The State of Hepatitis C Elimination from the Front Lines: A Qualitative Study of Provider-Perceived Gaps to Treatment Initiation.

BACKGROUND: Hepatitis C (HCV) is a curable chronic infection, but lack of treatment uptake contributes to ongoing morbidity and mortality. State and national strategies for HCV elimination emphasize the pressing need for people with HCV to receive treatment. OBJECTIVE: To identify provider-perceived barriers that hinder the initiation of curative HCV treatment and elimination of HCV in the USA. APPROACH: Qualitative semi-structured interviews with 36 healthcare providers who have evaluated patients with HCV in New York City, Western/Central New York, and Alabama. Interviews, conducted between 9/2021 and 9/2022, explored providers' experiences, perceptions, and approaches to HCV treatment initiation. Transcripts were analyzed using hybrid inductive and deductive thematic analysis informed by established health services and implementation frameworks. KEY RESULTS: We revealed four major themes: (1) Providers encounter professional challenges with treatment provision, including limited experience with treatment and perceptions that it is beyond their scope, but are also motivated to learn to provide treatment; (2) providers work toward building streamlined and inclusive practice settings-leveraging partnerships with experts, optimizing efficiency through increased access, adopting inclusive cultures, and advocating for integrated care; (3) although at times overwhelmed by patients facing socioeconomic adversity, increases in public awareness and improvements in treatment policies create a favorable context for providers to treat; and (4) providers are familiar with the relative advantages of improved HCV treatments, but the reputation of past treatments continues to deter elimination. CONCLUSIONS: To address the remaining barriers and facilitators providers experience in initiating HCV treatment, strategies will need to expand educational initiatives for primary care providers, further support local infrastructures and integrated care systems, promote public awareness campaigns, remove prior authorization requirements and treatment limitations, and address the negative reputation of outdated HCV treatments. Addressing these issues should be considered priorities for HCV elimination approaches at the state and national levels.

Care Integration for Hepatitis C Virus Treatment Through Facilitated Telemedicine Within Opioid Treatment Programs: Qualitative Study.

BACKGROUND: Telemedicine has the potential to remove geographic and temporal obstacles to health care access. Whether and how telemedicine can increase health care access for underserved populations remains an open question. To address this issue, we integrated facilitated telemedicine encounters for the management of hepatitis C virus (HCV), a highly prevalent condition among people with opioid use disorder (OUD), into opioid treatment programs (OTPs). In New York State, OTPs are methadone-dispensing centers that provide patient-centered, evidence-based treatment for OUD. We investigated the integration and impact of facilitated telemedicine into OTP workflows in these settings. OBJECTIVE: This study aims to understand OTP staff experiences with integrating facilitated telemedicine for HCV treatment into OTPs, including best practices and lessons learned. METHODS: We conducted semistructured interviews with 45 OTP staff members (13 clinical, 12 administrative, 6 physicians, and 14 support staff members) at least one year after the implementation of facilitated telemedicine for HCV management. We used hermeneutic phenomenological analysis to understand OTP staff experiences. RESULTS: We identified 4 overarching themes illustrating the successful integration of facilitated telemedicine for HCV care into OTPs. First, integration requires an understanding of the challenges, goals, and values of the OTP. As OTP staff learned about new, highly effective HCV therapies, they valued an HCV cure as a "win" for their patients and were excited about the potential to eliminate a highly prevalent infectious disease. Second, the integration of facilitated telemedicine into OTPs fosters social support and reinforces relationships between patients and OTP staff. OTP staff appreciated the ability to have "eyes on" patients during telemedicine encounters to assess body language, a necessary component of OUD management. Third, participants described high levels of interprofessional collaboration as a care team that included the blurring of lines between disciplines working toward a common goal of improving patient care. Study case managers were integrated into OTP workflows and established communication channels to improve patient outcomes. Fourth, administrators endorsed the sustained and future expansion of facilitated telemedicine to address comorbidities. CONCLUSIONS: OTP staff were highly enthusiastic about facilitated telemedicine for an underserved population. They described high levels of collaboration and integration comparable to relevant integrative frameworks. When situated within OTPs, facilitated telemedicine is a high-value application of telemedicine that provides support for underserved populations necessary for high-quality health care. These experiences support sustaining and scaling facilitated telemedicine in comparable settings and evaluating its ability to address other comorbidities. TRIAL REGISTRATION: ClinicalTrials.gov NCT02933970; https://clinicaltrials.gov/study/NCT02933970.

