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As prevention trials advance with autosomal dominant Alzheimer disease (ADAD) participants, understanding the similarities and differences between ADAD and "sporadic" late-onset AD (LOAD) is critical to determine generalizability of findings between these cohorts. Cognitive trajectories of ADAD mutation carriers (MCs) and autopsy-confirmed LOAD individuals were compared to address this question. Longitudinal rates of change on cognitive measures were compared in ADAD MCs (n = 310) and autopsy-confirmed LOAD participants (n = 163) before and after symptom onset (estimated/observed). LOAD participants declined more rapidly in the presymptomatic (preclinical) period and performed more poorly at symptom onset than ADAD participants on a cognitive composite. After symptom onset, however, the younger ADAD MCs declined more rapidly. The similar but not identical cognitive trajectories (declining but at different rates) for ADAD and LOAD suggest common AD pathologies but with some differences.

PURPOSE Breast cancer risk prediction models are used to identify high-risk women for early detection, targeted interventions, and enrollment into prevention trials. We sought to develop and evaluate a risk prediction model for breast cancer in US Black women, suitable for use in primary care settings. METHODS Breast cancer relative risks and attributable risks were estimated using data from Black women in three US population-based case-control studies (3,468 breast cancer cases; 3,578 controls age 30-69 years) and combined with SEER age- and race-specific incidence rates, with incorporation of competing mortality, to develop an absolute risk model. The model was validated in prospective data among 51,798 participants of the Black Women's Health Study, including 1,515 who developed invasive breast cancer. A second risk prediction model was developed on the basis of estrogen receptor (ER)–specific relative risks and attributable risks. Model performance was assessed by calibration (expected/observed cases) and discriminatory accuracy (C-statistic). RESULTS The expected/observed ratio was 1.01 (95% CI, 0.95 to 1.07). Age-adjusted C-statistics were 0.58 (95% CI, 0.56 to 0.59) overall and 0.63 (95% CI, 0.58 to 0.68) among women younger than 40 years. These measures were almost identical in the model based on estrogen receptor–specific relative risks and attributable risks. CONCLUSION Discriminatory accuracy of the new model was similar to that of the most frequently used questionnaire-based breast cancer risk prediction models in White women, suggesting that effective risk stratification for Black women is now possible. This model may be especially valuable for risk stratification of young Black women, who are below the ages at which breast cancer screening is typically begun.

Curable sexually transmitted infections (STIs) affect millions of people across the world. Besides unacceptably high HIV rates, South Africa also has the highest burden of STIs in the world. The aim of the study was to investigate temporal changes in STI incidence rates using the data from ~ 10,000 women who enrolled in several HIV prevention trials, KwaZulu-Natal, South Africa (2002-2016). We particularly focused on the changes in distribution of the most influential factors and their population-level impacts on STI incidence rates over time. Characteristics of the women were compared across the study periods: 2002-2004, 2005-2008, 2009-2011, and 2012-2016. Besides multivariable Cox regression models, population attributable risks were calculated for the significant factors. Despite the significant progress in prevention, testing, and treatment programs, infection rates increased substantially from 13.6 to 20.0 per 100 person-year over the study period. Our findings provided a compelling evidence for single/non-cohabiting South African women to be the most vulnerable population who consistently and substantially contributed to increasing STI rates during the 15 years of study duration (PAR%: 44%-47%). We also highlighted the impact of women's lack of knowledge related to their partner, using injectable contraceptives, less parity, and baseline STI positivity which were increased substantially over time. Our findings suggest that a significant proportion of STIs could be prevented by targeting single/non-cohabiting. These results may provide guidance in developing more effective STI prevention programs by targeting women at highest risk of infections and delivering more realistic messages.

Associations of incarceration with healthcare access and utilization among Black sexual minority men (BSMM) and differences in association among those with and without pre-incarceration symptoms of depression were measured. Secondary analysis using survey data from the longitudinal cohort HIV Prevention Trials Network 061 study was conducted among 1553 BSMM from six major U.S. cities from 2009 to 2011. We used modified log-binomial regression with robust standard errors to estimate associations of incarceration (reported at 6 month follow-up) on next six-month healthcare utilization and access (reported at the 12 month follow-up). We tested the significance of baseline depressive symptoms by incarceration interaction and reported differences in associations when observed. Participants with a history of incarceration were more likely to have depressive symptoms at baseline compared to those without. Recent incarceration was associated with almost twice the risk of mistrust in healthcare providers and emergency room utilization. Among men reporting depressive symptoms, a history of incarceration was associated with almost tripled risk of reporting providers do not communicate understandably. Among those with depression, one in five reported a missed visit regardless of incarceration status.

