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The opioid epidemic is one of the greatest public health problems that the USA faces. Opioid overdose death rates have increased steadily for more than a decade and doubled in 2013-17, as the highly potent synthetic opioid fentanyl entered the drug supply. Demographics of new HIV diagnoses among people who inject drugs are also changing, with more new HIV diagnoses occurring among White people, young people (aged 13-34 years), and people who reside outside large central metropolitan areas. Racial differences also exist in syringe sharing, which decreased among Black people and Hispanic people but remained unchanged among White people in 2005-15. Recent HIV outbreaks have occurred in rural areas of the USA, as well as among marginalised people in urban areas with robust HIV prevention and treatment services (eg, Seattle, WA). Multiple evidence-based interventions can effectively treat opioid use disorder and prevent HIV acquisition. However, considerable barriers exist precluding delivery of these solutions to many people who inject drugs. If the USA is serious about HIV prevention among this group, stigma must be eliminated, discriminatory policies must change, and comprehensive health care must be accessible to all. Finally, root causes of the opioid epidemic such as hopelessness need to be identified and addressed.

: This editorial review covers current trends in the epidemiology of HIV among people who inject drugs (PWID) in the United States, including four recent HIV outbreaks. We discuss gaps in the prevention and treatment cascades for HIV and medications for opioid disorder and propose lessons learned to prevent future HIV outbreaks. Over the last decade, North America has been in the throes of a major opioid epidemic, due in part to over-prescribing of prescription opiates, followed by increasing availability of cheap heroin, synthetic opioids (e.g. fentanyl), and stimulants (e.g. methamphetamine). Historically, HIV infection among PWID in the US had predominantly affected communities who were older, urban and Black. More recently, the majority of these infections are among younger, rural or suburban and Caucasian PWID. All four HIV outbreaks were characterized by a high proportion of women who inject drugs and underlying socioeconomic drivers such as homelessness and poverty. We contend that the US response to the HIV epidemic among PWID has been fractured. A crucial lesson is that when evidence-based responses to HIV prevention are undermined or abandoned because of moral objections, untold humanitarian and financial costs on public health will ensue. Restructuring a path forward requires that evidence-based interventions be integrated and brought to scale while simultaneously addressing underlying structural drivers of HIV and related syndemics. Failing to do so will mean that HIV outbreaks among PWID and the communities they live in will continue to occur in a tragic and relentless cycle.

IntroductionLimited data exist on acceptability of candidate pre-exposure prophylaxis (PrEP) regimens among US women. We evaluated PrEP experiences, attitudes and future use intentions among sexually active women who completed the US-based HIV Prevention Trials Network 069/AIDS Clinical Trials Group 5305 study.MethodsWomen participated in the study between March 2013 and November 2015. We analysed computer-assisted self-interview (CASI) surveys among 130 women and conducted in-depth interviews among a subset of 26 women from three sites. Interviews were conducted in mid/late-2015.ResultsMost women (57%) reported very good/excellent PrEP adherence on CASI, although 21% acknowledged over-reporting adherence at least some of the time. Commitment to preventing HIV infection, a sense of ownership of the study, and keeping pills stored in a visible location facilitated adherence. Adherence barriers included "simply forgetting" and being away from home. Most women interviewed did not intend to use PrEP in the future because of lack of perceived need due to their own (as opposed to their partners') low-risk behaviour and concerns about affordability - but not because of side effects or other characteristics of the regimens.DiscussionImproving HIV prevention options for US women will require access to affordable PrEP as well as expanding women's understanding of relationship- and community-level factors that increase their risk of acquiring HIV.

BackgroundMaraviroc (MVC) is a candidate drug for HIV preexposure prophylaxis (PrEP).ObjectiveTo assess the safety and tolerability of MVC-containing PrEP over 48 weeks in U.S. women at risk for HIV infection.DesignPhase 2 randomized, controlled, double-blinded study of 4 antiretroviral regimens used as PrEP. (ClinicalTrials.gov: NCT01505114).Setting12 clinical research sites of the HIV Prevention Trials Network and AIDS Clinical Trials Group.ParticipantsHIV-uninfected women reporting condomless vaginal or anal intercourse with at least 1 man with HIV infection or unknown serostatus within 90 days.InterventionMVC only, MVC-emtricitabine (FTC), MVC-tenofovir disoproxil fumarate (TDF), and TDF-FTC (control).MeasurementsAt each visit, clinical and laboratory (including HIV) assessments were done. Primary outcomes were grade 3 and 4 adverse events and time to permanent discontinuation of the study regimen. All randomly assigned participants were analyzed according to their original assignment.ResultsAmong 188 participants, 85% completed follow-up, 11% withdrew early, and 4% were lost to follow-up; 19% discontinued their regimen prematurely. The number discontinuing and the time to discontinuation did not differ among regimens. Grade 3 or 4 adverse events occurred in 5 (MVC), 13 (MVC-FTC), 9 (MVC-TDF), and 8 (TDF-FTC) participants; rates did not differ among regimens. One death (by suicide) occurred in the MVC-TDF group but was judged not to be related to study drugs. Of available plasma samples at week 48 (n = 126), 60% showed detectable drug concentrations. No new HIV infections occurred.LimitationsParticipants were not necessarily at high risk for HIV infection. The regimen comprised 3 pills taken daily. The study was not powered for efficacy.ConclusionMaraviroc-containing PrEP regimens were safe and well-tolerated compared with TDF-FTC in U.S. women. No new HIV infections occurred, although whether this was due to study drugs or low risk in the population is uncertain. Maraviroc-containing PrEP for women may warrant further study.Primary funding sourceNational Institutes of Health.

