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Background: Hepatitis C virus (HCV) continues to cause significant morbidity and mortality within the US, and disproportionately impacts those involved with the criminal justice system. Despite this, knowledge and attitudes regarding HCV treatment among adults on probation have not been well studied. We conducted a cross-sectional survey of adults on probation accessing on-site HCV testing and linkage services at the adult probation department in Denver, Colorado. The survey assessed general knowledge of HCV and HCV treatment, as well as attitudes surrounding HCV treatment that might reflect medical mistrust. We used bivariate and multivariable logistic regression to identify factors associated with previous HCV testing, previous HCV treatment, and HCV antibody positivity at the time the survey was conducted., Results: A total of 402 participants completed all or a portion of the survey. 69% of the participants were cis-gender men; 29% were white, 27% were Black, and 30% were Hispanic/Latinx. Fewer than half of participants correctly identified that HCV infection is commonly asymptomatic (46%), that there is currently no vaccine that prevents HCV (19%), and that reinfection after treatment is possible (47%). Very few participants felt that side-effects (9%) or cost of treatment (10%) were barriers to care. Many participants believed that racial disparities exist in the treatment of HCV (59%). The belief that people who use substances are treated inequitably by health care providers was also commonly reported (35% of participants). Self-reported injection drug use and higher HCV-related knowledge were positively associated with previous testing for HCV. Higher HCV-related knowledge was positively associated with HCV antibody positivity at the time of survey completion, though the magnitude of the association was small., Conclusion: Interventions are needed to increase knowledge of HCV, to improve access to HCV testing and treatment, and to reduce bias associated with HCV and substance use within the probation population., (© 2024. The Author(s).)

Background: Long-term outcome data after hepatitis C virus (HCV) treatment are limited, particularly for comparisons between persons with and without HIV., Methods: A5320 was a prospective cohort study that enrolled participants within 12 months of completing HCV DAA therapy, with or without sustained virologic response (SVR). The primary end point was composite: time to death or development of a targeted diagnosis. Component outcomes (death and targeted diagnosis) and liver-related events were also analyzed. The effects of HIV serostatus, HIV RNA and CD4, and liver disease stage on the outcomes were assessed. Follow-up was designated for 5 years., Results: Three hundred thirty-two participants enrolled: 184 with HIV/HCV (130 SVR) and 148 with HCV (125 SVR). The primary analysis was dominated by targeted diagnoses. Increased rates of targeted diagnoses were seen in HCV-HIV/SVR compared with HCV/SVR ( P = .016), with an incidence rate of 6.7 and 3.4 per 100 person-years, respectively. Among persons without HIV, higher rates of targeted diagnoses were observed in non-SVRs ( P = .007), 10.8 vs 3.4/100 person-years. No significant difference was seen by SVR status among those with HIV. There were 15 deaths; all liver-related deaths (n = 4) occurred in non-SVR groups., Conclusions: HCV cure following therapy reduces subsequent development of new clinical events, supporting the use of SVR as a predictor for clinical outcomes. Despite HIV control, a significant decrease in incident events or mortality was not demonstrated for people with HIV who achieved SVR, suggesting that coinfection attenuates the beneficial impact of SVR. Research is needed to better define mechanisms accounting for the long-term negative impact of controlled HIV infection., Competing Interests: Potential conflicts of interest. D.L.W.: research funds paid to his institution from Gilead Sciences outside the submitted work. M.K., R.L.M., R.M.M., and M.G.P.: no disclosure relevant to the current work., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Hepatitis C (HCV) poses a major public health problem in the USA. While early identification is a critical priority, subsequent linkage to a treatment specialist is a crucial step that bridges diagnosed patients to treatment, cure, and prevention of ongoing transmission. Emergency departments (EDs) serve as an important clinical setting for HCV screening, although optimal methods of linkage-to-care for HCV-diagnosed individuals remain unknown. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Linkage-to-Care Trial., Methods: The DETECT Hep C Linkage-to-Care Trial will be a single-center prospective comparative effectiveness randomized two-arm parallel-group superiority trial to test the effectiveness of linkage navigation and clinician referral among ED patients identified with untreated HCV with a primary hypothesis that linkage navigation plus clinician referral is superior to clinician referral alone when using treatment initiation as the primary outcome. Participants will be enrolled in the ED at Denver Health Medical Center (Denver, CO), an urban, safety-net hospital with approximately 75,000 annual adult ED visits. This trial was designed to enroll a maximum of 280 HCV RNA-positive participants with one planned interim analysis based on methods by O'Brien and Fleming. This trial will further inform the evaluation of cost effectiveness, disparities, and social determinants of health in linkage-to-care, treatment, and disease progression., Discussion: When complete, the DETECT Hep C Linkage-to-Care Trial will significantly inform how best to perform linkage-to-care among ED patients identified with HCV., Trial Registration: ClinicalTrials.gov ID: NCT04026867 Original date: July 1, 2019 URL: https://clinicaltrials.gov/ct2/show/NCT04026867., (© 2023. The Author(s).)

Background: Periodic surveillance of the hepatitis C virus (HCV) care cascade is important for tracking progress toward HCV elimination goals, identifying gaps in care, and prioritizing resource allocation. In the pre-direct-acting antiviral (DAA) era, it was estimated that 50% of HCV-infected individuals were diagnosed and that 16% had been prescribed interferon-based therapy. Since then, few studies utilizing nationally representative data from the DAA era have been conducted in the United States., Methods: We performed a cross-sectional study to describe the HCV care cascade in the United States using the Optum de-identified Clinformatics® Data Mart Database to identify a nationally representative sample of commercially insured beneficiaries between January 1, 2014 and December 31, 2019. We estimated the number of HCV-viremic individuals in Optum based on national HCV prevalence estimates and determined the proportion who had: (1) recorded diagnosis of HCV infection, (2) recorded HCV diagnosis and underwent HCV RNA testing, (3) DAA treatment dispensed, and (4) assessment for cure., Results: Among 120,311 individuals estimated to have HCV viremia in Optum during the study period, 109,233 (90.8%; 95% CI, 90.6%-91.0%) had a recorded diagnosis of HCV infection, 75,549 (62.8%; 95% CI, 62.5%-63.1%) had a recorded diagnosis of HCV infection and underwent HCV RNA testing, 41,102 (34.2%; 95% CI, 33.9%-34.4%) were dispensed DAA treatment, and 25,760 (21.4%; 95% CI, 21.2%-21.6%) were assessed for cure., Conclusions: Gaps remain between the delivery of HCV-related care and national treatment goals among commercially insured adults. Efforts are needed to increase HCV treatment among people diagnosed with chronic HCV infection to achieve national elimination goals., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Despite constituting the largest segment of the correctional population, individuals on court-ordered probation remain largely unstudied with respect to hepatitis C virus (HCV) testing and linkage-to-care. We conducted a retrospective, descriptive analysis to estimate prevalence of diagnosed HCV and the subsequent HCV care cascade among a cohort of individuals enrolled in an adult probation program over a 25-month period in Denver, Colorado., Methods: We utilized probabilistic matching with first and last name, sex, and birthdate to identify individuals enrolled in probation between July 1, 2016 and July 30, 2018 who had a medical record at the participating safety-net healthcare institution as of December 31, 2019. Electronic medical record data were queried for evidence of HCV testing and care through June 30, 2021. The state HCV registry was also queried for prevalence of reported HCV cases among the cohort., Results: This cohort included 8,903 individuals; 6,920 (78%) individuals had a medical record at the participating institution, and of these, 1,037 (15%) had ever been tested for HCV (Ab or RNA) and 308 (4% of those with a medical record, 30% of those tested) had detectable HCV RNA. Of these, 105 (34%) initiated HCV treatment, 89 (29%) had a subsequent undetectable HCV viral load, and 65 (21%) had documentation of HCV cure. Eleven percent of the total cohort had records of positive HCV Ab or RNA tests in the state HCV registry., Conclusions: This study demonstrates the importance of HCV screening and linkage-to-care for individuals enrolled in probation programs. A focus on this population could enhance progress towards HCV elimination goals., (© 2022. The Author(s).)

