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.

Assessing sex differences in viral load suppression and reported deaths using routinely collected program data from PEPFAR-supported countries in sub-Saharan Africa.

BACKGROUND: In sub-Saharan Africa, more women than men access HIV testing and treatment and may have better viral load suppression (VLS). We utilized routinely reported aggregated HIV program data from 21 sub-Saharan African countries to examine sex differences in VLS and death rates within antiretroviral therapy (ART) programs supported by the United States President's Emergency Plan for AIDS Relief (PEPFAR). METHODS: We included VLS and reported death data for persons aged 15 + years on ART from October-December 2020 disaggregated by sex and age for each subnational unit (SNU). We used linear mixed-model regression to estimate VLS proportion and negative binomial mixed-model regression to estimate the rates of death and death plus interruptions in treatment (IIT). All models were weighted for SNU-level ART population size and adjusted for sex, age, HIV/tuberculosis coinfection, country, and SNU; models for reported deaths and deaths plus IIT were also adjusted for SNU-level VLS. RESULTS: Mean VLS proportion was higher among women than men (93.0% vs. 92.0%, p-value < 0.0001) and 50 + than 15-49 age group (93.7% vs. 91.2%, p-value < 0.0001). The mean rate of reported deaths was higher among men than women (2.37 vs. 1.51 per 1000 persons, p-value < 0.0001) and 50 + than 15-49 age group (2.39 vs. 1.50 per 1000, p-value < 0.0001); the mean rate of reported deaths plus IIT was higher among men (30.1 in men vs. 26.0 in women per 1000, p-value < 0.0001) and higher among 15-49 than 50 + age group (34.7 vs. 22.6 per 1000, p-value < 0.0001). CONCLUSIONS: The mean rate of reported deaths was higher among men in most models despite adjusting for VLS. Further exploration into differences in care-seeking behaviors; coverage of screening, prophylaxis, and/or treatment of opportunistic infections; and more extensive testing options for men to include CD4 is recommended.

Impact of HIV treat-all and complementary policies on ART linkage in 13 PEPFAR-supported African countries.

BACKGROUND: In 2015, the World Health Organization recommended that all people living with HIV begin antiretroviral treatment (ART) regardless of immune status, a policy known as 'Treat-All to end AIDS', commonly referred to as Treat-All. Almost all low- and middle-income countries adopted this policy by 2019. This study describes how linkage to treatment of newly diagnosed persons changed between 2015 and 2018 and how complementary policies may have similarly increased linkage for 13 African countries. These countries adopted and implemented Treat-All policies between 2015 and 2018 and were supported by the U.S. Government's President's Emergency Plan for AIDS Relief (PEPFAR). The focuses of this research were to understand 1) linkage rates to ART initiation before and after the adoption of Treat-All in each country; 2) how Treat-All implementation differed across these countries; and 3) whether complementary policies (including same-day treatment initiation, task-shifting, reduced ART visits, and reduced ART pickups) implemented around the same time may have increased ART linkage. METHODS: HIV testing and treatment data were collected by PEPFAR country programs in 13 African countries from 2015 to 2018. These countries were chosen based on the completeness of policy data and availability of program data during the study period. Program data were used to calculate proxy linkage rates. These rates were compared relative to the Treat All adoption period and the adoption of complementary policies. RESULTS: The 13 countries experienced an average increase in ART linkage of 29.3% over the entire study period. In examining individual countries, all but two showed increases in linkage to treatment immediately after Treat All adoption. Across all countries, those that had adopted four or more complementary policies showed an average increased linkage of 39.8% compared to 13.9% in countries with fewer than four complementary policies. CONCLUSIONS: Eleven of 13 country programs examined in this study demonstrated an increase in ART linkage after Treat-All policy adoption. Increases in linkage were associated with complementary policies. When exploring new public health policies, policymakers may consider which complementary policies might also help achieve the desired outcome of the public health policy.

