Weeks Of Ribavirin Research Articles

Changes in renal function indices in chronic hepatitis C patients treated with sofosbuvir/daclatasvir, with or without ribavirin

Abstract Background Hepatitis C virus HCV infection is one of the main causes of chronic liver disease worldwide, Egypt has the highest national-level HCV prevalence in the world, Sofosbuvir/Daclatasvir (SOF/DAC) regimen widely used to treat HCV infection in Egypt. Aim of the Study to assess changes in renal indices during and after HCV treatment in chronic hepatitis C patients treated with sofosbuvir/daclatasvir, with or without ribavirin with normal baseline creatinine Methods This study was a real life data analysis which recruited a number of “509” patients who received (SOF/DAC) regimen for 12 weeks with or without ribavirin in New Cairo viral Hepatitis Treatment Center, one of the NCCVH specialized centers. According to Supreme Council and NCCVH Hepatitis C Updated Treatment Protocol included patients received either: Sofosbuvir (400mg) + Daclatasvir (60mg) for 12weeks orSofosbuvir (400mg) + Daclatasvir (60mg) + Ribavirin for 12weeks. All data for chronic HCV patients who treated with sofosbuvir /daclatasvir, with or without ribavirin with normal baseline creatinine and achieved SVR,were compared to assess changes in renal indices during and after HCV treatment Results At the end of treatment, the estimated glomerular filtration rate (eGFR) level was significantly decreased and the serum creatinine( Scr) levels were significantly increased compared with baseline levels (eGFR: 91.63 ± 26.41 vs 85.71 ± 24.86, P01 < 0.001; Scr: .87 ± .20 vs.92 ± .22, P01 < 0.001and no significant improvements were observed at 24 w post-treatment (eGFR: 89.65 ± 26.14vs 91.63 ± 26.41 ,P02 = 0.029; Scr: .89 ± .24. vs 87 ± .20, P02 = 0.020. Considering the difference in liver conditions, changes in renal function indices were compared between cirrhotic patients and non-cirrhotic patients. At the end of treatment, cirrhotic patients and non-cirrhotic patients had decreased eGFR levels and increased Scr levels at 24 w post-treatment, the eGFR and Scr levels were significantly improved in non-cirrhotic patients, while no obvious improvements were observed in cirrhotic patients. Conclusion Although DAAs are highly effective and well tolerated, at the end of treatment we found that: The eGFR level was significantly decreased and the Scr levels were significantly increased compared with baseline levels and no significant improvements were observed at 24 w post-treatment.Both Cirrhotic patients and non-cirrhotic patients had decreased eGFR levels and increased Scr levels at 24 w post-treatment but the eGFR and Scr levels were significantly improved in non-cirrhotic patients , while no obvious improvements were observed in cirrhotic patients.

Shortened therapy of eight weeks with paritaprevir/ritonavir/ombitasvir and dasabuvir is highly effective in people with recent HCV genotype 1 infection

Paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 12weeks are approved for treatment of chronic HCV genotype 1 infection. This study assessed the efficacy of shortened duration paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin for 8weeks among people with recent HCV infection. In this open-label single-arm trial conducted in Australia, England and New Zealand, adults with recent HCV (duration of infection <12months) received paritaprevir/ritonavir/ombitasvir and dasabuvir (with weight-based ribavirin for genotypes 1a and 1, no subtype) for 8weeks. The primary endpoint was sustained virological response at 12weeks post-treatment (SVR12) in the intention-to-treat (ITT) population. Thirty people (median age 38years, male 93%) commenced treatment (with ribavirin, 97%), of whom 77% (n=23) were HIV-positive, 93% (n=28) had genotype 1a infection and 53% (n=16) had ever injected drugs. Median maximum ALT in the preceding 12months was 433 IU/L (IQR 321, 1012). Acute clinical hepatitis with ALT>10xULN was documented in 83% (n=25); one participant (3%) had jaundice. At baseline, median estimated duration of infection was 30 weeks (range 11, 51), and median HCV RNA was 5.7 log10 IU/mL (range 2.7, 7.3). SVR12 was achieved in 97% (29/30; early discontinuation at week 2, n=1; per protocol 100%, 29/29). No relapse or reinfection was observed. In conclusion, paritaprevir/ritonavir/ombitasvir and dasabuvir (with ribavirin) for eight weeks were highly effective among HIV-positive and HIV-negative individuals with recent HCV infection. These data support the use of this shortened duration direct-acting antiviral regimen in this population.

