AIDS Clinical Trials Group Protocol Research Articles

Compartmental Pharmacokinetic Analysis of Oral Amprenavir with Secondary Peaks

Amprenavir is a protease inhibitor that has been shown to have secondary peaks postulated to be due to enterohepatic recycling. We propose a model to describe the pharmacokinetics of amprenavir which accommodates the secondary peak(s). A total of 82 healthy human immunodeficiency virus (HIV)-seronegative subjects were administered a single 600-mg dose of amprenavir as part of adult AIDS Clinical Trials Group protocol A5043. Serial blood samples were obtained over 24 h. Samples were analyzed for amprenavir and fit to a compartmental model using ADAPT II software, with all relevant parameters conditional with respect to bioavailability. The model accommodated secondary peaks by incorporating clearance out of the central compartment with delayed instantaneous release back into the gut compartment. The data were weighted by the inverse of the estimated measurement error variance; model discrimination was determined using Akaike's Information Criteria. A total of 76 subjects were evaluable in the study analysis. The data were best fit by a two-compartment model, with 98.7% of the subjects demonstrating a secondary peak. Amprenavir had a mean total clearance of 1.163 liters/h/kg of body weight (0.7), a central volume of distribution of 1.208 liters/kg (0.8), a peripheral volume of distribution of 8.2 liters/kg (0.81), and distributional clearance of 0.04 liters/h/kg (0.81). The time to the secondary peak was 7.86 h (0.17), and clearance into a recycling compartment was 0.111 liters/kg/h (0.74). Amprenavir pharmacokinetics has been well described using a two-compartment model with clearance to a recycling compartment and release back into the gut. The nature of the secondary peaks may be an important consideration for the interpretation of amprenavir plasma concentrations during therapeutic drug monitoring.

Hidden Markov models for settings with interval-censored transition times and uncertain time origin: application to HIV genetic analyses

The simplicity and flexibility of Markov models make them appealing for investigations of the acquisition of HIV drug-resistance mutations, whose presence can define specific Markov states. Because the exact time of acquiring a mutation is not observed during clinical research studies on HIV infection, it is important that methods for fitting such models accommodate interval-censored transition times. Furthermore, many such studies include patients with extensive treatment experience prior to the onset of the studies. Therefore, the virus in these patients may have already acquired resistance mutations by study entry. Retrospective data regarding the time on treatment, which is often known or known with error, provide information about the acquisition rates before the start of a study. Finally, variability in the genetic sequences of circulating HIV creates uncertainty in the Markov states. This paper considers approaches to fitting Markov models to data with interval-censored transition times when the time origin and the Markov states are known with error. The methods were applied to AIDS Clinical Trial Group protocol 398, a randomized comparison of mono- versus dual-protease inhibitor use in heavily pretreated patients. We found that the estimated rates of acquiring certain classes of mutations depended on the presence of others, and that the precision of these estimates can be considerably improved by inclusion of retrospective data.

Hemochromatosis (HFE) gene mutations and peripheral neuropathy during antiretroviral therapy

Peripheral neuropathy (PN) often complicates nucleoside reverse transcriptase inhibitor (NRTI) therapy of HIV infection and may involve mitochondrial dysfunction. Since iron deficiency is associated with some types of PN, and iron is essential for mitochondrial function, we tested the hypothesis that hemochromatosis (HFE) gene mutations influence susceptibility to NRTI-induced PN. Case-control study involving multicenter, AIDS Clinical Trials Group (ACTG) protocol 384 and ACTG Human DNA Repository specimens. Study participants were randomized to receive three- or four-drug antiretroviral therapy with didanosine (ddI) plus stavudine (d4T) or zidovudine plus lamivudine, given with efavirenz, nelfinavir, or both, with up to three years of follow-up. PN was ascertained based on signs and symptoms. HFE C282Y and H63D genotypes were determined, and associations with PN were assessed using logistic regression. : Of 509 participants, 147 (29%) developed PN, 73% of whom had been randomized to receive ddI plus d4T. Among ddI/d4T-ever-treated individuals, HFE C282Y heterozygotes developed PN on ddI/d4T significantly less often than C282Y non-carriers, adjusting for age, CD4 lymphocyte count and viral load at baseline, and concomitant antiretroviral drugs [6% vs. 35%, respectively, in whites; adjusted odds ratio (OR), 0.17; 95% confidence interval (CI) 0.03-0.83; P = 0.021]. Regardless of race/ethnicity, ddI/d4T-associated PN was uncommon in C282Y heterozygotes [race-adjusted OR, 0.30; 95% CI 0.09-0.96); P = 0.042]. Iron-loading HFE mutations such as C282Y are associated with a decreased risk of PN during antiretroviral therapy. This finding has potential implications for the prediction and prevention of NRTI-associated PN, particularly in populations at risk of iron deficiency.

