A Per-Protocol Analysis Using Inverse-Probability-of-Censoring Weights in a Randomized Trial of Initial Protease Inhibitor Versus Nonnucleoside Reverse Transcriptase Inhibitor Regimens in Children.

Protocol adherence may influence measured treatment effectiveness in randomized controlled trials. Using data from a multicenter trial (Europe and the Americas, 2002-2009) of children with human immunodeficiency virus type 1 who had been randomized to receive initial protease inhibitor (PI) versus nonnucleoside reverse transcriptase inhibitor (NNRTI) antiretroviral therapy regimens, we generated time-to-event intention-to-treat (ITT) estimates of treatment effectiveness, applied inverse-probability-of-censoring weights to generate per-protocol efficacy estimates, and compared shifts from ITT to per-protocol estimates across and within treatment arms. In ITT analyses, 263 participants experienced 4-year treatment failure probabilities of 41.3% for PIs and 39.5% for NNRTIs (risk difference = 1.8% (95% confidence interval (CI): -10.1, 13.7); hazard ratio = 1.09 (95% CI: 0.74, 1.60)). In per-protocol analyses, failure probabilities were 35.6% for PIs and 29.2% for NNRTIs (risk difference = 6.4% (95% CI: -6.7, 19.4); hazard ratio = 1.30 (95% CI: 0.80, 2.12)). Within-arm shifts in failure probabilities from ITT to per-protocol analyses were 5.7% for PIs and 10.3% for NNRTIs. Protocol nonadherence was nondifferential across arms, suggesting that possibly better NNRTI efficacy may have been masked by differences in within-arm shifts deriving from differential regimen forgiveness, residual confounding, or chance. A per-protocol approach using inverse-probability-of-censoring weights facilitated evaluation of relationships among adherence, efficacy, and forgiveness applicable to pediatric oral antiretroviral regimens.

"It's Almost Like Gay Sex Doesn't Exist:" Parent-Child Sex Communication According to Gay, Bisexual, and Queer Adolescent Sons.

Sex communication interventions facilitate positive sexual health outcomes with heterosexual adolescents. The same has yet to be established for male youth with same-sex attractions, behaviors, and identities. Our study describes the experiences of gay, bisexual and queer-identifying adolescent males with parent-child sex communication. We conducted 30 in-depth semi-structured interviews with a diverse group of 15 to 20 year-old gay, bisexual, and queer (GBQ) males. Interview transcripts were coded and themes were identified using thematic and content analysis. Narratives revealed that sex communication with parents occurs rarely, is heteronormative in content prior to adolescent males' disclosure as GBQ, and after disclosure is reactionary and based on stereotypes that associate this population with negative health outcomes. Parents were rated poorly as sex educators by adolescent males and the findings are mixed regarding perception of parents' knowledge about GBQ-specific information. Parents and healthcare providers were identified as preferred sources of sex information by GBQ adolescent males. Sex communication with parents throughout adolescence that excludes GBQ males' same-sex concerns is a missed opportunity for targeted sexual risk reduction. There are multiple ways healthcare providers can assist parents to plan age-appropriate, sexuality-inclusive, home-based discussions about sex for this group.

Use of altered informed consent in pragmatic clinical research.

There are situations in which the requirement to obtain conventional written informed consent can impose significant or even insurmountable barriers to conducting pragmatic clinical research, including some comparative effectiveness studies and cluster-randomized trials. Although certain federal regulations governing research in the United States (45 CFR 46) define circumstances in which any of the required elements may be waived, the same standards apply regardless of whether any single element is to be waived or whether consent is to be waived in its entirety. Using the same threshold for a partial or complete waiver limits the options available to institutional review boards as they seek to optimize a consent process. In this article, we argue that new standards are necessary in order to enable important pragmatic clinical research while at the same time protecting patients' rights and interests.

Ethical considerations in design of a study to evaluate a US Food and Drug Administration-approved indication: antivenom versus placebo for copperhead envenomation.

BACKGROUND: In 2000, the US Food and Drug Administration approved CroFab(®) Crotalidae Polyvalent Immune Fab, ovine (FabAV), which had received orphan drug designation, for use in patients with minimal to moderate North American crotaline envenomations including copperhead snakes. As existing evidence on the effectiveness of FabAV for this indication is limited, wide practice variation in its use exists. In order to provide more definitive clinical evidence as to the role of this treatment, a new randomized, placebo-controlled trial of FabAV specifically for copperhead bites was initiated. PURPOSE: In light of the existing US Food and Drug Administration approval, ethical considerations of participation in this trial have been raised. We discuss the ethical principles pertinent to this randomized, placebo-controlled trial with placebo arm. We apply an accepted framework for ethical research to this trial. Due to the evidence gap in the literature, wide-ranging treatment recommendations by medical experts, and broad practice variation, clinical equipoise exists in the treatment of copperhead envenomation with FabAV. The impact of this clinical equipoise on the value and scientific validity of the trial is discussed. The trial's risk-benefit ratio is also considered. Potential risks to the patients are minimized as the protocol includes a plan for rescue therapy in the event that patients progress to severe envenomation symptoms. Overall, risks are further minimized by the inclusion of an interim analysis with stopping rules based on demonstrated efficacy should the therapy clearly prove to be beneficial. CONCLUSION: Although a post-marketing clinical study of this nature is unusual for an approved indication, this trial adheres to all ethical preconditions found in existing guidelines for clinical research involving human subjects.

