Antiretroviral Clinical Trials Research Articles

Cardiometabolic Risk Profiles of Adolescents Living With Perinatally Acquired HIV in South Africa.

We assessed the Pathological Determinants of Atherosclerosis in Youth (PDAY) score and other potential cardiovascular disease risk factors in adolescents previously enrolled in the Children with HIV Early antiRetroviral (CHER) and International Maternal Pediatric Adolescent AIDS Clinical Trials Network P1060 clinical trials. Coronary artery and abdominal aorta (AA) PDAY scores were calculated for 56 participants over 15 years of age using a weighted combination of dyslipidemia, cigarette smoking, hypertension, obesity, and hyperglycemia. A PDAY score ≥1 is associated with early atherosclerosis. Fifty-six participants were enrolled: 46 (82.1%) on a single-tablet regimen of tenofovir disoproxil fumarate, lamivudine and dolutegravir. Median time on antiretroviral therapy was 15.8 [interquartile range (IQR): 15.8-16.5] years and median time on dolutegravir was 14 (IQR: 10.0-19.0) months. Fasting median high-density lipoprotein cholesterol was 20.1 mg/dL (IQR: 16.0-23.7) and median non-high-density lipoprotein cholesterol was 38.3 mg/dL (IQR: 30.8-44.3). The median systolic blood pressure was 115 mm Hg (IQR: 107-121). Median body mass index was 21.3 kg/m2 (IQR: 19.5-24.7) and median fasted serum glucose was 82.0 mg/dL (IQR: 75.7-87.3). Only 1 (2%) participant smoked cigarettes, but 5 (9%) smoked hookah pipe and 26 (46.4%) smoked cannabis. Thirty-one (55.4%) participants had coronary artery PDAY scores ≥1 and 33 (58.9%) had AA PDAY scores ≥1. Age was associated with an AA PDAY score ≥1 (P = 0.02) with a 0.06 increase in AA PDAY score for every month of age (95% confidence interval: 0.01-0.12, P = 0.01). Adolescents with perinatally acquired HIV appear at risk for cardiovascular disease. Specific tools for monitoring this risk are needed to institute appropriate preventive interventions.

Exploring the Decision-Making Process of People Living with HIV Enrolled in Antiretroviral Clinical Trials: A Qualitative Study of Decisions Guided by Trust and Emotions

The informed consent is an ethical and legal requirement for potential participants to enroll in a study. There is ample of evidence that understanding consent information and enrollment is challenging for participants in clinical trials. On the other hand, the reasoning process behind decision-making in HIV clinical trials remains mostly unexplored. This study aims to examine the decision-making process of people living with HIV currently participating in antiretroviral clinical trials and their understanding of informed consent. We conducted a qualitative socio-constructivist study using semi-structured interviews. Eleven participants were selected by purposive sampling in Argentina until data saturation was reached. A content analysis was performed. The findings highlight the fact that some participants decided to enroll on the spot, while others made the decision a few days later. In all cases, the decision was based on different aspects of trust (in doctors, in the clinical research site, in the clinical trials system) but also on emotions associated with HIV and/or treatment. Moreover, while people living with HIV felt truly informed after the consent dialogue with a researcher, consent forms were unintelligible and unfriendly. The immediacy of patient decision-making has rarely been described before. Enrollment in an HIV clinical trial is mainly a trust-based decision but this does not contradict the ethical values of autonomy, voluntariness, non-manipulation, and non‐exploitation. Thus, trust is a key issue to be included in reshaping professional practices to ensure the integrity of the informed consent process.

Response to: weight gain stopping/switch rules for antiretroviral clinical trials.

Response to: weight gain stopping/switch rules for antiretroviral clinical trials.

Approaches to accelerating the study of new antiretrovirals in pregnancy.