Risk of hepatitis B virus reactivation in hepatitis B virus+hepatitis C virus-co-infected patients with compensated liver cirrhosis treated with ombitasvir, paritaprevir/r+dasabuvir+ribavirin.

Hepatitis B virus may reactivate in patients with chronic hepatitis C treated with direct-acting antivirals. The aim of this study was to investigate the risk of hepatitis B virus (HBV) reactivation in HBV+hepatitis C virus (HCV)-co-infected patients with compensated liver cirrhosis treated with paritaprevir/ombitasvir/ritonavir, dasabuvir with ribavirin. We reviewed prospectively gathered data from a national cohort of 2070 hepatitis C virus patients with compensated liver cirrhosis who received reimbursed paritaprevir/ombitasvir/r, dasabuvir with ribavirin for 12weeks from the Romanian National Health Agency during 2015-2016. Twenty-five patients in this cohort were HBs antigen positive (1.2%); 15 untreated with nucleotide analogues agreed to enter the study. These patients were followed up: ALT monthly, serology for HBV and DNA viral load at baseline, EOT and SVR at 12weeks. Hepatitis B virus (HBV)-co-infected patients were all genotype 1b and 52% females, with a median age of 60years (51÷74); 76% were pretreated with peginterferon+ribavirin; 72% were with severe necroinflammatory activity on FibroMax assessment; 40% presented comorbidities; and all were HBe antigen negative. Hepatitis C virus (HCV) SVR response rate was 100%. Hepatitis B virus (HBV)-DNA viral load was undetectable in 7/15 (47%) before therapy, and for the other 8 patients, it varied between below 20 and 867IU/mL. Five patients (33%) presented virological reactivation (>2 log increase in HBV-DNA levels) during therapy. One patient presented with hepatitis associated with HBV reactivation, and two started anti-HBV therapy with entecavir. Hepatitis B virus (HBV) virological reactivation was present in 33% in our patients. Generally, HBV-DNA elevations were mild (<20000IU/mL); however, we report one case of hepatitis associated with HBV reactivation.

Use of a hepatitis C virus (HCV) RNA-positive donor in a treated HCV RNA-negative liver transplant recipient.

The shortage of livers has led most transplant centers to use extended criteria donors. Hepatitis C virus (HCV) RNA-positive donor organs are typically not given to patients who have cleared HCV. A 64-year-old male with chronic hepatitis C, genotype 1b was listed for LT with hepatocellular carcinoma. While on the waiting list, the patient was treated with sofosbuvir, ledipasvir, and ribavirin and achieved an HCV RNA <15IU/mL by week 10. At week 18 of a planned 24-week treatment course, the patient underwent deceased-donor LT and received an organ from an anti-HCV-positive donor. Treatment was stopped at LT. At week 3 post LT, HCV RNA was detectable and revealed a genotype 3 HCV infection, compatible with transplantation of an organ with established infection. With retreatment with sofosbuvir, daclatasvir, and ribavirin for 12weeks, the patient achieved a sustained virologic response. This report highlights how antiviral therapies can be used to optimize the outcomes of HCV-infected transplant patients.

Sofosbuvir plus daclatasvir with or without ribavirin is safe and effective for post-transplant hepatitis C recurrence and severe fibrosis and cirrhosis: A prospective study.

In 2012, an Italian Named Patient Program began for hepatitis C virus (HCV)-infected liver transplant (LT) recipients with advanced fibrosis, before approval of direct antiviral agents (DAA), to benefit severely ill patients. The aim of this "real-life" study was to assess treatment efficacy and safety with an extended course of daclatasvir (DCV) plus sofosbuvir (SOF) with or without ribavirin (RBV). All HCV LT recipients with severe fibrosis in 15 Italian transplant centers were treated with DCV+SOF±RBV for 24weeks; sustained virological response was assessed at 12weeks post-treatment (SVR12). Eighty-seven patients were enrolled (75.9% males, mean age 58.4±7.2years, 83.9% genotype 1, 81.6% cirrhosis); 52 (59.8%) received RBV. Overall, 79 obtained SVR12 (90.8%): 100% in F3 and 88.7% in cirrhotics (91.5% in Child-Pugh A, 83.3% in Child-Pugh B and C). According to the treatment group, SVR was 80% in DCV+SOF group and 98.1% in SOF+DCV+RBV. Two virological relapses occurred during follow-up in cirrhotic patients who received DCV+SOF. Four cirrhotic patients in DCV+SOF group and 1 in DCV+SOF+RBV group died on treatment. An extended course of SOF plus DCV for 24weeks, with or without RBV, is effective and well tolerated for the treatment of post-LT HCV recurrence with severe fibrosis.

