Biomedical subjects

Peter B Gilbert

Publications and source records attributed to Peter B Gilbert.

At least 19 recordsLinked to original sources

PubMed2006

Breastfeeding plus infant zidovudine prophylaxis for 6 months vs formula feeding plus infant zidovudine for 1 month to reduce mother-to-child HIV transmission in Botswana: a randomized trial: the Mashi Study.

CONTEXT: Postnatal transmission of human immunodeficiency virus-1 (HIV) via breastfeeding reverses gains achieved by perinatal antiretroviral interventions. OBJECTIVE: To compare the efficacy and safety of 2 infant feeding strategies for the prevention of postnatal mother-to-child HIV transmission. DESIGN, SETTING, AND PATIENTS: A 2 x 2 factorial randomized clinical trial with peripartum (single-dose nevirapine vs placebo) and postpartum infant feeding (formula vs breastfeeding with infant zidovudine prophylaxis) interventions. In Botswana between March 27, 2001, and October 29, 2003, 1200 HIV-positive pregnant women were randomized from 4 district hospitals. Infants were evaluated at birth, monthly until age 7 months, at age 9 months, then every third month through age 18 months. INTERVENTION: All of the mothers received zidovudine 300 mg orally twice daily from 34 weeks' gestation and during labor. Mothers and infants were randomized to receive single-dose nevirapine or placebo. Infants were randomized to 6 months of breastfeeding plus prophylactic infant zidovudine (breastfed plus zidovudine), or formula feeding plus 1 month of infant zidovudine (formula fed). MAIN OUTCOME MEASURES: Primary efficacy (HIV infection by age 7 months and HIV-free survival by age 18 months) and safety (occurrence of infant adverse events by 7 months of age) end points were evaluated in 1179 infants. RESULTS: The 7-month HIV infection rates were 5.6% (32 infants in the formula-fed group) vs 9.0% (51 infants in the breastfed plus zidovudine group) (P = .04; 95% confidence interval for difference, -6.4% to -0.4%). Cumulative mortality or HIV infection rates at 18 months were 80 infants (13.9%, formula fed) vs 86 infants (15.1% breastfed plus zidovudine) (P = .60; 95% confidence interval for difference, -5.3% to 2.9%). Cumulative infant mortality at 7 months was significantly higher for the formula-fed group than for the breastfed plus zidovudine group (9.3% vs 4.9%; P = .003), but this difference diminished beyond month 7 such that the time-to-mortality distributions through age 18 months were not significantly different (P = .21). CONCLUSIONS: Breastfeeding with zidovudine prophylaxis was not as effective as formula feeding in preventing postnatal HIV transmission, but was associated with a lower mortality rate at 7 months. Both strategies had comparable HIV-free survival at 18 months. These results demonstrate the risk of formula feeding to infants in sub-Saharan Africa, and the need for studies of alternative strategies. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00197587.

Anti-HIV Agents↗

PubMed2006

Peptide selection for human immunodeficiency virus type 1 CTL-based vaccine evaluation.

Dozens of human immunodeficiency virus-type 1 (HIV-1) vaccine candidates specifically designed to elicit cytotoxic T-lymphocyte (CTL) responses have entered the pipeline of clinical trials. Evaluating the immunogenicity and potential efficacy of these HIV-1 vaccine candidates is challenging in the face of the extensive viral genetic diversity of circulating strains. Standardized peptide reagents to define the magnitude and potential breadth of the T-cell response, especially to circulating strains of HIV-1, are needed. For this purpose we developed a biometric approach based on T-cell recognition pattern for defining standardized reagents. Circulating strains in the Los Alamos database were evaluated and standardized algorithms to define all potential T-cell epitopes (PTEs) were generated. While many unique PTEs could be identified, a finite number based upon prevalence of circulating strains in the database, which we define as vaccine-important PTEs (VIPs), were used to select a common standardized panel of HIV-1 peptides for CTL-based vaccine evaluation. The usability of PTE peptide set was manifested by detection of Nef-specific CTL responses in HIV-1 subtype B infections.

AIDS Vaccines↗

PubMed2006

On modeling HIV and T cells in vivo: assessing causal estimators in vaccine trials.