Trust but Verify: Lessons Learned for the Application of AI to Case-Based Clinical Decision-Making From Postmarketing Drug Safety Assessment at the US Food and Drug Administration.

Adverse drug reactions are a common cause of morbidity in health care. The US Food and Drug Administration (FDA) evaluates individual case safety reports of adverse events (AEs) after submission to the FDA Adverse Event Reporting System as part of its surveillance activities. Over the past decade, the FDA has explored the application of artificial intelligence (AI) to evaluate these reports to improve the efficiency and scientific rigor of the process. However, a gap remains between AI algorithm development and deployment. This viewpoint aims to describe the lessons learned from our experience and research needed to address both general issues in case-based reasoning using AI and specific needs for individual case safety report assessment. Beginning with the recognition that the trustworthiness of the AI algorithm is the main determinant of its acceptance by human experts, we apply the Diffusion of Innovations theory to help explain why certain algorithms for evaluating AEs at the FDA were accepted by safety reviewers and others were not. This analysis reveals that the process by which clinicians decide from case reports whether a drug is likely to cause an AE is not well defined beyond general principles. This makes the development of high performing, transparent, and explainable AI algorithms challenging, leading to a lack of trust by the safety reviewers. Even accounting for the introduction of large language models, the pharmacovigilance community needs an improved understanding of causal inference and of the cognitive framework for determining the causal relationship between a drug and an AE. We describe specific future research directions that underpin facilitating implementation and trust in AI for drug safety applications, including improved methods for measuring and controlling of algorithmic uncertainty, computational reproducibility, and clear articulation of a cognitive framework for causal inference in case-based reasoning.

Integrated Hepatitis C-Opioid Use Disorder Care Through Facilitated Telemedicine: A Randomized Trial.

Importance: Facilitated telemedicine may promote hepatitis C virus elimination by mitigating geographic and temporal barriers. Objective: To compare sustained virologic responses for hepatitis C virus among persons with opioid use disorder treated through facilitated telemedicine integrated into opioid treatment programs compared with off-site hepatitis specialist referral. Design, Setting, and Participants: Prospective, cluster randomized clinical trial using a stepped wedge design. Twelve programs throughout New York State included hepatitis C-infected participants (n = 602) enrolled between March 1, 2017, and February 29, 2020. Data were analyzed from December 1, 2022, through September 1, 2023. Intervention: Hepatitis C treatment with direct-acting antivirals through comanagement with a hepatitis specialist either through facilitated telemedicine integrated into opioid treatment programs (n = 290) or standard-of-care off-site referral (n = 312). Main Outcomes and Measures: The primary outcome was hepatitis C virus cure. Twelve programs began with off-site referral, and every 9 months, 4 randomly selected sites transitioned to facilitated telemedicine during 3 steps without participant crossover. Participants completed 2-year follow-up for reinfection assessment. Inclusion criteria required 6-month enrollment in opioid treatment and insurance coverage of hepatitis C medications. Generalized linear mixed-effects models were used to test for the intervention effect, adjusted for time, clustering, and effect modification in individual-based intention-to-treat analysis. Results: Among 602 participants, 369 were male (61.3%); 296 (49.2%) were American Indian or Alaska Native, Asian, Black or African American, multiracial, or other (ie, no race category was selected, with race data collected according to the 5 standard National Institutes of Health categories); and 306 (50.8%) were White. The mean (SD) age of the enrolled participants in the telemedicine group was 47.1 (13.1) years; that of the referral group was 48.9 (12.8) years. In telemedicine, 268 of 290 participants (92.4%) initiated treatment compared with 126 of 312 participants (40.4%) in referral. Intention-to-treat cure percentages were 90.3% (262 of 290) in telemedicine and 39.4% (123 of 312) in referral, with an estimated logarithmic odds ratio of the study group effect of 2.9 (95% CI, 2.0-3.5; P < .001) with no effect modification. Observed cure percentages were 246 of 290 participants (84.8%) in telemedicine vs 106 of 312 participants (34.0%) in referral. Subgroup effects were not significant, including fibrosis stage, urban or rural participant residence location, or mental health (anxiety or depression) comorbid conditions. Illicit drug use decreased significantly (referral: 95% CI, 1.2-4.8; P = .001; telemedicine: 95% CI, 0.3-1.0; P < .001) among cured participants. Minimal reinfections (n = 13) occurred, with hepatitis C virus reinfection incidence of 2.5 per 100 person-years. Participants in both groups rated health care delivery satisfaction as high or very high. Conclusions and Relevance: Opioid treatment program-integrated facilitated telemedicine resulted in significantly higher hepatitis C virus cure rates compared with off-site referral, with high participant satisfaction. Illicit drug use declined significantly among cured participants with minimal reinfections. Trial Registration: ClinicalTrials.gov Identifier: NCT02933970.

