Prior Hepatitis C Virus Treatment Research Articles

Risk of Hepatocellular Cancer in U.S. Patients With Compensated Cirrhosis Treated With Direct-Acting Antivirals Versus Interferon.

Few studies have examined the risk of de novo hepatocellular carcinoma (HCC) among hepatitis C virus (HCV)-infected patients with cirrhosis who received interferon (IFN)-free direct-acting antiviral (DAA) therapy relative to patients who received IFN-containing therapy or remained untreated. To estimate the risk of de novo HCC with DAA treatment in cirrhotic HCV patients compared to no anti-HCV treatment and those treated with IFN-based therapy. We identified patients with chronic HCV infection and compensated cirrhosis in the US Department of Veterans Affairs healthcare system treated with IFN (2005 to 2013) or DAAs (2013 to 2017). We compared the risk of de novo HCC for patients treated with DAAs, IFN-containing regimens or no treatment after accounting for differences in demographics, alcohol and drug abuse, comorbidities, laboratory values, healthcare utilisation, prior HCV treatment and HCC surveillance. A total of 53,847 patients contributed to untreated time, 27,147 patients contributed to DAA-treated time (15,641 contributed to both untreated and DAA-treated times) and 6809 patients contributed to IFN-treated time. HCC risk associated with DAA treatment was significantly lower than untreated [adjusted HR: 0.70 (95% CI: 0.65-0.74)]. The risk of HCC was not significantly different for patients treated with DAA compared with those treated with IFN [adjusted HR: 0.98 (95% CI: 0.87-1.10)]. The study shows a reduced risk of de novo HCC among patients with chronic HCV-related compensated cirrhosis who received DAA treatment compared to that of untreated patients. There were no differences in HCC risk between DAA-treated and IFN-treated patients.

Needle and syringe sharing among people who have recently injected drugs in Australia: The ETHOS Engage Study.

Understanding needle/syringe sharing is crucial for reducing hepatitis C virus (HCV) infection and reinfection. This study aimed to assess the prevalence and factors associated with needle/syringe sharing among people who inject drugs in Australia, including those previously receiving HCV treatment. The ETHOS Engage study was an observational cohort study which collected self-reported survey data on demographic and drug use information from people who inject drugs attending drug treatment clinics and needle and syringe programs over two waves between May 2018 and June 2021. Logistic regression was used to identify factors associated with needle/syringe sharing. Overall, 1555/2395 people enrolled in ETHOS Engage (65%) injected drugs in the past month. Among these, 432 (28%) reported needle/syringe sharing in the past month and 276 (18%) reported receptive sharing. Factors associated with receptive sharing included younger age (adjusted odds ratio [aOR] 1.72; 95% confidence interval [CI] 1.28-2.30), recent incarceration (aOR 2.04; 95% CI 1.40-2.94), more frequent injecting (≥daily vs. less than weekly; aOR 2.59; 95% CI 1.75-3.84) and unstable housing (aOR 1.78; 95% CI 1.26-2.52). Among 560 participants with prior HCV treatment, 87 (16%) reported receptive sharing with younger age (aOR 2.42; 95% CI 1.45-4.05) and daily or greater injection frequency (aOR 2.51; 95% CI 1.31-4.83) associated with receptive sharing. Needle/syringe sharing was common among this population accessing harm reduction services. This study identifies high-risk populations with needle/syringe sharing. Research is needed to optimise HCV treatment to ensure people with ongoing risk behaviours receive adequate harm reduction following treatment to prevent reinfection.

An Analysis of Social Determinants of Health and Their Implications for Hepatitis C Virus Treatment in People Who Inject Drugs: The Case of Baltimore.

Sixty-eight percent of the nearly 3.5 million people living with hepatitis C virus (HCV) in the United States are people who inject drugs (PWID). Despite effective treatments, uptake remains low in PWID. We examined the social determinants of health (SDoH) that affect the HCV care cascade. We conducted a secondary analysis of data from 720 PWID in a cluster-randomized trial. We recruited PWID from 12 drug-affected areas in Baltimore. Inclusion criteria were injection in the prior month or needle sharing in the past 6 months. Intake data consisted of a survey and HCV testing. Focusing on SDoH, we analyzed self-report of (1) awareness of HCV infection (in those with active or previously cured HCV) and (2) prior HCV treatment (in the aware subgroup). We used descriptive statistics and logistic regression for statistical analyses. The 342 participants were majority male and Black with a median age of 52 years. Women were more likely to be aware of their status but less likely to be treated. Having a primary care provider and HIV-positive status were associated with increased awareness and treatment. Unhoused people had 51% lower odds of HCV treatment. People who reported that other PWID had shared their HCV status with them had 2.3-fold higher odds of awareness of their own status. Further study of gender disparities in HCV treatment access is needed. Increased social support was associated with higher odds of HCV treatment, suggesting an area for future interventions. Strategies to identify and address SDoH are needed to end HCV.

