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.

Overreporting of adherence to hepatitis C direct-acting antiviral therapy and sustained virologic response among people who inject drugs in the HERO study.

BACKGROUND: Self-reported adherence to direct-acting antivirals (DAAs) to treat hepatitis C virus (HCV) among persons who inject drugs (PWID) is often an overreport of objectively measured adherence. The association of such overreporting with sustained virologic response (SVR) is understudied. This study among PWID aimed to determine a threshold of overreporting adherence that optimally predicts lower SVR rates, and to explore correlates of the optimal overreporting threshold. METHODS: This study analyzed per-protocol data of participants with adherence data (N = 493) from the HERO (Hepatitis C Real Options) study. Self-reported and objective adherence to a 12-week DAA regimen were measured using visual analogue scales and electronic blister packs, respectively. The difference (Δ) between self-reported and objectively measured adherence was calculated. We used the Youden index based on receiver operating characteristic (ROC) curve analysis to identify an optimal threshold of overreporting for predicting lower SVR rates. Factors associated with the optimal threshold of overreporting were identified by comparing baseline characteristics between participants at/above versus those below the threshold. RESULTS: The self-reported, objective, and Δ adherence averages were 95.1% (SD = 8.9), 75.9% (SD = 16.3), and 19.2% (SD = 15.2), respectively. The ≥ 25% overreporting threshold was determined to be optimal. The SVR rate was lower for ≥ 25% vs. < 25% overreporting (86.7% vs. 95.8%, p <.001). The factors associated with ≥ 25% Δ adherence were unemployment; higher number of days and times/day of injecting drugs; higher proportion of positive urine drug screening for amphetamine, methamphetamine, and oxycodone, and negative urine screening for THC (tetrahydrocannabinol)/cannabis. CONCLUSIONS: Self-reported DAA adherence was significantly greater than objectively measured adherence among PWID by 19.2%. Having ≥ 25% overreported adherence was associated with optimal prediction of lower SVR rates. PWID with risk factors for high overreporting may need to be more intensively managed to promote actual adherence.

Broadening and strengthening the health providers caring for patients with chronic hepatitis C may improve continuity of care.

BACKGROUND: Direct-acting antiviral (DAA) therapies for hepatitis C virus infection (HCV) lead to excellent rates of sustained virological response (SVR). However, loss to follow-up (LTFU) for SVR testing remains a challenge. We examine factors associated with LTFU in a real-world setting. METHODS: Adults who received DAA therapy for HCV in one of 26 centers across Australia during 2016-2021 were followed up for 2 years. Data sources included the patient medical records and the national Pharmaceutical and Medicare Benefits Schemes. Linkage to Medicare provided utilization data of other health-care providers and re-treatment with DAAs. LTFU was defined as no clinic attendance for SVR testing by at least 52 weeks after DAA treatment commencement. Multivariable logistic regression assessed factors associated with LTFU. RESULTS: In 3619 patients included in the study (mean age 52.0 years; SD = 10.5), 33.6% had cirrhosis (69.4% Child-Pugh class B/C), and 19.3% had HCV treatment prior to the DAA era. Five hundred and fifteen patients (14.2%) were LTFU. HCV treatment initiation in 2017 or later (adj-OR = 2.82, 95% confidence interval [CI] 2.25-3.54), younger age (adj-OR = 2.63, 95% CI 1.80-3.84), Indigenous identification (adj-OR = 1.99, 95% CI 1.23-3.21), current injection drug use or opioid replacement therapy (adj-OR = 1.66, 95% CI 1.25-2.20), depression treatment (adj-OR = 1.49, 95% CI 1.17-1.90), and male gender (adj-OR = 1.31, 95% CI 1.04-1.66) were associated with LTFU. CONCLUSIONS: These findings stress the importance of strengthening the network of providers caring for patients with HCV. In particular, services targeting vulnerable groups of patients such as First Nations Peoples, youth health, and those with addiction and mental health disorders should be equipped to treat HCV.

Hepatitis C treatment outcomes for Australian First Nations Peoples: equivalent SVR rate but higher rates of loss to follow-up.

