Efficacy of initial antiretroviral therapy for HIV-1 infection in adults: a systematic review and meta-analysis of 114 studies with up to 144 weeks' follow-up

Abstract

Background: A comprehensive assessment of initial HIV-1 treatment success may inform study design and treatment guidelines.

Methods: Group-based, systematic review and meta-analysis of initial antiretroviral therapy studies, in adults, of ≥ 48 weeks duration, reported through December 31, 2012. Size-weighted, intention-to-treat efficacy was calculated. Parameters of study design/eligibility, participant and treatment characteristics were abstracted. Multivariable, random effects, linear regression models with backwards, stepwise selection were then used to identify variables associated with efficacy.

Outcome measures: Antiviral efficacy (undetectable plasma viral load) and premature cessation of therapy.

Results: 114 studies were included (216 treatment groups; 40,124 participants; mean CD4 count 248 cells/µL [SD 81]; mean HIV-1 plasma viral load log10 4.9 [SD 0.2]). Mean efficacy across all groups was 60% (SD 16) over a mean 82 weeks' follow-up (SD 38). Efficacy declined over time: 66% (SD 16) at 48 weeks, 60% (SD 16) at 96 weeks, 52% (SD 18) at 144 weeks. The most common reason for treatment cessation was participant decision (11%, SD 6.6). Efficacy was higher with 'Preferred' than 'Alternative' regimens (as defined by 2013 United States antiretroviral guidelines): 75% vs. 65%, respectively, difference 10%; 95%CI 7.6 to 15.4; p<0.001. In 98 groups (45%) reporting efficacy stratified by pre-treatment viral load (< or ≥100,000 copies/mL), efficacy was greater for the lower stratum (70% vs. 62%, respectively, difference 8.4%; 95%CI 6.0 to 10.9; p<0.001). This difference persisted within 'Preferred' regimens. Greatest efficacy was associated with use of tenofovir-emtricitabine (vs. other nucleoside analogue backbones) and integrase strand transfer inhibitors (vs. other third drug classes).

Conclusion: Initial antiretroviral treatments for HIV-1 to date appear to have suboptimal long-term efficacy, but are more effective when commenced at plasma viral loads <100,000 copies/mL. Rising viral load should be considered an indication for starting treatment. Integrase inhibitors offer a treatment advantage (vs. other third drug classes).

Figure 1. PRISMA statement 2009 flow chart.

Diagram depicts each step of the study selection process undertaken in this systematic review and meta-analysis, including the reasons for exclusion.

Figure 2. Efficacy by year of study commencement.

Summary bubble plot displaying the change in weighted intention-to-treat antiviral efficacy of initial antiretroviral therapy by the year included studies were commenced. Each bubble represents an individual treatment group, proportional to size. SD, standard deviation.

Figure 3. Premature cessation of initial antiretroviral therapy by year of study commencement.

(A) Total cessation from all causes; (B) attributed to participant decision – withdrawal from study or lost to follow-up; (C) attributed to adverse events; and (D) due to study-defined virological failure. Studies were included in this analysis if total premature cessation was reported. SD, standard deviation.