The first efficacy trials--named STEP--of a T cell vaccine against HIV/AIDS began in 2004. The unprecedented structure of these trials raised new modeling and statistical challenges. Is it plausible that memory T cells, as opposed to antibodies, can actually prevent infection? If they fail at prevention, to what extent can they ameliorate disease? And how do we estimate efficacy in a vaccine trial with two primary endpoints, one traditional, one entirely novel (viral load after infection), and where the latter may be influenced by selection bias due to the former? In preparation for the STEP trials, biostatisticians developed novel techniques for estimating a causal effect of a vaccine on viral load, while accounting for post-randomization selection bias. But these techniques have not been tested in biologically plausible scenarios. We introduce new stochastic models of T cell and HIV kinetics, making use of new estimates of the rate that cytotoxic T lymphocytes--CTLs; the so-called killer T cells--can kill HIV-infected cells. Based on these models, we make the surprising discovery that it is not entirely implausible that HIV-specific CTLs might prevent infection--as the designers explicitly acknowledged when they chose the endpoints of the STEP trials. By simulating thousands of trials, we demonstrate that the new statistical methods can correctly identify an efficacious vaccine, while protecting against a false conclusion that the vaccine exacerbates disease. In addition to uncovering a surprising immunological scenario, our results illustrate the utility of mechanistic modeling in biostatistics.

AIDS Vaccines↗

PubMed2006

Maternal single-dose nevirapine versus placebo as part of an antiretroviral strategy to prevent mother-to-child HIV transmission in Botswana.

BACKGROUND: Single-dose nevirapine given to women and infants reduces mother-to-child HIV transmission, but nevirapine resistance develops in a large percentage of women. OBJECTIVE: To determine whether the maternal nevirapine dose could be eliminated in the setting of zidovudine prophylaxis. DESIGN, SETTING, AND PARTICIPANTS: A 2 x 2 factorial, randomized, clinical trial, with a double-blinded peripartum factor designed to assess the equivalence of maternal single-dose nevirapine versus placebo with respect to HIV transmission. A total of 709 HIV-infected pregnant women were randomized from four district hospitals in Botswana, resulting in 694 live first-born infants. HAART was available for women with AIDS. INTERVENTION: All women received a background of zidovudine from 34 weeks' gestation through delivery, and all infants received single-dose nevirapine at birth and zidovudine from birth through 1 month. Women were randomized to receive either single-dose nevirapine or placebo during labor. MAIN OUTCOME MEASURES: The primary endpoint was infant HIV infection by the 1-month visit. RESULTS: Of the 694 infants in this equivalence study, 15 (4.3%) of 345 in the maternal nevirapine arm were HIV infected by 1 month, versus 13 (3.7%) of 349 in the maternal placebo arm (95% confidence interval for difference, -2.4% to 3.8%), meeting pre-determined equivalence criteria. Nevirapine resistance at 1 month postpartum was detected in 45% of a random sample of women who received nevirapine. CONCLUSIONS: In the setting of maternal zidovudine and infant zidovudine plus single-dose nevirapine, infant HIV infection rates were similar whether women received single-dose nevirapine or placebo. This strategy avoids the potential for maternal nevirapine resistance.

Adult↗

PubMed2006

Interactive association of proviral load and IFN-gamma-secreting T cell responses in HIV-1C infection.

We investigated the interactive relationship between proviral DNA load and virus-specific IFN-gamma-secreting T cell responses in HIV-1C infection. The presence or absence of correlation, and inverse or direct type of correlation, if any, were dependent on targeted viral gene product. Responses to Gag p24 or to Pol were associated with lower proviral DNA load. Associations between proviral DNA load and T cell responses did not necessarily mirror relationships between plasma RNA load and T cell responses. An interaction analysis showed a synergy in that lower proviral DNA and lower plasma RNA load were associated with high Gag p24-specific IFN-gamma-secreting T cell response (interaction test P = 0.0003). Our findings support the idea that HIV proteins have differential value for vaccine design, and suggest that, for HIV-1C, Gag p24 may be one of the most attractive regions to include in vaccine designs to control both plasma RNA load and cell-associated proviral DNA load.