A long-acting injectable formulation of rilpivirine (RPV), a non-nucleoside reverse transcriptase inhibitor, is currently under investigation for use in human immunodeficiency virus (HIV) maintenance therapy. We previously characterized RPV metabolism after oral dosing and identified seven metabolites: four metabolites resulting from mono- or dioxygenation of the 2,6-dimethylphenyl ring itself or either of the two methyl groups located on that ring, one N-linked RPV glucuronide conjugate, and two O-linked RPV glucuronides produced via glucuronidation of mono- and dihydroxymethyl metabolites. However, as is true for most drugs, the metabolism of RPV after injection has yet to be reported. The phase II clinical trial HPTN 076 enrolled 136 HIV-uninfected women and investigated the safety and acceptability of long-acting injectable RPV for use in HIV pre-exposure prophylaxis. Through the analysis of plasma samples from 80 of these participants in the active product arm of the study, we were able to detect 2 metabolites after intramuscular injection of long-acting RPV, 2-hydroxymethyl-RPV, and RPV N-glucuronide. Of the total of 80 individuals, 72 participants exhibited detectable levels of 2-hydroxymethyl-RPV in plasma samples whereas RPV N-glucuronide was detectable in plasma samples of 78 participants. In addition, RPV N-glucuronide was detectable in rectal fluid, cervicovaginal fluid, and vaginal tissue. To investigate potential genetic variation in genes encoding enzymes relevant to RPV metabolism, we isolated genomic DNA and performed next-generation sequencing of CYP3A4, CYP3A5, UGT1A1 and UGT1A4. From these analyses, four missense variants were detected for CYP3A4 whereas one missense variant and one frameshift variant were detected for CYP3A5. A total of eight missense variants of UGT1A4 were detected, whereas two variants were detected for UGT1A1; however, these variants did not appear to account for the observed interindividual variability in metabolite levels. These findings provide insight into the metabolism of long-acting RPV and contribute to an overall understanding of metabolism after oral dosing versus injection. ClinicalTrials.gov Identifier: NCT02165202

HIV endpoint-driven clinical trials in Africa enroll women who are at heightened risk of acquiring HIV. In 2017, the South African Medical Research Council recommended the provision of oral pre-exposure prophylaxis (PrEP) in HIV prevention trials, at which time the Evidence for Contraceptive Options and HIV Outcomes trial was ongoing and began to provide PrEP on-site at some trial sites. We interviewed 132 women who initiated PrEP on-site at the Durban, South Africa trial site to explore PrEP use, and conducted phone-based interviews 4–6 months post-trial exit to explore post-trial PrEP access. PrEP uptake was high (42.6%). Among women initiating PrEP on-site, 87.9% felt at risk of acquiring HIV. Most women (> 90%) heard of PrEP for the first time from study staff and three-quarters who initiated PrEP on-site continued at trial-exit. PrEP use declined post-trial exit with more than 50% of women discontinuing PrEP, and barriers relating to access emerged.

Epidemiologists have for many decades reported on the patterns and distributions of diabetes within and between populations and have helped to elucidate the aetiology of the disease. This has helped raise awareness of the tremendous burden the disease places on individuals and societies; it has also identified key risk factors that have become the focus of diabetes prevention trials and helped shape public health recommendations. Recent developments in affordable high-throughput genetic and molecular phenotyping technologies have driven the emergence of a new type of epidemiology with a more mechanistic focus than ever before. Studies employing these technologies have identified gene variants or causal loci, and linked these to other omics data that help define the molecular processes mediating the effects of genetic variation in the expression of clinical phenotypes. The scale of these epidemiological studies is rapidly growing; a trend that is set to continue as the public and private sectors invest heavily in omics data generation. Many are banking on this massive volume of diverse molecular data for breakthroughs in drug discovery and predicting sensitivity to risk factors, response to therapies and susceptibility to diabetes complications, as well as the development of disease-monitoring tools and surrogate outcomes. To realise these possibilities, it is essential that omics technologies are applied to well-designed epidemiological studies and that the emerging data are carefully analysed and interpreted. One might view this as next-generation epidemiology, where complex high-dimensionality data analysis approaches will need to be blended with many of the core principles of epidemiological research. In this article, we review the literature on omics in diabetes epidemiology and discuss how this field is evolving. Graphical abstract Electronic supplementary material The online version of this article (10.1007/s00125-020-05246-w) contains a slide of the figure for download, which is available to authorised users.

The inability to access health services when needed is a critical barrier to HIV prevention, treatment, and care among men who have sex with men (MSM) and transgender women (TGW). Using data collected in HPTN 075, we explored factors associated with any any experienced healthcare-related stigma. HPTN 075 was a cohort study to assess the feasibility of recruiting and retaining MSM and TGW in clinical trials in sub-Saharan Africa. Of 401 MSM and TGW enrolled at four sites (Kisumu, Kenya; Blantyre, Malawi; Cape Town, Soweto, South Africa) 397 contributed to the analysis (79.9% cis-gender and 20.1% TGW). Of these, (45.3%; 180/397) reported one or more of healthcare-related stigma experiences. Most frequently reported experiences included fear to seek healthcare services (36.3%) and avoiding seeking such services because of discovery of MSM status (29.2%). Few men and TGW (2.5%) reported having been denied health services because of having sex with men. In multivariable analysis, more participants in Soweto [adjusted odds ratio (AOR) = 2.60] and fewer participants in Blantyre (AOR = 0.27) reported any healthcare-related stigma experiences, in comparison to participants in Kisumu. MSM and TGW that did not have a supportive gay community to rely on were more likely to report any healthcare-related stigma experiences (AOR = 1.46), whereas MSM and TGW who reported high social support and who never had engaged in transactional sex were less likely to report such experiences (AOR = 0.76 and AOR = 0.43, respectively). Our results suggest that encouraging support groups for MSM and TGW as well as training and sensitizing healthcare staff, and the general community, on MSM and TGW health issues and cultural competence may reduce stigma, improve access to healthcare, which could ultimately reduce HIV transmission.

