Hepatocellular carcinoma occurs frequently and early after treatment in HCV genotype 3 infected persons treated with DAA regimens.

BACKGROUND: There are conflicting data regarding the risk of hepatocellular carcinoma (HCC) after direct-acting antiviral agent (DAA) treatment. Risk of HCC in HCV genotype-3 infected persons after DAA therapy is not well known. METHODS: We prospectively studied HCV infected persons initiated on a DAA regimen between October 2014 and March 2017 at two centers in Pakistan. All persons were free of HCC at study initiation. HCC was confirmed based on characteristic CT scan findings. Patients were followed for 12 months after the completion of therapy. RESULTS: A total of 662 persons initiated treatment. Median age (IQR) was 50 (41, 57) years and 48.8% were male. At baseline, 49.4% were cirrhotic, 91% were genotype 3 and 91.9% attained SVR. Treatment regimens used were: Sofosbuvir (SOF)/ribavirin (RBV)/pegylated interferon (PEG-IFN), 25.2%; SOF/RBV, 62.4%; SOF/RBV/daclatasavir (DCV), 10.6%; SOF/DCV, 2.0%. Incident HCC was detected in 42 patients (12.8%) in the 12-month period after treatment completion and was exclusively observed in those with cirrhosis. In multivariable Cox regression analysis, SVR was associated with a reduction in HCC risk (HR, 95% CI: 0.35, 0.14,0.85). In Kaplan-Meier plots by treatment regimen, those treated with SOF/RBV, SOF/RBV/DCV, or SOF/DCV regimens had a shorter HCC-free survival compared with those treated with a SOF/RBV/PEG-IFN regimen. CONCLUSION: In a predominantly genotype 3 cohort, incident HCC occurred frequently and early after treatment completion, and exclusively in those with pre-treatment cirrhosis. SVR reduced the risk of HCC. Treating HCV infected persons before development of cirrhosis may reduce risk of HCC.

Pharmacological management of adverse events during treatment of chronic viral hepatitis in three Ivorian university hospitals
.

OBJECTIVE: This work aims to evaluate the therapeutic survey of adverse events during antiviral treatment of hepatitis in the three major University Hospitals in Abidjan. MATERIALS AND METHODS: A retrospective cross-sectional descriptive study of 203 patients from August 1, 2015, to July 31, 2018, enumerated adverse events during antiviral treatments, drugs used for their management, and their clinical or biological impact. RESULTS: The following was seen: hematological disorders during treatment with pegylated interferon α-2a (88.61%) and ribavirin (77.55%), pain syndrome when using pegylated interferon α-2a (90.5%), and digestive disorders while taking sofosbuvir (60.71%) and daclatasvir (66.67%). Hematological disorders were managed with filgrastim for neutropenia and oral iron or blood transfusion for anemia and/or thrombocytopenia. Pain syndrome was treated with paracetamol. As for digestive disorders, they were most often managed with activated charcoal. CONCLUSION: Correction of the adverse events was made either using causal treatment or using symptomatic drugs. However, some drugs, in particular hematopoietic factors, have been less used due to their costs.

Sofosbuvir-Based Therapy in Hepatitis C Virus-Infected Cancer Patients: A Prospective Observational Study.

BACKGROUND: Data are sparse on treatment of chronic hepatitis C virus (HCV) in cancer patients. We evaluated the efficacy and safety of sofosbuvir-based therapy (SOFBT) in cancer patients. METHODS: Patients treated with SOFBT at our center during 2014-2017 were included in a prospective observational study. Efficacy [sustained virologic response at 12 weeks after the end of treatment (SVR12)], cancer-related outcomes and adverse events (AEs) were assessed. RESULTS: We included 153 patients. Most were men (109; 71%), white (92; 60%), non-cirrhotic (105; 69%), and with HCV genotype 1 (110; 72%). The most common cancers were hepatocellular carcinoma (HCC) (27; 18%) and multiple myeloma (14; 9%). The overall SVR12 rate was 91% (128/141). SVR12 was 100% in patients treated with ledipasvir/sofosbuvir for 8 weeks. Of the 32 patients initially excluded from cancer clinical trials because of HCV, 27 (84%) were granted cancer therapy access after starting SOFBT. Six patients with indolent non-Hodgkin's lymphoma (NHL) received SOFBT without cancer treatment. Two achieved complete remission, one had partial remission, and two had stable cancer. Within 6 months after SOFBT, 5% (6/121) of patients in remission or with stable cancer, had progression or recurrence (two with HCC and one each with esophageal cancer, cholangiocarcinoma, NHL, and tonsillar cancer). No de novo HCCs occurred. AEs were most commonly grade 1-2 (90%). CONCLUSIONS: SOFBT in HCV-infected cancer patients is effective and safe, may permit access to investigational cancer therapy expanding treatment options, may induce remission of NHL, and may be used for 8 weeks.