Human immunodeficiency virus-1 and preconception care.

Human immunodeficiency virus-1 and preconception care.

Variations in Self-Rated Health Among Patients with HIV Infection

To assess how patients with HIV who are enrolled in a clinical trials cohort rate their health and to compare their ratings with those of patients with HIV from 2 other cohorts: the HIV Cost and Services Utilization Study (HCSUS), and Adult AIDS Clinical Trials Group protocol 320 (ACTG 320). We analyzed baseline information for the 1649 subjects enrolled in the Adult AIDS Clinical Trials Group Longitudinal Linked Randomized Trials (ALLRT) study prior to March 2002 who had self-rated health data available. We compared those results with results from 2 other groups: HCSUS, the only nationally representative sample of people in care for HIV in the U.S., which conducted baseline interviews in 1996 and 1997, and ACTG 320, a randomized, double-blinded, placebo-controlled trial comparing a 3-drug antiretroviral regimen with a 2-drug combination, which enrolled subjects in the same general time frame as HCSUS. We used t tests, Pearson correlations, and linear regression to determine factors associated with self-rated health and z scores to compare results between cohorts. The mean (SD) rating scale value on a 0-100 scale for ALLRT participants was 79.8 (16.8). Values were significantly lower for subjects who were older, had a history of injection drug use, had lower CD4 cell counts, or were beginning salvage antiretroviral therapy. Subjects in ALLRT reported significantly better self-rated health at baseline than those in HCSUS or ACTG 320 (11-12% higher rating scale values in ALLRT; p<0.05). When cohort differences were accounted for through regression and stratification, the differences in scores between subjects in ALLRT and HCSUS increased and the differences in scores between subjects in ALLRT and ACTG 320 diminished. Self-rated health varied significantly by age, CD4 count, injection drug use history, and salvage therapy status. Differences in self-rated health for clinical trials and non-clinical trials samples appear to be substantial and should be considered when applying trial results to clinical populations.

Food poisoning byDatura stramonium: an unusual case report

88 infected women and prevention of perinatal HIV-1 transmission. J Acquir Immune Defic Syndr 2002; 29: 484-94. 15. European Collaborative Study Group. HIV-infected pregnant women and vertical transmission in Europe since 1986. AIDS 2001; 15: 761-70. 16. Connor EM, Sperling RS, Gelber R, et al. Reduction of maternal-infant transmission of human immunodeficiency virus type 1 with zidovudine treatment. Pediatric AIDS Clinical Trials Group Protocol 076 Study Group. N Engl J Med 1994; 331: 1173-80. 17. European Collaborative Study Group. Exposure to antiretroviral therapy in utero or early life: the health of

Sa.75. Susceptibility of Viral Isolates of Pediatric AIDS Clinical Trials Group Protocol 351 to Pro 542 (Rcd4-Igg2) and Pro 140 (Mab to Ccr5)

Sa.75. Susceptibility of Viral Isolates of Pediatric AIDS Clinical Trials Group Protocol 351 to Pro 542 (Rcd4-Igg2) and Pro 140 (Mab to Ccr5)

Postpartum sterilization choices made by HIV-infected women.

