- The combination of 2 large studies (SMART and START, total N = 10,156) confirms the benefits of early and continuous HIV treatment.
- The authors demonstrate protective effects across a range of outcomes, including all-cause mortality, serious non-AIDS events, cardiovascular disease events, and cancer incidence (combined as both AIDS and non-AIDS cancers) across subgroups of age, sexes, the range of CD4 counts at enrollment, and among residents of high- and low-income countries.
- Although prior studies have identified the benefits of early and persistent antiretroviral therapy (ART), these data offer an important opportunity to calculate the magnitude of the individual health benefits of early and lifelong antiretroviral treatment.
The Strategies for Management of Antiretroviral Therapy (SMART) and Strategic Timing of AntiRetroviral Treatment (START) studies were important to assess the effect of ART treatment strategies on the risk of AIDS and non-AIDS related events. They established the immediate/continuous ART as the standard of care for (HIV)-positive persons.
To compare the incidence of cardiovascular disease (CVD) and cancer among patients, the authors conducted a pooled analysis of the 2 trials in which they compared the drug conservation arm (DC) in SMART and the deferred ART arm in START with the viral suppression arm (VS) in SMART and the immediate ART arm in START. The hypothesis was that treatment hazard ratios (HRs) would be similar in each study and that the pooled analysis would better quantify the relative difference between deferred/intermittent ART and immediate/continuous ART on the risk of AIDS- and non-AIDS related events.
Endpoints were AIDS, serious non-AIDS events (SNA), cardiovascular disease (CVD), cancer, and death.
Among 10,156 participants, there were 124 AIDS, 247 SNA, 117 cancers, 103 CVD, and 120 deaths. Interventions in each trial led to similar differences in CD4 count and viral suppression. Pooled HRs of deferred/intermittent ART versus immediate/continuous ART were for AIDS 3.63 (2.37–5.56); SNA 1.62 (1.25–2.09); CVD 1.59 (1.07–2.37); cancer 1.93 (1.32–2.83); and death 1.80 (1.24–2.61). Absolute risk differences between treatment groups were greater in SMART than START. Pooled HRs were similar across subgroups. Treatment group differences in CD4 count and viral suppression were similar in SMART and START.
Likely as a consequence, relative differences in risk of AIDS and SNA between immediate/continuous ART and deferred/intermittent ART were similar.
As the authors discuss, differences in cardioprotective effects might have been due to unique participant risk profiles, or challenges in detecting cardiovascular disease events, particularly in resource-limited settings, where an important minority of START study subjects were based.
The investigators found a statistically significant difference in protective effects of ART against cancer, with a greater benefit in the START versus the SMART therapy groups (HR 3.10 for continuous versus intermittent ART, compared with 1.37 for immediate versus deferred ART, p-value for interaction term .046). A major contributor to the benefit in START was through prevention of Kaposi sarcoma and non-Hodgkin lymphoma, which were reported in 21 and 4 participants in the delayed versus immediate treatment groups, respectively. This result was particularly meaningful in light of recent data suggesting a persistently high risk of both AIDS and non-AIDS cancers among individuals on long-term ART.