Adaptive sequential surveillance with network and temporal dependence.

Strategic test allocation is important for control of both emerging and existing pandemics (eg, COVID-19, HIV). It supports effective epidemic control by (1) reducing transmission via identifying cases and (2) tracking outbreak dynamics to inform targeted interventions. However, infectious disease surveillance presents unique statistical challenges. For instance, the true outcome of interest (positive infection status) is often a latent variable. In addition, presence of both network and temporal dependence reduces data to a single observation. In this work, we study an adaptive sequential design, which allows for unspecified dependence among individuals and across time. Our causal parameter is the mean latent outcome we would have obtained, if, starting at time t given the observed past, we had carried out a stochastic intervention that maximizes the outcome under a resource constraint. The key strength of the method is that we do not have to model network and time dependence: a short-term performance Online Super Learner is used to select among dependence models and randomization schemes. The proposed strategy learns the optimal choice of testing over time while adapting to the current state of the outbreak and learning across samples, through time, or both. We demonstrate the superior performance of the proposed strategy in an agent-based simulation modeling a residential university environment during the COVID-19 pandemic.

Dynamic choice HIV prevention intervention at outpatient departments in rural Kenya and Uganda.

OBJECTIVE: HIV prevention service delivery models that offer product choices, and the option to change preferences over time, may increase prevention coverage. Outpatient departments in sub-Saharan Africa diagnose a high proportion of new HIV infections, but are an understudied entry point to biomedical prevention. DESIGN: Individually randomized trial of dynamic choice HIV prevention (DCP) intervention vs. standard-of-care (SOC) among individuals with current/anticipated HIV exposure risk at outpatient departments in rural Kenya and Uganda (SEARCH; NCT04810650). METHODS: Our DCP intervention included 1) product choice (oral preexposure prophylaxis [PrEP] or postexposure prophylaxis [PEP]) with an option to switch over time, 2) HIV provider- or self-testing, 3) service location choice (community vs. clinic-based), and 4) provider training on patient-centered care. Primary outcome was proportion of follow-up covered by PrEP/PEP over 48 weeks assessed via self-report. RESULTS: We enrolled 403 participants (61% women; median 27 years, IQR 22-37). In the DCP arm, 86% ever chose PrEP, 15% ever chose PEP over 48 weeks; selection of HIV self-testing increased from 26 to 51% and of out-of-facility visits from 8 to 52%. Among 376 of 403 (93%) with outcomes ascertained, time covered by PrEP/PEP was higher in DCP (47.5%) vs. SOC (18.3%); difference = 29.2% (95% confidence interval: 22.7-35.7; P  < 0.001). Effects were similar among women and men (28.2 and 31.0% higher coverage in DCP, respectively) and larger during periods of self-reported HIV risk (DCP 64.9% vs. SOC 26.3%; difference = 38.6%; 95% confidence interval: 31.0-46.2; P  < 0.001). CONCLUSION: A dynamic choice HIV prevention intervention resulted in two-fold greater time covered by biomedical prevention products compared to SOC in general outpatient departments in eastern Africa.

Randomized Trial of a "Dynamic Choice" Patient-Centered Care Intervention for Mobile Persons With HIV in East Africa.

BACKGROUND: Persons with HIV (PWH) with high mobility face obstacles to HIV care engagement and viral suppression. We sought to understand whether a patient-centered intervention for mobile PWH would improve viral suppression and retention in care, and if so, which subgroups would benefit most. METHODS: In a randomized trial, we evaluated the effect of an intervention designed to address barriers to care among mobile (≥2 weeks out of community in previous year) PWH with viral nonsuppression or recent missed visits in Kenya and Uganda (NCT04810650). The intervention included dynamic choice of a "travel pack" (emergency antiretroviral therapy [ART] supply, discrete ART packaging, and travel checklist), multimonth and offsite refills, facilitated transfer to out-of-community clinics, and hotline access to a mobility coordinator. The primary outcome was viral suppression (<400 copies/mL) at 48 weeks. Secondary outcomes included retention in care and ART possession. RESULTS: From April 2021 to July 2022, 201 participants were enrolled and randomized (102 intervention, 99 control): 109 (54%) were female participants and 101 (50%) from Kenya; median age was 37 years (interquartile range: 29-43). At 48 weeks, there was no significant difference in viral suppression in intervention (85%) vs. control (86%). The intervention improved retention in care (risk ratio: 1.06[1.02-1.1]; P < 0.001) and ART possession (risk ratio: 1.07[1.03-1.11]; P < 0.001), with larger effect sizes among persons with baseline nonsuppression and high mobility (≥2 weeks out of community in previous 3 months). CONCLUSIONS: Mobile PWH-centered care should be considered for high-risk mobile populations, including nonsuppressed and highly mobile PWH, to improve retention in care and sustain viral suppression over time. TRIAL REGISTRATION: NCT04810650.