Sports medicine and ethics.

Physicians working in the world of competitive sports face unique ethical challenges, many of which center around conflicts of interest. Team-employed physicians have obligations to act in the club's best interest while caring for the individual athlete. As such, they must balance issues like protecting versus sharing health information, as well as issues regarding autonomous informed consent versus paternalistic decision making in determining whether an athlete may compete safely. Moreover, the physician has to deal with an athlete's decisions about performance enhancement and return to play, pursuit of which may not be in the athlete's long-term best interests but may benefit the athlete and team in the short term. These difficult tasks are complicated by the lack of evidence-based standards in a field influenced by the lure of financial gains for multiple parties involved. In this article, we review ethical issues in sports medicine with specific attention paid to American professional football.

Time to treatment disruption in children with HIV-1 randomized to initial antiretroviral therapy with protease inhibitors versus non-nucleoside reverse transcriptase inhibitors.

BACKGROUND: Choice of initial antiretroviral therapy regimen may help children with HIV maintain optimal, continuous therapy. We assessed treatment-naïve children for differences in time to treatment disruption across randomly-assigned protease inhibitor versus non-nucleoside reverse transcriptase inhibitor-based initial antiretroviral therapy. METHODS: We performed a secondary analysis of a multicenter phase 2/3, randomized, open-label trial in Europe, North and South America from 2002 to 2009. Children aged 31 days to <18 years, who were living with HIV-1 and treatment-naive, were randomized to antiretroviral therapy with two nucleoside reverse transcriptase inhibitors plus a protease inhibitor or non-nucleoside reverse transcriptase inhibitor. Time to first documented treatment disruption to any component of antiretroviral therapy, derived from treatment records and adherence questionnaires, was analyzed using Kaplan-Meier estimators and Cox proportional hazards models. RESULTS: The modified intention-to-treat analysis included 263 participants. Seventy-two percent (n = 190) of participants experienced at least one treatment disruption during study. At 4 years, treatment disruption probabilities were 70% (protease inhibitor) vs. 63% (non-nucleoside reverse transcriptase inhibitor). The unadjusted hazard ratio (HR) for treatment disruptions comparing protease inhibitor vs. non-nucleoside reverse transcriptase inhibitor-based regimens was 1.19, 95% confidence interval [CI] 0.88-1.61 (adjusted HR 1.24, 95% CI 0.91-1.68). By study end, treatment disruption probabilities converged (protease inhibitor 81%, non-nucleoside reverse transcriptase inhibitor 84%) with unadjusted HR 1.11, 95% CI 0.84-1.48 (adjusted HR 1.13, 95% CI 0.84-1.50). Reported reasons for treatment disruptions suggested that participants on protease inhibitors experienced greater tolerability problems. CONCLUSIONS: Children had similar time to treatment disruption for initial protease inhibitor and non-nucleoside reverse transcriptase inhibitor-based antiretroviral therapy, despite greater reported tolerability problems with protease inhibitor regimens. Initial pediatric antiretroviral therapy with either a protease inhibitor or non-nucleoside reverse transcriptase inhibitor may be acceptable for maintaining optimal, continuous therapy.

Randomized controlled trial of feeding a concentrated formula to infants born to women infected by human immunodeficiency virus.

OBJECTIVE: We tested the hypothesis that concentrated formula (CF) begun within the first 2 weeks of life increases growth in infants born to human immunodeficiency virus (HIV)-infected mothers. MATERIALS AND METHODS: HIV-exposed infants from the United States, the Bahamas, and Brazil were randomized in a double-blind, controlled trial to receive either a CF (87 kcal/100 mL [26 kcal/oz]) or a standard formula (SF; 67 kcal/100 mL [20 kcal/oz]) for 8 weeks. This article presents results for infants who were not determined to be HIV infected based on testing at 4 weeks. Primary outcomes were safety, tolerability, and growth in weight and length. RESULTS: Two thousand ninety-seven infants were enrolled, of whom 1998 were uninfected and had study formula dispensed. At weeks 4 and 8, uninfected infants receiving CF showed higher energy intake than those who were receiving SF (P < 0.001). By week 8, uninfected infants assigned to CF weighed more than infants receiving SF. There were no consistent differences in measures of tolerability, and rates of discontinuation or perceived formula intolerance were similar between treatment groups. CONCLUSIONS: A CF is well tolerated and results in increased weight gain compared with SF. Until the HIV status of an infant is reliably determined, early introduction of a CF in HIV-exposed children may have beneficial effects on growth. The role of early nutritional intervention remains to be determined for individuals living in countries with endemic malnutrition for whom formula feeding is a viable option.