Monitoring Emerging Human Immunodeficiency Virus Drug Resistance in Sub-Saharan Africa in the Era of Dolutegravir.

Dolutegravir-based regimens are now standard of care for human immunodeficiency virus treatment for millions of people around sub-Saharan Africa. To ensure its continued efficacy, monitoring of emerging drug resistance that inform a treatment strategy among those failing is crucial. In this report, we outline the US President's Emergency Plan for AIDS Relief to leverage viral load infrastructure to implement effective drug resistance surveillance in the countries it supports.

Universal Testing, Expanded Treatment, and Incidence of HIV Infection in Botswana.

BACKGROUND: The feasibility of reducing the population-level incidence of human immunodeficiency virus (HIV) infection by increasing community coverage of antiretroviral therapy (ART) and male circumcision is unknown. METHODS: We conducted a pair-matched, community-randomized trial in 30 rural or periurban communities in Botswana from 2013 to 2018. Participants in 15 villages in the intervention group received HIV testing and counseling, linkage to care, ART (started at a higher CD4 count than in standard care), and increased access to male circumcision services. The standard-care group also consisted of 15 villages. Universal ART became available in both groups in mid-2016. We enrolled a random sample of participants from approximately 20% of households in each community and measured the incidence of HIV infection through testing performed approximately once per year. The prespecified primary analysis was a permutation test of HIV incidence ratios. Pair-stratified Cox models were used to calculate 95% confidence intervals. RESULTS: Of 12,610 enrollees (81% of eligible household members), 29% were HIV-positive. Of the 8974 HIV-negative persons (4487 per group), 95% were retested for HIV infection over a median of 29 months. A total of 57 participants in the intervention group and 90 participants in the standard-care group acquired HIV infection (annualized HIV incidence, 0.59% and 0.92%, respectively). The unadjusted HIV incidence ratio in the intervention group as compared with the standard-care group was 0.69 (P = 0.09) by permutation test (95% confidence interval [CI], 0.46 to 0.90 by pair-stratified Cox model). An end-of-trial survey in six communities (three per group) showed a significantly greater increase in the percentage of HIV-positive participants with an HIV-1 RNA level of 400 copies per milliliter or less in the intervention group (18 percentage points, from 70% to 88%) than in the standard-care group (8 percentage points, from 75% to 83%) (relative risk, 1.12; 95% CI, 1.09 to 1.16). The percentage of men who underwent circumcision increased by 10 percentage points in the intervention group and 2 percentage points in the standard-care group (relative risk, 1.26; 95% CI, 1.17 to 1.35). CONCLUSIONS: Expanded HIV testing, linkage to care, and ART coverage were associated with increased population viral suppression. (Funded by the President's Emergency Plan for AIDS Relief and others; Ya Tsie ClinicalTrials.gov number, NCT01965470.).

Drug Resistance Mutations Among South African Children Living With HIV on WHO-recommended ART Regimens.

BACKGROUND: Children living with human immunodeficiency virus (HIV) (CLHIV) receiving antiretroviral therapy (ART) in resource-limited settings are susceptible to high rates of acquired HIV drug resistance (HIVDR), but few studies include children initiating age-appropriate World Health Organization (WHO)-recommended first-line regimens. We report data from a cohort of ART-naive South African children who initiated first-line ART. METHODS: ART-eligible CLHIV aged 0-12 years were enrolled from 2012 to 2014 at 5 public South African facilities and were followed for up to 24 months. Enrolled CLHIV received standard-of-care WHO-recommended first-line ART. At the final study visit, a dried blood spot sample was obtained for viral load and genotypic resistance testing. RESULTS: Among 72 successfully genotyped CLHIV, 49 (68.1%) received ABC/3TC/LPV/r, and 23 (31.9%) received ABC/3TC/EFV. All but 2 children on ABC/3TC/LPV/r were <3 years, and all CLHIV on ABC/3TC/EFV were ≥3 years. Overall, 80.6% (58/72) had at least one drug resistance mutation (DRM). DRMs to nonnucleoside reverse transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors (NRTIs) were found among 65% and 51% of all CLHIV, respectively, with no statistical difference by ART regimen. More CLHIV on ABC/3TC/EFV, 47.8% (11/23), were found to have 0 or only 1 effective antiretroviral drug remaining in their current regimen compared to 8.2% (4/49) on ABC/3TC/LPV/r. CONCLUSIONS: High levels of NNRTI and NRTI DRMs among CLHIV receiving ABC/3TC/LPV/r suggests a lasting impact of failed mother-to-child transmission interventions on DRMs. However, drug susceptibility analysis reveals that CLHIV with detectable viremia on ABC/3TC/LPV/r are more likely to have maintained at least 2 effective agents on their current HIV regimen than those on ABC/3TC/EFV.