DNA, Viral↗

PubMed2006

Statistical evaluation of HIV vaccines in early clinical trials.

The HIV pandemic is a pressing threat to global public health; HIV vaccine development is critical. Clinical evaluation of HIV vaccine candidates differs from the standard therapeutics trial framework primarily due to the fact that healthy individuals are studied. We present an early stage evaluation program developed for the HIV Vaccine Trials Network (HVTN) motivated by characteristics unique to the vaccine setting. The program consists of 3 prototypical stages (Phase I, Ib, II) that provide a unified yet flexible approach to the safety and immunogenicity evaluation of diverse vaccine regimens. The goal of these early trials is to narrow the number of candidate vaccines to the most promising candidates worthy of further study in efficacy trials.

AIDS Vaccines↗

PubMed2006

HIV-1 subtype C in vitro growth and coreceptor utilization.

Human immunodeficiency virus type 1 subtype C (HIV-1C) accounts for about 50% of all HIV infections in the pandemic and is the predominant subtype in the heavily burdened region of southern Africa. HIV-1C possesses unique genetic and phenotypic features that might be associated with biological differences compared to other subtypes. Here, we generated virus isolates from individuals at different stages of HIV-1C infection and investigated the chemokine receptor repertoire that the derived HIV-1C isolates may utilize for entry. Our results show that the R5 phenotype predominates among viruses in Botswana, with a lesser contribution of viruses showing the dualtropic X4R5 phenotype. No viruses of pure X4 phenotype were found, which suggests no discernable evolution of HIV-1C to a monotropic X4 phenotype as the epidemic ages in Botswana. Usage of other coreceptors was rare and apparently insignificant. These results enhance our understanding of HIV-1C biology, with implications for designing and testing therapeutic and prophylactic agents.

Cell Line↗

PubMed2006

Sensitivity analyses comparing outcomes only existing in a subset selected post-randomization, conditional on covariates, with application to HIV vaccine trials.

In many experiments, researchers would like to compare between treatments and outcome that only exists in a subset of participants selected after randomization. For example, in preventive HIV vaccine efficacy trials it is of interest to determine whether randomization to vaccine causes lower HIV viral load, a quantity that only exists in participants who acquire HIV. To make a causal comparison and account for potential selection bias we propose a sensitivity analysis following the principal stratification framework set forth by Frangakis and Rubin (2002, Biometrics58, 21-29). Our goal is to assess the average causal effect of treatment assignment on viral load at a given baseline covariate level in the always infected principal stratum (those who would have been infected whether they had been assigned to vaccine or placebo). We assume stable unit treatment values (SUTVA), randomization, and that subjects randomized to the vaccine arm who became infected would also have become infected if randomized to the placebo arm (monotonicity). It is not known which of those subjects infected in the placebo arm are in the always infected principal stratum, but this can be modeled conditional on covariates, the observed viral load, and a specified sensitivity parameter. Under parametric regression models for viral load, we obtain maximum likelihood estimates of the average causal effect conditional on covariates and the sensitivity parameter. We apply our methods to the world's first phase III HIV vaccine trial.

AIDS Vaccines↗

PubMed2006

A comparison of eight methods for the dual-endpoint evaluation of efficacy in a proof-of-concept HIV vaccine trial.

To support the design of the world's first proof-of-concept (POC) efficacy trial of a cell-mediated immunity-based HIV vaccine, we evaluate eight methods for testing the composite null hypothesis of no-vaccine effect on either the incidence of HIV infection or the viral load set point among those infected, relative to placebo. The first two methods use a single test applied to the actual values or ranks of a burden-of-illness (BOI) outcome that combines the infection and viral load endpoints. The other six methods combine separate tests for the two endpoints using unweighted or weighted versions of the two-part z, Simes', and Fisher's methods. Based on extensive simulations that were used to design the landmark POC trial, the BOI methods are shown to have generally low power for rejecting the composite null hypothesis (and hence advancing the vaccine to a subsequent large-scale efficacy trial). The unweighted Simes' and Fisher's combination methods perform best overall. Importantly, this conclusion holds even after the test for the viral load component is adjusted for bias that can be introduced by conditioning on a postrandomization event (HIV infection). The adjustment is derived using a selection bias model based on the principal stratification framework of causal inference.