BACKGROUND: First Nations Peoples of Australia are disproportionally affected by hepatitis C (HCV) infection. Through a prospective study we evaluated the outcome of direct-acting antiviral (DAA) therapy among First Nations Peoples with HCV infection. METHODS: Adults who initiated DAA therapy at one of 26 hospitals across Australia, 2016-2019 were included in the study. Clinical data were obtained from medical records and the Pharmaceutical and Medicare Benefits Schemes. Outcomes included sustained virologic response (SVR) and loss to follow-up (LTFU). A multivariable analysis assessed factors associated with LTFU. RESULTS: Compared to non-Indigenous Australians (n = 3206), First Nations Peoples (n = 89) were younger (p < 0.001), morel likely to reside in most disadvantaged (p = 0.002) and in regional/remote areas (p < 0.001), and had similar liver disease severity. Medicines for mental health conditions were most commonly dispensed among First Nations Peoples (55.2% vs. 42.8%; p = 0.022). Of 2910 patients with follow-up data, both groups had high SVR rates (95.3% of First Nations Peoples vs. 93.2% of non-Indigenous patients; p = 0.51) and 'good' adherence (90.0% vs. 86.9%, respectively; p = 0.43). However, 28.1% of First Nations Peoples were LTFU vs. 11.2% of non-Indigenous patients (p < 0.001). Among First Nations Peoples, younger age (adj-OR = 0.93, 95% CI 0.87-0.99) and treatment initiation in 2018-2019 vs. 2016 (adj-OR = 5.14, 95% CI 1.23-21.36) predicted LTFU, while higher fibrosis score was associated with better engagement in HCV care (adj-OR = 0.71, 95% CI 0.50-0.99). CONCLUSIONS: Our data showed that First Nations Peoples have an equivalent HCV cure rate, but higher rates of LTFU. Better strategies to increase engagement of First Nations Peoples with HCV care are needed.

Oral Zinc Supplementation Decreases the Risk of HCC Development in Patients With HCV Eradicated by DAA.

We have reported that the plasma zinc concentration gradually decreases with the progression of fibrosis and is related to hepatocellular carcinoma (HCC) development. The aim of this study was to examine the impact of the zinc concentration on HCC development (study 1) and the relationship between zinc intake and HCC development (study 2) in patients with hepatitis C virus (HCV) eradicated by direct-acting antivirals (DAAs). A total of 599 sustained virological response (SVR) patients treated with DAAs without a history of HCC were retrospectively analyzed in this study. Eighty patients received supplemental zinc (Zn treatment group), and 519 patients did not receive zinc (no Zn treatment group). In study 1, the cumulative incidence rate of HCC was compared between the Zn treatment group and the no Zn treatment group. In study 2, the risk factors for HCC development were examined in the no Zn treatment group. In study 1, in the Zn treatment group, HCC did not develop during follow-up, and the cumulative risk of HCC was significantly lower in the Zn treatment group than in the no Zn treatment group (P = 0.048). In study 2, the 1-year and 3-year cumulative incidence rates of HCC were 1.8% and 5.6%, respectively. The risk factors for HCC identified by multivariate analysis were male sex, cirrhosis, low platelet count before treatment, and low serum zinc concentration 12 weeks after the end of DAA therapy. Conclusion: The Zn concentration is related to HCC development in patients with HCV eradicated by DAA therapy. Oral zinc supplementation is recommended as a means of suppressing HCC development in patients who have achieved SVR.

Possible correlation between increased serum free carnitine levels and increased skeletal muscle mass following HCV eradication by direct acting antivirals.

We aimed to evaluate factors associated with changes in skeletal muscle mass in hepatitis C virus (HCV)-infected patients after treatment with direct-acting antivirals (DAAs). Consecutive HCV-infected patients after treatment with DAA were recruited into the study. Patients who achieved sustained virological response (SVR); and had complete clinical information, preserved serum samples at baseline and SVR48, and skeletal muscle mass evaluations based on the psoas muscle mass index (PMI) on computed tomography at baseline and ≥ 12 months were included. Altogether, 70.7% of patients (41/58) showed increased PMI after DAA therapy, and mean relative PMI was significantly higher after DAA therapy than at baseline. There were no significant associations between baseline clinical factors routinely examined in clinical practice and increased PMI. Among factors reported to be associated with skeletal muscle loss in patients with chronic liver disease, serum zinc levels and total and free carnitine levels increased significantly after DAA therapy and only changes in serum free carnitine levels were significantly associated with an increased PMI (r = 0305, P = 0.020). In conclusion, increased skeletal muscle mass after successful HCV eradication by DAAs was significantly associated with increased serum-free carnitine levels. L-carnitine supplementation may be beneficial in patients with low skeletal muscle mass after DAA.

Integrated treatment of hepatitis C virus infection among people who inject drugs: A multicenter randomized controlled trial (INTRO-HCV).