Objective The Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), widely used for detecting cognitive impairment in different neuropsychiatric conditions, is increasingly applied for measuring cognitive functioning in older individuals. Available normative data for RBANS Italian version suffer from under-representation of the older ages (>60 years) and are not corrected for education. Moreover, normative data are provided only for Indexes and Total scores. We thus administered RBANS Italian version in a larger sample of older adults, taking into account the effect of age, education and gender on all scores. Method We used a regression-based model to assess the effect of age, education, and gender on RBANS Subtests, Indexes and Total scores in a consecutive series of healthy cognitively normal volunteers aged 60–79 years (N = 158). The obtained norms were compared with the Italian original normative data by means of Wilcoxon rank-sum test. Results Multiple linear regression analyses showed that age and educational level significantly influence performances on most RBANS scores. A free-to-use Excel to calculate subject’s percentiles for any single score was developed. When compared with original normative values, our percentiles distribution of Indexes and Total scores did not reveal significant differences (p > .05). Conclusion The obtained normative data show good concordance with previous norms. The instrument seems not significantly affected by educational level. The possibility to correct for any single score could make RBANS a more precise measure for capturing subtle cognitive deficits in prevention studies.

Clinical trials play a critical role in evidence-based medicine, when rigorous scientific methodology is utilized to discover and test the effectiveness and safety of new drugs to prevent or cure diseases, including cancer. Participation in clinical trials thus becomes key to successful completion of these trials. Although it is estimated that >70% of Americans are inclined to participate in clinical trials, less than 5% of adult cancer patients participate in clinical trials. There is thus a large gap between those inclined to participate in clinical trials and actual participation in clinical trials. As with trials targeting men with prostate cancer (PCa) on active surveillance (AS), where the target population is mostly over 50 years of age, others have observed several challenges with recruitment and accrual in clinical trials. The participation rate is currently unavailable for men on primary and secondary chemoprevention trials. Additionally, with unanticipated environmental factors such as a pandemic or other natural emergencies that may severely impact the economy, personal property, travel and person-to person contact for study-related procedures, there is a need to continuously identify these challenges and determine solutions to recruitment barriers in chemoprevention trials to ensure timely completion of early phase trials. Recent studies regarding the impact of the pandemic on clinical trial recruitment have shown that cancer prevention trials were relatively more negatively impacted compared to cancer treatment trials. The goal of this manuscript is to review our experience in continuously evaluating the protocol and patient level challenges to recruiting subjects on AS for PCa in this cancer chemoprevention trial conducted at the Comprehensive Cancer Center (CCC) and report the contemporary strategies that we are utilizing to continue to recruit subjects in this trial. We provide data from our current trial as an example while discussing future strategies to improve overall clinical trial recruitment. These strategies can inform future design of contemporary cancer chemoprevention trials and, additionally, better select, focus and invest in strategies that are the most productive and efficient for recruiting target populations.

Background: Four of the largest HIV prevention trials have been conducted in sub-Saharan Africa, enrolling hundreds of thousands of participants in catchment areas of millions of people. The trials have focused on community-level interventions to increase diagnosis and initiation of antiretroviral therapy (ART) to improve health and reduce HIV transmission. Universal test-and-treat strategies are deployed to achieve viral suppression thereby reducing risk to uninfected persons, known as treatment as prevention (TasP). Purpose: We review the work that found HIV plasma load to correlate with transmission risk, demonstrated that ART could reduce genital tract viral expression, and showed early treatment to be beneficial for persons living with HIV, and that HIV-uninfected sexual partners were protected from infection. We review the seemingly inconsistent findings of the major TasP trials: the TasP [National Agency for AIDS Research (ANRS) 12249] study in South Africa, the SEARCH trial in Kenya and Uganda, the Botswana Combination Prevention Project Ya Tsie study, and the HIV Prevention Trials Network 071 (PopART) trial in Zambia and South Africa. Findings: All the trials reinforce the critical need to identify approaches to optimize programs and incentivize uptake and engagement in HIV testing and ART-based care in ways that consistently reduce HIV transmission. That other chronic conditions can be screened for and treated in the same infrastructures suggests added value of HIV investments. Conclusions: Implementation challenges are a principal frontier in the global struggle to reduce HIV transmission and mortality using TasP, complementing efforts to find a cure for HIV and an effective, deployable vaccine.

