Evaluating analytic models for individually randomized group treatment trials with complex clustering in nested and crossed designs.

Many individually randomized group treatment (IRGT) trials randomly assign individuals to study arms but deliver treatments via shared agents, such as therapists, surgeons, or trainers. Post-randomization interactions induce correlations in outcome measures between participants sharing the same agent. Agents can be nested in or crossed with trial arm, and participants may interact with a single agent or with multiple agents. These complications have led to ambiguity in choice of models but there have been no systematic efforts to identify appropriate analytic models for these study designs. To address this gap, we undertook a simulation study to examine the performance of candidate analytic models in the presence of complex clustering arising from multiple membership, single membership, and single agent settings, in both nested and crossed designs and for a continuous outcome. With nested designs, substantial type I error rate inflation was observed when analytic models did not account for multiple membership and when analytic model weights characterizing the association with multiple agents did not match the data generating mechanism. Conversely, analytic models for crossed designs generally maintained nominal type I error rates unless there was notable imbalance in the number of participants that interact with each agent.

Prevalence of Advanced HIV Disease, Cryptococcal Antigenemia, and Suboptimal Clinical Outcomes Among Those Enrolled in Care in Vietnam.

BACKGROUND: People living with advanced HIV disease are at high risk of morbidity and mortality. We assessed the prevalence of cryptococcal antigenemia (CrAg) and clinical outcomes among patients newly presenting with CD4 ≤100 cells/µL in Vietnam. SETTING: Twenty-two public HIV clinics in Vietnam. METHODS: During August 2015-March 2017, antiretroviral therapy (ART)-naïve adults presenting for care with CD4 ≤100 cells/µL were screened for CrAg. Those who consented to study enrollment were followed up for up to 12 months and assessed for clinical outcomes. RESULTS: Of 3504 patients with CD4 results, 1354 (38.6%) had CD4 ≤100 cells/µL, of whom 1177 (86.9%) enrolled in the study. The median age was 35 years (interquartile range 30-40); 872 (74.1%) of them were men, and 892 (75.8%) had CD4 <50 cells/µL. Thirty-six patients (3.1%) were CrAg-positive. Overall, 1151 (97.8%) including all who were CrAg-positive initiated ART. Of 881 patients (76.5%) followed up for ≥12 months, 623 (70.7%) were still alive and on ART at 12 months, 54 (6.1%) had transferred to nonstudy clinics, 86 (9.8%) were lost to follow-up, and 104 (11.8%) had died. Among all 1177 study participants, 143 (12.1%) died, most of them (123, 86.0%) before or within 6 months of enrollment. Twenty-seven patients (18.9%) died of pulmonary tuberculosis, 23 (16.1%) died of extrapulmonary tuberculosis, 8 (5.6%) died of Talaromyces marneffei infection, and 6 (4.2%) died of opioid overdose. Eight deaths (5.8%) occurred among the 36 CrAg-positive individuals. CONCLUSIONS: Late presentation for HIV care was common. The high mortality after entry in care calls for strengthening of the management of advanced HIV disease.

Risk scores for predicting early antiretroviral therapy mortality in sub-Saharan Africa to inform who needs intensification of care: a derivation and external validation cohort study.