Prevalence of Voluntary Medical Male Circumcision for HIV Infection Prevention - Chókwè District, Mozambique, 2014-2019.

Male circumcision is an important preventive strategy that confers lifelong partial protection (approximately 60% reduced risk) against heterosexually acquired HIV infection among males (1). In Mozambique, the prevalence of male circumcision was 51% when the voluntary medical male circumcision (VMMC) program began in 2009. The Mozambique Ministry of Health set a goal of 80% circumcision prevalence among males aged 10-49 years by 2019 (2). CDC analyzed data from five cross-sectional surveys of the Chókwè Health and Demographic Surveillance System (CHDSS) to evaluate progress toward the goal and guide ongoing needs for VMMC in Mozambique. During 2014-2019, circumcision prevalence among males aged 15-59 years increased 42%, from 50.1% to 73.5% (adjusted prevalence ratio [aPR] = 1.42). By 2019, circumcision prevalence among males aged 15-24 years was 90.2%, exceeding the national goal (2). However, circumcision prevalence among males in older age groups remained below 80%; prevalence was 62.7%, 54.5%, and 55.7% among males aged 25-34, 35-44, and 45-59 years, respectively. A multifaceted strategy addressing concerns about the safety of the procedure, cultural norms, and competing priorities that lead to lack of time could help overcome barriers to circumcision among males aged ≥25 years.

Forced Sexual Initiation and Early Sexual Debut and Associated Risk Factors and Health Problems Among Adolescent Girls and Young Women - Violence Against Children and Youth Surveys, Nine PEPFAR Countries, 2007-2018.

Adolescent girls and young women aged 13-24 years are disproportionately affected by HIV in sub-Saharan Africa (1), resulting from biologic, behavioral, and structural* factors, including violence. Girls in sub-Saharan Africa also experience sexual violence at higher rates than do boys (2), and women who experience intimate partner violence have 1.3-2.0 times the odds of acquiring HIV infection, compared with those who do not (3). Violence Against Children and Youth Survey (VACS) data during 2007-2018 from nine countries funded by the U.S. President's Emergency Plan for AIDS Relief (PEPFAR) were analyzed to estimate prevalence and assess factors associated with early sexual debut and forced sexual initiation.† Among adolescent girls and young women aged 13-24 years who ever had sex, the prevalence of lifetime sexual violence ranged from 12.5% to 49.3%, and forced sexual initiation ranged from 14.7% to 38.9%; early sexual debut among adolescent girls and young women aged 16-24 years ranged from 14.4% to 40.1%. In multiple logistic regression models, forced sexual initiation was associated with being unmarried, violence victimization, risky sexual behaviors, sexually transmitted infections (STIs), and poor mental health. Early sexual debut was associated with lower education, marriage, ever witnessing parental intimate partner violence during childhood, risky sexual behaviors, poor mental health, and less HIV testing. Comprehensive violence and HIV prevention programming is needed to delay sexual debut and protect adolescent girls and young women from forced sex.

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).

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.