OBJECTIVE: To assess if HIV-infected women made different choices for postpartum sterilization after implementation of the Pediatric AIDS Clinical Trials Group protocol 076 (November 1, 1994) compared to before implementation. STUDY DESIGN: A retrospective cohort study in which medical records were reviewed to obtain demographic, obstetric and HIV-related data from January 1993 through December 2002. HIV-infected women who completed a pregnancy by birth or abortion were divided into two comparison groups: "Pre-076" and "Post-076". The primary outcome was sterilization by postpartum tubal ligation.Results. Forty-two women (74%) in the Pre-076 group chose sterilization compared to 139 of 310 women (45%) in the Post-076 group (unadjusted OR 3.44, 95% CI 1.83, 6.47). Seventy-one percent of women younger than 21 years of age in the Pre-076 Group chose sterilization compared with only 35% of women younger than 21 years in the Post-076 group (p = 0.0136). Similarly, 78% of primiparous women chose sterilization after their first pregnancy in the Pre-076 group, compared to 14% in the Post-076 group (p < 0.001). CONCLUSIONS: Since the implementation of PACTG 076 protocol in November 1994, fewer HIV-infected women chose postpartum sterilization. The typical woman who now chooses postpartum sterilization is less likely to be young or primiparous than those who chose sterilization before PACTG Protocol 076 implementation.

Safety and Immunogenicity of an HIV‐1 Recombinant Canarypox Vaccine in Newborns and Infants of HIV‐1–Infected Women

Pediatric AIDS Clinical Trials Group protocol 326 is a study of 2 formulations of recombinant canarypox ALVAC vaccine (vCP205) against human immunodeficiency virus type 1 (HIV-1). HIV-1-exposed infants were randomized to receive 1 of 2 formulations of vCP205 or placebo at birth and 4, 8, and 12 weeks. The vaccines were safe. Lymphoproliferative responses were detected at > or =2 time points in 44%-56% of vaccinees and none of the placebo recipients. A cytotoxic T lymphocyte response on at least 1 occasion was detected in 62.5% of infants in cohort 1 (10(6.08) median tissue culture dose [TCID(50)] vaccine formulation) and 44% of infants in cohort 2 (10(6.33) TCID(50) vaccine formulation). Rare mucosal immunoglobulin A responses and no measurable vaccine-elicited serum antibodies were detected. In children, vCP205 appeared to be safe and immunogenic.

Performance Characteristics of HIV-1 Culture and HIV-1 DNA and RNA Amplification Assays for Early Diagnosis of Perinatal HIV-1 Infection

Lambert JS, Harris R, Stiehm R, et al. J Acquir Immune Defic Syndr. 2003;34:512–519The diagnosis of HIV infection in a newborn exposed to HIV in utero is a challenge. In the early years of the epidemic, HIV clinicians monitored the decline of HIV antibody levels for up to 2 years after birth to confirm that a child was not HIV-infected. HIV infection in infants is now typically made by the detection of viral DNA sequences in peripheral blood mononuclear cells by means of a DNA polymerase chain reaction (PCR). Plasma HIV-RNA measurements with PCR may also be valuable but has the theoretic limitation of false-negative reactions resulting from early treatment of the mother and infant. The purpose of this study was to evaluate the performance of HIV DNA PCR, HIV RNA PCR, and HIV culture to identify infected infants exposed to the virus in utero.Infants participating in the Pediatric AIDS Clinical Trials Group protocol 185.Specimens from the infants (24 infected and 100 uninfected) obtained prospectively were studied with standard nucleic acid–amplification assays and peripheral blood mononuclear cell microcultures. The sensitivities, specificities, and positive and negative predictive values were calculated for each of the 3 assay systems.At birth the sensitivity of culture, DNA PCR, and RNA PCR were 21%, 11%, and 27%, respectively. By 6 weeks, the sensitivity had improved to 90%, 83%, and 95%. The specificity was 99% to 100% for all assays at all times.The authors concluded that the diagnostic performance of the RNA PCR assay matched or exceeded that of culture and DNA PCR. Because RNA assays require less blood volume and often can be performed more quickly at reference laboratories, it is suggested that RNA assays may be used for early diagnosis of HIV infection in infants.This study demonstrates that RNA PCR assays are effective for the diagnosis of HIV infection. However, it must be noted that cryopreserved specimens were used for these PCR assays and may have impacted the sensitivity of the DNA PCR. Additionally, we have had 3 false-positive RNA PCR assays in 2 newborns and 1 adolescent exposed to HIV. A negative RNA PCR at or after 6 weeks of age strongly indicates that an infant is not infected.