BACKGROUND: Clinical scores to determine early (6-month) antiretroviral therapy (ART) mortality risk have not been developed for sub-Saharan Africa (SSA), home to 70% of people living with HIV. In the absence of validated scores, WHO eligibility criteria (EC) for ART care intensification are CD4 < 200/µL or WHO stage III/IV. METHODS: We used Botswana XPRES trial data for adult ART enrollees to develop CD4-independent and CD4-dependent multivariable prognostic models for 6-month mortality. Scores were derived by rescaling coefficients. Scores were developed using the first 50% of XPRES ART enrollees, and their accuracy validated internally and externally using South African TB Fast Track (TBFT) trial data. Predictive accuracy was compared between scores and WHO EC. RESULTS: Among 5553 XPRES enrollees, 2838 were included in the derivation dataset; 68% were female and 83 (3%) died by 6 months. Among 1077 TBFT ART enrollees, 55% were female and 6% died by 6 months. Factors predictive of 6-month mortality in the derivation dataset at p < 0.01 and selected for the CD4-independent score included male gender (2 points), ≥ 1 WHO tuberculosis symptom (2 points), WHO stage III/IV (2 points), severe anemia (hemoglobin < 8 g/dL) (3 points), and temperature > 37.5 °C (2 points). The same variables plus CD4 < 200/µL (1 point) were included in the CD4-dependent score. Among XPRES enrollees, a CD4-independent score of ≥ 4 would provide 86% sensitivity and 66% specificity, whereas WHO EC would provide 83% sensitivity and 58% specificity. If WHO stage alone was used, sensitivity was 48% and specificity 89%. Among TBFT enrollees, the CD4-independent score of ≥ 4 would provide 95% sensitivity and 27% specificity, whereas WHO EC would provide 100% sensitivity but 0% specificity. Accuracy was similar between CD4-independent and CD4-dependent scores. Categorizing CD4-independent scores into low (< 4), moderate (4-6), and high risk (≥ 7) gave 6-month mortality of 1%, 4%, and 17% for XPRES and 1%, 5%, and 30% for TBFT enrollees. CONCLUSIONS: Sensitivity of the CD4-independent score was nearly twice that of WHO stage in predicting 6-month mortality and could be used in settings lacking CD4 testing to inform ART care intensification. The CD4-dependent score improved specificity versus WHO EC. Both scores should be considered for scale-up in SSA.

Effect of tuberculosis screening and retention interventions on early antiretroviral therapy mortality in Botswana: a stepped-wedge cluster randomized trial.

BACKGROUND: Undiagnosed tuberculosis (TB) remains the most common cause of HIV-related mortality. Xpert MTB/RIF (Xpert) is being rolled out globally to improve TB diagnostic capacity. However, previous Xpert impact trials have reported that health system weaknesses blunted impact of this improved diagnostic tool. During phased Xpert rollout in Botswana, we evaluated the impact of a package of interventions comprising (1) additional support for intensified TB case finding (ICF), (2) active tracing for patients missing clinic appointments to support retention, and (3) Xpert replacing sputum-smear microscopy, on early (6-month) antiretroviral therapy (ART) mortality. METHODS: At 22 clinics, ART enrollees > 12 years old were eligible for inclusion in three phases: a retrospective standard of care (SOC), prospective enhanced care (EC), and prospective EC plus Xpert (EC+X) phase. EC and EC+X phases were implemented as a stepped-wedge trial. Participants in the EC phase received SOC plus components 1 (strengthened ICF) and 2 (active tracing) of the intervention package, and participants in the EC+X phase received SOC plus all three intervention package components. Primary and secondary objectives were to compare all-cause 6-month ART mortality between SOC and EC+X and between EC and EC+X phases, respectively. We used adjusted analyses, appropriate for study design, to control for baseline differences in individual-level factors and intra-facility correlation. RESULTS: We enrolled 14,963 eligible patients: 8980 in SOC, 1768 in EC, and 4215 in EC+X phases. Median age of ART enrollees was 35 and 64% were female. Median CD4 cell count was lower in SOC than subsequent phases (184/µL in SOC, 246/µL in EC, and 241/µL in EC+X). By 6 months of ART, 461 (5.3%) of SOC, 54 (3.2%) of EC, and 121 (3.0%) of EC+X enrollees had died. Compared with SOC, 6-month mortality was lower in the EC+X phase (adjusted hazard ratio, 0.77; 95% confidence interval, 0.61-0.97, p = 0.029). Compared with EC enrollees, 6-month mortality was similar among EC+X enrollees. CONCLUSIONS: Interventions to strengthen ICF and retention were associated with lower early ART mortality. This new evidence highlights the need to strengthen ICF and retention in many similar settings. Similar to other trials, no additional mortality benefit of replacing sputum-smear microscopy with Xpert was observed. TRIAL REGISTRATION: Retrospectively registered: ClinicalTrials.gov (NCT02538952).

