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National trends in gonorrhea rates may obscure informative local variations in morbidity. We used group-based trajectory models to identify groups of counties with similar gonorrhea rate trajectories among non-Hispanic White (NHW) and non-Hispanic Black (NHB) females using county-level data on gonorrhea cases in US females from 2003 to 2018. We assessed models with 1–15 groups and selected final models based on fit statistics and identification of divergent trajectory groups with distinct intercepts and/or slopes. We mapped counties by assigned trajectory group and examined the association of county characteristics with group membership. We identified 7 distinct gonorrhea trajectory groups for NHW females and 9 distinct trajectory groups for NHB females. All identified groups for NHW female morbidity experienced increasing gonorrhea rates with a limited range (11.6–183.3/100,000 NHW females in 2018); trajectories of NHB female morbidity varied widely in rates (146.6–966.0/1000 NHB females in 2018) and included 3 groups of counties that experienced a net decline in gonorrhea rates. Counties with higher NHW female morbidity had lower adult sex ratios, lower health insurance coverage, and lower marital rates among NHW adults. Counties with higher NHB female morbidity were more urban, experienced higher rates of poverty, and had lower rates of marriage among NHB adults. Morbidity patterns did not always follow geographic proximity, which could be explained by variation in social determinants of health. Our results demonstrated a highly heterogenous gonorrhea epidemic among NHW and NHB US females, which should prompt further analysis into the differential drivers of gonorrhea morbidity. [ABSTRACT FROM AUTHOR]

The absolute abundance of bacterial taxa in human host‐associated environments plays a critical role in reproductive and gastrointestinal health. However, obtaining the absolute abundance of many bacterial species is typically prohibitively expensive. In contrast, relative abundance data for many species are comparatively cheap and easy to collect (e.g., with universal primers for the 16S rRNA gene). In this paper, we propose a method to jointly model relative abundance data for many taxa and absolute abundance data for a subset of taxa. Our method provides point and interval estimates for the absolute abundance of all taxa. Crucially, our proposal accounts for differences in the efficiency of taxon detection in the relative and absolute abundance data. We show that modeling taxon‐specific efficiencies substantially reduces the estimation error for absolute abundance, and controls the coverage of interval estimators. We demonstrate the performance of our proposed method via a simulation study, a study of the effect of HIV acquisition on microbial abundances, and a sensitivity study where we jackknife the taxa with observed absolute abundances. [ABSTRACT FROM AUTHOR]

Background: Oral pre-exposure prophylaxis has been introduced in more than 70 countries, including many in sub-Saharan Africa, but women experience considerable barriers to daily pill-taking, such as stigma, judgement, and the fear of violence. Safe and effective long-acting agents for HIV prevention are needed for women. We aimed to evaluate the safety and efficacy of injectable cabotegravir compared with daily oral tenofovir diphosphate plus emtricitabine (TDF-FTC) for HIV prevention in HIV-uninfected women.Methods: HPTN 084 was a phase 3, randomised, double-blind, double-dummy, active-controlled, superiority trial in 20 clinical research sites in seven countries in sub-Saharan Africa. Participants were eligible for enrolment if they were assigned female sex at birth, were aged 18-45 years, reported at least two episodes of vaginal intercourse in the previous 30 days, were at risk of HIV infection based on an HIV risk score, and agreed to use a long-acting reversible contraceptive method. Participants were randomly assigned (1:1) to either active cabotegravir with TDF-FTC placebo (cabotegravir group) or active TDF-FTC with cabotegravir placebo (TDF-FTC group). Study staff and participants were masked to study group allocation, with the exception of the site pharmacist who was responsible for study product preparation. Participants were prescribed 5 weeks of daily oral product followed by intramuscular injections every 8 weeks after an initial 4-week interval load, alongside daily oral pills. Participants who discontinued injections were offered open-label daily TDF-FTC for 48 weeks. The primary endpoints of the study were incident HIV infection in the intention-to-treat population, and clinical and laboratory events that were grade 2 or higher in all women who had received at least one dose of study product. This study is registered with ClinicalTrials.gov, NCT03164564.Findings: From Nov 27, 2017, to Nov 4, 2020, we enrolled 3224 participants (1614 in the cabotegravir group and 1610 in the TDF-FTC group). Median age was 25 years (IQR 22-30); 1755 (54·7%) of 3209 had two or more partners in the preceding month. 40 incident infections were observed over 3898 person-years (HIV incidence 1·0% [95% CI 0·73-1·40]); four in the cabotegravir group (HIV incidence 0·2 cases per 100 person-years [0·06-0·52]) and 36 in the TDF-FTC group (1·85 cases per 100 person-years [1·3-2·57]; hazard ratio 0·12 [0·05-0·31]; p<0·0001; risk difference -1·6% [-1·0% to -2·3%]. In a random subset of 405 TDF-FTC participants, 812 (42·1%) of 1929 plasma samples had tenofovir concentrations consistent with daily use. Injection coverage was 93% of the total number of person-years. Adverse event rates were similar across both groups, apart from injection site reactions, which were more frequent in the cabotegravir group than in the TDF-FTC group (577 [38·0%] of 1519 vs 162 [10·7%] of 1516]) but did not result in injection discontinuation. Confirmed pregnancy incidence was 1·3 per 100 person-years (0·9-1·7); no congenital birth anomalies were reported.Interpretation: Although both products for HIV prevention were generally safe, well tolerated, and effective, cabotegravir was superior to TDF-FTC in preventing HIV infection in women.Funding: National Institute of Allergy and Infectious Diseases, ViiV Healthcare, and the Bill & Melinda Gates Foundation. Additional support was provided through the National Institute of Mental Health, the National Institute on Drug Abuse, and the Eunice Kennedy Shriver National Institute of Child Health and Human Development. ViiV Healthcare and Gilead Sciences provided pharmaceutical support. [ABSTRACT FROM AUTHOR]

In trials of oral HIV pre‐exposure prophylaxis (PrEP), multiple approaches have been used to measure adherence, including self‐report, pill counts, electronic dose monitoring devices, and biological measures such as drug levels in plasma, peripheral blood mononuclear cells, hair, and/or dried blood spots. No one of these measures is ideal and each has strengths and weaknesses. However, accurate estimates of adherence to oral PrEP are important as drug efficacy is closely tied to adherence, and secondary analyses of trial data within identified adherent/non‐adherent subgroups may yield important insights into real‐world drug effectiveness. We develop a statistical approach to combining multiple measures of adherence and show in simulated data that the proposed method provides a more accurate measure of true adherence than self‐report. We then apply the method to estimate adherence in the ADAPT study (HPTN 067) in South African women. [ABSTRACT FROM AUTHOR]

Background: Stepped-wedge designs (SWD) are increasingly used to evaluate the impact of changes to the process of care within health care systems. However, to generate definitive evidence, a correct sample size calculation is crucial to ensure such studies are properly powered. The seminal work of Hussey and Hughes (Contemp Clin Trials 28(2):182-91, 2004) provides an analytical formula for power calculations with normal outcomes using a linear model and simple random effects. However, minimal development and evaluation have been done for power calculation with non-normal outcomes on their natural scale (e.g., logit, log). For example, binary endpoints are common, and logistic regression is the natural multilevel model for such clustered data.Methods: We propose a power calculation formula for SWD with either normal or non-normal outcomes in the context of generalized linear mixed models by adopting the Laplace approximation detailed in Breslow and Clayton (J Am Stat Assoc 88(421):9-25, 1993) to obtain the covariance matrix of the estimated parameters.Results: We compare the performance of our proposed method with simulation-based sample size calculation and demonstrate its use on a study of patient-delivered partner therapy for STI treatment and a study that assesses the impact of providing additional benchmark prevalence information in a radiologic imaging report. To facilitate adoption of our methods we also provide a function embedded in the R package "swCRTdesign" for sample size and power calculation for multilevel stepped-wedge designs.Conclusions: Our method requires minimal computational power. Therefore, the proposed procedure facilitates rapid dynamic updates of sample size calculations and can be used to explore a wide range of design options or assumptions. [ABSTRACT FROM AUTHOR]

