Showing papers by "Joseph J. Eron published in 2011"

Prevention of HIV-1 Infection with Early Antiretroviral Therapy

Abstract: Background Antiretroviral therapy that reduces viral replication could limit the transmission of human immunodeficiency virus type 1 (HIV-1) in serodiscordant couples. Methods In nine countries, we...

Recurrent Signature Patterns in HIV-1 B Clade Envelope Glycoproteins Associated with either Early or Chronic Infections

Abstract: Here we have identified HIV-1 B clade Envelope (Env) amino acid signatures from early in infection that may be favored at transmission, as well as patterns of recurrent mutation in chronic infection that may reflect common pathways of immune evasion. To accomplish this, we compared thousands of sequences derived by single genome amplification from several hundred individuals that were sampled either early in infection or were chronically infected. Samples were divided at the outset into hypothesis-forming and validation sets, and we used phylogenetically corrected statistical strategies to identify signatures, systematically scanning all of Env. Signatures included single amino acids, glycosylation motifs, and multi-site patterns based on functional or structural groupings of amino acids. We identified signatures near the CCR5 co-receptor-binding region, near the CD4 binding site, and in the signal peptide and cytoplasmic domain, which may influence Env expression and processing. Two signatures patterns associated with transmission were particularly interesting. The first was the most statistically robust signature, located in position 12 in the signal peptide. The second was the loss of an N-linked glycosylation site at positions 413–415; the presence of this site has been recently found to be associated with escape from potent and broad neutralizing antibodies, consistent with enabling a common pathway for immune escape during chronic infection. Its recurrent loss in early infection suggests it may impact fitness at the time of transmission or during early viral expansion. The signature patterns we identified implicate Env expression levels in selection at viral transmission or in early expansion, and suggest that immune evasion patterns that recur in many individuals during chronic infection when antibodies are present can be selected against when the infection is being established prior to the adaptive immune response.

Timing of HAART initiation and clinical outcomes in human immunodeficiency virus type 1 seroconverters

Abstract: BACKGROUND To estimate the clinical benefit of highly active antiretroviral therapy (HAART) initiation vs deferral in a given month in patients with CD4 cell counts less than 800/μL. METHODS In this observational cohort study of human immunodeficiency virus type 1 seroconverters from CASCADE (Concerted Action on SeroConversion to AIDS and Death in Europe), we constructed monthly sequential nested subcohorts between January 1996 and May 2009, including all eligible HAART-naive, AIDS-free individuals with a CD4 cell count less than 800/μL. The primary outcome was time to AIDS or death in those who initiated HAART in the baseline month compared with those who did not, pooled across subcohorts and stratified by CD4 cell count. Using inverse probability-of-treatment weighted survival curves and Cox proportional hazards regression models, we estimated the absolute and relative effects of treatment with robust 95% confidence intervals (CIs). RESULTS Of 9455 patients with 52,268 person-years of follow-up, 812 (8.6%) developed AIDS and 544 (5.8%) died. In CD4 cell count strata of 200 to 349, 350 to 499, and 500 to 799/μL, HAART initiation was associated with adjusted hazard ratios (95% CIs) for AIDS/death of 0.59 (0.43-0.81), 0.75 (0.49-1.14), and 1.10 (0.67-1.79), respectively. In the analysis of all-cause mortality, HAART initiation was associated with adjusted hazard ratios (95% CIs) of 0.71 (0.44-1.15), 0.51 (0.33-0.80), and 1.02 (0.49-2.12), respectively. Numbers needed to treat (95% CIs) to prevent 1 AIDS event or death within 3 years were 21 (14-38) and 34 (20-115) in CD4 cell count strata of 200 to 349 and 350 to 499/μL, respectively. CONCLUSION Compared with deferring in a given month, HAART initiation at CD4 cell counts less than 500/μL (but not 500-799/μL) was associated with slower disease progression.

Antiretroviral Drug Resistance in HIV-1–Infected Patients Experiencing Persistent Low-Level Viremia During First-Line Therapy

Abstract: Population sequencing was performed for persons identified with persistent low-level viremia in 2 clinical trials. Persistent low-level viremia (defined as plasma HIV-1 RNA level >50 and <1000 copies/mL in at least 2 determinations over a 24-week period, after at least 24 weeks of antiretroviral therapy) was observed in 65 (5.6%) of 1158 patients at risk. New resistance mutations were detected during persistent low-level viremia in 37% of the 54 evaluable cases. The most common mutations were M184I/V (14 cases), K103N (9), and M230L (3). Detection of new mutations was associated with higher HIV-1 RNA levels during persistent low-level viremia.

Pre-Exposure Prophylaxis and Antiretroviral Resistance: HIV Prevention at a Cost?