IntroductionWomen who are pregnant or who could become pregnant experience delayed access to or underinformed use of important new antiretroviral (ARV) drugs because of traditional drug development processes that ostensibly aim to reduce potential harm but effectively fail to ensure that timely information about safe and effective use in pregnancy is available.DiscussionThe World Health Organization and International Maternal, Pediatric, Adolescent Antiretroviral Clinical Trials Network convened a year‐long workshop on “Approaches to Enhance and Accelerate Study of New Drugs for HIV and Associated Infections in Pregnant Women.” Workshop participants were tasked with defining key principles and optimal approaches to including pregnant women in pre‐ and post‐licensure trials in order to accelerate the availability of pharmacokinetic and safety data for new ARV agents in pregnancy. ARV efficacy in pregnancy and ARV efficacy for prevention of vertical transmission can be extrapolated from proof of efficacy in non‐pregnant adults, provided that drug levels in pregnancy are similar. However, short‐term safety and pharmacokinetics must be studied directly in pregnant women and should be conducted and included in initial licensure for all new ARVs. Accelerating the timeline for completion of pre‐clinical studies is essential for pregnancy short‐term safety and pharmacokinetic studies to be safely completed by the time a drug is licensed. Composite key pregnancy, birth and neonatal outcomes are critical for drugs expected to have broad use, and studies should be initiated at or soon after drug licensure. Teratogenicity risk cannot be feasibly assessed before drug licensure and will depend on robust post‐marketing surveillance systems. With some modifications, these principles will apply to ARVs used for prevention, two‐drug regimens, long‐acting ARVs and ARVs administered through novel delivery systems.ConclusionsImplementation of the proposed principles and framework will enhance and accelerate the study of new ARVs in pregnancy, resulting in more timely, equitable and informed access to new ARVs for pregnant women.

Weight gain stopping/switch rules for antiretroviral clinical trials.

aUniversity of Zimbabwe, Harare, Zimbabwe bAmsterdam Institute for Global Health and Development, UMC, University of Amsterdam, Amsterdam, The Netherlands. Correspondence to Vinie Kouamou, Unit of Internal Medicine, College of Health Sciences, University of Zimbabwe, PO Box A178, Avondale, Harare, Zimbabwe. E-mail: [email protected] Received 5 January, 2022 Revised 16 February, 2022 Accepted 21 February, 2022

Weight gain stopping/switch rules for antiretroviral clinical trials.

Obesity develops in a substantial number of people initiating and maintaining modern antiretroviral therapy. The comorbidities associated with obesity make significant weight gain and metabolic changes a major consideration in clinical trials studying different regimens' potency and safety. It is as yet unclear what role individual antiretrovirals or classes play in weight gain but the issue is a complex one for clinical trial design, especially when deciding when "too much" weight has been gained, in a context where we do not yet know if switching to alternative regimens will slow, halt or reverse weight gain or metabolic changes. In addition, clinician and trial participant opinion on acceptable weight gain may differ. We offer preliminary guidance for discussion for future antiretroviral clinical trial design.

The HIV drug optimization agenda: promoting standards for earlier investigation and approvals of antiretroviral drugs for use in adolescents living with HIV.

IntroductionMost clinical trials for new antiretroviral (ARV) agents are conducted among narrowly defined adult populations. Only after safety and efficacy have been clearly demonstrated among adults living with HIV are trials including adolescents, children and infants conducted. This approach contributes to significant delays in the availability of optimal new ARV regimens for infants, children and adolescents. This commentary discusses issues related to the inclusion of adolescents aged 12 to 18 years in initial HIV clinical phase 3 trials of novel antiretrovirals (ARVs) or conducting parallel phase 3 clinical trials among adolescents.DiscussionThe absorption, metabolic and excretion or elimination pathways for drugs do not significantly differ between adolescents and adults. In fact, dosing recommendations for ARVs are the same for adults and adolescents who meet the age and weight criteria. Although conducting clinical trials among adolescents present special challenges (e.g. consenting minors and concerns about trial completion and contraception), these challenges can be addressed to obtain high‐quality trial results. Importantly, new agents and optimized combinations have more favourable dosing schedules and side‐effect profiles and are more effective ARV agents with higher HIV drug resistance thresholds, which would be extremely beneficial to improve outcomes among HIV‐positive adolescents.ConclusionsAdolescents may not present with significantly different pharmacokinetic characteristics from those in adults. Including HIV‐positive adolescents in phase 3 ARV clinical trials, either with adults or in specific adolescent studies conducted in parallel, would allow adolescents to access promising, more effective treatment for HIV years earlier than with the current stepwise approach.

