Effectiveness of ART for Reducing HIV Transmission
A good-quality systematic review
(16) evaluated the association between use of ART and risk for HIV transmission from HIV-positive persons to uninfected sexual partners. It included 1 good-quality randomized, controlled trial
(17) and 7 observational studies
(18–24) (
Appendix Table 2).
The randomized, controlled trial (HIV Prevention Trials Network study 052) compared early ART initiation (started at enrollment) with delayed therapy (after CD4 count decreased to <0.250 × 10
9 cells/L or onset of symptoms) in HIV-infected patients with baseline CD4 counts of 0.350 to 0.550 × 10
9 cells/L and an HIV-negative partner
(17). Fifty-four percent of the 1763 couples were from Africa, with the remainder from Brazil, India, Thailand, and the United States. Ninety-seven percent of couples were heterosexual, and 94% were married. All couples received condoms and counseling. The trial was designed to follow patients for 5 years but was terminated early after meeting prespecified criteria for efficacy in interim analyses. At a median follow-up of 1.7 years, risk for seroconversion in HIV-negative partners was much lower in the early-therapy group than in the delayed-therapy group (0.3 vs. 2.2 per 100 person-years; hazard ratio [HR], 0.11 [95% CI, 0.04 to 0.32]). When restricted to cases that were genomically linked to the HIV-infected patient enrolled in the trial, the HR was 0.04 (CI, 0.01 to 0.27).
Results of the 7 observational studies
(18–24) included in the systematic review
(16) were consistent with the randomized trial
(17). Sample sizes ranged from 93 to 3408 couples, with typical follow-up between 1 and 3 years (range, 3 months to 9 years). All were cohort studies of HIV-serodiscordant, heterosexual couples from Africa, Italy, Spain, Brazil, or China. Six studies
(18–22, 24) were rated fair-quality and the seventh
(23) was a conference abstract. Three studies
(19, 21, 24) adjusted for possible confounding variables, such as age, sex, condom use, or frequency of sexual intercourse.
Six
(18–23) of the 7 observational studies reported that persons receiving ART had a lower risk for HIV transmission than untreated persons, for a pooled HR of 0.34 (CI, 0.13 to 0.92;
I 2 = 73%)
(16). Exclusion of 1 study with inadequate person-time data
(24) and 1 older study that included persons treated with monotherapy
(21) resulted in a pooled HR of 0.16 (CI, 0.07 to 0.35) and eliminated statistical heterogeneity (
I 2 = 0%). The treatment effect was also more pronounced when the analysis was restricted to couples in which the HIV-infected person had a CD4 count less than 0.200 × 10
9 cells/L (pooled HR, 0.06 [CI, 0.01 to 0.54])
(18–20, 22).
Effectiveness of Initiating ART at Different CD4 Cell Count Thresholds on Clinical Outcomes
The previous USPSTF review included good-quality randomized, controlled trials
(27–29) and observational studies
(30–37) that consistently found a lower risk for AIDS events and death with ART than with placebo or less-intensive regimens in patients with CD4 counts less than 0.200 × 10
9 cells/L. Evidence showing benefits of starting ART at higher CD4 cell counts was limited. Although a Swiss cohort study
(38) found that starting ART at CD4 counts greater than 0.350 × 10
9 cells/L was associated with a lower risk for death and progression to AIDS than starting at less than 0.350 × 10
9 cells/L, 3 U.S. cohort studies
(35–37) found no difference in risk between starting ART at CD4 counts between 0.350 and 0.500 × 10
9 cells/L versus delaying until CD4 counts were between 0.200 and 0.350 × 10
9 cells/L.
Two good-quality randomized trials
(17, 39) published since the previous USPSTF review and 1 subgroup analysis
(40) from another randomized trial evaluated the effects of initiating ART at different CD4 cell count thresholds (
Table 1). Five observational studies (reported in 7 publications)
(41–45, 48, 49), each of which combined data from 12 to 23 U.S., European, and Australian cohorts (ranging from 9000 to >60 000 participants and 2- to 5-year follow-up, with substantial overlap in the cohorts included in the studies), also evaluated the effects of starting ART at different CD4 cell count thresholds (
Table 1). All of the observational studies were rated fair-quality. None reported blinding of outcome assessors or persons analyzing data, and attrition rates were often not reported or were unclear. Although all studies adjusted for confounders, most provided insufficient information to determine baseline comparability of patients starting or not starting ART at different CD4 cell count strata.
A retrospective subgroup analysis of 477 patients in the SMART (Strategies for Management of Antiretroviral Therapy) randomized trial who were treatment-naive or had stopped therapy for at least 6 months found that ART initiation at CD4 counts less than 0.250 × 10
9 cells/L was associated with a higher risk for death or AIDS events than initiation at counts greater than 0.350 × 10
9 cells/L after a mean of 18 months (HR, 5.3 [CI, 1.3 to 9.6])
(40). The SMART trial was done in 33 primarily non–resource-poor countries. The HIV Prevention Trials Network study 052, conducted in 1763 patients from primarily resource-poor countries, also found initiation at CD4 counts less than 0.250 × 10
9 cells/L associated with a higher risk for death or AIDS events than initiation at counts greater than 0.350 × 10
9 cells/L after a median of 1.7 years (HR, 1.7 [CI, 1.1 to 2.5])
(17). Another randomized trial
(39) with 816 participants found that ART initiation at CD4 counts less than 0.200 × 10
9 cells/L was associated with higher mortality than initiation at 0.201 to 0.350 × 10
9 cells/L (HR, 4.0 [CI, 1.6 to 9.8];
P = 0.001), but this trial was conducted in Haiti and evaluated lower CD4 count cutoffs for treatment than those in the United States.