Association of Selected Phenotypic Markers of Lymphocyte Activation and Differentiation with Perinatal Human Immunodeficiency Virus Transmission and Infant Infection

This study of a subset of women and infants participating in National Institutes of Health Pediatric AIDS Clinical Trials Group protocol 185 evaluated lymphocyte phenotypic markers of immune activation and differentiation to determine their association with the likelihood of human immunodeficiency virus (HIV) transmission from the women to their infants and the potential for early identification and/or prognosis of infection in the infants. Lymphocytes from 215 human immunodeficiency virus type 1 (HIV)-infected women and 192 of their infants were analyzed by flow cytometry with an extended three-color panel of monoclonal antibodies. Women who did not transmit to their infants tended to have higher CD4+ T cells. Most notably, levels of total CD8+ T cells and CD8+ CD38+ cells made significant independent contributions to predicting the risk of mother-to-child transmission. Adjusting for HIV-1 RNA level at entry, a one percentage-point increase in these marker combinations was associated with a nine percent increase in the likelihood of maternal transmission. Total as well as naive CD4+ T cells were significantly higher in uninfected than infected infants. Total CD8+ cells, as well as CD8+ cells positive for HLA-DR+, CD45 RA+ HLA-DR+, and CD28+ HLA-DR+ were elevated in infected infants. Detailed immunophenotyping may be helpful in predicting which pregnant HIV-infected women are at increased risk of transmitting HIV to their infants. Increasing differences in lymphocyte subsets between infected and uninfected infants became apparent as early as six weeks of age. Detailed immunophenotyping may be useful in supporting the diagnosis of HIV infection in infants with perinatal HIV exposure.

The Rate of Serious Bacterial Infections Among HIV-Infected Children With Immune Reconstitution Who Have Discontinued Opportunistic Infection Prophylaxis

Receipt of highly active antiretroviral therapy is associated with a decrease in the incidence of opportunistic infections (OIs) among HIV-infected adults. The goal of Pediatric AIDS Clinical Trials Group protocol 1008 was to evaluate prospectively the incidence of serious bacterial infections (SBIs) and other OIs after discontinuation of OI and/or Pneumocystis jiroveci pneumonia (PCP) prophylaxis among HIV-infected pediatric subjects who experienced immune reconstitution while receiving stable antiretroviral therapy. HIV-infected children and adolescents, 2 to 21 years of age, who had received OI and/or PCP prophylaxis for > or =6 months were enrolled if they had sustained responses (>16 weeks before study entry) to antiretroviral therapy, with CD4+ cell percentages of > or =20% for patients >6 years of age or > or =25% for patients 2 to 6 years of age. Prophylaxis was discontinued at entry. To identify whether any correlation existed between functional immune reconstitution and protection from OIs, subjects were immunized with the hepatitis A virus vaccine. The association between the humoral immune response and the likelihood of developing an OI was evaluated. A total of 235 HIV-infected subjects from 43 participating sites had a median follow-up period of 132 weeks, yielding 547 person-years of observation. Twenty SBIs were observed among 19 subjects, resulting in an incidence rate of 3.66 SBIs per 100 person-years (95% confidence interval: 2.24-5.66 SBIs per 100 person-years). Sixteen of the events were presumed bacterial pneumonia, with 4 proven SBIs. One participant experienced 2 separate pneumonia episodes, of presumed bacterial cause. Ten subjects who developed SBIs had baseline CD4+ cell counts of > or =750 cells per mm3, and 15 had CD4+ cell percentages of > or =25% at the time of their SBIs. Two subjects died as a result of non-SBI-related causes. There were no statistically significant differences in changes over time in CD4+ cell counts or CD4+ cell percentages between subjects who experienced primary end points and those who did not. There was no evidence that baseline protease inhibitor use, gender, race/ethnicity, age, or CD4+ cell count or percentage affected the time to development of a SBI. OI or PCP prophylaxis can be withdrawn safely for HIV-infected pediatric patients who experience CD4+ cell recovery while receiving stable antiretroviral therapy. More studies are needed to assess the association between antibody responses to neoantigens and the development of SBIs.

