Effect Of Early Antiretroviral Therapy Research Articles

What Level of Risk Compensation Would Offset the Preventive Effect of Early Antiretroviral Therapy? Simulations From the TEMPRANO Trial.

Whether risk compensation could offset the preventive effect of early initiation of antiretroviral therapy (ART) on human immunodeficiency virus (HIV) transmission remains unknown. Using virological and behavioral data collected 12 months after inclusion in the TEMPRANO randomized trial of early ART (Abidjan, Côte d'Ivoire, 2009-2012), we estimated the risk of HIV transmission and compared it between the intervention (early ART; n=490) and control (deferred ART; n=467) groups. We then simulated increases in various sexual risk behaviors in the intervention group and estimated the resulting preventive effect. On the basis of reported values of sexual behaviors, we estimated that early ART had an 89% (95% confidence interval: 81, 95) preventive effect on the cumulative risk of HIV transmission over a 1-month period. This preventive effect remained significant for a wide range of parameter combinations and was offset (i.e., nonsignificant) only for dramatic increases in different sexual behaviors simulated simultaneously. For example, when considering a 2-fold increase in serodiscordance and the frequency of sexual intercourse together with a 33% decrease in condom use, the resulting preventive effect was 47% (95% confidence interval: -3, 74). An important reduction of HIV transmission may thus be expected from the scale-up of early ART, even in the context of behavioral change.

Impact of antiretroviral therapy (ART) timing on chronic immune activation/inflammation and end-organ damage.

The purpose of this review was to summarize recent studies on the effect of early antiretroviral therapy (ART) in HIV-infected patients on markers of immune activation/inflammation, viral persistence and serious non-AIDS events. Early ART, initiated within days to months of HIV infection, was associated with marked reduction in T-cell activation often reaching levels observed in HIV-uninfected individuals. However, the impact of early ART on markers of innate immune activation, microbial translocation and inflammation/coagulation was less clear. Early ART has also been associated with a significant reduction in the frequency of latently infected cells, which was greater if ART was initiated within days to weeks rather than months following infection. However, few studies have evaluated the relationship between immune activation and viral reservoirs, specifically following early ART. Early ART may potentially reduce serious non-AIDS events and associated mortality, but most of these studies have extrapolated from changes in surrogate markers, such as CD4 : CD8 ratio. Early ART was associated with beneficial effects on multiple markers of immune activation, inflammation and viral persistence. Longer term prospective studies are still needed to determine whether early ART translates to a significant reduction in serious non-AIDS events and mortality.

Effect of Early Antiretroviral Therapy on Sexual Behaviors and HIV-1 Transmission Risk Among Adults With Diverse Heterosexual Partnership Statuses in Côte d'Ivoire

Background. The effect of early initiation of antiretroviral therapy (ART; ie, at CD4+ T-cell counts >350 cells/mm3) on sexual behaviors and human immunodeficiency virus type 1 (HIV) transmission risk has not been documented in populations other than HIV-serodiscordant couples in stable relationships.Methods. On the basis of data from a behavioral study nested in a randomized, controlled trial (Temprano-ANRS12136) of early ART, we compared proportions of risky sex (ie, unprotected sex with a partner of negative/unknown HIV status) reported 12 months after inclusion between participants randomly assigned to initiate ART immediately (hereafter, “early ART”) or according to ongoing World Health Organization criteria. Group-specific HIV transmission rates were estimated on the basis of sexual behaviors and viral load–specific per-act HIV transmission probabilities. The ratio of transmission rates was computed to estimate the protective effect of early ART.Results. Among 957 participants (baseline median CD4+ T-cell count, 478 cells/mm3), 46.0% reported sexual activity in the past month; of these 46.0%, sexual activity for 41.5% involved noncohabiting partners. The proportion of subjects who engaged in risky sex was 10.0% in the early ART group, compared with 12.8% in the standard ART group (P = .17). After accounting for sexual behaviors and viral load, we estimated that the protective effect of early ART was 90% (95% confidence interval, 81%–95%).Conclusion. Twelve months after inclusion, patients in the early and standard ART groups reported similar sexual behaviors. Early ART decreased the estimated risk of HIV transmission by 90%, suggesting a major prevention benefit among seronegative sex partners in stable or casual relationships with seropositive individuals.

Effect of early anti-retroviral therapy on the pathogenic changes in mucosal tissues of SIV infected rhesus macaques

BackgroundThe gastrointestinal tissue plays an important role in the pathogenesis of HIV/SIV infection and serves as a viral reservoir in infected individuals under antiretroviral therapy (ART). However, the effect of ART administration in the very early stage of infection on HIV/SIV replication and pathogenesis in gastrointestinal tissue has not been fully studied. In this current study, rhesus monkeys infected with SIV were treated with ART starting at day 7 post-infection. The effect of early ART on SIV replication and infection-related pathogenic changes in mucosal tissues of the infected monkeys was examined.MethodsNuclear acids were extracted from snap frozen ileum and colon tissues and mesentery lymph nodes from SIV infected monkeys with or without ART. SIV RNA and DNA loads as well as levels of CD3, CD4 and cytokine mRNA were measured by PCR and RT PCR from the isolated nuclear acids. Tissue sections were stained by immuno-fluorescence labeled antibodies for CD3 and CD4.ResultsWithout ART treatment, these monkeys underwent a mild SIV infection with low viral loads and slightly decreased CD4+ T cell counts in peripheral blood. In ART treated monkeys, SIV RNA loads were undetectable in blood with normal CD4+ T cell counts, however, SIV RNA and DNA were detected in the intestinal tissues and mesentery lymph nodes although the levels were lower than those in untreated monkeys. The levels of CD3 and CD4 positive cells in the tissues were similar between the infected untreated monkeys and infected ART treated monkeys based on RT-PCR and immune-fluorescence staining of the tissue sections. Furthermore, compatible levels of IL-6, TNF-a, IL-1b and MyD88 mRNAs were detected in most of intestinal tissues and mesentery lymph nodes of infected ART treated and infected untreated monkeys.ConclusionsThese results suggest that early ART administration could not effectively inhibit SIV replication in intestinal tissues and mesentery lymph nodes and could not reduce the immune activation induced by SIV infection in the intestinal tissues.