Ledipasvir/sofosbuvir for treatment of hepatitis C virus in sofosbuvir-experienced, NS5A treatment-naïve patients: Findings from two randomized trials.

We report data from two similarly designed studies that evaluated the efficacy, safety, and optimal duration of ledipasvir/sofosbuvir (LDV/SOF)±ribavirin (RBV) for retreatment of chronic hepatitis C virus (HCV) in individuals who failed to achieve sustained virological response (SVR) with prior SOF-based, non-NS5A inhibitor-containing regimens. The RESCUE study enrolled HCV mono-infected adults with genotype (GT) 1 or 4. Non-cirrhotic participants were randomized to 12weeks of LDV/SOF or LDV/SOF+RBV. Compensated cirrhotic participants were randomized to LDV/SOF+RBV (12weeks) or LDV/SOF (24weeks). The AIDS Clinical Trials Group A5348 study randomized genotype 1 adults with HCV/HIV co-infection to LDV/SOF+RBV (12weeks) or LDV/SOF (24weeks). Both studies used SVR at 12weeks post-treatment (SVR12) as the primary endpoint. In the RESCUE study, 82 participants were randomized and treated, and all completed treatment. Overall, SVR12 was 88% (72/82); 81-100% in non-cirrhotic participants treated with LDV/SOF or LDV/SOF+RBV for 12weeks and 80-92% in cirrhotic participants treated with LDV/SOF+RBV for 12weeks or LDV/SOF for 24weeks. Adverse events (AEs), mostly mild-to-moderate in severity, were experienced by 78% of participants, with headache and fatigue most frequently reported. One serious AE, not related to treatment, was observed. No premature discontinuations of study drug, or deaths occurred. In the A5348 study, seven participants were randomized (cirrhotic n=1; GT1a n=5) and all attained SVR12, with no serious AEs or premature discontinuations. In this SOF-experienced, NS5A inhibitor-naïve population, which included participants with cirrhosis or HCV/HIV co-infection, high SVR12 rates were achieved.

Efficacy and safety of sofosbuvir plus ribavirin for treatment of cirrhotic patients with genotype 4 hepatitis C virus in real-life clinical practice.

Egypt has the highest hepatitis C virus (HCV) prevalence in the world. Sofosbuvir is a new highly effective drug for treatment of HCV infection. Compared to previous treatments, sofosbuvir-based regimens provide a higher cure rate, fewer side effects, and a two- to fourfold reduced duration of therapy. The aim of this study was to evaluate the antiviral efficacy, safety, and tolerability of sofosbuvir plus ribavirin in Egyptian patients with liver cirrhosis due to chronic HCV infection. We studied 2400 cirrhotic Egyptian patients with chronic HCV infection who were treated with dual therapy with sofosbuvir and ribavirin for 24weeks. Efficacy was determined by assessment of serum HCV RNA. Any adverse events during treatment were recorded. Two thousand four hundred cirrhotic Egyptian patients with chronic HCV infection treated with sofosbuvir and ribavirin for 24weeks were enrolled in the study. The mean age of the studied group (±SD) was 53.9±6.5years, 1549 (64.54%) were males, all were cirrhotic patients, 3.41% were treatment-experienced, the baseline mean HCV RNA concentration was 4.33×106 IU/mL, and 94.37% of the patients had completed the full course of therapy. The overall SVR12 rate was 71.2%. The most common adverse events were fatigue, myalgia, headache, insomnia, and anemia. One hundred thirty-five (5.63%) patients stopped treatment permanently due to the appearance of complications that prevented continuation of treatment. The sofosbuvir and ribavirin combination is safe and effective in treatment of HCV patients with liver cirrhosis. However, further studies are needed to establish the optimal treatment regimen for those cases.

A different perspective on sofosbuvir-ledipasvir treatment of patients with HCV genotype 1b cirrhosis: The ital-c network study.