Given the range of pre-exposure prophylaxis (PrEP) products currently being tested to prevent HIV in women, a standardized Acceptability and Use of PrEP Products Among Women Tool may facilitate comparisons of product acceptability and use across different geographies, trials, and users. We conducted three rounds of cognitive interviewing over 2 months in 2016, with 28 South African women who had experience participating in a range of PrEP product trials. The final instrument contained 41 items, including five new items that improved construct validity and 22 items modified for clarity. Changes were made due to unclear wording, difficulty answering, participant embarrassment, low response variability, and administrative formatting. Cognitive interviewing provided a means to address issues that would have inhibited this tool's ability to accurately collect data otherwise. This rapid, low-cost study provided valuable insight into participants' understanding of questions and demonstrated the utility of cognitive interviewing in international clinical trials.

Faced with a worldwide shortage of PPE with the COVID-19 pandemic, we describe approaches for supplying hard-to-forecast PPE demand in West Virginia under challenging replenishment conditions. We describe the implementation of these approaches under the aegis of a joint inter-agency task force convened by the West Virginia State Administration. In the face of a worldwide shortage of personal protective equipment (PPE) at the onset of the COVID-19 pandemic, we report on the challenge of supplying hard-to-forecast PPE demand in the state of West Virginia under challenging replenishment conditions. Part of the challenge included the lack of appropriate healthcare data in a largely rural state such as West Virginia. We describe the work of a joint interagency task force (JIATF) that assembled the data to implement a novel agent-based epidemiological model for forecasting PPE demand of patients with confirmed and suspected COVID-19, extending the capability of popular epidemiological models. On the supply side, we describe our extension of nonparametric approaches for setting inventory parameters necessitated by the combination of nonstandard lead-time distributions and autocorrelated demand. Our simulation studies, grounded in the practical need to replenish PPE stocks, demonstrate considerable improvements in both (a) forecast accuracy possible from our approach over extant epidemiological models, and (b) estimation improvement of our nonparametric inventory estimation approach over the extant approaches. We describe the detailed implementation of these methods under the aegis of the JIATF and discuss the relevance of our results beyond the COVID-19 pandemic to other public health emergencies and supply chain settings. History: This paper was refereed. Funding: This project was partially supported by the National Institutes of Health (NIH) National Institute of General Medical Sciences [Grant 2U54GM104942-02]. [ABSTRACT FROM AUTHOR]

Background Drug resistance testing aids in appropriate antiretroviral therapy selection to improve treatment success but may not be readily available. We evaluated the impact of switching to dolutegravir/lamivudine (DTG/3TC) using pooled data from the TANGO and SALSA trials in adults who were virologically suppressed with or without historical resistance results at screening. Methods Adults who were virologically suppressed (HIV-1 RNA <50 copies/mL for >6 months) with no prior virologic failure were randomized to switch to DTG/3TC (TANGO, n = 369; SALSA, n = 246) or continue their current antiretroviral regimen (CAR; TANGO, n = 372; SALSA, n = 247). Week 48 HIV-1 RNA ≥50 and <50 copies/mL (Snapshot algorithm, Food and Drug Administration; intention-to-treat exposed), CD4+ cell count, and safety were analyzed by availability of historical resistance results. Results Overall, 294 of 615 (48%) participants in the DTG/3TC group and 277 of 619 (45%) participants in the CAR group had no historical resistance results at screening. At week 48, proportions with Snapshot HIV-1 RNA ≥50 copies/mL were low (≤1.1%) and similar across treatment groups and by historical resistance results availability. High proportions (91%–95%) maintained virologic suppression through week 48, regardless of results availability. Across both subgroups of results availability, greater increases in CD4+ cell count from baseline to week 48 occurred with DTG/3TC vs CAR. No participants taking DTG/3TC had confirmed virologic withdrawal, regardless of historical resistance results availability. One participant undergoing CAR without historical resistance results had confirmed virologic withdrawal; no resistance was detected. Overall, DTG/3TC was well tolerated; few adverse events led to withdrawal. Conclusions Findings support DTG/3TC as a robust switch option for adults who are virologically suppressed with HIV-1 and no prior virologic failure, regardless of historical resistance results availability. Clinical trial registration TANGO: NCT03446573, https://clinicaltrials.gov/study/NCT03446573. SALSA: NCT04021290, https://clinicaltrials.gov/study/NCT04021290 [ABSTRACT FROM AUTHOR]