Tuberculosis treatment outcomes among people living with HIV diagnosed using Xpert MTB/RIF versus sputum-smear microscopy in Botswana: a stepped-wedge cluster randomised trial.

BACKGROUND: Xpert® MTB/RIF (Xpert) has high sensitivity for diagnosing tuberculosis (TB) compared to sputum-smear microscopy (smear) and can reduce time-to-diagnosis, time-to-treatment and potentially unfavorable patient-level treatment outcome. METHODS: People living with HIV (PLHIV) initiating antiretroviral therapy at 22 HIV clinics were enrolled and underwent systematic screening for TB (August 2012-November 2014). GeneXpert instruments were deployed following a stepped-wedge design at 13 centers from October 2012-June 2013. Treatment outcomes classified as an unfavorable outcome (died, treatment failure or loss-to-follow-up) or favorable outcome (cured and treatment completed). To determine outcome, smear was performed at month 5 or 6. Empiric treatment was defined as initiating treatment without/before receiving TB-positive results. Adjusting for intra-facility correlation, we compared patient-level treatment outcomes between patients screened using smear (smear arm)- and Xpert-based algorithms (Xpert arm). RESULTS: Among 6041 patients enrolled (smear arm, 1816; Xpert arm, 4225), 256 (199 per 2985 and 57 per 1582 person-years of follow-up in Xpert and smear arms, respectively; adjusted incidence rate ratio, 9.07; 95% confidence interval [CI]: 4.70-17.48; p < 0.001) received TB diagnosis and were treated. TB treatment outcomes were available for 203 patients (79.3%; Xpert, 157; smear, 46). Unfavorable outcomes were reported for 21.7% (10/46) in the smear and 13.4% (21/157) in Xpert arm (adjusted hazard ratio, 1.40; 95% CI: 0.75-2.26; p = 0.268). Compared to smear, in Xpert arm median days from sputum collection to TB treatment was 6 days (interquartile range [IQR] 2-17 versus 22 days [IQR] 3-51), p = 0.005; patients with available sputum test result had microbiologically confirmed TB in 59.0% (102/173) versus 41.9% (18/43), adjusted Odds Ratio [aOR], 2.00, 95% CI: 1.01-3.96, p = 0.048). In smear arm empiric treatment was 68.4% (39/57) versus 48.7% (97/199), aOR, 2.28, 95% CI: 1.24-4.20, p = 0.011), compared to Xpert arm. CONCLUSIONS: TB treatment outcomes were similar between the smear and Xpert arms. However, compared to the smear arm, more patients in the Xpert arm received a TB diagnosis, had a microbiologically confirmed TB, and had a shorter time-to-treatment, and had a lower empiric treatment. Further research is recommended to identify potential gaps in the Botswana health system and similar settings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02538952. Retrospectively registered on 2 September 2015.

Design and analysis of group-randomized trials in cancer: A review of current practices.

The purpose of this paper is to summarize current practices for the design and analysis of group-randomized trials involving cancer-related risk factors or outcomes and to offer recommendations to improve future trials. We searched for group-randomized trials involving cancer-related risk factors or outcomes that were published or online in peer-reviewed journals in 2011-15. During 2016-17, in Bethesda MD, we reviewed 123 articles from 76 journals to characterize their design and their methods for sample size estimation and data analysis. Only 66 (53.7%) of the articles reported appropriate methods for sample size estimation. Only 63 (51.2%) reported exclusively appropriate methods for analysis. These findings suggest that many investigators do not adequately attend to the methodological challenges inherent in group-randomized trials. These practices can lead to underpowered studies, to an inflated type 1 error rate, and to inferences that mislead readers. Investigators should work with biostatisticians or other methodologists familiar with these issues. Funders and editors should ensure careful methodological review of applications and manuscripts. Reviewers should ensure that studies are properly planned and analyzed. These steps are needed to improve the rigor and reproducibility of group-randomized trials. The Office of Disease Prevention (ODP) at the National Institutes of Health (NIH) has taken several steps to address these issues. ODP offers an online course on the design and analysis of group-randomized trials. ODP is working to increase the number of methodologists who serve on grant review panels. ODP has developed standard language for the Application Guide and the Review Criteria to draw investigators' attention to these issues. Finally, ODP has created a new Research Methods Resources website to help investigators, reviewers, and NIH staff better understand these issues.