Decision-making in HIV clinical trials: a study with patients enrolled in antiretroviral trials

ObjectiveTo explore the decisional process of people living with human immunodeficiency virus (HIV) currently enrolled in antiretroviral clinical trials. MethodCross-sectional retrospective study. Outcome variables were reasons to participate, perceived decisional role (Control Preference Scale), the Decisional Conflict Scale and the Decisional Regret Scale. Descriptive statistics were calculated, and associations among these variables and with sociodemographic and clinical characteristics were analyzed with non-parametric techniques. ResultsMain reasons to participate were gratitude towards Fundación Huesped (47%), the doctor's recommendation (32%), and perceived difficulty to access treatment in a public hospital (28%). Most patients thought that they made their decision alone (54.8%) or collaboratively with the physician (43%). Decisional conflict was low, with only some conflict in the support subscale (median=16.67). Education was the only significant correlate of the total decisional conflict score (higher in less educated patients; p=0.018), whereas education, recent diagnosis, living alone, lower age, being man and doctor's recommendation to go to Fundación Huésped related to higher conflict in different subscales. Nobody regretted to participate. ConclusionsThe decision making regarding participation in HIV trials, from the perspective of participants, was made respecting their autonomy and with very low decisional conflict. Currently, patients show no signs of regret. However, even in this favorable context, results highlight the necessity of enhancing the decision support in more vulnerable patients (e.g., less educated, recently diagnosed or with less social support), thus warranting equity in the quality of the decision making process.

Standardization of Quantitative Virological Assays for Antiretroviral Clinical Trials

The AIDS Clinical Trial Group (ACTG) was formed and funded by the National Institute of Allergy and Infectious Diseases (NIAID) in 1987 to enable multi-center clinical trials for the evaluation of treatments for HIV. As there were no licensed anti-retroviral drugs at that time large numbers of subjects and many testing sites were needed to adequately demonstrate clinical efficacy and make the drugs available for general treatment. Initially trial endpoints were based on evaluation of symptoms some of which were based on subjective judgment by clinicians. Measurements of CD4 positive cells were used to demonstrate progression from asymptomatic to symptomatic disease to AIDS. In order to shorten the length of the trials and obtain objective results it was necessary to identify virus specific markers of efficacy. Some of the first viral markers to be evaluated included HIV-1 p24 antigen as measured in serum, and the infectious outgrowth of HIV from peripheral blood mononuclear cells (PBMCs). These tests paved the way for more sensitive tests using HIV nucleic acid amplification to determine the copies of HIV genome in plasma. HIV RNA continues to be the best surrogate marker used today to evaluate the efficacy of new combinations of antiretroviral drugs.

Barriers to HIV Treatment Adherence: Findings from a Treatment Center in South-South, Nigeria

Aims: Non-adherence to treatment represents a significant challenge to anti-retroviral treatment goals. This study aimed to identify and explore perceived barriers to adherence in non-adherent HIV patients attending the University of Port Harcourt Teaching Hospital. Study Design: This was a descriptive, cross-sectional study of HAART experienced patients who had less than 95% adherence to their HAART medication. Place and Duration of Study: The study was carried out between May and June 2011 at the Antiretroviral treatment center of the University of Port Harcourt Teaching Hospital in the Southern part of Nigeria Original Research Article International Journal of TROPICAL DISEASE & Health, 4(12): 1233-1244, 2015 1234 Methodology: Data collection was via quantitative and qualitative methods. A structured interviewer administered questionnaire adapted from the Adult Antiretroviral Clinical Trials Group (AACTG) study was used to identify barriers to adherence. In addition, four focus group discussions (FGDs) were held with 27 purposively selected participants. Quantitative data was analyzed with SPSS version 18, while the FGDs were analyzed using thematic content analysis. Results: Ninety-six (96) patients, 39 (40.6%) males and 57 (59.4%) females with median age of 35.5 years participated in the study. Identified barriers to adherence included; being away from home during medication times 41 (42.7%), being busy with other things 35 (36.5%), forgetfulness 33 (34.4%), running out of pills 25 (26%), difficulty taking pills at specified times 25 (26.0%), the need to avoid side effects 16 (16.7%), and lack of a social support system 15 (15.6%). Barriers identified by the FGDs were fear of taking HIV drugs in front of others, sharing drugs with infected spouse, alcohol use, financial challenges, poor understanding about the effects of the drugs, forgetfulness, long clinic hours and poor attitude of health workers. Conclusion: Adherence counseling, use of reminder systems and treatment supporters are useful Public Health interventions for improving adherence and should be integrated into service delivery at this and other centers. In addition, better organization of the clinic, increasing staff strength and training will go a long way to address these barriers. Decentralization of HIV treatment centers to secondary and primary health facilities needs consideration.

