Patients With Autoimmune Hepatitis and Nonalcoholic Fatty Liver Disease: Characteristics, Treatment, and Outcomes.

GOAL: The objective of this study was to characterize an autoimmune hepatitis (AIH)/nonalcoholic fatty liver disease (NAFLD) overlap cohort, determine if they received standard of care treatment, and delineate their outcomes in comparison with patients with AIH or NAFLD alone. BACKGROUND: AIH is a relatively rare and heterogeneously presenting liver disease of unknown etiology. NAFLD is a leading cause of liver disease worldwide. AIH treatment includes steroids, which have adverse metabolic effects that can worsen NAFLD. No treatment guidelines are available to mitigate this side on AIH/NAFLD overlap patients. Few studies to date have examined these patients' characteristics, management practices, and outcomes. MATERIALS AND METHODS: A single-center, retrospective chart review study examining biopsy-proven AIH/NAFLD, AIH, and NAFLD patients. Characteristics, treatment, and 1- and 3-year outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) were evaluated. RESULTS: A total of 72 patients (36.1% AIH/NAFLD, 34.7% AIH, and 29.2% NAFLD) were included. AIH/NAFLD patients were found to be more often Hispanic/Latino, female, and with lower liver aminotransaminases, immunoglobulin G, and anti-smooth muscle antibody positivity. AIH/NAFLD patients were less likely to receive standard of care treatment. No significant differences in outcomes were seen between AIH/NAFLD and either AIH or NAFLD. CONCLUSIONS: Our study demonstrated that AIH/NAFLD patients have unique characteristics and are less likely to receive standard of care treatment compared with patients with AIH alone. Despite this, no difference in outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) was seen. Given NAFLD's rising prevalence, AIH/NAFLD cases will likely increase, and may benefit from alternative treatment guidelines to prevent worsening of NAFLD.

Clinical advances: pregnancy in gastroenterologic and hepatic conditions.

The fields of gastroenterology and hepatology, along with endoscopic practice, have seen significant changes and innovations to practice in just the past few years. These practice changes are not limited to gastroenterology, but maternal fetal medicine and the care of the pregnant person have become increasingly more sophisticated as well. Gastroenterologists are frequently called on to provide consultative input and/or perform endoscopy during pregnancy. To be able to provide the best possible care to these patients, gastroenterologists need to be aware of (and familiar with) the various nuances and caveats related to the care of pregnant patients who either have underlying gastrointestinal (GI) conditions or present with GI and liver disorders. Here, we offer a clinical update with references more recent than 2018, along with a few words about SARS-CoV-2 infection and its relevance to pregnancy.

An international survey on patterns of practice in NAFLD and expectations for therapies-The POP-NEXT project.

BACKGROUND AND AIMS: Differences between countries in NAFLD patient care pathways and management need to be understood prior to defining supranational guidelines. APPROACH AND RESULTS: We conducted an anonymous survey in France, Germany, Hong Kong, Italy, Romania, Spain, the United Kingdom, and the United States among physicians providing specialist care for patients with NAFLD. Modalities of patient referral, patterns of practice (diagnosis, staging, monitoring, and indications for liver biopsy), therapeutic management, and expectations for future NASH pharmacotherapies were assessed, with 664 physicians completing the survey. Referral to surveyed physicians (SPs) mostly came from primary care. Prior to referral, NAFLD was rarely diagnosed, and noninvasive tests were not performed. Screening for comorbidities by SPs was incomplete and cardiovascular risk not calculated. Elastometry in combination with a serum biomarker was the most common first-line method for fibrosis staging. Liver biopsy, when performed, was often delayed by at least 1 year after diagnosis. It was, however, recommended even if noninvasive methods indicated advanced fibrosis. Frequent, biannual monitoring was conducted, including HCC surveillance in Stage 3 fibrosis. SPs rarely implemented and followed dietary and lifestyle changes themselves, and local availability of such programs was highly heterogenous. SPs favored pharmacotherapy based on mechanism of action adapted to the stage of the disease, including for early stages such as steatohepatitis with mild fibrosis. CONCLUSIONS: This international survey revealed major deficiencies and delays in referral pathways, suboptimal screening for comorbidities or managing of lifestyle modifications by SPs, and limited local availability for nonpharmacological interventions. Monitoring practices are not aligned with current guidelines.