Direct-acting antivirals (DAAs) achieve high hepatitis C virus (HCV) cure rates and are forgiving to missed doses, but adherence-efficacy relationships have not been well defined. Traditional adherence measures (e.g. pill counts, self-report and pharmacy refills) over-estimate medication adherence. Newer technology-based tools have been used to provide more objective adherence data. Herein, electronic medication diaries (e-diaries), medication events monitoring system (MEMS ® ) caps, electronic blister packs, electronic pill boxes, video-based directly observed therapy (vDOT), artificial intelligence platforms (AIPs), and ingestible sensor systems are described, and compared based on existing studies using DAA. Percent adherence, predictors of adherence, and HCV cure rates utilizing these technologies are included. DAA adherence with e-diaries was 95-96%, MEMS ® caps and ingestible biosensors were between 95% and 97%, blister pack weekly dosing ranged 73-98%, and daily dosing 73-94%, whereas electronic pill boxes ranged between 39% and 89%, vDOT was 98% and AIP 91-96%. Despite a wide range of adherence, high sustained virologic response (SVR) rates (86-100%) were observed across all studies utilizing these different technology-based tools. Current data support the forgiveness of DAA therapies to missed doses using tools that provide more quantitative adherence measures compared with self-report and provide insight on adherence-efficacy relationships for contemporary DAA., Competing Interests: Conflict of interest statement: The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PLA has received consulting fees from Merck and ViiV. The remaining authors declared no conflicts of interest., (© The Author(s), 2022.)

Background: Early identification of HCV is a critical health priority, especially now that treatment options are available to limit further transmission and provide cure before long-term sequelae develop. Emergency departments (EDs) are important clinical settings for HCV screening given that EDs serve many at-risk patients who do not access other forms of healthcare. In this article, we describe the rationale and design of The Determining Effective Testing in Emergency Departments and Care Coordination on Treatment Outcomes (DETECT) for Hepatitis C (Hep C) Screening Trial., Methods: The DETECT Hep C Screening Trial is a multi-center prospective pragmatic randomized two-arm parallel-group superiority trial to test the comparative effectiveness of nontargeted and targeted HCV screening in the ED with a primary hypothesis that nontargeted screening is superior to targeted screening when identifying newly diagnosed HCV. This trial will be performed in the EDs at Denver Health Medical Center (Denver, CO), Johns Hopkins Hospital (Baltimore, MD), and the University of Mississippi Medical Center (Jackson, MS), sites representing approximately 225,000 annual adult visits, and designed using the PRECIS-2 framework for pragmatic trials. When complete, we will have enrolled a minimum of 125,000 randomized patient visits and have performed 13,965 HCV tests. In Denver, the Screening Trial will serve as a conduit for a distinct randomized comparative effectiveness trial to evaluate linkage-to-HCV care strategies. All sites will further contribute to embedded observational studies to assess cost effectiveness, disparities, and social determinants of health in screening, linkage-to-care, and treatment for HCV., Discussion: When complete, The DETECT Hep C Screening Trial will represent the largest ED-based pragmatic clinical trial to date and all studies, in aggregate, will significantly inform how to best perform ED-based HCV screening., Trial Registration: ClinicalTrials.gov ID: NCT04003454 . Registered on 1 July 2019., (© 2022. The Author(s).)

Background: Despite constituting the largest segment of the correctional population, individuals on probation remain largely unstudied with respect to hepatitis C virus (HCV) testing and linkage to care. We implemented an HCV testing and patient navigation program at an adult probation department., Methods: Adults were tested at a local probation department with a rapid point-of-care HCV antibody (Ab) assay followed by a laboratory-based HCV ribonucleic acid (RNA) assay if anti-HCV positive. All individuals received counseling rooted in harm reduction principles. Individuals testing positive for HCV Ab were immediately linked to a patient navigator in person or via telephone. The patient navigator assisted patients through cure unless the patient was lost to follow-up. Study participation involved an optional survey and optional point-of-care human immunodeficiency virus test., Results: Of 417 individuals tested, 13% were HCV Ab positive and 65% of those tested for HCV RNA (34 of 52) had detectable HCV RNA. Of the 14 individuals who linked to an HCV treatment provider, 4 completed treatment, as measured by pharmacy fill documentation in the electronic medical record, and 1 obtained sustained virologic response. One hundred ninety-three individuals tested for HIV; none tested positive., Conclusions: The study cohort had a higher HCV seroprevalence than the general population (13% vs 2%), but linkage to care, completion of HCV treatment, and successful test-of-cure rates were all low. This study indicates that HCV disproportionately impacts adults on probation and prioritizing support for testing and linkage to care could improve health in this population. Colocalization of HCV treatment within probation programs would reduce the barrier of attending a new institution and could be highly impactful., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Functional impairment of interferon, a natural antiviral component of the immune system, is associated with the pathogenesis and severity of COVID-19. We aimed to compare the efficacy of interferon beta-1a in combination with remdesivir compared with remdesivir alone in hospitalised patients with COVID-19., Methods: We did a double-blind, randomised, placebo-controlled trial at 63 hospitals across five countries (Japan, Mexico, Singapore, South Korea, and the USA). Eligible patients were hospitalised adults (aged ≥18 years) with SARS-CoV-2 infection, as confirmed by a positive RT-PCR test, and who met one of the following criteria suggestive of lower respiratory tract infection: the presence of radiographic infiltrates on imaging, a peripheral oxygen saturation on room air of 94% or less, or requiring supplemental oxygen. Patients were excluded if they had either an alanine aminotransferase or an aspartate aminotransferase concentration more than five times the upper limit of normal; had impaired renal function; were allergic to the study product; were pregnant or breast feeding; were already on mechanical ventilation; or were anticipating discharge from the hospital or transfer to another hospital within 72 h of enrolment. Patients were randomly assigned (1:1) to receive intravenous remdesivir as a 200 mg loading dose on day 1 followed by a 100 mg maintenance dose administered daily for up to 9 days and up to four doses of either 44 μg interferon beta-1a (interferon beta-1a group plus remdesivir group) or placebo (placebo plus remdesivir group) administered subcutaneously every other day. Randomisation was stratified by study site and disease severity at enrolment. Patients, investigators, and site staff were masked to interferon beta-1a and placebo treatment; remdesivir treatment was given to all patients without masking. The primary outcome was time to recovery, defined as the first day that a patient attained a category 1, 2, or 3 score on the eight-category ordinal scale within 28 days, assessed in the modified intention-to-treat population, defined as all randomised patients who were classified according to actual clinical severity. Safety was assessed in the as-treated population, defined as all patients who received at least one dose of the assigned treatment. This trial is registered with ClinicalTrials.gov, NCT04492475., Findings: Between Aug 5, 2020, and Nov 11, 2020, 969 patients were enrolled and randomly assigned to the interferon beta-1a plus remdesivir group (n=487) or to the placebo plus remdesivir group (n=482). The mean duration of symptoms before enrolment was 8·7 days (SD 4·4) in the interferon beta-1a plus remdesivir group and 8·5 days (SD 4·3) days in the placebo plus remdesivir group. Patients in both groups had a time to recovery of 5 days (95% CI not estimable) (rate ratio of interferon beta-1a plus remdesivir group vs placebo plus remdesivir 0·99 [95% CI 0·87-1·13]; p=0·88). The Kaplan-Meier estimate of mortality at 28 days was 5% (95% CI 3-7%) in the interferon beta-1a plus remdesivir group and 3% (2-6%) in the placebo plus remdesivir group (hazard ratio 1·33 [95% CI 0·69-2·55]; p=0·39). Patients who did not require high-flow oxygen at baseline were more likely to have at least one related adverse event in the interferon beta-1a plus remdesivir group (33 [7%] of 442 patients) than in the placebo plus remdesivir group (15 [3%] of 435). In patients who required high-flow oxygen at baseline, 24 (69%) of 35 had an adverse event and 21 (60%) had a serious adverse event in the interferon beta-1a plus remdesivir group compared with 13 (39%) of 33 who had an adverse event and eight (24%) who had a serious adverse event in the placebo plus remdesivir group., Interpretation: Interferon beta-1a plus remdesivir was not superior to remdesivir alone in hospitalised patients with COVID-19 pneumonia. Patients who required high-flow oxygen at baseline had worse outcomes after treatment with interferon beta-1a compared with those given placebo., Funding: The National Institute of Allergy and Infectious Diseases (USA)., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Final results from the long-term Viral Hepatitis C Infection Long-term Cohort Study (V-HICS) found low rates of hepatitis C virus (HCV) recurrence after direct-acting antiviral therapy in both HCV/human immunodeficiency virus (HIV)-coinfected (0.67/100 person-years) and HCV-infected (0.2/100 person-years) groups with >500 person-years of follow-up. Confirmed reinfections were in participants with HIV who reported high-risk behaviors., (© The Author(s) 2021. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