Expression of cyclo-oxygenase-2 and yap/taz in hepatocellular carcinoma in untreated and treated hepatitis C virus patients.

The pathogenesis of hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) differs according to whether prior treatment with interferon (IFN) vs. direct-acting antiviral agents (DAAs) was administered. Cyclo- oxygenase-2 (COX-2), yes-associated protein 1 (YAP), and transcriptional co-activator with PDZ-binding motif (TAZ) play acrucial role in hepatocarcinogenesis. However, their roles in untreated or treated HCV-related HCC development have not been clarified. Therefore, we performed an immunohistochemical study and stained tissue from 83 HCV-related HCC cases using antibodies against COX-2, YAP, and TAZ and correlated their expression with the clinicopathological characteri stics and survival data. The cases were subdivided into 3 groups based on prior HCV treatment. In the 3 groups, COX-2 was significantly higher in HCC tissue compared with adjacent non-tumour liver tissue. However, the expression of YAP/TAZ was not significantly different between HCC and adjacent non-tumour tissue. We further grouped HCC cases into YAP+/TAZ+ and YAP-/TAZ- cases. In the YAP+/TAZ+ cases, COX-2 was significantly associated with tumour size, tumour multifocality, and late pathologic stage. No significant difference was observed in COX-2 and TAZ expression as aresult of IFN or DAA treatment; however, YAP was significantly higher in IFN-treated HCC. Cyclo-oxygenase-2 overexpression may play arole in late HCC development, while YAP/TAZ could play an early role in HCC progression. Sustained expression of combined YAP/TAZ could mediate the poor prognostic role of COX-2.

Real-World Outcomes in Historically Underserved Patients with Chronic HepatitisC Infection Treated with Glecaprevir/Pibrentasvir.

IntroductionGlecaprevir/pibrentasvir is approved for treating chronic hepatitis C virus (HCV) genotypes (GT) 1–6. We evaluated real-world effectiveness, safety, and patient-reported outcomes of glecaprevir/pibrentasvir in underserved patient populations, focusing on persons who use drugs infected with HCV.MethodsData were pooled from nine countries (13 November 2017–31 January 2020). Patients had HCV GT1–6, with or without compensated cirrhosis, with or without prior HCV treatment and received glecaprevir/pibrentasvir consistent with local label at their physician’s discretion. Patients with prior direct-acting antiviral exposure were excluded from efficacy and quality-of-life analyses. The percentage of patients achieving sustained virologic response at post-treatment week 12 (SVR12) was assessed. Mean changes from baseline to SVR12 visit in 36-Item Short-Form Health Survey mental and physical component summary scores were reported. Safety was assessed in patients receiving at least one dose of glecaprevir/pibrentasvir.ResultsOf 2036 patients, 1701 (83.5%) received 8-week glecaprevir/pibrentasvir. In 1684 patients with sufficient follow-up, SVR12 rates were 98.0% (1651/1684) overall, 98.1% (1432/1459) in 8-week treated patients, 97.0% (519/535) in persons who use drugs, and greater than 95% across subgroups. Mean changes from baseline in mental and physical component summary scores were 3.7 and 2.4, respectively. One glecaprevir/pibrentasvir-related serious adverse event was reported; six glecaprevir/pibrentasvir-related adverse events led to discontinuation.ConclusionsGlecaprevir/pibrentasvir was highly effective, well tolerated, and improved quality of life in HCV-infected persons who use drugs and other underserved patients.Trial RegistrationThese multinational post-marketing observational studies are registered with ClinicalTrials.gov, number NCT03303599.Supplementary InformationThe online version contains supplementary material available at 10.1007/s40121-021-00455-1.

The Hepatitis C Continuum of Care Among HIV-Positive Persons with Heavy Alcohol Use in St. Petersburg, Russia.

This study describes the self-reported prevalence of hepatitis C virus (HCV) coinfection and the HCV care continuum among persons enrolled in the St PETER HIV Study, a randomized controlled trial of medications for smoking and alcohol cessation in HIV-positive heavy drinkers and smokers in St. Petersburg, Russia. Baseline health questionnaire data were used to calculate proportions and 95% confidence intervals for self-reported steps along the HCV continuum of care. The cohort included 399 HIV-positive persons, of whom 387 [97.0% (95% CI 95.3-98.7%)] reported a prior HCV test and 315 [78.9% (95% CI 74.9-82.9%)] reported a prior diagnosis of HCV. Among those reporting a diagnosis of HCV, 43 [13.7% (95% CI 9.9-17.4%)] had received treatment for HCV, and 31 [9.8% (95% CI 6.6-13.1%)] had been cured. Despite frequent HCV testing in this HIV-positive Russian cohort, the proportion reporting prior effective HCV treatment was strikingly low. Increased efforts are needed to scale-up HCV treatment among HIV-positive Russians in St. Petersburg.

