AIDS Clinical Trials Group Protocol Research Articles

Markers of intestinal immune activation and inflammation are not associated with preterm birth among women with low level HIV viremia.

Maternal markers of intestinal immune activation may be used to predict preterm birth (PTB) in pregnant women living with HIV. This study used de-identified samples from the International Maternal Pediatric Adolescent AIDS Clinical Trials Group (IMPAACT) Protocol P1025 study. Singleton pregnancies with ≥3ml plasma available and HIV viral load ≤400 copies/ml within 4weeks of specimen collection were included. Frequency matching of PTB cases and term birth controls was performed on basis of maternal race, number of available plasma specimens, and timing of plasma sample collection in a 1:1 ratio. Plasma progesterone, 25-hydroxy vitamin D, soluble CD14, intestinal fatty acid binding protein (I-FABP), Lipopolysaccharide (LPS)-binding protein, and inflammatory cytokines (IL-1B, IFN-gamma, IL-6, TNF-alpha) were measured. Generalized mixed linear regression modeling was used to examine the association between PTB and biomarkers, adjusting for covariates and confounders. Data analyses were performed using SAS 9.4 (Cary, NC). We included 104 PTB compared to 104 controls. Third trimester log2 IL-1B was lower among PTB versus term birth controls by univariate analysis (-1.50±2.26 vs. -.24±2.69, p=.01) though this association was no longer significant by regression modeling. In an uncontrolled, exploratory sub-analysis, subjects with prior PTB had increased odds of PTB with higher I-FABP [aOR 2.72, 95% CI 1.18-6.24] and lower IFN-gamma [aOR .23, 95% CI .12-.41] after adjustment for covariates and confounders. Intestinal immune activation measured by soluble CD14 or intestinal fatty acid binding protein was not associated with preterm birth among pregnant women with low-level HIV viremia.

Bayesian analysis for partly linear Cox model with measurement error and time-varying covariate effect.

The Cox proportional hazards model is commonly used to estimate the association between time-to-event and covariates. Under the proportional hazards assumption, covariate effects are assumed to be constant in the follow-up period of study. When measurement error presents, common estimation methods that adjust for an error-contaminated covariate in the Cox proportional hazards model assume that the true function on the covariate is parametric and specified. We consider a semiparametric partly linear Cox model that allows the hazard to depend on an unspecified function of an error-contaminated covariate and an error-free covariate with time-varying effect, which simultaneously relaxes the assumption on the functional form of the error-contaminated covariate and allows for nonconstant effect of the error-free covariate. We take a Bayesian approach and approximate the unspecified function by a B-spline. Simulation studies are conducted to assess the finite sample performance of the proposed approach. The results demonstrate that our proposed method has favorable statistical performance. The proposed method is also illustrated by an application to data from the AIDS Clinical Trials Group Protocol 175.

Pregnant Women, HIV, and Clinical Research to Prevent Perinatal Transmission in the 1990s

In 1994, American and French AIDS research showed that the drug AZT reduced the risk of HIV transmission from a pregnant HIV-positive woman to her fetus (perinatal transmission). Hailed as a breakthrough, the AIDS Clinical Trial Group protocol 076 (ACTG 076) soon became the standard of care in the US But ACTG 076 was too expensive for low-income countries where perinatal transmission rates were high; to find a more affordable prevention, the US principally funded studies in several low-income countries. Controversy over whether the short course of AZT studies was ethical, given their different standards of care and use of a placebo, erupted in 1997. These studies remain well known within the global health biomedical literature as illustrating differences between sending and receiving countries. But while rarely invoked within this literature, these two sets of studies have similarities that challenge this hierarchal division: both involved pregnant women as objects of clinical research instead of subjects of clinical care, reflective of the all-too-common focus in global health on disease containment rather than on health care, and both illustrate the ways the focus within global health has been on a solitary biomedical intervention rather than on discrimination, inequality, and poverty within and among countries.