BACKGROUND: The standard pathways of testing and treatment for hepatitis C virus (HCV) infection in tertiary healthcare are not easily accessed by people who inject drugs (PWID). The aim of this study was to evaluate the efficacy of integrated treatment of chronic HCV infection among PWID. METHODS AND FINDINGS: INTRO-HCV is a multicenter, randomized controlled clinical trial. Participants recruited from opioid agonist therapy (OAT) and community care clinics in Norway over 2017 to 2019 were randomly 1:1 assigned to the 2 treatment approaches. Integrated treatment was delivered by multidisciplinary teams at opioid agonist treatment clinics or community care centers (CCCs) for people with substance use disorders. This included on-site testing for HCV, liver fibrosis assessment, counseling, treatment, and posttreatment follow-up. Standard treatment was delivered in hospital outpatient clinics. Oral direct-acting antiviral (DAA) medications were administered in both arms. The study was not completely blinded. The primary outcomes were time-to-treatment initiation and sustained virologic response (SVR), defined as undetectable HCV RNA 12 weeks after treatment completion, analyzed with intention to treat, and presented as hazard ratio (HR) and odds ratio (OR) with 95% confidence intervals. Among 298 included participants, 150 were randomized to standard treatment, of which 116/150 (77%) initiated treatment, with 108/150 (72%) initiating within 1 year of referral. Among those 148 randomized to integrated care, 145/148 (98%) initiated treatment, with 141/148 (95%) initiating within 1 year of referral. The HR for the time to initiating treatment in the integrated arm was 2.2 (1.7 to 2.9) compared to standard treatment. SVR was confirmed in 123 (85% of initiated/83% of all) for integrated treatment compared to 96 (83% of initiated/64% of all) for the standard treatment (OR among treated: 1.5 [0.8 to 2.9], among all: 2.8 [1.6 to 4.8]). No severe adverse events were linked to the treatment. CONCLUSIONS: Integrated treatment for HCV in PWID was superior to standard treatment in terms of time-to-treatment initiation, and subsequently, more people achieved SVR. Among those who initiated treatment, the SVR rates were comparable. Scaling up of integrated treatment models could be an important tool for elimination of HCV. TRIAL REGISTRATION: ClinicalTrials.gov.no NCT03155906.

Decentralisation, integration, and task-shifting in hepatitis C virus infection testing and treatment: a global systematic review and meta-analysis.

BACKGROUND: Increasing access to hepatitis C virus (HCV) care and treatment will require simplified service delivery models. We aimed to evaluate the effects of decentralisation and integration of testing, care, and treatment with harm-reduction and other services, and task-shifting to non-specialists on outcomes across the HCV care continuum. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, WHO Global Index Medicus, and conference abstracts for studies published between Jan 1, 2008, and Feb 20, 2018, that evaluated uptake of HCV testing, linkage to care, treatment, cure assessment, and sustained virological response at 12 weeks (SVR12) in people who inject drugs, people in prisons, people living with HIV, and the general population. Randomised controlled trials, non-randomised studies, and observational studies were eligible for inclusion. Studies with a sample size of ten or less for the largest denominator were excluded. Studies were categorised according to the level of decentralisation: full (testing and treatment at same site), partial (testing at decentralised site and referral elsewhere for treatment), or none. Task-shifting was categorised as treatment by specialists or non-specialists. Data on outcomes across the HCV care continuum (linkage to care, treatment uptake, and SVR12) were pooled using random-effects meta-analysis. FINDINGS: Our search identified 8050 reports, of which 132 met the eligibility criteria, and an additional ten reports were identified from reference citations and grey literature. Therefore, the final synthesis included 142 studies from 34 countries (20 [14%] studies from low-income and middle-income countries) and a total of 489 996 patients (239 446 [49%] from low-income and middle-income countries). Rates of linkage to care were higher with full decentralisation compared with partial or no decentralisation among people who inject drugs (full 72% [95% CI 57-85] vs partial 53% [38-67] vs none 47% [11-84]) and among people in prisons (full 94% [79-100] vs partial 50% [29-71]), although the CIs overlap for people who inject drugs. Similarly, treatment uptake was higher with full decentralisation compared with partial or no decentralisation (people who inject drugs: full 73% [65-80] vs partial 66% [55-77] vs none 35% [23-48]; people in prisons: full 72% [48-91] vs partial 39% [17-63]), although CIs overlap for full versus partial decentralisation. The results in the general population studies were more heterogeneous. SVR12 rates were high (≥90%) across different levels of decentralisation in all populations. Task-shifting of care and treatment to a non-specialist was associated with similar SVR12 rates to treatment delivered by specialists. There was a severe or critical risk of bias for 46% of studies, and heterogeneity across studies tended to be very high (I2>90%). INTERPRETATION: Decentralisation and integration of HCV care to harm-reduction sites or primary care showed some evidence of improved access to testing, linkage to care, and treatment, and task-shifting of care and treatment to non-specialists was associated with similarly high cure rates to care delivered by specialists, across a range of populations and settings. These findings provide support for the adoption of decentralisation and task-shifting to non-specialists in national HCV programmes. FUNDING: Unitaid.