Efficacy and Safety of Ravidasvir Plus Sofosbuvir in Chronic Hepatitis C Infected Subjects Without Cirrhosis or with Compensated Cirrhosis: Interim Analysis Results of a Two-Stage, Open-Label, Multicentre, Phase 2/3 Trial

Background: In low- and middle-income countries, affordable direct-acting antivirals are urgently needed to treat hepatitis C virus (HCV) infection. The combination of ravidasvir, a pangenotypic NS5A inhibitor, and sofosbuvir has shown efficacy and safety in chronically HCV infected patients with genotype (GT) 4. The STORM-C-1 trial aims to assess the efficacy and safety of sofosbuvir plus ravidasvir in a more diverse population of adults chronically infected with HCV. Methods: STORM-C-1 is a two-stage, open-label, multicentre clinical trial in Malaysia and Thailand. HCV infected subjects with compensated cirrhosis (Metavir F4 and Child-Turcotte-Pugh class A) or without cirrhosis (Metavir F0-F3) were eligible to participate, regardless of HCV genotype, HIV infection status, prior interferon-based HCV treatment or source of HCV infection. Stage 1 results are reported here. Once-daily ravidasvir (200mg) and sofosbuvir (400mg) were prescribed for 12 (without cirrhosis) or 24 (with cirrhosis) weeks. The primary endpoint was sustained virologic response at 12 weeks post-treatment (SVR12). This trial is registered with ClinicalTrials.gov: NCT02961426 and the National Medical Research Register of Malaysia NMRR-16-747-29183. Findings: Between October 2016 and June 2017, 301 subjects were enrolled and 300 included in the full analysis set: 97 with GT1a, 27 GT1b, 2 GT2, 158 GT3, and 16 GT6; 81 (27%) had compensated cirrhosis; 90 (30%) had HIV co-infection; and 99 (33%) had prior interferon-based treatment. 291/300 subjects (97%, 95% CI 94%-99%) achieved SVR12. Three subjects prematurely discontinued study treatment due to adverse events. There were no deaths or treatment discontinuations due to the study drugs. Interpretation: In this first stage, ravidasvir plus sofosbuvir was found to be highly effective and well tolerated in all subgroups of this diverse adult population chronically infected with HCV. Trial Registration Number: This trial is registered with ClinicalTrials.gov: NCT02961426 and the National Medical Research Register of Malaysia NMRR-16-747-29183. Funding: Drugs for Neglected Diseases initiative; National Science and Technology Development Agency, Thailand; Department of Disease Control, Ministry of Public Health, Thailand; Ministry of Health, Malaysia. Conflict of Interest: Dr. Avihingsanon reports grants from National Science and Technology Development Agency (NSTDA) during the conduct of the study, and also from ViiV Healthcare outside of thesubmitted work. Tim Cressey and Nicolas Salvadori report a service agreement with DNDi.Isabelle Andrieux-Meyer, Caroline Menetrey, Francois Simon, Jean-Michel Piedagnel,Sasikala Siva, Alistair Swanson, Francois Bompart, Vishal Goyal, and Bernard Pecoul are employed by the Drugs for Neglected Diseases initiative. All other authors do not report any potential conflicts of interest. Ethical Approval: The initial protocol and all protocol amendments were reviewed and approved before implementation by the applicable individual institutional or national ethics committees. All subjects provided written informed consent.

Elbasvir and grazoprevir for hepatitis C virus genotype 1 infection in people with recent injecting drug use (DARLO-C): An open-label, single-arm, phase 4, multicentre trial.

