 HIV + pts w/ CD4 < 200 who had been on AZT for > 3mos randomized to 2-drug regimen (AZT + 3TC) vs. 3-drug regimen (AZT, 3TC, and indinavir)
2. RR 0.5 in 3-drug group for AIDS-associated complictions and death at median f/u 38 wks; also better responses in CD4 counts and HIV RNA levels

7. 3-drug regimens: simultaneous vs. sequential initiation of therapy (JAMA 280:35, 1998)
   1. 97 pts who had been on AZT x 6mos with HIV RNA levels > 20k/ml and CD4 50-400 randomized to:
      1. Indinavir 800 Q8h
      2. AZT 200 Q8h + Lamivudine 150 Q12h
      3. or all 3 together
   2. After 6mos of blinded therapy, all pts received open-label 3-drug therapy
   3. After 2y f/u, pts randomized to initial tx with all 3 had sig. higher rates of suppression of HIV RNA levels to < 500 and sig. higher increases of CD4 counts

8. 3-drug regimens: conversion to less intensive therapy after "induction"
   1. 309 pts; all given AZT, lamivudine, and indinavir until viral RNA below detectable levels (3-6mos) then randomized to 4mos of continuing all 3 drugs (rate of relapse--return of detectable viral RNA--4%), AZT + lamivudine (23%) or indinavir alone (23%) (NEJM 339:1261, 1998--JW)
   2. European trial with similar protocol except non-3-drug f/u tx was either AZT + lamivudine or AZT + indinavir; again showed sig. less relapse rate with continued 3-drug tx (NEJM 339:1269, 1998--JW)

9. 82 HIV-positive pts with CD4 200-500 on 3-drug therapy randozmied to Interleukin-2 (six 5-d courses, 8wks apart); 50% of the IL-2 group had tx-limiting side f/x (flu-like sx, LFT elevation); CD4 counts rose more in the IL-2 group and sig. more IL-2 recipients achieved HIV RNA levels < 50 copies/ml on "ultrasensitive" testing (67% vs. 36%) (JAMA 284:183, 2000--JW)
10. Antiretroviral-naive HIV-positive pts randomized to 1 of 6 antiretroviral regimens: 4 groups consisted of 2 nucleosides (AZT, 3TC, DDI, or D4T) plus either efavirenz or nelfinavir then switch to one of the 3 untried drugs in the event of treatment failure; the other 2 groups started with one of the nucleosides plus both efavirenz and nelfinavir. At median 2.3y f/u, the group that started with AZT-3TC-Efavirenz was sig. less likely to require a tx change than the other 3-drug groups; the 4-drug groups didn't have sig. lower likelihood of needing a tx change than any of the 3-drug combinations. DDI/D4T combination had sig. higher risk of treatment-related toxicity than other regimens (NEJM 349:2304, 2003--JW)
11. In a trial in 1,216 treatment-naive HIV+ adults randomized to (stavudine + lamivudine + (nevirapine, efavirenz, or both)); over 48wk f/u, the pts who received nevirapine and efavirenz had higher rates of drug toxicity than other groups; among the others, rate of virologic suppression was similar and comparable to regimens including protease inhibitors (Lancet 363:1253, 2004--JW)
12. In a trial in 1,147 treatment-naive HIV+ people randomized to (3 nucleoside RTIs, or 2 or 3 nucleoside RTI's + efavirenz); at 48wks, the efavirenz groups had sig. higher rates of virologic suppression (89% vs. 74%) (NEJM 350:1850, 2004--JW)
13. 3-drug vs. 4-drug regimens in antiretroviral-naive patients
    1. In a study in 765 treatment-naive pts with HIV randomized to abacavir vs. placebo (all also received zidovudine, lamivudine, and efavirenz), after median 144wk f/u, there were no sig. differences in change in CD4-cell count, sustained viral suppression rates, or drug toxicity (JAMA 296:769, 2006--JW)
14. Switching antiretroviral regimens before vs. after clinical resistance develops
    1. In a study of 161 antiretroviral-naive pts with HIV-1 RNA > 400 copies/mL randomized to (a regimen alternating Q3mos between stavudine + didanosine + efavirenz and zidovudine + lamivudine + nelfinavir, as long as viral load remained suppressed) vs. (either stavudine + didanosine + efavirenz or zidovudine + lamivudine + nelfinavir, until virologic failure occurred); at 48wks, sig. fewer alternating-regimen pts had virologic failure; no diff. in adverse effects (Ann. Int. Med. 139:148, 2004--JW)
15. Antiretroviral regimens in children
    1. 52 infants with HIV sequentally assigned to one of 3 antiretroviral regimens (AZT, 3TC, + NVP; AZT, 3TC, NVP, + Abacavir; D4T, 3TC, NVP, and nelfinavir.  At 4y, the group on the regimen including nelfinavir had sig. higher chance of having HIV-1 RNA levels < 400 copies/mL  (NEJM 350:2471, 2004--JW)

IX. Primary (acute) HIV infection

1. 50-80% of pts will have an acute viral sd.
2. Can often be dx?d with HIV core (p24) antigenemia
3. 77 pts with ?primary HIV infection?--(viral sd or known HIV exposure <3mos prior) and (p24+ or

1. Randomized to AZT 250 BID or placebo x 6mos; mean f/u 15mos
2. Mean duration of sx = 31days: fever, rash, HA, malaise, lethargy
3. AZT group had

1. Didn't significantly change duration of viral sd.
2. Fewer OI's (stat. sig) during f/u period
3. Greater CD4 counts throughout f/u period
4. No new mutations in reverse transcriptase gene seen in either group at end of tx period; this suggests that the tx did not induce AZT resistance.

X. Prevention of Perinatal transmission--See also "HIV in Pregnancy"

1. "ACTG-076Regimen" =
   1. AZT PO (100mg 5x/d) in 2nd and 3rd TM
   2. AZT IV (2mg/kg over 1h then 1mg/kg/h) during labor & delivery
   3. AZT PO (2mg/kg PO Q6h starting 8-12h after birth--if can't take PO, then IV 1.5mg/kg Q6h) to infant for 1st 6 weeks of life

2. As of 8/99 ACOG makes the following recommendations for HIV-infected women:

1. Offer scheduled c/s at 38wks with preoperative AZT per ACTG 076 protocol
2. Greatest risk reduction seems to occur for women with highest viral loads
3. No clear evidence for reduction of transmission if c/s is done after onset of labor or ROM

3. Recommendations from AAP (from Peds. 99:909, 1997) are as follows; they also recommend discussion of risk vs. benefit in all cases:

4. Combination therapy for prevention of vertical transmission:
   1. In an uncontrolled study, 445 women with HIV (median CD4 426, median viral load 4000/mm3), 75% antiretroviral-naive, tx'd with AZT monotherapy starting at 23wks then at 32wks Lamivudine was added; neonates received both x 6wks. Perinatal transmission rate was 1.6% (compared with 6.8% historical rate with AZT monotherapy. However, neonates in this study had sig. lower Hb and PMN counts than historical controls and 3 kids developed mitochondrial dysfunction (2 of whom died) (JAMA 285:2083, 2001--JW)