Explore the vast range of titles available.

Hepatitis C virus infection is a major cause of hepatocellular carcinoma worldwide. Interferon has been the major antiviral treatment, yielding viral clearance in approximately half of patients. New direct-acting antivirals substantially improved the cure rate to above 90%. However, access to therapies remains limited due to the high costs and under-diagnosis of infection in specific subpopulations, e.g., baby boomers, inmates, and injection drug users, and therefore, hepatocellular carcinoma incidence is predicted to increase in the next decades even in high-resource countries. Moreover, cancer risk persists even after 10 years of viral cure, and thus a clinical strategy for its monitoring is urgently needed. Several risk-predictive host factors, e.g., advanced liver fibrosis, older age, accompanying metabolic diseases such as diabetes, persisting hepatic inflammation, and elevated alpha-fetoprotein, as well as viral factors, e.g., core protein variants and genotype 3, have been reported. Indeed, a molecular signature in the liver has been associated with cancer risk even after viral cure. Direct-acting antivirals may affect cancer development and recurrence, which needs to be determined in further investigation.

Hepatitis C virus (HCV) is a hepatotropic RNA virus that causes progressive liver damage, which might result in liver cirrhosis and hepatocellular carcinoma. Globally, between 64 and 103 million people are chronically infected. Major risk factors for this blood-borne virus infection are unsafe injection drug use and unsterile medical procedures (iatrogenic infections) in countries with high HCV prevalence. Diagnostic procedures include serum HCV antibody testing, HCV RNA measurement, viral genotype and subtype determination and, lately, assessment of resistance-associated substitutions. Various direct-acting antiviral agents (DAAs) have become available, which target three proteins involved in crucial steps of the HCV life cycle: the NS3/4A protease, the NS5A protein and the RNA-dependent RNA polymerase NS5B protein. Combination of two or three of these DAAs can cure (defined as a sustained virological response 12 weeks after treatment) HCV infection in >90% of patients, including populations that have been difficult to treat in the past. As long as a prophylactic vaccine is not available, the HCV pandemic has to be controlled by treatment-as-prevention strategies, effective screening programmes and global access to treatment. Hepatitis C virus infection can cause acute and chronic hepatitis C, which are both characterized by inflammation of the liver. In this Primer, Manns et al. describe the latest developments against the global hepatitis C epidemic in the era of highly effective therapies.

Hepatitis C virus (HCV) has high global prevalence and can lead to liver complications and death. Access to direct-acting antivirals (DAAs) in Canada increased following several policy changes, however the real-world impact of expanded DAA access and increased use of these drugs is unknown. We aimed to determine the early change in rates of HCV-related hospitalizations overall and HCV-related hospitalizations with hepatocellular carcinoma (HCC) after expanded DAA access. We conducted a population-based time series analysis using national administrative health databases in Canada. Rates of HCV-related hospitalizations and HCV-related hospitalizations with HCC were enumerated monthly between April 2006 and March 2020. We used Autoregressive Integrated Moving Average (ARIMA) models with ramp functions in October 2014 and January 2017 to evaluate the impact of policies to expand DAA access on hospitalization outcomes. Rates of HCV-related hospitalizations in Canada increased between 2006 and 2014, and gradually declined thereafter. The decrease after October 2014, or the first policy change, was significant (p = 0.0355), but no further change was found after the second policy change in 2017 (p = 0.2567). HCV-related hospitalizations with HCC increased until end of 2013, followed by a plateau, before declining in 2016. No significant shifts were found after the first policy change in 2014 (p = 0.1291) nor the second policy change in 2017 (p = 0.6324). Subgroup analyses revealed that those aged 50-64 and males had observable declines in rates of HCV-related hospitalizations in the year prior to the first policy change. Expanding DAA access was associated with a drop in HCV-related hospitalizations in the overall Canadian population coinciding with the 2014 policy change. In light of the time required for HCV-related complications to manifest, continued ongoing research examining the real-world effectiveness of DAAs is required.