Background and AimsDirect‐acting antiviral therapy for hepatitis C virus (HCV) is effective, but few prospective studies among people with ongoing injecting drug use exist. This study evaluated the efficacy of elbasvir/grazoprevir in people with HCV genotype 1/4 (G1/4) infection and recent injecting drug use. An exploratory aim evaluated the feasibility of fingerstick point‐of‐care HCV RNA testing prior to and following treatment.MethodsDARLO‐C (http://clinicaltrials.gov: NCT02940691) is an open‐label phase 4 trial. Participants were recruited between May 2017 and March 2018 from two drug treatment clinics, two hospital clinics, and one community clinic in Australia. Inclusion criteria included recent injection drug use (previous 6 months) and HCV G1/4 infection. Exclusion criteria included prior HCV treatment and decompensated liver disease. Participants received elbasvir/grazoprevir once‐daily for 12 weeks. The primary endpoint was undetectable HCV RNA 12 weeks post‐treatment (SVR). Fingerstick whole‐blood samples were tested using the Xpert HCV Viral Load Fingerstick (Xpert HCV VL Fingerstick) assay and compared to the Aptima HCV Quant Dx Assay on plasma samples.ResultsOf a planned 150 participants, 32 were enrolled due to slower than anticipated recruitment [median age 46 years, 10 (31%) female, 29 (91%) G1a]. Eighteen (56%) were receiving opioid agonist therapy and 29 (91%) injected in the previous month. Twenty‐six (81%) of 32 completed treatment (lost to follow‐up, n = 5; incarceration, n = 1). There were no virological failures. Twenty‐four (75%, 95% CI 59%‐91%) of 32 achieved SVR. Two participants who completed treatment did not have SVR (loss to follow‐up, n = 1; refused test, n = 1). Among paired samples (n = 36), sensitivity of the Xpert HCV VL Fingerstick assay for HCV RNA detection was 100.0% (95% CI 75.3%‐100.0%) and specificity was 95.7% (95% CI 78.1%‐99.9%).ConclusionElbasvir/grazoprevir is effective among people with HCV G1 with recent injecting drug use. Implementation of point‐of‐care HCV RNA testing was feasible, but the high error rate requires investigation.

Network-based recruitment of people who inject drugs for hepatitis C testing and linkage to care.

Although oral direct-acting agent (DAA) therapies have the potential to reduce the burden of hepatitis C virus (HCV) infection, treatment uptake remains low, particularly among people who inject drugs (PWID). This study examined the feasibility of an innovative peer-based recruitment strategy to engage PWID in HCV testing and treatment. We interviewed an initial set of HCV antibody-positive PWID as 'primary indexes' to gather demographic, drug use, health information and drug network characteristics. Primary indexes were then briefly educated on HCV and its treatment and encouraged to recruit their injection drug 'network members' for HCV testing and linkage to care. Eligible network members were enrolled as 'secondary indexes' and completed the same index study procedures. In sum, 17 of 36 primary indexes initiated the recruitment of 64 network members who were HCV antibody positive and eligible to become indexes. In multivariable analysis, successful recruitment of at least one network member was positively associated with prior HCV treatment (OR 2.80; CI [1.01, 7.72]), daily or more injection drug use (OR 2.38; CI [1.04, 5.47]), and a higher number of injection drug network members (OR 1.20; CI [1.01, 1.42]). Among the 69 participants with chronic HCV not previously linked to HCV care at enrolment, 91% (n=63) completed a linkage to HCV care appointment, 45% (n=31) scheduled an appointment with an HCV provider, and 20% (n=14) initiated HCV therapy. These findings suggest a potential benefit for peer-driven, network-based interventions focused on HCV treatment-experienced PWID as a mechanism to increase HCV linkage to care.

Hepatitis C Direct-Acting Antiviral Treatment Selection, Treatment Failure, and Use of Drug-Drug Interactions in a State Medicaid Program.

Newer hepatitis C virus (HCV) treatments often provide high success rates with fewer adverse events, although the extent of all potential drug interactions is not fully known. To assess outcomes of receiving HCV treatment and subsequent sustained virologic response (SVR) based on patient and clinical characteristics, including direct-acting antiviral (DAA) drug-drug interactions (DDIs), in Medicaid members with chronic HCV. Comprehensive medical and pharmacy claims and prior authorization data were collected for HCV patients requesting treatment between January 2014 and June 2015. Outcomes of receiving treatment with DAAs and treatment failure based on SVR were analyzed according to demographics, prior/current HCV treatment, severity of DDIs, advancing liver disease, and comorbidities. Multivariable generalized linear models were employed, including a Bayesian sensitivity analysis. Among 3,412 Medicaid members with HCV, 13.6% received DAAs (n = 464), averaging 53.6 ± 10.0 years, with 52.8% female. Multivariable analyses indicated that higher odds of DAA treatment initiation were associated with older age, prior HCV treatment, and advancing liver disease. Some 4.8% of treatment failures occurred among 168 patients with reported SVRs, wherein a 3.218 times higher adjusted odds of treatment failure was associated with concomitant use of medications with DDIs classified as significant or potentially clinically significant by the University of Liverpool HEP Drug Interactions resource (P = 0.001). In a cohort of state Medicaid members with chronic HCV, a markedly higher adjusted odds of treatment failure was independently associated with DDIs classified as significant or potentially clinically significant, warranting continued inquiry and potential alternate treatments concerning conditions that require their use. This research was funded by an unrestricted research grant by Gilead Sciences. During the course of this study, all authors were either employed by the Oklahoma HealthCare Authority or engaged in contractual work for this employer. Keast, Holderread, and Skrepnek report unrelated research grants from AbbVie, Otsuka, and Amgen. Keast and Skrepnek acknowledge funding from Purdue Pharma for an unrelated research fellowship grant. Posters based on this work were presented at HepDart 2015 on December 6-10, 2015, in Grand Wailea, HI, and at Academy of Managed Care Nexus 2015 on October 26-29, 2015, in Orlando, FL.