A community-based dynamic choice model for HIV prevention improves PrEP and PEP coverage in rural Uganda and Kenya: a cluster randomized trial.

INTRODUCTION: Optimizing HIV prevention may require structured approaches for providing client-centred choices as well as community-based entry points and delivery. We evaluated the effect of a dynamic choice model for HIV prevention, delivered by community health workers (CHWs) with clinician support, on the use of biomedical prevention among persons at risk of HIV in rural East Africa. METHODS: We conducted a cluster randomized trial among persons (≥15 years) with current or anticipated HIV risk in 16 villages in Uganda and Kenya (SEARCH; NCT04810650). The intervention was a client-centred HIV prevention model, including (1) structured client choice of product (pre-exposure prophylaxis [PrEP] or post-exposure prophylaxis [PEP]), service location (clinic or out-of-clinic) and HIV testing modality (self-test or rapid test), with the ability to switch over time; (2) a structured assessment of patient barriers and development of a personalized support plan; and (3) phone access to a clinician 24/7. The intervention was delivered by CHWs and supported by clinicians who oversaw PrEP and PEP initiation and monitoring. Participants in control villages were referred to local health facilities for HIV prevention services, delivered by Ministry of Health staff. The primary outcome was biomedical prevention coverage: a proportion of 48-week follow-up with self-reported PrEP or PEP use. RESULTS: From May to July 2021, we enrolled 429 people (212 intervention; 217 control): 57% women and 35% aged 15-24 years. Among intervention participants, 58% chose PrEP and 58% chose PEP at least once over follow-up; self-testing increased from 52% (baseline) to 71% (week 48); ≥98% chose out-of-facility service delivery. Among 413 (96%) participants with the primary outcome ascertained, average biomedical prevention coverage was 28.0% in the intervention versus 0.5% in the control: a difference of 27.5% (95% CI: 23.0-31.9%, p<0.001). Impact was larger during periods of self-reported HIV risk: 36.6% coverage in intervention versus 0.9% in control, a difference of 35.7% (95% CI: 27.5-43.9, p<0.001). Intervention effects were seen across subgroups defined by sex, age group and alcohol use. CONCLUSIONS: A client-centred dynamic choice HIV prevention intervention, including the option to switch between products and CHW-based delivery in the community, increased biomedical prevention coverage by 27.5%. However, substantial person-time at risk of HIV remained uncovered.

Effect of a brief alcohol counselling intervention on HIV viral suppression and alcohol use among persons with HIV and unhealthy alcohol use in Uganda and Kenya: a randomized controlled trial.

INTRODUCTION: Unhealthy alcohol use significantly contributes to viral non-suppression among persons with HIV (PWH). It is unknown whether brief behavioural interventions to reduce alcohol use can improve viral suppression among PWH with unhealthy alcohol use in sub-Saharan Africa (SSA). METHODS: As part of the SEARCH study (NCT04810650), we conducted an individually randomized trial in Kenya and Uganda of a brief, skills-based alcohol intervention among PWH with self-reported unhealthy alcohol use (Alcohol Use Disorders Identification Test-Consumption [AUDIT-C], prior 3 months, ≥3/female; ≥4/male) and at risk of viral non-suppression, defined as either recent HIV viral non-suppression (≥400 copies/ml), missed visits, out of care or new diagnosis. The intervention included baseline and 3-month in-person counselling sessions with interim booster phone calls every 3 weeks. The primary outcome was HIV viral suppression (<400 copies/ml) at 24 weeks, and the secondary outcome was unhealthy alcohol use, defined by AUDIT-C or phosphatidylethanol (PEth), an alcohol biomarker, ≥50 ng/ml at 24 weeks. RESULTS: Between April and September 2021, 401 persons (198 intervention, 203 control) were enrolled from HIV clinics in Uganda (58%) and Kenya (27%) and alcohol-serving venues in Kenya (15%). At baseline, 60% were virally suppressed. Viral suppression did not differ between arms at 24 weeks: suppression was 83% in intervention and 82% in control arms (RR: 1.01, 95% CI: 0.93-1.1). Among PWH with baseline viral non-suppression, 24-week suppression was 73% in intervention and 64% in control arms (RR 1.15, 95% CI: 0.93-1.43). Unhealthy alcohol use declined from 98% at baseline to 73% in intervention and 84% in control arms at 24 weeks (RR: 0.86, 95% CI: 0.79-0.94). Effects on unhealthy alcohol use were stronger among women (RR 0.70, 95% CI: 0.56-0.88) than men (RR 0.93, 95% CI: 0.85-1.01) and among participants with a baseline PEth⩽200 ng/ml (RR 0.68, 95% CI: 0.53-0.87) versus >200 ng/ml (RR 0.97, 95% CI: 0.92-1.02). CONCLUSIONS: In a randomized trial of 401 PWH with unhealthy alcohol use and risk for viral non-suppression, a brief alcohol intervention reduced unhealthy alcohol use but did not affect viral suppression at 24 weeks. Brief alcohol interventions have the potential to improve the health of PWH in SSA by reducing alcohol use, a significant driver of HIV-associated co-morbidities.