Safety and Efficacy of Ledipasvir-Sofosbuvir With or Without Ribavirin for Chronic Hepatitis C in Children Ages 6-11.

Currently, there are no interferon-free treatments available for hepatitis C virus (HCV)-infected patients younger than 12 years. We evaluated the safety and effectiveness of the all-oral regimen ledipasvir-sofosbuvir ± ribavirin in HCV-infected children aged 6 to <12 years. In an open-label study, patients aged 6 to <12 years received ledipasvir 45 mg-sofosbuvir 200 mg as two fixed-dose combination tablets 22.5/100 mg once daily, with or without ribavirin, for 12 or 24 weeks, depending on HCV genotype and cirrhosis status. The primary efficacy endpoint was sustained virologic response 12 weeks after therapy (SVR12). Twelve patients underwent intensive pharmacokinetic sampling to confirm the appropriateness of the ledipasvir and sofosbuvir dosages. Ninety-two patients were enrolled (88 genotype 1, 2 genotype 3, and 2 genotype 4), with a median age of 9 years (range, 6-11). Most were perinatally infected (97%) and treatment-naive (78%). Two were confirmed to have cirrhosis, while the degree of fibrosis was unknown in 55 patients. The overall SVR12 rate was 99% (91/92; 95% confidence interval, 94%-100%). The single patient not reaching SVR relapsed 4 weeks after completing 12 weeks of treatment. The most common adverse events were headache and pyrexia. One patient had three serious adverse events, which were considered to be not related to study treatment: tooth abscess, abdominal pain, and gastroenteritis. The area under the concentration-time curve and maximum concentration values for sofosbuvir, its primary metabolite GS-331007, and ledipasvir were within predefined pharmacokinetic equivalence boundaries (50%-200%) compared to values in adults in phase 2/3 of the ledipasvir and sofosbuvir studies. Conclusion: Ledipasvir-sofosbuvir was well tolerated and highly effective in children 6 to <12 years old with chronic HCV.

Cost-effectiveness of sofosbuvir plus ribavirin therapy for hepatitis C virus genotype 2 infection in South Korea.

BACKGROUND AND AIM: For genotype 2 chronic hepatitis C (CHC), the efficacy and safety of sofosbuvir plus ribavirin therapy (SOF + RBV) was better than pegylated interferon plus ribavirin therapy (PR) at a greater drug cost. This study investigated the cost-effectiveness of SOF + RBV compared with PR for treatment-naïve genotype 2 CHC in South Korea. METHODS: Using a decision analytic Markov model, a cost-effectiveness analysis comparing SOF + RBV with PR or no treatment for treatment-naïve genotype 2 CHC was performed with probabilistic and deterministic sensitivity analyses from the payer's perspective in 2017. Three cohorts of patients aged 40-49, 50-59, and 60-69 years were simulated to progress through the fibrosis stages F0-F4 to end-stage liver disease, hepatocellular carcinoma, or death. Published and calculated data on the clinical efficacy of the regimen, health-related quality of life, costs, and transition probabilities were used. RESULTS: While the incremental cost-effectiveness ratio for PR was dominant over no treatment, the incremental cost-effectiveness ratios for SOF + RBV were $20 058 for the patients in their 40s, $19 662 for those in their 50s, and $22 278 for those in their 60s compared with PR. Probabilistic sensitivity analysis indicated an 89.0% probability for the SOF + RBV to be cost-effective at a willingness to pay of $29 754.4 (per-capita gross domestic product in 2017) for the patients in their 40s and 94.1% and 89.1% for the patients in their 50s and 60s, respectively. CONCLUSIONS: The SOF + RBV is a cost-effective option for genotype 2 treatment-naïve CHC patients, especially for the patients with liver cirrhosis in Korea.

Effect of cyclosporine A versus tacrolimus on the response to antiviral therapy after hepatitis C genotype-4 recurrence post-liver transplantation: A prospective cohort trial.