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.

Transitioning from interferon-based to direct antiviral treatment options: A potential shift in barriers and facilitators of treatment initiation among people who use drugs?

BackgroundMultiple barriers for accessing hepatitis C virus (HCV) treatment were identified during the interferon-based (IFN) treatment era for people who inject drugs (PWID). Whether these barriers persist since the introduction of IFN-free direct-acting antiviral (DAA) agents in Canada remains to be documented. This study examined temporal trends in HCV treatment initiation and associated factors during the transition from INF-based to all-oral DAA regimens. MethodsThe study population was drawn from a prospective cohort of PWID in Montreal, Canada. At three-month/one-year intervals between 2011 and 2017, participants with chronic HCV infection completed an interviewer-administered questionnaire on socio-demographic characteristics, drug use and health service utilisation, including HCV treatment. Time-updated Cox multivariate regression models, stratified by DAA + INF (2011-2013) and all-oral DAA (2014–2017) availability periods, were conducted to examine associations between time to HCV treatment initiation and associated barriers and facilitators. ResultsOf 308 participants (85% male, median age 42 [IQR: 33, 50]), 80 (26%) initiated HCV treatment during 915 person-years (PY). Incidence rates increased from 1.6 /100 PY (95%CI:0.9–2.6) in 2011 to 12.7 (10.6–15.1) in 2017 (p-trend = 0.0012). In multivariate analyses, visiting a primary care physician (2011–2013: aHR = 3.63[1.21–10.9]; 2014–2017: 2.52[1.10–5.77]) and frequent injection (0.23[0.05–0.99] and 0.49[0.24–0.99]) were consistently associated with treatment initiation. Participants aged >40 (2.27[1.24–4.13]), receiving opioid agonist therapy (OAT) (2.17[1.19–3.94]), and reporting prior HCV treatment (3.00[1.75–5.15]) were more likely to initiate treatment in the all-oral DAA period. ConclusionTreatment initiation increased between 2011 and 2017, but still remains low among PWID. Primary care visiting was a key facilitator regardless of the period, while engagement in OAT and health services, indicated by prior HCV treatment, increased the likelihood of treatment initiation in the DAA era. These findings suggest that access to health services is essential but not enough to scale up treatment in this population.

Liver stiffness regression after successful Hepatitis C treatment is independent of HIV coinfection.

The aim of the study was to assess the regression of liver stiffness after successful direct-acting antiviral (DAA) treatment in patients with hepatitis C virus (HCV) monoinfection and HCV/-HIV coinfection. In addition, we aimed to identify factors associated with liver stiffness regression. We studied patients treated with interferon-free DAA regimens with a sustained virological response at week 12 (SVR12 ) or 24 (SVR24 ) post-treatment. Liver stiffness was assessed by transient elastography (TE) before the initiation and after the end of treatment (median 12weeks). Of 214 enrolled patients, 85 (40%) were HCV monoinfected and 129 (60%) HCV/HIV coinfected. Baseline median TE values were 7.8kPa [interquartile range (IQR) 5.9-12.0 kPa] in mono-infected patients and 10.7kPa (IQR 7.8-17.0 kPa) in coinfected patients. Overall, the median TE value decreased from 10.1 to 6.8kPa (n=214; P<0.0001). There was no difference between mono- and coinfected patients (-2.2versus -3.3kPa, respectively; P=0.88), which was verified by an analysis of covariance (ANCOVA) adjusting for baseline TE values. Significant (≥ 30%) regression of liver stiffness was achieved by 45% of patients (54% with baseline TE≥7.1kPa). In multivariate analysis, a prior HCV treatment was a negative predictor of liver stiffness regression [odds ratio (OR) 0.31; P=0.001]. A higher baseline TE value was positively associated with achieving a significant regression (OR 1.06; P=0.02). HIV coinfection status, HCV genotype, age, sex, treatment duration, controlled attenuation parameter value, bilirubin concentration, platelet count and aspartate aminotransferase concentration were not associated with liver stiffness regression. Regression of liver stiffness after successful DAA treatment did not differ in patients with HCV monoinfection and those with HCV/HIV coinfection. Half of all patients achieved a significant (≥ 30%) regression. Prior treatment for HCV was a negative predictor for this endpoint, while a higher baseline TE value was positively associated with regression.