Abstract: Pre-exposure prophylaxis (PrEP), the use of antiretrovirals (ARVs) by human immunodeficiency virus (HIV)‐ uninfected individuals to prevent acquisition of the virus during high-risk sexual encounters, enjoyed its first 2 major successes with the Centre for the AIDS Programme of Research in South Africa (CAPRISA) 004 and the Pre-Exposure Prophylaxis Initiative (iPrEx) These successes were buoyed by additional positive results from the TDF2 and Partners PrEP trials Although no seroconverters in either arm of CAPRISA developed resistance to tenofovir, 2 participants in iPrEx with undetected, seronegative acute HIV infection were randomized to receive daily oral tenofovir-emtricitabine and resistance to emtricitabine was later discovered in both men A similar case in the TDF2 study resulted in resistance to both ARVs These cases prompted us to examine existing literature on the nature of resistance mutations elicited by ARVs used for PrEP Here, we discuss the impact of signature mutations selected by PrEP, how rapidly these emerge with daily ARV exposure, and the individual-level and public health consequences of ARV resistance

Clonal Sequences Recovered from Plasma from Patients with Residual HIV-1 Viremia and on Intensified Antiretroviral Therapy Are Identical to Replicating Viral RNAs Recovered from Circulating Resting CD4+ T Cells

Abstract: Despite successful antiretroviral therapy (ART), low-level viremia (LLV) may be intermittently detected in most HIV-infected patients. Longitudinal blood plasma and resting CD4(+) T cells were obtained from two patients on suppressive ART to investigate the source of LLV. Single-genome sequencing of HIV-1 env from LLV plasma was performed, and the sequences were compared to sequences recovered from limiting-dilution outgrowth assays of resting CD4(+) T cells. The circulating LLV virus clone was identical to virus recovered from outgrowth assays from pools of millions of resting CD4(+) T cells. Understanding the sources of LLV requires evaluation of all possible reservoirs of persistent HIV infection.

Cross-sectional detection of acute HIV infection: timing of transmission, inflammation and antiretroviral therapy.

Abstract: Background: Acute HIV infection (AHI) is a critical phase of infection when irreparable damage to the immune system occurs and subjects are very infectious. We studied subjects with AHI prospectively to develop better treatment and public health interventions. Methods: Cross-sectional screening was employed to detect HIV RNA positive, antibody negative subjects. Date of HIV acquisition was estimated from clinical history and correlated with sequence diversity assessed by single genome amplification (SGA). Twenty-two cytokines/chemokines were measured from enrollment through week 24. Results: Thirty-seven AHI subjects were studied. In 7 participants with limited exposure windows, the median exposure to HIV occurred 14 days before symptom onset. Lack of viral sequence diversification confirmed the short duration of infection. Transmission dates estimated by SGA/sequencing using molecular clock models correlated with transmission dates estimated by symptom onset in individuals infected with single HIV variants (mean of 28 versus 33 days). Only 10 of 22 cytokines/chemokines were significantly elevated among AHI participants at enrollment compared to uninfected controls, and only 4 participants remained seronegative at enrollment.

Potential Impact of Antiretroviral Therapy and Screening on Cervical Cancer Mortality in HIV-Positive Women in Sub-Saharan Africa: A Simulation

Abstract: BACKGROUND: Despite having high cervical cancer incidence and mortality rates screening for cervical precancerous lesions remains infrequent in sub-Saharan Africa. The need to screen HIV-positive women because of the higher prevalence and faster progression of cervical precancerous lesions may be heightened by the increased access to highly-active antiretroviral therapy (HAART). Policymakers need quantitative data on the effect of HAART and screening to better allocate limited resources. Our aim was to quantify the potential effect of these interventions on cervical cancer mortality. METHODS AND FINDINGS: We constructed a Markov state-transition model of a cohort of HIV-positive women in Cameroon. Published data on the prevalence progression and regression of lesions as well as mortality rates from HIV cervical cancer and other causes were incorporated into the model. We examined the potential impact on cumulative cervical cancer mortality of four possible scenarios: no HAART and no screening (NHNS) HAART and no screening (HNS) HAART and screening once on HAART initiation (HSHI) and HAART and screening once at age 35 (HS35). Our model projected that compared to NHNS lifetime cumulative cervical cancer mortality approximately doubled with HNS. It will require 262 women being screened at HAART initiation to prevent one cervical cancer death amongst women on HAART. The magnitudes of these effects were most sensitive to the rate of progression of precancerous lesions. CONCLUSIONS: Screening even when done once has the potential of reducing cervical cancer mortality among HIV-positive women in Africa. The most feasible and cost-effective screening strategy needs to be determined in each setting.