Hepatitis C Virus Elimination Programs in Louisiana and Washington: Importance of Screening and Surveillance Systems.

The US government has established a national goal of hepatitis C virus (HCV) elimination by 2030. To date, most HCV elimination planning and activity have been at the state level. Fifteen states presently have publicly available HCV elimination plans. In 2019, Louisiana and Washington were the first states to initiate 5-year funded HCV elimination programs. These states differ on motivation for pursuing HCV elimination and ranking on several indicators. Simultaneously, however, they have emphasized several similar elimination components including HCV screening promotion through public awareness, screening expansion, surveillance enhancement (including electronic reporting and task force development), and harm reduction. The 13 other states with published elimination plans have proposed the majority of the elements identified by Louisiana and Washington, but several have notable gaps. Louisiana's and Washington's comprehensive plans, funding approaches, and programs provide a useful framework that can move states and the nation toward HCV elimination.

Facilitated telemedicine for hepatitis C virus: Addressing challenges for improving health and life for people with opioid use disorder.

BACKGROUND: People who use drugs (PWUD) frequently delay or avoid obtaining medical care in traditional healthcare settings. Through a randomized controlled trial, we investigated facilitated telemedicine for hepatitis C virus (HCV) integrated into opioid treatment programmes. We sought to understand the experiences and meanings of facilitated telemedicine and an HCV cure among PWUD. METHODS: We utilized purposive sampling to interview 25 participants, 6-40 months after achieving an HCV cure. We interpreted and explicated common meanings of participants' experiences of an HCV cure obtained through facilitated telemedicine. RESULTS: Participants embraced facilitated telemedicine integrated into opioid treatment programmes as patient-centred care delivered in 'safe spaces' (Theme 1). Participants elucidated their experiences of substance use and HCV while committing to treatment for both entities. Facilitated telemedicine integrated into opioid treatment programmes enabled participants to avoid stigma encountered in conventional healthcare settings (Theme 2). Participants conveyed facing negative perceptions of HCV and substance use disorder. Improved self-awareness, acquired through HCV and substance use treatment, enabled participants to develop strategies to address shame and stigma (Theme 3). An HCV cure, considered by PWUD as a victory over a lethal infectious disease, promotes self-confidence, enabling participants to improve their health and lives (Theme 4). CONCLUSIONS: Integrating facilitated telemedicine into opioid treatment programmes addresses several healthcare barriers for PWUD. Similarly, obtaining an HCV cure increases their self-confidence, permissive to positive lifestyle changes and mitigating the negative consequences of substance use. PATIENT AND PUBLIC CONTRIBUTION: In this study of patient involvement, we interviewed patient-participants to understand the meaning of an HCV cure through facilitated telemedicine. Participants from a facilitated telemedicine pilot study provided essential input on the design and outcomes of a randomized controlled trial. Pilot study participants endorsed facilitated telemedicine in a testimonial video. They attended site initiation meetings to guide trial implementation. A Patient Advisory Committee (PAC) ensured that patient participants were active members of the research team. The PAC represented patients' voices through feedback on study procedures. A Sustainability Committee supported public involvement in the research process, including educational opportunities, feedback on implementation, and future sustainability considerations.

Scaling and Sustaining Facilitated Telemedicine to Expand Treatment Access Among Underserved Populations: A Qualitative Study.