Introduction A major change in the ethics framework for preventive HIV vaccine trials worldwide is the release of the UNAIDS 2021 ethical considerations in HIV prevention trials. This new guidance comes at an exciting time when there are multiple HIV vaccine efficacy trials in the field. Research Ethics Committees (RECs) or Institutional Review Boards are a most likely audience for these guidelines. Our objective is to highlight shifts in ethics recommendations from the earlier 2012 UNAIDS guidance. Discussion We review recommendations related to four key issues, namely standard of prevention, post‐trial access to safe and effective vaccines, enrolment of adolescents and enrolment of pregnant women. We outline implications and make recommendations for the ethics review process, including suggested lines of inquiry by RECs and responses by applicants. Conclusions There have been several shifts in the UNAIDS ethics guidance with implications for HIV vaccine researchers submitting applications for initial ethics review or re‐certification, and for RECs conducting such reviews. This review may assist RECs in a more efficient and consistent application of ethics recommendations. However, additional tools and training may further help stakeholders comply with new UNAIDS ethics recommendations during protocol development and ethics review.

BACKGROUND: Recruitment to randomised clinical trials can be challenging and slow recruitment has serious consequences. This study aimed to summarise and reflect on the challenges in enrolling young children to a multidrug-resistant TB (MDR-TB) prevention trial in South Africa.METHODS: Recruitment to the Tuberculosis Child Multidrug-resistant Preventive Therapy Trial (TB-CHAMP) was tracked using an electronic recruiting platform, which was used to generate a recruiting flow diagram. Structured personnel questionnaires, meeting minutes and workshop notes were thematically analysed to elucidate barriers and solutions.RESULT: Of 3,682 (85.3%) adult rifampicin (RIF) resistant index cases with pre-screening outcomes, 1597 (43.4%) reported having no children under 5 years in the household and 562 (15.3%) were RIF-monoresistant. More than nine index cases were pre-screened for each child enrolled. Numerous barriers to recruitment were identified. Thorough recruitment planning, customised tracking data systems, a dedicated recruiting team with strong leadership, adequate resources to recruit across large geographic areas, and excellent relationships with routine TB services emerged as key factors to ensure successful recruitment.CONCLUSION: Recruitment of children into MDR-TB prevention trials can be difficult. Several MDR-TB prevention trials are underway, and lessons learnt from TB-CHAMP will be relevant to these and other TB prevention studies.

Background Early in the SARS-CoV-2 pandemic, commentators warned that some COVID trials were inadequately conceived, designed and reported. Here, we retrospectively assess the prevalence of informative COVID trials launched in the first 6 months of the pandemic. Methods Based on prespecified eligibility criteria, we created a cohort of Phase 1/2, Phase 2, Phase 2/3 and Phase 3 SARS-CoV-2 treatment and prevention efficacy trials that were initiated from 2020-01-01 to 2020-06-30 using ClinicalTrials.gov registration records. We excluded trials evaluating behavioural interventions and natural products, which are not regulated by the U.S. Food and Drug Administration (FDA). We evaluated trials on 3 criteria of informativeness: potential redundancy (comparing trial phase, type, patient-participant characteristics, treatment regimen, comparator arms and primary outcome), trials design (according to the recommendations set-out in the May 2020 FDA guidance document on SARS-CoV-2 treatment and prevention trials) and feasibility of patient-participant recruitment (based on timeliness and success of recruitment). Results We included all 500 eligible trials in our cohort, 58% of which were Phase 2 and 84.8% were directed towards the treatment of SARS-CoV-2. Close to one third of trials met all three criteria and were deemed informative (29.9% (95% Confidence Interval 23.7–36.9)). The proportion of potentially redundant trials in our cohort was 4.1%. Over half of the trials in our cohort (56.2%) did not meet our criteria for high quality trial design. The proportion of trials with infeasible patient-participant recruitment was 22.6%. Conclusions Less than one third of COVID-19 trials registered on ClinicalTrials.gov during the first six months met all three criteria for informativeness. Shortcomings in trial design, recruitment feasibility and redundancy reflect longstanding weaknesses in the clinical research enterprise that were likely amplified by the exceptional circumstances of a pandemic.