The Spectrum of Hepatic Critical Care During Pregnancy: A Clinical Review.

Hepatic disease during pregnancy can result in the development of critical illness requiring special attention from a multidisciplinary team with a low threshold for tertiary care transfer to provide access to liver transplantation. Management of this population requires taking into consideration the benefit and risks of both mother and fetus. A myriad of diseases has been recognized, some being unique to pregnancy while others are common to the general population. We present a review of the literature on the diagnosis, management, and prognosis of these diseases to aid in the optimization of care in this special population.

Sustained Impact of the Coronavirus Disease 2019 Pandemic on Hepatitis C Virus Treatment Initiations in the United States.

BACKGROUND: Recent reports indicated declines in hepatitis C virus (HCV) testing during the first half of 2020 in the United States due to coronavirus disease 2019 (COVID-19), but the longer-term impact on HCV testing and treatment is unclear. METHODS: We obtained monthly state-level volumes of HCV antibody, RNA and genotype testing, and HCV treatment initiation, stratified by age and gender, spanning January 2019 until December 2020 from 2 large national laboratories. We performed segmented regression analysis for each state from a mixed-effects Poisson regression model with month as the main fixed predictor and state as a random intercept. RESULTS: During the pre-COVID-19 period (January 2019-March 2020), monthly HCV antibody and genotype tests decreased slightly whereas RNA tests and treatment initiations remained stable. Between March and April 2020, there were declines in the number of HCV antibody tests (37% reduction, P < .001), RNA tests (37.5% reduction, P < .001), genotype tests (24% reduction, P = .023), and HCV treatment initiations (31%, P < .001). Starting April 2020 through the end of 2020, there were significant increases in month-to-month HCV antibody (P < .001), RNA (P = .035), and genotype tests (P = .047), but only antibody testing rebounded to pre-COVID-19 levels. HCV treatment initiations remained low after April 2020 throughout the remainder of the year. CONCLUSIONS: HCV testing and treatment dropped by >30% during April 2020 at the start of the COVID-19 pandemic, but although HCV testing increased again later in 2020, HCV treatment rates did not recover. Efforts should be made to link HCV-positive patients to treatment and revitalize HCV treatment engagement by healthcare providers.

American Association for the Study of Liver Diseases Expert Panel Consensus Statement: Vaccines to Prevent Coronavirus Disease 2019 Infection in Patients With Liver Disease.

The aim of this document is to provide a concise scientific review of the currently available COVID-19 vaccines and those in development, including mRNA, adenoviral vectors, and recombinant protein approaches. The anticipated use of COVID-19 vaccines in patients with chronic liver disease (CLD) and liver transplant (LT) recipients is reviewed and practical guidance is provided for health care providers involved in the care of patients with liver disease and LT about vaccine prioritization and administration. The Pfizer and Moderna mRNA COVID-19 vaccines are associated with a 94%-95% vaccine efficacy compared to placebo against COVID-19. Local site reactions of pain and tenderness were reported in 70%-90% of clinical trial participants, and systemic reactions of fever and fatigue were reported in 40%-70% of participants, but these reactions were generally mild and self-limited and occurred more frequently in younger persons. Severe hypersensitivity reactions related to the mRNA COVID-19 vaccines are rare and more commonly observed in women and persons with a history of previous drug reactions for unclear reasons. Because patients with advanced liver disease and immunosuppressed patients were excluded from the vaccine licensing trials, additional data regarding the safety and efficacy of COVID-19 vaccines are eagerly awaited in these and other subgroups. Remarkably safe and highly effective mRNA COVID-19 vaccines are now available for widespread use and should be given to all adult patients with CLD and LT recipients. The online companion document located at https://www.aasld.org/about-aasld/covid-19-resources will be updated as additional data become available regarding the safety and efficacy of other COVID-19 vaccines in development.

Incidence of Complications from Percutaneous Biopsy in Chronic Liver Disease: A Systematic Review and Meta-Analysis.