At the 2021 Conference on Retroviruses and Opportunistic Infections, there was a focus on progress toward hepatitis C virus (HCV) microelimination in geographic regions and targeted populations. HCV elimination is facilitated by well-tolerated, highly effective HCV treatment that requires essentially no on-treatment monitoring in most patients, as highlighted by the MINMON (Minimal Monitoring Study or A5360) study, and that should be increasingly available to children with new data supporting feasible treatment in younger patients. Challenges to HCV elimination include HCV reinfection via sexual exposure in men who have sex with men (MSM) and continued barriers to diagnosis and access to HCV treatment. Hepatitis B virus (HBV) suppression may take years in HIV/HBV-coinfected patients. This may have important consequences as the risk for hepatocellular carcinoma was associated in a dose-dependent manner with HBV viral load and was lowest in those with sustained undetectable HBV, highlighting the need for HBV DNA monitoring during therapy. Public health programs should prioritize improving hepatitis A and hepatitis B vaccination in at-risk populations, including people with HIV, as vaccinations rates for these preventable diseases continue to be suboptimal in many settings. Fatty liver disease, heavy alcohol use, antiretroviral therapy, and COVID-19 infection were also examined as drivers of hepatic disease in HIV infection.

Background: Ledipasvir/sofosbuvir increases tenofovir plasma exposures by up to 98% with tenofovir disoproxil fumarate (TDF), and exposures are highest with boosted PIs. There are currently no data on the combined use of the newer tenofovir prodrug, tenofovir alafenamide (TAF), boosted PIs and ledipasvir/sofosbuvir., Objectives: To compare the plasma and intracellular pharmacokinetics and renal safety of TAF with ledipasvir/sofosbuvir when co-administered with boosted PIs., Methods: Persons with HIV between 18 and 70 years and on a boosted PI with TDF were eligible. The study was comprised of four phases: (1) TDF 300 mg with boosted PI; (2) TAF 25 mg with boosted PI; (3) TAF 25 mg with boosted PI and ledipasvir/sofosbuvir; and (4) TAF 25 mg with boosted PI. Pharmacokinetic sampling, urine biomarker collection [urine protein (UPCR), retinol binding protein (RBP) and β2 microglobulin (β2M) normalized to creatinine] and safety assessments occurred at the end of each phase. Plasma, PBMCs and dried blood spots were collected at each visit., Results: Ten participants were enrolled. Plasma tenofovir exposures were 76% lower and tenofovir-diphosphate (TFV-DP) concentrations in PBMCs increased 9.9-fold following the switch to TAF. Neither of these measures significantly increased with ledipasvir/sofosbuvir co-administration, nor did TAF plasma concentrations. No significant changes in estimated glomerular filtration rate or UPCR occurred, but RBP:creatinine and β2M:creatinine improved following the switch to TAF., Conclusions: Ledipasvir/sofosbuvir did not significantly increase plasma tenofovir or intracellular TFV-DP in PBMCs with TAF. These findings provide reassurance that the combination of TAF, boosted PIs and ledipasvir/sofosbuvir is safe in HIV/HCV-coinfected populations., (© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Hepatitis C virus (HCV) direct-acting antivirals are highly effective. Less is known about changes in markers of immune activation in persons with human immunodeficiency virus (HIV) in whom a sustained virologic response (SVR) is achieved., Methods: We conducted a nonrandomized clinical trial of 12 or 24 weeks of paritaprevir-ritonavir-ombitasvir plus dasabuvir (PrOD) with or without ribavirin in persons with HCV-1/HIV coinfection suppressed with antiretroviral therapy. Plasma HCV, soluble CD14 (sCD14), interferon-inducible protein 10, soluble CD163 (sCD163), interleukin 6 (IL-6), interleukin 18, monocyte chemoattractant protein (MCP-1), autotaxin (ATX), and Mac2-binding protein (Mac2BP) were measured over 48 weeks., Results: Participants were treated with PrOD for 12 (n = 9) or 24 (n = 36) weeks; the SVR rate at 12 weeks was 93%. At baseline, cirrhosis was associated with higher ATX and MCP-1, female sex with higher ATX and IL-6, older age with higher Mac2BP, higher body mass index with higher ATX, and HIV-1 protease inhibitor use with higher sCD14 levels. In those with SVR, interferon-inducible protein 10, ATX, and Mac2BP levels declined by week 2, interleukin 18 levels declined by the end of treatment, sCD14 levels did not change, and sCD163, MCP-1, and IL-6 levels changed at a single time point., Conclusions: During HIV/HCV coinfection, plasma immune activation marker heterogeneity is in part attributable to age, sex, cirrhosis, body mass index, and/or type of antiretroviral therapy. HCV treatment with paritaprevir-ritonavir-ombitasvir plus dasabuvir is highly effective and is associated with variable rate and magnitude of decline in markers of immune activation., Clinical Trials Registration: NCT02194998., (Published by Oxford University Press for the Infectious Diseases Society of America 2020.)

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., (© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Twenty-seven patients receiving prolonged inpatient antibiotic therapy for a serious bacterial infection received a single dose of dalbavancin 7-10 days before the planned end date to facilitate earlier hospital discharge. Eighty-one percent met criteria for clinical success, 7% experienced a potential adverse event, and 182 hospital days were averted., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Background: Direct-acting anti-virals (DAA) are highly effective for hepatitis C virus (HCV) treatment, but perceived risks of medication non-adherence may restrict access to care. Digital medicine programme (DMP) has improved adherence and outcomes for some conditions., Aims: To conduct a prospective, single-arm, open-label study across the United States to assess the impact of DMP on adherence and efficacy in adults with chronic HCV infection at high risk for non-adherence., Methods: Eligible participants were placed on the DMP to evaluate real-time adherence; primary outcome was sustained virological response (SVR) at ≥10 weeks post-treatment., Results: Between August 2017 and April 2019, 288 participants (Medicaid, 64.9%; psychiatric disorders, 61.1%; homeless, 9.4%) received DAAs for 8-12 weeks (sofosbuvir/velpatasvir or ledipasvir, 45%; glecaprevir/pibrentasvir, 55%). SVR was achieved in 99.1% of 218 participants who had HCV RNA assessed at ≥10 weeks post-treatment; of the 70 participants who did not have SVR assessed, 17 had SVR4 with HCV RNA assessed at a median (IQR; interquartile range) 5.6 weeks (4.1, 7.9) post-treatment; one completed treatment but did not have HCV RNA assessed, and 52 discontinued treatment early without assessment. Overall, the primary analysed participants (n = 218) actively used the DMP for median (range) 92.9% (12.5%, 100%) of their prescribed treatment time, and overall pill-taking adherence was 95.0% (57.1%, 100%). Participants reported the programme was useful and easy to use through satisfaction surveys., Conclusions: HCV treatment with DMP was accepted by patients and clinicians and may support HCV treatment outcomes among patients at high risk for treatment non-adherence (Clinical trials.gov NCT03164902)., (© 2020 John Wiley & Sons Ltd.)