WHAT IS KNOWN AND OBJECTIVE: The influence of immunosuppression on the response to antiviral therapy (AVT) for recurrent hepatitis C virus (HCV) infection in liver transplant (LT) recipients remains controversial, especially for the rarely investigated genotype 4. This study aims to compare the effects of the two widely used calcineurin inhibitors (CNIs) (cyclosporine A (CsA) and tacrolimus (Tac)) on the therapeutic response to different AVT regimens. METHODS: A prospective, dual-centre, cohort study of 126 Egyptian living donor liver transplant (LDLT) recipients with recurrent HCV genotype 4 infection, who were categorized into three groups according to the AVT used. Group I received pegylated interferon (Peg-IFN-α 2a) plus ribavirin (RBV) (n = 44), group II received the direct antiviral agent (DAA) sofosbuvir plus RBV (n = 52) and group III received daclatasvir and sofosbuvir (also DAAs) plus RBV (n = 30). Each group was further subdivided according to the primary immunosuppression (CsA or Tac). The sustained virological response (SVR) and relapse rates were considered the primary therapeutic outcomes of AVT. RESULTS: No significant intergroup differences were observed in the achievement of primary and secondary outcomes. SVR rates in the IFN-based regimen were 75% and 66.7% in CsA and Tac users and 81.2% and 83% in DAAs, respectively. Relapse rates in the IFN-based regimen were 10% and 16.7% in CsA and Tac users and 12.5% and 14.9% in DAAs, respectively. WHAT IS NEW AND CONCLUSION: Within the limitations of a relatively small study, CsA did not offer an advantage over Tac regarding the response to AVT after HCV genotype 4 recurrence in LDLT recipients.

Interprofessional team-based approach to patients with chronic hepatitis C and personality disorder: Three case studies.

Hepatitis C virus is a blood borne pathogen that infects 130 million people worldwide. After a prolonged period of slowly progressive liver injury, those infected are at risk of advancing to end stage liver disease, with its associated complications, and hepatocellular carcinoma. Rates of past and/or current substance use and behavioral comorbidities are higher among those infected with hepatitis C compared to the general population. A number of patient, provider and system barriers to care and treatment have led to low rates of treatment initiation in this population despite pharmacologic advances that have made hepatitis C a curable disease. Innovation in care delivery is considered a key strategy that will help reach more patients. We present three case studies of patients with chronic hepatitis C and multiple psychiatric comorbidities who were successfully engaged in care and treated for their chronic hepatitis C in our multidisciplinary primary care-based program.

Directly observed therapy of sofosbuvir/ribavirin +/- peginterferon with minimal monitoring for the treatment of chronic hepatitis C in people with a history of drug use in Chennai, India (C-DOT).

We assessed the feasibility of field-based directly observed therapy (DOT) with minimal monitoring to deliver HCV treatment to people with a history of drug use in Chennai, India. Fifty participants were randomized 1:1 to sofosbuvir+peginterferon alfa 2a+ribavirin (SOF+PR) for 12 weeks (Arm 1) vs sofosbuvir+ribavirin (SOF+R) for 24 weeks (Arm 2). SOF+R was delivered daily at participant chosen venues and weekly peginterferon injections at the study clinic. HCV RNA testing was performed to confirm active HCV infection and sustained virologic response 12 weeks after treatment completion (SVR12). No baseline genotyping or on-treatment viral loads were performed. Median age was 46 years. All were male and 20% had significant fibrosis/cirrhosis. All self-reported history of injection drug use, 18% recent noninjection drug use and 38% alcohol dependence. Six discontinued treatment (88% completed treatment in each arm). Of 22 who completed SOF+PR, all achieved SVR12 (22/25=88%); 15 of 22 who completed SOF+R achieved SVR12 (15/25=60%; P=.05). Among those completing SOF+R, SVR12 was significantly less common in participants reporting ongoing substance use (36% vs 100%) and missed doses. Active substance use and missed doses did not impact SVR with SOF+PR. Field-based DOT of HCV therapy without real-time HCV RNA monitoring was feasible; however, achieving 100% adherence was challenging. SOF+PR appeared superior to SOF+R in achieving SVR12, even when doses were missed with no discontinuations due to side effects. Further exploration of short duration treatment with peginterferon plus direct-acting antivirals is warranted.

Sofosbuvir plus ribavirin with or without peginterferon for the treatment of hepatitis C virus: Results from a phase 3b study in China.

