Combination antiretroviral therapy (cART) reduces HIV-associated morbidities and mortalities but cannot cure the infection. Given the difficulty of eradicating HIV-1, a functional cure for HIV-infected patients appears to be a more reachable short-term goal. We identified 14 HIV patients (post-treatment controllers [PTCs]) whose viremia remained controlled for several years after the interruption of prolonged cART initiated during the primary infection. Most PTCs lacked the protective HLA B alleles that are overrepresented in spontaneous HIV controllers (HICs); instead, they carried risk-associated HLA alleles that were largely absent among the HICs. Accordingly, the PTCs had poorer CD8+ T cell responses and more severe primary infections than the HICs did. Moreover, the incidence of viral control after the interruption of early antiretroviral therapy was higher among the PTCs than has been reported for spontaneous control. Off therapy, the PTCs were able to maintain and, in some cases, further reduce an extremely low viral reservoir. We found that long-lived HIV-infected CD4+ T cells contributed poorly to the total resting HIV reservoir in the PTCs because of a low rate of infection of naïve T cells and a skewed distribution of resting memory CD4+ T cell subsets. Our results show that early and prolonged cART may allow some individuals with a rather unfavorable background to achieve long-term infection control and may have important implications in the search for a functional HIV cure. There is a renewed scientific interest in developing strategies allowing long-term remission in HIV-1-infected individuals. Very rare (<1%) patients are able to spontaneously control viremia to undetectable levels (HIV controllers, HICs). However, the possibility to translate their mechanisms of control to other patients is uncertain. Starting antiretroviral therapy during primary infection may provide significant benefits to HIV-infected patients (i.e. reduction of viral reservoirs, preservation of immune responses, protection from chronic immune activation). Indeed, we have observed that some HIV-infected patients interrupting a prolonged antiretroviral therapy initiated close to primary infection are able to control viremia afterwards. We present here 14 of such post-treatment controllers (PTCs). We show that PTCs have achieved control of infection through mechanisms that are, at least in part, different from those commonly observed in HICs and that their capacity to control is likely related to early therapeutic intervention. We found that PTCs were able, after therapy interruption, to keep, and in some cases further reduce, a weak viral reservoir. This might be related to the low contribution of long-lived cells to the HIV-reservoir in these patients. Finally, we estimated the probability of maintaining viral control at 24 months post-early treatment interruption to be ∼15%, which is much higher than the one expected for spontaneous control.

The key attributes of CD8+ T cell protective immunity in human immunodeficiency virus (HIV) infection remain unclear. We report that CD8+ T cell responses specific for Gag and, in particular, the immunodominant p24 epitope KK10 correlate with control of HIV-1 replication in human histocompatibility leukocyte antigen (HLA)–B27 patients. To understand further the nature of CD8+ T cell–mediated antiviral efficacy, we performed a comprehensive study of CD8+ T cells specific for the HLA-B27–restricted epitope KK10 in chronic HIV-1 infection based on the use of multiparametric flow cytometry together with molecular clonotypic analysis and viral sequencing. We show that B27-KK10–specific CD8+ T cells are characterized by polyfunctional capabilities, increased clonal turnover, and superior functional avidity. Such attributes are interlinked and constitute the basis for effective control of HIV-1 replication. These data on the features of effective CD8+ T cells in HIV infection may aid in the development of successful T cell vaccines.

The CD4 cell count at which combination antiretroviral therapy should be started is a central, unresolved issue in the care of HIV-1-infected patients. In the absence of randomised trials, we examined this question in prospective cohort studies. We analysed data from 18 cohort studies of patients with HIV. Antiretroviral-naive patients from 15 of these studies were eligible for inclusion if they had started combination antiretroviral therapy (while AIDS-free, with a CD4 cell count less than 550 cells per microL, and with no history of injecting drug use) on or after Jan 1, 1998. We used data from patients followed up in seven of the cohorts in the era before the introduction of combination therapy (1989-95) to estimate distributions of lead times (from the first CD4 cell count measurement in an upper range to the upper threshold of a lower range) and unseen AIDS and death events (occurring before the upper threshold of a lower CD4 cell count range is reached) in the absence of treatment. These estimations were used to impute completed datasets in which lead times and unseen AIDS and death events were added to data for treated patients in deferred therapy groups. We compared the effect of deferred initiation of combination therapy with immediate initiation on rates of AIDS and death, and on death alone, in adjacent CD4 cell count ranges of width 100 cells per microL. Data were obtained for 21 247 patients who were followed up during the era before the introduction of combination therapy and 24 444 patients who were followed up from the start of treatment. Deferring combination therapy until a CD4 cell count of 251-350 cells per microL was associated with higher rates of AIDS and death than starting therapy in the range 351-450 cells per microL (hazard ratio [HR] 1.28, 95% CI 1.04-1.57). The adverse effect of deferring treatment increased with decreasing CD4 cell count threshold. Deferred initiation of combination therapy was also associated with higher mortality rates, although effects on mortality were less marked than effects on AIDS and death (HR 1.13, 0.80-1.60, for deferred initiation of treatment at CD4 cell count 251-350 cells per microL compared with initiation at 351-450 cells per microL). Our results suggest that 350 cells per microL should be the minimum threshold for initiation of antiretroviral therapy, and should help to guide physicians and patients in deciding when to start treatment.

Background: In the current context of dyslipidaema, hyperglycaema and lipodystrophia observed among HIV-seropositive subjects, it is important to study the risk of myocardial infarction (MI) in this population. The French Hospital Database on HIV, which includes a large number of seropositive subjects followed for substantial periods, offers the opportunity to analyse the impact of protease inhibitors (PI) on the risk of MI among men. Methods: Cox model was used to study the risk factors of MI occurrence. Standardized morbidity ratios (SMR) in men exposed to PI were calculated with data from the French general male population (FGMP) of the same age as reference. Results: Between 1996 and 1999, MI was diagnosed in 60 men among 88 029 person-years (PY), including 49 cases among men exposed to PI. In the Cox model, exposure to PI was associated with a higher risk of MI [relative hazard (RH), 2.56; 95% confidence interval (CI), 1.03–6.34]. The expected incidence in the FGMP was 10.8/10 000 PY. The SMR relative to the FGMP was 0.8 (95% CI, 0.5–1.3) for men exposed to PI for < 18 months (G1), 1.5 (95% CI, 0.8–2.5) for men exposed for 18–29 months (G2) and 2.9 (95% CI, 1.5–5.0) for men exposed for ≥ 30 months (G3). With G1 as reference, the SMR was 1.9 (95% CI, 1.0–3.1) for G2 and 3.6 (95% CI, 1.8–6.2) for G3. Conclusion: Our results point to a duration-related effect relationship between PI and MI, with a higher MI incidence rate among men exposed to PI for 18 months or more.