Ensemble and calibration multiply robust estimation for quantile treatment effect

ABSTRACT Quantile treatment effects can be important causal estimands in the evaluation of biomedical treatments or interventions for health outcomes such as birthweight and medical cost. However, the existing estimators require either a propensity score model or a conditional density vector model is correctly specified, which is difficult to verify in practice. In this paper, we allow multiple models for propensity score and conditional density vector, then construct a class of calibration estimators based on multiple imputation and inverse probability weighting approaches via empirical likelihood. The resulting estimators multiply robust in the sense that they are consistent if any one of these models is correctly specified. Moreover, we propose another class of ensemble estimators to reduce computational burden while ensuring multiple robustness. Simulations are performed to evaluate the finite sample performance of the proposed estimators. Two applications to the birthweight of infants born in the United States and AIDS Clinical Trials Group Protocol 175 data are also presented.

Sufficient dimension reduction and instrument search for data with nonignorable nonresponse

Consider a response variable subject to nonignorable nonresponse and a fully observed covariate vector. The purpose of our study is threefold. First, we study how to extend nonparametric sufficient dimension reduction to data with nonignorable nonresponse. Second, we utilize sufficient dimension reduction to search an instrument, a linear function of covariates that is related to the response variable but can be excluded from the propensity of nonignorable nonresponse, for the purpose of identifying unknown parameters in a semiparametric propensity and a nonparametric distribution of response variable and covariates. Third, we establish asymptotic results for parameter estimators based on sufficient dimension reduction and instrument search, and investigate the effect on the limiting distribution of parameter estimators due to instrument search. We evaluate the performance of proposed estimators in a Monte Carlo study and illustrate our method in an application to AIDS Clinical Trials Group Protocol 175 data.

A multiply robust Mann-Whitney test for non-randomised pretest-posttest studies with missing data

ABSTRACTPretest-posttest studies are a commonly used design by social scientists, medical and health researchers to examine the effect of a treatment or an intervention. We propose an empirical likelihood based Mann-Whitney test on the equality of the response distribution functions of the treatment and control arms for non-randomised pretest-posttest studies with missing responses. The proposed test is multiply robust in the sense that multiple working models can be postulated for the propensity score of treatment assignment, the missingness probability and the outcome regression, and the validity of the test only requires certain combinations of the working models to be correctly specified. Performances of the proposed test are examined through an application to the dataset from AIDS Clinical Trials Group Protocol 175 and simulation studies.

Diverse Human Immunodeficiency Virus-1 Drug Resistance Profiles at Screening for ACTG A5288: A Study of People Experiencing Virologic Failure on Second-line Antiretroviral Therapy in Resource-limited Settings.

Human immunodeficiency virus (HIV) drug resistance profiles are needed to optimize individual patient management and to develop treatment guidelines. Resistance profiles are not well defined among individuals on failing second-line antiretroviral therapy (ART) in low- and middle-income countries (LMIC). Resistance genotypes were performed during screening for enrollment into a trial of third-line ART (AIDS Clinical Trials Group protocol 5288). Prior exposure to both nucleoside reverse transcriptase inhibitors (NRTIs) and non-NRTIs and confirmed virologic failure on a protease inhibitor-containing regimen were required. Associations of drug resistance with sex, age, treatment history, plasma HIV RNA, nadir CD4+T-cell count, HIV subtype, and country were investigated. Plasma HIV genotypes were analyzed for 653 screened candidates; most had resistance (508 of 653; 78%) to 1 or more drugs. Genotypes from 133 (20%) showed resistance to at least 1 drug in a drug class, from 206 (32%) showed resistance to at least 1 drug in 2 drug classes, and from 169 (26%) showed resistance to at least 1 drug in all 3 commonly available drug classes. Susceptibility to at least 1 second-line regimen was preserved in 59%, as were susceptibility to etravirine (78%) and darunavir/ritonavir (97%). Susceptibility to a second-line regimen was significantly higher among women, younger individuals, those with higher nadir CD4+ T-cell counts, and those who had received lopinavir/ritonavir, but was lower among prior nevirapine recipients. Highly divergent HIV drug resistance profiles were observed among candidates screened for third-line ART in LMIC, ranging from no resistance to resistance to 3 drug classes. These findings underscore the need for access to resistance testing and newer antiretrovirals for the optimal management of third-line ART in LMIC.