BACKGROUND: Approaches to liver biopsy have changed over the past decade in patients with chronic liver disease. AIMS: We conducted a systematic review and meta-analysis on the incidence of all complications and technical failure associated with percutaneous liver biopsy. METHODS: We systematically searched PubMed and the Cochrane Library for cohort studies reporting on complications resulting from liver biopsy published between 2010 and 2020. Studies on participants of any age and sex, who underwent any percutaneous biopsy for non-focal liver disease, were selected. All events except mild pain, minor hematoma, vasovagal episodes, fever and fistula were defined as major complications. Random-effect model meta-analyses with and without covariates were performed, to examine the effect of publication year, patient characteristics, outcome collection, and biopsy type on incidences. RESULTS: We identified 30 studies reporting on complications resulting from percutaneous liver biopsy procedures (n = 64,356). Incidence of major complications was 2.44% (95% CI 0.85, 6.75), with mortality at 0.01% (95% CI 0.00, 0.11), hospitalization at 0.65% (95% CI 0.38, 1.11), major bleeding at 0.48% (95% CI 0.22, 1.06), and moderate/severe pain at 0.34% (95% CI 0.08, 1.37). Minor complications at 9.53% (95% CI 3.68, 22.5) were mainly pain at 12.9% (95% CI 5.34, 27.9). Technical failure was high at 0.91% (95% CI 0.27, 3.00). Decreasing patient age significantly increased incidence of hospitalization and major bleeding (P < 0.0001). Hospitalization incidence also significantly increased with disease severity. CONCLUSIONS: Incidence of major (2.4%) and minor (9.5%) complications, and technical failure (0.91%) in percutaneous liver biopsies continues.

Cost-effectiveness of Antenatal Rescreening Among Pregnant Women for Hepatitis C in the United States.

To inform proposed changes in hepatitis C virus (HCV) screening guidelines in the United States, we assessed the cost-effectiveness of HCV antenatal rescreening for women without evidence of HCV during a prior pregnancy, using a previously published model. Universal HCV rescreening among pregnant women was cost-effective (incremental cost-effectiveness ratio, $6000 per quality-adjusted life-year) and should be recommended nationally.

Changing epidemiology, implications, and recommendations for hepatitis C in women of childbearing age and during pregnancy.

Despite the remarkable advances in HCV treatment brought about by the advent of direct-acting antivirals, HCV remains a global public health concern. One particular concern relates to the rising prevalence of HCV in women of childbearing age. Active HCV during pregnancy is associated with cholestasis of pregnancy as well as the risk of mother-to-child transmission. Guidelines are increasingly recommending universal screening during pregnancy, while the treatment of HCV during pregnancy is an area of ongoing research.

Potential Bias and Misconceptions in Liver Transplantation for Alcohol- and Obesity-Related Liver Disease.

INTRODUCTION: Bias and misconceptions surrounding alcohol-related liver disease (ALD) and obesity-related liver disease (OLD) may lead to transplant listing inequities. The aim of this study was to evaluate patients, medical students, residents, fellows, and attending physicians for bias and misconceptions regarding liver transplantation (LT) for patients with ALD and OLD. METHODS: Participants took a survey asking them whether patients with ALD who continue/discontinue drinking alcohol or patients with OLD who do/do not commit to a weight loss program deserve equal LT rights. A Likert scale was used for their responses. Participants also estimated 5-year survival and advanced fibrosis recurrence after LT. The primary outcome of the study was bias measured by expected agreement or disagreement to questions using a Likert scale, significant underestimation of a 5-year survival rate after LT, and significant overestimation of 5-year advanced fibrosis recurrence after LT. RESULTS: A total of 381 participants were included in the analysis: 153 residents/fellows, 31 attending physicians, 98 medical students, and 99 patients. A higher percentage from all 4 participating groups either were neutral or disagreed with equal LT rights for patients with ALD who discontinue drinking compared with patients with OLD who commit to weight loss program. The attending physician group was the only group with a majority estimating >60% 5-year survival after LT in patients with ALD and OLD (P < 0.05). All 4 groups had a majority estimate >20% 5-year advanced fibrosis recurrence in patients with ALD and OLD (P > 0.05). DISCUSSION: There seems to be current bias and misconceptions regarding LT for patients with ALD and OLD.