Background: Opioid treatment programs are an essential component of the management of opioid use disorder (OUD). They have also been proposed as "medical homes" to expand health care access for underserved populations. We utilized telemedicine as a method to increase access for hepatitis C virus (HCV) care among people with OUD. Methods: We interviewed 30 staff and 15 administrators regarding the integration of facilitated telemedicine for HCV into opioid treatment programs. Participants provided feedback and insight for sustaining and scaling facilitated telemedicine for people with OUD. We utilized hermeneutic phenomenology to develop themes related to telemedicine sustainability in opioid treatment programs. Results: Three themes emerged on sustaining the facilitated telemedicine model: (1) Telemedicine as a Technical Innovation in Opioid Treatment Programs, (2) Technology Transcending Space and Time, and (3) COVID-19 Disrupting the Status Quo. Participants identified skilled staff, ongoing training, technology infrastructure and support, and an effective marketing campaign as key to maintaining the facilitated telemedicine model. Participants highlighted the study-supported case manager's role in managing the technology to transcend temporal and geographical challenges for HCV treatment access for people with OUD. COVID-19 fueled changes in health care delivery, including facilitated telemedicine, to expand the opioid treatment program's mission as a medical home for people with OUD. Conclusions: Opioid treatment programs can sustain facilitated telemedicine to increase health care access for underserved populations. COVID-19-induced disruptions promoted innovation and policy changes recognizing telemedicine's role in expanding health care access to underserved populations. ClinicalTrials.gov Identifier: NCT02933970.

High Satisfaction with Patient-Centered Telemedicine for Hepatitis C Virus Delivered to Substance Users: A Mixed-Methods Study.

Background: While telemedicine may increase health care access for vulnerable populations, data are limited on whether people with opioid use disorder (PWOUD) are satisfied with telemedicine. We assessed PWOUD satisfaction with telemedicine and identified factors that increase telemedicine satisfaction. Methods: We conducted a mixed-methods study among hepatitis C virus (HCV)-infected persons enrolled at 12 opioid treatment programs (OTPs) throughout New York State. Participants successfully completed HCV treatment either through telemedicine integrated into OTPs (N = 238) or through offsite referral (N = 106). We evaluated Patient Satisfaction Questionnaire (PSQ) response scores at the initial and final health care encounters and subsequently interviewed telemedicine study participants (N = 25) to assess their experiences with telemedicine. Results: All participants (N = 344) successfully completed HCV treatment. We observed no differences in PSQ scores between telemedicine and in-person encounters (98.3% and 98.7% of telemedicine participants provided PSQ scores of satisfied or highly satisfied at each timepoint, respectively). Study participants indicated that attributes associated with high telemedicine encounter satisfaction included: (1) communicating study information, (2) gaining trust, and (3) delivering patient-centered care. Participants weighted "General Satisfaction" and "Time Spent with Doctor" higher than "Accessibility and Convenience," and female participants were significantly more satisfied than males. Satisfaction with health care delivery among all participants increased significantly comparing timepoints. Conclusions: Participants were highly satisfied with HCV telemedicine encounters equivalent to in-person encounters. Communication augments trust facilitating delivery of patient-centered care through telemedicine. Participants value empathy and trust with providers over accessibility and convenience. In summary, PWOUD are highly satisfied with the facilitated telemedicine model and value empathetic and trusting providers. ClinicalTrials.gov Identifier: NCT02933970.

Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy.

BACKGROUND: Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection. METHODS: We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S. RESULTS: Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4. CONCLUSIONS: We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.

Age- and risk factor-based serologic screening for Hepatitis C virus among an Urban, high-risk population.