Multiple robustness estimation in causal inference

Estimation of average treatment effect is crucial in causal inference for evaluation of treatments or interventions in biostatistics, epidemiology, econometrics, sociology. However, existing estimators require either a propensity score model, an outcome vector model, or both is correctly specified, which is difficult to verify in practice. In this paper, we allow multiple models for both the propensity score models and the outcome models, and then construct a weighting estimator based on observed data by using two-sample empirical likelihood. The resulting estimator is consistent if any one of those multiple models is correctly specified, and thus provides multiple protection on consistency. Moreover, the proposed estimator can attain the semiparametric efficiency bound when one propensity score model and one outcome vector model are correctly specified, without requiring knowledge of which models are correct. Simulations are performed to evaluate the finite sample performance of the proposed estimators. As an application, we analyze the data collected from the AIDS Clinical Trials Group Protocol 175.

Antiretroviral Concentrations in Hair Strongly Predict Virologic Response in a Large Human Immunodeficiency Virus Treatment-naive Clinical Trial.

Concentrations of antiretrovirals in hair are associated with virologic outcomes in cohorts of human immunodeficiency virus (HIV)-positive individuals but have never been examined in a clinical trial. We show for the first time the predictive utility of hair antiretroviral concentrations in a large HIV treatment-naive trial (AIDS Clinical Trials Group protocol A5257).

Development and application of a multiplex assay for the simultaneous measurement of antibody responses elicited by common childhood vaccines

Because vaccine co-administration can affect elicited immune responses, it is important to evaluate new vaccines in the context of pre-existing vaccination schedules. This is particularly necessary for new pediatric vaccines, as the World Health Organization’s infant immunization program already schedules several vaccines to be administered during the first months of life. To facilitate the assessment of inter-vaccine interference, we developed a pediatric vaccine multiplex assay (PVMA) to simultaneously measure antibodies against vaccines commonly administered to infants, including hepatitis B, Haemophilus influenzae type B, diphtheria, tetanus, pertussis, rubella, and respiratory syncytial virus (RSV). Comparison of antibody concentrations determined by enzyme-linked immunosorbent assays (ELISAs) and the PVMA demonstrated that the PVMA is highly sensitive, specific, reproducible, and accurate. Moreover, the PVMA requires half the time to assess a cohort compared to ELISAs, and only costs marginally more. Demonstrating the utility of the assay, we employed the PVMA to assess vaccine interference in the setting of a candidate vaccine, using the infant HIV vaccines from the completed Pediatric AIDS Clinical Trials Group (PACTG) protocols 230 and 326 as examples. There was no substantial difference in antibody concentrations between vaccine and placebo recipients, which suggests that HIV vaccination did not disrupt antibody responses elicited by routine pediatric vaccines. Thus, the PVMA is a reliable, high-throughput technique that requires minimal sample volume to measure multiple antibody concentrations concurrently, and is an efficient alternative to ELISAs for the measurement of vaccine-elicited antibody responses in large cohorts.

Changing Patterns and Factors Associated With Mode of Delivery Among Pregnant Women With Human Immunodeficiency Virus Infection in the United States.

To describe patterns and factors associated with mode of delivery among pregnant women with human immunodeficiency virus (HIV) infection in the United States in relation to evolving HIV-in-pregnancy guidelines. We conducted an analysis of two observational studies, Pediatric AIDS Clinical Trials Group and International Maternal Pediatric Adolescent AIDS Clinical Trials Network Protocol P1025, which enrolled pregnant women with HIV infection from 1998 to 2013 at more than 60 U.S. acquired immunodeficiency syndrome clinical research sites. Multivariable analyses of factors associated with an HIV-indicated cesarean delivery (ie, for prevention of mother-to-child transmission) compared with other indications were conducted and compared according to prespecified time periods of evolving HIV-in-pregnancy guidelines: 1998-1999, 2000-2008, and 2009-2013. Among 6,444 pregnant women with HIV infection, 21% delivered in 1998-1999, 58% in 2000-2008, and 21% in 2009-2013; 3,025 (47%) delivered by cesarean. Cesarean delivery increased from 30% in 1998 to 48% in 2013. Of all cesarean deliveries, repeat cesarean deliveries increased from 16% in 1998 to 42% in 2013; HIV-indicated cesarean deliveries peaked at 48% in 2004 and then dropped to 12% by 2013. In multivariable analyses, an HIV diagnosis during pregnancy, initiation of antiretroviral therapy in the third trimester, a plasma viral load 500 copies/mL or greater, and delivery between 37 and 40 weeks of gestation increased the likelihood of an HIV-indicated cesarean delivery. In analyses by time period, an HIV diagnosis during pregnancy, initiation of antiretroviral therapy in the third trimester, and a plasma viral load of 500 copies/mL or greater were progressively more likely to be associated with an HIV-indicated cesarean delivery over time. Almost 50% of pregnant women with HIV infection underwent cesarean delivery. Over time, the rate of repeat cesarean deliveries increased, whereas the rate of HIV-indicated cesarean deliveries decreased; cesarean deliveries were more likely to be performed in women at high risk of mother-to-child transmission. These findings reinforce the need for both early diagnosis and treatment of HIV infection in pregnancy and the option of vaginal delivery after cesarean among pregnant women with HIV infection.