Delivering Prevention Interventions to People Living with HIV in Clinical Care Settings: Results of a Cluster Randomized Trial in Kenya, Namibia, and Tanzania.

We conducted a group randomized trial to assess the feasibility and effectiveness of a multi-component, clinic-based HIV prevention intervention for HIV-positive patients attending clinical care in Namibia, Kenya, and Tanzania. Eighteen HIV care and treatment clinics (six per country) were randomly assigned to intervention or control arms. Approximately 200 sexually active clients from each clinic were enrolled and interviewed at baseline and 6- and 12-months post-intervention. Mixed model logistic regression with random effects for clinic and participant was used to assess the effectiveness of the intervention. Of 3522 HIV-positive patients enrolled, 3034 (86 %) completed a 12-month follow-up interview. Intervention participants were significantly more likely to report receiving provider-delivered messages on disclosure, partner testing, family planning, alcohol reduction, and consistent condom use compared to participants in comparison clinics. Participants in intervention clinics were less likely to report unprotected sex in the past 2 weeks (OR = 0.56, 95 % CI 0.32, 0.99) compared to participants in comparison clinics. In Tanzania, a higher percentage of participants in intervention clinics (17 %) reported using a highly effective method of contraception compared to participants in comparison clinics (10 %, OR = 2.25, 95 % CI 1.24, 4.10). This effect was not observed in Kenya or Namibia. HIV prevention services are feasible to implement as part of routine care and are associated with a self-reported decrease in unprotected sex. Further operational research is needed to identify strategies to address common operational challenges including staff turnover and large patient volumes.

A Brief Screening Tool to Assess the Risk of Contracting HIV Infection Among Active Injection Drug Users.

OBJECTIVE: To incorporate preexposure prophylaxis and other biomedical or intensive behavioral interventions into the care of injection drug users (IDUs), health care providers need validated, rapid, risk screening tools for identifying persons at highest risk of incident HIV infection. METHODS: To develop and validate a brief screening tool for assessing the risk of contracting HIV (ARCH), we included behavioral and HIV test data from 1904 initially HIV-uninfected men and women enrolled and followed in the AIDS Linked to the Intravenous Experience prospective cohort study between 1988 and 2008. Using logistic regression analyses with generalized estimating equations, we identified significant predictors of incident HIV infection, then rescaled and summed their regression coefficients to create a risk score. RESULTS: The final logistic regression model included age, engagement in a methadone maintenance program, and a composite injection risk score obtained by counting the number of the following 5 behaviors reported during the past 6 months: injection of heroin, injection of cocaine, sharing a cooker, sharing needles, or visiting a shooting gallery. The area under the receiver operating characteristic curve was 0.720; possible scores on the index ranged from 0 to 100 and a score 46 or greater had a sensitivity of 86.2% and a specificity of 42.5%, appropriate for a screening tool. DISCUSSION: We developed an easy to administer 7-question screening tool with a cutoff that is predictive of incident HIV infection in a large prospective cohort of IDUs in Baltimore. The ARCH-IDUs screening tool can be used to prioritize persons who are injecting illicit drugs for consideration of preexposure prophylaxis and other intensive HIV prevention efforts.

Correlates of prevalent HIV infection among adults and adolescents in the Kisumu incidence cohort study, Kisumu, Kenya.