AIDS Vaccines↗

PubMed2005

HIV-1 virologic and immunologic progression and initiation of antiretroviral therapy among HIV-1-infected subjects in a trial of the efficacy of recombinant glycoprotein 120 vaccine.

The first trial of the efficacy of a human immunodeficiency virus (HIV)-1 vaccine was conducted in North America and The Netherlands between 1998 and 2003. This multicenter, randomized, placebo-controlled trial of a recombinant glycoprotein 120 vaccine included 5403 initially HIV-negative volunteers who were monitored for 3 years. The 368 subjects who acquired HIV-1 infection were monitored for 2 years by use of the following postinfection end points: plasma HIV-1 RNA level (viral load), CD4+ lymphocyte count, initiation of antiretroviral therapy (ART), and HIV-1-related clinical outcomes. This article reports the study results that pertain to the effect of vaccination on the postinfection end points. The time until initiation of ART and the time until virologic failure or initiation of ART were similar in the vaccine arm and the placebo arm. The pre-ART viral load and CD4+ lymphocyte count trajectories were also comparable between the groups. Evidently, the vaccine did not affect HIV-1 disease progression.

AIDS Vaccines↗

PubMed2005

Failure time analysis of HIV vaccine effects on viral load and antiretroviral therapy initiation.

The world's first efficacy trial of a preventive HIV vaccine was completed in 2003. Study participants who became HIV infected were followed for 2 years and monitored for HIV viral load and initiation of antiretroviral therapy (ART). In order to determine if vaccination may have altered HIV progression in persons who acquired HIV, a pre-specified objective was to compare the time until a composite endpoint between the vaccine and placebo arms, where the composite endpoint is the first event of ART initiation or viral failure (HIV viral load exceeds a threshold x(vl) copies/ml). Specifically, with vaccine efficacy, VE(tau, x(vl)), defined as one minus the ratio (vaccine/placebo) of the cumulative probability of the composite endpoint (with failure threshold x(vl)) occurring by tau months, the aim was to estimate the four parameters {VE(tau, x(vl)): x(vl) is an element of {1500, 10,000, 20,000, 55,000} copies/ml} with simultaneous 95% confidence bands. A Gaussian multipliers simulation method is devised for constructing confidence bands for VE(tau, x(vl)) with x(vl) spanning multiple discrete values or a continuous range. The new method is evaluated in simulations and is applied to the vaccine trial data set.

AIDS Vaccines↗

PubMed2005

Correlation between immunologic responses to a recombinant glycoprotein 120 vaccine and incidence of HIV-1 infection in a phase 3 HIV-1 preventive vaccine trial.

BACKGROUND: An objective of the first efficacy trial of a candidate vaccine containing recombinant human immunodeficiency virus (HIV) type 1 envelope glycoprotein 120 (rgp120) antigens was to assess correlations between antibody responses to rgp120 and the incidence of HIV-1 infection. METHODS: Within the randomized trial (for vaccinees, n=3598; for placebo recipients, n=1805), binding and neutralizing antibody responses to rgp120 were quantitated. A case-cohort design was used to study correlations between antibody levels and HIV-1 incidence. RESULTS: Peak antibody levels were significantly inversely correlated with HIV-1 incidence. The relative risk (RR) of infection was 0.63 (95% confidence interval, 0.45-0.89) per log(10) higher neutralization titer against HIV-1(MN), and the RRs of infection for second-, third-, and fourth-quartile responses of antibody blocking of gp120 binding to soluble CD4 versus first-quartile responses (the lowest responses) were 0.35, 0.28, and 0.22, respectively. CONCLUSIONS: Despite inducing a complex, robust immune response, the vaccine was unable to reduce the incidence of HIV-1. Two interpretations of the correlative results are that the levels of antibodies (i) caused both an increased (low responders) and decreased (high responders) risk of HIV-1 acquisition or (ii) represented a correlate of susceptibility to HIV-1 but had no causal effect on susceptibility. Although the data cannot definitively discriminate between these 2 explanations, (ii) appears to be more likely.

