Critical issues in the treatment of hepatitis C virus infection in methadone maintenance patients

AIMS: Hepatitis C virus (HCV) infection is a common chronic complication of injection drug use. Methadone maintenance programs contain large numbers of patients infected with HCV. This paper reviews HCV infection with emphasis on the medical care of HCV-infected, or HCV and human immunodeficiency virus co-infected, patients on methadone or buprenorphine maintenance. METHODS: Literature searches using PubMed, PsycINFO and SocINDEX were used to identify papers from 1990-present on antiviral therapy for HCV in methadone maintenance patients and on liver transplantation in methadone maintenance patients. RESULTS: Injection drug use is the most significant risk factor for HCV infection in most western countries. The prevalence of HCV antibody is high in injection drug users (53-96%) and in patients enrolled in methadone maintenance programs (67-96%). Studies of antiviral therapy for HCV in methadone maintenance patients show rates of sustained virological response (SVR), defined as negative HCV-RNA 24 weeks after the end of treatment, of 28-94%. In studies with contrast groups, no significant differences in SVR between methadone and contrast groups were found. Excellent completion rates of antiviral therapy (72-100%) were found in five of six studies. There are many barriers to methadone maintenance patients' receiving antiviral therapy, and research on overcoming barriers is discussed. Liver transplantation has been successful in methadone maintenance patients but has not been utilized widely. CONCLUSION: High quality medical care for all aspects of HCV infection can be provided to methadone maintenance patients. The literature supports the effectiveness of such services, but the reality is that most patients do not receive them.     

Monitoring hepatitis C virus treatment rates in an Opioid Treatment Program:A longitudinal study

BACKGROUND Direct-acting antivirals(DAAs) are recommended for the treatment of hepatitis C virus(HCV) infection in patients treated with methadone or buprenorphine.AIM To assess HCV treatment rates in an Opioid Treatment Program(OTP).METHODS This longitudinal study included 501 patients(81.4% men, median age: 45 years; interquartile range: 39-50 years) enrolled in an OTP between October 2015 and September 2017. Patients were followed until September 2019. Data on sociodemographics, substance use, HCV infection, human immunodeficiency virus(HIV) infection and laboratory parameters were collected at entry. We analyzed medical records to evaluate HCV treatment. Kaplan-Meier methods and Cox regression models were used to analyze the DAA treatment uptake and to identify treatment predictors.RESULTS Prevalence of HCV and HIV infection was 70% and 34%, respectively. Among anti-HCV-positive(n = 336) patients, 47.2%, 41.3%, and 31.9% used alcohol,cannabis, and cocaine, respectively. HCV-RNA tests were positive in 233(69.3%) patients. Twentyeight patients(8.3%) cleared the infection, and 59/308(19.1%) had received interferon-based treatment regimens before 2015. Among 249 patients eligible, 111(44.6%) received DAAs. Treatment rates significantly increased over time from 7.8/100 person-years(p-y)(95%CI: 5.0-12.3) in 2015 to 18.9/100 p-y(95%CI: 11.7-30.3) in 2019. In a multivariate analysis, patients with HIV co-infection were twice as likely to receive DAAs(HR = 1.94, 95%CI: 1.21-3.12) than patients with HCV mono-infection. Current drug use was an independent risk factor for not receiving treatment against infection(HR = 0.48, 95%CI: 0.29-0.80).CONCLUSION HCV treatment is evolving in patients with HCV-HIV co-infection. Ongoing drug use while in an OTP might negatively impact the readiness to treat infection.     

Reinfection with hepatitis C virus following sustained virological response in injection drug users