Hepatitis C virus (HCV) screening among individuals born between 1945 and 1965 (ie birth cohort) may augment risk factor-based screening. We assessed HCV seropositivity among injection drug users (IDUs) and birth cohort members from New York City. We assessed HCV risk factors and seropositivity in 7722 participants from community health, HIV prevention, syringe exchange and drug treatment programmes. A total of 26.6% were HCV seropositive, 55.8% were born between 1945 and 1965, and 82.2% had ever injected drugs. Among all participants, HCV seropositivity was higher among IDUs compared to non-IDUs (60.5% versus 7.7%, odds ratio (OR) = 18.5, 95% confidence interval (CI) [16.2, 21.1], P < .0001) and among birth cohort members compared to non-birth cohort members (31.3% versus 22.3%, OR = 1.6, 95%CI [1.4, 1.8], P < .0001). Within the birth cohort, HCV seroprevalence among IDUs was 68.5% versus 11.8%, OR = 16.2, 95%CI [13.7, 19.3]. After adjustment, HCV seroprevalence was higher in IDUs, previously incarcerated, whites (<42 years) and 'other races' (versus blacks), HIV-infected, those who snorted heroin, those with liver disease history, and those who had sex with an HCV-seropositive partner. HCV seroprevalence among IDU, birth cohort members, was considerably higher than among the general population. In this high-risk, urban population, the association between IDU and HCV seropositivity was approximately ten times that between birth cohort membership and HCV seropositivity.

A framework for patient-centered telemedicine: Application and lessons learned from vulnerable populations.

Virtual technologies can facilitate clinical monitoring, clinician-patient interactions, and enhance patient-centered approaches to healthcare delivery. Telemedicine, two-way communication between a healthcare provider and a patient not in the same physical location, emphasizes patient preference and convenience by substituting the transportation of patients with information transfer. We present a framework for implementation of a comprehensive, dynamic, patient-centered telemedicine network deployed in 12 opioid treatment programs (OTP) located throughout New York State (NYS). The program aims to effectively manage hepatitis C virus (HCV) infection via telemedicine with co-administration of HCV and substance use medications. We have found that the Sociotechnical System model with emphasis on patient-centered factors provides a framework for telemedicine deployment and implementation to a vulnerable population. The issue of interoperability between the telemedicine platform and the electronic health record (EHR) system as well as clinical information retrieval for medical decision-making are challenges with implementation of a comprehensive, dynamic telemedicine system. Targeting telemedicine to a vulnerable population requires additional consideration of trust in the security and confidentiality of the telemedicine system. Our contribution is the valuable lessons learned from implementing a comprehensive, dynamic, patient-centered telemedicine system among an OTP network throughout NYS as applied to a vulnerable population that can be generalized to other difficult-to-reach populations.

Integrated, Co-located, Telemedicine-based Treatment Approaches for Hepatitis C Virus Management in Opioid Use Disorder Patients on Methadone.

BACKGROUND: Despite high hepatitis C virus (HCV) prevalence, opioid use disorder (OUD) patients on methadone rarely engage in HCV treatment. We investigated the effectiveness of HCV management via telemedicine in an opioid substitution therapy (OST) program. METHODS: OUD patients on methadone underwent biweekly telemedicine sessions between a hepatologist and physician assistant during the entire HCV treatment course. All pretreatment labs (HCV RNA, genotype, and noninvasive fibrosis assessments) were obtained onsite and direct-acting antivirals were coadministered with methadone using modified directly observed therapy. We used multiple correspondence analysis, least absolute shrinkage and selection operator, and logistic regression to identify variables associated with pursuit of HCV care. RESULTS: Sixty-two HCV RNA-positive patients (24% human immunodeficiency virus [HIV] infected, 61% male, 61% African American, 25.8% Hispanic) were evaluated. All patients were stabilized on methadone and all except 4 were HCV genotype 1 infected. Advanced fibrosis/cirrhosis was present in 34.5% of patients. Of the 45 treated patients, 42 (93.3%) achieved viral eradication. Of 17 evaluated patients who were not treated, 5 were discontinued from the drug treatment program or did not follow up after the evaluation, 2 had HIV adherence issues, and 10 had insurance authorization issues. Marriage and a mental health diagnosis other than depression were the strongest positive predictors of treatment pursuit, whereas being divorced, separated, or widowed was the strongest negative predictor. CONCLUSIONS: HCV management via telemedicine integrated into an OST program is a feasible model with excellent virologic effectiveness. Psychosocial and demographic variables can assist in identification of subgroups with a propensity or aversion to pursue HCV treatment.

Efficacy and safety of glecaprevir/pibrentasvir in patients with chronic HCV infection and psychiatric disorders: An integrated analysis.