Potential challenges to sustained viral load suppression in the HIV treatment programme in South Africa: a narrative overview.

BACKGROUND: South Africa, with one of the highest HIV prevalences in the world, introduced the universal test and treat (UTT) programme in September 2016. Barriers to sustained viral suppression may include drug resistance in the pre-treated population, non-adherence, acquired resistance; pharmacokinetics and pharmacodynamics, and concurrent use of alternative treatments. OBJECTIVE: The purpose of this review is to highlight potential challenges to achieving sustained viral load suppression in South Africa (SA), a major expectation of the UTT initiative. METHODOLOGY: Through the PRISMA approach, published articles from South Africa on transmitted drug resistance; adherence to ARV; host genetic factors in drug pharmacokinetics and pharmacodynamics, and interactions between ARV and herbal medicine were searched and reviewed. RESULTS: The level of drug resistance in the pre-treated population in South Africa has increased over the years, although it is heterogeneous across and within Provinces. At least one study has documented a pre-treated population with moderate (> 5%) or high (> 15%) levels of drug resistance in eight of the nine Provinces. The concurrent use of ARV and medicinal herbal preparation is fairly common in SA, and may be impacting negatively on adherence to ARV. Only few studies have investigated the association between the genetically diverse South African population and pharmacokinetics and pharmacodynamics of ARVs. CONCLUSION: The increasing levels of drug resistant viruses in the pre-treated population poses a threat to viral load suppression and the sustainability of first line regimens. Drug resistance surveillance systems to track the emergence of resistant viruses, study the burden of prior exposure to ARV and the parallel use of alternative medicines, with the goal of minimizing resistance development and virologic failure are proposed for all the Provinces of South Africa. Optimal management of the different drivers of drug resistance in the pre-treated population, non-adherence, and acquired drug resistance will be beneficial in ensuring sustained viral suppression in at least 90% of those on treatment, a key component of the 90-90-90 strategy.

Expanding the epidemiological understanding of hepatitis C in South Africa: Perspectives from a patient cohort in a rural town.

BACKGROUND: The epidemiology of hepatitis C virus (HCV) in the general population of South Africa (SA) is incompletely understood. A high HCV prevalence in key populations is known, but data are limited in terms of a broader understanding of transmission risks in our general population. OBJECTIVES: To investigate a patient cohort with HCV infection clustering in a rural SA town, in order to identify possible HCV transmission risks, virological characteristics, phylogenetic data and treatment outcomes. METHODS: A cluster of patients with positive HCV serology, previously identified from laboratory records, were contacted by a local district hospital and offered confirmatory testing for HCV viraemia where needed. Those with confirmed HCV RNA were invited to a local hospital visit, where relevant demographic information was recorded, clinical assessment performed and a confidential questionnaire administered. HCV population-based sequencing was performed on HCV NS3/4A, NS5A and NS5B using polymerase chain reaction-specific or M13 universal primers, and sequences were aligned using BioEdit 7.2.5. Phylogenetic trees were constructed. Clinical assessments included liver fibrosis determination with FibroScan (cut-off ≥12.5 kPa = F4). Patients were offered treatment, and sustained virological response (SVR) was confirmed by undetectable HCV RNA at least 12 weeks after the end of treatment. RESULTS: Twenty-one patients, all from the same town, median (interquartile range (IQR)) age 64 (59 - 70) years, 57% female, were evaluated. Of these, 24% (n=5) were HIV co-infected, stable on antiretrovirals. The median (IQR) alanine aminotransferase level was 51 (31 - 89) U/L, with fibrosis distribution including 29% F1, 29% F2, 9% F3 and 33% F4 METAVIR fibrosis. Virologically, two genotypes were observed: 62% (n=13) genotype (GT) 1b and 38% (n=8) GT5a. No patient had ever used injecting drugs, 14% (n=3) had received blood products before 1992, and 9.5% (n=2) had undergone traditional healer-administered scarification. All (n=21) reported attendance at a single primary care clinic in the past, with most (n=20) recalling having received parenteral therapies at the clinic. Phylogenetic analysis of the HCV NS5A and NS5B regions confirmed GT1b and GT5a genotypes and formed two separate clusters within their respective genotypes, suggesting a common source for each genotype infection. Most patients received treatment with sofosbuvir/daclatasvir, 1 was treated with sofosbuvir/velpatasvir, and 1 was re-treated with sofosbuvir/velpatasvir/voxilaprevir. Per protocol SVR was 95%, with the non-SVR patient successfully re-treated. CONCLUSIONS: Data from a rural town cluster of patients suggest parenteral medical exposure as the probable common source of hepatitis C transmission risk. The cohort was of older age with a significant number having advanced fibrosis or cirrhosis, suggesting HCV acquisition in the distant past. Using a simplified care approach, treatment outcomes were very good.