Background and Aim: Despite that 60–90% of injection drug users (IDUs) are infected with hepatitis C virus (HCV) infection, IDUs are often denied therapy based on concerns of reinfection following treatment. However, there are little data in this regard. We evaluated HCV re‐infection following sustained virologic response (SVR) among HCV‐infected IDUs having received HCV treatment in a multidisciplinary program. Methods: Following treatment, participants were encouraged to return at follow‐up intervals of 1 year and illicit drug use histories were obtained. In those with SVR, HCV RNA testing by PCR was performed to determine if relapse or reinfection occurred. Results: Among 58 receiving HCV treatment between January 2002 and December 2006, 60% (35 of 58) achieved an SVR. Patients were followed for a median of 2.0 years following SVR (range, 0.4–5.0 years), with ongoing illicit and injection drug use reported in 54% (19 of 35) and 46% (16 of 35). Of the 35 with SVR, 28 remained HCV RNA negative during follow‐up (80%), with four lost to follow‐up and one dying of hepatocellular carcinoma and two cases of reinfection were observed (2 of 35). The rates of reinfection were 3.2 per 100 p‐y (95% CI:0.4, 11.5) overall and 5.3 per 100 p‐y (95% CI:0.6, 19.0) among those reporting injecting following SVR (n = 16). One of two participants with HCV re‐infection spontaneously cleared virus following reinfection. Conclusion: The rate of reinfection following treatment for HCV infection among current and former IDUs engaged in a multidisciplinary program is low.     

Treatment of hepatitis C virus infection with direct‐acting antiviral drugs is safe and effective in patients with hemoglobinopathies

Progression of liver fibrosis in patients with hemoglobinopathies is strongly related to the severity of iron overload and the presence of chronic hepatitis C virus (HCV) infection. Effective iron chelation therapy and HCV infection eradication may prevent liver complications. The European Association for the Study of the Liver guidelines recommend interferon‐free regimens for the treatment of HCV infection in patients with hemoglobinopathies. However, data regarding the use of direct‐acting antiviral drugs (DAAs) in this patient population are few. This observational study evaluated the safety and efficacy of therapy with DAAs in an Italian cohort of patients with hemoglobinopathies, chronic HCV infection and advanced liver fibrosis. Between March 2015 and December 2016, 139 patients received DAAs and completed 12 weeks of follow up after the end of treatment for the evaluation of sustained virological response (12SVR). The 12SVR (93.5%) was comparable with that typically observed in cirrhotic patients without hemoglobinopathies. Three patients died during the period of observation of causes unrelated to DAAs. One patient did not achieve a virological response and five (3.6%) relapsed during 12 weeks of follow‐up after the end of therapy. In addition, patients showed significant reductions in serum ferritin at 12 weeks to levels similar to those observed in a control group of 39 patients with thalassemia major without HCV infection, who adhered to chelation therapy and had no overt iron overload. In conclusion, the use of DAAs appears to be safe and effective in patients with hemoglobinopathies and advanced liver disease due to HCV.     

Effect and Safety of Daclatasvir‐Asunaprevir Combination Therapy for Chronic Hepatitis C Virus Genotype 1b ‐Infected Patients on Hemodialysis

The prevalence of anti‐hepatitis C virus (HCV)antibodies is higher in hemodialysis patients than in the general population, and several studies have reported poor vital prognosis in HCV‐infected dialysis patients because infection with HCV is not only the cause of cirrhosis and hepatocellular carcinoma, but also a risk factor for cardiovascular disease. Although sustained virologic response (SVR) is achievable with interferon and ribavirin in dialysis patients, SVR rates are lower, and the use of ribavirin is challenging because of the risk of hemolytic anemia. Recently, interferon‐ribavirin free direct acting antivirals (DAAs) treatment has shown strong efficacy and fewer adverse events for chronic HCV infection patients without using dialysis, but there are few reports about DAAs for such patients. Thus, we conducted a study to examine the effect and safety of daclatasvir and asunaprevir in chronic hepatitis C virus genotype 1b‐infected hemodialysis patients. We treated 10 patients: seven males and three females. Before treatment, we detected resistance‐associated variants on the NS5A region, which is the L31M site variant, in two patients. Although two patients showed resistance‐associated variant, all the patients showed quick disappearance of HCV RNA in the serum and achieved a SVR12. During this therapy, no patients displayed abnormal liver function during treatment. Two patients experienced diarrhea and another one patient complained of nausea soon after treatment but these were relieved by symptomatic therapy. We report good results of treatment for chronic hepatitis C virus genotype 1b ‐infected patients on hemodialysis with all oral DAAs (daclatasvir and asunaprevir).     