Background Consensus definitions for the diagnosis of invasive fungal diseases (IFDs) were updated in 2020 to increase the certainty of IFD for inclusion in clinical trials, for instance by increasing biomarker cutoff limits to define positivity. To date, there is a paucity of data as to the impact of the revised definitions on clinical trials. Methods In this study, we sought to determine the impact of the new definitions on classifying invasive aspergillosis (IA), the most common invasive mold disease in immunocompromised patients. We reclassified 226 proven and probable IA cases plus 139 possible IFD cases in the Aspergillus Technology Consortium (AsTeC) and in an antifungal prophylaxis trial (BMT CTN 0101) using the new criteria. Results Fewer cases met the more stringent diagnostic 2020 criteria after applying the reclassification criteria to define probable IA. Of 188 evaluable probable cases, 41 (22%) were reclassified to 40 possible IA and 1 probable IFD. Reclassification to possible IFD occurred in 22% of hematologic malignancy (HM) patients, 29% of hematopoietic cell transplant (HCT) patients, and in no lung transplant (LT) patients. Date of diagnosis was established a median (range) of 3 (1–105) days later in 15% of probable IA cases using the new criteria. Applying the new definitions to the BMT CTN 0101 trial, the power to detect the same odds ratio decreased substantially. Conclusions The updated IA consensus definitions may impact future trial designs, especially for antifungal prophylaxis studies., Using more stringent consensus diagnostic definitions for Invasive Aspergillosis, more than 20% of cases in hematopoietic cell transplant and hematologic malignancies patients that met earlier definitions no longer meet diagnostic criteria. This has important implications for antifungal prevention trials.

Mathematical models predict that community-wide access to HIV testing-and-treatment can rapidly and substantially reduce new HIV infections. Yet several large universal test-and-treat HIV prevention trials in high-prevalence epidemics demonstrated variable reduction in population-level incidence. To elucidate patterns of HIV spread in universal test-and-treat trials we quantified the contribution of geographic-location, gender, age and randomized-HIV- intervention to HIV transmissions in the 30-community Ya Tsie trial in Botswana (estimated trial population: 175,664). Deep-sequence phylogenetic analysis revealed that most inferred HIV transmissions within the trial occurred within the same or between neighboring communities, and between similarly-aged partners. Transmissions into intervention communities from control communities were more common than the reverse post-baseline (30% [12.2 – 56.7] versus 3% [0.1 – 27.3]) than at baseline (7% [1.5 – 25.3] versus 5% [0.9 – 22.9]) compatible with a benefit from treatment-as-prevention. Our findings suggest that population mobility patterns are fundamental to HIV transmission dynamics and to the impact of HIV control strategies.

Endpoints that provide an early identification of treatment effects are needed to implement type 1 diabetes prevention trials more efficiently. To this end, we assessed whether metabolic endpoints can be used to detect a teplizumab effect on rapid β-cell decline within 3 months after treatment in high-risk individuals in the TrialNet teplizumab trial. Glucose and C-peptide response curves (GCRCs) were constructed by plotting mean glucose and C-peptide values from 2-hour oral glucose tolerance tests on a 2-dimensional grid. Groups were compared visually for changes in GCRC shape and movement. GCRC changes reflected marked metabolic deterioration in the placebo group within 3 months of randomization. By 6 months, GCRCs resembled typical GCRCs at diagnosis. In contrast, GCRC changes in the teplizumab group suggested metabolic improvement. Quantitative comparisons, including two novel metabolic endpoints that indicate GCRC changes, the Within Quadrant Endpoint (WQE) and the Ordinal Directional Endpoint (ODE), were consistent with visual impressions of an appreciable treatment effect at 3 and 6-month timepoints. In conclusion, an analytic approach combining visual evidence with novel endpoints, demonstrated that Teplizumab delays rapid metabolic decline, and improves the metabolic state within 3 months after treatment; this effect extends for at least 6 months.

The specificity of subject selection is crucial for T1D prevention trials. GCRCs are glucose and C-peptide values at 30 to 120-minute OGTT timepoints plotted on a glucose (y-axis) and C-peptide (x-axis) grid. Since GCRCs change characteristically on the grid during T1D progression, the identification of GCRC phenotypes among screening OGTTs would refine selection for T1D prevention trials. We aimed to determine if AUC glucose (AUCglu) and AUC C-peptide (AUCpep) identify GCRCs at screening that match GCRCs specific to times pre-diagnosis. We analyzed OGTT data from DPT-1 and TrialNet (TN) participants, both antibody positive (Ab+) populations. AUCglu and AUCpep of 52 TN participants at screening were matched to AUCglu and AUCpep 1.5 yrs pre-diagnosis in 162 DPT-1 participants (AUCglu means: 152.7 vs. 152.3 mg/dl; AUCpep means: 3.7 vs. 3.7 ng/dl, respectively). By matching the AUC values at TN screening to the DPT-1 AUC values 1.5 yrs pre-diagnosis, we were able to match GCRCs at TN screening to the DPT-1 GCRCs 1.5 yrs pre-diagnosis. Figure 1 shows the matched GCRCs obtained by matching AUC values. In conclusion, AUCglu and AUCpep can identify GCRCs at screening that match GCRCs specific to a time before diagnosis, even across Ab+ populations. This novel finding should considerably enhance the metabolic specificity of subject selection for T1D prevention trials. Disclosure H. M. Ismail: None. B. M. Nathan: None. M. A. Atkinson: None. L. Dimeglio: Advisory Panel; Self; MannKind Corporation. J. Sosenko: None. D. D. Cuthbertson: None. M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. A. Steck: None. H. Rodriguez: Advisory Panel; Self; Provention Bio, Inc., Other Relationship; Self; Merck & Co., Inc., Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Eli Lilly and Company, Medtronic, Precigen, Inc., Provention Bio, Inc., Takeda Pharmaceutical Co., Tolerion, Inc. S. E. Gitelman: Advisory Panel; Self; Provention Bio, Inc., Tolerion, Inc., Consultant; Self; Avotres Inc., Biolojic, Research Support; Self; Intrexon, Janssen Research & Development, LLC, Provention Bio, Inc., Tolerion, Inc. K. C. Herold: Consultant; Self; Provention Bio, Inc., Viela Bio, Consultant; Spouse/Partner; Provention Bio, Inc. J. S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Oramed Pharmaceuticals, Inc., Orgenesis Inc., Tolerion, Inc., Viacyte, Inc., Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics, Inc., Consultant; Self; AstraZeneca, Avotres Inc., Bayer AG, IM Therapeutics, Novo Nordisk, Precigen, Inc., Provention Bio, Inc., Sanofi, Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc.

