Monika Vainorius

Safety profile of boceprevir and telaprevir in chronic hepatitis C: Real world experience from HCV-TARGET

BACKGROUND & AIMS The safety profiles of boceprevir and telaprevir in the treatment of chronic hepatitis C, administered in academic and community centres across the United States, were evaluated. METHODS In 90 medical centres, patients with chronic HCV received pegylated interferon, ribavirin, and either telaprevir or boceprevir per local standard of care. Demographic, adverse event, clinical, and virological data were collected during treatment and follow-up. RESULTS A total of 2084 patients (97% HCV genotype 1) received at least one dose of a protease inhibitor. At baseline, 38% of patients had cirrhosis, and 57% had received at least one prior treatment for hepatitis C. Serious adverse events occurred in 12% of patients receiving protease inhibitor therapy. Overall, 66% of patients experienced anaemia, leading to frequent ribavirin dose reductions (42%) and erythropoietin use (37%); 11% received blood transfusion. More than 90% of patients had adverse events that led to a prescription, treatment, or dosage change, and 39% of patients discontinued treatment early, most commonly because of adverse events (18%) or lack of efficacy (16%). Hepatic decompensation events occurred in 3% of all patients. Age, female gender, cirrhosis, HCV genotype 1 subtype, creatinine clearance, platelet levels, albumin levels and haemoglobin levels were independent predictors of anaemia. Five deaths occurred. Overall, 52% of all patients achieved a sustained virologic response. CONCLUSIONS In academic and community centres, where chronic hepatitis C patients commonly have advanced liver disease, triple therapy was associated with a high rate of adverse events and involved frequent treatment modifications and adverse event management.

Safety and efficacy of current direct‐acting antiviral regimens in kidney and liver transplant recipients with hepatitis C: Results from the HCV‐TARGET study

Data outside of clinical trials with direct‐acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct‐acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. Conclusion: In a large prospective observational cohort study, direct‐acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090‐1101).

Safety and Efficacy of Current DAA Regimens in Kidney and Liver Transplant Recipients with Hepatitis C: Results from the HCV-TARGET Study.

Data outside of clinical trials with direct‐acting antiviral regimens with or without ribavirin as treatment of chronic hepatitis C virus in solid organ transplant recipients are limited. Liver transplant (LT), kidney transplant (KT), and dual liver kidney (DLK) transplant recipients from the Hepatitis C Therapeutic Registry and Research Network database, a multicenter, longitudinal clinical care treatment cohort, treated with direct‐acting antiviral regimens between January 1, 2014, and February 15, 2016, were included to assess safety and efficacy. Included were 443 posttransplant patients (KT = 60, LT = 347, DLK = 36); 42% had cirrhosis, and 54% had failed prior antiviral therapy. Most had genotype (GT) 1 (87% with 52% GT1a, 27% GT1b, and 8% GT1 no subtype) and were treated with sofosbuvir (SOF)/ledipasvir ± ribavirin (85%) followed by SOF + daclatasvir ± ribavirin (9%) and ombitasvir/paritaprevir/ritonavir + dasabuvir ± ribavirin (6%). Rates of sustained virologic response (SVR) at 12 weeks were available on 412 patients, and 395 patients (95.9%) achieved SVR at 12 weeks: 96.6%, 94.5%, and 90.9% among LT, KT, and DLK transplant recipients, respectively. Ribavirin did not influence SVR rates and was more often used in those with higher BMI, higher estimated glomerular filtration rate and lower creatinine. Female gender, baseline albumin ≥3.5 g/dL, baseline total bilirubin ≤1.2 mg/dL, absence of cirrhosis, and hepatic decompensation predicted SVR at 12 weeks. Six episodes of acute rejection (n = 2 KT, 4 LT) occurred, during hepatitis C virus treatment in 4 and after cessation of treatment in 2. Conclusion: In a large prospective observational cohort study, direct‐acting antiviral therapy with SOF/ledipasvir, ombitasvir/paritaprevir/ritonavir + dasabuvir, and SOF plus daclatasvir was efficacious and safe in LT, KT, and DLK transplant recipients; ribavirin did not influence SVR, and graft rejection was rare. (Hepatology 2017;66:1090‐1101).

Effectiveness and safety of sofosbuvir plus ribavirin for the treatment of HCV genotype 2 infection: results of the real-world, clinical practice HCV-TARGET study

Objective Due to a high efficacy in clinical trials, sofosbuvir (SOF) and ribavirin (RBV) for 12 or 16 weeks is recommended for treatment of patients with HCV genotype (GT) 2 infection. We investigated safety and effectiveness of these regimens for GT2 in HCV-TARGET participants. Design HCV-TARGET, an international, prospective observational study evaluates clinical practice data on novel antiviral therapies at 44 academic and 17 community medical centres in North America and Europe. Clinical data were centrally abstracted from medical records. Selection of treatment regimen and duration was the investigators choice. The primary efficacy outcome was sustained virological response 12 weeks after therapy (SVR12). Results Between December 2013 and April 2015, 321 patients completed 12 weeks (n=283) or 16 weeks (n=38) of treatment with SOF and RBV. Prior treatment experience and cirrhosis was more frequent among patients in the 16-week regimen compared with 12 weeks (52.6% vs 27.6% and 63.2% vs 21.9%, respectively). Overall, SVR12 was 88.2%. The SVR12 in patients without cirrhosis was 91.0% and 92.9% for 12 or 16 weeks of therapy, respectively. In patients with cirrhosis treated for 12 or 16 weeks, SVR12 was 79.0% and 83%. In the multivariate analysis, liver cirrhosis, lower serum albumin and RBV dose at baseline were significantly associated with SVR12. Common adverse events (AEs) included fatigue, anaemia, nausea, headache, insomnia, rash and flu-like symptoms. Discontinuation due to AEs occurred in 2.8%. Conclusions In this clinical practice setting, SOF and RBV was safe and effective for treatment of patients with HCV GT2 infection. Trial registration number NCT01474811.