AIDS Vaccines↗

PubMed2005

Accuracy and precision of estimating intervention efficacy when the timing of observed events differ by treatment arm.

Randomization in clinical trials minimizes differences between treatment arms, allowing observed treatment differences to be attributable to an intervention. For prospective clinical trials, we examine the effects on inference when other specified treatment arm differences are also present. These differences are imposed using three measures: time between the unobserved failure event (e.g., HIV infection) and its detection, visit schedule adherence and dropout. Our context of interest is trials with non-recurrent time-to-event outcomes and fixed visit intervals, where treatment efficacy is measured either by a hazard ratio or by a ratio of cumulative incidence functions. Moderate treatment differences in visit adherence, either through missed visits or additional unscheduled visits, were not found to cause substantial bias or to reduce power. However, both differential loss to follow-up (when coincidentally dependent on risk of failure) and differential time between event and detection should be of concern in designing clinical trials. Efforts to re-capture subjects at the end of study for failure assessment are helpful in some contexts, and may be considered in study planning.

Biometry↗

PubMed2005

Covariability of selected amino acid positions for HIV type 1 subtypes C and B.

We studied covariability of selected amino acid positions in globally dominant HIV-1 subtype C viruses. The analyzed sequences spanned the V3 loop, Gag p17, Gag p24, and five CTL epitope-rich regions in Gag, Nef, and Tat. The corresponding regions in HIV-1 subtype B were also evaluated. The analyses identified a great number of covarying pairs and triples of sites in the HIV-1B V3 loop (173 site pairs, 242 site triples). Several of these interactions were found in the earlier studies [e.g., the V3 loop covariability analyses by Korber et al. (Proc Natl Acad Sci USA 1993;90:7176-7180) and Bickel et al. (AIDS Res Hum Retroviruses 1996;12:1401-1411)] and have known biological significance. However, generally these key covarying sites did not covary in the HIV-1C V3 loop (total 17 covarying site pairs), suggesting that the V3 loop may have subtype differences in functional or structural operating characteristics. Covariability of positions 309 and 312 was observed in the immunodominant region HIV-1C Gag 291-320 but no covariability was found in the corresponding region of HIV-1B, and vice versa for Nef 122-141; these findings may reflect subtype-specific covariability within immunologically relevant regions. Gag p17 exhibited greater covariability and less diversity for HIV-1B than HIV-1C, raising the hypothesis that Gag p17 is highly immunodominant in HIV-1B and is especially important for HIV-1B vaccines. Information on covariability should be better exploited in assessments of HIV-1 diversity and how to surmount it with vaccine design.

Amino Acid Sequence↗

PubMed2005

Prognostic significance of DCC and p27Kip1 in colorectal cancer.

The progression of colorectal cancer is a multistage process associated with specific molecular alterations. The stepwise accumulation of these multiple genetic mutations progressively results in the acquisition of neoplastic cell behavior. The genetic abnormalities associated with the expression of metastatic phenotype, therefore, may be of prognostic significance in the clinical treatment of colorectal cancer patients. In this study, the immunohistochemical expression of the deleted in colorectal cancer gene (DCC) and p27Kip1 was assessed in 168 paraffin-embedded, formalin-fixed tumors of patients with stage II and III colorectal cancer. Kaplan-Meier survival curves and log-rank statistics were used to analyze survival times after curative primary tumor resection, and Cox proportional hazards models were used to adjust the assessment of demographic and clinical covariates. Loss of DCC or p27Kip1 expression had no influence on survival in patients with stage II or III colorectal cancer. The 5-year survival rates of DCC-positive and DCC-negative tumors were 51.8% and 35.7% (P=0.40), respectively. The 5-year survival rate of patients with p27Kip1-positive tumors was 47.9%, whereas the rate for patients with p27Kip1-negative tumors was 38.8% (P=0.68). After adjustment for all evaluated variables, neither DCC or p27Kip1 was found to be a predictor of survival (risk ratio for DCC, 0.98; 95% confidence interval, 0.66-1.56; P=0.92; risk ratio for p27Kip1, 0.87; 95% confidence interval, 0.58-1.29; P=0.49). The present study demonstrated that the expression of neither DCC nor p27Kip1 was predictive in poor survival outcome in patients with stage II or III colorectal cancer.