Geographic location of antiretroviral clinical trials in HIV infected pediatric patients

Some medicines regulatory authorities are encouraging research in pediatrics. However, children are a vulnerable population, and previous studies have suggested that research is increasingly being conducted outside of developed countries. The purpose of this study is to determine the location of trials in the pediatric population with human immunodeficiency virus (HIV). Not applicable. Clinical trials registered in the largest international clinical trials registry (clinicaltrials.gov) evaluating antiretrovirals in pediatric HIV infected patients were included. Data were collected on the location, funding, study purpose, design, initiation date, age of subjects, and medication classes tested. We assessed frequencies of characteristics of pediatric HIV trials registered in the clinicaltrials.gov database. Overall, 288 studies were included in the analysis. Most trials were conducted in ages 12-17 years (83 %), followed by studies in those <6 years (25 %) and 6-11 years (21 %). The location of most trials included at least one site in developed countries (83 %). The number of trials completed exclusively in developing countries increased from 1989 to 2011. The majority of pediatric antiretroviral trials registered in clinicaltrials.gov were conducted in adolescent subjects in developed countries. The number of pediatric HIV studies in developing countries increased while studies conducted in developed countries decreased similar to trends of HIV.

Evaluating the Effect of Early Versus Late ARV Regimen Change if Failure on an Initial Regimen: Results From the AIDS Clinical Trials Group Study A5095

The current goal of initial antiretroviral (ARV) therapy is suppression of plasma human immunodeficiency virus (HIV)-1 RNA levels to below 200 copies per milliliter. A proportion of HIV-infected patients who initiate antiretroviral therapy in clinical practice or antiretroviral clinical trials either fail to suppress HIV-1 RNA or have HIV-1 RNA levels rebound on therapy. Frequently, these patients have sustained CD4 cell counts responses and limited or no clinical symptoms and, therefore, have potentially limited indications for altering therapy which they may be tolerating well despite increased viral replication. On the other hand, increased viral replication on therapy leads to selection of resistance mutations to the antiretroviral agents comprising their therapy and potentially cross-resistance to other agents in the same class decreasing the likelihood of response to subsequent antiretroviral therapy. The optimal time to switch antiretroviral therapy to ensure sustained virologic suppression and prevent clinical events in patients who have rebound in their HIV-1 RNA, yet are stable, is not known. Randomized clinical trials to compare early versus delayed switching have been difficult to design and more difficult to enroll. In some clinical trials, such as the AIDS Clinical Trials Group (ACTG) Study A5095, patients randomized to initial antiretroviral treatment combinations, who fail to suppress HIV-1 RNA or have a rebound of HIV-1 RNA on therapy are allowed to switch from the initial ARV regimen to a new regimen, based on clinician and patient decisions. We delineate a statistical framework to estimate the effect of early versus late regimen change using data from ACTG A5095 in the context of two-stage designs. In causal inference, a large class of doubly robust estimators are derived through semiparametric theory with applications to missing data problems. This class of estimators is motivated through geometric arguments and relies on large samples for good performance. By now, several authors have noted that a doubly robust estimator may be suboptimal when the outcome model is misspecified even if it is semiparametric efficient when the outcome regression model is correctly specified. Through auxiliary variables, two-stage designs, and within the contextual backdrop of our scientific problem and clinical study, we propose improved doubly robust, locally efficient estimators of a population mean and average causal effect for early versus delayed switching to second-line ARV treatment regimens. Our analysis of the ACTG A5095 data further demonstrates how methods that use auxiliary variables can improve over methods that ignore them. Using the methods developed here, we conclude that patients who switch within 8 weeks of virologic failure have better clinical outcomes, on average, than patients who delay switching to a new second-line ARV regimen after failing on the initial regimen. Ordinary statistical methods fail to find such differences. This article has online supplementary material.

