N Engl J Med. 2006 Nov 30;355(22):2283-96.
CD4+ count-guided interruption of antiretroviral treatment.
METHODS:
We randomly assigned persons infected with HIV who had a CD4+ cell count of more than 350 per cubic millimeter to the continuous use of antiretroviral therapy (the viral suppression group) or the episodic use of antiretroviral therapy (the drug conservation group). Episodic use involved the deferral of therapy until the CD4+ count decreased to less than 250 per cubic millimeter and then the use of therapy until the CD4+ count increased to more than 350 per cubic millimeter. The primary end point was the development of an opportunistic disease or death from any cause. An important secondary end point was major cardiovascular, renal, or hepatic disease.
RESULTS:
A total of 5472 participants (2720 assigned to drug conservation and 2752 to viral suppression) were followed for an average of 16 months before the protocol was modified for the drug conservation group. At baseline, the median and nadir CD4+ counts were 597 per cubic millimeter and 250 per cubic millimeter, respectively, and 71.7% of participants had plasma HIV RNA levels of 400 copies or less per milliliter. Opportunistic disease or death from any cause occurred in 120 participants (3.3 events per 100 person-years) in the drug conservation group and 47 participants (1.3 per 100 person-years) in the viral suppression group (hazard ratio for the drug conservation group vs. the viral suppression group, 2.6; 95% confidence interval [CI], 1.9 to 3.7; P<0.001). Hazard ratios for death from any cause and for major cardiovascular, renal, and hepatic disease were 1.8 (95% CI, 1.2 to 2.9; P=0.007) and 1.7 (95% CI, 1.1 to 2.5; P=0.009), respectively. Adjustment for the latest CD4+ count and HIV RNA level (as time-updated covariates) reduced the hazard ratio for the primary end point from 2.6 to 1.5 (95% CI, 1.0 to 2.1).
CONCLUSIONS:
Episodic antiretroviral therapy guided by the CD4+ count, as used in our study, significantly increased the risk of opportunistic disease or death from any cause, as compared with continuous antiretroviral therapy, largely as a consequence of lowering the CD4+ cell count and increasing the viral load. Episodic antiretroviral therapy does not reduce the risk of adverse events that have been associated with antiretroviral therapy.
2. NA-ACCORD study: Observational cohort study, n=17,000; the lower you let your CD4 drop before you started therapy, the higher your risk of death.
N Engl J Med. 2009 Apr 30;360(18):1815-26.
Effect of early versus deferred antiretroviral therapy for HIV on survival.
METHODS:
We conducted two parallel analyses involving a total of 17,517 asymptomatic patients with HIV infection in the United States and Canada who received medical care during the period from 1996 through 2005. None of the patients had undergone previous antiretroviral therapy. In each group, we stratified the patients according to the CD4+ count (351 to 500 cells per cubic millimeter or >500 cells per cubic millimeter) at the initiation of antiretroviral therapy. In each group, we compared the relative risk of death for patients who initiated therapy when the CD4+ count was above each of the two thresholds of interest (early-therapy group) with that of patients who deferred therapy until the CD4+ count fell below these thresholds (deferred-therapy group).
RESULTS:
In the first analysis, which involved 8362 patients, 2084 (25%) initiated therapy at a CD4+ count of 351 to 500 cells per cubic millimeter, and 6278 (75%) deferred therapy. After adjustment for calendar year, cohort of patients, and demographic and clinical characteristics, among patients in the deferred-therapy group there was an increase in the risk of death of 69%, as compared with that in the early-therapy group (relative risk in the deferred-therapy group, 1.69; 95% confidence interval [CI], 1.26 to 2.26; P<0.001). In the second analysis involving 9155 patients, 2220 (24%) initiated therapy at a CD4+ count of more than 500 cells per cubic millimeter and 6935 (76%) deferred therapy. Among patients in the deferred-therapy group, there was an increase in the risk of death of 94% (relative risk, 1.94; 95% CI, 1.37 to 2.79; P<0.001).