We estimated HIV prevalence and identified correlates of HIV infection among 1106 men and women aged 16-34 years residing in Kisumu, Kenya. Demographic, sexual, and other behavioural data were collected using audio computer-assisted self-interview in conjunction with a medical examination, real-time parallel rapid HIV testing, and laboratory testing for pregnancy, gonorrhoea, chlamydia, syphilis, and herpes simplex virus type 2. Multivariate logistic regression was used to identify variables associated with prevalent HIV infection by gender. Overall HIV prevalence was 12.1%. HIV prevalence among women (17.1%) was approximately two-and-one-half times the prevalence among men (6.6%). Odds of HIV infection in men increased with age (aOR associated with one-year increase in age = 1.21, CI = 1.07-1.35) and were greater among those who were uncircumcised (aOR = 4.42, CI = 1.41-13.89) and those who had an herpes simplex virus type 2-positive (aOR = 3.13, CI = 1.12-8.73) test result. Odds of prevalent HIV infection among women also increased with age (aOR associated with one-year increase in age = 1.16, CI = 1.04-1.29). Women who tested herpes simplex virus type 2 positive had more than three times the odds (aOR = 3.85, CI = 1.38-10.46) of prevalent HIV infection compared with those who tested herpes simplex virus type 2 negative. Tailored sexual health interventions and programs may help mitigate HIV age and gender disparities.

Village-randomized clinical trial of home distribution of zinc for treatment of childhood diarrhea in rural Western kenya.

BACKGROUND: Zinc treatment shortens diarrhea episodes and can prevent future episodes. In rural Africa, most children with diarrhea are not brought to health facilities. In a village-randomized trial in rural Kenya, we assessed if zinc treatment might have a community-level preventive effect on diarrhea incidence if available at home versus only at health facilities. METHODS: We randomized 16 Kenyan villages (1,903 eligible children) to receive a 10-day course of zinc and two oral rehydration solution (ORS) sachets every two months at home and 17 villages (2,241 eligible children) to receive ORS at home, but zinc at the health-facility only. Children's caretakers were educated in zinc/ORS use by village workers, both unblinded to intervention arm. We evaluated whether incidence of diarrhea and acute lower respiratory illness (ALRI) reported at biweekly home visits and presenting to clinic were lower in zinc villages, using poisson regression adjusting for baseline disease rates, distance to clinic, and children's age. RESULTS: There were no differences between village groups in diarrhea incidence either reported at the home or presenting to clinic. In zinc villages (1,440 children analyzed), 61.2% of diarrheal episodes were treated with zinc, compared to 5.4% in comparison villages (1,584 children analyzed, p<0.0001). There were no differences in ORS use between zinc (59.6%) and comparison villages (58.8%). Among children with fever or cough without diarrhea, zinc use was low (<0.5%). There was a lower incidence of reported ALRI in zinc villages (adjusted RR 0.68, 95% CI 0.46-0.99), but not presenting at clinic. CONCLUSIONS: In this study, home zinc use to treat diarrhea did not decrease disease rates in the community. However, with proper training, availability of zinc at home could lead to more episodes of pediatric diarrhea being treated with zinc in parts of rural Africa where healthcare utilization is low. TRIAL REGISTRATION: ClinicalTrials.gov NCT00530829.

Prevalence and correlates of violence exposure among HIV-infected adolescents.

Violence exposure among HIV-infected adolescents was estimated using Poisson regression and adjusted event rate ratios (ERR). Of 166 urban adolescents (99 perinatally infected youth [PIY]; 67 behaviorally infected youth [BIY]) 52.5% (n = 85) experienced violence; 79% (n = 131) witnessed violence. Sexual violence was experienced by 18% (6 PIY, 24 BIY) before age 13 years and by 15% (6 PIY, 19 BIY) during adolescence. BIY were significantly more likely than PIY to have experienced and witnessed violence. Controlling for transmission, ever-bartered sex (ERR = 1.92, CI [1.31 to 2.81], p = .009) and family disruptions (ERR = 1.19, CI [1.03 to 1.39], p = .022) were associated with violence victimization. Family disruptions (ERR = 1.17, CI [1.05 to 1.30], p = .004), female gender (ERR = 1.32, CI [1.05 to 1.66], p = .017), and heterosexual orientation (ERR = 1.48, CI = [1.11 to 1.97], p = .006) were associated with witnessing violence.