Iterative Partial Least Squares with Right‐Censored Data Analysis: A Comparison to Other Dimension Reduction Techniques

In the linear model with right-censored responses and many potential explanatory variables, regression parameter estimates may be unstable or, when the covariates outnumber the uncensored observations, not estimable. We propose an iterative algorithm for partial least squares, based on the Buckley-James estimating equation, to estimate the covariate effect and predict the response for a future subject with a given set of covariates. We use a leave-two-out cross-validation method for empirically selecting the number of components in the partial least-squares fit that approximately minimizes the error in estimating the covariate effect of a future observation. Simulation studies compare the methods discussed here with other dimension reduction techniques. Data from the AIDS Clinical Trials Group protocol 333 are used to motivate the methodology.

Postpartum Sterilization Choices Made by HIV-Infected Women

Objective.To assess if HIV-infected women made different choices for postpartum sterilization after implementation of the Pediatric AIDS Clinical Trials Group protocol 076 (November 1, 1994) compared to before implementation.Study design.A retrospective cohort study in which medical records were reviewed to obtain demographic, obstetric and HIV-related data from January 1993 through December 2002. HIV-infected women who completed a pregnancy by birth or abortion were divided into two comparison groups: “Pre-076” and “Post-076”. The primary outcome was sterilization by postpartum tubal ligation.Results.Forty-two women (74%) in the Pre-076 group chose sterilization compared to 139 of 310 women (45%) in the Post-076 group (unadjusted OR 3.44, 95 % CI 1.83, 6.47). Seventy-one percent of women younger than 21 years of age in the Pre-076 Group chose sterilization compared with only 35% of women younger than 21 years in the Post-076 group (p=0.0136). Similarly, 78% of primiparous women chose sterilization after their first pregnancy in the Pre-076 group, compared to 14% in the Post-076 group (p&lt; 0.001).Conclusions.Since the implementation of PACTG 076 protocol in November 1994, fewer HIV-infected women chose postpartum sterilization. The typical woman who now chooses postpartum sterilization is less likely to be young or primiparous than those who chose sterilization before PACTG Protocol 076 implementation.

Tests for treatment group differences in the hazards for survival, before and after the occurrence of an intermediate event

In many settings, one would expect that the hazard for a terminal event would change with the occurrence of an intermediate event. For example, in an AIDS clinical trial, it is of interest to assess whether there is a difference between treatments in the hazards for death prior to drop in Karnofsky performance score and in the hazards subsequent to the drop in Karnofsky score. Tests for the effect of treatment on these hazard functions, separately or jointly, are useful in conjunction with tests of overall survival. We consider four Cox regression models for the hazard function, constructed by allowing for various combinations of time-dependent stratification and time-dependent covariates, both of which are based on the occurrence of the intermediate event. Assuming a Markov transition model from the intermediate to the terminal event, partial likelihoods can be used for inference, enabling the use of standard statistical software for computation. We develop analytic approximations for the power of the derived score tests for treatment differences in the hazard functions and evaluate them through simulations. We apply our results to AIDS Clinical Trials Group (ACTG) protocol 021.