Background: Incidence and risk factors for nongonococcal urethritis (NGU) remain poorly defined. We conducted a cohort study to estimate the incidence of NGU and identify risk factors in men who have sex with women.Methods: We enrolled cisgender male sexually transmitted disease clinic attendees 16 years or older who reported exclusively female partners. At enrollment and 6 monthly follow-up visits, men underwent a clinical examination, provided urethral swab and urine specimens, completed a sexual behavior survey and biweekly diaries, and were tested for Chlamydia trachomatis (CT) and Mycoplasma genitalium (MG) using Aptima assays (Hologic, Inc). Nongonococcal urethritis was defined as ≥5 polymorphonuclear leukocytes per high-power field plus either urethral symptoms or visible discharge. We estimated the incidence of NGU overall, asymptomatic and symptomatic NGU, non-CT/non-MG NGU, and CT/MG-associated NGU using Poisson regression for clustered outcomes. We performed relative risk binomial regression for clustered data to identify characteristics associated with incident NGU.Results: From August 2014 to July 2018, 307 participants at risk for NGU contributed 109.4 person-years. Median age was 32 years, and 52% were White. At enrollment, 107 men had NGU; of these, 88% were symptomatic, 27% had CT, and 22% had MG. Fifty men had 60 cases of incident NGU (incidence rate, 56 per 100 person-years; 95% confidence interval, 43-74). Unlike prevalent NGU at enrollment, CT/MG-associated incident NGU was rare (incidence rate, 7; 95% confidence interval [CI], 4-15), and most (78%) incident NGU was asymptomatic. Risk factors for incident NGU were ≤ high school education (adjusted rate ratio [ARR], 2.45; 95% CI, 1.19-5.00), history of CT (ARR, 2.15; 95% CI, 1.08-4.27), history of NGU (ARR, 2.67; 95% CI, 1.27-5.62), and NGU at enrollment (ARR, 2.03; 95% CI, 1.04-3.98). Neither condom use nor having a new partner was associated with incident NGU; Black race was only associated with incident symptomatic and non-CT/non-MG NGU.Conclusions: Incidence of NGU was high, predominantly non-CT/non-MG and asymptomatic. Future studies should investigate the etiology and clinical significance of asymptomatic NGU. [ABSTRACT FROM AUTHOR]

Treatment effect heterogeneity is commonly investigated in meta-analyses to identify if treatment effects vary across studies. When conducting an aggregate level data meta-analysis it is common to describe the magnitude of any treatment effect heterogeneity using the I-squared statistic, which is an intuitive and easily understood concept. The effect of a treatment might also vary across clusters in a cluster randomized trial, or across centres in multi-centre randomized trial, and it can be of interest to explore this at the analysis stage. In cross-over trials and other randomized designs, in which clusters or centres are exposed to both treatment and control conditions, this treatment effect heterogeneity can be identified. Here we derive and evaluate a comparable I-squared measure to describe the magnitude of heterogeneity in treatment effects across clusters or centres in randomized trials. We further show how this methodology can be used to estimate treatment effect heterogeneity in an individual patient data meta-analysis. [ABSTRACT FROM AUTHOR]

The stepped wedge cluster randomized design has received increasing attention in pragmatic clinical trials and implementation science research. The key feature of the design is the unidirectional crossover of clusters from the control to intervention conditions on a staggered schedule, which induces confounding of the intervention effect by time. The stepped wedge design first appeared in the Gambia hepatitis study in the 1980s. However, the statistical model used for the design and analysis was not formally introduced until 2007 in an article by Hussey and Hughes. Since then, a variety of mixed-effects model extensions have been proposed for the design and analysis of these trials. In this article, we explore these extensions under a unified perspective. We provide a general model representation and regard various model extensions as alternative ways to characterize the secular trend, intervention effect, as well as sources of heterogeneity. We review the key model ingredients and clarify their implications for the design and analysis. The article serves as an entry point to the evolving statistical literatures on stepped wedge designs. [ABSTRACT FROM AUTHOR]

Background: US guidelines recommend routine human immunodeficiency virus (HIV) screening of all adults and adolescents at least once. The population-level impact of this strategy is unclear and will vary across the country.Methods: We constructed a static linear model to estimate the optimal ages and incremental impact of adding 1-time routine HIV screening to risk-based, prenatal, symptom-based, and partner notification testing. Using surveillance data and published studies, we parameterized the model at the national level and for 2 settings representing subnational variability in the rates and distribution of infection: King County, WA and Philadelphia County, PA. Screening strategies were evaluated in terms of the percent of tests that result in new diagnoses (test positivity), cumulative person-years of undiagnosed infection, and the number of symptomatic HIV/acquired immune deficiency syndrome cases.Results: Depending on the frequency of risk-based screening, routine screening test positivity was maximized at ages 30 to 34 years in the national model. The optimal age for routine screening was higher in a setting with a lower proportion of cases among men who have sex with men. Across settings, routine screening resulted in incremental reductions of 3% to 8% in years of undiagnosed infection and 3% to 11% in symptomatic cases, compared with reductions of 36% to 69% and 41% to 76% attributable to risk-based screening.Conclusions: Although routine HIV screening may contribute meaningfully to increased case detection in persons not captured by targeted testing programs in some settings, this strategy will have a limited impact on population-level outcomes. Our findings highlight the importance of a multipronged testing strategy with continued investment in risk-based screening programs. [ABSTRACT FROM AUTHOR]

Stepped wedge designed trials are a type of cluster‐randomized study in which the intervention is introduced to each cluster in a random order over time. This design is often used to assess the effect of a new intervention as it is rolled out across a series of clinics or communities. Based on a permutation argument, we derive a closed‐form expression for an estimate of the intervention effect, along with its standard error, for a stepped wedge design trial. We show that these estimates are robust to misspecification of both the mean and covariance structure of the underlying data‐generating mechanism, thereby providing a robust approach to inference for the intervention effect in stepped wedge designs. We use simulations to evaluate the type 1 error and power of the proposed estimate and to compare the performance of the proposed estimate to the optimal estimate when the correct model specification is known. The limitations, possible extensions, and open problems regarding the method are discussed. [ABSTRACT FROM AUTHOR]

Background: Standard counseling at nongonococcal urethritis (NGU) diagnosis includes advice to abstain from sex for at least 7 days and until symptoms resolve.Methods: From December 2014 to July 2018, we enrolled men who have sex with men and received azithromycin (1 g) for NGU at the Public Health-Seattle and King County STD Clinic. Over 12 weeks of follow-up, participants reported daily urethral symptoms and sexual activity on web-based diaries. Nongonococcal urethritis was defined as urethral symptoms or visible urethral discharge plus 5 or greater polymorphonuclear leukocytes per high-power field. Time of symptom resolution was defined as the first of 5 consecutive asymptomatic days.Results: Of 100 participants with NGU and no Chlamydia trachomatis (CT)/Mycoplasma genitalium (MG) coinfection, 36 (36%), 22 (22%), and 42 (42%) had CT-NGU, MG-NGU, and non-CT/non-MG NGU, respectively. Among men with MG-NGU, 94% had a macrolide resistance mutation. For all etiologies, median time to symptom resolution after azithromycin was 7 days (95% confidence interval [CI], 5-9); 37% had symptoms lasting longer than 7 days. For men with CT-NGU, MG-NGU, and non-CT/non-MG NGU, median time to symptom resolution was 4 days (95% CI, 2-6; 16% >7 days), undefined days (95% CI, 7 to undefined; 60% >7 days), and 7 days (95% CI, 5-11; 46% >7 days), respectively. Median time to first sexual activity (any type) was 12 days (95% CI, 11-17); it was 16 days (95% CI, 12-18) to first urethral sexual exposure. Twenty-seven percent did not avoid urethral exposure for the recommended period.Conclusions: Counseling at NGU diagnosis should educate patients that symptoms may persist more than 7 days, particularly for non-CT NGU, and emphasize the rationale for the 7-day abstinence period. [ABSTRACT FROM AUTHOR]

