Clinical Research in Hepatology in the COVID-19 Pandemic and Post-Pandemic Era: Challenges and the Need for Innovation.

The severe acute respiratory syndrome coronavirus 2 pandemic has drastically altered all facets of clinical care and research. Clinical research in hepatology has had a rich tradition in several domains, including the discovery and therapeutic development for diseases such as hepatitis B and C and studying the natural history of many forms of chronic liver disease. National Institutes of Health, foundation, and industry funding have provided important opportunities to advance the academic careers of young investigators while they strived to make contributions to the field. Instantaneously, however, all nonessential research activities were halted when the pandemic started, forcing those involved in clinical research to rethink their research strategy, including a shift to coronavirus disease 2019 research while endeavoring to maintain their preexisting agenda. Strategies to maintain the integrity of ongoing studies, including patient follow-up, safety assessments, and continuation of investigational products, have included a shift to telemedicine, remote safety laboratory monitoring, and shipping of investigational products to study subjects. As a revamp of research is being planned, unique issues that face the research community include maintenance of infrastructure, funding, completion of studies in the predetermined time frame, and the need to reprogram career path timelines. Real-world databases, biomarker and long-term follow up studies, and research involving special groups (children, the homeless, and other marginalized populations) are likely to face unique challenges. The implementation of telemedicine has been dramatically accelerated and will serve as a backbone for the future of clinical research. As we move forward, innovation in clinical trial design will be essential for conducting optimized clinical research.

Antibody avidity-based approach to estimate population-level incidence of hepatitis C.

BACKGROUND & AIMS: Accurate HCV incidence estimates are critical for monitoring progress towards HCV elimination goals, including an 80% reduction in HCV incidence by 2030. Moreover, incidence estimates can help guide prevention and treatment programming, particularly in the context of the US opioid epidemic. METHODS: An inexpensive, Genedia-based HCV IgG antibody avidity assay was evaluated as a platform to estimate cross-sectional, population-level primary HCV incidence using 1,840 HCV antibody and RNA-positive samples from 875 individuals enrolled in 5 cohort studies in the US and India. Using samples collected <2 years following HCV seroconversion, the mean duration of recent infection (MDRI) was calculated by fitting a maximum likelihood binomial regression model to the probability of appearing recent. Among samples collected ≥2 years post-HCV seroconversion, an individual-level false recent ratio (FRR) was calculated by estimating the probability of appearing recent using an exact binomial test. Factors associated with falsely appearing recent among samples collected ≥2 years post seroconversion were determined by Poisson regression with generalized estimating equations and robust variance estimators. RESULTS: An avidity index cut-off of <40% resulted in an MDRI of 113 days (95% CI 84-146), and FRRs of 0.4% (95% CI 0.0-1.2), 4.6% (95% CI 2.2-8.3), and 9.5% (95% CI 3.6-19.6) among individuals who were HIV-uninfected, HIV-infected, and HIV-infected with a CD4 count <200/µl, respectively. No variation was seen between HCV genotypes 1 and 3. In hypothetical scenarios of high-risk settings, a sample size of <1,000 individuals could reliably estimate primary HCV incidence. CONCLUSIONS: This cross-sectional approach can estimate primary HCV incidence for the most common genotypes. This tool can serve as a valuable resource for program and policy planners seeking to monitor and reduce HCV burden. LAY SUMMARY: Determining the rate of new hepatitis C virus (HCV) infections in a population is critical to monitoring progress toward HCV elimination and to appropriately guide control efforts. However, since HCV infections are most often initially asymptomatic, it is difficult to estimate the rate of new HCV infections without following HCV-uninfected people over time and repeatedly testing them for HCV infection. Here, we present a novel, resource-efficient method to estimate the rate of new HCV infections in a population using data from a single timepoint.

Clinicians' Views of Hepatitis C Virus Treatment Candidacy With Direct-Acting Antiviral Regimens for People Who Inject Drugs.