Willingness to participate in research among black patients with liver disease: A national cross-sectional study.

In the United States, Black people are disproportionately diagnosed with hepatitis C virus (HCV) compared with White people but are under-represented in HCV studies. In this US-based cross-sectional telephone survey study, we assessed willingness to participate (WTP) in health/medical research and attitudes and beliefs that may influence WTP among Black patients with HCV. Two hundred participants who had current or prior HCV diagnosis and self-identified as Black or African American were recruited from a national HCV cohort study and an outpatient hepatology clinic. WTP responses ranged from 1 (not at all willing) to 5 (very willing). Multivariable models were used to identify factors associated with the overall mean WTP score. In addition, an open-ended question solicited strategies to help increase research participation from the Black community. Overall, participants reported moderate WTP in research (Mean [95% Confidence Interval (CI)] = 3.78 [3.68, 3.88]). Of 13 types of research presented, participants reported lowest WTP for randomized controlled trials of medications (Mean [95% CI] = 2.31 [2.11, 2.50]). The initial multivariable model identified higher subjective knowledge of research as positively associated with WTP (Parameter estimate [95% CI] = 0.15 [0.02, 0.27]). Sensitivity analyses also identified higher perceived benefits of research as an additional factor associated with WTP. Qualitative findings indicate that greater community-based outreach efforts would increase accessibility of research opportunities. When given the opportunity to participate, Black participants with HCV reported moderate WTP in health/medical research. Research sponsors and investigators should employ community-based outreach to expand access and awareness of research opportunities.

Patient-reported outcomes 12 months after hepatitis C treatment with direct-acting antivirals: Results from the PROP UP study.

BACKGROUND & AIMS: The long-term impact of hepatitis C virus (HCV) therapy with all-oral direct-acting antivirals (DAAs) on patient-reported outcomes (PROs) has not been well-described. We characterized changes in PROs from pre-treatment to 12 months post-treatment in a real-world cohort. METHODS: PROP UP was a multi-centre observational cohort study of 1601 patients treated with DAAs at 11 US gastroenterology/hepatology practices from 2015 to 2017. PROs were evaluated pre-treatment (T1) and 12 months post-treatment (T5). A minimally important change (MIC) threshold was prespecified as >5% change in PRO scores from T1 to T5. Multivariable analyses identified predictors of change. RESULTS: Three-quarters of patients were 55 or older; 45% were female, 60% were white, 33% were black, nearly half had cirrhosis. The most commonly-prescribed DAA regimens were sofosbuvir-based (83%) and grazoprevir/elbasvir (11%). Study retention was >95%. On average, small improvements were observed at 3 months post-treatment in all PROs and sustained at 12 months post-treatment among patients with sustained virologic response (SVR). Clinically meaningful improvements were achieved in fatigue (mean change score: -3.7 [-4.2, -3.1]), sleep (mean change score: -3.1 [-3.7, -2.5]), abdominal pain (mean change score: -2.6 [-3.3, -1.9]) and functional well-being (mean change score: -7.0 [-6.0, -8.0]). Symptom improvements were generally not sustained with no SVR (n = 52). Patients with cirrhosis and MELD ≥12 had the greatest improvements in functional well-being (-12.9 [-17.6, -8.1]). CONCLUSIONS: The improvements in patient-reported outcomes reported by patients who achieved SVR following HCV DAA therapy were durable at 12 months post-treatment.