T1D staging is used for eligibility criteria in T1D prevention trials, but recent findings suggest that using glucose alone, without measures of insulin secretion, to define T1D progression may group together highly heterogeneous individuals. Thus, utilizing the large TrialNet Pathway to Prevention cohort, we aimed to examine heterogeneity for T1D-related characteristics, including risk for T1D, among 1,325 Ab+ individuals who upon OGTT screening were in the highest AUC glucose quintile (≥151 mg/dL) within the nondiabetic range. Within that highest AUC glucose quintile, we compared T1D characteristics of participants in the highest (≥8.03 ng/mL, n=378) vs. the lowest ( In conclusion, despite similar AUC glucose values, C-peptide levels identified individuals with greatly different characteristics, including a near 3-fold difference in 5-yr T1D risk of those in lowest vs. highest C-peptide quintiles. Using glucose without C-peptide to define T1D stages results in pronounced heterogeneity, which can lower the ability to demonstrate efficacy in T1D prevention trials. Disclosure M. J. Redondo: Advisory Panel; Self; Provention Bio, Inc. J. Sosenko: None. D. D. Cuthbertson: None. B. M. Nathan: None. E. K. Sims: None. M. Tosur: Advisory Panel; Self; Provention Bio, Inc. I. Libman: Advisory Panel; Self; Novo Nordisk. J. S. Skyler: Advisory Panel; Self; Abvance Therapeutics, ADOCIA, Oramed Pharmaceuticals, Inc., Orgenesis Inc., Tolerion, Inc., Viacyte, Inc., Board Member; Self; Applied Therapeutics, Dexcom, Inc., Intarcia Therapeutics, Inc., Consultant; Self; AstraZeneca, Avotres Inc., Bayer AG, IM Therapeutics, Novo Nordisk, Precigen, Inc., Provention Bio, Inc., Sanofi, Stock/Shareholder; Self; Applied Therapeutics, Dexcom, Inc. C. Evans-molina: Advisory Panel; Self; Provention Bio, Inc., Consultant; Self; Dompe, Other Relationship; Self; Bristol-Myers Squibb Company, Nimbus Pharmaceuticals, Pfizer Inc. M. A. Atkinson: None. Funding National Institute of Diabetes and Digestive and Kidney Diseases; National Institute of Allergy and Infectious Diseases; Eunice Kennedy Shriver National Institute of Child Health and Human Development; JDRF

The value of a pre-diagnostic surrogate endpoint for T1D prevention trials is based on detection of efficacy and association with T1D. Thus, among multiple antibody+, dysglycemic individuals with baseline and 6-month OGTTs, we assessed metabolic endpoints for: 1) detecting a delay in metabolic decline from baseline to 6 months between placebo and teplizumab groups in the TrialNet teplizumab T1D prevention trial (TN 10), and 2) predicting T1D by metabolic change from baseline to 6 months in the TrialNet Pathway to Prevention study (TN01). The Table shows that the 6-month change in C-peptide (Cpep) measures (AUC and 30-0 minute) differed significantly between placebo and teplizumab groups, but not the change in glucose AUC. However, prediction of T1D, indicated by receiver operating curve AUC (ROCAUC), tended to be more accurate for 6-month change of glucose AUC than for Cpep changes. Although detection of a teplizumab effect by Cpep measures was comparable to that of combined measures (Index60 and Cpep AUC/glucose AUC), the latter were more accurate predictors. In conclusion, among metabolic endpoints there was discordance between detection of a teplizumab effect and prediction accuracy of T1D. However, such discordance suggests that metabolic endpoints provide more insight into understanding effects of teplizumab and other preventive treatments than the T1D endpoint alone. Disclosure E. K. Sims: None. D. D. Cuthbertson: None. L. M. Jacobsen: None. K. C. Herold: Consultant; Self; Provention Bio, Inc., Viela Bio, Consultant; Spouse/Partner; Provention Bio, Inc. J. Sosenko: None.

