Management of dialysis patients with hepatitis C virus in the era of direct-acting antiviral therapy

The clinical use of direct-acting antivirals (DAAs) for hepatitis C virus (HCV) infection has dramatically changed management of patients with HCV liver disease since 2014; this is also true for patients undergoing dialysis. Due to the high tolerability and antiviral efficacy of anti-HCV therapy, most dialysis patients with HCV infection should currently be candidates for this treatment. Many patients with HCV antibodies no longer have HCV infection, and it is difficult to identify patients with actual HCV infection based only on HCV antibody assays. Despite the high rate of successful HCV eradication, the risk of liver-related events such as hepatocellular carcinoma (HCC), the major complication of HCV infection, persists even after HCV cure, and patients at risk of HCC should undergo continuous HCC surveillance. Finally, the rarity of HCV reinfection and the survival benefit of HCV eradication in dialysis patients should be explored in further studies.     

Risk factors for liver-related and non-liver-related mortality following a sustained virological response after direct-acting antiviral treatment for hepatitis C virus infection in a real-world cohort

A direct-acting antiviral (DAA)-induced sustained virological response (SVR) reduces the risk of mortality. However, the risk factors associated with liver-related and non-liver-related mortality following a SVR after DAA treatment are unclear. We assessed the incidence and risk factors of liver-related and non-liver-related mortality in 1180 patients who achieved a SVR after DAA treatment. During the follow-up period after DAA treatment (median duration, 1099 [range: 84–2345] days), 53 (4.5%) patients died: 15 due to liver-related mortality, 25 due to non-liver-related mortality and 13 due to unknown causes. The all-cause, liver-related and non-liver-related mortality rates were 14.9, 4.2 and 7.0/1000 person-years, respectively. In a multivariate analysis, the development of hepatocellular carcinoma (HCC) after DAA treatment (p = .009; hazard ratio [HR], 31.484), an estimated glomerular filtration rate (eGFR) at baseline ≤61.68 ml/min/1.73 m² (p = .015; HR, 6.607), and an α-fetoprotein level post-treatment ≥7.6 ng/ml (p = .041; HR, 18.490) were significantly associated with liver-related mortality. Furthermore, eGFR ≤67.94 ml/min/1.73 m² at baseline (p = .012; HR, 3.407) and albumin–bilirubin (ALBI) grade ≥ 2 at SVR (p = .024; HR, 3.449) were significantly associated with non-liver-related mortality. Early diagnosis and therapeutic interventions for HCC development after DAA treatment are important to reduce liver-related mortality. The ALBI grade, which reflects the hepatic functional reserve, is a useful predictor of non-liver-related mortality after a SVR induced by DAA treatment. Furthermore, the renal dysfunction caused by metabolic syndrome may affect prognosis even after eliminating hepatitis C virus.     

Real-world study of hepatitis C treatment with direct-acting antivirals in patients with drug abuse and opioid agonist therapy

Background: Limited data exist evaluating the treatment outcomes with direct-acting antivirals (DAAs) in patients with drug use in the community setting. We aim to assess the treatment response of DAAs in this subset of patients with or without the opioid agonist therapy (OAT).

Methods: All the hepatitis C virus (HCV) infected patients treated with DAAs were retrospectively analyzed. Patients were stratified into two groups by the presence or absence of abusing alcohol, cocaine and heroin. All the patients who were assigned to the abuser group had positive urine toxicology with one of the drugs during the DAA treatment. The primary assessment was the sustained virologic response (SVR12) at 12 weeks post-treatment (SVR12).

Results: Among the 314 patients, 152, 128 and 58 were patients with drug use, non-drug use and receiving OAT. Among the patients with injectable or non-injectable drug use treatment, completion rate was 99% (151/152) and SVR12 was 93.4%. Among the patients with no drug use treatment, completion rate was 95% (122/128) and SVR12 was 88.3%. Among patients receiving OAT alone, SVR12 was 100%, and in patients with OAT?+?other drug use, SVR12 was 96.5%. None of the patients included in this study discontinued the treatment due to adverse events associated with treatment medications.

Conclusions: In this community-based study, DAAs are safe, effective with high overall SVR12 in patients with active drug use (injectable and non-injectable) and OAT enrolled patients. These results support the removal of drug use as a barrier to DAA therapy.     