BACKGROUND AND AIM: Sofosbuvir is a nucleotide analog inhibitor of the hepatitis C virus (HCV) NS5B RNA polymerase with pangenotypic potency. This phase 3b study evaluated the safety and efficacy of sofosbuvir + ribavirin ± peginterferon in Chinese patients infected with HCV genotype 1, 2, 3, or 6. METHODS: Patients with genotype 1 or 6 received sofosbuvir + peginterferon/ribavirin for 12 weeks or sofosbuvir + ribavirin for 24 weeks, depending on prior treatment and interferon eligibility. Patients with genotype 2 or 3 received sofosbuvir + ribavirin for 12 or 24 weeks, respectively. The primary endpoint was sustained virologic response at 12 weeks after the end of treatment (SVR12). RESULTS: Of 389 patients, 42% had genotype 1, 16% genotype 2, 32% genotype 3, and 9% genotype 6. Half were male, 58% were treatment-naïve, and 15% had cirrhosis. SVR12 rates for patients receiving 12 weeks of sofosbuvir + peginterferon/ribavirin were 94% (95% confidence interval [CI], 87-98%) for HCV genotype 1 and 97% (95% CI, 84-100%) for genotype 6. SVR12 rates for those receiving sofosbuvir + ribavirin for 24 weeks were 95% (95% CI, 87-99%) for genotype 1, 100% (95% CI, 40-100%) for genotype 6, and 95% (95% CI, 90-98%) for genotype 3. For genotype 2 patients receiving sofosbuvir + ribavirin for 12 weeks, the SVR12 rate was 92% (95% CI, 83-97%). Twenty patients (5%) relapsed. Ten (3%) experienced serious adverse events. Three (< 1%) discontinued treatment because of adverse events, of whom one died because of treatment-unrelated adverse events. CONCLUSIONS: Sofosbuvir-based regimens were highly effective and safe in Chinese patients with HCV genotype 1, 2, 3, or 6, suggesting sofosbuvir could serve as the backbone for HCV treatment in China irrespective of genotype.

Eight-Week Hepatitis C Treatment with New Direct Acting Antivirals Has a Better Safety Profile While Being Effective in the Treatment-Naïve Geriatric Population Without Liver Cirrhosis and Hepatitis C Virus-RNA < 6 Million IU/mL.

AIM: Results of recent studies have confirmed the efficacy of an 8-week course of ledipasvir/sofosbuvir (LDV/SOF) in patients who are non-cirrhotics, native to treatment, are infected with hepatitis C (HCV) genotype 1, and have HCV viral load < 6 million IU/mL. However, there are limited data on a shortened treatment course in patients who are over the age of 65. METHODS: A retrospective study was performed to examine the safety, tolerability, and sustained viral response rates (SVR) of the 8-week LDV/SOF therapy compared to the 12-week LDV/SOF therapy among non-cirrhotic, treatment-naïve, genotype 1 HCV patients with viral load < 6 million IU/mL who are 65 years of age or older. RESULTS: A total of 454 patients were identified of which 182 non-cirrhotic, genotype 1 HCV-RNA < 6 million IU/mL patients received the 8-week LDV/SOF treatment and 272 received the 12-week LDV/SOF treatment. Mean [± standard deviation (SD)] aspartate aminotransferase to platelet ratio index score for the entire cohort was 0.45 ± 0.03. The mean (± SD) age for the 8-week treatment was 69.7 (± 7) years, 54.7% male and 45.3% female. The mean (± SD) age of the 12-week treatment was 71.7 (± 3) years, 56.4% male and 43.6% female. Overall, SVR-12 for the 8-week regimen was 93% and SVR-12 for the 12-week regimen was 95%. For the 182 treated with the 8-week LDV/SOF treatment, there were no serious adverse events requiring hospitalization or signs of liver failure requiring transplantation. Overall, the 8-week treatment patient cohort experienced less fatigue, headache, dry mouth, and diarrhea. This finding was statistically significant with a P value < 0.001. CONCLUSION: Eight-week LDV/SOF therapy in treatment-naive, non-cirrhotic, genotype 1 HCV patients with RNA < 6 million IU/mL was found safe, better tolerated, effective, and required less upfront cost when compared with the 12-week LDV/SOF treatment regimen in properly selected geriatric population.

Comparison of Sofosbuvir Plus Ribavirin Treatment with Pegylated Interferon Plus Ribavirin Treatment for Chronic Hepatitis C Genotype 2.