Tom Dishion, a pioneer in prevention science, was one of the first to recognize the importance of adapting interventions to the needs of individual families. Building towards this goal, we suggest that prevention trials be used to assess baseline target moderated mediation (BTMM), where preventive intervention effects are mediated through change in specific targets, and the resulting effect varies across baseline levels of the target. Four forms of BTMM found in recent trials are discussed including compensatory, rich-get-richer, crossover, and differential iatrogenic effects. A strategy for evaluating meaningful preventive effects is presented based on preventive thresholds for diagnostic conditions, midpoint targets and proximal risk or protective mechanisms. Methods are described for using the results from BTMM analyses of these thresholds to estimate indices of intervention risk reduction or increase as they vary over baseline target levels, and potential cut points are presented for identifying subgroups that would benefit from program adaptation because of weak or potentially iatrogenic program effects. Simulated data are used to illustrate curves for the four forms of BTMM effects and how implications for adaptation change when untreated control group outcomes also vary over baseline target levels.

Background We assessed age-related associations between substance use and sexual risk behavior using data from three HIV prevention trials that enrolled young African American women. Methods We used integrative data analysis to pool data from 1862 individuals aged 16–25 years. We used time-varying effect models to examine associations between substance use (alcoholic drinks per month, recent marijuana use, cigarettes smoked per day) and sexual risk behaviors (monthly frequency of vaginal sex, multiple sex partners, condomless sex), adjusting for the fixed effect of trial. Results In models that included all three substances, cigarette smoking was not associated with any outcome. Alcohol quantity was associated with greater frequency of sex at all ages, an increased likelihood of having multiple sex partners from about age 17–24 years, and an increased likelihood of condomless sex after about age 18.5 years. Associations between alcohol quantity and sex frequency were relatively stable; associations with having multiple sex partners and condomless sex increased beginning at about age 22 years. Marijuana use was associated with greater sex frequency at approximate ages 16.5–24 years and an increased likelihood of having multiple sex partners at ages 18–24 years. Associations with sex frequency were relatively stable; associations with having multiple sex partners increased from about age 18 and peaked at about age 23 years. Conclusions We observed developmentally-dependent relationships between both alcohol and marijuana and sexual risk behavior. The findings underscore the need to address substance-related sexual risk among young African American women and may inform optimal timing of intervention.

Background The HIV Prevention Trials Network (HPTN) 067/Alternative Dosing to Augment PrEP Pill Taking (ADAPT) Study evaluated the feasibility of daily and nondaily human immunodeficiency virus (HIV) preexposure prophylaxis (PrEP) regimens among high-risk populations, including men who have sex with men (MSM) and transgender women, in Bangkok, Thailand and Harlem, New York. We used a mathematical model to predict the efficacy and effectiveness of different dosing regimens. Methods An individual-based mathematical model was used to simulate annual HIV incidence among MSM cohorts. PrEP efficacy for covered sex acts, as defined in the HPTN 067/ADAPT protocol, was estimated using subgroup efficacy estimates from the preexposure prophylaxis initiative (iPrEx) trial. Effectiveness was estimated by comparison of the HIV incidence with and without PrEP use. Results We estimated that PrEP was highly protective (85%–96% efficacy across regimens and sites) for fully covered acts. PrEP was more protective for partially covered acts in Bangkok (71%–88% efficacy) than in Harlem (62%–81% efficacy). Our model projects 80%, 62%, and 68% effectiveness of daily, time-driven, and event-driven PrEP for MSM in Harlem compared with 90%, 85%, and 79% for MSM in Bangkok. Halving the efficacy for partially covered acts decreases effectiveness by 8–9 percentage points in Harlem and by 5–9 percentage points in Bangkok across regimens. Conclusions Our analysis suggests that PrEP was more effective among MSM in Thailand than in the United States as a result of more fully covered sex acts and more pills taken around partially covered acts. Overall, nondaily PrEP was less effective than daily PrEP, especially in the United States where the sex act coverage associated with daily use was substantially higher.

Literature data revealed that the benefits of consuming omega-3 fatty acid (n-3FA) supplements such as fish oil with the goal of reducing the incidence of chronic diseases such as cardiovascular disease and cancer remain controversial. The purpose of this commentary is to discuss factors that may account for the inconsistency of results across different studies. Critical review of the published data, including our own preclinical and clinical studies, strongly suggests that customized clinical prevention trials are needed to resolve the above-mentioned controversy. Specifically, in order to develop a personalized cancer prevention strategy, more attention should be given to multiple factors including the dose of the n-3FA, the specific placebo used as a comparator, duration of administration, type of intervention (primary vs secondary prevention trial), specific compound (DHA vs EPA vs their metabolites), the ratio of n-3FA:n-6FA and the target population tested (high vs average risk).