Hepatitis C care cascade before and during the direct-acting antiviral eras in New South Wales,Australia: A population-based linkage study

The hepatitis C virus (HCV) care cascade characterization is important for monitoring progress towards HCV elimination. This study evaluated HCV care cascade and factors associated with treatment during pre-DAA (2011–2012 and 2013–2015) and DAA (2016–2018) eras in New South Wales (NSW), Australia. We conducted a cohort study of people with an HCV notification (1993 to 2017) through end 2018, linked to administrative datasets, including HCV treatment and non-hospital services. Those aged <18 years, died within first 6 months of study period or notification, and who had successful HCV treatment in period before were excluded. Sex-specific spontaneous viral clearance was incorporated to estimate treatment-eligible population. The study population in each period were cumulative and brought forward from one period to the next. Among 115,667 people with HCV notification, 87,063 fulfilled eligibility criteria. During 2011 to 2012, 2013 to 2015, and 2016 to 2018, cumulative HCV notifications were 71,677, 77,969, and 80,017; 52,016, 56,793, and 57,467 were eligible for treatment; 29%, 48%, and 64% confirmed HCV RNA positive; and 0.6%, 5%, and 38% initiated HCV treatment, respectively. Birth cohort 1945 to 1964 (vs. ≥1965), males, non-Aboriginal ethnicity, regional/rural area of residence, and HCV/HIV co-infection were associated with higher treatment uptake. Incarceration and drug dependence were associated with higher treatment uptake during the DAA era. In Australia, many marginalized populations including those incarcerated and those with drug dependence have equitable treatment uptake in the DAA era. Targeted strategies are required to enhance treatment uptake for females and Aboriginal populations.     

Low prevalences of HBV and HCV infection in patients with primary biliary cirrhosis in Taiwan: A case control study

To study the role of hepatitis B virus (HBV) and hepatitis C virus (HCV) infection in patients with primary biliary cirrhosis (PBC) against the background of HBV and HCV infection in the general population, serum specimens from a consecutive series of 27 patients with PBC and 108 age/sex matched ‘healthy subjects’ as control group were submitted to assays for hepatitis B surface antigen (HBsAg), antibody to hepatitis B core antigen (anti-HBc), antibody to hepatitis B surface antigen (anti-HBs) and antibodies to hepatitis C virus (anti-HCV). None of the patients with PBC were HBsAg or anti-HCV positive while 17 (15.7%) and 6 (5.6%) of ‘healthy’ controls were HBsAg positive and anti-HCV positive (P= 0.017 and 0.26). Patients with PBC also had a significantly lower prevalence of HBV infection than matched controls (70.4%vs 88.9%, P= 0.022). The results suggest that neither HBV nor HCV plays any significant role in the pathogenesis of PBC, and that PBC would not develop or be masked in patients with HBV or HCV infection.     

Effectiveness and safety of elbasvir/grazoprevir therapy in patients with chronic HCV infection: Results from the Spanish HEPA‐C real‐world cohort

In randomized controlled trials of patients with chronic HCV infection, elbasvir/grazoprevir (EBR/GZR) demonstrated high cure rates and a good safety profile. This study assessed the effectiveness and safety of EBR/GZR, with and without ribavirin, in a real‐world HCV patient cohort. HEPA‐C is a collaborative, monitored national registry of HCV patients directed by the Spanish Association for the Study of the Liver and the Networked Biomedical Research Centre for Hepatic and Digestive Diseases. Patients entered into HEPA‐C between December 2016 and May 2017, and treated with EBR/GZR with at least end‐of‐treatment response data, were included. Demographic, clinical and virologic data were analysed, and adverse events (AEs) recorded. A total of 804 patients were included in the study. The majority were male (57.9%), with a mean age of 60 (range, 19‐92) years. Genotype (GT) distribution was GT 1, 86.8% (1a, 14.3%; 1b, 72.5%); GT 4, 13.2% and 176 patients (21.9%) were cirrhotic. Overall, among 588 patients with available data, 570 (96.9%) achieved sustained virologic response at 12 weeks post‐treatment (SVR12). SVR12 rates by genotype were GT 1a, 97.7%; GT 1b, 98.6%; and GT 4, 98.1%. No significant differences in SVR12 according to fibrosis stage were observed. Eighty patients experienced an AE, resulting in treatment discontinuation in three. In this large cohort of patients with chronic HCV managed in a real‐world setting in Spain, EBR/GZR achieved high rates of SVR12, comparable to those observed in randomized controlled trials, with a similarly good safety profile.     

Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma

Background/Aims: The influence of the infecting virus genotype on the progression of the underlying liver disease in patients with chronic hepatitis C virus (HCV) infection remains controversial. The aim of this study was to investigate the prevalence of HCV genotypes in Spanish patients with chronic HCV infection and to elucidate the relationship between the infecting genotype and severity of the disease.Methods: A cross-sectional, retrospective analysis of frequency distribution of HCV genotypes was carried out in 414 Spanish patients with chronic HCV infection, including 243 patients with asymptomatic or minimally symptomatic chronic hepatitis, 112 patients with cirrhosis and hepatocellular carcinoma and 59 patients with decompensated cirrhosis. HCV genotype was determined by restriction fragment length polymorphisms of the 5′ non-coding region.Results: Infection with HCV genotype 1b was found in 72% of patients with chronic hepatitis and in more than 90% of patients with cirrhosis, with or without hepatocellular carcinoma. Older age, infection with genotype 1b and absence of overt parenteral exposure as a possible source of infection were associated with cirrhosis and hepatocellular carcinoma by univariate analysis and this association was confirmed by regression analysis.Conclusions: HCV genotype 1b is associated with advanced liver disease in our geographical area. However, this may be related to a cohort-effect caused by over-representation of genotype 1b in older patients with more advanced disease, because, in our country, this HCV genotype appeared earlier in time and is therefore associated with more prolonged periods of infection.     