The effectiveness of a 12-week course of sofosbuvir-ledipasvir in treatment-experienced HCV genotype 1b-infected patients with cirrhosis is still under debate. Our primary endpoint was to compare the sustained virological response at post-treatment week 12 (SVR12) of sofosbuvir-ledipasvir in combination with ribavirin for 12weeks, and sofosbuvir-ledipasvir alone for 24weeks. This was a prospective observational study that enrolled 424 (195 naive, 229 experienced; 164 treated for 12weeks with Ribavirin and 260 with sofosbuvir-ledipasvir alone for 24weeks) consecutive HCV genotype 1b-infected patients with cirrhosis. The SVR12 rates were 93.9% and 99.2% in patients treated for 12 and 24weeks, respectively (P=.002). The baseline characteristics of patients treated for 12weeks were significantly different from those treated for 24weeks as regards their younger age (P=.002), prevalence of Child-Pugh class A (P=.002), lower MELD scores (P=.001) and smaller number of nonresponders (P=.04). The shorter treatment was significantly associated with a lower SVR12 in univariate and multivariate analyses (P=.007 and P=.008, respectively). The SVR rate was unaffected by age, gender, BMI, Child-Pugh class, MELD score or previous antiviral treatment. Patients receiving ribavirin experienced more episodes of ascites and headache but less recurrence of hepatocellular carcinoma (HCC), and were prescribed more diuretics and cardiopulmonary drugs. No patient discontinued treatment. The therapeutic regimen of sofosbuvir-ledipasvir plus ribavirin administered for 12weeks was less effective than sofosbuvir-ledipasvir alone given for 24weeks. At odds with European guidelines, the recommended 12-week treatment with sofosbuvir-ledipasvir alone might be suboptimal for this setting of patients.

Efficacy and safety of telaprevir with natural human interferon-β and ribavirin in Japanese chronic hepatitis C patients with depression.

To assess the efficacy and safety of telaprevir (TVR) when used in combination with natural human interferon-β (IFN-β) and ribavirin (RBV) for genotype 1 patients with depression compared to IFN-β/RBV therapy in Japan. We also examined the efficacy of the TVR/IFN-β/RBV therapy in treatment failure genotype 2 patients with depression. For the genotype 1 patients, 30 patients received TVR (750mg every 8h) for 12weeks combined with IFN-β and RBV for 24weeks (Group A), and 30 received IFN-β and RBV for 48weeks (Group B). For the genotype 2 patients, 14 patients were dosed only with the TVR-based regimen. The sustained virologic response (SVR) rates for Group A and Group B were 63.3% and 20.0%, respectively (P = 0.001, likelihood ratio test). The SVR rate for genotype 2 patients previously treated with pegylated IFN and/or RBV was 71.4%. No patient dropped out due to exacerbation of depression. The trend of platelet counts after the drugs were given was similar in the TVR/IFN-β/RBV therapy group and the IFN-β/RBV therapy group. Common resistance-associated variants of TVR were identified in 4 of the 13 patients who did not achieve SVR. This study showed that an addition of TVR to IFN-β/RBV therapy raised SVR in previously treated and untreated genotype 1 patients and previously treated genotype 2 patients with chronic hepatitis C and depression.

HEPATITIS-C GENOTYPE-3A INFECTION;

Objectives: In last decade, “treatment of chronic hepatitis-C revolved frominterferon based therapy to most effective interferon free therapy with new direct antiviraldrugs like Sofosbuvir and ribavirin” which is recommended for all genotypes of HCV infection.Treatment response in Chronic Hepatitis-C is affected both by viral and human factors. Weconducted this study “to evaluate the effect of human factor like (IL28B-rs12979860 non-CC)genotyping in response to Sofosbuvir based dual therapy in Hepatitis-C Genotype-3a infection”in population of Khyber PukhtoonKhwa (KPK). Setting: This open labeled, multi-center studywas conducted in Peshawar-Khyber PukhtoonKhwa (KPK). Period: March-2016 to August-2016.Method: Total of 70patients were enrolled. After doing “PCR for HCV-RNA-Viral level, Viral-Genotyping and Human genotyping for IL-28B, patients were put on Sofosbuvir and ribavirin for24-weeks”. Patients were assigned into two groups (1:1), “having 35 in each, including group-Aas those having favorable CC (IL28B- rs12979860-CC) genotyping and group-B as thosehaving unfavorable non-CC (IL28B-rs12979860-non-CC) genotyping”. The primary end pointwas “Sustained Virological response12 (SVR12), which is HCV-RNA level&lt;40IU/ml at 12-weeksafter completion of therapy in these two groups”. Results: Among 70-patients, male-femaleratio was 57.15% (n=40) and 42.85% (n=30) respectively. Each group has 35-cases. Rate ofSVR12 was 88.57% (n=31/35) in group-A, 91.42% (n=32/35) in group-B, having P-value&lt;05.Conclusion: This study confirm that “unlike interferon, unfavorable non-CC (IL28B-rs12979860-non-CC) genotyping have no or minimal role in treatment response to Sofosbuvir in Hepatitis-Cgenotype-3a infections”.