Direct-acting antiviral agents (DAAs) have modified the management of chronic hepatitis C virus (HCV) infection, including HCV-related cryoglobulinemic vasculitis (CryoVas). However, patients might experience vasculitis relapse, and no reliable predictors of CryoVas relapse after sustained virologic response (SVR) have been established. We aimed to describe HCV-CryoVas relapse rates and factors associated with it. An international multicenter cohort where patients with HCV-CryoVas from Egypt, France, and Italy treated with DAA were analyzed retrospectively. Factors associated with relapse-free survival were evaluated in a multivariate-adjusted model. Of 913 patients, 911 (99.8%) obtained SVR. After 35 months of the median follow-up, 798 patients (87.4%) had sustained remission of vasculitis, while 115 (12.6%) experienced CryoVas relapse. By the time of relapse, skin involvement was present in 100%, renal involvement in 85.2%, and peripheral neuropathy in 81.7%. Relapses were treated with glucocorticoids in 90.9%, associated with plasma exchange, cyclophosphamide, or rituximab in 50%, 37.3%, and 6.4%, respectively. The cumulative incidence of CryoVas relapse was 0.7% (95% CI 0.3-1.4), 12.3% (95% CI 10.2-14.6), and 13.1% (95% CI 11.0-15.5) at 12, 24, and 36 months after DAA treatment, respectively. Independent baseline risk factors associated with CryoVas relapse were male sex, skin ulcers, kidney involvement at baseline, and peripheral neuropathy at the end of DAA treatment. Death occurred in 11 relapsers, mainly due to infections. A substantial proportion of patients with CryoVas experience relapse after DAA-induced SVR. Relapses are moderate-to-severe and affect survival after 24 months, mainly due to infections. Independent risk factors for relapse or death were found.

Key Points Patients co-infected with HCV and HIV are at increased risk of accelerated disease progression, resulting in higher rates of liver decompensation and death compared with patients monoinfected with HCV HIV accelerates HCV-related fibrosis progression through multiple mechanisms HIV suppression seems to reduce fibrosis progression and decrease rates of hepatic decompensation among co-infected patients Successful HCV therapy is associated with a halting of fibrosis progression and decreased complications from end-stage liver disease, but historical rates of sustained virologic response have been significantly lower among co-infected patients than those for chronic HCV monoinfection Promising data exist for all-oral direct-acting antiviral agents suggesting improved efficacy and tolerability, which supports their use in co-infection HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection. However, with multiple direct acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients. In this Review, the authors address the epidemiology, natural history, pathogenesis and management of HIV and HCV co-infection. HCV and HIV co-infection is associated with accelerated hepatic fibrosis progression and higher rates of liver decompensation and death compared to HCV monoinfection, and liver disease is a leading cause of non-AIDS-related mortality among HIV-infected patients. New insights have revealed multiple mechanisms by which HCV and HIV lead to accelerated disease progression, specifically that HIV infection increases HCV replication, augments HCV-induced hepatic inflammation, increases hepatocyte apoptosis, increases microbial translocation from the gut and leads to an impairment of HCV-specific immune responses. Treatment of HIV with antiretroviral therapy and treatment of HCV have independently been shown to delay the progression of fibrosis and reduce complications from end-stage liver disease among co-infected patients. However, rates of sustained virologic response with PEG-IFN and ribavirin have been significantly inferior among co-infected patients compared with HCV-monoinfected patients, and treatment uptake has remained low given the limited efficacy and tolerability of current HCV regimens. With multiple direct-acting antiviral agents in development to treat HCV, a unique opportunity exists to redefine the treatment paradigm for co-infected patients, which incorporates data on fibrosis stage as well as potential drug interactions with antiretroviral therapy.