Background: Direct-acting antiviral (DAA) therapies for hepatitis C virus (HCV) result in initial cure rates of 95% to 99% and re-treatment cure rates of 95%. Nevertheless, given the sheer magnitude of infected persons, some will ultimately fail multiple DAA therapies, and re-treatment of these persons has not been adequately studied., Methods: We evaluated treated an HIV-infected man with cirrhosis from genotype 1b HCV who had failed 3 DAA regimens., Results: We treated and cured our "particularly difficult-to-cure" patient with sofosbuvir plus glecaprevir/pibrentasvir plus ribavirin for 24 weeks. We discuss the literature on potential biological factors behind his treatment failures such as lack of HCV seroconversion during his infection course, and multiple failures of hepatitis B seroconversion after vaccination, and the rationale for choosing his curative salvage regimen., Discussion: There are no clinical trials-proven re-treatment regimens for "particularly difficult-to-cure" patients. Multiple patient- and virus-related factors that do not affect cure rates in treatment-naive patients may need to be considered in choosing a re-treatment regimen for these patients. These regimens may need to include combinations drugs that are not available in single-tablet form, addition of ribavirin, and longer durations of treatment than standard., (© The Author(s) 2020. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Aims: AIDS Clinical Trials Group study A5334s evaluated the pharmacokinetics of raltegravir before and during combined administration of ombitasvir, paritaprevir/ritonavir, plus dasabuvir (OBV/PTV/r + DSV) and weight-based ribavirin in human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfected adults. The pharmacokinetics of OBV/PTV/r + DSV during raltegravir coadministration were also characterized., Methods: Adults living with HIV/HCV coinfection receiving steady-state raltegravir (400 mg twice daily) with 2 nucleos(t)ide analogues were enrolled. Pharmacokinetics of raltegravir were assessed prior to HCV therapy, and 4 weeks later following initiation of OBV/PTV/r (25/150/100 mg) once daily + DSV (250 mg) twice daily. Geometric mean ratios (GMRs) and 90% confidence intervals (CIs) were used to compare the following: raltegravir pharmacokinetics with HCV therapy (week 4) vs before HCV therapy (week 0); OBV/PTV/r and DSV pharmacokinetics vs historical healthy controls; raltegravir pharmacokinetics at week 0 vs historical control adults living with HIV., Results: Eight of 11 participants had decreased raltegravir exposures after initiation of HCV therapy. The GMRs (90% CI) for maximum concentration and area under the concentration-time curve of raltegravir with vs without HCV therapy were 0.68 (0.38-1.19) and 0.82 (0.58-1.17), respectively. Comparing OBV/PTV/r pharmacokinetics in healthy controls, A5334s study participants demonstrated generally lower maximum concentration and area under the concentration-time curve values by 41-82% and 4-73%, respectively. Raltegravir exposures tended to be higher in A5334s study participants compared to adults living with HIV., Conclusions: The majority of participants' plasma raltegravir exposures were lower after initiation of HCV therapy in coinfected adults; however, confidence intervals were wide., (© 2019 The British Pharmacological Society.)

Hepatitis B virus (HBV) coinfection is common in persons with human immunodeficiency virus (HIV) infection, contributing significantly to morbidity and mortality. Many currently used HIV antiretroviral therapy (ART) regimens provide potent anti-HBV activity and it is recommended that HBV-HIV coinfected persons be treated with ART regimens containing tenofovir. ART has multiple benefits, including increasing rates of HBV clearance after initial infection and potent suppression of HBV DNA in chronic infection. Nevertheless, long-term studies have yet to demonstrate a profound positive impact of ART on HBV-related fibrosis progression and development of endstage liver disease., (Copyright © 2019 Elsevier Inc. All rights reserved.)

At the 2019 Conference on Retroviruses and Opportunistic Infections (CROI), there was a major focus on hepatitis C virus (HCV) elimination and improving each component of the hepatitis C care cascade. Many interventions showed promising improvements in diagnosis and linkage to care. Settings with robust access to direct-acting antivirals (DAAs) continue to demonstrate the role of HCV treatment as prevention. However, substantial barriers to accessing curative therapy remain. Reinfection after treatment presents an important barrier to elimination, particularly in some populations of men who have sex with men (MSM). MSM without HIV infection are at an elevated risk for sexual acquisition of HCV, and several studies reported HCV rates that were as high as those seen in MSM living with HIV. There was also a focus on HCV and HBV in pregnant women. Rates of HCV infection in women of child-bearing potential have increased, making prenatal diagnosis a priority. In the first study of HCV treatment during pregnancy, sofosbuvir/ledipasvir started at 28 weeks of gestation led to cure in 8 pregnant women. Hepatitis B virus (HBV)-active antiretrovirals are generally effective in suppressing HBV but have low rates of surface antigen loss despite long term treatment. Initial results from novel laboratory assessments of intrahepatic HBV viral infection events were presented, hopefully paving the way for more effective HBV treatment strategies to control and potentially cure HBV.

Glecaprevir coformulated with pibrentasvir (G/P) is approved to treat hepatitis C virus (HCV) infection and was highly efficacious in phase 2 and 3 studies. Treating HCV genotype (GT) 3 infection remains a priority, as these patients are harder to cure and at a greater risk for liver steatosis, fibrosis progression and hepatocellular carcinoma. Data were pooled from five phase 2 or 3 trials that evaluated 8-, 12- and 16-week G/P in patients with chronic HCV GT3 infection. Patients without cirrhosis or with compensated cirrhosis were either treatment-naïve or experienced with interferon- or sofosbuvir-based regimens. Safety and sustained virologic response 12 weeks post-treatment (SVR12) were assessed. The analysis included 693 patients with GT3 infection. SVR12 was achieved by 95% of treatment-naïve patients without cirrhosis receiving 8-week (198/208) and 12-week (280/294) G/P. Treatment-naïve patients with cirrhosis had a 97% (67/69) SVR12 rate with 12-week G/P. Treatment-experienced, noncirrhotic patients had SVR12 rates of 90% (44/49) and 95% (21/22) with 12- and 16-week G/P, respectively; 94% (48/51) of treatment-experienced patients with cirrhosis treated for 16 weeks achieved SVR12. No serious adverse events (AEs) were attributed to G/P; AEs leading to study drug discontinuation were rare (<1%). G/P was well-tolerated and efficacious for patients with chronic HCV GT3 infection, regardless of cirrhosis status or prior treatment experience. Eight- and 12-week durations were efficacious for treatment-naïve patients without cirrhosis and with compensated cirrhosis, respectively; 16-week G/P was efficacious in patients with prior treatment experience irrespective of cirrhosis status., (© 2018 The Authors. Journal of Viral Hepatitis Published by John Wiley & Sons Ltd.)