Retreatment with sofosbuvir, ledipasvir, and add-on ribavirin for patients who failed daclatasvir and asunaprevir combination therapy

The optimal retreatment regimen for patients with hepatitis C virus (HCV) infection who failed interferon-free, direct-acting antiviral (DAA) therapy is undetermined. In this study, we aimed to evaluate the efficacy and safety of 12-week retreatment with ledipasvir (LDV) and sofosbuvir (SOF) with add-on ribavirin (RBV) for patients who previously failed to respond to HCV-NS5A inhibitor, daclatasvir (DCV), and HCV-NS3 inhibitor, asunaprevir (ASV), therapy. This multicenter, prospective study enrolled 15 patients with genotype-1 HCV infection who failed DCV/ASV combination therapy. They were retreated with SOF, LDV, and RBV for 12weeks and underwent physical examinations and blood tests at baseline, during treatment, and after therapy. At baseline and relapse, NS3/NS5A and NS5B resistance-associated variants (RAVs) were evaluated. Of the 15 enrolled patients, 73.3% (11/15), 86.7% (13/15), and 0% (0/15) had RAVs in NS3 D168A/V/T/E, NS5A L31I/M/F/V plus Y93H, and NS5B S282T, respectively. Overall, 86.7% (13/15) of patients achieved a sustained viral response, and all patients completed therapy. No patients experienced severe adverse events. Two patients who failed to respond to SOF, LDV, and RBV combination therapy were elderly women, had the IL28B non-TT genotype, and NS5A RAVs in L31I/Y93H or NS5A A92K at baseline. This study revealed that SOF, LDV, and RBV combination therapy was effective and well-tolerated for patients with genotype-1 HCV infection who failed DCV and ASV combination therapy. Thus, RBV added to DAA therapy for difficult-to-treat patients might improve treatment outcomes.

Treatment with sofosbuvir and ledipasvir without ribavirin for 12weeks is highly effective for recurrent hepatitis C virus genotype 1b infection after living donor liver transplantation: a Japanese multicenter experience.

The optimal therapy for recurrent hepatitis C virus (HCV) infection after liver transplantation has not yet been established. This study aimed to clarify the efficacy and safety of interferon-free therapy with sofosbuvir and ledipasvir without ribavirin for 12weeks in Japanese patients with HCV genotype 1b infection after living donor liver transplantation. A cohort study of living donor liver transplant recipients with recurrent HCV genotype 1b infection treated with sofosbuvir (400mg/day) and ledipasvir (90mg/day) was performed at six liver transplant centers in Japan. Fifty-four patients were treated with sofosbuvir and ledipasvir. Thirty-eight patients (70%) were treatment experienced, including 17 patients who had undergone prior direct-acting-antiviral-based triple therapy. Ten patients had resistance-associated substitutions at L31 or Y93 in the NS5A region of the HCV genome. Fifty-three patients completed the 12-week treatment protocol; treatment was discontinued in one patient who developed pneumonia at 4weeks and died thereafter. All 53 patients who completed the treatment regimen achieved a sustained virological response 12weeks after completion of treatment. Treatment was well tolerated in most patients, but seven patients developed serious adverse events, including hemorrhagic duodenal ulcers (n=3), infection (n=2), pleural effusion (n=1), and alveolar hemorrhage (n=1). Sofosbuvir and ledipasvir treatment without ribavirin for 12weeks was highly effective in achieving a sustained virological response in Japanese patients who developed recurrent HCV genotype 1b infection after living donor liver transplantation.

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 24weeks, sofosbuvir/velpatasvir for 12weeks 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.