New long-acting HIV treatment products have the potential to change the HIV epidemic in the United States and globally. Phase 3 clinical trials of HIV treatments tend to underrepresent populations bearing a disproportionate burden of the HIV epidemic—including women, racial minorities, trans and gender-diverse people, older adults, the unhoused, people who inject drugs, those in rural areas, individuals with mental illness, and other marginalized groups. These populations commonly face significant challenges in adhering to daily HIV treatment regimens. Conducting clinical trials of long-acting treatment targeting specific unmet medical needs of these populations can improve understanding of optimal care approaches, broaden the indication for use of long-acting products, and inform treatment guidelines, all of which can influence reimbursement and access policies. Innovative trial designs and programmatic implementation can improve inclusivity for long-acting therapy. This article summarizes discussions of a multistakeholder workshop on study designs for long-acting HIV treatments. [ABSTRACT FROM AUTHOR]

Background: The COVID-19 pandemic has demonstrated the need for efficient and comprehensive, simultaneous assessment of multiple combined novel therapies for viral infection across the range of illness severity. Randomized Controlled Trials (RCT) are the gold standard by which efficacy of therapeutic agents is demonstrated. However, they rarely are designed to assess treatment combinations across all relevant subgroups. A big data approach to analyzing real-world impacts of therapies may confirm or supplement RCT evidence to further assess effectiveness of therapeutic options for rapidly evolving diseases such as COVID-19. Methods: Gradient Boosted Decision Tree, Deep and Convolutional Neural Network classifiers were implemented and trained on the National COVID Cohort Collaborative (N3C) data repository to predict the patients' outcome of death or discharge. Models leveraged the patients' characteristics, the severity of COVID-19 at diagnosis, and the calculated proportion of days on different treatment combinations after diagnosis as features to predict the outcome. Then, the most accurate model is utilized by eXplainable Artificial Intelligence (XAI) algorithms to provide insights about the learned treatment combination impacts on the model's final outcome prediction. Results: Gradient Boosted Decision Tree classifiers present the highest prediction accuracy in identifying patient outcomes with area under the receiver operator characteristic curve of 0.90 and accuracy of 0.81 for the outcomes of death or sufficient improvement to be discharged. The resulting model predicts the treatment combinations of anticoagulants and steroids are associated with the highest probability of improvement, followed by combined anticoagulants and targeted antivirals. In contrast, monotherapies of single drugs, including use of anticoagulants without steroid or antivirals are associated with poorer outcomes. Conclusions: This machine learning model by accurately predicting the mortality provides insights about the treatment combinations associated with clinical improvement in COVID-19 patients. Analysis of the model's components suggests benefit to treatment with combination of steroids, antivirals, and anticoagulant medication. The approach also provides a framework for simultaneously evaluating multiple real-world therapeutic combinations in future research studies. [ABSTRACT FROM AUTHOR]

Purpose: Rural communities are among the most underserved and resource‐scarce populations in the United States. However, there are limited data on COVID‐19 outcomes in rural America. This study aims to compare hospitalization rates and inpatient mortality among SARS‐CoV‐2‐infected persons stratified by residential rurality. Methods: This retrospective cohort study from the National COVID Cohort Collaborative (N3C) assesses 1,033,229 patients from 44 US hospital systems diagnosed with SARS‐CoV‐2 infection between January 2020 and June 2021. Primary outcomes were hospitalization and all‐cause inpatient mortality. Secondary outcomes were utilization of supplemental oxygen, invasive mechanical ventilation, vasopressor support, extracorporeal membrane oxygenation, and incidence of major adverse cardiovascular events or hospital readmission. The analytic approach estimates 90‐day survival in hospitalized patients and associations between rurality, hospitalization, and inpatient adverse events while controlling for major risk factors using Kaplan‐Meier survival estimates and mixed‐effects logistic regression. Findings: Of 1,033,229 diagnosed COVID‐19 patients included, 186,882 required hospitalization. After adjusting for demographic differences and comorbidities, urban‐adjacent and nonurban‐adjacent rural dwellers with COVID‐19 were more likely to be hospitalized (adjusted odds ratio [aOR] 1.18, 95% confidence interval [CI], 1.16‐1.21 and aOR 1.29, CI 1.24‐1.1.34) and to die or be transferred to hospice (aOR 1.36, CI 1.29‐1.43 and 1.37, CI 1.26‐1.50), respectively. All secondary outcomes were more likely among rural patients. Conclusions: Hospitalization, inpatient mortality, and other adverse outcomes are higher among rural persons with COVID‐19, even after adjusting for demographic differences and comorbidities. Further research is needed to understand the factors that drive health disparities in rural populations. [ABSTRACT FROM AUTHOR]