Estimating the Effect of PrEP in Black Men Who Have Sex with Men: A Framework to Utilize Data from Multiple Non-Randomized Studies to Estimate Causal Effects.

Black men who have sex with men (MSM) are disproportionately burdened by the HIV epidemic in the US. The effectiveness of pre-exposure prophylaxis (PrEP) in preventing HIV infection has been demonstrated through randomized placebo-controlled clinical trials in several populations. Importantly, no such trial has been conducted exclusively among Black MSM in the US, and it would be unethical and infeasible to do so now. To estimate the causal effects of PrEP access, initiation, and adherence on HIV risk, we utilized causal inference methods to combine data from two non-randomized studies that exclusively enrolled Black MSM. The estimated relative risks of HIV were: (i) 0.52 (95% confidence interval: 0.21, 1.22) for individuals with versus without PrEP access, (ii) 0.48 (0.12, 0.89) for individuals who initiated PrEP but were not adherent versus those who did not initiate, and (iii) 0.23 (0.02, 0.80) for individuals who were adherent to PrEP versus those who did not initiate. Beyond addressing the knowledge gap around the effect of PrEP in Black MSM in the US, which may have ramifications for public health, we have provided a framework to combine data from multiple non-randomized studies to estimate causal effects, which has broad utility.

Prevalence of SARS-CoV-2 Infection among Children and Adults in 15 US Communities, 2021

During January-August 2021, the Community Prevalence of SARS-CoV-2 Study used time/location sampling to recruit a cross-sectional, population-based cohort to estimate SARS-CoV-2 seroprevalence and nasal swab sample PCR positivity across 15 US communities. Survey-weighted estimates of SARS-CoV-2 infection and vaccine willingness among participants at each site were compared within demographic groups by using linear regression models with inverse variance weighting. Among 22,284 persons >2 months of age and older, median prevalence of infection (prior, active, or both) was 12.9% across sites and similar across age groups. Within each site, average prevalence of infection was 3 percentage points higher for Black than White persons and average vaccine willingness was 10 percentage points lower for Black than White persons and 7 percentage points lower for Black persons than for persons in other racial groups. The higher prevalence of SARS-CoV-2 infection among groups with lower vaccine willingness highlights the disparate effect of COVID-19 and its complications.

Adaptive Time-Location Sampling for COMPASS: A SARS-CoV-2 Prevalence Study in Fifteen Diverse Communities in the United States.

BACKGROUND: COVID-19 has placed a disproportionate burden on underserved racial and ethnic groups, community members working in essential industries, those living in areas of high population density, and those reliant on in-person services such as transportation. The goal of this study was to estimate the cross-sectional prevalence of SARS-CoV-2 (active SARS-CoV-2 or prior SARS-CoV-2 infection) in children and adults attending public venues in 15 sociodemographically diverse communities in the United States and to develop a statistical design that could be rigorously implemented amidst unpredictable stay-at-home COVID-19 guidelines. METHODS: We used time-location sampling with complex sampling involving stratification, clustering of units, and unequal probabilities of selection to recruit individuals from selected communities. We safely conducted informed consent, specimen collection, and face-to-face interviews outside of public venues immediately following recruitment. RESULTS: We developed an innovative sampling design that adapted to constraints such as closure of venues, changing infection hotspots, and uncertain policies. We updated both the sampling frame and the selection probabilities over time using information acquired from prior weeks. We created site-specific survey weights that adjusted sampling probabilities for nonresponse and calibrated to county-level margins on age and sex at birth. CONCLUSIONS: Although the study itself was specific to COVID-19, the strategies presented in this article could serve as a case study that can be adapted for performing population-level inferences in similar settings and could help inform rapid and effective responses to future global public health challenges.

Composite Indices of Social Determinants of Health: Overview, Measurement Gaps, and Research Priorities for Health Equity.

The goal of health equity is for all people to have opportunities and resources for optimal health outcomes regardless of their social identities, residence in marginalized communities, and/or experience with oppressive systems. Social determinants of health (SDOH)-the conditions in which we are born, grow, live, work, and age-are inextricably tied to health equity. Advancing health equity thus requires reliable measures of SDOH. In the United States, comprehensive individual-level data on SDOH are difficult to collect, may be inaccurate, and do not capture all dimensions of inequitable outcomes. Individual area-based indicators are widely available, but difficult to use in practice. Numerous area-level composite indices are available to describe SDOH, but there is no consensus on which indices are most appropriate to use. This article presents an analytic taxonomy of currently available SDOH composite indices and compares their components and predictive ability, providing insights into gaps and areas for further research.