Respiratory adverse effects of Sofosbuvir-based regimens for treatment of chronic hepatitis C virus

BackgroundHepatitis C virus (HCV) infection is one of the main causes of chronic liver disease worldwide and new drugs were licensed for its treatment. Quite a few studies worked on spectrum of respiratory side effects associated with those new therapies. This work aimed to evaluate respiratory side effects associated with sofosbuvir-based regimens used for treatment of chronic HCV. MethodsThis study included 418 patients with HCV infection classified into 3 groups according to the treatment regimen: Group 1 (IFN-Sof-Rib): received triple therapy of sofosbuvir, pegylated interferon (Peg IFN)-α and ribavirin for 12weeks. Group 2 (Sof-Rib): received combined therapy of sofosbuvir, and ribavirin for 24weeks, and Group 3 (Sof-Dacl-Rib): received triple therapy of sofosbuvir, daclatasvir and ribavirin for 12weeks. All patients underwent baseline assessment including history taking, clinical examination, routine laboratory investigations, α-feto-protein, polymerase chain reaction for HCV RNA, abdominal ultrasound, and electrocardiogram. Patients then were followed monthly during the course of treatment for any respiratory side effects. Plain chest X-ray, high resolution computed tomography, spirometry, bronchial challenge test, and/or fiberoptic bronchoscopy and bronchoalveolar lavage were performed as indicated. ResultsCough was the commonest symptom in all groups (5.9%, 13%, and 7% in groups 1, 2, and 3 respectively). Obstructive ventilatory defect was the prominent pattern in the three groups without statistically significant difference (p=0.181). Bronchitis was the most common finding in the three groups (2.2%, 5.8% and 3.5% in group 1, 2, and 3 respectively). It was followed by upper respiratory tract infection (URTI) in group 2 (4.5%). URTI and bronchial hyperresponsiveness (BHR) occurred equally in group 1 (1.5%) and group 3 (1.7%). ConclusionSofosbuvir-based regimens used for treatment of chronic HCV infection are considered safe with minor respiratory adverse effects. However, larger multicenter studies are required for further assessment.

ITPA polymorphism effects on decrease of hemoglobin during sofosbuvir and ribavirin combination treatment for chronic hepatitis C.

Polymorphisms in the inosine triphosphatase (ITPA) gene is associated with anemia induced by peg-interferon (PEG-IFN) plus ribavirin (RBV) treatment for patients with chronic hepatitis C virus (HCV) infection. However, the effect of ITPA polymorphism on sofosbuvir plus RBV treatment is unknown. Two hundred and forty-four patients with chronic HCV genotype 2 infection without decompensated liver cirrhosis were treated with sofosbuvir plus RBV for 12weeks. The effects of ITPA polymorphism on hemoglobin levels and RBV dose reduction and treatment response were analyzed. ITPA (rs1127354) was genotyped using the Invader assay. Multivariate regression analysis was performed to identify factors associated with sustained virological response (SVR). Overall, SVR12 was achieved in 231 (94.7%) patients, based on intention to treat analysis. During the therapy, reduction of hemoglobin levels was significantly greater in ITPA genotype CC patients than CA/AA patients. Therefore, the cumulative proportion of patients with RBV dose reduction was significantly higher and total dose of RBV was significantly lower in patients with CC genotype compared to CA/AA genotypes. SVR12 rates were similar between ITPA genotypes CC and CA/AA (94.7 and 94.4%, respectively, P=0.933). Multivariate logistic regression analysis identified FIB4 index <3.25 (odds ratio [OR], 9.388 for ≥3.25; P=0.005) and low body weight (OR, 1.059, for high body weight; P=0.017) as independent predictors for SVR12. ITPA polymorphism influences hemoglobin levels and incidence of RBV dose reduction during sofosbuvir plus RBV therapy. However, ITPA genotype CC patients can expect a curative effect equivalent to CA/AA patients for chronic HCV genotype 2 infection.

Sofosbuvir/Velpatasvir: A Review in Chronic Hepatitis C.