Background: Timely diagnosis of infant HIV infection is essential for antiretroviral therapy (ART) initiation. In a randomized controlled trial, we found the Texting Improves Testing (TextIT) intervention (a theory-based text messaging system) to be efficacious for improving infant HIV testing rates and maternal retention in prevention of mother-to-child HIV transmission (PMTCT) programs. Using an implementation science approach, we aimed to evaluate real-world effectiveness of the intervention. Methods and findings: In a pragmatic, cluster-randomized, stepped-wedge trial with 2 time periods of observation, we randomly allocated 10 clinics to begin implementing the intervention immediately and 10 clinics to begin implementing 6 months later. To approximate real-world conditions, inclusion criteria were broad. Women at clinics implementing the intervention received up to 14 text messages during pregnancy and after delivery and had the option to respond to text messages, call, or send inquiry text messages to a designated clinic phone. The primary outcomes were infant HIV testing and maternal retention in care during the first 8 weeks after delivery. We used modified Poisson regression with robust variance estimation to estimate the relative risk and 95% confidence intervals (CIs). Generalized estimating equations were applied on individual-level data to account for clustering by site. Between February 2015 and December 2016, 4,681 women were assessed for study participation, and 2,515 were included. Participant characteristics at enrollment did not differ by study arm. Overall median age was 27 years (interquartile range [IQR] 23–30), median gestational age was 30 weeks (IQR 28–34), 99% were receiving ART, and 87% who enrolled during intervention phases owned a phone. Of 2,326 infants analyzed, 1,466 of 1,613 (90.9%) in the intervention group and 609 of 713 (85.4%) in the control group met the primary outcome of HIV virologic testing performed before 8 weeks after birth (adjusted relative risk [aRR] 1.03; 95% CI 0.97–1.10; P = 0.3). Of 2,472 women analyzed, 1,548 of 1,725 (90%) in the intervention group and 571 of 747 (76%) in the control group met the primary outcome of retention in care during the first 8 weeks after delivery (aRR 1.12; 95% CI 0.97–1.30; P = 0.1). This study had two main limitations. Staff at all facilities were aware of ongoing observation, which may have contributed to increased rates of infant HIV testing and maternal retention in care at both intervention and control facilities, and programmatic initiatives to improve maternal and infant retention in care were ongoing at all facilities at the time of this study, which likely limited the ability to demonstrate effectiveness of the trial intervention. Conclusions: In this study, a larger proportion of infants in the intervention group received HIV testing compared with the control group, but the difference was small and not statistically significant. There was also a nonsignificant increase in maternal postpartum retention in the intervention periods. Despite the lack of a significant effect of the intervention, key lessons emerged, both for strengthening PMTCT and for implementation research in general. Perhaps most important, improving the implementation of usual care may have been sufficient to substantially improve infant HIV testing rates. Trial registration: ClinicalTrials.gov Trial Number NCT02350140. In a study in Kenya, Thomas Odeny and co-workers investigate the value of text reminders for infant HIV testing and retaining mothers in care. Author summary: Why was this study done?: Low retention of mother–infant pairs in postpartum HIV care poses a major threat to successful elimination of mother-to-child HIV transmission in sub-Saharan Africa. The increase in the number of mobile phone connections in sub-Saharan Africa has been spectacular, presenting a unique opportunity to add mobile technology for health (mHealth) to the armamentarium for turning the tide of HIV. We developed the Texting Improves Testing (TextIT) intervention to improve uptake of infant HIV testing and maternal retention in postpartum HIV care in a high–HIV-burden setting. Text messages were designed using behavioral theory. Women received up to 14 text messages during pregnancy and after delivery. Messages were tailored based on recipient's gestational age, name, preferred time, desired language (English, Kiswahili, or Dholuo), date of delivery, and infant's name. Participants had the option to respond to text messages, call, or send inquiry text messages. In a randomized controlled efficacy trial, we found that the TextIT intervention significantly improved rates of infant HIV testing and maternal retention in postpartum HIV care. To achieve policy change leading to broader implementation of this evidence-based intervention, we sought to provide evidence of effectiveness under real-world routine care conditions. What did the researchers do and find?: Using an implementation science approach, we designed a cluster randomized, stepped-wedge trial with 2 time periods of observation. We randomly allocated 10 health facilities to begin implementing the intervention immediately, while the remaining 10 began implementing approximately 6 months later. Consistent with real-world implementation conditions, inclusion criteria were minimal. Women were offered the opportunity to receive text messages if they were ≥18 years old or emancipated minors and between 28 weeks' gestation and delivery. We found that 1,466 of 1,613 (90.9%) infants in the intervention group underwent HIV testing within 8 weeks after birth compared to 609 of 713 (85.4%) in the control group. We also found that 1,548 of 1,725 (90%) women in the intervention group were retained in care during the first 8 weeks after delivery compared to 571 of 747 (76%) in the control group. What do these findings mean?: We observed nonsignificant increases in infant HIV testing and maternal retention in postpartum care associated with short message service (SMS) text messaging. Nevertheless, HIV testing of >90% aligns with the global target of diagnosing >90% of all children living with HIV. Recognizing that strict adherence to statistical thresholds in implementation research may not provide optimal guidance for public health practice, interpretation of estimates of improvement in such studies should be contextualized in terms of the costs and benefits of implementing at scale. [ABSTRACT FROM AUTHOR]

Background: Timely diagnosis of infant HIV infection is essential for antiretroviral therapy (ART) initiation. In a randomized controlled trial, we found the Texting Improves Testing (TextIT) intervention (a theory-based text messaging system) to be efficacious for improving infant HIV testing rates and maternal retention in prevention of mother-to-child HIV transmission (PMTCT) programs. Using an implementation science approach, we aimed to evaluate real-world effectiveness of the intervention.Methods and Findings: In a pragmatic, cluster-randomized, stepped-wedge trial with 2 time periods of observation, we randomly allocated 10 clinics to begin implementing the intervention immediately and 10 clinics to begin implementing 6 months later. To approximate real-world conditions, inclusion criteria were broad. Women at clinics implementing the intervention received up to 14 text messages during pregnancy and after delivery and had the option to respond to text messages, call, or send inquiry text messages to a designated clinic phone. The primary outcomes were infant HIV testing and maternal retention in care during the first 8 weeks after delivery. We used modified Poisson regression with robust variance estimation to estimate the relative risk and 95% confidence intervals (CIs). Generalized estimating equations were applied on individual-level data to account for clustering by site. Between February 2015 and December 2016, 4,681 women were assessed for study participation, and 2,515 were included. Participant characteristics at enrollment did not differ by study arm. Overall median age was 27 years (interquartile range [IQR] 23-30), median gestational age was 30 weeks (IQR 28-34), 99% were receiving ART, and 87% who enrolled during intervention phases owned a phone. Of 2,326 infants analyzed, 1,466 of 1,613 (90.9%) in the intervention group and 609 of 713 (85.4%) in the control group met the primary outcome of HIV virologic testing performed before 8 weeks after birth (adjusted relative risk [aRR] 1.03; 95% CI 0.97-1.10; P = 0.3). Of 2,472 women analyzed, 1,548 of 1,725 (90%) in the intervention group and 571 of 747 (76%) in the control group met the primary outcome of retention in care during the first 8 weeks after delivery (aRR 1.12; 95% CI 0.97-1.30; P = 0.1). This study had two main limitations. Staff at all facilities were aware of ongoing observation, which may have contributed to increased rates of infant HIV testing and maternal retention in care at both intervention and control facilities, and programmatic initiatives to improve maternal and infant retention in care were ongoing at all facilities at the time of this study, which likely limited the ability to demonstrate effectiveness of the trial intervention.Conclusions: In this study, a larger proportion of infants in the intervention group received HIV testing compared with the control group, but the difference was small and not statistically significant. There was also a nonsignificant increase in maternal postpartum retention in the intervention periods. Despite the lack of a significant effect of the intervention, key lessons emerged, both for strengthening PMTCT and for implementation research in general. Perhaps most important, improving the implementation of usual care may have been sufficient to substantially improve infant HIV testing rates.Trial Registration: ClinicalTrials.gov Trial Number NCT02350140. [ABSTRACT FROM AUTHOR]

