In-Person vs Electronic Directly Observed Therapy for Tuberculosis Treatment Adherence: A Randomized Noninferiority Trial.

Importance: Electronic directly observed therapy (DOT) is used increasingly as an alternative to in-person DOT for monitoring tuberculosis treatment. Evidence supporting its efficacy is limited. Objective: To determine whether electronic DOT can attain a level of treatment observation as favorable as in-person DOT. Design, Setting, and Participants: This was a 2-period crossover, noninferiority trial with initial randomization to electronic or in-person DOT at the time outpatient tuberculosis treatment began. The trial enrolled 216 participants with physician-suspected or bacteriologically confirmed tuberculosis from July 2017 to October 2019 in 4 clinics operated by the New York City Health Department. Data analysis was conducted between March 2020 and April 2021. Interventions: Participants were asked to complete 20 medication doses using 1 DOT method, then switched methods for another 20 doses. With in-person therapy, participants chose clinic or community-based DOT; with electronic DOT, participants chose live video-conferencing or recorded videos. Main Outcomes and Measures: Difference between the percentage of medication doses participants were observed to completely ingest with in-person DOT and with electronic DOT. Noninferiority was demonstrated if the upper 95% confidence limit of the difference was 10% or less. We estimated the percentage of completed doses using a logistic mixed effects model, run in 4 modes: modified intention-to-treat, per-protocol, per-protocol with 85% or more of doses conforming to the randomization assignment, and empirical. Confidence intervals were estimated by bootstrapping (with 1000 replicates). Results: There were 173 participants in each crossover period (median age, 40 years [range, 16-86 years]; 140 [66%] men; 80 [37%] Asian and Pacific Islander, 43 [20%] Black, and 71 [33%] Hispanic individuals) evaluated with the model in the modified intention-to-treat analytic mode. The percentage of completed doses with in-person DOT was 87.2% (95% CI, 84.6%-89.9%) vs 89.8% (95% CI, 87.5%-92.1%) with electronic DOT. The percentage difference was -2.6% (95% CI, -4.8% to -0.3%), consistent with a conclusion of noninferiority. The 3 other analytic modes yielded equivalent conclusions, with percentage differences ranging from -4.9% to -1.9%. Conclusions and Relevance: In this trial, the percentage of completed doses under electronic DOT was noninferior to that under in-person DOT. This trial provides evidence supporting the efficacy of this digital adherence technology, and for the inclusion of electronic DOT in the standard of care. Trial Registration: ClinicalTrials.gov Identifier: NCT03266003.

Comparison of DNA testing strategies in monitoring human papillomavirus infection prevalence through simulation.

BACKGROUND: HPV DNA diagnostic tests for epidemiology monitoring (research purpose) or cervical cancer screening (clinical purpose) have often been considered separately. Women with positive Linear Array (LA) polymerase chain reaction (PCR) research test results typically are neither informed nor referred for colposcopy. Recently, a sequential testing by using Hybrid Capture 2 (HC2) HPV clinical test as a triage before genotype by LA has been adopted for monitoring HPV infections. Also, HC2 has been reported as a more feasible screening approach for cervical cancer in low-resource countries. Thus, knowing the performance of testing strategies incorporating HPV clinical test (i.e., HC2-only or using HC2 as a triage before genotype by LA) compared with LA-only testing in measuring HPV prevalence will be informative for public health practice. METHOD: We conducted a Monte Carlo simulation study. Data were generated using mathematical algorithms. We designated the reported HPV infection prevalence in the U.S. and Latin America as the "true" underlying type-specific HPV prevalence. Analytical sensitivity of HC2 for detecting 14 high-risk (oncogenic) types was considered to be less than LA. Estimated-to-true prevalence ratios and percentage reductions were calculated. RESULTS: When the "true" HPV prevalence was designated as the reported prevalence in the U.S., with LA genotyping sensitivity and specificity of (0.95, 0.95), estimated-to-true prevalence ratios of 14 high-risk types were 2.132, 1.056, 0.958 for LA-only, HC2-only, and sequential testing, respectively. Estimated-to-true prevalence ratios of two vaccine-associated high-risk types were 2.359 and 1.063 for LA-only and sequential testing, respectively. When designated type-specific prevalence of HPV16 and 18 were reduced by 50 %, using either LA-only or sequential testing, prevalence estimates were reduced by 18 %. CONCLUSION: Estimated-to-true HPV infection prevalence ratios using LA-only testing strategy are generally higher than using HC2-only or using HC2 as a triage before genotype by LA. HPV clinical testing can be incorporated to monitor HPV prevalence or vaccine effectiveness. Caution is needed when comparing apparent prevalence from different testing strategies.

Evaluation of using composite HPV genotyping assay results to monitor human papillomavirus infection burden through simulation.