Background: We evaluated the impact of opioid substitution therapy (OST) on the completion, adherence, efficacy, and safety of the 3-direct-acting antiviral regimen of ombitasvir, paritaprevir (identified by AbbVie and Enanta) co-dosed with ritonavir, and dasabuvir ± ribavirin among patients infected with hepatitis C virus (HCV) genotype (GT) 1, with or without compensated cirrhosis., Methods: Data were pooled from GT1-infected patients enrolled in 12 phase II/III/IIIb clinical trials and categorized by use of OST. Patients with ongoing drug use were excluded. HCV treatment completion, treatment adherence (≥90%), sustained virologic response at post-treatment week 12 (SVR12), and adverse events were assessed., Results: Of 4747 patients, 3% (n = 149) received OST. Among patients receiving OST vs those not receiving OST, 82% (n = 122) vs 52% (n = 2409) had GT1a infection; 76% (n = 113) vs 61% (n = 2792) were treatment naïve; and 17% (n = 25) vs 18% (n = 830) had cirrhosis, respectively. The proportion of patients completing HCV treatment did not differ between those receiving and not receiving OST (97% [n = 144] vs 98% [n = 4510], respectively), whereas adherence to treatment was reduced in patients receiving vs those not receiving OST (88% [n = 105] vs 97% [n = 4057], respectively). SVR12 was similar between patients receiving and not receiving OST (94% [n = 140] vs 96% [n = 4405], respectively; P = .273). Treatment was well tolerated., Conclusions: Although treatment adherence was lower in patients receiving OST vs those not receiving OST, treatment completion and SVR12 were similar between groups. These data support the use of direct-acting antiviral therapies in patients receiving OST.

Hepatitis C virus (HCV) recurrence rates were similar between those with HCV/HIV co-infection (0.35/100 person-years) and HCV infection (0.42/100 person-years). Low rates of recurrence likely represent enrollment of an HIV population at low risk for recurrence. Care should be taken not to label all HCV/HIV co-infected patients as being at high risk for HCV recurrence.

At the 2018 Conference on Retroviruses and Opportunistic Infections (CROI), there was a major focus on hepatitis C virus (HCV) elimination and improving each component of the hepatitis C care cascade. Several countries and cohorts have demonstrated the remarkable impact that universal HCV testing and unrestricted access to hepatitis C treatment can have on markedly reducing incident HCV infections and HCV infection prevalence, including in people who inject drugs and HIV/HCV-coinfected populations. However, in many settings, substantial barriers to widespread HCV treatment remain, including undiagnosed HCV infection, particularly in populations outside the standard "baby boomer" birth cohort (ie, born 1945-1965); restricted access to hepatitis C treatment in those with known HCV infection; reinfection with HCV; and migration of HCV-infected populations. Many innovative programs have successfully implemented HCV testing and treatment outside of traditional care settings, expanding access for harder-to-reach populations, which will be crucial to successful elimination efforts. Outbreaks of hepatitis A virus (HAV) infection continue to occur in among men who have sex with men and homeless populations in the United States, Europe, and Southeast Asia, highlighting the need for improved HAV vaccination programs for populations at risk.

Purpose of Review: This review provides an overview of HCV resistance-associated substitutions (RASs) with a focus on NS3 protease and NS5A inhibitor resistance. Treatment approaches for managing resistance are also covered including the use of newly approved therapies with improved resistance profiles., Recent Findings: HCV RASs are frequently selected if the patient is not cured during treatment; NS5A RASs persist for prolonged periods of time (years) after treatment failure and may adversely impact retreatment responses. Newly approved regimens with improved potency and resistance profiles are less impacted by resistance and provide the best retreatment options for patients who previously failed DAA therapy. The clinical impact of HCV RASs has been lessened significantly with the introduction of new DAA treatment regimens. Routine testing for resistance is unlikely to impact retreatment approaches if newer regimens are accessible. Knowledge of factors, such as the presence of cirrhosis and prior treatment regimens, remain as the key to optimizing retreatment approaches.

Background & Aims: Hepatitis C virus (HCV) therapy that is highly efficacious, pangenotypic, with a high barrier to resistance and short treatment duration is desirable. The efficacy and safety of 8- and 12-week treatments with glecaprevir (ABT-493; NS3/4A protease inhibitor) and pibrentasvir (ABT-530; NS5A inhibitor) were evaluated in non-cirrhotic patients with chronic HCV genotype 1-6 infection., Methods: SURVEYOR-I and SURVEYOR-II were phase II, open-label, multicenter, dose-ranging trials including patients with chronic HCV genotype 1-6 infection who were either previously untreated or treated with pegylated interferon plus ribavirin. Patients received once-daily glecaprevir plus pibrentasvir at varying doses with or without ribavirin for 8 or 12weeks. The primary efficacy endpoint was the percentage of patients with a sustained virologic response at post-treatment week 12 (SVR12)., Results: Of the 449 patients who received varying doses of glecaprevir plus pibrentasvir, 25%, 29%, 39%, and 8% had HCV genotype 1, 2, 3, and 4-6 infection, respectively. Twelve-week treatment achieved SVR12 in 97-100%, 96-100%, 83-94%, and 100% in genotypes 1, 2, 3, and 4-6, respectively. Eight-week treatment with 300mg glecaprevir plus 120mg pibrentasvir in genotype 1-, 2-, or 3-infected patients yielded 97-98% SVR12 with no virologic failures. Three (0.7%) patients discontinued treatment due to adverse events; most events were mild (grade 1) in severity. No post-nadir alanine aminotransferase elevations were observed., Conclusions: Glecaprevir plus pibrentasvir was well tolerated and achieved high sustained virologic response rates in HCV genotypes 1-6-infected patients without cirrhosis following 8- or 12-week treatment durations., Lay Summary: The combination of direct-acting antivirals glecaprevir and pibrentasvir comprise a once-daily, all-oral, pangenotypic treatment for HCV genotype 1-6 infection. This article describes results from two phase II trials investigating a range of doses at treatment durations of 8 or 12weeks in 449 patients without cirrhosis. Efficacy of the optimal dose, as determined by rates of sustained virologic response at post-treatment week 12, ranged from 92%-100%; treatment was well tolerated and significant laboratory abnormalities were rare., Clinical Trial Registration: clinicaltrials.gov Identifiers: NCT02243280 and NCT02243293. http://www.clinicaltrials.gov/show/NCT02243280, http://www.clinicaltrials.gov/show/NCT01939197., (Copyright © 2017. Published by Elsevier B.V.)

Viral resistance to direct-acting antiviral drugs may impact their effectiveness during treatment of hepatitis C virus (HCV) infection. Most data on HCV drug resistance concern genotypes 1 and 3. The clinical impact of resistance to HCV nonstructural protein 5A (NS5A) inhibitors and a practical approach to indications and methods for resistance testing are discussed.

At the 2017 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle, Washington, hepatitis C virus (HCV) infection was a major focus in the context of HIV-associated liver disease. Well-tolerated direct-acting antiviral (DAA) regimens have enabled effective treatment of the populations that are hardest to cure, including those with decompensated cirrhosis, and many studies examined the impact of HCV cure on hepatitis and extrahepatic outcomes. Scaling up access to DAA, and the impact that their universal availability can have on reducing prevalence were key topics. There was much discussion of what is needed to eliminate HCV on local and global levels and a focus on ensuring that the populations hardest to reach can access treatment. Prevention of new infections and reinfection will be key to sustaining the benefits of scaled-up HCV treatment, with particular attention to populations at elevated risk for HCV reinfection, including HIV-infected men who have sex with men (MSM) as well as some HIV-uninfected MSM on preexposure prophylaxis. In the hepatitis B virus (HBV) arena, a landmark phase III trial demonstrated that tenofovir disoproxil fumarate given to HBV-infected pregnant women at week 28 of gestation, in combination with postpartum HBV vaccination and hepatitis B immunoglobulin, resulted in zero mother-to-child transmissions of HBV.