WGO Guidance for the Care of Patients With COVID-19 and Liver Disease.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the least deadly but most infectious coronavirus strain transmitted from wild animals. It may affect many organ systems. Aim of the current guideline is to delineate the effects of SARS-CoV-2 on the liver. Asymptomatic aminotransferase elevations are common in coronavirus disease 2019 (COVID-19) disease. Its pathogenesis may be multifactorial. It may involve primary liver injury and indirect effects such as "bystander hepatitis," myositis, toxic liver injury, hypoxia, and preexisting liver disease. Higher aminotransferase elevations, lower albumin, and platelets have been reported in severe compared with mild COVID-19. Despite the dominance of respiratory disease, acute on chronic liver disease/acute hepatic decompensation have been reported in patients with COVID-19 and preexisting liver disease, in particular cirrhosis. Metabolic dysfunction-associated fatty liver disease (MAFLD) has a higher risk of respiratory disease progression than those without MAFLD. Alcohol-associated liver disease may be severely affected by COVID-19-such patients frequently have comorbidities including metabolic syndrome and smoking-induced chronic lung disease. World Gastroenterology Organization (WGO) recommends that interventional procedures such as endoscopy and endoscopic retrograde cholangiopancreatography should be performed in emergency cases or when they are considered strictly necessary such as high risk varices or cholangitis. Hepatocellular cancer surveillance may be postponed by 2 to 3 months. A short delay in treatment initiation and non-surgical approaches should be considered. Liver transplantation should be restricted to patients with high MELD scores, acute liver failure and hepatocellular cancer within Milan criteria. Donors and recipients should be tested for SARS-CoV-2 and if found positive donors should be excluded and liver transplantation postponed until recovery from infection.

Medication Non-adherence in a Prospective, Multi-center Cohort Treated with Hepatitis C Direct-Acting Antivirals.

BACKGROUND: The prevalence and risk factors for non-adherence to direct-acting antivirals (DAAs) for chronic hepatitis C virus (HCV) in clinical practice settings are under-studied. OBJECTIVES: (1) To quantify DAA non-adherence in the total cohort and among subgroups with and without mental health conditions, alcohol use, and substance use, and (2) to investigate patient- and treatment-level risk factor non-adherence. DESIGN: Prospective, observational cohort study. PARTICIPANTS: A total of 1562 patients receiving DAAs between January 2016 and October 2017 at 11 US medical centers including academic and community practices. MAIN MEASURES: Self-reported medication non-adherence, defined as any missed doses in the past 7 days, surveyed early (T2: at 4 ± 2 weeks) and late in treatment (T3: 2-3 weeks prior to end of treatment). Non-adherence to post-treatment follow-up visits was defined as absence of lab results after DAA therapy completion. KEY RESULTS: Of 1447 patients, 162 (11%) reported non-adherence at T2 or T3. Medical records indicated 262 (17%) of the 1562 participants had not returned for post-treatment visits. At baseline, 37% of patients reported mental health conditions, 15% reported alcohol use, and 23% reported using substances in the previous year. Baseline characteristics associated with DAA non-adherence included alcohol use (OR 1.96), younger age (< 35 years vs. > 55 years: OR 3.40), non-white race (OR > 2.26), and DAA treatment cohort, but not substance use or mental health condition. Non-adherence to follow-up exhibited association with younger age and a higher baseline overall symptom burden. Among 1287 patients with evaluable sustained virologic response (SVR) data, 53 patients (4%) did not achieve SVR. The bivariate correlation between adherence and SVR was negligible (r = 0.01). CONCLUSIONS: DAA non-adherence was low and SVR rates were high. Mental health conditions, substance use, and alcohol use should not disqualify patients from DAA therapy. Patients with alcohol use disorder before DAA therapy initiation may benefit from targeted on-treatment support.

Cost-effectiveness of Universal Hepatitis C Virus Screening of Pregnant Women in the United States.