Treatment of Chronic Hepatitis C in the Age of Direct-Acting Antivirals with Emphasis on First Generation Inhibitors of HCV NS3/4A Protease

The past standard-of-care (SOC) for treatment of the chronic hepatitis C virus (HCV) was the combination of peginterferon with ribavirin (P + R). Sustained virologic response (SVR) for patients with HCV, genotype 1, was less than 50%. The new emerging SOC, Triple Therapy, using direct-acting antivirals (DAAs) with P + R will improve SVR for HCV genotype 1 infection to approximately 75%. Telaprevir and boceprevir are inhibitors of HCV NS3/4A serine protease and will be the first DAAs for treatment of patients with chronic hepatitis C. The treatment provider must effectively manage dosage and adherence to the regimen to avoid emergence of resistant variants of HCV. Close monitoring of patients, awareness of drug interactions, management of known telaprevir and boceprevir side effects, and strategies for reduction or discontinuation of individual drugs in the treatment regimen will be critical to ultimate success of triple therapy.     

Buprenorphine versus methadone maintenance therapy: a randomized double-blind trial with 405 opioid-dependent patients

Aims To assess the efficacy of buprenorphine compared with methadone maintenance therapy for opioid dependence in a large sample using a flexible dosing regime and the marketed buprenorphine tablet. Design Patients were randomized to receive buprenorphine or methadone over a 13‐week treatment period in a double‐blind, double‐dummy trial. Setting Three methadone clinics in Australia. Participants Four hundred and five opioid‐dependent patients seeking treatment. Intervention Patients received buprenorphine or methadone as indicated clinically using a flexible dosage regime. During weeks 1–6, patients were dosed daily. From weeks 7–13, buprenorphine patients received double their week 6 dose on alternate days. Measurements Retention in treatment, and illicit opioid use as determined by urinalysis. Self‐reported drug use, psychological functioning, HIV‐risk behaviour, general health and subjective ratings were secondary outcomes. Findings Intention‐to‐treat analyses revealed no significant difference in completion rates at 13 weeks. Methadone was superior to buprenorphine in time to termination over the 13‐week period (Wald χ² = 4.371, df = 1, P = 0.037), but not separately for the single‐day or alternate‐day dosing phases. There were no significant between‐group differences in morphine‐positive urines, or in self‐reported heroin or other illicit drug use. The majority (85%) of the buprenorphine patients transferred to alternate‐day dosing were maintained in alternate‐day dosing. Conclusions Buprenorphine did not differ from methadone in its ability to suppress heroin use, but retained approximately 10% fewer patients. This poorer retention was due possibly to too‐slow induction onto buprenorphine. For the majority of patients, buprenorphine can be administered on alternate days.     

Treatment of Hepatitis C virus infection in Italy: A consensus report from an expert panel

Hepatitis C virus (HCV) infection remains one of the main causes of chronic liver disease worldwide. The advent of direct-acting antivirals (DAAs) has significantly improved the course of patients with chronic HCV infection (CHC), due to the ability of these drugs to achieve high rates of sustained virological response (SVR). These exceedingly high rates of SVR and the excellent safety data have been confirmed in real life practice. Evolving guidelines have been issued by national and international scientific societies in accordance with the progression of clinical knowledge and the availability of new DAAs. These recommendations, however, may not be applied universally because of delays in drugs reimbursability in different countries and because some National Health Systems identify only patients with advanced disease as a treatment priority. Italy in this regard is a prototype about DAAs treatment of CHC patients.With the aim to assess the Italian treatment experience with DAAs and to respond to unmet needs in treatment optimization of antiviral therapy in specific settings of CHC patients, a group of Italian experts met in Stresa in February 2017. The summary of the considerations arising from this two-day meeting and some statements regarding a few open issues are reported in this position paper.     

Interferon-free direct-acting antiviral therapy for acute hepatitis C virus infection in HIV-infected individuals: A literature review

Dramatic rises in hepatitis C virus (HCV) coinfection rates in human immunodeficiency virus (HIV)-infected individuals have been observed recently, largely attributable to increasing recreational drug use combined with increased testing for HCV. In the era of direct-acting antiviral (DAA) therapy, treatment of acute HCV infection in HIV-infected individuals with short durations of these drugs may potentially reduce the disease and economic burden associated with HCV infection as well as reducing the likelihood of onward HCV transmission. We performed an extensive literature search of PubMed, Embase and Google Scholar up to 05 September 2017 for clinical trials of acute HCV infection in HIV-infected individuals. In the studies identified, rates of sustained virologic response at 12 weeks post-treatment (SVR12) ranged from 21% with 6 weeks of therapy up to 92% with 12 weeks of therapy with sofosbuvir and ribavirin. Ledipasvir/sofosbuvir for 6 weeks achieved an SVR of 77%. No HIV-related events occurred regardless of whether patients were receiving antiretroviral therapy (ART) and DAAs were well tolerated. Data is currently limited with regards to optimal regimens and durations of therapy, which need to be tailored based on potential interactions with concurrent ART and consideration for the fact that patients with higher baseline HCV RNA levels may require an extended duration of treatment.     