Effect of Early Antiretroviral Therapy during Primary HIV-1 Infection on Cell-Associated HIV-1 Dna and Plasma HIV-1 Rna

Early initiation of combination antiretroviral therapy (ART) during primary HIV-1 infection may prevent the establishment of large viral reservoirs, possibly resulting in improved control of plasma viraemia rebound after ART cessation. Levels of cell-associated HIV-1 DNA and plasma HIV-1 RNA were measured longitudinally in 32 acutely and recently infected patients, who started ART ≤120 days after the estimated date of infection, and interrupted ART after 18 months (median) of continuous therapy. Averages of HIV-1 DNA and RNA concentrations present in blood 30-365 days after therapy interruption (median duration 300 days, range 195-358) were compared between patients who started ART ≤60 days after the estimated date of infection (early starters), those who started between 61 and 120 days (later starters), and, for HIV-1 RNA only, with 89 untreated participants of the Swiss HIV Cohort Study with documented seroconversion and longitudinal measurements collected 90-455 days after the first positive HIV test. In early ART starters, average levels of plasma HIV-1 RNA and cell-associated HIV-1 DNA after treatment interruption were 1 log(10) (P=0.008) and 0.4 log(10) (P=0.03) lower compared with later starters. Average post-treatment plasma HIV-1 RNA levels in early starters were significantly lower, respectively, compared with untreated controls (-1.2 log(10); P<0.0004). Early treatment initiation within 2 months after HIV infection compared with later therapy initiation resulted in reduced levels of plasma viraemia and proviral HIV-1 DNA for ≥1 year after subsequent ART cessation. Plasma HIV-1 RNA levels in early starters were also significantly lower than in untreated controls.

Effect of early antiretroviral therapy on the risk of AIDS/death in HIV-infected infants

In the absence of treatment, rapid progression to AIDS occurs in approximately 20% of HIV-1-infected infants over the first year of life. The prognosis of these children has considerably improved with highly active antiretroviral therapy. As data from well resourced countries are lacking, the objective of this collaborative study was to evaluate the impact of early treatment in vertically infected infants. Children born to HIV-infected mothers between 1 September 1996 and 31 December 2004, who were diagnosed with HIV and free of AIDS before 3 months, were eligible. Demographics and pregnancy data, details of antiretroviral therapy, and clinical outcome were collected from 11 European countries. The risk of AIDS or death, by whether or not an infant started treatment before 3 months of age, was estimated by Kaplan-Meier survival analysis and Cox proportional hazards models. Among 210 children, 21 developed AIDS and three died. Baseline characteristics of the 124 infants treated before 3 months were similar to those of the 86 infants treated later. The risk of developing AIDS/death at 1 year was 1.6 and 11.7% in the two groups, respectively (P < 0.001). Deferring treatment was associated with increased risk of progression [crude hazard ratio 5.0; 95% confidence interval (CI) 2.0-12.6; P = 0.001] that persisted after adjusting for cohort in multivariate models (adjusted hazard ratio 3.0; 95% CI 1.2-7.9; P = 0.021). In HIV-1 vertically infected infants, starting antiretroviral therapy before the age of 3 months is associated with a significant reduction in progression to AIDS and death.

Incomplete HIV Type 1 Antibody Evolution and Seroreversion in Acutely Infected Individuals Treated with Early Antiretroviral Therapy

The diagnosis of human immunodeficiency virus type 1 (HIV-1) infection by standard tests relies on the formation of HIV-1-specific antibodies. Early treatment of acute HIV-1 infection may have unique immunologic effects on host cellular and humoral responses. Rare cases of HIV-1 seroreversion have been reported for patients with advanced or rapidly progressive disease. Here, we report seroreversion that occurred in subjects with acute HIV-1 infection who initiated early antiretroviral therapy. A total of 150 patients with symptomatic acute or early onset HIV-1 infection that was treated with antiretroviral therapy were observed prospectively by means of monthly clinical and laboratory evaluation, which included serial HIV enzyme-linked immunosorbent assay and Western blots, until a fully evolved HIV-1 antibody response was documented. Three patients who initiated antiretroviral therapy a mean interval of 8 days (range, 1-16 days) after presentation and were observed for a mean duration of 50.2 months (range, 40.2-55.7 months) did not develop a fully evolved HIV-1 antibody response or demonstrated complete or partial HIV-1 seroreversion, despite maintenance of cytomegalovirus-specific humoral responses. Virologic suppression and seroreversion (complete or partial) occurred a mean duration of 4.1 months (range, 2.3-5.7 months) and 15.5 months (range, 6.7-26.3 months), respectively, after the initiation of therapy. All patients maintained complete virologic suppression while receiving therapy and had an undetectable HIV-1 RNA load at the time of seroreversion. Early antiretroviral therapy associated with durable virologic suppression in acute HIV-1 infection may abrogate the formation or detection of HIV-1-specific antibodies. Ongoing antigenic stimulation may be required to maintain HIV-1-specific humoral responses. Incomplete evolution of the HIV-1 antibody response and/or presence of seroreversion (although infrequently observed) underscore the potential unique immunologic effect of early antiretroviral therapy in patients with primary HIV-1 infection.