BACKGROUND: Sofosbuvir plus ribavirin (RBV) therapy showed higher sustained virological response at 12 weeks after treatment (SVR12) than pegylated interferon (peg-IFN) plus RBV; however, liver function, fibrosis, and hepatocellular carcinoma markers have not been assessed so far. SUMMARY: Patients (n = 21) receiving Sofosbuvir plus RBV and those (n = 24) receiving peg-IFN plus RBV were enrolled in this study. Changes in alanine aminotransferase (ALT) and α-fetoprotein (AFP) levels, platelet (PLT) counts, FIB-4, and aspartate aminotransferase-to-platelet ratio index (APRI) in both groups were assessed in patients achieving SVR12. Also, fibrosis regression was assessed using pathophysiological biomarkers, such as hyaluronic acid, bone morphogenetic protein 7 (BMP-7), and connective tissue growth factor (CTGF) in the Sofosbuvir plus RBV group. In both groups, while the reduction in ALT levels was significant that of AFP was not. Compared with the baseline, although serum PLT count at the end of treatment (EOT) was significantly higher in the Sofosbuvir plus RBV group, it was significantly lower in the peg-IFN plus RBV group. Although a significant decline in fibrosis markers such as FIB-4 and APRI was observed between the baseline and at EOT in the Sofosbuvir plus RBV group, no significant change of these markers was observed in the peg-IFN plus RBV group. Moreover, BMP-7 and CTGF were significantly lower at EOT than the baseline in the Sofosbuvir plus RBV group. Key Message: The treatment with Sofosbuvir plus RBV results in not only a higher SVR, but also improves the liver function and the degree of fibrosis.

Cost-effectiveness of the highly effective direct-acting antivirals in the treatment of chronic hepatitis C in Hong Kong.

BACKGROUND AND AIM: In Asia-Pacific where cost is a major concern, peginterferon plus ribavirin (PR) often remain as the standard of care in chronic hepatitis C (CHC) treatment, while the direct-acting antivirals (DAAs) are commonly recommended as retreatment. Newer DAAs can achieve a sustained virological response (SVR) of nearly 100% with pan-genotypic coverage, that is "Highly Effective DAAs." We aimed to investigate the most desirable cost range for the Highly Effective DAAs using Hong Kong as an example. METHODS: Markov modeling was performed using PR as the reference strategy. The cost-effectiveness of the Highly Effective DAAs was compared with sofosbuvir-PR (first-line and rescue) and boceprevir-PR therapies. A 50-year-old genotype 1b hepatitis C virus (HCV) infected treatment-naïve patient with METAVIR F3 was used as the base case scenario to reflect the commonest HCV genotype in Hong Kong. RESULTS: The use of PR would incur a lifetime cost of US$35,854 and effectiveness of 14.85 quality-adjusted life-year (QALY). Sofosbuvir-PR as first-line treatment was dominated by other regimes. If Sofosbuvir-PR rescue therapy was used, the drug cost of Highly Effective DAAs should be set below US$43,553, with a cost-effectiveness ratio (CER) of US$3035/QALY compared with PR. In regions where Boceprevir-PR was still used as first-line therapy, the desirable drug cost of Highly Effective DAAs would be below US$56,985 to achieve a CER of US$5427/QALY. CONCLUSIONS: The most desirable costs of the Highly Effective DAAs would be below US$43,553 if Sofosbuvir-PR rescue therapy is used and below US$56,985 if Boceprevir-PR therapy is used.

Dual treatment with sofosbuvir plus ribavirin is as effective as triple therapy with pegylated interferon plus sofosbuvir plus ribavirin in predominant genotype 3 patients with chronic hepatitis C.

BACKGROUND AND AIM: Sofosbuvir (SOF) was the first directly acting antiviral made available for chronic hepatitis C (CHC) in India. We describe our "real life" experience of using SOF with ribavirin (RBV) with or without pegylated interferon (Peg-IFN) in predominant genotype 3 patients with CHC. METHODS: A total of 158 patients (men 99 [62.6%], mean age 40.3 ± 12.8 years) with CHC treated with dual therapy (SOF + RBV) for 24 weeks or triple therapy (Peg-IFN + SOF + RBV) for 12 weeks were included prospectively. Patients with co-infection, decompensated liver disease, and post-organ transplantation were excluded. Data were analysed for the preference of treatment regimen, end of treatment response (ETR), sustained virological response at 12 weeks, and side effects. RESULTS: Genotype 3 was the predominant genotype (105 [66.4%]) followed by genotype 1 (40 [25.3%]) and genotype 4 (13[8.2%]). Forty-eight (30.37%) patients had cirrhosis (LSM ≥ 13 kPa), and 30 (19%) were treatment experienced with Peg-IFN + RBV. A total of 103 (65.18%) patients received dual therapy, and 55 (34.81%) received triple therapy. Resentment to receive injections, inaccessibility to a facility, fear of injection or its side effects, and financial constraints were the reasons to refuse triple therapy. All patients in triple therapy group and all but two patients (98%) in the dual therapy group attained ETR. All those who achieved ETR achieved sustained virological response at 12 weeks in both groups. But for anemia in three patients (two in triple, one in dual therapy), there were no major side effects. CONCLUSIONS: Most patients with CHC prefer an oral treatment with directly acting antivirals. Both oral and interferon-based regimens achieve high response rate.