Hepatocellular carcinoma and hepatitis C virus treatments: The bold and the beautiful

The occurrence of hepatocellular carcinoma (HCC) is one of the most serious complications of hepatitis C virus (HCV) infection. Recently, effective antiviral medications have made sustained viral response (SVR) or cure a realistic therapeutic goal for most chronic HCV patients. Given HCV's tumorigenic propensity, it is not surprising that achieving SVR is helpful in preventing HCC. This review briefly summarizes and discusses the existing evidence on the relationship between hepatic carcinogenesis and viral eradication by antivirals, which is mainly divided into interferon-based and direct-acting antivirals (DAAs) based therapy. DAAs have changed the treatment landscape of chronic HCV, reaching high rates of SVR even in patients with advanced cirrhosis, with few contraindications and little side effects. Although some early reports suggested that DAA treatment increased the chance of HCC occurrence, more subsequent observational studies have refuted this theory. The probability of HCC recurrence after HCV eradication appears to be decreasing over time following SVR. Despite virological suppression/cure, individuals with liver cirrhosis are still at risk of HCC and should be monitored. There is a considerable need for markers/scores to predict the long-term risk of HCC in patients with HCV-related liver disease who attain SVR with direct-acting antivirals.     

Factors associated with treatment failure of patients with psychiatric diseases and injecting drug users in the treatment of genotype 2 or 3 hepatitis C chronic infection

Background: Genotype 2/3 hepatitis C virus (HCV) has a good response to treatment with peginterferon and ribavirin. Patients with psychiatric disorders and injecting drug users (IDUs) are considered ‘difficult to treat’ and are often excluded from treatment despite the lack of evidence supporting this decision. Aims: To investigate the outcome and factors associated with treatment failure in these groups. Methods: This is an observational study of a cohort of patients infected by genotype 2/3 HCV. IDUs and patients with psychiatric diseases were not excluded from treatment. We performed an intention‐to‐treat analysis to evaluate factors related to treatment failure. Results: A sustained virological response (SVR) was achieved in 91 of the 125 patients treated (72.8%). Patients with chronic psychotic disorders or former IDUs had SVR rates similar to other groups. After multivariate analysis, independent factors associated with treatment failure were liver cirrhosis [odds ratio (OR) 3.4, 95% confidence interval (CI) 1.1–10.4], a history of depression and not being on antidepressants at the commencement of HCV treatment (OR 4.4, 95% CI 1.2–16) and active IDUs (OR 7.3, 95% CI 1.77–30.4). Conclusions: Patients with a history of depression who were not receiving antidepressants and active IDUs are more likely to fail treatment for genotype 2/3 HCV and will need additional support.     

Peginterferon plus Ribavirin for chronic hepatitis C in opiate addicts on methadone/buprenorphine maintenance therapy

BackgroundIn developed countries hepatitis C is prevalently transmitted by intravenous drug users (IDUs). The problems associated with management of HCV hepatitis in these patients have, in the past, discouraged treatment.AimTo evaluate efficacy, safety and tolerability of a standard Peginterferon (Peg-IFN) α-2b or α-2a plus Ribavirin treatment in IDUs who were receiving methadone or buprenorphine.MethodsA multi-centre prospective observational study performed from September 2003 to September 2006 in Central Italy (Umbria and Marches regions). A shared care model of HCV management was used which integrated a multidimensional, multidisciplinary approach.ResultsSixty-five subjects were evaluated and 52 satisfied inclusion criteria. Forty-five completed treatment (25 with Peg-IFN α-2b, 20 with Peg-IFN α-2a), a total of 37 showed a biochemical/virological response at the end of treatment (ITT 71.1%), 26 had a sustained virological response (ITT 50%; 38.4% of cases genotype 1-4, 61.6% genotype 3-2).ConclusionsThe results indicate that patients on maintenance treatment with methadone/buprenorphine can be treated for HCV. The success rate was fairly good; tolerability and side effects were similar to those reported in non-IDU patients. Close cooperation with specialists in drug addiction and psychiatrists is however essential for success.     