Biomarkers, Tumor↗

PubMed2005

Two-sample tests for comparing intra-individual genetic sequence diversity between populations.

Consider a study of two groups of individuals infected with a population of a genetically related heterogeneous mixture of viruses, and multiple viral sequences are sampled from each person. Based on estimates of genetic distances between pairs of aligned viral sequences within individuals, we develop four new tests to compare intra-individual genetic sequence diversity between the two groups. This problem is complicated by two levels of dependency in the data structure: (i) Within an individual, any pairwise distances that share a common sequence are positively correlated; and (ii) for any two pairings of individuals which share a person, the two differences in intra-individual distances between the paired individuals are positively correlated. The first proposed test is based on the difference in mean intra-individual pairwise distances pooled over all individuals in each group, standardized by a variance estimate that corrects for the correlation structure using U-statistic theory. The second procedure is a nonparametric rank-based analog of the first test, and the third test contrasts the set of subject-specific average intra-individual pairwise distances between the groups. These tests are very easy to use and solve correlation problem (i). The fourth procedure is based on a linear combination of all possible U-statistics calculated on independent, identically distributed sequence subdatasets, over the two levels (i) and (ii) of dependencies in the data, and is more complicated than the other tests but can be more powerful. Although the proposed methods are empirical and do not fully utilize knowledge from population genetics, the tests reflect biology through the evolutionary models used to derive the pairwise sequence distances. The new tests are evaluated theoretically and in a simulation study, and are applied to a dataset of 200 HIV sequences sampled from 21 children.

Base Sequence↗

PubMed2004

Breakthrough infections during phase 1 and 2 prime-boost HIV-1 vaccine trials with canarypox vectors (ALVAC) and booster dose of recombinant gp120 or gp160.

Candidate human immunodeficiency virus (HIV)-1 vaccines that elicit cytotoxic T lymphocytes may modulate HIV infection, requiring a prototype evaluation to assess participants who become infected with HIV. Of 1497 participants in canarypox HIV-1 vaccine prime-boost trials, 28 (1.9%) acquired HIV-1 infection after vaccination. Median plasma HIV-1 RNA levels (vaccinees, 4.78 log10 copies/mL; placebo recipients, 4.27 log10 copies/mL) and CD4 cell counts (vaccinees, 552 cells/mm3; placebo recipients, 657 cells/mm3) before administration of antiretroviral therapy (ART) and time to a composite end point (plasma HIV-1 RNA level >55,000 copies/mL, CD4 cell count <350 cells/mm3, or initiation of ART) did not differ significantly between vaccinees and placebo recipients (P =.4, P =.1, and P =.7, respectively). Persons who acquire HIV-1 infection while enrolled in HIV-1 vaccine trials can be successfully followed after infection, to determine whether vaccines alter the course of HIV-1 infection.

AIDS Vaccines↗

PubMed2004

Tests for comparing mark-specific hazards and cumulative incidence functions.

It is of interest in some applications to determine whether there is a relationship between a hazard rate function (or a cumulative incidence function) and a mark variable which is only observed at uncensored failure times. We develop nonparametric tests for this problem when the mark variable is continuous. Tests are developed for the null hypothesis that the mark-specific hazard rate is independent of the mark versus ordered and two-sided alternatives expressed in terms of mark-specific hazard functions and mark-specific cumulative incidence functions. The test statistics are based on functionals of a bivariate test process equal to a weighted average of differences between a Nelson-Aalen-type estimator of the mark-specific cumulative hazard function and a nonparametric estimator of this function under the null hypothesis. The weight function in the test process can be chosen so that the test statistics are asymptotically distribution-free. Asymptotically correct critical values are obtained through a simple simulation procedure. The testing procedures are shown to perform well in numerical studies, and are illustrated with an AIDS clinical trial example. Specifically, the tests are used to assess if the instantaneous or absolute risk of treatment failure depends on the amount of accumulation of drug resistance mutations in a subject's HIV virus. This assessment helps guide development of anti-HIV therapies that surmount the problem of drug resistance.

Anti-Retroviral Agents↗