Objective-To estimate the effect of combined antiretroviral therapy (cART) on mortality among HIV-infected individuals after appropriate adjustment for time-varying confounding by indication.Design-A collaboration of 12 prospective cohort studies from Europe and the United States (the HIV-CAUSAL Collaboration) that includes 62,760 HIV-infected, therapy-naïve individuals followed for an average of 3.3 years. Inverse probability weighting of marginal structural models was used to adjust for measured confounding by indication. Conclusions-We estimated that cART halved the average mortality rate in HIV-infected individuals. The mortality reduction was greater in those with worse prognosis at the start of follow-up. Results

Combination antiretroviral therapy (cART) greatly improves survival and quality of life of HIV-1-infected patients; however, cART must be continued indefinitely to prevent viral rebound and associated disease progression. Inducing HIV-1-specific immune responses with a therapeutic immunization has been proposed to control viral replication after discontinuation of cART as an alternative to "cART for life." We report safety, tolerability, and immunogenicity results associated with a control of viral replication for a therapeutic vaccine using autologous monocyte-derived dendritic cells (MD-DCs) pulsed with autologous heat-inactivated whole HIV. Patients on cART with CD4(+) >450 cells/mm(3) were randomized to receive three immunizations with MD-DCs or with nonpulsed MD-DCs. Vaccination was feasible, safe, and well tolerated and shifted the virus/host balance. At weeks 12 and 24 after cART interruption, a decrease of plasma viral load setpoint ≥1 log was observed in 12 of 22 (55%) versus 1 of 11 (9%) and in 7 of 20 (35%) versus 0 of 10 (0%) patients in the DC-HIV-1 and DC-control groups, respectively. This significant decrease in plasma viral load observed in immunized recipients was associated with a consistent increase in HIV-1-specific T cell responses. These data suggest that HIV-1-specific immune responses elicited by therapeutic DC vaccines could significantly change plasma viral load setpoint after cART interruption in chronic HIV-1-infected patients treated in early stages. This proof of concept supports further investigation of new candidates and/or new optimized strategies of vaccination with the final objective of obtaining a functional cure as an alternative to cART for life.

Potent antiretroviral therapy (ART) suppresses HIV-1 viral replication and results in decreased morbidity and mortality. However, prolonged treatment is associated with drug-induced toxicity, emergence of drug-resistant viral strains, and financial constraints. Structured therapeutic interruptions (STIs) have been proposed as a strategy that could boost HIV-specific immunity, through controlled exposure to autologous virus over limited time periods, and subsequently control viral replication in the absence of ART. Here, we analyzed the impact of repeated STIs on virological and immunological parameters in a large prospective STI study. We show that: (i) the plateau virus load (VL) reached after STIs correlated with pretreatment VL, the amount of viral recrudescence during the treatment interruptions, and the off-treatment viral rebound rate; (ii) the magnitude and the breadth of the HIV-specific CD8 ؉ T lymphocyte response, despite marked interpatient variability, increased overall with STI. However, the quantity and quality of the post-STI response was comparable to the response observed before any therapy; (iii) individuals with strong and broad HIVspecific CD8 ؉ T lymphocyte responses at baseline retained these characteristics during and after STI; (iv) the increase in HIV-specific CD8 ؉ T lymphocyte frequencies induced by STI was not correlated with decreased viral set point after STI; and (v) HIV-specific CD4 ؉ T lymphocyte responses increased with STI, but were subsequently maintained only in patients with low pretreatment and plateau VLs. Overall, these data indicate that STI-induced quantitative boosting of HIV-specific cellular immunity was not associated with substantial change in viral replication and that STI was largely restoring pretherapy CD8 ؉ T cell responses in patients with established infection.