HIV Infection and Zidovudine Use in Childbearing Women

Objective. The risk of vertical HIV transmission from mother to child has been shown to be markedly decreased through HIV education, counseling, testing, and zidovudine (ZDV) use. The US Public Health Service published guidelines in 1994 for the use of ZDV on the basis of results of the AIDS Clinical Trials Group Protocol, a multicenter clinical trial of ZDV. The Public Health Service followed these guidelines with recommendations for routine HIV counseling and testing with informed consent for all pregnant women. New Jersey adopted these guidelines as the standard of care and created a program implementing the standard in all hospitals with maternity units. The purpose of this report was to study the trends in the rate of HIV infection in childbearing women over the past decade and to follow patterns of use of ZDV in the HIV-positive women, as a marker for the success of New Jersey9s policy and program to reduce mother-to-child transmission. Methods. Since 1988 in New Jersey, blood from heel-stick filter papers has been tested for the presence of HIV antibody through anonymous, unlinked surveys. Excess blood from screening for inborn errors of metabolism for all infants who were born in the state from July through September of each year was tested using a Food and Drug Administration–approved HIV-1 and Western blot test. Age, race, and ethnicity were recorded, as well as the results from the HIV-1 and Western blot tests. Since 1994, specimens confirmed to be HIV-1 positive by Western blot test were tested for the presence of ZDV, and the results were recorded. Results. The number of New Jersey women included in the study for the period 1990 through 2002 numbered 372305. The percentage of childbearing women who tested positive for HIV declined by 55% during the period, although the declines were not uniform in all subgroups. In the early 1990s, women who were Conclusions. Reducing perinatal HIV transmission is a priority for the New Jersey Department of Health and Senior Services. Reducing perinatal transmission can be accomplished by reducing the number of infants who are exposed perinatally or decreasing the percentage of exposed infants for whom transmission occurs or both. The decrease in prevalence of HIV-positive status in childbearing women is in opposition to an overall increasing trend in prevalence rates. This decrease is thought to be attributable in part to the positive impact of numerous education and prevention programs but may also be the result of a voluntary decision on the part of HIV-infected women not to become pregnant or not to carry to term. In addition, the cohort of women who became infected in the early years of the epidemic may be aging out of their childbearing years, may have more advanced disease with a concomitant difficulty with fertility and carrying to term, or may have died. In New Jersey, a greater proportion of women with newly diagnosed HIV disease are past their childbearing years as compared with earlier years. Increased use of ZDV is thought to be attributable to several factors: dissemination of information to health care providers via continuing medical education activities; dissemination of information to the public, in particular to women; outreach via community-based organizations; and New Jersey Department of Health and Senior Service regulations and policies for mandatory counseling and voluntary testing of all pregnant women. A recent addition to New Jersey9s comprehensive program to decrease perinatal transmission occurred in 2002 with dissemination to hospitals of the department9s standard of care for women who present in labor with unknown HIV status. Physicians, nurses, and hospitals play vital roles in preventing vertical transmission of HIV by providing preconception and postconception counseling, testing with consent of pregnant women, and treatment for HIV-positive mothers, including administration of ZDV. This study not only provides an estimate of the prevalence of HIV infection in the population of childbearing women but also provides a means of examining the vertical transmission of HIV infection from mother to child. Continued research on this subpopulation as well as on other groups will provide additional knowledge to help in the overall goal of reducing HIV prevalence.

Pharmacokinetics and Safety of Stavudine in HIV‐Infected Pregnant Women and Their Infants: Pediatric AIDS Clinical Trials Group Protocol 332

This study evaluates the safety, tolerance, and pharmacokinetics of stavudine (d4T) in human immunodeficiency virus (HIV)-infected zidovudine (ZDV)-intolerant/refusing pregnant women and of single-dose d4T in their infants. Women received d4T and lamivudine (3TC) from enrollment until labor. During labor, women received oral 3TC and either intravenous or oral d4T. Infants received ZDV and 3TC for 6 weeks and a single dose of oral d4T at weeks 1 and 6. Mean maternal antenatal d4T pharmacokinetics (terminal plasma half-life [T1/2], 83.5+/-16.8 min; area under the plasma-concentration time curve [AUC0-infinity), 81.6+/-22.0 microg.min/mL; n=6) were not significantly different from those during labor (T(1/2), 87.3+/-24.7 min; AUC0-infinity, 88.1+/-16.6 microg.min/mL; n=6). Umbilical-cord and maternal plasma concentrations were not significantly different from one another. The oral clearance of d4T in infants was significantly greater at week 6 versus week 1 (6.8+/-1.0 vs. 5.6+/-1.2 mL/min/kg). There were no toxicities, in women or infants, that required discontinuation or modification of the study drug. No infants had positive HIV viral diagnostic tests. d4T with or without 3TC is a potential alternative to ZDV for HIV-infected pregnant women.