Multiphenotype association study of patients randomized to initiate antiretroviral regimens in AIDS Clinical Trials Group protocol A5202.

High-throughput approaches are increasingly being used to identify genetic associations across multiple phenotypes simultaneously. Here, we describe a pilot analysis that considered multiple on-treatment laboratory phenotypes from antiretroviral therapy-naive patients who were randomized to initiate antiretroviral regimens in a prospective clinical trial, AIDS Clinical Trials Group protocol A5202. From among 5 9545 294 polymorphisms imputed genome-wide, we analyzed 2544, including 2124 annotated in the PharmGKB, and 420 previously associated with traits in the GWAS Catalog. We derived 774 phenotypes on the basis of context from six variables: plasma atazanavir (ATV) pharmacokinetics, plasma efavirenz (EFV) pharmacokinetics, change in the CD4+ T-cell count, HIV-1 RNA suppression, fasting low-density lipoprotein-cholesterol, and fasting triglycerides. Permutation testing assessed the likelihood of associations being by chance alone. Pleiotropy was assessed for polymorphisms with the lowest P-values. This analysis included 1181 patients. At P less than 1.5×10, most associations were not by chance alone. Polymorphisms with the lowest P-values for EFV pharmacokinetics (CYPB26 rs3745274), low-density lipoprotein -cholesterol (APOE rs7412), and triglyceride (APOA5 rs651821) phenotypes had been associated previously with those traits in previous studies. The association between triglycerides and rs651821 was present with ATV-containing regimens, but not with EFV-containing regimens. Polymorphisms with the lowest P-values for ATV pharmacokinetics, CD4 T-cell count, and HIV-1 RNA phenotypes had not been reported previously to be associated with that trait. Using data from a prospective HIV clinical trial, we identified expected genetic associations, potentially novel associations, and at least one context-dependent association. This study supports high-throughput strategies that simultaneously explore multiple phenotypes from clinical trials' datasets for genetic associations.

Genome-wide association study of virologic response with efavirenz-containing or abacavir-containing regimens in AIDS clinical trials group protocols.

Efavirenz and abacavir are components of recommended first-line regimens for HIV-1 infection. We used genome-wide genotyping and clinical data to explore genetic associations with virologic failure among patients randomized to efavirenz-containing or abacavir-containing regimens in AIDS Clinical Trials Group (ACTG) protocols. Virologic response and genome-wide genotype data were available from treatment-naive patients randomized to efavirenz-containing (n=1596) or abacavir-containing (n = 786) regimens in ACTG protocols 384, A5142, A5095, and A5202. Meta-analysis of association results across race/ethnic groups showed no genome-wide significant associations (P < 5 × 10) with virologic response for either efavirenz or abacavir. Our sample size provided 80% power to detect a genotype relative risk of 1.8 for efavirenz and 2.4 for abacavir. Analyses focused on CYP2B genotypes that define the lowest plasma efavirenz exposure stratum did not show associations nor did analysis limited to gene sets predicted to be relevant to efavirenz and abacavir disposition. No single polymorphism is associated strongly with virologic failure with efavirenz-containing or abacavir-containing regimens. Analyses to better consider context, and that minimize confounding by nongenetic factors, may show associations not apparent here.

Phenome-wide Association Study Relating Pretreatment Laboratory Parameters With Human Genetic Variants in AIDS Clinical Trials Group Protocols.