BACKGROUND: Direct-acting antivirals (DAAs) are curative in most persons with chronic hepatitis C virus (HCV) infection. However, high cost and concerns about adherence and reinfection may present continued barriers to treatment, particularly for people who inject drugs (PWID). OBJECTIVE: To understand changes in assessments of treatment candidacy, given advances in treatment. METHODS: Clinicians attending the Liver Meeting® in 2014 who reported prescribing HCV treatment in the past three years were invited to complete a survey regarding HCV treatment decisions. Participants assessed their likelihood to treat HCV in PWID in association with time of abstinence from injection drug use and what impacts their decision to provide treatment using interferon and DAAs. RESULTS: 108 clinicians completed the survey; 10% were willing to treat an active PWID (last injection within 30 days) using interferon-containing regimens, and 15% with all-oral regimens. For each increasing time interval of injection abstinence, there was an increase in the odds of a clinician reporting willingness to treat with DAAs (Odds Ratio (OR) 2.57, 95% CI 2.18, 3.03) and with interferon-based treatment (OR 2.22 (95% CI 1.90, 2.61), Reinfection and medication cost were cited as most important concerns when determining candidacy. CONCLUSIONS: A cure is now the norm in HCV treatment, and there is an increasing need to address the barriers to treating PWID, the population with the highest burden of infection. Understanding treatment candidacy assessments is essential to improving uptake. This study provides insight into how clinicians view treatment candidacy in this era of DAAs and can help identify supportive treatment environments and concurrent programs.

An on-site community-based model for hepatitis C screening, diagnosis, and treatment among people who inject drugs in Kerman, Iran: The Rostam study.

BACKGROUND: People who inject drugs (PWID) are at high risk for hepatitis C virus (HCV) infection and its complications in many countries, including Iran. This pilot study aimed to evaluate the effect of a community-based HCV model of care on HCV testing and treatment initiation among PWID in Kerman, Iran. METHODS: This study is part of the Rostam study and is a non-randomized trial evaluating the effect of on-site HCV- antibody rapid testing, venipuncture for HCV RNA testing, and treatment eligibility assessment on HCV testing and treatment initiation among PWID. Recruitment, interviews, and HCV screening, diagnosis, and treatment were all conducted at a community-based drop-in center (DIC) serving PWID clients. RESULTS: A total of 171 PWID (median age of 39 years and 89.5% male) were recruited between July 2018 and May 2019. Of 62 individuals who were HCV antibody positive, 47 (75.8%) were HCV RNA positive. Of RNA-positive individuals, 36 (76.6%) returned for treatment eligibility assessment. Of all the 36 participants eligible for treatment, 34 (94.4%) initiated HCV antiviral therapy. A sustained virologic response at 12 weeks post-treatment was 76.5% (26/34) in the intention-to-treat (ITT group) analysis and 100% (23/23) in the per-protocol (PP group) analysis. CONCLUSION: Our integrated on-site community-based HCV care model within a DIC setting suggested that HCV care including HCV testing and treatment uptake can be successfully delivered outside of hospitals or specialized clinics; a model which is more likely to reach PWID and can provide significant progress towards HCV elimination among this population.

Treatment cascade for hepatitis C virus in young adult people who inject drugs in San Francisco: Low number treated.

OBJECTIVE: To understand the number of young adult people who inject drugs (PWID) with hepatitis C virus (HCV) infection accessing direct-acting antiviral (DAA) treatment and their barriers and facilitators to treatment uptake. METHODS: Using prospective cohort data from young adult PWID in San Francisco with newly identified HCV infection, we calculated the number who: (i) accepted referral to DAA therapy, (ii) initiated DAA therapy, (iii) completed DAA therapy, and (iv) achieved sustained virologic response (SVR) or cure. Behavioral survey data identified possible barriers and facilitators to DAA therapy. RESULTS: Of 60 young adult PWID with new HCV infection identified between February 2015 and January 2018, thirty accepted a referral to HCV care; five initiated and completed HCV treatment and achieved cure. Barriers to DAA uptake included fear of medical establishments, competing basic needs, and delaying care because they were feeling well. CONCLUSION: While few HCV-positive young adult PWID engaged in DAA therapy, all those who did achieved cure. Youth-tailored services that overcome the stigma and marginalization related to injection drug use are needed to improve treatment uptake.

Inclusion of special populations in clinical research: important considerations and guidelines.