Background & Aims: The combination of ABT-493 (NS3/4A protease inhibitor) plus ABT-530 (NS5A inhibitor) has shown high rates of sustained virologic response at post-treatment week 12 (SVR12) in noncirrhotic patients infected with hepatitis C virus (HCV) genotypes (GTs) 1-6. We describe 2 open-label phase 2 studies investigating the efficacy and safety of ABT-493 plus ABT-530 with or without ribavirin (RBV) in GT1- or GT3-infected patients with compensated cirrhosis., Methods: Patients with GT1 infection received 200 mg ABT-493 plus 120 mg ABT-530 for 12 weeks. Patients with GT3 infection were randomized 1:1 to receive 300 mg ABT-493 plus 120 mg ABT-530 with or without once-daily 800 mg RBV for 12 weeks; treatment-experienced patients who were not treated with RBV received 16 weeks of therapy. Efficacy was measured by SVR12, defined as an HCV-RNA level less than 25 IU/mL. Adverse events and laboratory parameters were evaluated throughout the study., Results: Twenty-seven patients with GT1 infection and 55 patients with GT3 infection were enrolled. The majority were treatment-naive (84%) and male (65%). In patients with GT1 infection, SVR12 was achieved by 96% (26 of 27; 95% confidence interval [CI], 82-99) of patients, with 1 relapse. Among GT3-infected patients, SVR12 was achieved in 96% (27 of 28; 95% CI, 82-99) of patients in the RBV-free arm (1 relapse), and in 100% (27 of 27; 95% CI, 88-100) in the RBV-containing arm. The most common adverse events were headache, fatigue, and nausea. Laboratory abnormalities were rare; no patient discontinued treatment., Conclusions: In cirrhotic HCV GT1- or GT3-infected patients, ABT-493 plus ABT-530 with or without RBV achieved SVR12 rates of 96%-100% and was well tolerated. ClinicalTrials.gov identifiers NCT02243280 and NCT02243293., (Copyright © 2016 AGA Institute. Published by Elsevier Inc. All rights reserved.)

The increased life expectancy of persons infected with human immunodeficiency virus (HIV) treated with antiretroviral therapy (ART) has resulted in renewed attention to non-HIV-related diseases exacerbated by HIV infection. Coinfection with hepatitis C virus (HCV) is a particular area of concern, as the global prevalence has been estimated at 2.5-5 million people. In this article, we discuss the epidemiology of HCV infection and reinfection, HCV-related liver disease progression in the era of effective ART, and the efficacy of emerging HCV treatment strategies in persons with HIV/HCV coinfection. New data regarding treatment of persons with HIV/HCV coinfection suggest that HCV treatment should be a priority in those with HIV. Results from recent studies using all-oral HCV regimens have shown high rates of sustained virologic response in both clinical trials and real-world settings. A multidisciplinary approach to HCV treatment in those with HIV is recommended for optimal patient management. Following HCV cure, practitioners also need to be mindful of the risks for HCV reinfection and educate patients on protective measures., (© The Author 2016. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail journals.permissions@oup.com.)

At the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston, Massachusetts, hepatitis C virus (HCV) infection remained a major theme in the context of HIV-associated liver disease, although other causes of liver disease garnered increased attention, including fatty liver disease, hepatitis B, and the impact of HIV disease itself on the liver. Although no data from phase III studies of HCV direct-acting antiviral (DAA) drugs for the treatment of HIV/HCV coinfection were presented at CROI 2016, a broad range of HCV DAA-related topics were presented, including accumulating experience with real-world performance of DAA-based regimens outside of clinical trials, drug interactions between DAA and antiretroviral drugs, treatment of acute HCV infection, and retreatment of individuals whose DAA-based regimens failed and those in whom resistance to DAA drugs emerged. A summary of select abstracts from CROI 2016 is presented, including discussion of clinical relevance where appropriate and areas for future research.

Background: Effective, pangenotypic treatments for hepatitis C virus (HCV) infection are needed., Objective: To assess the safety and efficacy of sofosbuvir with velpatasvir in patients infected with HCV genotypes 1 to 6., Design: Randomized, phase 2, open-label study. (ClinicalTrials.gov: NCT01858766)., Setting: 48 U.S. sites., Patients: 377 treatment-naive noncirrhotic patients. In part A, patients infected with HCV genotypes 1 to 6 were randomly assigned to sofosbuvir, 400 mg, with velpatasvir, 25 or 100 mg, for 12 weeks. In part B, patients with genotype 1 or 2 HCV infection were randomly assigned to sofosbuvir, 400 mg, and velpatasvir, 25 or 100 mg, with or without ribavirin for 8 weeks., Measurements: Sustained virologic response at 12 weeks (SVR12)., Results: In part A, SVR12 rates were 96% (26 of 27) with velpatasvir, 25 mg, and 100% (28 of 28) with velpatasvir, 100 mg, for genotype 1; 93% (25 of 27) in both groups for genotype 3; and 96% (22 of 23) with velpatasvir, 25 mg, and 95% (21 of 22) with velpatasvir, 100 mg, for genotypes 2, 4, 5, and 6. In part B, for genotype 1, SVR12 rates were 87% (26 of 30) with velpatasvir, 25 mg; 83% (25 of 30) with velpatasvir, 25 mg, plus ribavirin; 90% (26 of 29) with velpatasvir, 100 mg; and 81% (25 of 31) with velpatasvir, 100 mg, plus ribavirin. For genotype 2, SVR12 rates were 77% (20 of 26) with velpatasvir, 25 mg; 88% (22 of 25) with velpatasvir, 25 mg, plus ribavirin; 88% (23 of 26) with velpatasvir, 100 mg; and 88% (23 of 26) with velpatasvir, 100 mg, plus ribavirin. Adverse events included fatigue (21%), headache (20%), and nausea (12%). One patient committed suicide., Limitation: The study was open-label, no inferential statistics were planned, and sample sizes were small., Conclusion: Twelve weeks of sofosbuvir, 400 mg, and velpatasvir, 100 mg, was well-tolerated and resulted in high SVR in patients infected with HCV genotypes 1 to 6., Primary Funding Source: Gilead Sciences.

Hepatitis C virus (HCV) coinfection is prevalent in patients with human immunodeficiency virus (HIV) and has an accelerated disease course. Direct-acting antiviral (DAA) therapies that do not require interferon increase response rates to levels identical to those seen in HCV monoinfection. However, drug-drug interaction between antiretrovirals and HCV medication is the major consideration in deciding on the appropriate HCV therapeutic approach in patients with HIV. This article summarizes the currently available data with HCV DAAs in patients with HIV, and focuses on predicting and managing drug interaction to facilitate successful DAA-based HCV therapy in those with HIV., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Unlabelled: The analysis of inflammatory cytokines and chemokines produced during hepatitis C virus (HCV) infection has advanced our understanding of viral-host interactions and identified predictors of treatment response. Administration of interferons (IFNs) made it difficult to interpret biomarkers of immune activation during treatment. Direct-acting antiviral (DAA) regimens without IFN are now being used to treat HCV with excellent efficacy. To gain insight into HCV-host interactions occurring before, during, and after HCV treatment, we performed a case-control study that measured serial plasma levels of IFN-γ-inducible protein 10 (IP-10), monocyte chemoattractant protein 1 (MCP-1), macrophage inflammatory protein 1 beta (MIP-1β), and interleukin-18 (IL-18) in 131 patients with chronic HCV treated with sofosbuvir (SOF) plus ribavirin (RBV). A linear regression analysis using baseline factors identified strong positive associations between elevated alanine aminotransferase and pretreatment IP-10 and between the presence of cirrhosis and elevated pretreatment IL-18. Mean IP-10, MCP-1, MIP-1β, and IL-18 levels all decline on therapy, but display different dynamics late in treatment and after cessation of therapy. On treatment, IP-10 and MIP-1β levels were significantly higher in individuals who achieved sustained virological response (SVR). Logistic regression analyses examining treatment response in all patients demonstrated significant associations between higher baseline MIP-1β levels and smaller decreases in MIP-1β early in treatment and SVR. Higher early MIP-1β levels were also significantly associated with SVR in subsets of patients with cirrhosis and individuals with genotype 3 (GT3) infection, two factors associated with decreased responsiveness to treatment., Conclusion: Changes in IP-10 levels mirror HCV RNA, suggesting that IP-10 is an indicator of innate immune viral recognition. MIP-1β levels remain elevated in GT2/3 patients who achieved SVR, suggesting differential immune activation in those who respond to SOF/RBV therapy and a potential role in predicting treatment responses., (© 2015 by the American Association for the Study of Liver Diseases.)