Background. Phenome-Wide Association Studies (PheWAS) identify genetic associations across multiple phenotypes. Clinical trials offer opportunities for PheWAS to identify pharmacogenomic associations. We describe the first PheWAS to use genome-wide genotypic data and to utilize human immunodeficiency virus (HIV) clinical trials data. As proof-of-concept, we focused on baseline laboratory phenotypes from antiretroviral therapy-naive individuals.Methods. Data from 4 AIDS Clinical Trials Group (ACTG) studies were split into 2 datasets: Dataset I (1181 individuals from protocol A5202) and Dataset II (1366 from protocols A5095, ACTG 384, and A5142). Final analyses involved 2547 individuals and 5 954 294 imputed polymorphisms. We calculated comprehensive associations between these polymorphisms and 27 baseline laboratory phenotypes.Results. A total of 10 584 (0.17%) polymorphisms had associations with P < .01 in both datasets and with the same direction of association. Twenty polymorphisms replicated associations with identical or related phenotypes reported in the Catalog of Published Genome-Wide Association Studies, including several not previously reported in HIV-positive cohorts. We also identified several possibly novel associations.Conclusions. These analyses define PheWAS properties and principles with baseline laboratory data from HIV clinical trials. This approach may be useful for evaluating on-treatment HIV clinical trials data for associations with various clinical phenotypes.

Ethics of cancer clinical trials in low-resource settings.

Debates surrounding the appropriate design and conduct of clinical research in low-resource settings have bedeviled the scientific, policy, and bioethics communities for decades. Historically, controversies primarily involved trials related to infectious disease. With the growing globalization of cancer clinical trials and the recognition of cancer as a public health threat in developing as well as developed countries, these debates will increasingly engage the cancer research community. The paradigmatic case that sparked discussion of the ethics of international clinical trials concerned the development of antiretroviral therapies to prevent vertical transmission of HIV from pregnant women to their newborn infants. In 1994, the AIDS Clinical Trials Group published results of the Pediatric AIDS Clinical Trials Group Protocol 076 trial (hereafter, 076), a study conducted in the United States and France that compared an intensive and prolonged regimen of perinatal zidovudine to placebo.1 The 076 regimen reduced the risk of vertical transmission from 25.5% to 8.3%, and it rapidly became the standard of care for HIV-infected pregnant women in developed nations. Most of the world's burden of HIV, however, resided in low-resource areas such as sub-Saharan Africa, areas in which the 076 regimen was infeasible for financial and logistical reasons. Thus, numerous research teams set out to identify less expensive, less logistically demanding approaches to the problem of perinatal transmission. Because standards of care in low-resource countries after the publication of the 076 study did not include zidovudine, most teams compared potentially feasible new interventions against placebo controls. In 1997, Lurie and Wolfe2 and Angell3 ignited a firestorm with the charge that placebo-controlled trials of perinatal short-course zidovudine, one of the regimens under study as a feasible alternative to the 076 regimen, unethically denied proven effective therapy to control-group participants. Pointing out that placebo-controlled studies of interventions to reduce the incidence of vertical HIV transmission were no longer acceptable in developed countries, they claimed that the use of placebos in developing-world trials represented an unethical double standard. Angell, invoking the memory of the infamous Tuskegee syphilis study, claimed that “acceptance of this ethical relativism could result in widespread exploitation of vulnerable Third World populations for research programs that could not be carried out in the sponsoring country.”3 Study sponsors and other commentators disputed this position, arguing that placebo controls were necessary to assess the efficacy and feasibility of the short-course regimen as compared with the absence of antiretroviral treatment and that no patients were made worse off by trial participation relative to the local standard of care.4,5 Cancer, too, is increasingly a disease of the developing world. According to the American Cancer Society, 56% of cancer cases and 64% of cancer deaths in 2008 occurred in the economically developing world.6 Such statistics highlight a pressing need for high-quality research to identify feasible, evidence-based therapeutic strategies appropriate for low-resource settings. Despite the public health urgency of cancer in the developing world, along with the globalization of industry-sponsored clinical research, the ethics of cancer clinical trials in low-resource settings have received little attention.7,8 However, recent controversies suggest that these trials may come under increased scrutiny.9–13 What are the appropriate standards for the design and conduct of such trials? Ethical criteria for clinical research are generally held to universally.14 Differences in health service priorities and wide disparities in background conditions, however, raise the possibility that the questions asked and the methods used to answer them might justifiably vary across regions. Two questions relevant to clinical trials in low-resource settings are particularly vexing. First, what is the proper control group for evaluating investigational treatments in this setting? As with HIV, investigators conducting cancer trials—especially those based at developed-world institutions or funded by developed-world sources—must decide whether trials should compare novel interventions to the developed-world standard of care, or if it is acceptable, or even preferable, to evaluate them against locally available treatments. Second, must these trials have the potential to benefit the host population? These questions, which encompass what sponsors and investigators owe both to study participants and to host communities, remain unsettled to this day.15