A central assumption in the design and conduct of non-inferiority trials is that the active-control therapy will have the same degree of effectiveness in the planned non-inferiority trial as in the prior placebo-controlled trials used to define the non-inferiority margin. This is referred to as the 'constancy' assumption. If the constancy assumption fails, decisions based on the chosen non-inferiority margin may be incorrect, and the study runs the risk of approving an inferior product or failing to approve a beneficial product. The constancy assumption cannot be validated in a trial without a placebo arm, and it is unlikely ever to be met completely. When there are strong, observable predictors of constancy, such as dosing and adherence to the active-control product, we can specify conditions where the constancy assumption will likely fail. We propose a method for using measurable predictors of active-control effectiveness to specify non-inferiority margins targeted to the planned study population characteristics. We describe a pre-specified method, using baseline characteristics or post-baseline predictors in the active-control arm, to adapt the non-inferiority margin at the end of the study if constancy is violated. Adaptive margins can help adjust for constancy violations that will inevitably occur in real clinical trials, while maintaining pre-specified levels of Type I error and power. [ABSTRACT FROM AUTHOR]

The stepped wedge design is often used to evaluate interventions as they are rolled out across schools, health clinics, communities, or other clusters. Most models used in the design and analysis of stepped wedge trials assume that the intervention effect is immediate and constant over time following implementation of the intervention (the “exposure time”). This is known as the IT (immediate treatment effect) assumption. However, recent research has shown that using methods based on the IT assumption when the treatment effect varies over exposure time can give extremely misleading results. In this manuscript, we discuss the need to carefully specify an appropriate measure of the treatment effect when the IT assumption is violated and we show how a stepped wedge trial can be powered when it is anticipated that the treatment effect will vary as a function of the exposure time. Specifically, we describe how to power a trial when the exposure time indicator (ETI) model of Kenny et al. (Statistics in Medicine, 41, 4311–4339, 2022) is used and the estimand of interest is a weighted average of the time-varying treatment effects. We apply these methods to the ADDRESS-BP trial, a type 3 hybrid implementation study designed to address racial disparities in health care by evaluating a practice-based implementation strategy to reduce hypertension in African American communities. [ABSTRACT FROM AUTHOR]

Background: Many US health departments have implemented Data to Care interventions, which use HIV surveillance data to identify persons who are inadequately engaged in HIV medical care and assist them with care reengagement, but the effectiveness of this strategy is uncertain.Methods: We conducted a stepped-wedge, cluster-randomized evaluation of a Data to Care intervention in King County, Washington, 2011 to 2014. Persons diagnosed as having HIV for at least 6 months were eligible based on 1 of 2 criteria: (1) viral load (VL) greater than 500 copies/mL and CD4 less than 350 cells/μL at the last report in the past 12 months or (2) no CD4 or VL reported to the health department for at least 12 months. The intervention included medical provider contact, patient contact, and a structured individual interview. Health department staff assisted patients with reengagement using health systems navigation, brief counseling, and referral to support services. We clustered all eligible cases in the county by the last known medical provider and randomized the order of clusters for intervention, creating contemporaneous intervention and control periods (cases in later clusters contributed person-time to the control period at the same time that cases in earlier clusters contributed person-time to the intervention period). We compared the time to viral suppression (VL <200 copies/mL) for individuals during intervention and control periods using a Cox proportional hazards model.Results: We identified 997 persons (intention to treat [ITT]), 18% of whom had moved or died. Of the remaining 822 (modified ITT), 161 (20%) had an undetectable VL reported before contact and 164 (20%) completed the individual interview. The hazard ratio (HR) for time to viral suppression did not differ between the intervention and control periods in ITT (HR, 1.21 [95% confidence interval, 0.85-1.71]) or modified ITT (HR, 1.18 [95% confidence interval, 0.83-1.68]) analysis.Conclusions: The Data to Care intervention did not impact time to viral suppression. [ABSTRACT FROM AUTHOR]

US federal guidelines recommend that medical providers test all adolescents and adults for HIV infection at least once before the age of 64. The wide age range included in these guidelines may limit their utility and impact. We created an arithmetic model to estimate how HIV screening at different ages would impact the total number of years of undiagnosed HIV infection in the population and the number of persons developing clinical manifestations of HIV/AIDS. Our base case model assumed that age of infection in the screened population was the same as the estimated age of infection among all persons diagnosed with HIV in the United States in 2010. We parameterized a second model assuming age of infection was similar to the younger age distribution observed in African Americans. In the base case model, the number of years of undiagnosed HIV infection and number of persons with clinical manifestations of HIV/AIDS were both minimized by screening at age 34. If age of infection was similar to that estimated to occur among African Americans, testing at age 24 and 27 would minimize the number of years of undiagnosed infection and clinical cases, respectively. For both parameterization scenarios, testing between the ages of 21 and 38 resulted in outcomes within 10% of the model's estimated optimal age for screening. Focusing HIV screening on a narrower age range than is currently recommended may improve the impact of routine HIV screening efforts. [ABSTRACT FROM AUTHOR]

Background: The risk of incident high-risk human papillomavirus (HR-HPV) infection associated with recent sexual behaviors is undefined in mid-adult women (defined as women aged 25-65 years).Methods: Triannually, 420 female online daters aged 25-65 years submitted vaginal specimens for HPV testing and completed health and sexual behavior questionnaires. The cumulative incidence of and risk factors for incident HR-HPV detection were estimated by Kaplan-Meier and Cox proportional hazards methods.Results: The 12-month cumulative incidence of HR-HPV detection was 25.4% (95% confidence interval [CI], 21.3%-30.1%). Current hormonal contraceptive use was positively associated with incident HR-HPV detection. Lifetime number of male sex partners was also positively associated but only among women not recently sexually active with male partners. In analysis that adjusted for hormonal contraceptive use and marital status, women reporting multiple male partners or male partners who were new, casual, or had ≥1 concurrent partnership had a hazard of incident HR-HPV detection that was 2.81 times (95% CI, 1.38-5.69 times) that for women who reported no male sex partners in the past 6 months. Thus, among women with multiple male partners or male partners who were new, casual, or had ≥1 concurrent partnership, approximately 64% of incident HR-HPV infections were attributable to one of those partners.Conclusions: Among high-risk mid-adult women with recent new male partners, multiple male partners, or male partners who were casual or had ≥1 concurrent partnership, about two thirds of incident HR-HPV detections are likely new acquisitions, whereas about one third of cases are likely redetections of prior infections. [ABSTRACT FROM AUTHOR]

Transgender individuals constitute an important focus for HIV prevention, but studies in this population present some unique methodologic and operational challenges. We consider issues related to sampling, sample size, number of sites, and trial cost. We discuss relevant design issues for evaluating interventions in both HIV-negative and HIV-infected transgender populations, as well as a method for assessing the impact of an intervention on population HIV incidence. We find that HIV-endpoint studies of transgender individuals will likely require fewer participants but more sites and have higher operational costs than HIV prevention trials in other populations. Because any intervention targeted to transgender individuals will likely include antiretroviral drugs, small scale studies looking at potential interactions between antiretroviral therapy and hormone therapy are recommended. Finally, assessing the impact of an intervention targeted to transgender individuals will require better information on the contribution of such individuals to the population HIV incidence. [ABSTRACT FROM AUTHOR]

Objective: Sexual liaisons between older men and younger women have been linked to greater risk of HIV acquisition. This study aims to (1) identify psychosocial and behavioral factors associated with age-discordant (partner $5 years) versus age-concordant partnerships (- 1 < partner ≥5) and (2) examine the association between partner age discordance and young South African women's sexual behavior. Methods: We used generalized estimating equations to analyze responses from 656 sexually experienced women (aged 13-20 years) from rural Mpumalanga province. Results: Partner age discordance was associated with greater odds of reporting both more frequent sex [adjusted odd ratio (aOR) = 1.77; 95% confidence interval (CI): 1.20 to 2.60] and having a partner with concurrent partnerships (aOR = 1.77; 95% CI: 1.22 to 2.57). Age-discordant partnerships were associated with greater odds of casual partnerships (aOR = 1.50; 95% CI: 1.06 to 2.13), having a partner with concurrent partnerships (aOR = 1.71; 95% CI: 1.19 to 2.46), and more frequent intercourse (ie, having sex at least 2 or 3 times per month) (aOR = 2.04; 95% CI: 1.39 to 3.00). They were associated with lower odds of reporting condom use at last sex (aOR = 0.70; 95% CI: 0.50 to 0.98) and always using condoms (aOR = 0.53; 95% CI: 0.32 to 0.88) in age-discordant partnerships. Conclusions: Our findings suggest that a history of age-discordant partnerships, and to a lesser extent having an age-discordant partner, is linked to HIV risk among young South African women; however, the link between partner age discordance and HIV risk may be more strongly related to the characteristics of age-discordant partnerships than to the characteristics of young women who form such partnerships. [ABSTRACT FROM AUTHOR]