Safety of direct acting antiviral treatment for hepatitis C in oncologic setting: A clinical experience and a literature review

With a globally estimated 58 million people affected by, chronic hepatitis C virus (HCV) infection still represents a hard challenge for scientific community. A chronic course can occur among patients with a weak innate ad adaptive response with cirrhosis and malignancies as main consequences. Oncologic patients undergoing chemotherapy represent a special immunocompromised population predisposed to HCV reactivation (HCVr) with undesirable changes in cancer treatment and outcome. Aim of the study highlight the possibility of HCVr in oncologic population eligible to chemotherapy and its threatening consequences on cancer treatment; underline the importance of HCV screening before oncologic therapy and the utility of direct aging antivirals (DAAs). A comprehensive overview of scientific literature has been made. Terms searched in PubMed were: “HCV reactivation in oncologic setting” “HCV screening”, “second generation DAAs”. Pharmacokinetic and Pharmacodynamics characteristics of DAAs are reported, along with drug - drug interactions among chemotherapeutic drug classes regimens and DAAs. Clinical trials conducted among oncologic adults with HCV infection eligible to both chemotherapy and DAAs were analyzed. Viral eradication with DAAs in oncologic patients affected by HCV infection is safe and helps liver recovery, allowing the initiation of cancer treatment no compromising its course and success.     

Treatment of chronic hepatitis C in patients with drug dependence: time to change the rules?

AIMS: Approximately 170 million people world-wide are chronically infected with the hepatitis C virus (HCV). While the seroprevalence in the general population ranges between 0.2 and 2%, 50-90% of injection drug users are chronically HCV-infected. However, most patients who are drug abusers are still excluded from treatment of chronic HCV infection with interferon (IFN)-alpha. Due to the recent treatment advances resulting in sustained response rates between 50 and 80%, it becomes increasingly important to reflect the still existing contraindications and restrictions for IFN-alpha treatment, especially for patients with intravenous drug use (IDU) with or without psychiatric comorbidity. METHODS: We reviewed clinical trials that focus on the treatment of chronic hepatitis C in patients with drug addiction published between 1987 and 2003. FINDINGS: Only seven clinical trials investigating HCV treatment among drug users were found: four open prospective uncontrolled trials and three controlled trials. Thus far, no trials using pegylated IFN-alpha have been conducted. Data about sustained response and adherence in HCV-infected methadone substituted patients were either comparable to control groups or to representative clinically controlled trials using the same treatment regimen (IFN-alpha monotherapy or combined with ribavirin). Patients with former or present drug abuse seem more likely to discontinue treatment early. HCV-infected IDUs tended to be older with higher inflammatory activity and stage of fibrosis when interferon treatment was started. Psychiatric comorbidity did not negatively influence adherence or treatment outcome. CONCLUSIONS: There is no clinical evidence suggesting that HCV treatment with IFN-alpha should be limited to IDUs or methadone substituted patients. However, more prospective controlled trials on HCV treatment for patients with IDU are needed to establish and apply new rules and guidelines.     

Telemedicine HCV treatment in department of corrections results in high SVR in era of direct‐acting antivirals

Chronic hepatitis C virus (HCV) is common in the Department of Corrections (DOC). Telemedicine is an effective way to treat HCV. The goal of this report was to demonstrate high SVR rate in DOC patients using telemedicine irrespective of the HCV genotype (GT) and DAAs used. Demographic, clinical and laboratory data were prospectively collected. A total of 870 DOC patients were evaluated and completed HCV therapy June 2015‐December 2019 with SVR data were included. The mean age was 50 years, 90% were male, 63% were Caucasian, the majority (79%) had GT 1, 92% were treatment naive, and 80% had advanced fibrosis (FIB‐4 ≥ 3.25 and/or transient elastography ≥ 9.5 kPa). The overall SVR was 97% and was similar among all DAAs irrespective of age, sex, race, HIV status, fibrosis level, GT, ribavirin use, prior treatment experience or DAA duration. We conclude that HCV treatment in the DOC through telemedicine is achievable and highly effective with overall SVR 97%, irrespective of the underlying GT or DAA regimen used and can eliminate HCV in this microenvironment and reduce the overall burden of HCV.     