Four observational studies
(42–45, 48) consistently found that ART initiation at CD4 counts between 0.350 and 0.500 × 10
9 cells/L was associated with a lower risk for death than deferred or no ART. One other study
(49) found a reduction in risk that was not statistically significant. The HIV-CAUSAL (HIV Cohorts Analyzed Using Structural Approaches to Longitudinal data) collaboration
(43), the largest study in our review (62 760 participants from 12 cohorts), found that ART initiation at CD4 counts of 0.350 to 0.500 × 10
9 cells/L was associated with a lower risk for death than noninitiation at these counts after 3.3 years of follow-up (adjusted HR, 0.55 [CI, 0.41 to 0.74]). Similarly, the NA-ACCORD (North American AIDS Cohort Collaboration on Research and Design)
(44), with 17 517 participants from 22 cohorts, found that ART initiation at CD4 counts of 0.351 to 0.500 × 10
9 cells/L was associated with a lower risk for death than deferred treatment at these CD4 cell counts after 3 years of follow-up (adjusted RR, 0.61 [CI, 0.46 to 0.83]). In 2 studies
(45, 49), ART initiation at CD4 counts greater than 0.350 × 10
9 cells/L was also associated with a lower risk for the combined outcome of AIDS-defining events and death than deferred or no ART initiation. One other study
(48) found a reduction in risk that was not statistically significant.
Studies on ART initiation at CD4 counts greater than 0.500 × 10
9 cells/L were less consistent. The NA-ACCORD cohort study
(44) found that ART initiation at CD4 counts greater than 0.500 × 10
9 cells/L was associated with lower mortality than deferred therapy (adjusted RR, 0.54 [CI, 0.35 to 0.83]) and the HIV-CAUSAL collaboration
(43) found a lower mortality risk that was not statistically significant (adjusted HR, 0.77 [CI, 0.58 to 1.0]). Another analysis from the HIV-CAUSAL Collaboration
(42) that directly compared ART initiation at CD4 counts greater than 0.500 × 10
9 cells/L with initiation at greater than 0.350 × 10
9 cells/L found no difference in mortality (HR, 0.99 [CI, 0.89 to 1.2]). Two other large cohort studies found that ART initiation at CD4 counts greater than 0.500 × 10
9 cells/L was associated with no difference in risk for death when compared with noninitiation
(48) or slightly delayed initiation
(49). In all 4 studies, absolute mortality rates were low (2% to 5%) in patients with CD4 counts greater than 0.500 × 10
9 cells/L.
Results were also mixed for the combined outcome of death plus AIDS-defining events (not reported in the NA-ACCORD study
[44]). The HIV-CAUSAL collaboration
(42) found that ART initiation at CD4 counts greater than 0.500 × 10
9 cells/L was associated with a lower risk for AIDS-defining events or death than initiation at greater than 0.350 × 10
9 cells/L (HR, 0.72 [CI, 0.64 to 0.81]). Two other studies
(48, 49) found no clear association between starting or not starting ART at CD4 counts greater than 0.500 × 10
9 cells/L and risk for AIDS-defining events or death.
Longer-Term Harms Associated With ART
The 2005 USPSTF review included results from the large, ongoing DAD (Data Collection on Adverse Events of Anti-HIV Drugs) study (23 468 participants), which found that increased risk for myocardial infarction was associated with longer exposure to ART (adjusted RR, 1.3 per year of exposure [CI, 1.1 to 1.4 per year of exposure]), although absolute event rates were low (3.5 per 1000 person-years)
(50).
Subsequent analyses from the DAD study
(51–53) and 3 other cohort studies
(54–56) reported cardiovascular harms associated with ART through 4 to 6 years of follow-up (
Appendix Table 3). Sample sizes ranged from 2952 to more than 30 000 persons. All of the studies were rated good-quality except 1, which was rated fair-quality because of lack of detail about baseline patient characteristics and blinding of study personnel
(54). All studies adjusted for multiple confounders.
Like the earlier DAD results, the most recent analysis found that longer exposure to indinavir alone (adjusted RR, 1.1 per year of exposure [CI, 1.1 to 1.2 per year of exposure]), ritonavir-boosted indinavir (adjusted RR, 1.2 per year of exposure [CI, 1.1 to 1.3 per year of exposure]), and ritonavir-boosted lopinavir (adjusted RR, 1.1 per year of exposure [CI, 1.0 to 1.2 per year of exposure]) were each associated with a slightly higher risk for myocardial infarction than nonuse
(53). No other protease inhibitor was associated with increased myocardial risk.
Evidence on the association between the nucleoside reverse transcriptase inhibitor abacavir and risk for myocardial infarction is mixed. Although 2 studies
(53, 55) found that abacavir was associated with increased risk (adjusted RRs, 1.7 and 2.0), 2 others
(54, 56) found no association (adjusted HRs, 0.6 and 1.2).
The DAD study also found that recent didanosine use was associated with increased myocardial infarction risk (adjusted RR, 1.4 [CI, 1.1 to 1.8]), but found no association when analyses were based on cumulative didanosine exposure
(53). No association was found between use of other nucleoside reverse transcriptase inhibitors or the nonnucleoside reverse transcriptase inhibitors nevirapine or efavirenz and increased risk for cardiovascular events
(53).
Comments
0 Comments