Introduction: Multiple antiretroviral agents have demonstrated efficacy for human immunodeficiency virus (HIV) pre‐exposure prophylaxis (PrEP). As a result, clinical trials of novel agents have transitioned from placebo‐ to active‐controlled designs; however, active‐controlled trials do not provide an estimate of efficacy versus no use of PrEP. Counterfactual placebo comparisons using other data sources could be employed to provide this information. Methods: We compared the active‐controlled study (HPTN 084) of injectable cabotegravir (CAB‐LA) versus daily oral emtricitabine/tenofovir disoproxil fumarate (FTC/TDF) among women from seven countries in Africa to three external, contemporaneous randomized HIV prevention trials from which we constructed counterfactual placebo estimates. We used direct standardization via analysis weights to achieve the same distribution of person‐years between the external study and HPTN 084, across strata predictive of HIV risk (country and selected risk covariates). We estimated prevention efficacy against a counterfactual placebo to provide information on the use of CAB‐LA and FTC/TDF compared to no intervention. We compared the counterfactual placebo findings for FTC/TDF to previous placebo‐controlled trials, adjusted for observed adherence to daily pills. Results: Distribution of age and baseline prevalence of gonorrhoea and chlamydia were similar among matched counterfactual placebo and observed HPTN 084 arms after standardization. Counterfactual estimates of CAB‐LA versus placebo in all three settings showed a consistent risk reduction of 93%–94%, with lower bounds of the confidence intervals above 72%. Observed adherence (quantifiable tenofovir in plasma) in HPTN 084 was 54%–56%, and estimated efficacy of daily oral FTC/TDF against a counterfactual placebo was consistent with a predicted risk reduction of 39%–40% for this level of daily pill use. Conclusions: Counterfactual placebo rates of HIV acquisition derived from external trial data in similar locations and time can be used to support estimates of placebo‐based efficacy of a novel HIV prevention agent. External trial data must be standardized to be representative of the clinical trial cohort testing the novel HIV prevention agent, accounting for confounders. [ABSTRACT FROM AUTHOR]

Introduction: Successful global treatment as prevention (TasP) requires identifying HIV-positive individuals at high risk for transmitting HIV, and having impact via potential infections averted. This study estimated the frequency and predictors of numbers of HIV transmissions and bacterial sexually transmitted infection (STI) acquisition among sexually active HIV-positive individuals in care from three representative global settings.Methods: HIV-positive individuals (n=749), including heterosexual men, heterosexual women and men who have sex with men (MSM) in HIV care, were recruited from Chiang Mai (Thailand), Rio De Janeiro (Brazil) and Lusaka (Zambia). Participants were assessed on HIV and STI sexual transmission risk variables, psychosocial characteristics and bacterial STIs at enrolment and quarterly for 12 months (covering 15 months). Estimated numbers of HIV transmissions per person were calculated using reported numbers of partners and sex acts together with estimates of HIV transmissibility, accounting for ART treatment and condom use.Results: An estimated 3.81 (standard error, (SE)=0.63) HIV transmissions occurred for every 100 participants over the 15 months, which decreased over time. The highest rate was 19.50 (SE=1.68) for every 100 MSM in Brazil. In a multivariable model, country×risk group interactions emerged: in Brazil, MSM had 2.85 (95% CI=1.45, 4.25, p<0.0001) more estimated transmissions than heterosexual men and 3.37 (95% CI=2.01, 4.74, p<0.0001) more than heterosexual women over the 15 months. For MSM and heterosexual women, the combined 12-month STI incidence rate for the sample was 22.4% (95% CI=18.1%, 27.3%; incidence deemed negligible in heterosexual men). In the multivariable model, MSM had 12.3 times greater odds (95% CI=4.44, 33.98) of acquiring an STI than women, but this was not significant in Brazil. Higher alcohol use on the Alcohol Use Disorders Identification Test (OR=1.04, 95% CI=1.01, 1.08) was also significantly associated with increased STI incidence. In bivariate models for both HIV transmissions and STI incidence, higher depressive symptoms were significant predictors.Conclusions: These data help to estimate the potential number of HIV infections transmitted and bacterial STIs acquired over time in patients established in care, a group typically considered at lower transmission risk, and found substantial numbers of estimated HIV transmissions. These findings provide an approach for evaluating the impact (in phase 2 studies) and potentially cost-effectiveness of global TasP efforts. [ABSTRACT FROM AUTHOR]

Background: Oral and fingernail human papillomavirus (HPV) detection may be associated with HPV-related carcinoma risk at these nongenital sites and foster transmission to the genitals. We describe the epidemiology of oral and fingernail HPV among mid-adult women.Methods: Between 2011 and 2012, 409 women aged 30 to 50 years were followed up for 6 months. Women completed health and behavior surveys and provided self-collected oral, fingernail, and vaginal specimens at enrollment and exit for type-specific HPV DNA testing. Concordance of type-specific HPV detection across anatomical sites was described with κ statistics. Using generalized estimating equations or exact logistic regression, we measured the univariate associations of various risk factors with type-specific oral and fingernail HPV detection.Results: Prevalence of detecting HPV in the oral cavity (2.4%) and fingernails (3.8%) was low compared with the vagina (33.1%). Concordance across anatomical sites was poor (κ < 0.20 for all comparisons). However, concurrent vaginal infection with the same HPV type (odds ratio [OR], 101.0; 95% confidence interval [CI], 31.4-748.6) and vaginal HPV viral load (OR per 1 log10 viral load increase, 2.2; 95% CI, 1.5-5.5) were each associated with fingernail HPV detection. Abnormal Papanicolaou history (OR, 11.1; 95% CI, 2.8-infinity), lifetime number of male vaginal sex partners at least 10 (OR vs. 0-3 partners, 5.0; 95% CI, 1.2-infinity), and lifetime number of open-mouth kissing partners at least 16 (OR vs. 0-15 partners, infinity; 95% CI, 2.6-infinity, by exact logistic regression) were each associated with oral HPV detection.Conclusions: Although our findings support HPV DNA deposition or autoinoculation between anatomical sites in mid-adult women, the rarity of HPV in the oral cavity and fingernails suggests that oral/fingernail HPV does not account for a significant fraction of HPV in genital sites. [ABSTRACT FROM AUTHOR]

The use of stepped wedge designs in cluster-randomized trials and implementation studies has increased rapidly in recent years but there remains considerable debate regarding the merits of the design. We discuss three key issues in the design and analysis of stepped wedge trials — time-on-treatment effects, treatment effect heterogeneity and cohort studies. [ABSTRACT FROM AUTHOR]

Background Liquid bead microarray antibody (LBMA) assays are used to assess pathogen–cancer associations. However, studies analyze LBMA data differently, limiting comparability. Methods We generated 10,000 Monte Carlo-type simulations of log-normal antibody distributions (exposure) with 200 cases and 200 controls (outcome). We estimated type I error rates, statistical power, and bias associated with t -tests, logistic regression with a linear exposure and with the exposure dichotomized at 200 units, 400 units, the mean among controls plus two standard deviations, and the value corresponding to the optimal sensitivity and specificity. We also applied these models, and data visualizations (kernel density plots, receiver operating characteristic (ROC) curves, predicted probability plots, and Q–Q plots), to two empirical datasets to assess the consistency of the exposure–outcome relationship. Results All strategies had acceptable type I error rates (0.03 ≤ P ≤ 0.048), except for the dichotomization according to optimal sensitivity and specificity, which had a type I error rate of 0.27. Among the remaining methods, logistic regression with a linear predictor ( Power = 1.00) and t -tests ( Power = 1.00) had the highest power to detect a mean difference of 1.0 MFI (median fluorescence intensity) on the log scale and were unbiased. Dichotomization methods upwardly biased the risk estimates. Conclusion These results indicate that logistic regression with linear predictors and unpaired t -tests are superior to logistic regression with dichotomized predictors for assessing disease associations with LBMA data. Logistic regression with continuous linear predictors and t -tests are preferable to commonly used LBMA dichotomization methods. [ABSTRACT FROM AUTHOR]