Although direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) infection are highly efficacious and safe, treatment initiation is often limited in patients with neuropsychiatric disorders due to concerns over reduced treatment adherence and drug-drug interactions. Here, we report adherence, efficacy, safety and patient-reported outcomes (PROs) from an integrated analysis of registrational studies using the pangenotypic DAA regimen of glecaprevir and pibrentasvir (G/P). Patients with chronic HCV genotypes 1-6 infection with compensated liver disease (with or without cirrhosis) receiving G/P for 8, 12 or 16 weeks were included in this analysis. Patients were classified as having a psychiatric disorder based on medical history and/or co-medications. Primary analyses assessed treatment adherence, efficacy (sustained virologic response at post-treatment week 12; SVR12), safety and PROs. Among 2522 patients receiving G/P, 789 (31%) had a psychiatric disorder with the most common diagnoses being depression (64%; 506/789) and anxiety disorders (27%; 216/789). Treatment adherence was comparably high (>95%) in patients with and without psychiatric disorders. SVR12 rates were 97.3% (768/789; 95% CI = 96.2-98.5) and 97.5% (1689/1733; 95% CI = 96.7-98.2) in patients with and without psychiatric disorders, respectively. Among patients with psychiatric disorders, SVR12 rates remained >96% by individual psychiatric diagnoses and co-medication classes. Overall, most adverse events (AEs) were mild-to-moderate in severity with serious AEs and AEs leading to G/P discontinuation occurring at similarly low rates in both patient populations. In conclusion, G/P treatment was highly efficacious, well-tolerated and demonstrated high adherence rates in patients with chronic HCV infection and psychiatric disorders.

Patient Reaction to Telemedicine for Clinical Management of Hepatitis C Virus Integrated into an Opioid Treatment Program.

Background and Introduction: Virtual integration of hepatitis C virus (HCV) infection management within the opioid treatment program (OTP) through telemedicine may overcome limited treatment uptake encountered when patients are referred offsite. To evaluate the diffusion of telemedicine within the OTP, we conducted a pilot study to assess acceptance of and satisfaction with telemedicine among 45 HCV-infected opioid use disorder (OUD) patients on methadone.Materials and Methods: We administered a modified 11-item telemedicine satisfaction questionnaire after the initial HCV telemedicine evaluation, when initiating HCV treatment, and 3 months post-HCV treatment completion. Among a patient subset, a semistructured interview further assessed issues of participant referral to the telemedicine program as well as convenience and confidentiality with the telemedicine encounters.Results: Patients demonstrated their acceptance of telemedicine-based encounters by referral of additional participants. They highlighted the convenience of on-site treatment with a liver specialist through recognition of the benefit of "one-stop shopping." They also expressed confidence in the privacy and confidentiality of telemedicine encounters.Discussion: In this pilot study, telemedicine appears to be well accepted as a modality for HCV management among OUD patients on methadone. Virtual integration of medical and behavioral therapy through telemedicine warrants further investigation for its use in this population.Conclusions: In this pilot study, we found that a largely racial minority population of substance users grew to accept telemedicine over time with diminished privacy and confidentiality concerns. Telemedicine was well accepted within the OTP community as reflected by participant referral to the program.

Hepatic Pharmacokinetics and Pharmacodynamics With Ombitasvir/Paritaprevir/Ritonavir Plus Dasabuvir Treatment and Variable Ribavirin Dosage.

Background: It is unknown whether ribavirin (RBV) coadministration modifies the early rate of decline of hepatitis C virus (HCV) RNA in the liver versus plasma compartments, specifically. Methods: This partially randomized, open-label, phase 2 study enrolled treatment-naive, noncirrhotic patients with HCV genotype 1a. Patients were randomized 1:1 into Arms A and B, and then enrolled in Arm C. Patients received ombitasvir/paritaprevir/ritonavir plus dasabuvir for 12 weeks with either: no RBV for the first 2 weeks followed by weight-based dosing thereafter (Arm A), weight-based RBV for all 12 weeks (Arm B), or low-dose RBV (600 mg) once daily for all 12 weeks. Fine needle aspiration (FNA) was used to determine HCV RNA decline within liver. Results: Baseline HCV RNA was higher and declined more rapidly in plasma than liver; however, RBV dosing did not impact either median plasma or liver HCV RNA decline during the first 2 weeks of treatment. Liver-to-plasma drug concentrations were variable over time. The most common adverse event was pain associated with FNA. Conclusions: Coadministration of RBV had minimal visible impact on the plasma or liver kinetics of HCV RNA decline during the first 2 weeks of treatment, regardless of RBV dosing.