We combined behavioral survey data from the human immunodeficiency virus (HIV) Prevention Trials Network 068 study with phylogenetic information to determine if cluster membership was associated with characteristics of young women and their partners. Clusters were more likely to involve young women from specific villages and schools, indicating some localized transmission.Supplemental digital content is available in the text.

South Africa has the highest burden of Human Immunodeficiency Virus (HIV) infections in the world. There is also growing evidence that an individual’s risk of contracting HIV is increased by the presence of other sexually transmitted infections (STIs). Primary objective of this study was to examine the association between the prevalence of STIs in a cohort of South African women who enrolled in HIV prevention trials (2002–2012). The current study linked the individual-factors with the community-level characteristics using geo-referencing. This multi-level data was analysed in generalized additive mixed models (GAMMS) settings. In the multivariate logistic regression model, younger age [Odds Ratio (OR):4.30, 95%CI: 3.20, 5.77 and OR:2.72, 95% CI: 2.02, 3.66 for age

The limiting antigen (LAg)-avidity assay is a serologic assay used for cross-sectional HIV incidence testing. We compared the results obtained with the LAg-avidity assay using dried blood spot (DBS) samples stored at room temperature (18°C–25°C) or stored frozen at −80°C with results obtained from matched plasma samples. Matched DBS and plasma samples (306 paired samples) were collected in the HIV Prevention Trials Network (HPTN) 068 trial in South Africa (2012–2014). The DBS were stored at room temperature before testing. Matched DBS and plasma samples (100 paired samples) from the Consortium for the Evaluation and Performance of HIV Incidence Assays (CEPHIA) were collected in 2016 and were stored at −80°C. All DBS testing was performed in 2017. Differences in normalized optical density (ODn) were compared between matched DBS and plasma samples. For DBS samples stored at room temperature (HPTN 068), the average difference in ODn values for plasma versus DBS was 1.49 (95% confidence intervals [CI]: 1.36–1.62). In contrast, when DBS samples were stored at −80°C (CEPHIA), the average difference in ODn values for plasma versus DBS was −0.22 (95% CI: −0.32 to −0.13). DBS samples stored at room temperature should not be used for cross-sectional HIV incidence testing with the LAg-avidity assay.

Background: Multiple studies are evaluating how to prevent SARS-CoV-2 infection. Interventions are wide ranging and include vaccines, prophylactic drugs, public health safety measures, and behavioural interventions. Heterogeneity in the outcomes measured and reported is leading to research waste and inefficiency, slowing worldwide identification and implementation of effective methods to prevent infection. A core outcome set (COS) for studies of interventions to prevent SARS-CoV-2 infection has recently been developed, identifying infection as a critical outcome to measure. This paper examines how SARS-CoV-2 infection outcomes are measured in registered COVID-19 prevention trials and considers how this can be improved. Methods: We searched the Cochrane COVID-19 Study Register to identify and review SARS-CoV-2 infection outcomes in prevention trials, including the rationale for choice of outcome measurement. We included phase 3 and 4 trials of COVID-19 prevention interventions. Early phase trials and studies relating to the transmission, treatment or management of COVID-19 were excluded. Results: We identified 430 entries in the register, of which 199 unique prevention trials were included across eight settings and 12 intervention types. Fifteen (8%) trials did not include any SARS-CoV-2 infection outcomes. The remaining 184 (92%) studies included a total of 268 SARS-CoV-2 infection outcomes, of which 32 (17%) did not specify how infection would be measured. Testing (i.e. formal diagnostic test) as a standalone method for determining infection was used in 57 (31%) trials, whereas defining infection by symptoms alone was used in 16 (9%) trials. All other trials (n=79, 43%) included multiple infection outcomes, defined in different ways. Discussion: There is considerable variation in how SARS-CoV-2 infection is measured within and across different interventions and settings. Furthermore, few studies report the rationale for outcome selection and measurement. Better transparency and standardisation of SARS-CoV-2 infection measurement is needed for the findings from prevention trials to inform decision-making.

Despite older racial and ethnic minorities (REMs) being more likely to develop dementia they are underrepresented in clinical trials focused on neurological disorders. Inclusion of REMs in dementia prevention studies is vital to reducing the impact of disparities in dementia risk. We conducted a systematic review to characterize the number of REM enrolled in brain health and prevention randomized controlled trials (RCTs). RTCs published from January 1, 2004 to April 21, 2020 were included. Participants were normal cognitive adults aged 45 years and older who participated in a Phase II or Phase III U.S. based preventative trial. Analyses were performed to examine differences in trial characteristics between RCTs that did and those that did not report race/ethnicity and to calculate the pooled proportion of each racial/ethnic group in randomized brain healthy prevention trials. A total of 42 studies consisting of 100,748 participants were included in the final analyses. A total of 26 (62%) reported some racial/ethnic identity data. The pooled proportion of REM participants was 0.256 (95% CI, 0.191, 0.326). There is a lack of racial/ethnic reporting of participants and REMs remain underrepresented in brain health prevention RCTs.