Fibromyalgia syndrome in chronic hepatitis C virus (HCV) infection patients: A potential association and pathogenic role

BackgroundHigher prevalence of fibromyalgia (FM) among chronic hepatitis-C virus (HCV) suspects virally-mediated pathway.Aim of the workTo determine the frequency and clinical characteristics of FM in Egyptian patients with chronic HCV and to evaluate its relationship to viral load.Patients and methods150 Egyptian patients with chronic HCV and 150 controls were included. Liver function tests, thyroid stimulating hormone (TSH), HCV antibodies, HCV-ribonucleic acid (RNA) and abdominal ultrasonography were done. FM was diagnosed according to 2010 American College of Rheumatology (ACR) classification criteria.ResultsThe mean age of the patients was 54.1 ± 8.4 years and they were 94 females: 56 males; and the mean duration of HCV was 6.9 ± 3.2 years. Fatigue, arthralgia, arthritis, morning stiffness, weakness, sicca-like symptoms, depression, cognitive, sleep disturbances and irritable bowel syndrome (IBS) were significantly more frequent in HCV patients. Twenty six patients with HCV (17.3%) and 4 (2.7%) of the controls had FM. HCV patients with FM had significantly higher widespread pain index, symptom severity score, visual analogue scale (VAS), tender points count and stiffness than controls with FM. HCV patients with FM had significant higher VAS score, fatigue and depression than without FM. Rates of hematological features, autoantibodies, liver enzymes, abdominal US findings, patients with viral load > 800,000 IU/L were comparable.ConclusionThere is increased rate of fibromyalgia in chronic HCV patients and is associated with higher pain intensity, tender point count, symptom severity and fatigue. FM in patients with HCV infection is not related to viral load of HCV.     

Hepatitis C virus testing,liver disease assessment and treatment uptake among people who inject drugs pre‐ and post‐universal access to direct‐acting antiviral treatment in Australia: The LiveRLife study

Gaps in hepatitis C virus (HCV) testing, diagnosis, liver disease assessment and treatment uptake among people who inject drugs (PWID) persist. We aimed to describe the cascade of HCV care among PWID in Australia, prior to and following unrestricted access to direct‐acting antiviral (DAA) treatment. Participants enrolled in an observational cohort study between 2014 and 2018 provided fingerstick whole‐blood samples for dried blood spot, Xpert HCV Viral Load and venepuncture samples. Participants underwent transient elastography and clinical assessment by a nurse or general practitioner. Among 839 participants (mean age 43 years), 66% were male (n = 550), 64% (n = 537) injected drugs in the previous month, and 67% (n = 560) reported currently receiving opioid substitution therapy. Overall, 45% (n = 380) had detectable HCV RNA, of whom 23% (n = 86) received HCV treatment within 12 months of enrolment. HCV treatment uptake increased from 2% in the pre‐DAA era to 38% in the DAA era. Significant liver fibrosis (F2‐F4) was more common in participants with HCV infection (38%) than those without (19%). Age 50 years or older (aOR, 2.88; 95% CI, 1.18‐7.04) and attending a clinical follow‐up with nurse (aOR, 3.19; 95% CI, 1.61‐6.32) or physician (aOR, 11.83; 95% CI, 4.89‐28.59) were associated with HCV treatment uptake. Recent injection drug use and unstable housing were not associated with HCV treatment uptake. HCV treatment uptake among PWID has increased markedly in the DAA era. Evaluation of innovative and simplified models of care is required to further enhance treatment uptake.     