Background: The combination of daclatasvir, a hepatitis C virus (HCV) NS5A inhibitor, and the NS5B inhibitor sofosbuvir has shown efficacy in patients with HCV monoinfection. Data are lacking on the efficacy and safety of this combination in patients coinfected with human immunodeficiency virus type 1 (HIV-1)., Methods: This was an open-label study involving 151 patients who had not received HCV treatment and 52 previously treated patients, all of whom were coinfected with HIV-1. Previously untreated patients were randomly assigned in a 2:1 ratio to receive either 12 weeks or 8 weeks of daclatasvir at a standard dose of 60 mg daily (with dose adjustment for concomitant antiretroviral medications) plus 400 mg of sofosbuvir daily. Previously treated patients were assigned to undergo 12 weeks of therapy at the same doses. The primary end point was a sustained virologic response at week 12 after the end of therapy among previously untreated patients with HCV genotype 1 who were treated for 12 weeks., Results: Patients had HCV genotypes 1 through 4 (83% with genotype 1), and 14% had compensated cirrhosis; 98% were receiving antiretroviral therapy. Among patients with genotype 1, a sustained virologic response was reported in 96.4% (95% confidence interval [CI], 89.8 to 99.2) who were treated for 12 weeks and in 75.6% (95% CI, 59.7 to 87.6) who were treated for 8 weeks among previously untreated patients and in 97.7% (95% CI, 88.0 to 99.9) who were treated for 12 weeks among previously treated patients. Rates of sustained virologic response across all genotypes were 97.0% (95% CI, 91.6 to 99.4), 76.0% (95% CI, 61.8 to 86.9), and 98.1% (95% CI, 89.7 to 100), respectively. The most common adverse events were fatigue, nausea, and headache. There were no study-drug discontinuations because of adverse events. HIV-1 suppression was not compromised., Conclusions: Among previously untreated HIV-HCV coinfected patients receiving daclatasvir plus sofosbuvir for HCV infection, the rate of sustained virologic response across all genotypes was 97.0% after 12 weeks of treatment and 76.0% after 8 weeks. (Funded by Bristol-Myers Squibb; ALLY-2 ClinicalTrials.gov number, NCT02032888.).

Background: Sofosbuvir is a chain-terminating nucleotide analogue inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase that is efficacious in subjects with HCV genotype 1-6 infection. Sofosbuvir resistance is primarily conferred by the S282T substitution in NS5B., Methods: NS5B sequencing and susceptibility testing of HCV from subjects infected with genotypes 1-6 who participated in phase 2 and 3 sofosbuvir clinical trials was performed., Results: No NS5B variants present at baseline among 1645 sofosbuvir-treated subjects were associated with treatment failure; sofosbuvir susceptibility was within 2-fold of reference. Among 282 subjects who did not achieve sustained virologic response, no novel sofosbuvir resistance-associated variants were identified, and the NS5B changes observed did not confer significant reductions in sofosbuvir susceptibility. In 1 subject with S282T observed at relapse 4 weeks after sofosbuvir monotherapy, the resistant variant (13.5-fold reduced sofosbuvir susceptibility, replication capacity <2% of control) became undetectable by deep sequencing 12 weeks after treatment. L159F and V321A were identified as treatment-emergent variants but did not confer resistance to sofosbuvir in the replicon system., Conclusions: These data demonstrate a uniform susceptibility of subject-derived HCV to sofosbuvir, and also show that selection of sofosbuvir-resistant HCV is exceedingly rare and is associated with a significant reduction in viral fitness., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

We measured interferon γ-induced protein 10 (IP-10) levels in 428 patients at baseline, week 1, and week 2 of all-oral treatment for hepatitis C virus (HCV) infection. An increased baseline IP-10 level was associated with a T allele in the IL28B gene, an increased alanine aminotransferase level in treatment-naive but not experienced patients, and an increased body mass index. At week 1, the mean decline in plasma IP-10 levels was the same in treatment-naive and treatment-experienced patients (-49%), whereas during week 2 the mean decline in IP-10 levels in treatment-naive patients (-14%) was significantly larger than in treatment-experienced patients (-2%; P = .0176). IP-10 thus may be a surrogate marker of the rate of intracellular viral replication complex decay., (© The Author 2014. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

An internal ribosome entry site (IRES) initiates protein synthesis in RNA viruses, including the hepatitis C virus (HCV). We have discovered ligand-responsive conformational switches in viral IRES elements. Modular RNA motifs of greatly distinct sequence and local secondary structure have been found to serve as functionally conserved switches involved in viral IRES-driven translation and may be captured by identical cognate ligands. The RNA motifs described here constitute a new paradigm for ligand-captured switches that differ from metabolite-sensing riboswitches with regard to their small size, as well as the intrinsic stability and structural definition of the constitutive conformational states. These viral RNA modules represent the simplest form of ligand-responsive mechanical switches in nucleic acids.

Background and Aims: Previous studies suggest that low serum 25-hydroxyvitamin D [25(OH) D] levels are associated with reduced responsiveness to interferon and ribavirin therapy. We investigated the impact of vitamin D metabolites on HCV and cellular gene expression in cultured hepatoma cells., Methods: HCV Replicon cell lines stably expressing luciferase reporter constructs (genotype 1b and 2a replicon) or JC1-Luc2a were incubated in the presence of vitamin D2, vitamin D3 or 1,25-dihydroxyvitamin D3 (1,25(OH)2D3). Presence of HCV was quantified by a luciferase reporter assay and immunoblot of the Core protein. Synergy of interferon-alpha A/D (IFN-α) and 1,25(OH)2D3 was evaluated using the Chou-Talalay method. Cellular gene expression by microarray analysis using Illumina Bead Chips and real-time quantitative PCR., Results: Vitamin D2, D3 and 1,25(OH)2D3 each demonstrated anti-HCV activity at low micro molar concentrations. In vitro conversion from D3 to 25(OH)D3 was shown by LC/MS/MS. Combination indices of 1,25(OH)2D3 and IFN-α demonstrated a synergistic effect (0.23-0.46) and significantly reduced core expression by immunoblot. Differentially expressed genes were identified between Huh7.5.1 cells in the presence and absence of 1,25(OH)2D3 and HCV. Genes involved with classical effects of vitamin D metabolism and excretion were activated, along with genes linked to autophagy such as G-protein coupled receptor 37 (GPR37) and Hypoxia-inducible factor 1-alpha (HIF1a). Additionally, additive effects of 1,25(OH)2D3 and IFN-α were seen on mRNA expression of chemokine motif ligand 20 (CCL20)., Conclusions: This study shows that vitamin D reduces HCV protein production in cell culture synergistically with IFN-α. Vitamin D also activates gene expression independently and additively with IFN-α and this may explain its ability to aid in the clearance of HCV in vivo.