Purpose Reductions in risk behaviors are common following enrollment in human immunodeficiency virus (HIV) prevention studies. We develop methods to quantify the proportion of change in risk behaviors that can be attributed to regression to the mean versus study participation and other factors. Methods A novel model that incorporates both regression to the mean and study participation effects is developed for binary measures. The model is used to estimate the proportion of change in the prevalence of “unprotected sex in the past 6 months” that can be attributed to study participation versus regression to the mean in a longitudinal cohort of women at risk for HIV infection who were recruited from ten U.S. communities with high rates of HIV and poverty. HIV risk behaviors were evaluated using audio computer-assisted self-interviews at baseline and every 6 months for up to 12 months. Results The prevalence of “unprotected sex in the past 6 months” declined from 96% at baseline to 77% at 12 months. However, this change could be almost completely explained by regression to the mean. Conclusions Analyses that examine changes over time in cohorts selected for high- or low- risk behaviors should account for regression to the mean effects. [ABSTRACT FROM AUTHOR]

Background There is conflicting evidence on whether prior azithromycin (AZM) exposure is associated with reduced susceptibility to AZM (AZMRS) among persons infected with Neisseria gonorrhoeae (NG). Methods The study population included Public Health–Seattle and King County Sexual Health Clinic (SHC) patients with culture-positive NG infection at ≥1 anatomic site whose isolates were tested for AZM susceptibility in 2012–2019. We used multivariate logistic regression to examine the association of time since last AZM prescription from the SHC in ≤12 months with subsequent diagnosis with AZMRS NG (minimum inhibitory concentration [MIC], ≥2.0 µg/mL) and used linear regression to assess the association between the number of AZM prescriptions in ≤12 months and AZM MIC level, controlling for demographic, behavioral, and clinical characteristics. Results A total of 2155 unique patients had 2828 incident NG infections, 156 (6%) of which were caused by AZMRS NG. AZMRS NG was strongly associated with receipt of AZM from the SHC in the prior 29 days (adjusted odds ratio, 6.76; 95% confidence interval [CI], 1.76 to 25.90) but not with receipt of AZM in the prior 30–365 days. Log AZM MIC level was not associated with the number of AZM prescriptions within ≤12 months (adjusted correlation, 0.0004; 95% CI, –.04 to.037) but was associated with number of prescriptions within <30 days (adjusted coefficient, 0.56; 95% CI,.13 to.98). Conclusions Recent individual-level AZM treatment is associated with subsequent AZMRS gonococcal infections. The long half-life and persistence of subtherapeutic levels of AZM may result in selection of resistant NG strains in persons with recent AZM use. [ABSTRACT FROM AUTHOR]

We examined parameters of sexual partnerships, including respondents’ participation in concurrency, belief that their partner had concurrent partnerships (partners’ concurrency), and partnership intervals, among the 2099 women in HIV Prevention Trials Network 064, a study of women at high risk for HIV infection, in 10 U.S. communities.We analyzed baseline survey responses about partnership dates to determine prevalence of participants’ and partners’ concurrency, intervals between partnerships, knowledge of whether recent partners had undergone HIV testing, and intercourse frequency during the preceding 6 months.Prevalence of participants’ and partners’ concurrency was 40% and 36%, respectively; 24% respondents had both concurrent partnerships and nonmonogamous partners. Among women with >1 partner and no concurrent partnerships themselves, the median gap between partners was 1 month. Multiple episodes of unprotected vaginal intercourse with ≥2 of their most recent partners was reported by 60% of women who had both concurrent partnerships and nonmonogamous partners, 50% with only concurrent partners and no partners’ concurrency, and 33% with only partners’ concurrency versus 14% of women with neither type of concurrency (P < 0.0001). Women who had any involvement with concurrency were also more likely than women with no concurrency involvement to report lack of awareness of whether recent partners had undergone HIV testing (participants’ concurrency 41%, partners’ concurrency 40%, both participants’ and partners’ concurrency 48%, neither 17%; P < 0.0001).These network patterns and short gaps between partnerships may create substantial opportunities for HIV transmission in this sample of women at high risk for HIV infection. [ABSTRACT FROM AUTHOR]

The development of interventions for systemic pre-exposure prophylaxis (PrEP) faces several significant challenges following the US Food and Drug Administration's approval of emtricitabine/tenofovir (FTC/TDF) for HIV prevention. This development is particularly complex because of inconsistency of efficacy results of FTC/TDF PrEP trials for HIV prevention.Possible designs for a PrEP phase 3 efficacy trial are obtained by considering scenarios for potential experimental PrEP and control regimens, including consideration of placebo and active controls, longer acting PrEP and alternate dosing schedules.Noninferiority (NI) trials with hazard ratio NI margins ranging from 1.10 to 1.25 can be justified in the contexts of the 3 PrEP trials demonstrating efficacy of FTC/TDF. However, these HIV endpoint trials may require extremely large number of participants, particularly in settings where FTC/TDF has been shown to reduce the risk of HIV acquisition. NI trials also are often difficult to interpret because they depend on previous placebo-controlled efficacy results. Superiority trials for PrEP are plausible in settings where FTC/TDF efficacy is not yet established, possibly due to low adherence (ie, women at risk as in FemPrEP and VOICE): a new product with potential for higher adherence and potency would be a promising candidate in this setting.Following Food and Drug Administration's approval of FTC/TDF for PrEP, trials to establish efficacy of new PrEP regimens require stringent design standards, together with rigorous debate about adherence within study populations and many important ethical issues. [ABSTRACT FROM AUTHOR]

Heterosexual HIV-1-serodiscordant couples are increasingly recognized as an important source of new HIV-1 infections in sub-Saharan Africa. A simple risk assessment tool could be useful for identifying couples at highest risk for HIV-1 transmission.Using data from 3 prospective studies of HIV-1-serodiscordant couples from 7 African countries and standard methods for development of clinical prediction rules, the authors derived and validated a risk scoring tool developed from multivariate modeling and composed of key predictors for HIV-1 risk that could be measured in standard research and clinical settings.The final risk score included age of the HIV-1-uninfected partner, married and/or cohabiting partnership, number of children, unprotected sex, uncircumcised male HIV-1-uninfected partner, and plasma HIV-1 RNA in the HIV-1-infected partner. The maximum risk score was 12, scores ≥5 were associated with an annual HIV-1 incidence of >3%, and couples with a score ≥6 accounted for only 28% of the population but 67% of HIV-1 transmissions. The area under the curve for predictive ability of the score was 0.74 (95% confidence interval: 0.70 to 0.78). Internal and external validation showed similar predictive ability of the risk score, even when plasma viral load was excluded from the risk score.A discrete combination of clinical and behavioral characteristics defines highest risk HIV-1-serodiscordant couples. Discriminating highest risk couples for HIV-1 prevention programs and clinical trials using a validated risk score could improve research efficiency and maximize the impact of prevention strategies for reducing HIV-1 transmission. [ABSTRACT FROM AUTHOR]

Background. Reliable methods for estimating the incidence of human immunodeficiency virus (HIV) infection are needed to monitor the epidemic, identify at-risk populations, and evaluate HIV prevention strategies. We used a multifaceted approach to estimate HIV incidence in the HIV Prevention Trials Network (HPTN) 064 study.Methods. The HPTN 064 study enrolled 2067 HIV-seronegative women and 32 HIV-seropositive women with no prior HIV infection diagnosis. Women were followed for up to 12 months. HIV incidence estimates were based on (1) detection of acute HIV infection, (2) documentation of HIV seroconversion, and (3) detection of recent HIV infection, using a multiassay algorithm (MAA).Results. Two women had acute HIV infection at enrollment, 4 seroconverted, and 2 were identified as recently infected at enrollment using the MAA. The annual HIV incidence estimate based on acute infection at enrollment (2.52% [95% confidence interval {CI}, .17%–9.33%], using a 14-day window period) was higher than the estimate based on seroconversion (0.24% [95% CI, .07%–.62%]; P = .027). Incidence estimates obtained using the MAA at enrollment and at the end of study were 0.25% (95% CI, .03%–.93%) and 0.13% (95% CI, .006%–.76%), respectively.Conclusions. We detected a high frequency of acute infection at enrollment. Cross-sectional HIV incidence estimates obtained using the MAA were similar to the longitudinal estimate based on HIV seroconversion.Clinical Trials Registration. NCT00995176. [ABSTRACT FROM AUTHOR]