Multiply Robust Estimation in Regression Analysis With Missing Data

Doubly robust estimators are widely used in missing-data analysis. They provide double protection on estimation consistency against model misspecifications. However, they allow only a single model for the missingness mechanism and a single model for the data distribution, and the assumption that one of these two models is correctly specified is restrictive in practice. For regression analysis with possibly missing outcome, we propose an estimation method that allows multiple models for both the missingness mechanism and the data distribution. The resulting estimator is consistent if any one of those multiple models is correctly specified, and thus provides multiple protection on consistency. This estimator is also robust against extreme values of the fitted missingness probability, which, for most doubly robust estimators, can lead to erroneously large inverse probability weights that may jeopardize the numerical performance. The numerical implementation of the proposed method through a modified Newton–Raphson algorithm is discussed. The asymptotic distribution of the resulting estimator is derived, based on which we study the estimation efficiency and provide ways to improve the efficiency. As an application, we analyze the data collected from the AIDS Clinical Trials Group Protocol 175.

Genomewide association study of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202

Atazanavir-associated hyperbilirubinemia can cause premature discontinuation of atazanavir and avoidance of its initial prescription. We used genomewide genotyping and clinical data to characterize determinants of atazanavir pharmacokinetics and hyperbilirubinemia in AIDS Clinical Trials Group protocol A5202. Plasma atazanavir pharmacokinetics and indirect bilirubin concentrations were characterized in HIV-1-infected patients randomized to atazanavir/ritonavir-containing regimens. A subset had genomewide genotype data available. Genomewide assay data were available from 542 participants, of whom 475 also had data on estimated atazanavir clearance and relevant covariates available. Peak bilirubin concentration and relevant covariates were available for 443 participants. By multivariate analysis, higher peak on-treatment bilirubin levels were found to be associated with the UGT1A1 rs887829 T allele (P=6.4×10(-12)), higher baseline hemoglobin levels (P=4.9×10(-13)), higher baseline bilirubin levels (P=6.7×10(-12)), and slower plasma atazanavir clearance (P=8.6×10(-11)). For peak bilirubin levels greater than 3.0 mg/dl, the positive predictive value of a baseline bilirubin level of 0.5 mg/dl or higher with hemoglobin concentrations of 14 g/dl or higher was 0.51, which increased to 0.85 with rs887829 TT homozygosity. For peak bilirubin levels of 3.0 mg/dl or lower, the positive predictive value of a baseline bilirubin level less than 0.5 mg/dl with a hemoglobin concentration less than 14 g/dl was 0.91, which increased to 0.96 with rs887829 CC homozygosity. No polymorphism predicted atazanavir pharmacokinetics at genomewide significance. Atazanavir-associated hyperbilirubinemia is best predicted by considering UGT1A1 genotype, baseline bilirubin level, and baseline hemoglobin level in combination. Use of ritonavir as a pharmacokinetic enhancer may have abrogated genetic associations with atazanavir pharmacokinetics.