Parameters for sample size estimation from a group-randomized HIV prevention trial in HIV clinics in sub-Saharan Africa.

Sample size calculations for a group-randomized trial (GRT) require an estimate of the expected intraclass correlation coefficient (ICC). However, few ICC estimates from GRTs in HIV/AIDS research have been published, leaving investigators with little data on which to base expectations. We used data from a multi-country study to estimate ICCs for variables related to physical and mental health and HIV risk behaviors. ICCs for perceptions of physical and mental health tended to be higher than those for HIV risk behavior variables, which were higher than ICCs for CD4 count. Covariate adjustment for country and socio-demographic variables reduced most ICC estimates. For risk behavior variables, adjustment for country and socio-demographic variables reduced ICC estimates by as much as 84 %. Variability in ICC estimates has important implications for study design, as a larger ICC reduces power. ICC estimates presented in this analysis will allow more precise sample size estimates for future GRTs.

Correlates of health attitudes among homosexual and bisexual men.

There is increased emphasis on physician attention to the overall health and wellness of homosexual and bisexual men, though little is known about the health-related attitudes of these groups. This study determined factors associated with the health attitudes of homosexual and bisexual men and identified preferred sources of health information. For this study, the 2008 ConsumerStyles panel survey was used to create three health attitude scales and to determine factors associated with each scale. The three scales were labeled: (1) health motivation; (2) relationship with health care provider; and (3) self-perception of health literacy. In addition to other factors, higher scores for health motivation and relationship with health care provider were associated with black compared with white men. In contrast, lower scores for self-perception of health literacy were associated with black compared with white men. For information on an unfamiliar health condition, most homosexual and bisexual men chose the Internet. Black homosexual and bisexual men reported being motivated to be healthy and working well with their health care provider to manage their health. However, their perception of their own health literacy [corrected] was low compared with the white men. Attempts to improve health literacy through Internet sites may be helpful in improving health attitudes and reducing negative health outcomes.

Cost-utility analysis of the housing and health intervention for homeless and unstably housed persons living with HIV.

We present a cost-utility analysis based on data from the Housing and Health (H&H) Study of rental assistance for homeless and unstably housed persons living with HIV in Baltimore, Chicago and Los Angeles. As-treated analyses found favorable associations of housing with HIV viral load, emergency room use, and perceived stress (an outcome that can be quantitatively linked to quality of life). We combined these outcome data with information on intervention costs to estimate the cost-per-quality-adjusted-life-year (QALY) saved. We estimate that the cost-per-QALY-saved by the HIV-related housing services is $62,493. These services compare favorably (in terms of cost-effectiveness) to other well-accepted medical and public health services.

Development of a clinical screening index predictive of incident HIV infection among men who have sex with men in the United States.

BACKGROUND: To implement biomedical and other intensive HIV prevention interventions cost-effectively, busy care providers need validated, rapid, risk screening tools for identifying persons at highest risk of incident infection. METHODS: To develop and validate an index, we included behavioral and HIV test data from initially HIV-uninfected men who have sex with men who reported no injection drug use during semiannual interviews in the VaxGen VAX004 study and Project Explore HIV prevention trials. Using generalized estimating equations and logistic regression analyses, we identified significant predictors of incident HIV infection, then weighted and summed their regression coefficients to create a risk index score. RESULTS: The final logistic regression model included age, and the following behaviors reported during the past 6 months: total number of male sex partners, total number of HIV-positive male sex partners, number of times the participant had unprotected receptive anal sex with a male partner of any HIV status, number of times the participant had insertive anal sex with an HIV-positive male partner, whether the participant reported using poppers, and whether they reported using amphetamines. The area under the receiver operating characteristic curve was 0.74, possible scores on index range from 0 to 47 and a score ≥10 had as sensitivity of 84% and a specificity of 45%, levels appropriate for a screening tool. CONCLUSIONS: We developed an easily administered and scored 7-item screening index with a cutoff that is predictive of HIV seroconversion in 2 large prospective cohorts of US men who have sex with men. The index can be used to prioritize patients for intensive HIV prevention efforts (eg, preexposure prophylaxis).