BACKGROUND: Researchers often group various HPV types into composite measures based on vaccine subtypes, oncogenic potential, or phylogenetic position. Composite prevalence estimates based on PCR genotyping assay results have been calculated to assess HPV infection burden and to monitor HPV vaccine effectiveness. While prevention and intervention strategies can be made based on these prevalence estimates, the discussion on how well these prevalence estimates measure the true underlying infection burdens is limited. METHODS: A simulation study was conducted to evaluate accuracy of using composite genotyping assay results to monitor HPV infection burden. Data were generated based on mathematical algorithms with prespecified type-specific infection burdens, assay sensitivity, specificity, and correlations between various HPV types. Estimated-to-true prevalence rate ratios and percent reduction of vaccine types were calculated. RESULTS: When "true" underlying type-specific infection burdens were prespecified as the reported prevalence in U.S. and genotyping assay with sensitivity and specificity (0.95, 0.95) was used, estimated-to-true infection prevalence ratios were 2.35, 2.29, 2.18, and 1.46, for the composite measures with 2 high-risk vaccine, 4 vaccine, 14 high-risk and 37 HPV types, respectively. Estimated-to-true prevalence ratios increased when prespecified "true" underlying infection burdens or assay specificity declined. When prespecified "true" type-specific infections of HPV 6, 11, 16 and 18 were reduced by 50%, the composite prevalence estimate of 4 vaccine types only decreased by 17% which is much lower than 48% reduction in the prespecified "true" composite prevalence. CONCLUSIONS: Composite prevalence estimates calculated based on panels of genotyping assay results generally over-estimate the "true" underlying infection burdens and could under-estimate vaccine effectiveness. Analytical specificity of genotyping assay is as or more important than analytical sensitivity and should be considered in selecting assay to monitor HPV.

High and persistent HIV seroincidence in men who have sex with men across 47 U.S. cities.

OBJECTIVE: To provide HIV seroincidence data among men who have sex with men (MSM) in the United States and to identify predictive factors for seroconversion. METHODS: From 1998-2002, 4684 high-risk MSM, age 18-60 years, participated in a randomized, placebo-controlled HIV vaccine efficacy trial at 56 U.S. clinical trial sites. Demographics, behavioral data, and HIV status were assessed at baseline and 6 month intervals. Since no overall vaccine efficacy was detected, data were combined from both trial arms to calculate HIV incidence based on person-years (py) of follow-up. Predictors of seroconversion, adjusted hazards ratio (aHR), were evaluated using a Cox proportional hazard model with time-varying covariates. RESULTS: Overall, HIV incidence was 2.7/100 py and was relatively uniform across study sites and study years. HIV incidence was highest among young men and men reporting unprotected sex, recreational drug use, and a history of a sexually transmitted infection. Independent predictors of HIV seroconversion included: age 18-30 years (aHR = 2.4; 95% CI 1.4,4.0), having >10 partners (aHR = 2.4; 95% CI 1.7,3.3), having a known HIV-positive male sex partner (aHR = 1.6; 95% CI 1.2, 2.0), unprotected anal intercourse with HIV positive/unknown male partners (aHR = 1.7; 95% CI 1.3, 2.3), and amphetamine (aHR = 1.6; 95% CI 1.1, 2.1) and popper (aHR = 1.7; 95% CI 1.3, 2.2) use. CONCLUSIONS: HIV seroincidence was high among MSM despite repeated HIV counseling and reported declines in sexual risk behaviors. Continuing development of new HIV prevention strategies and intensification of existing efforts will be necessary to reduce the rate of new HIV infections, especially among young men.

Enhancing HIV communication between parents and children: efficacy of the Parents Matter! Program.

We examine efficacy of the Parents Matter! Program (PMP), a program to teach African-American parents of preadolescents sexual communication and HIV-prevention skills, through a multicenter, randomized control trial. A total of 1115 parent-child participants were randomized to one of three intervention arms (enhanced, brief, control). Percentages and 95% confidence intervals compare parents' perception of child readiness to learn about sexual issues, communication effectiveness, and dyad concordance from baseline to 12 months postintervention. Wilcoxon rank sum tests compare the changes in scores measuring communication content in HIV/AIDS, abstinence, and condom use. Compared to control, parents in the enhanced arm increased perception of child readiness to learn about sex (16% vs. 29%; p < .001), and a greater proportion of parent-child dyads reported concordant responses on communication topics: HIV/AIDS (15%, 95% CI = 8-21%; p < .001), abstinence (13%, 95% CI = 7-20%; p < .001), condoms (15%, 95% CI = 9-22%; p < .001). Increases in communication scores in HIV/AIDS, abstinence, and condom use were greater in the enhanced arm than control (p < 0.01). We conclude that the enhanced PMP can help parents educate children about HIV and prepare children to avoid sexual risk.

High susceptibility to repeated, low-dose, vaginal SHIV exposure late in the luteal phase of the menstrual cycle of pigtail macaques.