A once-daily, single-tablet, pangenotypic regimen comprising the hepatitis C virus (HCV) NS5B polymerase inhibitor sofosbuvir and the HCV NS5A inhibitor velpatasvir (sofosbuvir/velpatasvir; Epclusa®) was recently approved for the treatment of adults with chronic HCV genotype 1, 2, 3, 4, 5 or 6 infection in the USA, EU and Canada. In the phase III ASTRAL trials, once-daily oral sofosbuvir/velpatasvir for 12weeks provided very high rates of sustained virological response at 12weeks post treatment (SVR12) in treatment-naive and -experienced patients with chronic HCV genotype 1-6 infection, including those with compensated cirrhosis or HIV-1 co-infection. High SVR12 rates were also observed with sofosbuvir/velpatasvir plus ribavirin for 12weeks in patients with chronic HCV genotype 1-6 infection and decompensated cirrhosis. Sofosbuvir/velpatasvir was generally well tolerated, with low rates of adverse events. Thus, sofosbuvir/velpatasvir represents a valuable treatment option in adults with chronic HCV genotype 1-6 infection, including those with compensated or decompensated cirrhosis, previous treatment experience or HIV-1 co-infection.

Ombitasvir/Paritaprevir/Ritonavir: A Review in Chronic HCV Genotype 4 Infection.

A fixed-dose tablet comprising the NS5A inhibitor ombitasvir, the NS3/4A inhibitor paritaprevir and ritonavir (ombitasvir/paritaprevir/ritonavir) (Technivie(®), Viekirax(®)) is available for use, in combination with ribavirin, for the treatment of chronic hepatitis C virus (HCV) genotype 4 infection. High sustained virological response rates at 12weeks post-treatment (SVR12) were achieved in treatment-naive or -experienced patients with chronic HCV genotype 4 infection, including patients without cirrhosis who received ombitasvir plus paritaprevir and ritonavir in combination with ribavirin for 12weeks (SVR12 100%) (PEARL-I trial), patients with compensated cirrhosis who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 or 16weeks (SVR12 97 and 98%) (AGATE-I trial), or Egyptian patients without cirrhosis who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12weeks (SVR12 94%) or with compensated cirrhosis who received ombitasvir/paritaprevir/ritonavir plus ribavirin for 12 or 24weeks (SVR12 97 and 93%) (AGATE-II trial). Ombitasvir/paritaprevir/ritonavir was generally well tolerated in patients with chronic HCV genotype 4 infection without cirrhosis or with compensated cirrhosis in clinical trials. There have been postmarketing reports of hepatic decompensation and hepatic failure, which mainly occurred in patients with advanced cirrhosis who received regimens containing ombitasvir/paritaprevir/ritonavir. In conclusion, ombitasvir/paritaprevir/ritonavir is a valuable option for use in patients with chronic HCV genotype 4 infection without cirrhosis or with compensated cirrhosis.

Plasma and intracellular ribavirin concentrations are not significantly altered by abacavir in hepatitis C virus-infected patients.

The objective of this study was to evaluate the effects of abacavir on intracellular ribavirin triphosphate and plasma ribavirin trough concentrations. Hepatitis C virus-infected subjects who had been cured or failed prior treatment were randomized to 8 weeks of ribavirin alone (N = 14; weight-based dosing) or weight-based ribavirin + abacavir (N = 14; 300 mg orally every 12 h). Ribavirin trough concentrations were measured on days 14, 28, 42 and 56; PBMCs for ribavirin triphosphate determination were sampled on days 28 and 56, pre-dose and at 6 and 12 h post-dose. ClinicalTrials.gov: NCT01052701. Twenty-six subjects completed the study (24 males, 17 Caucasians, median age 52 years); 2 were excluded for missed pharmacokinetic visits. Fourteen subjects received ribavirin + abacavir and 12 received ribavirin alone. Mean ± SD plasma ribavirin trough concentrations (μg/mL) on days 14, 28, 42 and 56, respectively, were not significantly different with coadministration of abacavir (1.54 ± 0.60, 1.93 ± 0.54, 2.14 ± 0.73 and 2.54 ± 1.05) compared with ribavirin alone (1.48 ± 0.32, 2.08 ± 0.41, 2.32 ± 0.47 and 2.60 ± 0.62) (P > 0.40). Mean ribavirin triphosphate intracellular concentrations (pmol/10(6) cells) on days 28 and 56, respectively, did not differ statistically between abacavir users (11.98 ± 9.86 and 15.87 ± 12.52) and non-users (15.91 ± 15.58 and 15.93 ± 12.69) (P > 0.4). Adverse events were mild or moderate, except for three grade 3 occurrences of transaminitis, cholecystitis and low absolute neutrophil count that resolved and were judged not attributable to study medications. Abacavir did not significantly alter ribavirin or ribavirin triphosphate concentrations.