Baseline findings of an HIV incidence cohort study to prepare for future HIV prevention clinical trials in Kisumu, Kenya.

INTRODUCTION: In an analysis of baseline findings of an HIV incidence cohort study, an assessment was made of HIV prevalence among persons presenting for enrollment and any differences in demographic characteristics between persons not enrolled compared to those enrolled. We also described and compared HIV risk behaviors in males and females enrolled in the study. METHODOLOGY: A computer-assisted survey was administered to collect baseline demographic and HIV risk data from 1,277 men and women aged 18-34 years. Testing for HIV and other sexually transmitted infections (STI) was conducted. Out of 1,277 persons prescreened for eligibility, 625 were enrolled. RESULTS: HIV prevalence of all persons who completed screening was 14.8% (females: 21.1%; males: 8.1%). The odds of being enrolled in the study were higher for persons 18-24 years compared to those 30-34 years of age [adjusted odds ratio (AOR)=2.18, CI=1.13, 4.21] and males compared to females [AOR=2.07, CI=1.43, 2.99]. Among those enrolled in the study, the most prevalent HIV risk behaviors were unprotected sex (49%), alcohol use (45%), and transactional sex (30%) in the last three months. Compared to females, a significantly greater proportion of males reported using any alcohol or recreational drug in the last three months, a history of oral sex, sex with partner other than a spouse or main partner, ever having a blood transfusion, ever being treated for an STI, and having knowledge of their last HIV test result. CONCLUSION: The Kisumu Field Station successfully recruited individuals with HIV risk characteristics for the HIV incidence cohort study.

Risk factors for non-adherence and loss to follow-up in a three-year clinical trial in Botswana.

BACKGROUND: Participant non-adherence and loss to follow-up can compromise the validity of clinical trial results. An assessment of these issues was made in a 3-year tuberculosis prevention trial among HIV-infected adults in Botswana. METHODS AND FINDINGS: Between 11/2004-07/2006, 1995 participants were enrolled at eight public health clinics. They returned monthly to receive bottles of medication and were expected to take daily tablets of isoniazid or placebo for three years. Non-adherence was defined as refusing tablet ingestion but agreeing to quarterly physical examinations. Loss to follow-up was defined as not having returned for appointments in ≥60 days. Between 10/2008-04/2009, survey interviews were conducted with 83 participants identified as lost to follow-up and 127 identified as non-adherent. As a comparison, 252 randomly selected adherent participants were also surveyed. Multivariate logistic regression analysis was used to identify associations with selected risk factors. Men had higher odds of being non-adherent (adjusted odds ratio (AOR), 2.24; 95% confidence interval [95%CI] 1.24-4.04) and lost to follow-up (AOR 3.08; 95%CI 1.50-6.33). Non-adherent participants had higher odds of reporting difficulties taking the regimen or not knowing if they had difficulties (AOR 3.40; 95%CI 1.75-6.60) and lower odds associated with each year of age (AOR 0.95; 95%CI 0.91-0.98), but other variables such as employment, distance from clinic, alcohol use, and understanding study requirements were not significantly different than controls. Among participants who were non-adherent or lost to follow-up, 40/210 (19.0%) reported that they stopped the medication because of work commitments and 33/210 (15.7%) said they thought they had completed the study. CONCLUSIONS: Men had higher odds of non-adherence and loss to follow-up than women. Potential interventions that might improve adherence in trial participants may include:targeting health education for men, reducing barriers, clarifying study expectations, educating employers about HIV/AIDS to help reduce stigma in the workplace, and encouraging employers to support employee health. TRIAL REGISTRATION: ClinicalTrials.gov NCT00164281.