Paritaprevir and Ritonavir Liver Concentrations in Rats as Assessed by Different Liver Sampling Techniques.

The liver is crucial to pharmacology, yet substantial knowledge gaps exist in the understanding of its basic pharmacologic processes. An improved understanding for humans requires reliable and reproducible liver sampling methods. We compared liver concentrations of paritaprevir and ritonavir in rats by using samples collected by fine-needle aspiration (FNA), core needle biopsy (CNB), and surgical resection. Thirteen Sprague-Dawley rats were evaluated, nine of which received paritaprevir/ritonavir at 30/20 mg/kg of body weight by oral gavage daily for 4 or 5 days. Drug concentrations were measured using liquid chromatography-tandem mass spectrometry on samples collected via FNA (21G needle) with 1, 3, or 5 passes (FNA1, FNA3, and FNA5); via CNB (16G needle); and via surgical resection. Drug concentrations in plasma were also assessed. Analyses included noncompartmental pharmacokinetic analysis and use of Bland-Altman techniques. All liver tissue samples had higher paritaprevir and ritonavir concentrations than those in plasma. Resected samples, considered the benchmark measure, resulted in estimations of the highest values for the pharmacokinetic parameters of exposure (maximum concentration of drug in serum [Cmax] and area under the concentration-time curve from 0 to 24 h [AUC0-24]) for paritaprevir and ritonavir. Bland-Altman analyses showed that the best agreement occurred between tissue resection and CNB, with 15% bias, followed by FNA3 and FNA5, with 18% bias, and FNA1 and FNA3, with a 22% bias for paritaprevir. Paritaprevir and ritonavir are highly concentrated in rat liver. Further research is needed to validate FNA sampling for humans, with the possible derivation and application of correction factors for drug concentration measurements.

Diagnostic accuracy of intracellular uptake rates calculated using dynamic Gd-EOB-DTPA-enhanced MRI for hepatic fibrosis stage.

PURPOSE: To assess the diagnostic accuracy of intracellular uptake rates (Ki ), and other quantitative pharmacokinetic (PK) parameters, for hepatic fibrosis stage; to compare this accuracy with a previously published semiquantitative metric, contrast enhancement index (CEI); and to assess variability of these parameters between liver regions. MATERIALS AND METHODS: This was a case-control study design. Dynamic Gd-EOB-DTPA-enhanced 1.5T magnetic resonance imaging (MRI) was performed prospectively in 22 subjects with varying known stages of hepatic fibrosis. PK parameters and CEI were derived from the whole livers and from three fixed regions of interest (ROIs) in all subjects. Spearman rank correlation coefficients were computed to assess the relationship between fibrosis stages and each parameter. Receiver operating characteristic (ROC) curves were constructed to discriminate severe fibrosis (stages 3-4) from nonsevere fibrosis (stages 0-2). The coefficient of variation (CV) was calculated to assess variability in parameters between ROIs. RESULTS: Ki and fibrosis stage were significantly correlated (R = -0.55, 95% confidence interval [CI] [-0.79, -0.14], P = 0.01). Area under ROC curve (AUC) in distinguishing severe from nonsevere fibrosis for Ki was 0.84 (95% CI [0.65,1.00]), and for CEI was 0.64 (95% CI [0.39, 0.89]) (P = 0.0248). CV for Ki and CEI were 33.4 and 5.8, respectively. The only other parameter in the PK model having significant correlation with fibrosis stage was absolute arterial blood flow (Fa ) (R = -0.48, 95% CI [-0.75,-0.05], P = 0.03). CONCLUSION: Hepatocyte intracellular uptake rate, Ki , derived from dynamic contrast-enhanced MRI, correlates with fibrosis stage and may contribute to a noninvasive biomarker of hepatic fibrosis. LEVEL OF EVIDENCE: 2 J. Magn. Reson. Imaging 2017;45:1177-1185.