Systematic Review: Interferon-Free Direct-Acting Antiviral Therapy for Hepatitis C Virus Genotype 6

Introduction: Treatment of Hepatitis C Virus (HCV) has evolved rapidly over the past years, shifting from interferon-based to interferon-free direct-acting antivirals (DAA) therapy. HCV genotype 6 (GT6) is predominantly distributed in Southeast Asia and in some region of East Asia, therefore, data on GT6 response to DAA therapy from major clinical trials is relatively limited. The objective of this systematic review is to summarize the clinical outcome of the interferon-free DAA regimens specifically on HCV GT6 patients and to determine possible factors affecting the treatment outcomes. Methods: Electronic literature search of PubMed, EMBASE, and The Cochrane Library databases were conducted using the term: “genotype 6” AND (sofosbuvir OR glecaprevir OR “direct-acting antiviral”). Two-step screening was done, excluding studies with interferon-based treatment. The data from the selected studies were extracted using case report form and further subdivided by cirrhosis status and prior HCV treatment history to find the relevance of patient characteristics and treatment outcomes. Results: A total of 18 studies were selected (total 816 GT6 patients were included); 11 were experimental studies and 7 were observational studies. The quality of evidence was fair due to intermediate risk of bias and high heterogeneities among each study. Studies of glecaprevir/pibrentasvir (n=4), ledipasvir/sofosbuvir (n=8), sofosbuvir/velpatasvir with or without voxilaprevir (n=3), sofosbuvir/daclatasvir (n=2) and sofosbuvir with ribavirin (n=3) achieved 98-100%, 64-100%, 100%, 88-94% and 91-100% sustained virologic response rates (SVR12), respectively. Almost all studies of sofosbuvir/ledipasvir obtained >90% SVR12 except for one real-world study from Myanmar that yielded a distinct SVR12 of 64%. At least 9 out of 14 patients who experienced virologic failure had cirrhosis while 2 were treatment-experienced. Serious adverse events across all genotypes occurred at rates Conclusion: This systematic review suggests that interferon-free DAA regimens are safe and highly efficacious for HCV GT6 patients. Patients with cirrhosis were shown to have lower odds of achieving SVR12 whereas prior treatment does not appear to be associated with the outcomes. The limitation of this study is the small number of GT6 population, hence, further high-quality studies with sufficient numbers of GT6 patients are encouraged to support the conclusion.962_A Figure 1. SVR12 range of each regimen962_B Figure 2. AE (Adverse Events) reported in major RCTs

Anti-E1E2 antibodies status prior therapy favors direct-acting antiviral treatment efficacy

Presence of anti-E1E2 antibodies was previously associated with spontaneous cure of hepatitis C virus (HCV) and predictive before treatment of a sustained virological response (SVR) to bi- or tri-therapy in naïve or experienced patients, regardless of HCV genotype. We investigated the impact of anti-E1E2 seroprevalence at baseline on treatment response in patients receiving direct-acting antiviral (DAA) therapy. We screened anti-E1E2 antibodies by ELISA in serum samples collected at treatment initiation for two groups of patients: 59 with SVR at the end of DAA treatment and 44 relapsers after DAA treatment. Nineteen patients received a combination of ribavirin (RBV) or PEG-interferon/ribavirin with sofosbuvir or daclatasvir and others received interferon-free treatment with DAA±RBV. HCV viral load was measured at different time points during treatment in a subgroup of patients. A significant association was observed between presence of anti-E1E2 and HCV viral load<6log10 prior treatment. Among patients with anti-E1E2 at baseline, 70% achieved SVR whereas among patients without anti-E1E2, only 45% achieved SVR. Conversely, 66% of patients experiencing DAA-failure were anti-E1E2 negative at baseline. In the multivariate analysis, presence of anti-E1E2 was significantly associated with SVR after adjustment on potential cofounders such as age, sex, fibrosis stage, prior HCV treatment and alanine aminotransferase (ALT) level. The presence of anti-E1E2 at treatment initiation is a predictive factor of SVR among patients treated with DAA and more likely among patients with low initial HCV viral load (<6log10). Absence of anti-E1E2 at baseline could predict DAA-treatment failure.

Sustained virological response to ombitasvir/paritaprevir/ritonavir and dasabuvir treatment for hepatitis C: Real-world data from a large healthcare provider.