Adaptive Strategies for Retention in Care among Persons Living with HIV.

BACKGROUND: Optimizing retention in human immunodeficiency virus (HIV) treatment may require sequential behavioral interventions based on patients' response. METHODS: In a sequential multiple assignment randomized trial in Kenya, we randomly assigned adults initiating HIV treatment to standard of care (SOC), Short Message Service (SMS) messages, or conditional cash transfers (CCT). Those with retention lapse (missed a clinic visit by ≥14 days) were randomly assigned again to standard-of-care outreach (SOC-Outreach), SMS+CCT, or peer navigation. Those randomly assigned to SMS or CCT who did not lapse after 1 year were randomly assigned again to either stop or continue the initial intervention. Primary outcomes were retention in care without an initial lapse, return to the clinic among those who lapsed, and time in care; secondary outcomes included adjudicated viral suppression. Average treatment effect (ATE) was calculated using targeted maximum likelihood estimation with adjustment for baseline characteristics at randomization and certain time-varying characteristics at rerandomization. RESULTS: Among 1809 participants, 79.7% of those randomly assigned to CCT (n=523/656), 71.7% to SMS (n=393/548), and 70.7% to SOC (n=428/605) were retained in care in the first year (ATE: 9.9%; 95% confidence interval [CI]: 5.4%, 14.4% and ATE: 4.2%; 95% CI: -0.7%, 9.2% for CCT and SMS compared with SOC, respectively). Among 312 participants with an initial lapse who were randomly assigned again, 69.1% who were randomly assigned to a navigator (n=76/110) returned, 69.5% randomly assigned to CCT+SMS (n=73/105) returned, and 55.7% randomly assigned to SOC-Outreach (n=54/97) returned (ATE: 14.1%; 95% CI: 0.6%, 27.6% and ATE: 11.4%; 95% CI: -2.2%, 24.9% for navigator and CCT+SMS compared with SOC-Outreach, respectively). Among participants without lapse on SMS, continuing SMS did not affect retention (n=122/180; 67.8% retained) versus stopping (n=151/209; 72.2% retained; ATE: -4.4%; 95% CI: -16.6%, 7.9%). Among participants without lapse on CCT, those continuing CCT had higher retention (n=192/230; 83.5% retained) than those stopping (n=173/287; 60.3% retained; ATE: 28.6%; 95% CI: 19.9%, 37.3%). Among 15 sequenced strategies, initial CCT, escalated to navigator if lapse occurred and continued if no lapse occurred, increased time in care (ATE: 7.2%, 95% CI: 3.7%, 10.7%) and viral suppression (ATE: 8.2%, 95% CI: 2.2%, 14.2%), the most compared with SOC throughout. Initial SMS escalated to navigator if lapse occurred, and otherwise continued, showed similar effect sizes compared with SOC throughout. CONCLUSIONS: Active interventions to prevent retention lapses followed by navigation for those who lapse and maintenance of initial intervention for those without lapse resulted in best overall retention and viral suppression among the strategies studied. Among those who remained in care, discontinuation of CCT, but not SMS, compromised retention and suppression. (Funded by National Institutes of Health grants R01 MH104123, K24 AI134413, and R01 AI074345; ClinicalTrials.gov number, NCT02338739.).

Improving care engagement for mobile people living with HIV in rural western Kenya.