Efficacy of NNRTI-based antiretroviral therapy initiated during acute HIV infection.

Abstract: OBJECTIVE Characterize responses to non-nucleoside reverse transcriptase inhibitor (NNRTI)-based antiretroviral treatment (ART) initiated during acute HIV infection (AHI). DESIGN This was a prospective, single-arm evaluation of once-daily, co-formulated emtricitabine/tenofovir/efavirenz initiated during AHI. METHODS The primary endpoint is the proportion of responders with HIV RNA less than 200 copies/ml by week 24. We examined time to viral suppression and CD8 cell activation in relation to baseline participant characteristics. We compared time to viral suppression and viral dynamics using linear mixed-effects models between acutely infected participants and chronically infected controls. RESULTS Between January 2005 and May 2009, 61 AHI participants were enrolled. Of participants whose enrollment date allowed 24 and 48 weeks of follow-up, 47 of 51 (92%) achieved viral suppression to less than 200 copies/ml by week 24, and 35 of 41 (85.4%) to less than 50 copies/ml by week 48. The median time from ART initiation to suppression below 50 copies/ml was 93 days (range 14-337). Higher HIV RNA levels at ART initiation (P = 0.02), but not time from estimated date of infection to ART initiation (P = 0.86), were associated with longer time to viral suppression. The median baseline frequency of activated CD8+CD38+HLA-DR+ T cells was 67% (range 40-95), and was not significantly associated with longer time to viral load suppression (P = 0.15). Viremia declined to less than 50 copies/ml more rapidly in AHI than chronically infected participants. Mixed-model analysis demonstrated similar phase I HIV RNA decay rates between acute and chronically infected participants, and more rapid viral decline in acutely infected participants in phase II. CONCLUSION Once-daily emtricitabine/tenofovir/efavirenz initiated during AHI achieves rapid and sustained HIV suppression during this highly infectious period.

Meta-analysis of randomized trials on the association of prophylactic acyclovir and HIV-1 viral load in individuals coinfected with herpes simplex virus-2.

Abstract: Objective To summarize the randomized evidence regarding the association between acyclovir use and HIV-1 replication as measured by plasma HIV-1 RNA viral load among individuals coinfected with herpes simplex virus (HSV)-2.

Recruitment of HIV/AIDS treatment-naïve patients to clinical trials in the highly active antiretroviral therapy era: influence of gender, sexual orientation and race.

Abstract: Background—In the United States, women, racial/ethnic minorities and persons who acquire HIV infection through heterosexual intercourse represent an increasing proportion of HIV infected persons, yet are frequently underrepresented in clinical trials. We assessed the demographic predictors of trial participation in antiretroviral naive patients. Methods—Patients were characterized as trial participants if highly-active antiretroviral therapy (HAART) was initiated within a clinical trial. Prevalence ratios (PR) were obtained using binomial regression. Results—Between 1996–2006, 30% of 738 treatment naive patients initiated HAART in a clinical trial. Trial participation rates for MSM, heterosexual men, and women were respectively 36.5%, 29.6% and 24.3%. After adjustment for other factors, heterosexual men appeared less likely to participate in trials compared to MSM (PR: 0.79, 95%CI 0.57, 1.11) while women were as likely to participate as MSM (PR 0.97, 95%CI 0.68, 1.39). The participation rate in blacks (25.9%) was lower compared to non-blacks (37.5%) (adjusted PR 0.80, 95%CI 0.60, 1.06). Conclusions—In our clinical setting gender did not appear to impact participation in HIV treatment trials but blacks were slightly less likely to participate in these trials. Considering the substantial proportion of HIV patients who are black, future trials need to consider strategies to incorporate underrepresented populations.

Pilot study demonstrating effectiveness of targeted education to improve informed consent understanding in AIDS clinical trials

Abstract: Assessing and improving informed consent understanding is equally important as obtaining consent from participants in clinical trial research, but developing interventions to target gaps in participants' informed consent understanding remains a challenge. We used a randomized controlled study design to pilot test an educational intervention to improve actual informed consent understanding of new enrollees in the Adult AIDS Clinical Trial Group (AACTG). Questionnaires were administered to 24 enrollees to assess their baseline understanding on eight elements of informed consent associated with AIDS clinical trials. Enrollees who scored 18/21(85%) or less were randomly assigned to in-person, targeted education (intervention), or delayed education (control). Two follow-up assessments were administered. Repeated measures ANOVA was performed to determine intervention effectiveness in improving actual informed consent understanding over time. Actual understanding improved at the immediate post-intervention time point with a significant score difference of 2.5 when comparing the intervention and delayed groups. In addition, there was a significant score difference of 3.2 when comparing baseline to three-month follow-up for the two groups, suggesting a statistically significant intervention effect to improve actual understanding of the basic elements of informed consent. The findings demonstrated that one-time targeted education can improve actual informed consent understanding one week after the intervention, but retention of these concepts may require periodic monitoring to ensure comprehension throughout the course of a clinical trial.