Impact of transitioning from HIV clinical trials to routine medical care on clinical outcomes and patient perceptions

Participation in antiretroviral therapy clinical trials (ART-RCTs) offers many advantages including access to new drugs, close monitoring, and cost savings. These same benefits may pose a risk to patients ending ART-RCTs and returning to routine care; as they may experience changes to their drug regimen, decreased monitoring, and new out-of-pocket costs. We aimed to evaluate this transition and determine its effects on viral outcomes and patient perceptions. A retrospective cohort was assembled from participants of naïve ART-RCTs at the University of Pennsylvania between 1 January 2000 and 31 December 2009. Data were collected in the 12 months prior to and after trial completion. Multivariable logistic regression was used to evaluate viral failure rates and to identify factors associated with viral failure. Qualitative interviews were held with a subset of patients. Content analysis was used to identify thematic differences between patients with viral failure and those with viral suppression. In total, 116 patients enrolled in 5 ART-RCTs from 2000 to 2009. Viral failure was observed in 39 patients (34%). Nonwhites, high enrollment CD4 count, and trial completion in 1999–2002 were risk factors for failure. Patients transitioning from ART-RCTs to routine care had a 20% increased odds of failure (Adjusted Odds Ratio 1.20 (95% CI [0.37, 3.88])). Nine patients with viral suppression and three with viral failure in the year after trail completion were interviewed. Suppressed patients were more eager to continue trial participation, nervous about leaving the trial, and felt prepared to return to routine care. In contrast, those with viral failure were less concerned about the transition. These findings suggest that the posttrial period may be a vulnerable time for patients. Patients without a healthy fear of transitioning from ART-RCTs to routine care may be at increased risk of viral failure. Focus should be given to assisting patients during this transition.

Recruitment and retention of diverse populations in antiretroviral clinical trials: practical applications from the gender, race and clinical experience study.

Women, particularly women of color, remain underrepresented in antiretroviral (ARV) clinical trials. To evaluate sex-based differences in darunavir/ritonavir-based therapy, the Gender, Race And Clinical Experience (GRACE) study was designed to enroll and retain a high proportion of women representative of the racial/ethnic demographics of women with HIV/AIDS in the United States. The recruitment and retention strategies used in GRACE are described in this article. Recruitment and retention strategies targeting women included selecting study sites that focused on women, involving community consultants, site-specific enrollment plans, access to other ARV drugs, study branding, site and patient toolkits, targeted public relations, site grants for patient support, and subsidized child care and transportation. The recruitment strategies were successful; 287 (67%) women were enrolled, primarily women of color (black, n=191 [67%], Hispanic, n=60 [21%]). Despite the focus on retention, a greater proportion of women (32.8%) discontinued compared with men (23.2%). The successes of GRACE in enrolling a representative population of women were rooted in pretrial preparation, engagement of community advisors, enrollment quotas, choice of study sites and site support. Lessons learned from GRACE may be applied to future study design. Further focus on factors that influence discontinuation is warranted.

Sex-Based Outcomes of Darunavir–Ritonavir Therapy: The GRACE (Gender, Race, and Clinical Experience) Study

In 2006, an estimated 1 106 400 adults and adolescents in the United States were living with HIV or AIDS (1). Of the new cases of HIV reported in 2006, 27% were women, and 45% were black (2). Since the beginning of the epidemic, women have accounted for an increasing proportion of persons with the disease (3). Furthermore, women of color are disproportionately affected: 64% and 15% of women living with HIV/AIDS in the United States in 2005 were black and Hispanic, respectively, yet these groups collectively represent only approximately 25% of the U.S. female population (3, 4). Women, and particularly women of color, have been underrepresented in antiretroviral clinical trials for treatment-experienced patients (5). This may reflect challenges in both recruiting and retaining women in clinical trials as a whole and highlights barriers to continuous medical care for this population, such as family commitments, job-related time constraints, or other socioeconomic factors. These observations have been noted in clinical trials of several other therapeutic areas (6–9), including cardiovascular, lung, and cancer research, suggesting that the challenges of recruiting women and persons or color are not specific to trials of antiretroviral therapy. An analysis (6) of the enrollment of women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute showed that studies of congestive heart failure enrolled only 26% women, although women account for 43% of patients with congestive heart failure. Likewise, examination of high-impact cancer studies published in 2006 (10) showed that women were underrepresented in studies of non–sex-specific types of cancer, averaging only 38.8% of enrolled participants. This has resulted in a paucity of clinical data for diverse populations. Although sex-based analyses are required for registration trials (11), studies with less than 25% female enrollment generally have limited statistical power to assess sex differences, thereby limiting sex-based conclusions in most trials (12). The recruitment and retention of women in clinical trials are essential to provide accurate information on the efficacy and safety of therapeutic agents in all patients and, ultimately, to guide treatment decisions for women (13, 14). Darunavir, a protease inhibitor, combined with a low dose of ritonavir, was initially introduced as a therapeutic option (600/100 mg twice daily) for treatment-experienced patients with HIV (15). Subsequently, darunavir–ritonavir was approved for use in treatment-naive adults (800/100 mg once daily) and treatment-experienced children (aged 6 to 17 years; weight-dependent twice-daily dosing) (15). In the POWER (Performance Of TMC114/r When evaluated in treatment-Experienced patients with PI [protease inhibitor] Resistance) and TITAN (TMC114/r In Treatment-experienced pAtients Naive to Lopinavir) trials, which assessed the efficacy and safety of darunavir–ritonavir, the number of women enrolled was approximately 10% to 21% of the overall population (16, 17). In the ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects) trial, treatment-naive women accounted for 30% of patients in the darunavir–ritonavir group, with results showing similar safety and efficacy between the sexes at week 96 and no differences in discontinuation rates due to adverse events (18). To expand the clinical data available for darunavir–ritonavir in treatment-experienced women, the GRACE (Gender, Race, And Clinical Experience) trial, conducted from 6 October 2006 to 19 December 2008, was specifically designed and powered to assess sex-based differences in efficacy and to evaluate the incidence of adverse events (5). The study was also designed to enroll a high proportion of treatment-experienced North American women to reflect the distribution and demographic characteristics of women with HIV in the United States. We report the efficacy outcomes and incidence of adverse events in women and men who received darunavir–ritonavir-based therapy over 48 weeks during the GRACE study; data on outcomes by race and ethnicity will be presented elsewhere.