ADAPTIVE TIME LOCATION SAMPLING FOR COMPASS, A SARS-COV-2 PREVALENCE STUDY IN FIFTEEN DIVERSE COMMUNITIES IN THE UNITED STATES.

The COVPN 5002 (COMPASS) study aimed to estimate the prevalence of SARS-CoV-2 (active SARS-CoV-2 or prior SARS-CoV-2 infection) in children and adults attending public venues in 15 socio-demographically diverse communities in the United States. To protect against potential challenges in implementing traditional sampling strategies, time-location sampling (TLS) using complex sampling involving stratification, clustering of units, and unequal probabilities of selection was used to recruit individuals from neighborhoods in selected communities. The innovative design adapted to constraints such as closure of venues; changing infection hotspots; and uncertain policies. Recruitment of children and the elderly raised additional challenges in sample selection and implementation. To address these challenges, the TLS design adaptively updated both the sampling frame and the selection probabilities over time using information acquired from prior weeks. Although the study itself was specific to COVID-19, the strategies presented in this paper could serve as a case study that can be adapted for performing rigorous population-level inferences in similar settings and could help inform rapid and effective responses to future global public health challenges.

Pregnancy rates and clinical outcomes among women living with HIV enrolled in HPTN 052.

HPTN 052 was a multi-country clinical trial of cART for preventing heterosexual HIV-1 transmission. The study allowed participation of pregnant women and provided access to cART and contraceptives. We explored associations between pregnancy and clinical measures of HIV disease stage and progression. Of 869 women followed for 5.70 (SD = 1.62) years, 94.7% were married/cohabitating, 96% initiated cART, and 76.3% had >2 past pregnancies. Of 337 women who experienced pregnancy, 89.3% were from countries with lower contraceptive coverage, 56.1% first started cART with PI-based regimens and 57.6% were 25-34 years old. Mean cART duration and condom use were similar among pregnant and nonpregnant individuals. Adjusting for confounders, viral load suppression (VLS) was not (aHR(CI) = 0.82(0.61, 1.08)) and CD4 was slightly associated with decreased rates of first pregnancy over time (aHR(CI) = 0.9(0.84, 0.95)); baseline VLS was associated with increased (aRR(CI) = 2.48(1.71, 3.59)) and baseline CD4 was slightly associated with decreased number of pregnancies (aRR(CI) = 0.9(0.85,0.96)) over study duration. Partner seroconversion was univariably associated with higher rates of first pregnancy (HR(CI) = 2.02(1.32,3.07)). Despite a background of higher maternal morbidity and mortality rates, our findings suggest that becoming pregnant does not pose a threat to maternal health in women with HIV when there is access to medical care and antiretroviral treatment.

Geographic Variation in HIV Testing Among Transgender and Nonbinary Adults in the United States.

BACKGROUND: Transgender and nonbinary (TNB) populations are disproportionately affected by HIV and few local health departments or HIV surveillance systems collect/report data on TNB identities. Our objective was to estimate the prevalence of HIV testing among TNB adults by US county and state, with a focus on the Ending the HIV Epidemic (EHE) geographies. METHODS: We applied a Bayesian hierarchical spatial small area estimation model to data from the 2015 US Transgender Survey, a large national cross-sectional Internet-based survey. We estimated the county- and state-level proportion of TNB adults who ever tested or tested for HIV in the last year by gender identity, race/ethnicity, and age. RESULTS: Our analysis included 26,100 TNB participants with valid zip codes who resided in 1688 counties (54% of all 3141 counties that cover 92% of the US population). The median county-level proportion of TNB adults who ever tested for HIV was 44% (range 10%-80%) and who tested in the last year was 17% (range 4%-44%). Within most counties, testing was highest among transgender women, black respondents, and people aged ≥25 years. HIV testing was lowest among nonbinary people and young adults aged <25 years. The proportion of TNB adults who tested within the last year was very low in most EHE counties and in all 7 rural states. CONCLUSIONS: HIV testing among TNB adults is likely below national recommendations in the majority of EHE geographies. Geographic variation in HIV testing patterns among TNB adults indicates that testing strategies need to be tailored to local settings.

Islet Autoimmunity is Highly Prevalent and Associated With Diminished ß-Cell Function in Patients With Type 2 Diabetes in the Grade Study.