BACKGROUND: Antiretroviral therapy (ART) assures major gains in health outcomes among people living with HIV, however, this benefit may not be realized by all due to care interruptions. Mobile populations comprise a subgroup that is likely to have sub-optimal care engagement, resulting in discontinuation of ART. We sought to evaluate the barriers to care engagement among highly mobile individuals living with HIV and explore options aimed at improving engagement in care for this group. METHODS: Qualitative in-depth interviews were conducted in 2020 among a purposive sample of twelve persons living with HIV and eight health care providers in western Kenya, within a mixed methods study of mobility in communities participating in the SEARCH trial (NCT01864603). We explored the barriers to care engagement among mobile individuals living with HIV and explored different options aimed at enhancing care engagement. These included options such as a coded card containing treatment details, alternative drug packaging to conceal drug identity, longer refills to cover travel period, wrist bands with data storage capability to enable data transfer and "warm handoff" by providers to new clinics upon transfer. Data were inductively analyzed to understand the barriers and acceptability of potential interventions to address them. RESULTS: Stigma and lack of disclosure, rigid work schedules, and unpredictability of travel were major barriers to care engagement for highly mobile individuals living with HIV. Additionally, lack of flexibility in clinic schedules and poor provider attitude were identified as health-system-associated barriers to care engagement. Options that enhance flexibility, convenience and access to care were viewed as the most effective means of addressing the barriers to care by both patients and providers. The most preferred option was a coded card with treatment details followed by alternative drug packaging to conceal drug identity due to stigma and longer refills to cover travel periods. CONCLUSION: Highly mobile individuals living with HIV desire responsive, flexible, convenient and patient-centered care delivery models to enhance care engagement. They embraced simple health delivery improvements such as coded cards, alternative drug packaging and longer refills to address challenges of mobility.

Uptake of a patient-centred dynamic choice model for HIV prevention in rural Kenya and Uganda: SEARCH SAPPHIRE study.

INTRODUCTION: Person-centred HIV prevention delivery models that offer structured choices in product, testing and visit location may increase coverage. However, data are lacking on the actual uptake of choices among persons at risk of HIV in southern Africa. In an ongoing randomized study (SEARCH; NCT04810650) in rural East Africa, we evaluated the uptake of choices made when offered in a person-centred, dynamic choice model for HIV prevention. METHODS: Using the PRECEDE framework, we developed a persont-centred, Dynamic Choice HIV Prevention (DCP) intervention for persons at risk of HIV in three settings in rural Kenya and Uganda: antenatal clinic (ANC), outpatient department (OPD) and in the community. Components include: provider training on product choice (predisposing); flexibility and responsiveness to client desires and choices (pre-exposure prophylaxis [PrEP]/post-exposure prophylaxis [PEP], clinic vs. off-site visits and self- or clinician-based HIV testing) (enabling); and client and staff feedback (reinforcing). All clients received a structured assessment of barriers with personalized plans to address them, mobile phone access to clinicians (24 hours/7 days/week) and integrated reproductive health services. In this interim analysis, we describe the uptake of choices of product, location and testing during the first 24 weeks of follow-up (April 2021-March 2022). RESULTS: A total of 612 (203 ANC, 197 OPD and 212 community) participants were randomized to the person-centred DCP intervention. We delivered the DCP intervention in all three settings with diverse populations: ANC: 39% pregnant; median age: 24 years; OPD: 39% male, median age 27 years; and community: 42% male, median age: 29 years. Baseline choice of PrEP was highest in ANC (98%) vs. OPD (84%) and community (40%); whereas the proportion of adults selecting PEP was higher in the community (46%) vs. OPD (8%) and ANC (1%). Personal preference for off-site visits increased over time (65% at week 24 vs. 35% at baseline). Interest in alternative HIV testing modalities grew over time (38% baseline self-testing vs. 58% at week 24). CONCLUSIONS: A person-centred model incorporating structured choice in biomedical prevention and care delivery options in settings with demographically diverse groups, in rural Kenya and Uganda, was responsive to varying personal preferences over time in HIV prevention programmes.

Defining and estimating effects in cluster randomized trials: A methods comparison.

Across research disciplines, cluster randomized trials (CRTs) are commonly implemented to evaluate interventions delivered to groups of participants, such as communities and clinics. Despite advances in the design and analysis of CRTs, several challenges remain. First, there are many possible ways to specify the causal effect of interest (eg, at the individual-level or at the cluster-level). Second, the theoretical and practical performance of common methods for CRT analysis remain poorly understood. Here, we present a general framework to formally define an array of causal effects in terms of summary measures of counterfactual outcomes. Next, we provide a comprehensive overview of CRT estimators, including the t-test, generalized estimating equations (GEE), augmented-GEE, and targeted maximum likelihood estimation (TMLE). Using finite sample simulations, we illustrate the practical performance of these estimators for different causal effects and when, as commonly occurs, there are limited numbers of clusters of different sizes. Finally, our application to data from the Preterm Birth Initiative (PTBi) study demonstrates the real-world impact of varying cluster sizes and targeting effects at the cluster-level or at the individual-level. Specifically, the relative effect of the PTBi intervention was 0.81 at the cluster-level, corresponding to a 19% reduction in outcome incidence, and was 0.66 at the individual-level, corresponding to a 34% reduction in outcome risk. Given its flexibility to estimate a variety of user-specified effects and ability to adaptively adjust for covariates for precision gains while maintaining Type-I error control, we conclude TMLE is a promising tool for CRT analysis.