BACKGROUND: Trials that involve human participants call for experiments or observations that are performed in a clinical research setting. Currently, there are over 16,000 clinical trials open in the United States. Despite continuing efforts to include "special populations" in clinical trials, there are gaps in participation for people who are either minors or elderly adults, are from historically under-represented minorities, or live in rural communities. The inclusion of these special populations in clinical trials research is essential for conclusions that benefit all populations. Data suggest that study partic-ipation rates for special populations have fallen to levels that could endanger the successful performance of some types of research. This is particularly concerning in the 21st century, where demographic trends in the United States continue to shift towards an older and Hispanic population with fewer rural dwellers. Trends in New Mexico and other minority-majority states mirror many of these shifts. RELEVANCE FOR PATIENTS: In this review, we highlight improvement strategies for enhanced clinical trial participation by members of special populations. Key drivers for disparate clinical trials participation and outcomes often include differences in genetics, physiology, and perceptions of mistrust towards researchers. To overcome these barriers, we focus on best practices in recruitment strategies from the perspectives of the participants, the researchers and the institutions that support clinical trials.

Development and validation of a novel scale for measuring interpersonal factors underlying injection drug using behaviours among injecting partnerships.

BACKGROUND: People who inject drugs with sexual partners or close friends have high rates of syringe/ancillary equipment sharing and HIV and hepatitis C virus (HCV) infection. Although evidence suggests that interpersonal factors underlie these higher risk profiles, there is no quantitative measure of how interpersonal factors operate within injecting relationships. We aimed to develop and validate a quantitative scale to assess levels of injecting drug-related interpersonal factors associated with risky injecting behaviours within injecting partnerships. METHODS: We conducted qualitative interviews with 45 people who inject drugs (PWID) who reported having injecting partners to inform item development, and tested these items in a quantitative study of 140 PWID from San Francisco, USA, to assess internal reliability (Cronbach's alpha) and validity (convergent, and discriminant validity). RESULTS: With results from the qualitative interview data, we developed the Interpersonal Dynamics in Injecting Partnerships (IDIP) scale with 54 final items for 5 subscales of injecting-related interpersonal factors. Exploratory factor analysis revealed 5 factors ("trust", "power", "risk perception", "intimacy", and "cooperation") with eigenvalues of 14.32, 6.18, 3.55, 2.46, and 2.14, explaining 57% of the variance, and indicating good internal reliability (alpha: 0.92-0.68). Strong convergent validity was observed in bivariate logistic regression models where higher levels of trust, intimacy, and cooperation within partnerships were positively associated with partners sharing needles and injecting equipment, whereas higher levels of power and risk perception were negatively associated with partners sharing needles and injecting equipment. CONCLUSIONS: These findings offer strong evidence that the IDIP scale provides a psychometrically sound measure of injecting drug-related interpersonal dynamics. This measurement tool has the potential to facilitate additional investigations into the individual and collective impact of trust, intimacy, power, cooperation, and risk perception on injection drug using behaviours and engagement in HIV and HCV testing and treatment among PWID in a variety of settings.

The use of telemedicine to provide pediatric critical care consultations to pediatric trauma patients admitted to a remote trauma intensive care unit: a preliminary report.

OBJECTIVE: Injured pediatric patients in remote communities are often cared for at trauma centers that may be underserved with respect to pediatric specialty services. The objective of this study is to describe a pilot telemedicine project that allows a remote trauma center's adult intensive care unit to obtain nontrauma, nonsurgical-related pediatric critical care consultations for acutely injured children. DESIGN: Nonconcurrent cohort design. SETTING: A remote, level II trauma center's shock-trauma intensive care unit and a tertiary care children's hospital pediatric intensive care unit. PATIENTS: Analyses were conducted on cohorts of pediatric trauma patients (<16 yrs) consecutively admitted to the remote adult intensive care unit, including historical control patients and patients who received and did not receive telemedicine consultations. INTERVENTIONS: Telemedicine consultations were obtained at the discretion of the remote intensive care unit provider for nontrauma, nonsurgical medical issues. MEASUREMENTS AND RESULTS: The Injury Severity Score and Trauma and Injury Severity Score were used to assess severity of injury and predicted mortality rates, respectively, for the patient cohorts. Parental and provider satisfaction with the telemedicine consultations was also described. Thirty-nine consultations were conducted on 17 patients from the 97 pediatric patients admitted during the 2-yr study. Patients who received consultations were younger (5.5 yrs vs. 13.3 yrs, p <.01) and were more severely injured (mean Injury Severity Score = 18.3 vs. 14.7, p =.07). Severity-adjusted mortality rates were consistent with Trauma and Injury Severity Score expectations. Satisfaction surveys suggested a high level of provider and parental satisfaction. CONCLUSIONS: Our report of a trauma intensive care unit based pediatric critical care telemedicine program demonstrates that telemedicine consultations to a remote intensive care unit are feasible and suggests a high level of satisfaction among providers and parents.