Islet autoimmunity may contribute to ß-cell dysfunction in type 2 diabetes (T2D). Its prevalence and clinical significance have not been rigorously determined. In this ancillary study to the Glycemia Reduction Approaches in Diabetes-A Comparative Effectiveness (GRADE) Study, we investigated the prevalence of cellular and humoral islet autoimmunity in patients with T2D duration 4·0±3·0 y, HbA1c 7·5±0·5% on metformin alone. We measured T cell autoreactivity against islet proteins, islet autoantibodies against GAD65, IA2, ZnT8, and ß-cell function. Cellular islet autoimmunity was present in 41·3%, humoral islet autoimmunity in 13·5%, and both in 5·3%. ß-cell function calculated as iAUC-CG and ΔC-peptide(0- 30)/Δglucose(0-30) from an oral glucose tolerance test was lower among T cell-positives (T+) than T cell-negatives (T-) using two different adjustments for insulin sensitivity (iAUC-CG: 13·2% [95% CI 0·3, 24·4%] or 11·4% [95% CI 0·4, 21·2%] lower; ΔC-peptide(0-30)/Δglucose(0-30)) 19% [95% CI 3·1, 32·3%] or 17·7% [95% CI 2·6, 30·5%] lower). T+ patients had 17% higher HbA1c (95% CI 0·07, 0·28) and 7·7 mg/dL higher fasting plasma glucose levels (95% CI 0·2,15·3) than T- patients. We conclude that islet autoimmunity is much more prevalent in T2D patients than previously reported. T cell-mediated autoimmunity is associated with diminished ß-cell function and worse glycemic control.

Association between live childhood vaccines and COVID-19 outcomes: a national-level analysis.

We investigated whether countries with higher coverage of childhood live vaccines [BCG or measles-containing-vaccine (MCV)] have reduced risk of coronavirus disease 2019 (COVID-19)-related mortality, while accounting for known systems differences between countries. In this ecological study of 140 countries using publicly available national-level data, higher vaccine coverage, representing estimated proportion of people vaccinated during the last 14 years, was associated with lower COVID-19 deaths. The associations attenuated for both vaccine variables, and MCV coverage became no longer significant once adjusted for published estimates of the Healthcare access and quality index (HAQI), a validated summary score of healthcare quality indicators. The magnitude of association between BCG coverage and COVID-19 death rate varied according to HAQI, and MCV coverage had little effect on the association between BCG and COVID-19 deaths. While there are associations between live vaccine coverage and COVID-19 outcomes, the vaccine coverage variables themselves were strongly correlated with COVID-19 testing rate, HAQI and life expectancy. This suggests that the population-level associations may be further confounded by differences in structural health systems and policies. Cluster randomised studies of booster vaccines would be ideal to evaluate the efficacy of trained immunity in preventing COVID-19 infections and mortality in vaccinated populations and on community transmission.

Persistence of oral pre-exposure prophylaxis (PrEP) among adolescent girls and young women initiating PrEP for HIV prevention in Kenya.

The Determined, Resilient, Empowered, AIDS-free, Mentored, and Safe (DREAMS) Initiative aims to reduce HIV infections among adolescent girls and young women (AGYW) in Africa. Oral pre-exposure prophylaxis (PrEP) is offered through DREAMS in Kenya to eligible AGYW in high burden counties including Kisumu and Homa Bay. This study examines PrEP persistence among AGYW in high burden community-based PrEP delivery settings. We evaluated PrEP persistence among AGYW in the DREAMS PrEP program in Kisumu and Homa Bay using survival analysis and programmatic PrEP refill data collected between March through December 2017. Among 1,259 AGYW who initiated PrEP during the study period, the median persistence time in the program was 56 days (95% CI: 49-58 days) and the proportion who persisted 3 months later was 37% (95% CI: 34-40%). Persistence varied by county (p < 0.001), age at PrEP initiation (p = 0.002), marital status (p = 0.008), transactional sex (p = 0.002), gender-based violence (GBV) experience (p = 0.009) and current school attendance (p = 0.001) at DREAMS enrollment. Persistence did not vary with orphan status, food insecurity, condom use, age at first sexual encounter or engagement in age-disparate sex at DREAMS enrollment. Targeted strategies are needed to improve AGYW retention in the PrEP program.

Association between live childhood vaccines and COVID-19 outcomes: a national-level analysis.