CONCLUSIONS:
The early initiation of antiretroviral therapy before the CD4+ count fell below two prespecified thresholds significantly improved survival, as compared with deferred therapy.
3. HPTN-052 trial: multicountry RCT, n=1700, studying the effect of antiretrovirals on transmission of HIV between serodiscordant couples. Couples who were randomized to the group where the infected partner was treated with antiretrovirals had a 95% reduction in HIV transmission. Out of the 800 or 900 people in couples randomized to treatment, there was only one case of HIV transmission, and that was early on before the person was virally suppressed, meaning that the incidence of HIV transmission from a virally suppressed person was 0%. Let me re-iterate: 0%.
N Engl J Med. 2011 Aug 11;365(6):493-505.
Prevention of HIV-1 infection with early antiretroviral therapy.
METHODS:
In nine countries, we enrolled 1763 couples in which one partner was HIV-1-positive and the other was HIV-1-negative; 54% of the subjects were from Africa, and 50% of infected partners were men. HIV-1-infected subjects with CD4 counts between 350 and 550 cells per cubic millimeter were randomly assigned in a 1:1 ratio to receive antiretroviral therapy either immediately (early therapy) or after a decline in the CD4 count or the onset of HIV-1-related symptoms (delayed therapy). The primary prevention end point was linked HIV-1 transmission in HIV-1-negative partners. The primary clinical end point was the earliest occurrence of pulmonary tuberculosis, severe bacterial infection, a World Health Organization stage 4 event, or death.
RESULTS:
As of February 21, 2011, a total of 39 HIV-1 transmissions were observed (incidence rate, 1.2 per 100 person-years; 95% confidence interval [CI], 0.9 to 1.7); of these, 28 were virologically linked to the infected partner (incidence rate, 0.9 per 100 person-years, 95% CI, 0.6 to 1.3). Of the 28 linked transmissions, only 1 occurred in the early-therapy group (hazard ratio, 0.04; 95% CI, 0.01 to 0.27; P<0.001). Subjects receiving early therapy had fewer treatment end points (hazard ratio, 0.59; 95% CI, 0.40 to 0.88; P=0.01).
CONCLUSIONS:
The early initiation of antiretroviral therapy reduced rates of sexual transmission of HIV-1 and clinical events, indicating both personal and public health benefits from such therapy. (Funded by the National Institute of Allergy and Infectious Diseases and others; HPTN 052 ClinicalTrials.gov number, NCT00074581.).
Truvada = emtricitabine (NRTI) and tenofovir (NRTI)
- Truvada + Efavirenz (NNRTI) = Atripla. (One pill qD, but contains efavirenz and so can make you crazy)
- Truvada + Raltegravir (II) (BID dosing)
- Truvada + Boosted Atazanavir (PI) (i.e. Atazanavir/Ritonavir) (Ataz needs acidic environment, CI in people on PPIs)
- Truvada + Boosted Darunavir (PI) (i.e. Darunavir/Ritonavir) (Daru can set off sulfa allergies)
5. Side effects of anti-retrovirals: NRTI
- All can cause lactic acidosis, nausea/vomiting, Hep B flare if the drug is stopped
- AZT/zidovudine: black-box warning for BM suppression: aplastic anemia/neutropenia
- d4t/ddI (ddI = don't do it): pancreatitis, neuropathy, lactic acidosis, lipodystrophy
- Tenofovir: increased creatinine, proteinuria. Incidence of renal insufficiency ~0.5%. Can cause fanconi's syndrome.
- Abacavir: can cause abacavir hypersensitivity syndrome, which starts as flu-like symptoms, with GI symptoms, and then a sepsis-like picture with shock vitals. One can screen for likelihood of this happening with HLA B*5701 testing (people with a certain SNP there are much more likely to get this).
6. Side effects of anti-retrovirals: NNRTI
- Efavirenz: nightmares, hallucinations, feeling hung over, dissociative symptoms. 23% have CNS side effects, usually goes away. This drug is teratogenic.