BACKGROUND: Hepatitis C virus' (HCV) chronic prevalence among pregnant women in the United States doubled nationally from 2009-2014 (~0.7%), yet many cases remain undiagnosed. Screening pregnant women is not recommended by the Society of Maternal-Fetal Medicine or the Centers for Disease Control and Prevention, despite new American Association For the Study of Liver Diseases (AASLD)/Infectious Diseases Society of America (IDSA) guidelines recommending screening for this group. We assessed the cost-effectiveness of HCV screening for pregnant women in the United States. METHODS: An HCV natural history Markov model was used to evaluate the cost-effectiveness of universal HCV screening of pregnant women, followed by treatment after pregnancy, compared to background risk-based screening from a health-care payer perspective. We assumed a HCV chronic prevalence of 0.73% among pregnant women, based on national data. We assumed no Medicaid reimbursement restrictions by fibrosis stage at baseline, but explored differing restrictions in sensitivity analyses. We assessed costs (in US dollars) and health outcomes (in quality-adjusted life-years [QALYs]) over a lifetime horizon, using new HCV drug costs of $25 000/treatment. We assessed mean incremental cost-effectiveness ratios (ICERs) under a willingness-to-pay threshold of $50 000/QALY gained. We additionally evaluated the potential population impact. RESULTS: Universal antenatal screening was cost-effective in all treatment eligibility scenarios (mean ICER <$3000/QALY gained). Screening remained cost-effective at a prevalence of 0.07%, which is the lowest estimated prevalence in the United States (in Hawaii). Screening the ~5.04 million pregnant women in 2018 could result in the detection and treatment of 33 000 women, based on current fibrosis restrictions. CONCLUSIONS: Universal screening for HCV among pregnant women in the United States is cost-effective and should be recommended nationally.

Patient-reported symptoms during and after direct-acting antiviral therapies for chronic hepatitis C: The PROP UP study.

BACKGROUND & AIMS: A comprehensive analysis of changes in symptoms and functioning during and after direct-acting antiviral (DAA) therapy for chronic hepatitis C virus (HCV) infection has not been conducted for patients treated in real-world clinical settings. Therefore, we evaluated patient-reported outcomes (PROs) in a diverse cohort of patients with HCV treated with commonly prescribed DAAs. METHODS: PROP UP is a US multicenter observational study of 1,601 patients with HCV treated with DAAs in 2016-2017. PRO data were collected at baseline (T1), early on-treatment (T2), late on-treatment (T3) and 3-months post-treatment (T4). PRO mean change scores were calculated from baseline and a minimally important change (MIC) threshold was set at 5%. Regression analyses investigated patient and treatment characteristics independently associated with PRO changes on-treatment and post-treatment. RESULTS: Of 1,564 patients, 55% were male, 39% non-white, 47% had cirrhosis. Sofosbuvir/ledipasvir was prescribed to 63%, sofosbuvir/velpatasvir to 21%, grazoprevir/elbasvir to 11%, and paritaprevir/ombitasvir/ritonavir + dasabuvir to 5%. During DAA therapy, mean PRO scores improved slightly in the overall cohort, but did not reach the 5% MIC threshold. Between 21-53% of patients experienced >5% improved PROs while 23-36% experienced >5% worse symptoms. Of 1,410 patients with evaluable sustained virologic response (SVR) data, 95% achieved SVR. Among those with SVR, all mean PRO scores improved, with the 5% MIC threshold met for fatigue, sleep disturbance, and functioning well-being. Regression analyses identified subgroups, defined by age 35-55, baseline mental health issues and a higher number of health comorbidities as predictors of PRO improvements. CONCLUSIONS: In real-world clinical practices, we observed heterogeneous patient experiences during and after DAA treatment. Symptom improvements were more pronounced in younger patients, those with baseline mental health issues and multiple comorbidities. LAY SUMMARY: Patients who received direct-acting antiviral medications for hepatitis C at several liver centers in the US did not generally experience significant changes in baseline symptoms during treatment. We observed a full range of patient experiences with some patients experiencing substantial symptom improvements, yet others experiencing less improvements and some even experiencing a worsening of symptoms. The 1,346 patients who were cured of hepatitis C experienced improvements in fatigue, sleep disturbance, and functional well-being, and trends for improved pain and depression; whereas the 64 who were not cured experienced minimal improvements. Clinicaltrial.gov: NCT02601820.

Glecaprevir/Pibrentasvir Treatment in Liver or Kidney Transplant Patients With Hepatitis C Virus Infection.