Universal HIV Testing and Treatment With Patient-Centered Care Improves ART Uptake and Viral Suppression Among Adults Reporting Hazardous Alcohol Use in Uganda and Kenya.

OBJECTIVES: Determine whether patient-centered, streamlined HIV care achieves higher antiretroviral therapy (ART) uptake and viral suppression than the standard treatment model for people with HIV (PWH) reporting hazardous alcohol use. DESIGN: Community cluster-randomized trial. METHODS: The Sustainable East Africa Research in Community Health trial (NCT01864603) compared an intervention of annual population HIV testing, universal ART, and patient-centered care with a control of baseline population testing with ART by country standard in 32 Kenyan and Ugandan communities. Adults (15 years or older) completed a baseline Alcohol Use Disorders Identification Test-Consumption (AUDIT-C) and were classified as no/nonhazardous (AUDIT-C 0-2 women/0-3 men) or hazardous alcohol use (≥3 women/≥4 men). We compared year 3 ART uptake and viral suppression of PWH reporting hazardous use between intervention and control arms. We compared alcohol use as a predictor of year 3 ART uptake and viral suppression among PWH, by arm. RESULTS: Of 11,070 PWH with AUDIT-C measured, 1723 (16%) reported any alcohol use and 893 (8%) reported hazardous use. Among PWH reporting hazardous use, the intervention arm had higher ART uptake (96%) and suppression (87%) compared with control (74%, adjusted risk ratio [aRR] = 1.28, 95% CI: 1.19 to 1.38; and 72%, aRR = 1.20, 95% CI: 1.10 to 1.31, respectively). Within arm, hazardous alcohol use predicted lower ART uptake in control (aRR = 0.86, 95% CI: 0.78 to 0.96), but not intervention (aRR = 1.02, 95% CI: 1.00 to 1.04); use was not predictive of suppression in either arm. CONCLUSIONS: The Sustainable East Africa Research in Community Health intervention improved ART uptake and viral suppression among PWH reporting hazardous alcohol use and eliminated gaps in ART uptake between PWH with hazardous and no/nonhazardous use. Patient-centered HIV care may decrease barriers to HIV care for PWH with hazardous alcohol use.

Monitoring SARS-CoV-2 incidence and seroconversion among university students and employees: a longitudinal cohort study in California, June-August 2020.

OBJECTIVES: To identify incident SARS-CoV-2 infections and inform effective mitigation strategies in university settings, we piloted an integrated symptom and exposure monitoring and testing system among a cohort of university students and employees. DESIGN: Prospective cohort study. SETTING: A public university in California from June to August 2020. PARTICIPANTS: 2180 university students and 738 university employees. PRIMARY OUTCOME MEASURES: At baseline and endline, we tested participants for active SARS-CoV-2 infection via quantitative PCR (qPCR) test and collected blood samples for antibody testing. Participants received notifications to complete additional qPCR tests throughout the study if they reported symptoms or exposures in daily surveys or were selected for surveillance testing. Viral whole genome sequencing was performed on positive qPCR samples, and phylogenetic trees were constructed with these genomes and external genomes. RESULTS: Over the study period, 57 students (2.6%) and 3 employees (0.4%) were diagnosed with SARS-CoV-2 infection via qPCR test. Phylogenetic analyses revealed that a super-spreader event among undergraduates in congregate housing accounted for at least 48% of cases among study participants but did not spread beyond campus. Test positivity was higher among participants who self-reported symptoms (incidence rate ratio (IRR) 12.7; 95% CI 7.4 to 21.8) or had household exposures (IRR 10.3; 95% CI 4.8 to 22.0) that triggered notifications to test. Most (91%) participants with newly identified antibodies at endline had been diagnosed with incident infection via qPCR test during the study. CONCLUSIONS: Our findings suggest that integrated monitoring systems can successfully identify and link at-risk students to SARS-CoV-2 testing. As the study took place before the evolution of highly transmissible variants and widespread availability of vaccines and rapid antigen tests, further research is necessary to adapt and evaluate similar systems in the present context.

Weight Change Following Switch to Dolutegravir for HIV Treatment in Rural Kenya During Country Roll-Out.