Opportunistic treatment of hepatitis C virus infection (OPPORTUNI-C): study protocol for a pragmatic stepped wedge cluster randomized trial of immediate versus outpatient treatment initiation among hospitalized people who inject drugs.

BACKGROUND: Scaled-up direct-acting antiviral (DAA) treatment of hepatitis C virus (HCV) infection among people who inject drugs (PWID) is crucial to reach the World Health Organization HCV elimination targets within 2030. One of the critical obstacles to HCV care in this population is the lack of treatment models within specialist healthcare adapted to marginalized individuals. METHODS: OPPORTUNI-C is a pragmatic stepped wedge cluster randomized trial comparing the efficacy of immediate initiation of HCV treatment with the current standard of care among PWID admitted for inpatient care. Screening for HCV RNA will be performed as soon as possible after admission. The intervention includes immediate non-invasive liver disease assessment, counseling, and initiation of pan-genotypic DAA treatment with individualized follow-up. Standard of care is a referral to outpatient care at discharge. To mimic usual clinical practice as closely as possible, we will use a pragmatic clinical trial approach utilizing clinical infrastructure, broad eligibility criteria, flexible intervention delivery, clinically relevant outcomes, and collection of data readily available from the electronic patient files. The stepped wedge design involves a sequential rollout of the intervention over 16 months, in which seven participating clusters will be randomized from standard of care to intervention in a stepwise manner. Randomization will be stratified according to cluster size to keep high prevalence clusters separated. The trial will include approximately 220 HCV RNA positive individuals recruited from departments of internal medicine, addiction medicine, and psychiatry at Akershus University Hospital, Oslo University Hospital, and Lovisenberg Diaconal Hospital, Oslo, Norway. Individuals not able or willing to give informed consent and those with ongoing HCV assessment or treatment will be excluded. The primary outcome is treatment completion, defined as dispensing of the final prescribed DAA package from the pharmacy within 6 months after inclusion. Secondary outcomes include treatment uptake, virologic response, reinfection incidence, and resistance-associated substitutions. DISCUSSION: Representing a novel model of care suited to reach and engage marginalized PWID in HCV care, this study will inform HCV elimination efforts locally and internationally. If the model proves efficacious and feasible, it should be considered for broader implementation, replacing the current standard of care. TRIAL REGISTRATION: ClinicalTrials.gov, NCT04220645. Registered on 7 January 2020.

Geographically Focused Collocated Hepatitis C Screening and Treatment in Los Angeles's Skid Row.

BACKGROUND: The inequitable prevalence of hepatitis C (HCV) in the homeless is a clinical and public health concern. Prior research estimates, at least one-quarter of homeless persons have been infected with HCV, yet linkage to care and treatment uptake remains marginal. AIM: To evaluate the feasibility of treating HCV in a homeless population. METHODS: Retrospective study of homeless individuals treated for HCV. Demographic information including risk factors was collected. Univariate analyses were performed. The proportion of patients linked to care and sustained viral response at 12 weeks post-treatment (SVR12) was measured. RESULTS: During the study period, 6767 individuals were screened for HCV. A total of 769 (11.4%) were found to have detectable HCV antibodies. Of the individuals with detectable HCV antibodies, 443 (57.6%) were viremic. Of the 443 viremic patients, 375 (84.7%) were linked to care. Among them, 59 patients began antiviral treatment and 95% (56/59) completed the course of therapy. The ITT was 83.1% (49/59), and the per-protocol virologic cure rate was 100% (49/49). CONCLUSION: The favorable linkage to care and cure outcomes in our study suggests that homeless persons may be more likely to engage in HCV screening and treatment when these services are located in the community for their use. Our study further lends support to the efficacy of care coordination programs to encourage movement through the HCV care continuum in vulnerable populations.

Role of zinc supplementation in the management of chronic liver diseases: A systematic review and meta-analysis.