Fluctuations in susceptibility to HIV or SHIV during the menstrual cycle are currently not fully documented. To address this, the time point of infection was determined in 19 adult female pigtail macaques vaginally challenged during their undisturbed menstrual cycles with repeated, low-dose SHIV(SF162P3) exposures. Eighteen macaques (95%) first displayed viremia in the follicular phase, as compared with 1 macaque (5%) in the luteal phase (P < 0.0001). Due to a viral eclipse phase, we estimated a window of most frequent virus transmission between days 24 and 31 of the menstrual cycle, in the late luteal phase. Thus, susceptibility to vaginal SHIV infection is significantly elevated in the second half of the menstrual cycle when progesterone levels are high and when local immunity may be low. Such susceptibility windows have been postulated before but not definitively documented. Our data support the findings of higher susceptibility to HIV in women during progesterone-dominated periods including pregnancy and contraceptive use.

Pediatricians' role and practices regarding provision of guidance about sexual risk reduction to parents.

A randomly selected nationally representative sample of 508 practicing pediatricians was surveyed in order to identify factors associated with physician delivery of primary prevention to parents about sexual risk reduction (SRR). A full 86% (n = 435) reported that provision of SRR guidance is equally or more important than other guidance provided to parents. Among the 435, only 121 (28%) provided SRR guidance to >75% of parents of their adolescent patients. Multivariate analyses revealed barriers of: lack of training, lack of request from parents, and awkwardness. To promote parent-child communication, physicians suggested high-quality brochures for parents (84%); a list of resources (74%); and tools to facilitate parent-child discussions (63%). Pediatricians and parents are important components of sexual risk prevention efforts for adolescents. Editors' Strategic Implications: The findings related to the perceived importance-but infrequent delivery-of SRR communication between pediatricians and parents of adolescents have implications for training and information dissemination in pediatric practices, as well as other health and reproductive health settings.

Efficacy of a parent-based sexual-risk prevention program for African American preadolescents: a randomized controlled trial.

OBJECTIVE: To evaluate the efficacy of a parent-based sexual-risk prevention program for African American preadolescents. DESIGN: Randomized controlled trial. SETTING: Community-based study conducted in Athens, Georgia; Atlanta, Georgia; and Little Rock, Arkansas from 2001 to 2004. PARTICIPANTS: From 1545 inquiries, 1115 African American parent-preadolescent dyads (child, aged 9-12 years) formed the analytic sample. INTERVENTION: Participants were randomized into 1 of 3 study arms: enhanced communication intervention (five 2 1/2-hour sessions), single-session communication intervention (one 2 1/2-hour session), and general health intervention (control, one 2 1/2-hour session). OUTCOME MEASURES: Continuous measures of parent-preadolescent sexual communication and parental responsiveness to sex-related questions at preintervention, postintervention, and at 6- and 12-month follow-ups; and dichotomous measure of preadolescent sexual risk (having engaged in or intending to engage in sexual intercourse at 12-month follow-up). RESULTS: Using intent-to-treat participants, differences of mean change from baseline for continuous measures and relative risk for the dichotomous measure of sexual risk were calculated. Participants in the enhanced intervention had higher mean changes from baseline scores, indicating more sexual communication and responsiveness to sexual communication at each assessment after intervention for all continuous measures than those in the control intervention and single-session intervention. Preadolescents whose parents attended all 5 sessions of the enhanced intervention had a likelihood of sexual risk at the 12-month follow-up of less than 1.00 relative to those whose parents attended the control (relative risk, 0.65; 95% confidence interval, 0.41-1.03) and single-session (relative risk, 0.62; 95% confidence interval, 0.40-0.97) interventions. CONCLUSIONS: These results provide preliminary evidence for the efficacy of a parenting program designed to teach sexual communication skills to prevent sexual risk in preadolescents. TRIAL REGISTRATION; clinicaltrials.gov Identifier: NCT00137943.

The weighted generalized estimating equations approach for the evaluation of medical diagnostic test at subunit level.

Sensitivity and specificity are common measures used to evaluate the performance of a diagnostic test. A diagnostic test is often administrated at a subunit level, e.g. at the level of vessel, ear or eye of a patient so that the treatment can be targeted at the specific subunit. Therefore, it is essential to evaluate the diagnostic test at the subunit level. Often patients with more negative subunit test results are less likely to receive the gold standard tests than patients with more positive subunit test results. To account for this type of missing data and correlation between subunit test results, we proposed a weighted generalized estimating equations (WGEE) approach to evaluate subunit sensitivities and specificities. A simulation study was conducted to evaluate the performance of the WGEE estimators and the weighted least squares (WLS) estimators (Barnhart and Kosinski, 2003) under a missing at random assumption. The results suggested that WGEE estimator is consistent under various scenarios of percentage of missing data and sample size, while the WLS approach could yield biased estimators due to a misspecified missing data mechanism. We illustrate the methodology with a cardiology example.