INTRODUCTION: Switch to dolutegravir (DTG) in treatment-experienced people living with HIV (PLH) is associated with excess weight gain in some settings; data are limited from rural low-income settings with low obesity prevalence. METHODS: In rural Kenya, we conducted a retrospective cohort study at 8 HIV clinics and a single-site prospective cohort study including adults switching to DTG during countrywide transition to DTG/tenofovir DF(TDF)/emtricitabine as first-line HIV treatment. In the retrospective analysis, we used preswitch data to model postswitch weight trajectory had each participant not switched to DTG and contrasted observed vs. predicted postswitch weight. In the prospective analysis, we measured weight post-DTG switch and evaluated predictors of 6-month weight change. RESULTS: Our retrospective cohort included 4445 PLH who switched to DTG between 2018 and 2020. Mean 12-month weight change was 0.6 kg preswitch and 0.8 kg postswitch. Among those on TDF throughout (n = 3374; 83% on efavirenz preswitch), 12-month postswitch weight was 0.7 kg more than predicted for women (95% CI: 0.4, 1.0) and similar among men (0.04 kg; 95% CI -0.3, 0.4). In our prospective cohort (n = 135, 100% female), mean 6-month weight change was +0.4 kg (IQR -1.1, 2.0 kg). Predicted gain varied by baseline food insecurity: +1.1 kg (95% CI: 0.34, 1.87) among food secure, -0.09 kg (95% CI -0.71, 0.54) among moderate insecure, and +0.27 kg (95% CI -0.82, 1.36) among severe insecurity. CONCLUSION: In contrast to some reports of large weight gain following switch to DTG, we observed small weight increases in women and no weight change in men following DTG switch when on TDF throughout. Weight gain may be attenuated by food insecurity, though was modest even among food secure.

Efficient and robust approaches for analysis of sequential multiple assignment randomized trials: Illustration using the ADAPT-R trial.

Personalized intervention strategies, in particular those that modify treatment based on a participant's own response, are a core component of precision medicine approaches. Sequential multiple assignment randomized trials (SMARTs) are growing in popularity and are specifically designed to facilitate the evaluation of sequential adaptive strategies, in particular those embedded within the SMART. Advances in efficient estimation approaches that are able to incorporate machine learning while retaining valid inference can allow for more precise estimates of the effectiveness of these embedded regimes. However, to the best of our knowledge, such approaches have not yet been applied as the primary analysis in SMART trials. In this paper, we present a robust and efficient approach using targeted maximum likelihood estimation (TMLE) for estimating and contrasting expected outcomes under the dynamic regimes embedded in a SMART, together with generating simultaneous confidence intervals for the resulting estimates. We contrast this method with two alternatives (G-computation and inverse probability weighting estimators). The precision gains and robust inference achievable through the use of TMLE to evaluate the effects of embedded regimes are illustrated using both outcome-blind simulations and a real-data analysis from the Adaptive Strategies for Preventing and Treating Lapses of Retention in Human Immunodeficiency Virus (HIV) Care (ADAPT-R) trial (NCT02338739), a SMART with a primary aim of identifying strategies to improve retention in HIV care among people living with HIV in sub-Saharan Africa.

Estimators for the value of the optimal dynamic treatment rule with application to criminal justice interventions.

Given an (optimal) dynamic treatment rule, it may be of interest to evaluate that rule - that is, to ask the causal question: what is the expected outcome had every subject received treatment according to that rule? In this paper, we study the performance of estimators that approximate the true value of: (1) an a priori known dynamic treatment rule (2) the true, unknown optimal dynamic treatment rule (ODTR); (3) an estimated ODTR, a so-called "data-adaptive parameter," whose true value depends on the sample. Using simulations of point-treatment data, we specifically investigate: (1) the impact of increasingly data-adaptive estimation of nuisance parameters and/or of the ODTR on performance; (2) the potential for improved efficiency and bias reduction through the use of semiparametric efficient estimators; and, (3) the importance of sample splitting based on the cross-validated targeted maximum likelihood estimator (CV-TMLE) for accurate inference. In the simulations considered, there was very little cost and many benefits to using CV-TMLE to estimate the value of the true and estimated ODTR; importantly, and in contrast to non cross-validated estimators, the performance of CV-TMLE was maintained even when highly data-adaptive algorithms were used to estimate both nuisance parameters and the ODTR. In addition, we apply these estimators for the value of the rule to the "Interventions" study, an ongoing randomized controlled trial, to identify whether assigning cognitive behavioral therapy (CBT) to criminal justice-involved adults with mental illness using an ODTR significantly reduces the probability of recidivism, compared to assigning CBT in a non-individualized way.

Two-Stage TMLE to reduce bias and improve efficiency in cluster randomized trials.