Results of sofosbuvir-based combination therapy for chronic hepatitis C cohort of Indian patients in real-life clinical practice.

BACKGROUND AND AIM: The introduction of sofosbuvir has revolutionized the treatment of chronic hepatitis C. This study was planned to observe whether the efficacy and tolerability of sofosbuvir-based regimens demonstrated in phase 3 clinical trial results translate into real-life clinical practice. METHODS: This prospective, non-randomized observational study conducted in Dayanand Medical College and Hospital, Punjab, included all consecutive treatment-naïve patients with chronic hepatitis C (genotypes 1-5) who were treated with sofosbuvir-based regimens. Response to therapy was assessed at week 4 (rapid virological response), week 12 or 24 (end of treatment response), and 12 weeks after cessation of therapy (sustained virological response [SVR]). RESULTS: Of 947 patients diagnosed with chronic hepatitis C virus and considered for treatment with direct-acting antivirals, 736 patients (77.1%) opted for treatment (age 45.1 ± 10.1 years, 64% men, genotype 3 [80%], genotype 1 [14.7%], and genotype 4 [4.9%]). Viral load was high (>600 000 IU/mL) in 361/736 (49%); 330 patients (44.8%) had cirrhosis (80 [14.3%] were decompensated). Patients with genotypes 1, 4, and 5 (n = 135) were treated with triple drug regime (pegylated interferon, ribavirin, and sofosbuvir) for 12 weeks. Patients with genotype 3 (n = 589) were treated either with dual therapy (sofosbuvir and ribavirin) for 24 weeks (n = 405) or triple therapy for 12 weeks (n = 184). SVR was achieved in 453/473 (95.8%). SVR rates did not differ among different genotypes but were higher in non-cirrhotics. CONCLUSION: Sofosbuvir-based treatment regimens achieve high SVR rates in real-life cohort of Indian patients with chronic hepatitis C infection (including those with cirrhosis).

Real-World Experiences with the Combination Treatment of Ledipasvir plus Sofosbuvir for 12 Weeks in HCV Genotype 1-Infected Japanese Patients: Achievement of a Sustained Virological Response in Previous Users of Peginterferon plus Ribavirin with HCV NS3/4A Inhibitors.

The aim of this study was to characterize the treatment response and serious adverse events of ledipasvir plus sofosbuvir therapies in Japanese patients infected with hepatitis C virus (HCV) genotype 1 (GT1). This retrospective study analyzed 240 Japanese HCV GT1 patients treated for 12 weeks with 90 mg of ledipasvir plus 400 mg of sofosbuvir daily. Sustained virological response at 12 weeks post-treatment (SVR12) was achieved in 236 of 240 (98.3%) patients. Among treatment-naïve patients, SVR12 was achieved in 136 of 138 (98.6%) patients, and among treatment-experienced patients, SVR12 was achieved in 100 of 102 (98.0%) patients. In patients previously treated with peginterferon plus ribavirin with various HCV NS3/4A inhibitors, 100% SVR rates (25/25) were achieved. Two relapsers had HCV NS5A resistance-associated variants (RAVs), but no HCV NS5B-S282 was observed after they relapsed. We experienced two patients with cardiac events during treatment. In conclusion, combination of ledipasvir plus sofosbuvir for 12 weeks is a potential therapy for HCV GT1 patients. Caution is needed for HCV NS5A RAVs, which were selected by HCV NS5A inhibitors and cardiac adverse events.

[Treatment of HCV genotype 2 infection]. / Lécba pacientu infikovaných virem hepatitidy C genotypu 2.