Resistance to direct-acting antiviral (DAA) agents against hepatitis C virus (HCV) infection is driven by the selection of mutations at different positions in the NS3 protease, NS5B polymerase and NS5A proteins. With the exception of NS5B nucleos(t)ide inhibitors, most DAAs possess a low genetic barrier to resistance, with significant cross-resistance between compounds belonging to the same family. However, a specific mutation profile is associated with each agent or drug class and varies depending on the genotype/subtype (e.g., genotype 1b showed higher rates of sustained virological response (SVR) and a higher genetic barrier for resistance than genotype 1a). Moreover, some resistance mutations exist as natural polymorphisms in certain genotypes/subtypes at frequencies that require baseline drug resistance testing before recommending certain antivirals. For example, the polymorphism Q80K is frequently found among genotype 1a (19-48%) and is associated with resistance to simeprevir. Similarly, L31M and Y93H, key resistance mutations to NS5A inhibitors, are frequently found (6-12%) among NS5A genotype 1 sequences. In particular, the presence of these polymorphisms may be of relevance in poorly interferon-responsive patients (i.e., null responders and non-CC IL28B) under DAA-based therapies in combination with pegylated interferon-α plus ribavirin. The relevance of pre-existing resistance mutations for responses to interferon-free DAA therapies is unclear for most regimens and requires further study., (Copyright © 2014 Elsevier B.V. All rights reserved.)

HIV-1 non-B subtype variants were found in 37.8% of 296 newly diagnosed persons in northwest Spain over the past 5 years. Subtype F was the most prevalent non-B subtype (29.6%) and displayed preferential transmission among MSM. Virologic response rates to antiretroviral therapy were lower among F subtypes compared to B subtypes at weeks 24 (31% vs. 78.3%), 48 (51.7% vs. 85.2%), and 96 (61.1% vs. 94.3%) of therapy. Subtype F was independently associated with virological response at 24 weeks.

Unlabelled: This phase II trial assessed the efficacy and safety of a combination regimen of the nonstructural protein (NS)5A inhibitor ledipasvir (LDV), NS3 protease inhibitor vedroprevir (VDV), non-nucleoside NS5B inhibitor tegobuvir (TGV), and ribavirin (RBV) in treatment-naïve patients with chronic hepatitis C virus (HCV) genotype 1 without cirrhosis. Patients were randomized 1:2 to LDV 30 mg once daily (QD; Arm 1; n = 46) or LDV 90 mg QD (Arm 2; n = 94); patients in both arms also received VDV 200 mg QD, TGV 30 mg twice-daily, and RBV 1,000-1,200 mg/day. Patients in Arm 2 with vRVR, defined as HCV RNA below the lower limit of quantification (LLOQ) from treatment weeks 2 to 10, were randomized 1:1 to stop treatment at 12 weeks or continue for 24 weeks. Sustained virologic response 12 weeks after treatment (SVR12) was higher in patients receiving 90 mg of LDV for 24 weeks (63%), compared with LDV 90 mg for 12 weeks (54%) and LDV 30 mg for 24 weeks (48%). In patients with very rapid virologic response (vRVR) in Arm 2, SVR12 was achieved by 68% and 81% of patients treated for 12 and 24 weeks, respectively. Virologic breakthrough was more common in patients with HCV genotype 1a and was associated with resistance-associated variants for all three direct-acting antiviral agents (DAAs); however, in all but 1 patient who relapsed, resistance-associated variants directed against only one or two of the DAAs were detected. The most common adverse events were fatigue, headache, nausea, rash, and diarrhea., Conclusion: In patients with HCV genotype 1, an interferon-free regimen containing LDV/VDV/TGV/RBV was well tolerated and led to SVR12 in up to 63% of patients. LDV 90 mg is currently being investigated in combination with the nucleotide polymerase inhibitor, sofosbuvir., (© 2014 by the American Association for the Study of Liver Diseases.)

In the United States, an estimated 0.8-1.4 million persons are living with chronic hepatitis B virus (HBV) infection. Among these persons, as many as 70% were born in countries of Asia, Africa, or other regions where HBV is moderately or highly endemic (hepatitis B surface antigen [HBsAg] prevalence ≥2%). HBV-associated cirrhosis and liver cancer are major health problems for these populations. Most persons with HBV were infected at birth or during early childhood and are asymptomatic until advanced liver disease develops. To address these concerns, CDC recommends HBsAg testing for all persons born in these areas and linkage to medical care and preventive services for those who are infected. In 2012, CDC awarded funds to nine sites to implement this recommendation. This report describes programs at three sites (New York, New York; Minneapolis-St. Paul, Minnesota; and San Diego, California) that conducted HBV testing, in clinical or community settings, and referred for medical evaluation and care those persons whose HBsAg test results were positive. During October 2012-March 2014, the three sites tested 4,727 persons for HBV infection; 310 (6.6%) were HBsAg-positive. Among the HBsAg-positive persons, 94% were informed of their results, 90% were counseled, 86% were referred for care, and 66% attended their scheduled first medical visit. These projects demonstrate that community-based programs can identify infected persons among populations with a high prevalence of HBV infection and refer HBsAg-positive persons for care. Individualized efforts to assist patients with accessing and receiving health-care services ("patient navigation services") can increase the number of persons who follow up on referrals and receive recommended care.

The treatment for patients infected with hepatitis C virus (HCV) genotype 1 has undergone major changes with the availability of direct-acting antivirals. Triple therapy, containing telaprevir or boceprevir, first-wave NS3 protease inhibitors, in combination with peginterferon and ribavirin, improved rates of sustained virologic response compared with peginterferon and ribavirin alone in patients with HCV genotype 1. However, the development of drug-resistant variants is a concern. In patients treated with telaprevir or boceprevir, different patterns of resistance are observed for the two major HCV genotype 1 subtypes, 1a and 1b. Genotype 1b is associated with a lower rate of resistant variant selection and better response to triple therapy compared with genotype 1a. Similar subtype-specific patterns have been observed for investigational direct-acting antivirals, including second-wave NS3 protease inhibitors, NS5A inhibitors and non-nucleoside NS5B inhibitors. This review explores resistance to approved and investigational direct-acting antivirals for the treatment of HCV, focusing on the differences between genotype 1a and genotype 1b. Finally, given the importance of HCV genotype 1 subtype on resistance and treatment outcomes, clinicians must also be aware of the tests currently available for genotype subtyping and their limitations., (© 2014 John Wiley & Sons Ltd.)

Objectives: To report the rates of grade IV adverse events and hepatitis C virus (HCV) treatment discontinuation associated with the use of telaprevir, pegylated interferon, and ribavirin., Design: Retrospective cohort analysis., Methods: The study included patients coinfected with HIV and HCV who underwent HCV treatment in a clinic-based setting with telaprevir, pegylated interferon, and ribavirin. The United States of America National Institutes of Health Division of AIDS grading system was used to rate severity of adverse events., Results: Of the 24 consecutive patients treated for HCV using telaprevir/pegylated interferon/ribavirin, 50% (12/24) developed serious adverse events and 29% (7/24) discontinued HCV treatment due to adverse events, despite an intensive multidisciplinary monitoring approach., Conclusion: In this HIV clinic-based experience, a high rate of grade IV adverse events and treatment discontinuations were observed associated with HCV telaprevir-based treatment. Careful consideration of the risks and benefits of telaprevir-based therapy should be undertaken, given prospects for interferon-sparing therapy in the near future.

The addition of hepatitis C virus (HCV) protease inhibitors (PIs) to interferon and ribavirin therapy has significantly improved the efficacy of treatment for HCV infection. However, for patients who do not respond to therapy, the selection of HCV variants with resistance to PIs is likely. Resistant variants, such as R155K and A156T/V, result in extensive cross-resistance to other HCV PIs. Despite the rapid and frequent appearance of PI-resistant HCV variants, the long-term clinical implications are unknown. In particular, progress in the development of other HCV antivirals, such as NS5A inhibitors, next-generation NS3 protease inhibitors, and NS5B nucleoside and nonnucleoside inhibitors, has provided a broad selection of potent antivirals such that interferon-free therapy is a reality. Promising results from early stages of interferon-free trials will be reviewed.