Cluster randomized trials (CRTs) randomly assign an intervention to groups of individuals (e.g., clinics or communities) and measure outcomes on individuals in those groups. While offering many advantages, this experimental design introduces challenges that are only partially addressed by existing analytic approaches. First, outcomes are often missing for some individuals within clusters. Failing to appropriately adjust for differential outcome measurement can result in biased estimates and inference. Second, CRTs often randomize limited numbers of clusters, resulting in chance imbalances on baseline outcome predictors between arms. Failing to adaptively adjust for these imbalances and other predictive covariates can result in efficiency losses. To address these methodological gaps, we propose and evaluate a novel two-stage targeted minimum loss-based estimator to adjust for baseline covariates in a manner that optimizes precision, after controlling for baseline and postbaseline causes of missing outcomes. Finite sample simulations illustrate that our approach can nearly eliminate bias due to differential outcome measurement, while existing CRT estimators yield misleading results and inferences. Application to real data from the SEARCH community randomized trial demonstrates the gains in efficiency afforded through adaptive adjustment for baseline covariates, after controlling for missingness on individual-level outcomes.

The optimal dynamic treatment rule superlearner: considerations, performance, and application to criminal justice interventions.

The optimal dynamic treatment rule (ODTR) framework offers an approach for understanding which kinds of patients respond best to specific treatments - in other words, treatment effect heterogeneity. Recently, there has been a proliferation of methods for estimating the ODTR. One such method is an extension of the SuperLearner algorithm - an ensemble method to optimally combine candidate algorithms extensively used in prediction problems - to ODTRs. Following the ``causal roadmap," we causally and statistically define the ODTR and provide an introduction to estimating it using the ODTR SuperLearner. Additionally, we highlight practical choices when implementing the algorithm, including choice of candidate algorithms, metalearners to combine the candidates, and risk functions to select the best combination of algorithms. Using simulations, we illustrate how estimating the ODTR using this SuperLearner approach can uncover treatment effect heterogeneity more effectively than traditional approaches based on fitting a parametric regression of the outcome on the treatment, covariates and treatment-covariate interactions. We investigate the implications of choices in implementing an ODTR SuperLearner at various sample sizes. Our results show the advantages of: (1) including a combination of both flexible machine learning algorithms and simple parametric estimators in the library of candidate algorithms; (2) using an ensemble metalearner to combine candidates rather than selecting only the best-performing candidate; (3) using the mean outcome under the rule as a risk function. Finally, we apply the ODTR SuperLearner to the ``Interventions" study, an ongoing randomized controlled trial, to identify which justice-involved adults with mental illness benefit most from cognitive behavioral therapy to reduce criminal re-offending.

Two or more significant life-events in 6-months are associated with lower rates of HIV treatment and virologic suppression among youth with HIV in Uganda and Kenya.

Youth living with HIV in sub-Saharan Africa have poor HIV care outcomes. We determined the association of recent significant life-events with HIV antiretroviral treatment (ART) initiation and HIV viral suppression in youth aged 15-24 years living with HIV in rural Kenya and Uganda. This was a cross-sectional analysis of 995 youth enrolled in the SEARCH Youth study. At baseline, providers assessed recent (within 6 months) life-events, defined as changes in schooling/employment, residence, partnerships, sickness, incarceration status, family strife or death, and birth/pregnancy, self-reported alcohol use, being a parent, and HIV-status disclosure. We examined the frequencies of events and their association with ART status and HIV viral suppression (<400 copies/ul). Recent significant life-events were prevalent (57.7%). Having >2 significant life-events (aOR = 0.61, 95% CI:0.45-0.85) and consuming alcohol (aOR = 0.61, 95% CI:0.43-0.87) were associated with a lower odds of HIV viral suppression, while disclosure of HIV-status to partner (aOR = 2.39, 95% CI:1.6-3.5) or to family (aOR = 1.86, 95% CI:1.3-2.7), being a parent (aOR = 1.8, 95% CI:1.2-2.5), and being single (aOR = 1.6, 95% CI:1.3-2.1) had a higher odds. This suggest that two or more recent life-events and alcohol use are key barriers to ART initiation and achievement of viral suppression among youth living with HIV in rural East Africa.Trial registration: ClinicalTrials.gov identifier: NCT03848728..

The Association Between Social Network Characteristics and Tuberculosis Infection Among Adults in 9 Rural Ugandan Communities.