Background: Current WHO guidelines recommend antiretroviral therapy (ART) initiation at CD4 counts ≤#350 cells/µL. Increasing this threshold has been proposed, with a primary goal of reducing HIV-1 infectiousness. Because the quantity of HIV-1 in plasma is the primary predictor of HIV-1 transmission, consideration of plasma viral load in ART initiation guidelines is warranted. Methods: Using per-sex-act infectivity estimates and cross-sectional sexual behavior data from 2,484 HIV-1 infected persons with CD4 counts >350 enrolled in a study of African heterosexual HIV-1 serodiscordant couples, we calculated the number of transmissions expected and the number potentially averted under selected scenarios for ART initiation: I) CD4 count <500 cells/µL, ii) viral load ≥10,000 or ≥50,000 copies/µL and iii) universal treatment. For each scenario, we estimated the proportion of expected infections that could be averted, the proportion of infected persons initiating treatment, and the ratio of these proportions. Results: Initiating treatment at viral load ≥50,000 copies/µL would require treating 19.8% of infected persons with CD4 counts >350 while averting 40.5% of expected transmissions (ratio 2.0); treating at viral load ≥10,0000 copies/µL had a ratio of 1.5. In contrast, initiation at CD4 count <500 would require treating 41.8%, while averting 48.4% (ratio 1.1). Conclusion: Inclusion of viral load in ART initiation guidelines could permit targeting ART resources to HIV-1 infected persons who have a higher risk of transmitting HIV-1. Further work is needed to estimate costs and feasibility. [ABSTRACT FROM AUTHOR]

The meta-analytic approach to evaluating surrogate end points assesses the predictiveness of treatment effect on the surrogate toward treatment effect on the clinical end point based on multiple clinical trials. Definition and estimation of the correlation of treatment effects were developed in linear mixed models and later extended to binary or failure time outcomes on a case-by-case basis. In a general regression setting that covers nonnormal outcomes, we discuss in this paper several metrics that are useful in the meta-analytic evaluation of surrogacy. We propose a unified 3-step procedure to assess these metrics in settings with binary end points, time-to-event outcomes, or repeated measures. First, the joint distribution of estimated treatment effects is ascertained by an estimating equation approach; second, the restricted maximum likelihood method is used to estimate the means and the variance components of the random treatment effects; finally, confidence intervals are constructed by a parametric bootstrap procedure. The proposed method is evaluated by simulations and applications to 2 clinical trials. [ABSTRACT FROM AUTHOR]

Background. Knowledge of factors that affect per-act infectivity of human immunodeficiency virus type 1 (HIV-1) is important for designing HIV-1 prevention interventions and for the mathematical modeling of the spread of HIV-1. Methods. We analyzed data from a prospective study of African HIV-1-serodiscordant couples. We assessed transmissions for linkage within the study partnership, based on HIV-1 sequencing. The primary exposure measure was the HIV-1-seropositive partners' reports of number of sex acts and condom use with their study partner. Results. Of 3297 couples experiencing 86 linked HIV-1 transmissions, the unadjusted per-act risks of unprotected male-to-female (MTF) and female-to-male (FTM) transmission were 0.0019 (95% confidence interval [CI], .0010-.0037) and 0.0010 (95% CI, .00060-.0017), respectively. After adjusting for plasma HIV-1 RNA of the HIV-1-infected partner and herpes simplex virus type 2 serostatus and age of the HIV-1-uninfected partner, we calculated the relative risk (RR) for MTF versus FTM transmission to be 1.03 (P 5 .93). Each log10 increase in plasma HIV-1 RNA increased the per-act risk of transmission by 2.9-fold (95% CI, 2.2-3.8). Self-reported condom use reduced the per-act risk by 78% (RR 5 0.22 [95% CI, .11-.42]). Conclusions. Modifiable risk factors for HIV-1 transmission were plasma HIV-1 RNA level and condom use, and, in HIV-1-uninfected partners, herpes simplex virus 2 infection, genital ulcers, Trichomonas vaginalis, vaginitis or cervicitis, and male circumcision. [ABSTRACT FROM AUTHOR]

Background. Viral load may influence the course of human papillomavirus type 16 (HPV-16) infection.Methods. This case-control study was nested within the 2-year Atypical Squamous Cells of Undetermined Significance and Low-Grade Squamous Intraepithelial Lesion Triage Study, in which women were followed semiannually for HPV and cervical intraepithelial neoplasia (CIN). Case patients (n = 62) were women diagnosed with CIN3 following HPV-16–positive detection at a follow-up visit. HPV-16–positive controls (n = 152) without CIN2 or CIN3 were matched to cases based on the follow-up visit in which viral load was measured. Real-time polymerase chain reaction was used for HPV-16 DNA quantification.Results. The risk of CIN3 increased with increasing HPV-16 DNA load at the follow-up visit (odds ratio, 1.63; 95% confidence interval, 1.33–1.99 per 1 log10 unit increase); the association was not affected by whether HPV-16 was present at enrollment. When HPV-16 was present at both enrollment and follow-up, viral load remained high among cases (P = .77) but decreased substantially among controls (P = .004). Among women with HPV-16 found initially during follow-up, viral load in the first HPV-16–positive sample was associated with short-term persistence; load was higher in those with infection, compared with those without infection, 1 visit after the initial positivity (P = .001).Conclusions. Viral load of newly detected infections and changes in viral load predict persistence and progression of HPV-16 infections. [ABSTRACT FROM PUBLISHER]

The article presents a study which explores the challenges in the design of studies of interventions for the human immunodeficiency virus (HIV) prevention in the U.S. The study cites the elements of an HIV prevention program including a target population, an intervention, and a mechanism for delivery and uptake of the intervention. It concludes that trials for implementing HIV prevention interventions are feasible within the U.S.

Background: The risk of sexual transmission of HIV-1 is strongly associated with the level of HIV-1 RNA in plasma making reduction in HIV-1 plasma levels an important target for HIV-1 prevention interventions. A quantitative understanding of the relationship of plasma HIV-1 RNA and HIV-1 transmission risk could help predict the impact of candidate HIV-1 prevention interventions that operate by reducing plasma HIV-1 levels, such as antiretroviral therapy (ART), therapeutic vaccines, and other non-ART interventions. Methodology/Principal Findings: We use prospective data collected from 2004 to 2008 in East and Southern African HIV-1 serodiscordant couples to model the relationship of plasma HIV-1 RNA levels and heterosexual transmission risk with confirmation of HIV-1 transmission events by HIV-1 sequencing. The model is based on follow-up of 3381 HIV-1 serodiscordant couples over 5017 person-years encompassing 108 genetically-linked HIV-1 transmission events. HIV-1 transmission risk was 2.27 per 100 person-years with a log-linear relationship to log10 plasma HIV-1 RNA. The model predicts that a decrease in average plasma HIV-1 RNA of 0.74 log10 copies/mL (95% CI 0.60 to 0.97) reduces heterosexual transmission risk by 50%, regardless of the average starting plasma HIV-1 level in the population and independent of other HIV-1-related population characteristics. In a simulated population with a similar plasma HIV-1 RNA distribution the model estimates that 90% of overall HIV-1 infections averted by a 0.74 copies/mL reduction in plasma HIV-1 RNA could be achieved by targeting this reduction to the 58% of the cohort with plasma HIV-1 levels ≥4 log10 copies/mL. Conclusions/Significance: This log-linear model of plasma HIV-1 levels and risk of sexual HIV-1 transmission may help estimate the impact on HIV-1 transmission and infections averted from candidate interventions that reduce plasma HIV-1 RNA levels. [ABSTRACT FROM AUTHOR]