Issues Regarding Use of Hormonal Contraceptives in Clinical Trials of Antiretroviral Therapy

Objective Over 30% of HIV-infected adults and adolescents in the United States are female, yet women make up less than 20% of participants in most antiretroviral clinical trials. We sought to understand how policies regarding fertility regulation might have influenced women's participation in Adult AIDS Clinical Trials Group (AACTG) antiretroviral trials. Methods We reviewed AACTG and the National Institute of Allergy and Infectious Diseases Division of AIDS (DAIDS) policies relating to the eligibility of women of reproductive potential to participate in antiretroviral clinical trials from 1996 to the present. We focused specifically on policies related to the documentation of women's reproductive potential, contraceptive requirements stratified by the FDA Use-in-Pregnancy categories, the management of incident pregnancies for female study subjects, and the impact of previous limited antiretroviral use in pregnancy and eligibility for antiretroviral-naive clinical trials. Results Before 1998, most AACTG protocols specified that ‘adequate birth control’ should be used during clinical trials and for 3 months afterwards, but there was no standard definition of adequate birth control. Most protocols implied that it was the woman's responsibility to prevent pregnancy. In 1998, a focus group on pregnancy issues and antiretroviral agents recommended that adequate birth control should be practised by both heterosexually active women and men on study. Adequate birth control was defined as either abstinence, hormonal plus barrier methods, or two barrier methods. In 2000, women of reproductive potential were explicitly defined as all adult and adolescent women except those who have undergone surgical sterilization, hysterectomy, bilateral oophorectomy or menopause, or whose male partners have documented azoospermia from a vasectomy or other condition. Source documentation of sterilization, menopause or azoospermia was required to confirm a lack of reproductive potential for study subjects. Women of reproductive potential were required to use at least one non-hormonal contraceptive method for trials involving FDA category A, B and most category C drugs, and were required to use two non-hormonal contraceptive methods for some category C drugs (efavirenz) and all category D and X drugs. Hormonal contraceptive methods were thought to be possibly ineffective when prescribed with some antiretroviral agents, and so could not fulfill the contraceptive requirement. IUD were discouraged because of the potential increased risk of pelvic inflammatory disease. In 2002, the source documentation requirement for women not of reproductive potential was relaxed for trials of category A, B and C drugs with the exception of efavirenz; however, the contraceptive requirements were not changed. Most antiretroviral trials require that female study subjects who become pregnant discontinue study medications unless there are adequate safety data in pregnancy. Most clinical trials for antiretroviral-naive study subjects exclude women with limited previous exposure to zidovudine or nevirapine during a pregnancy. Conclusion The vast majority of HIV-infected women in the United States are of child-bearing age, and so fertility regulation policies may have a substantial impact on women's eligibility for and participation in antiretroviral clinical trials. The burden of pregnancy prevention disproportionately affects women, including those who are not heterosexually active but are still thought to be ‘of reproductive potential’. We need better and more complete data regarding the safety, pharmacokinetics and efficacy of newer antiretroviral agents in pregnancy and in conjunction with hormonal contraceptives. In addition, antiretroviral-naive clinical trials should consider whether the exclusion of women with previous limited antiretroviral exposure in pregnancy is truly justified.