Ignoring the group in group-level HIV/AIDS intervention trials: a review of reported design and analytic methods.

OBJECTIVES: Studies evaluating the efficacy of HIV/AIDS interventions often involve the random assignment of groups of participants or the treatment of participants in groups. These studies require analytic methods that take within-group correlation into account. We reviewed published studies to determine the extent to which within-group correlation was dealt with properly. DESIGN: We reviewed group-randomized trials (GRTs) and individually randomized group treatment (IRGT) trials published in HIV/AIDS and general public health journals 2005-2009. METHODS: At least two of the authors reviewed each article, recording descriptive characteristics, sample size estimation methods, analytic methods, and judgments about whether the methods took intraclass correlation into account properly. RESULTS: Of those articles including sufficient information to judge whether analytic methods were correct, only 24% used only appropriate methods for dealing with the intraclass correlation. The percentages differed substantially for GRTs (41.7%) and IRGT trials (8.0%). Most of the articles (69.2%) also made no mention of a priori sample size estimation. CONCLUSION: A majority of the articles in our review reported analyses ignoring the intraclass correlation. This practice may result in underestimated variance, inappropriately small P values, and incorrect conclusions about the effectiveness of interventions. Previous trials that were analyzed incorrectly need to be re-analyzed, and future trials should be designed and analyzed with appropriate methods. Also, journal reviewers and editors need to be aware of the special requirements for design and analysis of GRTs and IRGT trials and judge the quality of articles reporting on such trials according to appropriate standards.

Intraclass correlation associated with therapists: estimates and applications in planning psychotherapy research.

It is essential that outcome research permit clear conclusions to be drawn about the efficacy of interventions. The common practice of nesting therapists within conditions can pose important methodological challenges that affect interpretation, particularly if the study is not powered to account for the nested design. An obstacle to the optimal design of these studies is the lack of data about the intraclass correlation coefficient (ICC), which measures the statistical dependencies introduced by nesting. To begin the development of a public database of ICC estimates, the authors investigated ICCs for a variety outcomes reported in 20 psychotherapy outcome studies. The magnitude of the 495 ICC estimates varied widely across measures and studies. The authors provide recommendations regarding how to select and aggregate ICC estimates for power calculations and show how researchers can use ICC estimates to choose the number of patients and therapists that will optimize power. Attention to these recommendations will strengthen the validity of inferences drawn from psychotherapy studies that nest therapists within conditions.

Male circumcision as an HIV prevention intervention in the U.S.: Influence of health care providers and potential for risk compensation.

OBJECTIVE: The study aims to assess the acceptability of male circumcision as an HIV prevention intervention and the potential for risk compensation in the continental U.S. METHODS.: ConsumerStyles 2008 survey was used to identify correlates of 1) a "likely" or "very likely" response among uncircumcised men to "How likely are you to get circumcised if your health care provider told you that circumcision would reduce your chance of becoming HIV infected?" and 2) agreement or neutrality with a statement indicating that given the protective effects of circumcision for heterosexual men shown by research, men do not have to worry about risks like not wearing condoms during sex or having more sex partners (assessed potential for risk compensation). RESULTS: Response rate was 50.6% (10,108/19,996). Overall, 13.1% of uncircumcised men reported they would be likely to get circumcised if their health care provider told them it would reduce the risk of HIV infection through sex with infected women. Nearly 18% of all men responded in a way indicating a potential for risk compensation if circumcised. CONCLUSIONS: Tailored educational materials about the benefits and risks, including risk compensation, associated with male circumcision as an HIV prevention intervention should be made available to health care providers and specific groups.