Differential virulence of Mycobacterium avium strains isolated from HIV-infected patients with disseminated M. avium complex disease.

The role that colonization with Mycobacterium avium plays in the development of disseminated disease is unclear. In this study, we determined whether all M. avium strains isolated from the portals of M. avium infection are capable of crossing the mucosal border and causing infection. The patients in this study were enrolled in AIDS Clinical Trial Group protocol 341. The patients were divided into 3 groups; 2 groups differed in their immunological and clinical risk for M. avium disease. A third group (n=22 patients) had culture-documented disseminated M. avium complex disease at the time of entry in the study. Eight of 22 patients had M. avium isolated from both a colonized site and blood or bone marrow specimens. All 8 patients had distinct M. avium strains; 2 patients had a polyclonal infection. The virulence properties of 13 strains were determined, including invasion of gastrointestinal cells and replication in macrophages. There were significant differences in the virulence properties, and these differences may provide insight into the interplay between microbial pathogenesis and host defense.

Maternal toxicity and pregnancy complications in human immunodeficiency virus–infected women receiving antiretroviral therapy: PACTG 316

ObjectiveThe purpose of this study was to evaluate rates of maternal toxicity, pregnancy complications, and peripartum morbidity by type and duration of antiretroviral therapy (ART) during pregnancy. Study designThe Pediatric AIDS Clinical Trials Group (PACTG) Protocol 316 (PACTG 316) study evaluated the addition of intrapartum/neonatal nevirapine to background ART to reduce perinatal transmission of human immunodeficiency virus-1 (HIV-1). For this secondary analysis, women were categorized into one of six groups on the basis of ART during pregnancy (monotherapy [monoRx], combination without protease inhibitor [PI], combination with PI), and start time (early: before or during first trimester; late: second or third trimester). ResultsOne thousand four hundred seven women were included: 288 monoRx late, 34 monoRx early, 327 combo, no PI late, 175 combo, no PI early, 320 combo, PI late, and 263 combo, PI early. Symptoms and laboratory abnormalities of moderate grade or more occurred in less than 5% of women. Only gestational diabetes (highest in combo PI early) varied significantly by therapy group. ConclusionIn HIV-infected women receiving prenatal care and ART, adverse events were uncommon.

Growth patterns reflect response to antiretroviral therapy in HIV-positive infants: potential utility in resource-poor settings.

Laboratory monitoring of HIV-infected children is the current standard of care in the United States to guide the appropriate use of antiretroviral therapy (ART). Although ART is becoming a reality in some developing countries, laboratory monitoring of ART is costly, necessitating creative approaches to monitoring. As an initial step to guide monitoring of HIV progression in low resource settings, we assessed the utility of the physical examination to predict clinical progression of HIV. We conducted a retrospective cohort study of HIV-infected children using data from Pediatric AIDS Clinical Trials Group Protocol 300. We developed a clinical predictive model, and compared the utility of the clinical model to the change in HIV RNA viral load as diagnostic tests of ART failure. The clinical model incorporated treatment regimen, age, and height velocity: a three-level clinical predictive model provided likelihood ratios of 0.3, 3.9, and 14. For decline in RNA the likelihood ratios were 0.2 (> 1 log decline), 1.4, and 3.5 (> log increase). We developed a simple clinical predictive model that was able to predict clinical progression of HIV after initiation of new ART. The clinical model performed similarly to using changes in HIV RNA viral load. These data should be validated internationally and prospectively, because the test subjects were from a resource rich environment and growth patterns in undernourished children may be impacted differently by HIV and its treatment. The model was most pertinent to children 36 months of age or younger, and was conducted in children receiving monotherapy and dual therapy.