Genome-wide association study of peripheral neuropathy with D-drug-containing regimens in AIDS Clinical Trials Group protocol 384

Stavudine (d4T) was, until recently, one of the most widely prescribed antiretroviral drugs worldwide. While there has been a major shift away from d4T use in resource-limited countries, a large number of patients have previously received (or continue to receive) d4T, and many have developed peripheral neuropathy. The identification of genetic predictors of increased risk might suggest novel therapeutic targets for such patients. In AIDS Clinical Trials Group protocol 384, antiretroviral-naïve patients were randomized to d4T/didanosine (ddI)- or zidovudine/lamivudine-containing regimens. Data from d4T/ddI recipients were analyzed for genome-wide associations (approximately 1 million genetic loci) with new onset distal sensory peripheral neuropathy. Analyses involved 254 patients (49 % White, 34 % Black, 17 % Hispanic), comprising 90 peripheral neuropathy cases (32 grade 1, 35 grade 2, 23 grade 3) and 164 controls. After correcting for multiple comparisons, no polymorphism was consistently associated with neuropathy among all patients, among White, Black, and Hispanic patients analyzed separately, both in genome-wide analyses (threshold, P < 5.0 × 10−8) and focused on 46 neuropathy-associated genes (threshold, P < 3.5 × 10−5). In the latter analyses, the lowest P values were in KIF1A among Whites (rs10199388, P = 8.4 × 10−4), in LITAF among Blacks (rs13333308, P = 6.0 × 10−6), and in NEFL among Hispanics (rs17763685, P = 5.6 × 10−6). Susceptibility to d4T/ddI-associated neuropathy is not explained by a single genetic variant with a marked effect.Electronic supplementary materialThe online version of this article (doi:10.1007/s13365-014-0235-9) contains supplementary material, which is available to authorized users.

Infant Growth Outcomes After Maternal Tenofovir Disoproxil Fumarate Use During Pregnancy

To determine whether maternal use of tenofovir disoproxil fumarate for treatment of HIV in pregnancy predicts fetal and infant growth. The study population included HIV-uninfected live-born singleton infants of mothers enrolled in the International Maternal Pediatric Adolescent AIDS Clinical Trials Group protocol P1025 (born 2002-2011) in the United States and exposed in utero to a combined (triple or more) antiretroviral regimen. Infant weight at birth and 6 months was compared between infants exposed and unexposed to tenofovir in utero using 2-sample t test, χ test, and multivariable linear and logistic regression models, including demographic and maternal characteristics. Among 2025 infants with measured birth weight, there was no difference between those exposed (N = 630, 31%) versus unexposed to tenofovir in mean birth weight (2.75 vs. 2.77 kg, P = 0.64) or mean gestational age- and sex-adjusted birth weight z-score (WASZ) (0.14 vs. 0.14, P = 0.90). Among 1496 infants followed for 6 months, there was no difference in mean weight at 6 months between tenofovir-exposed (N = 457, 31%) and tenofovir-unexposed infants (7.64 vs. 7.59 kg, P = 0.52) or in mean WASZ (0.29 vs. 0.26, P = 0.61). Tenofovir exposure during the second/third trimester, relative to no exposure, significantly predicted underweight (WASZ < 5%) at age 6 months [odds ratio (95% confidence interval): 2.06 (1.01 to 3.95), P = 0.04]. Duration of tenofovir exposure did not predict neonatal or infant growth. By most measures, in utero exposure to tenofovir did not significantly predict infant birth weight or growth through 6 months of age.

Interleukin-7 promotes HIV persistence during antiretroviral therapy

AbstractHIV persists in latently infected memory CD4+ T cells during antiretroviral therapy (ART). When administered to HIV-infected subjects receiving suppressive ART, interleukin-7 (IL-7) increases the number of CD4+ T cells by promoting their survival and proliferation. However, little is known about the impact of IL-7 on HIV persistence during ART. By isolating large numbers of CD4+ T cells from HIV-infected subjects, we demonstrate that IL-7 enhances viral production in productively infected cells but does not disrupt viral latency in latently infected cells. When administered to virally suppressed subjects, IL-7 led to the rapid proliferation of memory CD4+ T cells, which resulted in a 70% increase in the absolute number of circulating CD4+ T cells harboring integrated HIV DNA 4 weeks after therapy. The genetic diversity of the viral reservoir increased transiently in the majority of the subjects studied before returning to baseline values. Altogether, our results indicate that IL-7 promotes the mechanisms of HIV persistence during ART by enhancing residual levels of viral production and inducing proliferation of latently infected cells, and suggest that IL-7 does not represent a suitable candidate therapeutic strategy for HIV eradication. This trial was registered at www.clinicaltrials.gov as #NCT00099671 (AIDS Clinical Trials Group protocol 5214).