Efficacy of Sofosbuvir Plus Ribavirin With or Without Peginterferon-Alfa in Patients With Hepatitis C Virus Genotype 3 Infection and Treatment-Experienced Patients With Cirrhosis and Hepatitis C Virus Genotype 2 Infection

We conducted an open-label, randomized, phase 3 trial to determine the efficacy and safety of sofosbuvir and ribavirin, with and without peginterferon-alfa, in treatment-experienced patients with cirrhosis and hepatitis C virus (HCV) genotype 2 infection and treatment-naïve or treatment-experienced patients with HCV genotype 3 infection. The study was conducted at 80 sites in Europe, North America, Australia, and New Zealand Patients were randomly assigned (1:1:1) to groups given sofosbuvir and ribavirin for 16 weeks (n= 196); sofosbuvir and ribavirin for 24 weeks (n= 199); or sofosbuvir, peginterferon-alfa, and ribavirin for 12 weeks (n= 197). The primary end point was the percentage of patients with HCV RNA <15 IU/mL 12 weeks after stopping therapy (sustained virologic response [SVR12]). From October 2013 until April 2014, we enrolled and treated 592 patients-48 with genotype 2 HCV and compensated cirrhosis who had not achieved SVR with previous treatments and 544 with genotype 3 HCV (279 treatment-naïve and 265 previously treated). Overall, 219 patients (37%) had compensated cirrhosis. The last post-treatment week 12 patient visit was in January2015. Rates of SVR12 among patients with genotype 2 HCV were 87% and 100%, for those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 94% for those receiving sofosbuvir, peginterferon, and ribavirin for 12weeks. Rates of SVR12 among patients with genotype 3 HCV were 71% and 84% in those receiving 16 and 24 weeks of sofosbuvir and ribavirin, respectively, and 93% in those receiving sofosbuvir, peginterferon, and ribavirin. On-treatment virologic failure occurred in 3 patients with HCV genotype 3a receiving sofosbuvir and ribavirin for 24 weeks. The most common adverse events were fatigue, headache, insomnia, and nausea. Overall, 1% of patients discontinued treatment due to adverse events. Among patients with genotype 3 HCV infection, including a large proportion of treatment-experienced patients with cirrhosis, the combination of sofosbuvir, peginterferon, and ribavirin for 12 weeks produces high rates of SVR. Treatment-experienced patients with cirrhosis and genotype 2 HCV infection had high rates of SVR in all groups. EudraCT ID 2013-002641-11.

Ombitasvir/paritaprevir/r and dasabuvir plus ribavirin in HCV genotype 1-infected patients on methadone or buprenorphine

Hepatitis C virus (HCV)-infected patients with a history of injection drug use have low rates of initiation and completion of interferon-based therapies. This study evaluated efficacy, safety, and pharmacokinetics of a 12-week all-oral regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin in HCV genotype 1-infected patients on stable opioid replacement therapy. This was a phase II, multicenter, open-label, single-arm study in treatment-naïve or peginterferon/ribavirin treatment-experienced HCV genotype 1-infected patients on methadone or buprenorphine±naloxone. Patients received 12weeks of co-formulated ombitasvir/paritaprevir/ritonavir (25mg/150mg/100mg once daily) and dasabuvir (250mg twice daily)+weight-based ribavirin. The primary efficacy endpoint was sustained virologic response 12 weeks post-treatment. Thirty-eight non-cirrhotic patients on chronic methadone (n=19) or buprenorphine (n=19) were enrolled. A total of 37 patients (97.4%) had a sustained virologic response 12 weeks post-treatment. No patient had a viral breakthrough or relapse. One patient discontinued due to serious adverse events unrelated to study drug (cerebrovascular accident and sarcoma). The most frequent adverse events were nausea, fatigue, and headache. Eight patients had on-treatment hemoglobin concentrations <10g/dl. Pharmacokinetic analyses indicated no clinically meaningful impact of methadone or buprenorphine on ombitasvir, paritaprevir, ritonavir, dasabuvir, or dasabuvir M1 metabolite exposures. No dose adjustments of methadone or buprenorphine were required. The interferon-free regimen of ombitasvir/paritaprevir/ritonavir and dasabuvir+ribavirin for 12weeks was well tolerated and achieved sustained virologic response in 97.4% of patients on opioid substitution therapy in this study. This all-oral regimen may provide an effective alternative to interferon-based therapies for HCV-infected patients with a history of injection drug use.