Background and Objectives: Understanding the time course of sexual partnerships is important for understanding sexual behaviour, transmission risks for sexually transmitted infections (STI) and development of mathematical models of disease transmission.Study Design: The authors describe issues and biases relating to censoring, truncation and sampling that arise when estimating partnership duration. Recommendations for study design and analysis methods are presented and illustrated using data from a sexual-behaviour survey that enrolled individuals from an adolescent-health clinic and two STD clinics. Survey participants were queried, for each of (up to) four partnerships in the last 3 months, about the month and year of first sex, the number of days since last sex and whether partnerships were limited to single encounters. Participants were followed every 4 months for up to 1 year.Results: After adjustment for censoring and truncation, the estimated median duration of sexual partnerships declined from 9 months (unadjusted) to 1.6 months (adjusted). Similarly, adjustment for censoring and truncation reduced the bias in relative risks for the effect of age in a Cox model. Other approaches, such as weighted estimation, also reduced bias in the estimated duration distribution.Conclusion: Methods are available for estimating partnership duration from censored and truncated samples. Ignoring censoring, truncation and other sampling issues results in biased estimates. [ABSTRACT FROM AUTHOR]

Purpose: Partnership formation and dissolution rates are primary determinants of sexually transmitted infection (STI) transmission dynamics. Methods: The authors used data on persons'' lifetime sexual experiences from a 2003–2004 random digit dialing survey of Seattle residents aged 18–39 years (N =1,194) to estimate age- and gender-specific partnership formation and dissolution rates. Partnership start and end dates were used to estimate participants'' ages at the start of each partnership and partnership durations, and partnerships not enumerated in the survey were imputed. Results: Partnership formation peaked at age 19 at 0.9 (95% confidence interval [CI]: 0.76–1.04) partnerships per year and decreased to 0.1 to 0.2 after age 30 for women and peaked at age 20 at 1.4 (95% CI: 1.08–1.64) and declined to 0.5 after age 30 for men. Nearly one fourth (23.7%) of partnerships ended within 1 week and more than one half (51.2%) ended within 12 weeks. Most (63.5%) individuals 30 to 39 years of age had not formed a new sexual partnership in the past 3 years. Conclusion: A large proportion of the heterosexual population is no longer at substantial STI risk by their early 30s, but similar analyses among high-risk populations may give insight into reasons for the profound disparities in STI rates across populations. [Copyright &y& Elsevier]

The article focuses on the growing diplomatic relations between Iran and the U.S. It mentions that after the governments of the U.S. and Great Britain condemned Iran's nuclear development and plan, the Iranian government refused to attend the January 2010 London Conference on Afghanistan. The U.S. president Barack Obama has announced that improving foreign relations with Iran is one of the most important issues of the government. It further discusses about the relation shared by Iran and Afghanistan and also mentions about the factors that led to trouble relations between Iran and the U.S.

The article presents a study which aims to develop a prediction model for HIV acquisition among men who have sex with men (MSM). Data from Public Health - Seattle and King County (PHSKC) Sexually Transmitted Disease (STD) Clinic were used to develop the model while it was validated using the data from the Project Explore. Results show that the use of methamphetamine or inhaled nitrates and a history or diagnosis of bacterial STD are among the strongest predictors of HIV acquisition.

Vulvar/vaginal human papillomavirus (HPV) infections may precede cervical infections, and certain low-risk types may display vaginal tropism. We evaluated whether incident infections in young women display site-specific preferences by HPV-risk group or phylogenetic species. Although incident infections were more likely to be detected in the vulva/vagina than in the cervix (odds ratio, 4.38 [95% confidence interval, 2.51-7.63]), the majority were first detected at both sites. Low- or undetermined-risk types were more likely than high-risk types to be first detected in the vulva/vagina (P = .03). Site-by-species differences were not statistically significant. Our results suggest that low- or undetermined-risk HPV types preferentially infect vaginal epithelium. [ABSTRACT FROM AUTHOR]

Background. In contrast to the wealth of data on human papillomavirus (HPV) infections in women, much less is known about HPV in men. Methods. Between June 2003 and March 2006, a total of 240 heterosexually active male university students 18-20 years of age were recruited for participation in a cohort study of HPV infection. Genital cell samples were collected, at 4-month intervals, for HPV-DNA analysis by polymerase chain reaction. The subjects maintained a Web-based journal of sexual activity. Results. At 24 months, the cumulative incidence of new infection of any genital HPV type was 62.4% (95% confidence interval [CI], 52.6%-72.2%). Acquisition rates did not differ by genital site (i.e., glans, penile shaft, or scrotum) of initial detection ( ). The most commonly detected types were HPV-84 and HPV-16. In Pp.86 multivariate analysis, a report of a new sex partner during the prior 0-4 (hazards ratio [HR], 2.0 [95% CI, 1.3- 3.0]) and 5-8 (HR, 1.8 [95% CI, 1.2-2.7]) months and a history of smoking (HR, 1.6 [95% CI, 1.1-2.4]) were associated with an elevated risk of HPV acquisition. Conclusion. Genital HPV infection is common and multifocal in young men, and its incidence is higher than that reported for similar cohorts of young women. The high rates of HPV infection in men should be considered when strategies for the prevention of HPV infection in female adolescents and young women are being developed. [ABSTRACT FROM AUTHOR]

The article evaluates a partner notification program for gonorrhea and chlymydial infection that involves community-wide access to free patient-delivered partner therapy (PDPT) and use of case-report forms to triage patients to receive partner notification assistance. The article suggests that a public health program that promotes routine use of PDPT and referral of selected patients for partner notification assistance appears to have improved partner notification outcomes.

Quantitative polymerase chain reaction (PCR)-based tests are used in several different scientific fields to determine levels of a target DNA sequence of interest (the target molecule). The accuracy of quantitative PCR-based tests can be assessed by using the assay to determine the number of copies of the target molecule in a sample with a known concentration of the target molecule. For example, a sample with a known concentration of a target DNA sequence is serially diluted into replicate aliquots and these are tested to determine if the observed quantity of the target is close to the expected quantity (given the concentration in the original sample and the dilution). Statistical methods that are conventionally used to assess the accuracy of these assays do not take into account the variability in the number of target molecules in each aliquot from the original sample. We develop methods that take into account this extra variation and which determine the accuracy of quantitative PCR-based tests in estimating the number of target molecules based on a set of assays of serial dilutions from an original sample with a known concentration of target molecules. These methods are applied to data from an experiment to test the accuracy of a real-time PCR assay at low HIV-1 DNA copy levels. Copyright © 2006 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Abstract: Cluster randomized trials (CRT) are often used to evaluate therapies or interventions in situations where individual randomization is not possible or not desirable for logistic, financial or ethical reasons. While a significant and rapidly growing body of literature exists on CRTs utilizing a “parallel” design (i.e. I clusters randomized to each treatment), only a few examples of CRTs using crossover designs have been described. In this article we discuss the design and analysis of a particular type of crossover CRT – the stepped wedge – and provide an example of its use. [Copyright &y& Elsevier]

Group randomized trials (GRT) are often designed with relatively little preliminary data available to estimate key parameters. In this paper, however, the opposite situation is considered-very good baseline data are available on the primary outcome of interest. These data can then be used to inform key design and analysis decisions such as (i) should the trial be designed as an unmatched or pair-matched study, or stratified in some other fashion; (ii) is analysis of 'change from baseline' preferable to using end-of-study data alone; and (iii) what power might be expected by pursuing these various strategies. The results are applied to a GRT for sexually transmitted diseases prevention in Peru. Copyright © 2005 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Polymerase chain reaction (PCR) based tests are commonly used to diagnose various infections. Such tests are assumed to be highly 'sensitive', however, no consensus definition of, or method for estimating, sensitivity exists. Hughes and Totten proposed that sensitivity be defined as a function of the number of target DNA molecules in the sample with specificity corresponding to the case where there is no target DNA molecule present. They then developed parametric, non-parametric and semi-parametric models for estimating the sensitivity curve. In this paper a general model is proposed that yields their three models as special cases when specificity is assumed to be 1.0. We also extend the general model to incorporate covariates. Simulation studies are used to compare the different estimators. The methods are applied to data from a PCR-based test for Mycoplasma genitalium. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]