There are limited data on the effect and evolution of risk factors for hepatocellular carcinoma (HCC) in patients with virologically cured hepatitis C virus (HCV) infection. We conducted a retrospective cohort study of patients with HCV who achieved sustained virological response with direct-acting antivirals from 130 Veterans Administration hospitals during 2014-2018, followed through 2021. Cox proportional hazards models were constructed at 3 landmark times (baseline and 12 and 24 months after sustained virological response) to examine associations between demographic, clinical, and behavioral factors and HCC risk, stratified by cirrhosis status. Among 92,567 patients (32% cirrhosis), 3,247 cases of HCC were diagnosed during a mean follow-up of 2.5 years. In patients with cirrhosis, male sex (hazard ratios [HR]: 1.89, 1.93, and 1.99), cirrhosis duration ≥5 years (HR: 1.71, 1.79, and 1.34), varices (HR: 1.73, 1.60, and 1.56), baseline albumin (HR: 0.48, 0.47, and 0.49), and change in albumin (HR: 0.82 and 0.90) predicted HCC risk at each landmark time. HCV genotype 3, previous treatment, bilirubin, smoking, and race influenced HCC risk at baseline, but their effects attenuated over time. In patients without cirrhosis, diabetes (HR: 1.54, 1.42, and 1.47) and hypertension (HR: 1.59, 1.65, and 1.74) were associated with HCC risk at all landmark times. Changes in fibrosis-4 scores over time were associated with HCC risk both in patients with and without cirrhosis. Risk factors for HCC were different in patients with and without cirrhosis and some also evolved during follow-up. These factors can help with risk stratification and HCC surveillance decisions in patients with cured HCV.

Chronic hepatitis C virus (HCV) infection contributes to substantial morbidity and mortality among adults living with HIV. Cascades of HCV care support monitoring of program performance, but data from Asia are limited. We assessed regional HCV coinfection and cascade outcomes among adults living with HIV in care from 2010-2020. Patients ≥18 years old with confirmed HIV infection on antiretroviral therapy (ART) at 11 clinical sites in Cambodia, China, India, Indonesia, South Korea, Thailand and Vietnam were included. HCV- and HIV-related treatment and laboratory data were collected from those with a positive HCV antibody (anti-HCV) test after January 2010. An HCV cascade was evaluated, including proportions positive for anti-HCV, tested for HCV RNA or HCV core antigen (HCVcAg), initiated on HCV treatment, and achieved sustained virologic response (SVR). Factors associated with screening uptake, treatment initiation, and treatment response were analyzed using Fine and Gray's competing risk regression model. Of 24,421 patients, 9169 (38%) had an anti-HCV test, and 971 (11%) had a positive result. The proportion with positive anti-HCV was 12.1% in 2010-2014, 3.9% in 2015-2017, and 3.8% in 2018-2020. From 2010 to 2014, 34% with positive anti-HCV had subsequent HCV RNA or HCVcAg testing, 66% initiated HCV treatment, and 83% achieved SVR. From 2015 to 2017, 69% with positive anti-HCV had subsequent HCV RNA or HCVcAg testing, 59% initiated HCV treatment, and 88% achieved SVR. From 2018 to 2020, 80% had subsequent HCV RNA or HCVcAg testing, 61% initiated HCV treatment, and 96% achieved SVR. Having chronic HCV in later calendar years and in high-income countries were associated with increased screening, treatment initiation or achieving SVR. Older age, injecting drug use HIV exposure, lower CD4 and higher HIV RNA were associated with reduced HCV screening or treatment initiation. Our analysis identified persistent gaps in the HCV cascade of care, highlighting the need for focused efforts to strengthen chronic HCV screening, treatment initiation, and monitoring among adult PLHIV in the Asia region.