Medical and Behavioral Approaches to Engage People Who Inject Drugs Into Care for Hepatitis C Virus Infection.

Direct-acting antivirals for hepatitis C virus infection may revolutionize treatment among persons with substance use disorders. Despite persons with substance use disorders having the highest hepatitis C virus prevalence and incidence, the vast majority have not engaged into care for the infection. Previously, interferon-based treatments, with substantial side effects and the propensity to exacerbate mental health conditions, were major disincentives to pursuit of care for the infection. Direct-acting antivirals with viral eradication rates of >90%, significantly improved side effect profiles, and shorter treatment duration are dramatic improvements over prior treatment regimens that should promote widespread hepatitis C virus care among persons with substance use disorders. The major unmet need is strategies to promote persons with substance use disorders engagement into care for hepatitis C virus. Although physical integration of treatment for substance use and co-occurring conditions has been widely advocated, it has been difficult to achieve. Telemedicine offers an opportunity for virtual integration of behavioral and medical treatments that could be supplemented by conventional interventions such as hepatitis C virus education, case management, and peer navigation. Furthermore, harm reduction and strategies to reduce viral transmission are important to cease reinfection among persons with substance use disorders. Widespread prescription of therapy for hepatitis C virus infection to substance users will be required to achieve the ultimate goal of global virus elimination. Combinations of medical and behavioral interventions should be used to promote persons with substance use disorders engagement into and adherence with direct-acting antiviral-based treatment approaches. Ultimately, either physical or virtual colocation of hepatitis C virus and substance use treatment has the potential to improve adherence and consequently treatment efficacy.

Fibrosis Progression in Patients With Chronic Hepatitis C Virus Infection.

BACKGROUND: Fibrosis progression varies markedly in hepatitis C virus (HCV)-infected individuals. We investigated factors that influence fibrosis progression in chronic HCV infection. METHODS: HCV-infected patients who underwent at least 2 liver biopsies were included in this study. Associations between fibrosis progression and epidemiologic, virologic, and disease-associated factors were analyzed using logistic regression and multistate Markov modeling. RESULTS: We analyzed 936 biopsy specimens obtained from 378 individuals. Mean age (±SD) at first biopsy was 48.3 ± 9.3 years, 59.3% of patients were male, 59.9% were white, and 86.7% were infected with HCV genotype 1. Fibrosis progression and cirrhosis occurred in 57.4% and 5.8%, respectively. Fibrosis progression between the first and last biopsies was associated with lower fibrosis in the first biopsy specimen (P < .001) and with the occurrence of at least 1 flare in the alanine aminotransferase (ALT) level (>200 U/L; P = .007). We found the highest fibrosis progression rate between stages 0 and 1 and the lowest between stages 2 and 3. Increased necroinflammation and higher ALT level were associated with faster progression. HCV genotype 3-infected patients were more likely to progress to cirrhosis (P < .001). CONCLUSIONS: Fibrosis progression in HCV is not linear but varies according to stage, with the highest progression in patients with the lowest fibrosis severity. Patients who experience flares in the ALT level are also more likely to progress.

Intrahepatic and Peripheral CXCL10 Expression in Hepatitis C Virus-Infected Patients Treated With Telaprevir, Pegylated Interferon, and Ribavirin.

UNLABELLED: We assessed peripheral and liver CXCL10 levels in 15 patients treated with telaprevir/pegylated interferon/ribavirin. Induction of peripheral CXCL10 messenger RNA (mRNA) peaked (mean fold-induction [±SD], 3.1 ± 1.9) between treatment hour 6 and day 2, while induction of intrahepatic CXCL10 mRNA peaked (mean fold-induction [±SD], 1.3 ± 0.54) at hour 10 or day 4. Peripheral CXCL10 levels were higher at treatment hour 10 (P = .032) and day 2 (P = .009) in patients with undetectable virus 2 weeks after treatment initiation. Treatment hour 10 (P = .023) and peak (P = .034) intrahepatic CXCL10 levels were also higher in these patients. CXCL10 did not distinguish treatment responders from nonresponders. In conclusion, CXCL10 identified very rapid virological response in patients treated with a direct-acting antiviral. CLINICAL TRIALS REGISTRATION: NCT00892697.