BACKGROUND: Social network analysis can elucidate tuberculosis transmission dynamics outside the home and may inform novel network-based case-finding strategies. METHODS: We assessed the association between social network characteristics and prevalent tuberculosis infection among residents (aged ≥15 years) of 9 rural communities in Eastern Uganda. Social contacts named during a census were used to create community-specific nonhousehold social networks. We evaluated whether social network structure and characteristics of first-degree contacts (sex, human immunodeficiency virus [HIV] status, tuberculosis infection) were associated with revalent tuberculosis infection (positive tuberculin skin test [TST] result) after adjusting for individual-level risk factors (age, sex, HIV status, tuberculosis contact, wealth, occupation, and Bacillus Calmette-Guérin [BCG] vaccination) with targeted maximum likelihood estimation. RESULTS: Among 3 335 residents sampled for TST, 32% had a positive TST results and 4% reported a tuberculosis contact. The social network contained 15 328 first-degree contacts. Persons with the most network centrality (top 10%) (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.1]) and the most (top 10%) male contacts (1.5 [1.3-1.9]) had a higher risk of prevalent tuberculosis, than those in the remaining 90%. People with ≥1 contact with HIV (adjusted risk ratio, 1.3 [95% confidence interval, 1.1-1.6]) and ≥2 contacts with tuberculosis infection were more likely to have tuberculosis themselves (2.6 [ 95% confidence interval: 2.2-2.9]). CONCLUSIONS: Social networks with higher centrality, more men, contacts with HIV, and tuberculosis infection were positively associated with tuberculosis infection. Tuberculosis transmission within measurable social networks may explain prevalent tuberculosis not associated with a household contact. Further study on network-informed tuberculosis case finding interventions is warranted.

Effect of a one-time financial incentive on linkage to chronic hypertension care in Kenya and Uganda: A randomized controlled trial.

BACKGROUND: Fewer than 10% of people with hypertension in sub-Saharan Africa are diagnosed, linked to care, and achieve hypertension control. We hypothesized that a one-time financial incentive and phone call reminder for missed appointments would increase linkage to hypertension care following community-based screening in rural Uganda and Kenya. METHODS: In a randomized controlled trial, we conducted community-based hypertension screening and enrolled adults ≥25 years with blood pressure ≥140/90 mmHg on three measures; we excluded participants with known hypertension or hypertensive emergency. The intervention was transportation reimbursement upon linkage (~$5 USD) and up to three reminder phone calls for those not linking within seven days. Control participants received a clinic referral only. Outcomes were linkage to hypertension care within 30 days (primary) and hypertension control <140/90 mmHg measured in all participants at 90 days (secondary). We used targeted minimum loss-based estimation to compute adjusted risk ratios (aRR). RESULTS: We screened 1,998 participants, identifying 370 (18.5%) with uncontrolled hypertension and enrolling 199 (100 control, 99 intervention). Reasons for non-enrollment included prior hypertension diagnosis (n = 108) and hypertensive emergency (n = 32). Participants were 60% female, median age 56 (range 27-99); 10% were HIV-positive and 42% had baseline blood pressure ≥160/100 mmHg. Linkage to care within 30 days was 96% in intervention and 66% in control (aRR 1.45, 95%CI 1.25-1.68). Hypertension control at 90 days was 51% intervention and 41% control (aRR 1.22, 95%CI 0.92-1.66). CONCLUSION: A one-time financial incentive and reminder call for missed visits resulted in a 30% absolute increase in linkage to hypertension care following community-based screening. Financial incentives can improve the critical step of linkage to care for people newly diagnosed with hypertension in the community.

Providers' Attitudes and Experiences with Pre-Exposure Prophylaxis Implementation in a Population-Based Study in Kenya and Uganda.

Pre-exposure prophylaxis (PrEP) implementation is underway across sub-Saharan Africa. However, little is known about health care providers' experiences with PrEP provision in generalized epidemic settings, particularly outside of selected risk groups. In this study (NCT01864603), universal access to PrEP was offered to adolescents and adults at elevated risk during population-level HIV testing in rural Kenya and Uganda. Providers received training on PrEP prescribing and support from local senior clinicians. We conducted in-depth interviews with providers (n = 19) in four communities in Kenya and Uganda to explore the attitudes and experiences with implementation. Transcripts were coded and analyzed using interpretivist methods. Providers had heterogenous attitudes toward PrEP in its early implementation: some expressed enthusiasm, while others feared being blamed for "failures" (HIV seroconversions) if participants were nonadherent, or that offering PrEP would increase "immorality." Providers supported PrEP usage among HIV-serodifferent couples, whose mutual support for daily pill-taking facilitated harmony and protection from HIV. Providers reported challenges with counseling on "seasons of risk," and safely stopping and restarting PrEP. They felt uptake was hampered for women by difficulties negotiating with partners, and for youth by parental consent requirements. They believed PrEP continuation was hindered by transportation costs, stigma, pill burden, and side effects, and was facilitated by counseling, proactive management of side effects, and home/community-based provision. Providers are critical "implementation actors" in interventions to promote adoption of new technologies such as PrEP. Dedicated training and ongoing support for providers may facilitate successful scale-up.