Therapy with ombitasvir/paritaprevir/ritonavir plus dasabuvir is effective and safe for the treatment of genotypes 1 and 4 hepatitis C virus (HCV) infection in patients with severe renal impairment: A multicentre experience

Limited data are available on direct‐acting antivirals for treating hepatitis C virus (HCV) infection in patients with severe renal impairment. The aim of this study was to evaluate the effectiveness and safety of ombitasvir/paritaprevir/ritonavir (OBV/PTV/r) ± dasabuvir (DSV) ± ribavirin (RBV) in patients with stage 4 or 5 chronic kidney disease (CKD) and HCV genotype 1 or 4 infection in real clinical practice, and to investigate pharmacological interactions. This retrospective study included patients treated with OBV/PTV/r+DSV±RBV or OBV/PTV/r+RBV with CKD stage 4 (eGFR: 15‐29 mL/min/1.73m²) or 5 (eGFR<15 mL/min/1.73m² or requiring dialysis) and HCV infection by genotypes 1 and 4 between April 2015 and October 2015 in nine Spanish centres. Sustained virological response at 12 weeks (SVR12) was assessed, and clinical and laboratory data, fibrosis stage, adverse events and pharmacological interactions were reported. Forty‐six patients were included: 10 (21.7%) had CKD stage 4 and 36 (78.2%) CKD stage 5. Seventeen (36.9%) had cirrhosis. SVR12 rate in the intention‐to‐treat population was 95.7%. Twenty‐one (45.6%) received RBV, which was discontinued in two (9.5%) patients. Anaemia (haemoglobin <10 g/dl) occurred in 12 patients (57.1%) with RBV vs 10 (40.0%) without RBV (P=.246). Renal function remained stable during antiviral therapy. Nine patients (19.5%) experienced serious adverse events unrelated to antiviral therapy. Concomitant medication was discontinued or modified in 41.3% of patients. In conclusion, the effectiveness of OBV/PTV/r±DSV±RBV in patients with CKD 4‐5 was similar to that observed in those with normal renal function and was not associated with severe adverse events.     

Real-World Safety,Effectiveness, and Patient-Reported Outcomes in Patients with Chronic Hepatitis C Virus Infection Treated with Glecaprevir/Pibrentasvir: Updated Data from the German Hepatitis C-Registry (DHC-R)

Using data from the German Hepatitis C-Registry (Deutsche Hepatitis C-Register, DHC-R), we report the real-world safety and effectiveness of glecaprevir/pibrentasvir (GLE/PIB) treatment and its impact on patient-reported outcomes (PROs) in underserved populations who are not typically included in clinical trials, yet who will be crucial for achieving hepatitis C virus (HCV) elimination. The DHC-R is an ongoing, non-interventional, multicenter, prospective, observational cohort study on patients treated for chronic HCV infection in Germany. The data cutoff was 17 January 2021. The primary effectiveness endpoint was sustained virologic response at post-treatment Week 12 (SVR12). Safety outcomes were assessed in all patients receiving GLE/PIB. PROs were assessed using the SF-36 survey. Of 2354 patients, 1964 had valid SVR12 data (intention-to-treat analysis). Of these, 1905 (97.0%) achieved SVR12 with rates similar across the comorbidities analyzed, except for people who actively use drugs (PWUD (active)) (86.4%). Excluding those who discontinued treatment and did not achieve SVR12, or were reinfected with HCV, the rate was 99.3%, with similar results regardless of comorbidity. PWUD (active) and those with psychiatric disorders had the most meaningful improvements in PROs. Adverse events (AEs) occurred in 631/2354 patients (26.8%), and serious AEs in 44 patients (1.9%). GLE/PIB was highly effective and well tolerated in this real-world study of patient groups key to HCV elimination.     

Efficacy and safety of telaprevir (TVR) triple therapy in a ‘real‐life’ cohort of 102 patients with HCV genotype 1: interim analysis after 24 weeks of treatment

Since 2011, telaprevir (TVR)‐based triple therapy is the new treatment standard for hepatitis C genotype 1 virus infection. The aim of our retrospective interim analysis encompassing the first 24 weeks on TVR‐based triple therapy was to assess ‘real‐life’ antiviral efficacy and side effects in a large single‐centre cohort, both in comparison with the data obtained in large prospective clinical trials. In total, we treated 102 patients: 24 treatment‐naïve patients, 58 patients pretreated with PEG‐IFN/RBV (thereof: 28 with nonresponse, 25 with relapse, five unknown) and 20 patients who previously had received nonpegylated interferon. 74 of 102 patients were assigned with HCV genotype 1b; 34 of 102 patients were treated in the context of liver cirrhosis. 72 of 102 patients have reached treatment week 24 (mean treatment duration 31 weeks). In the ITT analysis, overall response rates were at: week 4: 66%; week 12: 85%; and week 24: 78%. So far, 24 patients discontinued treatment prematurely, of those, 10 patients were due to virological failure. Haematological side effects were frequent (40% anaemia), as were ‘flu‐like’ symptoms (94%), rash (65%) and pruritus (79%). According to our interim ITT analysis encompassing up to 24 weeks of TVR‐based triple therapy, our ‘real‐life’ antiviral effects are comparable to the results of large multicentric clinical trials. However, TVR‐based triple therapy exhibited a high frequency of side effects requiring multiple therapeutic interventions. Notably, in our ‘real‐life’ cohort, no lethal case was observed so far.