The Daunting Career of the Physician-Investigator.

For many years, physician-investigators have had a particularly difficult time with their academic careers, so that they have been labeled an endangered species. In this Invited Commentary, the author defines three career paths for physician-investigators-clinical researcher, clinician-scientist, and physician-scientist. Each of these pathways has common and distinct challenges that should be studied and potential improvements that should be evaluated through pilot research projects.The first challenge that all physician-investigators face is securing funding. Physicians are funded by their clinical activities, which often lures physician-investigators to increase their clinical work, particularly when research funding from the National Institutes of Health is difficult to secure and seemingly arbitrarily granted. The second challenge is an appointments, promotion, and tenure system that is not responsive to the needs of faculty working across clinical care and research, particularly when it comes to evaluating team science. Physician-investigators not working full-time in either discipline then may have trouble being promoted. The third challenge is the increasing burdens of clinical activities, particularly with the advent of electronic medical records.In this issue, two articles address overcoming the challenges faced by physician-investigators, one from the National Institutes of Health to grow the workforce and the other to offer organizational and individual solutions to support these investigators in faculty roles. These solutions are encouraging, but data about the extent of the challenges and the potential effects of the solutions are needed to make the physician-investigator career path less daunting.

A comparison of height and weight velocity as a part of the composite endpoint in pediatric HIV.

BACKGROUND: HIV adversely affects growth in children. Pediatric AIDS Clinical Trial Group (PACTG) protocols often use weight velocity [changes in weight z-score for age (WAZ)] as a part of the composite endpoint for phase II and III clinical trials. However, WAZ and height velocity (HAZ) have not been critically compared for their utility as part of the composite endpoint. METHODS: HAZ and WAZ were compared to predict laboratory and clinical progression of HIV in a retrospective cohort study of HIV-infected children with data from PACTG Protocol 300. RESULTS: In both bivariable and multivariable analyses, changes in HAZ were more closely linked to subsequent progression than WAZ. Children with improved HAZ were somewhat less likely to exhibit virological failure [odds ratio (OR), 0.76; 95% confidence interval (CI) 0.51-1.14], than children with improved WAZ (OR, 1.45; 95% CI, 0.99,2.11). Children who had improved HAZ were less likely to exhibit immunological failure (OR, 0.7; 95% CI, 0.49-1.00), than children with improved WAZ (OR, 1.13; 95% CI, 0.82-1.57). Children who had improved HAZ were less likely to have other forms of clinical progression of HIV (OR, 0.55; 95% CI, 0.31-0.99), than children who had improved WAZ (OR, 1.0; 95% CI, 1.58-1.94). CONCLUSIONS: Increases in HAZ were associated with reduced risk of subsequent clinical progression and subsequent immune reconstitution and weakly associated with declines in HIV RNA. Changes in WAZ were not associated with laboratory outcomes relevant to pediatric HIV infection. Height velocity should be considered as a component of a composite clinical endpoint in future PACTG trials.

Growth, survival and viral load in symptomatic childhood human immunodeficiency virus infection.

BACKGROUND: The relationships among weight and height growth, viral load and survival in HIV-infected children remain unclear. OBJECTIVES: To determine whether weight or height growth velocity independently predicts survival and to investigate associations of weight, height and head circumference growth velocities with viral loads in symptomatic HIV-infected children. METHODS: We analyzed data from a prospective antiretroviral study utilizing clinical endpoints (PACTG 152). Viral load [log(RNA PCR)] and anthropometric measures 12 weeks before and after viral load measures were available in 494 of 831 children. Interval changes during 24 weeks in z-scores for weight-for-age (DeltaWAZ), height-for-age (DeltaHAZ) and head circumference-for-age (DeltaHCZ) were used as growth velocity surrogates. Logistic regression determined whether DeltaWAZ and/or DeltaHAZ correlated with survival when age, viral load and CD4+ cell count were controlled. Bivariate analysis assessed correlation among viral load and DeltaWAZ, DeltaHAZ and/or DeltaHCZ. RESULTS: Survival related significantly to height growth velocity (P = 0.03, n = 434) but not to weight growth velocity (P = 0.84, n = 446) or head circumference growth velocity (P = 0.67, n = 148). Viral load was not significantly associated with changes in weight-, height-, or head circumference-for-age z scores (P = 0.86, n = 235; P = 0.07, n = 226; and P = 0.09, n = 165, respectively) in children <30 months of age or with changes in weight- or height-for-age z scores (P = 0.27, n = 259; P = 0.11, n = 251) in older children. CONCLUSIONS: Height growth velocity predicted survival independently of age, viral load and CD4+ cell count. Weight, height and head circumference growth velocities were not significantly associated with viral load in symptomatic HIV-infected children in this large prospective trial of nucleoside reverse transcriptase therapy.