INTRODUCTION AND OBJECTIVES: Zinc deficiency has been associated with poor prognosis in chronic liver disease. This systematic review and meta-analysis aimed to evaluate the role of zinc supplementation in the management of chronic liver diseases. MATERIALS AND METHODS: We searched MEDLINE, LILACS, EMBASE, and Cochrane CENTRAL databases from inception to August 2018. We included randomized controlled trials evaluating adult patients with chronic liver disease of any etiology receiving zinc supplementation. Studies with other designs or evaluating chronic conditions other than liver disease were excluded. Two reviewers independently screened and extracted data from eligible studies. Study quality was assessed using the Cochrane Collaboration's tool for assessing risk of bias in randomized studies. RESULTS: Of 1315 studies screened, 13 were included. Six assessed chronic hepatitis C treatment, with a relative risk of 0.83 indicating no protective effect of zinc supplementation on the improvement of sustained virological response. Three evaluated response to hepatic encephalopathy treatment, with a relative risk of 0.66 indicating a favorable effect of zinc supplementation on clinical improvement of this condition. Of four studies evaluating the management of cirrhosis, two analyzed the effect of zinc supplementation on serum albumin levels, with no statistical difference between zinc and placebo groups. CONCLUSIONS: Clinical trials assessing zinc supplementation in liver diseases do not show benefits in terms of clinical improvement or disease halting. There are possible benefits of zinc supplementation on hepatic encephalopathy, however, this is based on limited evidence. This research question is still open for evaluation in larger, well-designed, clinical trials.

Outcomes of Direct-Acting Antiviral Treatment of Psychiatric Patients with Comorbid Hepatitis C Virus Infection.

BACKGROUND: The highest burden of hepatitis C virus (HCV) infection is seen in patients with psychiatric disorders who have been excluded from traditional treatments with Interferon due to treatment-emergent neuropsychiatric adverse effects. The goal of this study is to determine the tolerability, treatment retention, and efficacy of direct-acting antivirals with psychiatric disorders and comorbid substance use disorders in real-life settings. METHODS: This is a retrospective cohort observational study of HCV patients treated with direct-acting antivirals between January 2016 and December 2018. Patients were stratified and sub-stratified based on their psychiatric diagnosis and substance use. The primary assessment was the sustained virologic response at 12 weeks post-treatment (SVR12). RESULTS: Among the 291 patients analyzed, patients with psychiatric diagnosis and non-psychiatric patients made up 51.2% (n = 149) and 48.8% (n = 142) respectively. Majority of the patients included in the study were African-Americans (68.7%, n = 200). Overall, 95.3% (142/149) and 94.4% (134/142) of psychiatric and non-psychiatric patients, respectively, achieved SVR12 and treatment response was similar between the groups (p = 0.72). Among psychiatric patients, only the prior treatment status was identified as a predictor of treatment response (OR 0.153, 95% CI 0.03-0.79; p = 0.05). No statistical difference was observed among the patients with SVR12 based on their primary psychiatric diagnoses or by comorbid substance abuse. CONCLUSION: The results of our study show that direct-acting antiviral treatments are well tolerated in psychiatric patients, and an overwhelming majority of patients achieved SVR12. Our study highlights the need to integrate HCV screening with treatment linkage in psychiatry and primary care practice.

Lack of impact of protease inhibitor resistance-associated mutations on the outcome of HIV-1-infected patients switching to darunavir-based dual therapy.

Background: Little is known about the impact of baseline resistance-associated mutations (RAMs) on the outcomes of alternative therapeutic strategies such as dual regimens. We assessed the efficacy of boosted darunavir plus raltegravir (DRV + RAL) dual regimen as a simplification strategy in virologically suppressed patients with protease inhibitors RAMs.Methods: Retrospective, multicentre study on the evolution of 228 heavily pretreated patients who switched to boosted DRV + RAL according to genotypic sensitivity score (GSS). Patients were classified as full susceptible (GSS = 2; n = 177), or with reduced darunavir susceptibility (GSS < 2; n = 51).Results: Median (range) number of prior antiretroviral regimens was 9 (6-14), with a median (range) of 2 (1-3), 4 (3-6), and 5 (2-9) major mutations to non-nucleoside reverse transcriptase inhibitors, nucleoside reverse transcriptase inhibitors, and protease inhibitors, respectively. The median time of virological suppression before simplification was 49 months (IQR 39.8-63.5). Patients with reduced darunavir GSS showed a higher number of protease inhibitors-RAMs (9.3 vs 4.5, p < .01) and were suppressed for longer time (median, 61 months). At week 96, the rate of virological failure was low (two cases, 0.9%; 95% confidence interval, CI, 0.4-2.7%), and the efficacy, excluding non-virological reasons, was 96.8% (95%CI, 90.2-98.4%), without differences according to GSS or protease inhibitors-RAMs. Furthermore, significant improvements in CD4+ counts and CD4/CD8 ratio were observed (p < .01) in both groups.Conclusions: Treatment simplification to a dual regimen of boosted DRV + RAL after long-term virological suppression was not associated with a high risk of treatment failure, even in patients harbouring protease inhibitors-resistant HIV infection.