- Nevirapine: hepatic necrosis, increased risk with increased CD4 counts.
7. Side effects of anti-retrovirals: Protease inhibitors
- All cause nausea, vomiting, diarrhea, dyslipidemia
- Mostly metabolized through CYP 3A4 so mad drug interactions
- Darunavir: has sulfa moiety, avoid in people with sulfa allergy. Well tolerated.
- Ritonavir: bad nausea/vomiting/diarrhea
- Atazanavir: indirect hyperbilirubinemia, like Gilbert's syndrome (conjugation enzyme defect). Benign. Resolves if you stop the drug.
8. Drug interactions:
- Significant interactions with statins, which are also CYP3A4 metabolized.
- 24-hour area under the curve for simvastatin increased by more than 3,000% when it was coadministered with saquinavir/ritonavir. {source}
- 24-hour area under the curve for atorvastatin increased more than 800% and the maximum concentration (Cmax) increased more than 760% when coadministered with tipranavir/ritonavir {source}
- Other interactions: benzodiazepines (also CYP 3A4), ergot-derived agents, and agents known to be CYP affectors (rifampin, st.John's wort, etc)
9. New HAART agents:
- Rilpivirine = NNRTI, replaces efavirenz in atripla to make a new combo pill called Complera. Hopefully just as good as atripla but doesn't make you as crazy. Not for people with high viral loads
- Stribild, which is a quad pill. Truvada + Elvitegravir and cobicistat (booster). Lots of GI side effects.
- Dolutegravir, which is a nice integrase inhibitor with qD dosing (better than raltegravir's BID dosing), and while raltegravir has a low barrier to resistance, Dolu is highly potent and seems mutation resistant.
10. Pre-exposure prophylaxis: it works!
N Engl J Med. 2012 Aug 2;367(5):399-410. doi: 10.1056/NEJMoa1108524. Epub 2012 Jul 11.
Antiretroviral prophylaxis for HIV prevention in heterosexual men and women.
METHODS:
We conducted a randomized trial of oral antiretroviral therapy for use as preexposure prophylaxis among HIV-1-serodiscordant heterosexual couples from Kenya and Uganda. The HIV-1-seronegative partner in each couple was randomly assigned to one of three study regimens--once-daily tenofovir (TDF), combination tenofovir-emtricitabine (TDF-FTC), or matching placebo--and followed monthly for up to 36 months. At enrollment, the HIV-1-seropositive partners were not eligible for antiretroviral therapy, according to national guidelines. All couples received standard HIV-1 treatment and prevention services.
RESULTS:
We enrolled 4758 couples, of whom 4747 were followed: 1584 randomly assigned to TDF, 1579 to TDF-FTC, and 1584 to placebo. For 62% of the couples followed, the HIV-1-seronegative partner was male. Among HIV-1-seropositive participants, the median CD4 count was 495 cells per cubic millimeter (interquartile range, 375 to 662). A total of 82 HIV-1 infections occurred in seronegative participants during the study, 17 in the TDF group (incidence, 0.65 per 100 person-years), 13 in the TDF-FTC group (incidence, 0.50 per 100 person-years), and 52 in the placebo group(incidence, 1.99 per 100 person-years), indicating a relative reduction of 67% in the incidence of HIV-1 with TDF (95% confidence interval [CI], 44 to 81; P<0.001) and of 75% with TDF-FTC (95% CI, 55 to 87; P<0.001). Protective effects of TDF-FTC and TDF alone against HIV-1 were not significantly different (P=0.23), and both study medications significantly reduced the HIV-1 incidence among both men and women. The rate of serious adverse events was similar across the study groups. Eight participants receiving active treatment were found to have been infected with HIV-1 at baseline, and among these eight, antiretroviral resistance developed in two during the study.
CONCLUSIONS:
Oral TDF and TDF-FTC both protect against HIV-1 infection in heterosexual men and women.
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