We investigated whether countries with higher coverage of childhood live vaccines [BCG or measles-containing-vaccine (MCV)] have reduced risk of COVID-19 related mortality, accounting for known systems differences between countries. In this ecological study of 140 countries using publicly available national-level data, higher vaccine coverage, representing estimated proportion of people vaccinated during the last 15 years, was associated with lower COVID-19 deaths. The associations attenuated for both vaccine variables, and MCV coverage became no longer significant once adjusted for a validated summary score accounting for life expectancy and healthcare quality indicators, the Healthcare access and quality index (HAQI). The magnitude of association between BCG coverage and COVID-19 death rate varied according to HAQI, and MCV coverage had little effect on the association between BCG and COVID-19 deaths. While there are associations between live vaccine coverage and COVID-19 outcomes, the vaccine coverage variables themselves were strongly correlated with COVID-19 testing rate, HAQI, and life expectancy. This suggests that the population-level associations may be further confounded by differences in structural health systems and policies. Cluster randomized studies of booster vaccines would be ideal to evaluate the efficacy of trained immunity in preventing COVID-19 infections and mortality in vaccinated individuals and on community transmission.

Acceptability of Long-Acting Injectable Cabotegravir (CAB LA) in HIV-Uninfected Individuals: HPTN 077.

Long-acting injectable PrEP could offer an alternative to daily oral PrEP, improve adherence and protection, if found acceptable, safe and effective. HPTN 077 evaluated injectable cabotegravir safety, tolerability and pharmacokinetics among HIV-uninfected males and females in sequentially-enrolled cohorts of two dosing strategies. We compared acceptability of product attributes, prevention preferences and future interest in injectable PrEP (FIIP) by region, sex-at-birth, arm and cohort and used multivariable analysis to identify FIIP determinants. Baseline injectable PrEP preferences were higher in non-U.S. sites and increased in both regions over time. In multivariable models, FIIP was most strongly associated with acceptability of product attributes, was higher in non-U.S. sites and more altruistic participants. Treatment arm and report of pain were not associated with FIIP. Injectable acceptability was highest in non-U.S. sites. Preferences for injectable versus other PrEP methods were higher among U.S. males than females, but higher among males and females in non-U.S. settings.

Methods for generalized change-point models: with applications to human immunodeficiency virus surveillance and diabetes data.

In many epidemiological and biomedical studies, the association between a response variable and some covariates of interest may change at one or several thresholds of the covariates. Change-point models are suitable for investigating the relationship between the response and covariates in such situations. We present change-point models, with at least one unknown change-point occurring with respect to some covariates of a generalized linear model for independent or correlated data. We develop methods for the estimation of the model parameters and investigate their finite-sample performances in simulations. We apply the proposed methods to examine the trends in the reported estimates of the annual percentage of new human immunodeficiency virus (HIV) diagnoses linked to HIV-related medical care within 3 months after diagnosis using HIV surveillance data from the HIV prevention trial network 065 study. We also apply our methods to a dataset from the Pima Indian diabetes study to examine the effects of age and body mass index on the risk of being diagnosed with type 2 diabetes.

Cabotegravir Is Not Associated With Weight Gain in Human Immunodeficiency Virus-uninfected Individuals in HPTN 077.

Studies in human immunodeficiency virus (HIV)-infected individuals suggest excess weight gain with integrase inhibitor-based antiretroviral therapy. The HIV Prevention Trials Network Study 077 evaluated changes in weight and fasting metabolic parameters in HIV-uninfected individuals randomized to cabotegravir or a placebo. No differences between arms were found for change in weight or fasting metabolic parameters overall or for subgroups.

Acceptability of a long-acting injectable HIV prevention product among US and African women: findings from a phase 2 clinical Trial (HPTN 076).

INTRODUCTION: High HIV incidence and low adherence to daily oral PrEP among women underscore the need for more acceptable and easier to use HIV prevention products. Global demand for injectable contraception suggests that new, long-acting, injectable formulations could meet this need. We examine acceptability of a long-acting injectable PrEP among HIV-uninfected women in Zimbabwe, South Africa and two United States phase 2 trial sites. METHODS: Quantitative surveys were administered at the first, fourth and sixth injection visits. Focus group discussions (FGD) were conducted after the sixth injection visit. We compared the acceptability of injectable product attributes, prevention preferences and future interest in injectable PrEP by site and arm and ran longitudinal ordinal logistic regression models to identify determinants of future interest in injectable PrEP. RESULTS: Between April 2015 and February 2017, the trial enrolled 136 (100 African, 36 US) women with a median age of 31 years. Most participants (>75%) rated injectable attributes as very acceptable. While few reported rash or other side effects, 56% to 67% reported injection pain, with nonsignificant differences over time and between arms. During FGDs, participants described initial fear of the injectable and variable experiences with pain. Most US and African participants preferred injectable PrEP to daily oral pills (56% to 96% vs. 4% to 25%). Future interest in using injectable PrEP was associated with acceptability of product attributes and was higher in African than US sites. In FGDs, participants described multiple reasons for trial participation, including a combination of monetary, health-related and altruistic motivations. While associated with future interest in use in univariate models, neither altruistic nor personal motivations remained significant in the multivariate model. CONCLUSIONS: This study found that long-acting injectable PrEP is acceptable among African and US women experiencing product use. Acceptability of product attributes better predicted future interest in injectable use than experience of pain. This is reassuring as a single-dose regimen of a different product has advanced to phase 3 trials. Finally, the study suggests that future demand for an injectable PrEP by women may be greater in African than US settings, where the risk of HIV is highest.