All‐oral direct‐acting antiviral therapy in HCV‐advanced liver disease is effective in real‐world practice: observations through HCV‐TARGET database

Chronic hepatitis C virus therapy in patients with advanced liver disease remains a clinical challenge. HCV‐TARGET collects data in patients treated at tertiary academic and community centres.

Effectiveness and safety of sofosbuvir-based regimens for chronic HCV genotype 3 infection: results of the HCV-TARGET study

BACKGROUND Sofosbuvir (SOF) is active against all hepatitis C virus (HCV) genotypes, and SOF-based therapies lead to high rates of sustained virologic response (SVR). However, genotype 3 (GT3) HCV remains a challenge with lower SVR rates reported, particularly in patients with cirrhosis. This study reports the effectiveness and safety of SOF-based therapy in patients with GT3 HCV treated in clinical practice. METHODS Hepatitis C Virus Therapeutic Registry and Research Network is an international, prospective observational study evaluating patients treated in usual clinical practice. Patients with GT3 HCV were analyzed to assess predictors of treatment response and adverse events using descriptive statistics and multivariable logistic regression. RESULTS Treatment outcomes were available for 197 patients treated with SOF and ribavirin (RBV), with or without peginterferon, including 54% with cirrhosis and 49% who failed prior therapy. Of 178 patients treated with SOF/RBV, 60% achieved SVR at 12 weeks (SVR12), compared with 84% of 19 patients treated with SOF/peginterferon/RBV. For patients treated with SOF/RBV, the SVR12 rate was 58% in treatment-naive patients with cirrhosis, and 42% in those with cirrhosis who failed prior therapy. In noncirrhotic patients, SVR12 rates were 89% in treatment-naive and 88% in treatment-experienced patients. After controlling for age and sex, absence of cirrhosis (odds ratio [OR], 6.4; 95% confidence interval [CI], 2.78-14.74), albumin levels ≥3.2 g/dL (OR, 12.48; 95% CI, 3.86-40.33), and platelet count >10(5) cells/µL (OR, 7.44; 95% CI, 3.51-15.78) were associated with greater odds of SVR12 CONCLUSIONS:  SVR rates were acceptable in patients with GT3 HCV without cirrhosis; however, in those with cirrhosis, treatment with SOF/RBV was suboptimal, highlighting the need for new therapies for this population.

Safety and Effectiveness of Ledipasvir and Sofosbuvir, With or Without Ribavirin, in Treatment-Experienced Patients with Genotype 1 Hepatitis C Virus Infection and Cirrhosis

BACKGROUND & AIMS: We aimed to evaluate the safety and effectiveness of 12 or 24 weeks treatment with ledipasvir and sofosbuvir, with or without ribavirin, in treatment‐experienced patients with hepatitis C virus (HCV) genotype 1 infection and cirrhosis in routine clinical practice. Patients were followed in a multi‐center, prospective, observational cohort study (HCV‐TARGET). METHODS: We collected data from 667 treatment‐experienced adults with chronic genotype 1 HCV infection who began treatment with ledipasvir and sofosbuvir, with or without ribavirin, from 2011 through September 15, 2016, according to the regional standards of care, at academic (n = 39) and community (n = 18) centers in the United States, Canada, Germany, and Israel. Information was collected from medical records and abstracted into a unique centralized data core. Independent monitors systematically reviewed data entries for completeness and accuracy. Demographic, clinical, adverse event, and virologic data were collected every 12 weeks during treatment and during the follow‐up period. The primary efficacy endpoint was sustained virologic response, defined as a level of HCV RNA below the lower limit of quantification or undetectable at a minimum 64 days after the end of treatment (SVR12). The per‐protocol population (n = 610) was restricted to patients who completed 12 or 24 weeks of treatment (±2 weeks) and had final virologic outcomes available. RESULTS: The per‐protocol analysis revealed that 579 patients (93.8%) achieved an SVR12, including 50/51 patients who received ledipasvir and sofosbuvir for 12 weeks (98%), 384/408 patients who received ledipasvir and sofosbuvir for 24 weeks (94.1%), 68/70 patients who received ledipasvir and sofosbuvir with ribavirin for 12 weeks (97.1%), and 57/60 patients who received ledipasvir and sofosbuvir with ribavirin for 24 weeks (95%). On multivariate analysis, neither treatment duration nor the addition of ribavirin was associated with SVR12. Compensated cirrhosis (odds ratio [OR] compared to decompensated cirrhosis, 2.41; 95% CI, 1.16‐5.02), albumin ≥ 3.5 g/dL (OR, 3.15; 95% CI 1.46–6.80), or total bilirubin ≤ 1.2 mg/dL (OR 3.34; 95% CI, 1.59–7.00) were associated with SVR12. CONCLUSIONS: In an analysis of safety and effectiveness data from the HCV‐TARGET study, we found treatment with ledipasvir and sofosbuvir, with or without ribavirin, to be effective and well tolerated by treatment‐experienced patients with genotype 1 HCV infection and compensated cirrhosis. There were no significant differences in rate of SVR12 among patients treated with ledipasvir and sofosbuvir for 12 or 24 weeks, with or without ribavirin. Patients with decompensated cirrhosis appear to benefit from the addition of ribavirin or extension of ledipasvir and sofosbuvir treatment to 24 weeks. ClinicalTrials.gov no: NCT10474811.