Treatment with ombitasvir/paritaprevir/ritonavir and dasabuvir, with or without ribavirin (OPrD±RBV), was the first interferon-free direct-acting antiviral for hepatitis C virus (HCV) introduced to Israel's national basket of health services in February 2015. Patients with HCV genotype 1 (GT1) and advanced fibrosis (F3-F4) were eligible for treatment in 2015. This study aimed to characterize patients initiating OPrD±RBV and assess sustained virological response (SVR). A retrospective cohort study was performed using the database of Maccabi Healthcare Services (MHS), a 2-million-member health plan in Israel. The study population included adults who initiated OPrD±RBV through December 2015 per health basket criteria. A gap in medication fills (>14days between a fill's run-out and the next fill) was used to estimate adherence. SVR was defined by the viral tests at least 12-week post-treatment. The study population consisted of 403 patients (56.3% male), with a mean age of 60.7years (SD 11.0). Overall, 71.0% were naïve to prior HCV treatment, and 95.6% were treated with a 12-week regimen. A total of 348 patients (86.4%) completed the regimen in the usual time frame (highly adherent), whereas 8.2% completed with a gap, and 4.7% purchased less than the recommended dose. SVR rates overall and among highly adherent patients were 395/403 (98.0%; 95% CI 96.1-99.1) and 346/348 (99.4%; 95% CI 97.9-99.9), respectively. GT1b patients on 12-week regimens attained SVR rates of 194/196 (fibrosis F3) and 170/176 (cirrhosis). After a first year of provision of OPrD±RBV with good adherence, high SVR rates were achieved in various patient subgroups and comorbidities.

The higher prevalence of truncal obesity and diabetes in American than Chinese patients with chronic hepatitis C might contribute to more rapid progression to advanced liver disease.

Chronic hepatitis C virus (HCV) infection is the leading cause of cirrhosis and hepatocellular carcinoma (HCC) in the United States (US) and an emerging cause in China. To compare the clinical characteristics of hepatitis C patients in the US and China, and factors influencing disease stage. Prospective study of 2 cohorts of HCV patients recruited at 1 site in the US and 3 sites in China. Standardised questionnaire on risk factors and medical history were used and diagnosis of cirrhosis and HCC was based on pre-defined criteria. One thousand nine hundred and fifty seven patients (1000 US and 957 China) were enrolled. US patients were more likely to be men (61.4% vs 48.5%), older (median age 57 vs 53 years), obese (38.4% vs 16.8%) and diabetic (21.8% vs 10.8%). A significantly higher per cent of US patients had cirrhosis (38.2% vs 16.0%) and HCC (14.1% vs 2.7%). Investigator estimated time at infection in US was 10 years earlier than in Chinese patients but US patients were more likely to have advanced disease even after stratifying for duration of infection. Study site in the US, older age, truncal obesity, diabetes and prior HCV treatment were significant predictors of advanced disease on multivariate analysis. HCV patients in the US had more advanced liver disease than those in China. We speculate that underlying fatty liver disease may be a major contributor to this difference, and management of glycometabolic abnormalities should occur in parallel with anti-viral therapy to achieve optimal outcomes.

Attitudes and potential barriers towards hepatitis C treatment in patients with and without HIV coinfection.

This study aimed to assess attitudes and potential barriers towards treatment in patients with hepatitis C virus (HCV) infection, comparing those with and without HIV coinfection. A cross-sectional survey of 82 HCV-infected adults with and without HIV was conducted in greater Los Angeles between November 2013 and July 2015. Overall, there were 53 (64.6%) with HIV coinfection, 20 (25.0%) with self-reported cirrhosis, and 22 (26.8%) with a history of prior HCV treatment. Of all, 93.2% wanted HCV treatment, but 45.9% were unwilling/unable to spend anything out of pocket, 29.4% were waiting for new therapies, and 23.5% were recommended to defer HCV treatment. HIV/HCV-coinfected patients were more likely to want treatment within one year (90.2% versus 68.2%, p = 0.02), more willing to join a clinical trial (74.5% versus 8.0%, p < 0.01), more willing to take medications twice daily (86.3% versus 61.5%, p = 0.01), and more likely to prefer hepatitis C treatment by an infectious diseases/HIV physician (36.7% versus 4.0%, p < 0.01). Of all, 77.1% of coinfected patients were willing to change antiretroviral therapy if necessary to treat HCV, but only 48.0% of patients were willing to take a medication if it had not been studied in HIV-positive patients. Treatment preferences differ between HIV/HCV-coinfected and HCV-monoinfected patients. Despite a strong willingness among the study cohort to start HCV treatment, other factors such as cost, access to medications, and provider reluctance may be delaying treatment initiation.