Quality of life in HIV-infected individuals receiving antiretroviral therapy is related to adherence

This study assesses changes in quality of life (QoL) over time among HIV-infected individuals receiving antiretroviral therapy (ART) and evaluates how this relates to ART adherence. Prospective, longitudinal data were examined from 1050 participants in two large, randomized, multi-centre antiretroviral clinical trials. QoL was assessed by the SF-12; adherence by the Terry Beirn Community Programs for Clinical Research on AIDS Antiretroviral Medication Self-report. Participants included 20% women, 53% African Americans, 16% Latinos; mean age was 39 years; mean baseline CD4+ cell count 230 cells/mm3; 89% were ART-naïve at entry. Baseline physical and mental health summary QoL scores were 45.4 and 42.9, comparable to scores reported in other advanced HIV populations. Significant improvements in mean QoL scores were seen for the group as a whole after 1 to 4 months on new ART regimens, and persisted for 12 months. Participants reporting 100% ART adherence achieved significantly higher QoL scores at 12 months compared to those with poorer adherence, particularly if 100% adherence was consistent (p<0.001). Those with at least 80% ART adherence had smaller gains in QoL at 12 months when compared to baseline, while those with <80% adherence had worsening of QoL. In this analysis, ART adherence was associated with improved QoL, particularly if adherence was sustained.

Growth as a part of the composite endpoint in paediatric antiretroviral clinical trials.

Paediatric HIV is a rapidly emerging disease in many resource-poor countries. Survival into adulthood is possible for HIV-infected children provided that they receive effective antiretroviral therapy (ART). Large trials comparing multiple regimens of ART in children of resource-poor countries have not been completed. Design of those trials will need to incorporate both lessons learned from trials completed in developed countries as well as unique aspects of the developing countries in which they are conducted. Trial design will necessarily include close attention to the endpoint, and in children, special consideration will need to be given to growth as a component of the endpoint--whether or not growth should be a component of the composite endpoint, and if so, how.

Increasing prevalence of resistance mutations in antiretroviral-naïve individuals with established HIV-1 infection from 1996-2002 in St. Louis

BACKGROUND: Transmission of drug-resistant virus in HIV-1 infected individuals is well documented, particularly in patients with primary infection. Prevalence in chronically infected antiretroviral-naïve patients is reportedly low. Routine genotyping in this population is not recommended. PURPOSE: The purpose of this study was to evaluate resistance profiles in patients with established HIV infection in St. Louis. METHOD: We selected specimens from drug-naïve individuals (CD4 >300 cells/mL and VL >1000 copies/mL) with established HIV infection between 1996-2002. 62 of 75 specimens were available for genotyping. We excluded patients with evidence of acute HIV infection and long-term nonprogressors. RESULTS: The overall prevalence of resistance was 11% (7/62). From 1996 to 1998, a prevalence of 4% was observed (1/27 individuals). During the subsequent period from 1999 to 2002, the frequency increased to 17% (6/35 participants; p = .08; 95% CI 5-29%). CONCLUSION: The results suggest that the prevalence of primary resistance is increasing in our region to the point that it justifies genotypic testing in all individuals before the initiation of antiretroviral therapy. This has to be considered when designing antiretroviral clinical trials.

Design of antiretroviral clinical trials for HIV-1 infected pregnant women and their newborn infants

Antiretroviral therapy has been highly successful in reducing mother to child transmission of human immunodeficiency virus-1 infection in pregnant women. However, the treatment regimens are intensive, difficult to deliver in less developed countries, and there are limited pharmacology studies addressing critical questions regarding maternal safety and fetal risk. There are currently 3 pharmacologically diverse classes of antiretroviral agents with inadequate information available to define drug disposition necessary to determine appropriate dose regimens and limited data on long-term adverse events. This article summarizes representative clinical studies for selected antiretrovirals that provide a framework for continuing the necessary clinical research to extend successful outcomes in developed countries to human immunodeficiency virus-1 infected pregnant women and infants world-wide and minimize the risk of long-term adverse effects.