Effectiveness of Seasonal Influenza Vaccination in Children in Senegal During a Year of Vaccine Mismatch: A Cluster-randomized Trial.

BACKGROUND: The population effects of influenza vaccination in children have not been extensively studied, especially in tropical, developing countries. In rural Senegal, we assessed the total (primary objective) and indirect effectiveness of a trivalent inactivated influenza vaccine (IIV3). METHODS: In this double-blind, cluster-randomized trial, villages were randomly allocated (1:1) for the high-coverage vaccination of children aged 6 months through 10 years with either the 2008-09 northern hemisphere IIV3 or an inactivated polio vaccine (IPV). Vaccinees were monitored for serious adverse events. All village residents, vaccinated and unvaccinated, were monitored for signs and symptoms of influenza illness using weekly home visits and surveillance in designated clinics. The primary outcome was all laboratory-confirmed symptomatic influenza. RESULTS: Between 23 May and 11 July 2009, 20 villages were randomized, and 66.5% of age-eligible children were enrolled (3918 in IIV3 villages and 3848 in IPV villages). Follow-up continued until 28 May 2010. There were 4 unrelated serious adverse events identified. Among vaccinees, the total effectiveness against illness caused by the seasonal influenza virus (presumed to all be drifted A/H3N2, based on antigenic characterization data) circulating at high rates among children was 43.6% (95% confidence interval [CI] 18.6-60.9%). The indirect effectiveness against seasonal A/H3N2 was 15.4% (95% CI -22.0 to 41.3%). The total effectiveness against illness caused by the pandemic influenza virus (A/H1N1pdm09) was -52.1% (95% CI -177.2 to 16.6%). CONCLUSIONS: IIV3 provided statistically significant, moderate protection to children in Senegal against circulating, pre-2010 seasonal influenza strains, but not against A/H1N1pdm09, which was not included in the vaccine. No indirect effects were measured. Further study in low-resource populations is warranted. CLINICAL TRIALS REGISTRATION: NCT00893906.

Design Issues in Transgender Studies.

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

Serial plasma metabolites following hypoxic-ischemic encephalopathy in a nonhuman primate model.

Biomarkers that indicate the severity of hypoxic-ischemic brain injury and response to treatment and that predict neurodevelopmental outcomes are urgently needed to improve the care of affected neonates. We hypothesize that sequentially obtained plasma metabolomes will provide indicators of brain injury and repair, allowing for the prediction of neurodevelopmental outcomes. A total of 33 Macaca nemestrina underwent 0, 15 or 18 min of in utero umbilical cord occlusion (UCO) to induce hypoxic-ischemic encephalopathy and were then delivered by hysterotomy, resuscitated and stabilized. Serial blood samples were obtained at baseline (cord blood) and at 0.1, 24, 48, and 72 h of age. Treatment groups included nonasphyxiated controls (n = 7), untreated UCO (n = 11), UCO + hypothermia (HT; n = 6), and UCO + HT + erythropoietin (n = 9). Metabolites were extracted and analyzed using comprehensive two-dimensional gas chromatography coupled with time-of-flight mass spectrometry and quantified by PARAFAC (parallel factor analysis). Using nontargeted discovery-based methods, we identified 63 metabolites as potential biomarkers. The changes in metabolite concentrations were characterized and compared between treatment groups. Further comparison determined that 8 metabolites (arachidonic acid, butanoic acid, citric acid, fumaric acid, lactate, malate, propanoic acid, and succinic acid) correlated with early and/or long-term neurodevelopmental outcomes. The combined outcomes of death or cerebral palsy correlated with citric acid, fumaric acid, lactate, and propanoic acid. This change in circulating metabolome after UCO may reflect cellular metabolism and biochemical changes in response to the severity of brain injury and have potential to predict neurodevelopmental outcomes.