Timing of initiation of anti-retroviral therapy predicts post-treatment control of SIV replication.

One approach to 'functional cure' of HIV infection is to induce durable control of HIV replication after the interruption of antiretroviral therapy (ART). However, the major factors that determine the viral 'setpoint' level after treatment interruption are not well understood. Here we combine data on ART interruption following SIV infection for 124 total animals from 10 independent studies across 3 institutional cohorts to understand the dynamics and predictors of post-treatment viral control. We find that the timing of treatment initiation is an important determinant of both the peak and early setpoint viral levels after treatment interruption. During the first 3 weeks of infection, every day of delay in treatment initiation is associated with a 0.22 log₁₀ copies/ml decrease in post-rebound peak and setpoint viral levels. However, delay in initiation of ART beyond 3 weeks of infection is associated with higher post-rebound setpoint viral levels. For animals treated beyond 3 weeks post-infection, viral load at ART initiation was the primary predictor of post-rebound setpoint viral levels. Potential alternative predictors of post-rebound setpoint viral loads including cell-associated DNA or RNA, time from treatment interruption to rebound, and pre-interruption CD8+ T cell responses were also examined in the studies where these data were available. This analysis suggests that optimal timing of treatment initiation may be an important determinant of post-treatment control of HIV. Author summary: HIV infection can be effectively treated with antiretroviral therapy. However, the virus persists in a latent form despite treatment, and 'rebounds' to high levels if treatment is stopped. A number of approaches are now being investigated that might reduce the level of viral rebound following treatment interruption. However, little is known about how variation in infection history (e.g., timing of treatment initiation) influences rebound and may bias observed effects of trial treatments. Here, we aggregated data across multiple studies of SIV infection (a non-human primate model of HIV) to investigate what factors determined the level of viral rebound after treatment interruption. We found that the time from infection to when antiretroviral therapy was initiated was a major factor influencing average viral levels in the first months post treatment. Over the first three weeks of SIV infection, delaying treatment reduced levels of viral rebound when treatment was stopped. This is assumed to occur because increased exposure to the virus induces a more potent immune response. However, after three weeks, later initiation of antiretroviral therapy was associated with higher SIV levels after stopping treatment. Future work is needed to investigate whether the same patterns of viral rebound are seen in HIV infection. [ABSTRACT FROM AUTHOR]