Integrated treatment of hepatitis C virus infection among people who inject drugs: study protocol for a randomised controlled trial (INTRO-HCV).

BACKGROUND: A large proportion of people who inject drugs (PWID) living with hepatitis C virus (HCV) infection have not been treated. It is unknown whether inclusion of HCV diagnostics and treatment into integrated substance use disorder treatment and care clinics will improve uptake and outcome of HCV treatment in PWID. The aim is to assess the efficacy of integrating HCV treatment to PWID and this paper will present the protocol for an ongoing trial. METHODS: INTRO-HCV is a multicentre, randomised controlled clinical trial that will compare the efficacy of integrated treatment of HCV in PWID with the current standard treatment. Integrated treatment includes testing for HCV, assessing liver fibrosis with transient elastography, counselling, treatment delivery, follow-up and evaluation provided by integrated substance use disorder treatment and care clinics. Most of these clinics for PWID provide opioid agonist therapy while some clinics provide low-threshold care without opioid agonist therapy. Standard care involves referral to further diagnostics, treatment and treatment follow-up given in a hospital outpatient clinic with equivalent medications. The differences between the delivery platforms in the two trial arms involve use of a drop-in approach rather than specific appointment times, no need for additional travelling, less blood samples taken during treatment, and treatment given from already known clinicians. The trial will recruit approximately 200 HCV infected individuals in Bergen and Stavanger, Norway. The primary outcomes are time to treatment initiation and sustained virologic response, defined as undetectable HCV RNA 12 weeks after end of treatment. Secondary outcomes are cost-effectiveness, treatment adherence, changes in quality of life, fatigue and psychological well-being, changes in drug use, infection related risk behaviour, and risk of reinfection. The target group is PWID with HCV diagnosed receiving treatment and care within clinics for PWID. DISCUSSION: This study will inform on the effects of an integrated treatment program for HCV in clinics for PWID compared to standard care aiming to increase access to treatment and improving treatment adherence. If the integrated treatment model is found to be safe and efficacious, it can be considered for further scale-up. TRIAL REGISTRATION: ClinicalTrials.gov.no. NCT03155906.

Sustained virologic response with 6 weeks or less of direct-acting antiviral therapy for chronic hepatitis C: Experience at a veterans affairs healthcare system.

BACKGROUND AND AIM: Duration of treatment for chronic hepatitis C infection has been shortened since the introduction of highly effective direct-acting antivirals (DAAs). Presented is our experience in successful treatment of veterans with chronic hepatitis C infection, with a shorter than currently recommended duration of therapy. METHODS: Retrospective chart review of veterans with chronic hepatitis C infection who received more than 1 week and up to 6 weeks (8-42 days) of DAA therapy with the initiation day between January 1, 2015, and October 15, 2018, at Bay Pines Veterans Affairs Healthcare System. Successful treatment was defined by a sustained virologic response at 12 weeks (SVR-12) since the end of treatment. RESULTS: Of the 1841 veterans treated, 27 met the criteria for this review. Overall, SVR-12 was achieved in 92.6% of veterans treated for a duration of more than 1 week and up to 6 weeks. Amongst those who completed only 4 weeks of therapy, 93.3% achieved SVR-12. All four veterans (100%) treated for a duration of more than 4 weeks and up to 6 weeks achieved SVR-12. CONCLUSIONS: Amongst the chronically infected hepatitis C population, a subpopulation who could achieve SVR with a shorter course of treatment than currently recommended does exist. A prospective study of a larger scale will likely provide helpful data in this regard. Our findings could be an impetus for further work.

Integrated care for methadone maintenance patients with hepatitis C virus infection.