Hepatitis C virus cirrhosis: prolonged sustained virological response in a patient after low-dose antiviral treatment

Hepatitis C virus (HCV) infection is the most frequent cause of chronic liver disease in the western world. The 'gold standard' treatment of chronic HCV infection currently involves the administration of pegylated interferon alpha (PEG-IFN) and ribavirin. The success of this therapy is demonstrated by sustained virological responses (SVR). Randomized trials and practice guidelines have reported that compensated HCV cirrhosis is an indication for treatment with PEG-IFN and ribavirin, not only to obtain SVR but also to increase survival and to reduce the development of cirrhotic sequelae. In particular, the literature has reported that antiviral treatment was associated with histological improvement of fibrosis in cirrhotic patients with SVR. Recently, the same authors have evaluated the efficacy and safety of different doses of antiviral treatment in patients with chronic HCV infection. The use of interferon has been limited due to associated side effects, particularly in cirrhotic patients. Consequently, therapeutic decisions should be made on an individual basis. The Authors report a case of a patient with compensated HCV liver cirrhosis, with associated severe thrombocytopenia and oesophageal varices, in which the administration of antiviral therapy at a dose lower than the therapeutic 'gold standard' has achieved SVR and consequently improved clinical status.     

Hepatitis C virus-associated hepatocellular carcinoma after sustained virologic response

The introduction of a direct-acting antiviral(DAA) for patients with hepatitis C virus(HCV) infection, could lead to higher sustained virologic response(SVR)rates with fewer adverse events, and it could shorten the treatment duration relative to the interferon era. Although most recent clinical studies have demonstrated that the occurrence rates of hepatocellular carcinoma(HCC) are decreased by SVR with both interferon-based and interferon-free-regimens, there are several reports about the unexpected observation of high rates of early tumor occurrence and recurrence in patients with HCV-related HCC undergoing interferon-free therapy despite SVR. Several mechanisms of HCC occurrence and rapid immunological changes, including cytokines and chemokines during and after DAA treatment, have also been reported. We focused on the possibilities that HCC occurs or recurs during and after DAA treatment, based on the reported clinical and basic studies. Further studies and observations will be needed to determine the short-term and long-term effects on hepatocarcinogenesis caused by the eradication of HCV with DAAs. New serum biomarkers and a follow-up system for HCV-patients with SVR should be established.     

Interferon‐free therapies for patients with chronic hepatitis C genotype 3 infection: A systematic review

Treatment of hepatitis C virus (HCV) infection with genotype 3 remains a challenge. The HCV elimination rate with direct‐acting antivirals (DAAs) is lower than the values reported for other HCV genotypes. In addition, genotype 3‐infected patients have a higher risk of disease progression and hepatocellular carcinoma. The aim of this study was to review the relevant literature concerning the treatment of HCV genotype 3 patients with interferon‐free regimens. A literature search was conducted in the PubMed/Medline, Embase and Web of Science electronic databases. Trials enrolling patients with chronic hepatitis C infection treated with DAAs with or without ribavirin were included. Two investigators independently evaluated the trials for inclusion criteria, risk of bias and data extraction. The primary outcome was sustained virological response (SVR). In total, 323 references were identified, and 29 met the inclusion criteria: 18 general clinical trials, three general observational studies, three studies in patients with decompensated liver cirrhosis and four studies in HIV–HCV‐coinfected patients. Overall, 4068 genotype 3 patients were included. As compared with sofosbuvir and ribavirin for 24 weeks, sofosbuvir/velpatasvir for 12 weeks or sofosbuvir plus daclatasvir plus ribavirin for 12 weeks provided higher SVR rates, particularly in patients with cirrhosis. Treatment of patients with decompensated cirrhosis remains a great challenge. Sofosbuvir/ledipasvir+ribavirin for 12 weeks were associated with an SVR of 85% in these patients. In summary, treatment of HCV genotype 3 patients is improving rapidly, and this population may no longer be considered a difficult‐to‐treat subgroup in the near future.