Well-tolerated, ribavirin-free, pangenotypic hepatitis C virus (HCV) treatments for transplant recipients remain a high priority. Once-daily glecaprevir/pibrentasvir demonstrates high rates of sustained virologic response at 12 weeks posttreatment (SVR12) across all major HCV genotypes (GTs). This trial evaluated the safety and efficacy of glecaprevir/pibrentasvir for patients with chronic HCV GT1-6 infection who had received a liver or kidney transplant. MAGELLAN-2 was a phase 3, open-label trial conducted in patients who were ≥3 months posttransplant. Patients without cirrhosis who were HCV treatment-naive (GT1-6) or treatment-experienced (GT1, 2, 4-6; with interferon-based therapy with or without sofosbuvir, or sofosbuvir plus ribavirin) received glecaprevir/pibrentasvir (300/120 mg) once daily for 12 weeks. The primary endpoint compared the percentage of patients receiving glecaprevir/pibrentasvir with SVR12 to a historic SVR12 rate based on the standard of care. Safety of glecaprevir/pibrentasvir was assessed. In total, 80 liver transplant and 20 kidney transplant patients participated in the trial. Most patients had no or minimal fibrosis (80% had fibrosis scores F0-F1) and were infected with HCV GT1 (57%) or GT3 (24%). The overall SVR12 was 98% (n/N = 98/100; 95% confidence interval, 95.3%-100%), which exceeded the prespecified historic standard-of-care SVR12 threshold of 94%. One patient experienced virologic failure. One patient discontinued because of an adverse event considered to be unrelated to treatment; this patient achieved SVR12. Adverse events were mostly mild in severity, and laboratory abnormalities were infrequent. CONCLUSION: Once-daily glecaprevir/pibrentasvir for 12 weeks is a well-tolerated and efficacious, ribavirin-free treatment for patients with chronic HCV GT1-6 infection who have received a liver or kidney transplant. (ClinicalTrials.gov NCT02692703.) (Hepatology 2018; 00:000-000).

Resistance analysis in patients with genotype 1-6 HCV infection treated with sofosbuvir/velpatasvir in the phase III studies.

BACKGROUND & AIMS: The fixed-dose combination of sofosbuvir/velpatasvir was highly efficacious in patients infected with genotype (GT)1-6 hepatitis C virus (HCV) in the ASTRAL studies. This analysis evaluated the impact of baseline resistance-associated substitutions (RASs) on treatment outcome and emergence of RASs in patients infected with HCV GT1-6 who were treated with sofosbuvir/velpatasvir. METHODS: Non-structural protein 5A and 5B (NS5A and NS5B) deep sequencing was performed at baseline and at the time of relapse for all patients treated with sofosbuvir/velpatasvir for 12 weeks (n = 1,778) in the ASTRAL-1-3, ASTRAL-5 and POLARIS-2-3 studies. RESULTS: Patients with 37 known and 19 novel HCV subtypes were included in these analyses. Overall, 28% (range 9% to 61% depending on genotype) had detectable NS5A class RASs at baseline, using a 15% sequencing assay cut-off. There was no significant effect of baseline NS5A class RASs on sustained virologic response at week 12 (SVR12) with sofosbuvir/velpatasvir; the SVR12 rate in the presence of NS5A class RASs was 100% and 97%, in patients with GT1a and GT1b infection, respectively, and 100% in patients with GT2 and GT4-6 infections. In GT3 infection, the SVR rate was 93% and 98% in patients with and without baseline NS5A class RASs, respectively. The overall virologic failure rate was low (20/1,778 = 1.1%) in patients treated with sofosbuvir/velpatasvir. Single NS5A class resistance was observed at virologic failure in 17 of the 20 patients. CONCLUSIONS: Sofosbuvir/velpatasvir taken for 12 weeks once daily resulted in high SVR rates in patients infected with GT1-6 HCV, irrespective of baseline NS5A RASs. NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients. LAY SUMMARY: Sofosbuvir/velpatasvir taken once daily for 12 weeks resulted in high sustained virologic response rates in patients infected with HCV, irrespective of the presence of NS5A resistance-associated variants prior to treatment. Single class NS5A inhibitor resistance, but not sofosbuvir resistance, was detected in the few patients with virologic failure. These data highlight the high barrier to resistance of this regimen for the treatment of chronic HCV across all genotypes in the vast majority of patients.