The majority of patients undergoing methadone maintenance treatment (MMT) are neither examined nor treated for hepatitis C virus (HCV) infection. We aimed to evaluate an integrated referral model in the management of HCV among MMT patients. This retrospective study included 390 HCV-infected MMT patients between April 2015 and May 2017. Patients who tested positive for HCV antibodies were referred to a liver clinic by MMT case managers or psychiatrists. Patients who agreed to receive anti-HCV treatment were treated with pegylated interferon and ribavirin. The rate of patient engagement at a liver clinic increased from 14.1% to 58.2% after integrated care. Multiple logistic regression analysis showed that higher education level (odds ratio [OR], 1.62; 95% confidence interval [CI], 1.01-2.60) and elevated ALT level (OR, 4.30; 95% CI, 2.70-6.85) were independently associated with patients who accepted referral. Active drug use (OR, 0.52; 95% CI, 0.31-0.85) was inversely associated with referral acceptance. Of the 112 patients who met the criteria for anti-HCV therapy, 66 (58.9%) were treated with pegylated interferon and ribavirin. Finally, the rate of treatment completion and sustained virological response (SVR) was 65.2% and 54.5%, respectively, among the 66 patients. Treatment completion (OR, 39.67; 95% CI, 7.80-201.62) was found to be the only independent factor associated with SVR achievement. Although integrated care by psychiatrists and hepatologists significantly increased the rates of engagement and acceptance of antiviral treatment for HCV-infected MMT patients, only a minority of MMT patients achieved successful treatment.

Hepatitis C treatment uptake and response among human immunodeficiency virus/hepatitis C virus-coinfected patients in a large integrated healthcare system.

U.S. guidelines recommend that patients coinfected with human immunodeficiency virus (HIV) and hepatitis C virus (HCV) be prioritized for HCV treatment with direct-acting antiviral agents (DAAs), but the high cost of DAAs may contribute to disparities in treatment uptake and outcomes. We evaluated DAA initiation and effectiveness in HIV/HCV-coinfected patients in a U.S.-based healthcare system during October 2014-December 2017. Of 462 HIV/HCV-coinfected patients, 276 initiated DAAs (70% cumulative proportion treated over three years). Lower likelihood of DAA initiation was observed among patients with Medicare (government-sponsored insurance) versus commercial insurance (adjusted rate ratio [aRR] = 0.62, 95% CI = 0.46-0.84), patients with drug abuse diagnoses (aRR = 0.72, 95% CI = 0.54-0.97), patients with CD4 cell count <200 cells/µl versus ≥500 (aRR = 0.45, 95% CI = 0.23-0.91), and patients without prior HCV treatment (aRR = 0.68, 95% CI = 0.48-0.97). There were no significant differences in DAA initiation by age, gender, race/ethnicity, socioeconomic status, HIV transmission risk, alcohol use, smoking, fibrosis level, HIV RNA levels, antiretroviral therapy use, hepatitis B infection, or number of outpatient visits. Ninety-five percent of patients achieved sustained virologic response (SVR). We found little evidence of sociodemographic disparities in DAA initiation among HIV/HCV-coinfected patients, and SVR rates were high. Efforts are needed to increase DAA uptake among coinfected Medicare enrollees, patients with drug abuse diagnoses, patients with low CD4 cell count, and patients receiving first-time HCV treatment.

Integrated care of severe infectious diseases to people with substance use disorders; a systematic review.

BACKGROUND: Various integrated care models have been used to improve treatment completion of medications for chronic hepatitis B virus (HBV), chronic hepatitis C virus (HCV), Mycobacterium tuberculosis (TB), and Human immunodeficiency virus (HIV) among people with substance use disorders (SUD). We have conducted a systematic review to evaluate whether integrated models have impacts of the treatment of infectious diseases among marginalized people with SUD. METHODS: We searched MEDLINE/PubMed (1946 to 2018, on July 26, 2018) and Embase (from 1974 to 2018, on July 26, 2018) for randomized controlled trials (RCTs) and cohort studies evaluating diverse integrated models' effects on sustained virological response (SVR), HIV suppression, HBV curation or suppression, completion of TB treatment regimen among people with SUD. The included studies were assessed qualitatively. RESULTS: Altogether, 1640 studies, and references to 1135 related reviews and RCTs were considered, and only seven RCTs and three cohort studies fulfilled the inclusion criteria. We identified nine integrated care models. Two studies, one RCT and one cohort study, showed a significant effect of their integrated models. The RCT evaluated psychosocial treatment, opioid agonist treatment (OAT) and directly observed TB treatment, and found a significant increase in TB treatment completions among intervention group compared to control group (60% versus 13%, p < 0.01). The cohort study including OAT and TB treatments had an effect on TB treatment completion in hospitalized patients (89% versus 73%, p = 0.03). Eight out of ten studies showed no significant effects of their integrated care models on defined outcomes. One of which having included 363 participants in a RCT showed no effect on SVR compared to the control group when the results adjusted for active substance use and alcohol dependence in a post-hoc analysis (11% versus 7%, p = 0.49). CONCLUSIONS: The findings indicate uncertainty on the effects of integrated care models' on treatment for severe infectious diseases among people with SUD. Some studies point toward that integrated models could improve care of people with SUD, yet high-quality studies and preferably, sufficiently sized clinical trials are needed to conclude on the degree of impact.