The clinical and metabolic interactions between hepatitis C virus (HCV) infection and diabetes mellitus (DM) are well documented. The study aimed to compare HCV-infected patients with and without DM. The analysis included 18,968 patients treated with direct-acting antivirals (DAAs) between 2015 and 2023, whose data were collected retrospectively. In the study population, 2179 patients (11.5%) were diagnosed with DM. Compared to the non-diabetic population, they were male-dominated ( p  = 0.003), had a significantly higher proportion of patients aged ≥ 50 years ( p  < 0.001), and were more burdened with comorbidities ( p  < 0.001). The most common HCV genotype was 1b with a significantly higher prevalence in the diabetic group ( p  < 0.001). Liver disease advancement was higher in diabetic patients, with 17.9% advanced fibrosis and 48% cirrhosis compared to 13.2% ( p  < 0.001) and 21.8% ( p  < 0.001) in the non-diabetic population. The effectiveness of DAA therapy in patients with DM was significantly lower compared to the population without diabetes, both in intent-to-treat analysis 93.1% vs. 94.6%, p  = 0.015, and per-protocol analysis 96.8% vs. 97.7%, p  = 0.0128, however, logistic regression analysis did not confirm the role of diabetes as an independent predictor of treatment failure, suggesting that in the absence of other negative prognostic factors, DM alone does not reduce the chances of cure.

People with substance use disorders (SUD) have a high prevalence of chronic hepatitis C virus (HCV) infection and mental health disorders. We aimed to assess the impact of integrated HCV treatment on psychological distress measured by Hopkins-symptom-checklist-10 (SCL-10). This multi-center randomized controlled trial evaluated psychological distress as a secondary outcome of integrated HCV treatment (INTRO-HCV trial). From 2017 to 2019, 289 participants were randomly assigned to receive either integrated or standard HCV treatment with direct-acting antiviral therapy. Integrated HCV treatment was delivered in eight decentralized outpatient opioid agonist therapy clinics and two community care centers; standard treatment was delivered in internal medicine outpatient clinics at centralized hospitals. Participants in the integrated treatment arm had a sustained virologic response of 93% compared to 73% for those in standard treatment arm. Psychological distress was assessed using SCL-10 prior to initiation of HCV treatment and 12 weeks after treatment completion. The mean SCL-10 score prior to HCV treatment was 2.2 (standard deviation [SD]: 0.7) for patients receiving integrated HCV treatment and 2.2 (SD: 0.8) for those receiving standard HCV treatment. Twelve weeks after the end of treatment, the mean SCL-10 score change was − 0.1 (− 0.3;0.0) in the integrated compared to the standard arm. Psychological distress did not substantially change during the treatment period and was not significantly different between the treatment arms.

Various immune checkpoint proteins have been linked to cirrhosis. This study aimed to explore the association between plasma levels of these proteins measured one year after successful HCV treatment and persistently liver stiffness (defined as liver stiffness measurement (LSM) ≥ 12.5 kPa) five years after HCV treatment in people with HIV (PWH). We conducted a retrospective study involving 39 patients with HIV/HCV-coinfection who had advanced fibrosis or cirrhosis and achieved sustained virologic response (SVR). Plasma samples were obtained one year after treatment, and levels of immune checkpoints along with inflammatory biomarkers were evaluated using a Luminex 200TM analyzer. Statistical analyses were performed using Generalized Linear Models (GLMs) with a gamma distribution. Spearman correlation tests were used to analyze the correlation between significant immune checkpoints and inflammatory biomarkers. Although LSM values showed a decreasing trend over the years following successful HCV treatment, this trend was not statistically significant due to substantial variability among PWH. Persistently high liver stiffness was observed in 61.5% of patients five years after HCV treatment. Elevated plasma levels of soluble BTLA, PD-1, and TIM-3 one year after HCV treatment were associated with persistently liver stiffness five years later. These significant immune checkpoints were found to correlate with inflammatory biomarkers in PWH with persistently high liver stiffness. In conclusion, increased plasma concentrations of immune checkpoints one year after successful HCV therapy were linked to persistently high liver stiffness five years later, particularly BTLA, PD-1, and TIM-3. This suggests a potential immunopathological mechanism in ongoing liver stiffness post-HCV eradication.