INTRODUCTION: Hepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide. AIMS: Retrospectively evaluate the results of therapy of patients with genotype 2 HCV treated during last 15 years at the Department of Infectious Diseases University Hospital Brno and Faculty of Medicine Masaryk University Brno, Czech Republic. PATIENTS AND METHODS: 15 patients (9 men, 6 women, mean age 54.73 ± 13.83 years, median 54 years) with chronic genotype 2 infection were treated at in our department during last 15 years. It is the biggest group of patients with this diagnosis treated in the Czech Republic. Proportion of genotype 2 subtypes was following: 1 times subtype 2a, 2 times subtype 2a/2c, 5 times subtype 2b, in the rest 7 cases only genotype 2 was determined without possibility to determinate subtype. RESULTS: 9 patients were treated with the combination of peginterferon α-2a (180 µg once weekly subcutaneously) and ribavirin (1 000 or 1 200 mg daily according to the weight) for 24 weeks in the years 2002-2015, sustained virological response (SVR) achieved 6 of them (67 %). Two relapses and one breakthrough were recorded. 7 patients were treated with combination of sofosbuvir (400 mg daily) and ribavirin (1 000 or 1 200 mg daily according to the weight) for 12 weeks in the years 2015-2016 - 6 of them were treatment naïve, one after breakthrough in previous therapy. All of these 7 patients achieved SVR (100 %). CONCLUSIONS: Genotype 2 therapy still not represents serious therapeutic problem. The number of difficultly treatable patients is gradually increasing in many well-developed countries during last several years. However the therapeutic possibilities are quickly developing.Key words: chronic hepatitis C - genotype 2 - pegylated interferon - ribavirin - sofosbuvir.

Nucleotide polymerase inhibitor sofosbuvir plus ribavirin for hepatitis C.

BACKGROUND: The standard treatment for hepatitis C virus (HCV) infection is interferon, which is administered subcutaneously and can have troublesome side effects. We evaluated sofosbuvir, an oral nucleotide inhibitor of HCV polymerase, in interferon-sparing and interferon-free regimens for the treatment of HCV infection. METHODS: We provided open-label treatment to eight groups of patients. A total of 40 previously untreated patients with HCV genotype 2 or 3 infection were randomly assigned to four groups; all four groups received sofosbuvir (at a dose of 400 mg once daily) plus ribavirin for 12 weeks. Three of these groups also received peginterferon alfa-2a for 4, 8, or 12 weeks. Two additional groups of previously untreated patients with HCV genotype 2 or 3 infection received sofosbuvir monotherapy for 12 weeks or sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks. Two groups of patients with HCV genotype 1 infection received sofosbuvir and ribavirin for 12 weeks: 10 patients with no response to prior treatment and 25 with no previous treatment. We report the rate of sustained virologic response 24 weeks after therapy. RESULTS: Of the 40 patients who underwent randomization, all 10 (100%) who received sofosbuvir plus ribavirin without interferon and all 30 (100%) who received sofosbuvir plus ribavirin for 12 weeks and interferon for 4, 8, or 12 weeks had a sustained virologic response at 24 weeks. For the other patients with HCV genotype 2 or 3 infection, all 10 (100%) who received sofosbuvir plus peginterferon alfa-2a and ribavirin for 8 weeks had a sustained virologic response at 24 weeks, as did 6 of 10 (60%) who received sofosbuvir monotherapy. Among patients with HCV genotype 1 infection, 21 of 25 previously untreated patients (84%) and 1 of 10 with no response to previous therapy (10%) had a sustained virologic response at 24 weeks. The most common adverse events were headache, fatigue, insomnia, nausea, rash, and anemia. CONCLUSIONS: Sofosbuvir plus ribavirin for 12 weeks may be effective in previously untreated patients with HCV genotype 1, 2, or 3 infection. (Funded by Pharmasset and Gilead Sciences; ClinicalTrials.gov number, NCT01260350.).

Sofosbuvir for previously untreated chronic hepatitis C infection.

BACKGROUND: In phase 2 trials, the nucleotide polymerase inhibitor sofosbuvir was effective in previously untreated patients with chronic hepatitis C virus (HCV) genotype 1, 2, or 3 infection. METHODS: We conducted two phase 3 studies in previously untreated patients with HCV infection. In a single-group, open-label study, we administered a 12-week regimen of sofosbuvir plus peginterferon alfa-2a and ribavirin in 327 patients with HCV genotype 1, 4, 5, or 6 (of whom 98% had genotype 1 or 4). In a noninferiority trial, 499 patients with HCV genotype 2 or 3 infection were randomly assigned to receive sofosbuvir plus ribavirin for 12 weeks or peginterferon alfa-2a plus ribavirin for 24 weeks. In the two studies, the primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: In the single-group study, a sustained virologic response was reported in 90% of patients (95% confidence interval, 87 to 93). In the noninferiority trial, a sustained response was reported in 67% of patients in both the sofosbuvir-ribavirin group and the peginterferon-ribavirin group. Response rates in the sofosbuvir-ribavirin group were lower among patients with genotype 3 infection than among those with genotype 2 infection (56% vs. 97%). Adverse events (including fatigue, headache, nausea, and neutropenia) were less common with sofosbuvir than with peginterferon. CONCLUSIONS: In a single-group study of sofosbuvir combined with peginterferon-ribavirin, patients with predominantly genotype 1 or 4 HCV infection had a rate of sustained virologic response of 90% at 12 weeks. In a noninferiority trial, patients with genotype 2 or 3 infection who received either sofosbuvir or peginterferon with ribavirin had nearly identical rates of response (67%). Adverse events were less frequent with sofosbuvir than with peginterferon. (Funded by Gilead Sciences; FISSION and NEUTRINO ClinicalTrials.gov numbers, NCT01497366 and NCT01641640, respectively.).