Aciclovir treatment for human immunodeficiency virus-1: is the “juice worth the squeeze?”.

Abstract: H immunodeficiency virus (HIV)-1 is first and foremost a sexually transmitted disease, and sexually transmitted disease (STD) coinfections are expected. In both developed and developing countries, herpes simplex virus (HSV)-2 is a common, incurable coinfection of HIV-1.1 The early observation that HSV-2 coinfection speeds the course of HIV-1 disease progression led to a series of observational reports and clinical reports designed to demonstrate a therapeutic benefit for aciclovir, none of which have proved entirely convincing: these results are summarized in a meta-analysis2 published nearly 15 years ago. Most of the trials included in this analysis were performed before the effects on aciclovir on viral load could be measured, and patients with advanced disease were studied. As part of a recent study designed to evaluate the ability of aciclovir to reduce transmission of HIV from an HIV-1/HSV-2 coinfected patient,3 the apparent effects of aciclovir on blood viral load and HIV-1 disease progression were monitored.4 However, in the current article in STD, Vickerman et al.5 used these data to model the potential cost-effectiveness of aciclovir treatment in HIV-1 infected women who did not yet qualify (by CD4 count) for the effective antiretroviral therapy. The authors concluded that aciclovir might delay the need for more effective, conventional antiretroviral treatment and—by offering some form of treatment to patients with high CD4 counts—keep more people in care. But this exercise belies a critical question: can we expect HIV treatment providers to use aciclovir for HIV therapy? Clinical studies almost “too numerous to count” have drawn an association between HSV-2 and the acquisition of HIV-1.6 The best explanations for this “synergy” include increased HIV-1 genital tract shedding of HIV-1 caused by HSV-2-induced inflammation7,8 or transmission of HSV-2 to an uninfected partner, causing tissue ulcers and inflammation, increasing the probability of subsequent transmission of HIV-1.9 Two trials of oral aciclovir for HSV-2 positive, HIV-negative subjects have been completed, both designed to reduce the acquisition of HIV-110,11: aciclovir did not prevent HSV-2 acquisition in either trial. And in people who acquired HIV-1 in spite of aciclovir the viral set point was not affected,12 suggesting that neither “ramp-up viremia” or viral integration, or the host responses were affected. Why did aciclovir fail to prevent HIV acquisition? Potential explanations include (i) study participants were not adherent to treatment, regardless of the argument that aciclovir is well-tolerated; (ii) aciclovir cannot prevent HSV-2 shedding13 or genital ulcers14; or (iii) HSV-2 reactivation causes submucosal inflammatory changes (at least in a few people studied) that may extend long beyond ulcer healing, resulting in persistent increased risk for HIV acquisition.15 Another study was undertaken to determine if aciclovir might reduce the infectiousness of people coinfected with HSV-2 and HIV-1.3 Support for this approach came from several directions: (i) once daily valaciclovir significantly reduces HSV-2 transmission to HSV-2–negative partners16; (ii) aciclovir reduces genital tract shedding of HIV-1,7,8although this effect of aciclovir may not be entirely reliable.13 Celum et al. studied 3408 HIV-discordant couples in 14 countries.3 The index case suffered HSV-2 and HIV-1 coinfection, whereas sexual partners were HIV-1 negative. The index case was given 400 mg aciclovir twice daily or placebo. Conventional antiretroviral therapy (ART) was deferred because HIV-1 infected subjects were enrolled with CD4 counts above the recommended ART treatment threshold. In this study aciclovir did not reduce HIV-1 transmission, although occurrence of genital ulcers was reduced by more than 70%. At the end of this “long and winding road,” the results have circled back to the earliest observation: that HSV-2 coinfection might increase HIV-1 disease progression enough to justify treatment with aciclovir.2,4 In the transmission prevention study mentioned earlier in the text,3 Lingappa et al.4 studied the HIV-1 infected index cases and found that aciclovir appeared to slow progression of HIV-1 disease by 16% compared to the placebo-treated group, predominantly due to

High clade C HIV-1 viremia: how did we get here and where are we going?

Abstract: After HIV-1 transmission, viral replication leads to a peak in blood plasma viral load, and over a short period the virus declines to a stable concentration [1]. The steady state concentration of virus in blood plasma, generally referred to as the viral ‘set point,’ correlates directly with the rate of clinical disease progression and the CD4 cell count depletion [2]. In addition, HIV-1 transmission probability can be correlated with the viral load in blood [3,4] and genital secretions [4].