Treatment Discontinuation, Adherence, and Real-World Effectiveness Among Patients Treated with Ledipasvir/Sofosbuvir in the United States

IntroductionLedipasvir/sofosbuvir (LDV/SOF) for hepatitis C virus (HCV) treatment provides an oral interferon-free treatment regimen with high rates of sustained virologic response (SVR). This study assessed treatment discontinuation, factors associated with treatment completion, and real-world effectiveness.MethodsPatients with HCV treated with LDV/SOF between October 2014 and June 2015 and enrolled in a large US health plan were identified. Expected treatment duration was calculated based on IDSA/AASLD treatment guidelines and US labels using data for genotype, initial treatment regimen, baseline cirrhosis, and prior treatments. Logistic regression was used to identify factors associated with treatment completion, controlling for patient characteristics.ResultsThe study included 1483 LDV/SOF patients. Mean age was 59.7 years, most were male (63.9%), had commercial insurance (51.9%), and were treatment-naïve (85.6%). Cirrhosis or end stage liver disease was present in 46.1%. Among patients with an expected 8-week treatment regimen, 49.4% were treated for longer. Most patients (99.8%) with expected 12-week treatment durations were adherent to the expected treatment duration. Treatment-experienced patients [odds ratio (OR) 0.124, p < 0.001] and those on Medicare (OR 0.382, p = 0.039) had lower odds of completing the expected treatment regimen, while males were more likely to complete treatment than females (OR 3.235, p = 0.003). SVR12 in patients treated with LDV/SOF was 89.4% (n = 76/85).ConclusionHalf of patients eligible for an 8-week treatment regimen with LDV/SOF were treated longer, while most patients with a 12-week regimen were adherent to the expected treatment duration. Prior HCV treatment, female gender, and Medicare Advantage insurance were associated with lower odds of treatment completion. Overall SVR12 was 89.4%.FundingMerck & Co. Inc.Electronic supplementary materialThe online version of this article (doi:10.1007/s40121-017-0163-0) contains supplementary material, which is available to authorized users.

Effectiveness of All-Oral Antiviral Regimens in 996 Human Immunodeficiency Virus/Hepatitis C Virus Genotype 1–Coinfected Patients Treated in Routine Practice

Large cohorts are needed to assess human immunodeficiency virus (HIV)/hepatitis C virus (HCV) real-world treatment outcomes. We examined the effectiveness of ledipasvir/sofosbuvir with or without ribavirin (LDV/SOF ± RBV) and ombitasvir/ paritaprevir/ritonavir plus dasabuvir (OPrD) ± RBV in HIV/HCV genotype 1 (GT1)-coinfected patients initiating HCV therapy in clinical practice. Observational intent-to-treat cohort analysis using the Veterans Affairs Clinical Case Registry to identify HIV/HCV GT1-coinfected veterans initiating 12 weeks of LDV/SOF ± RBV or OPrD ± RBV. Multivariate models of sustained virologic response (SVR) included age, race, cirrhosis, proton pump inhibitor (PPI) prescription, prior HCV treatment, body mass index, genotype subtype, and HCV treatment regimen. Nine hundred ninety-six HIV/HCV GT1-coinfected veterans initiated therapy: 757 LDV/SOF, 138 LDV/SOF + RBV, 28 OPrD, and 73 OPrD + RBV. Overall SVR was 90.9% (823/905); LDV/SOF 92.1% (631/685), LDV/SOF + RBV 86.3% (113/131), OPrD 88.9% (24/27), and OPrD + RBV 88.7% (55/62). SVR was 85.9% (176/205) and 92.4% (647/700) in those with and without cirrhosis (P = .006). SVR was similar between African Americans (90.5% [546/603]) and all others (91.7% [277/302]). PPI use with LDV/SOF ± RBV did not affect SVR (89.7% [131/146] with PPI and 91.5% [613/670] without PPI). Cirrhosis was predictive of reduced SVR (0.51 [95% confidence interval {CI}, .31-.87]; P = .01). Median creatinine change did not differ among patients receiving LDV/SOF and tenofovir disoproxil fumarate (TDF) without a protease inhibitor (PI) (0.18 [interquartile range {IQR}, 0.08-0.30]; n = 372), LDV/SOF and TDF/PI (0.17 [IQR, 0.04-0.30]; n = 100), and LDV/SOF without TDF (0.15 [IQR, 0.00-0.30]; n = 423). SVR rates in HIV/HCV GT1-coinfected patients were high. African American race or PPI use with LDV/SOF ± RBV was not associated with lower SVR rates, but cirrhosis was. Renal function did not worsen on LDV/SOF regimens with TDF.