The combination of simeprevir and sofosbuvir is more effective than that of peginterferon, ribavirin, and sofosbuvir for patients with hepatitis C-related Child's class A cirrhosis.

BACKGROUND & AIMS: The efficacy and safety of interferon-free regimens for the treatment of chronic hepatitis C virus (HCV) infections require further evaluation and comparison with those of interferon-containing regimens. We compared a regimen of peginterferon, ribavirin, and sofosbuvir with a regimen of simeprevir and sofosbuvir in patients with HCV infection and unfavorable treatment features. METHODS: We performed a prospective open-label study of 82 patients with chronic HCV genotype 1a infection and Child's grade A cirrhosis enrolled from 2 clinics at a single center in Atlanta, Georgia, from December 2013 through January 2014. Fifty patients (61%) had not responded to treatment with peginterferon and ribavirin (null responders), and 32 (39%) were therapy naive; 39 (48%) were African American. Subjects were assigned randomly to groups given simeprevir (150 mg/day) and sofosbuvir (400 mg/day) (n = 58 in the final analysis) or peginterferon alfa 2b (1.5 mcg/kg/wk), ribavirin (1000-1200 mg/day), and sofosbuvir (400 mg/day) (n = 24 in the final analysis). Both regimens were given for 12 weeks. The primary trial end point was the proportion of patients with undetectable HCV-RNA levels 12 weeks after therapy completion (SVR12). RESULTS: A significantly greater percentage of patients (93%) given simeprevir and sofosbuvir achieved an SVR12 than those given the interferon-containing regimen (75%) (P = .02). Patients given the interferon-containing regimen had a significantly higher rate of virologic relapse than patients given simeprevir and sofosbuvir (P = .009), as well as worse self-reported outcomes and more side effects. Quality-of-life scores were higher in patients with SVR12 than those without, regardless of treatment regimen. CONCLUSIONS: In a prospective study of patients with chronic HCV genotype 1a infection and cirrhosis (48% African American and 61% prior null responders), a 12-week regimen of simeprevir and sofosbuvir produced a significantly higher rate of SVR12 and was better tolerated, with a lower viral relapse rate, than a 12-week regimen of peginterferon, ribavirin, and sofosbuvir. Clinicaltrials.gov no: NCT021683615.

Sofosbuvir with peginterferon-ribavirin for 12 weeks in previously treated patients with hepatitis C genotype 2 or 3 and cirrhosis.

UNLABELLED: Sofosbuvir (SOF) in combination with ribavirin (RBV) for 12 or 24 weeks is the current standard of care for patients infected with hepatitis C virus (HCV) genotypes 2 and 3, respectively. However, in clinical trials treatment-experienced patients, particularly those with cirrhosis, had suboptimal sustained virological response (SVR) rates. We assessed the efficacy and safety of sofosbuvir plus peginterferon and ribavirin (SOF+Peg-IFN+RBV) administered for 12 weeks to treatment-experienced patients with HCV genotypes 2 and 3, with and without cirrhosis. We enrolled 47 patients in this open-label, nonrandomized, uncontrolled phase 2 study. The primary endpoint was the proportion of patients with SVR at 12 weeks after cessation of study treatment (SVR12). The overall rate of SVR12 was 89% (95% confidence interval [CI]: 77-97). Rates of SVR12 were higher in patients with genotype 2 than in those with genotype 3, 96% (95% CI: 78-100) and 83% (95% CI: 62-95), respectively. Rates of SVR12 were similar in patients with and without cirrhosis: for genotype 2, 93% of patients with cirrhosis and 100% of patients without cirrhosis achieved SVR12, and for genotype 3, the SVR12 rate was 83% in patients both with and without cirrhosis. One patient discontinued study treatment because of an adverse event and four patients experienced serious adverse events. The most common adverse events were influenza-like illness, fatigue, anemia, and neutropenia. CONCLUSION: In treatment-experienced patients with HCV genotypes 2 and 3, 12-week administration of SOF+Peg-IFN+RBV provided high SVR rates, irrespective of cirrhosis status. No safety concerns were identified.