https://aasldpubs.onlinelibrary.wiley.com/doi/epdf/10.1002/hep.25762

The diagnosis and management of non-alcoholic fatty liver disease: practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association

https://www.emcdda.europa.eu/attachements.cfm/att_231442_EN_INT17_easl-recommendations-on-treatment-of-hepatitis-C.pdf

EASL Recommendations on Treatment of Hepatitis C

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 ...

https://www.nejm.org/doi/pdf/10.1056/NEJMoa1214853

Sofosbuvir for previously untreated chronic hepatitis C infection

Background In phase 2 studies, treatment with the all-oral combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor ledipasvir resulted in high rates of sustained virologic response among previously untreated patients with hepatitis C virus (HCV) genotype 1 infection. Methods We conducted a phase 3, open-label study involving previously untreated patients with chronic HCV genotype 1 infection. Patients were randomly assigned in a 1:1:1:1 ratio to receive ledipasvir and sofosbuvir in a fixed-dose combination tablet once daily for 12 weeks, ledipasvir–sofosbuvir plus ribavirin for 12 weeks, ledipasvir–sofosbuvir for 24 weeks, or ledipasvir–sofosbuvir plus ribavirin for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. Results Of the 865 patients who underwent randomization and were treated, 16% had cirrhosis, 12% were black, and 67% had HCV genotype 1a infection. The rates of sustained virologic response were 99% (95% confide...

/pdf/ledipasvir-and-sofosbuvir-for-untreated-hcv-genotype-1-3gq8e2dq7a.pdf

Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 Infection

Methods In this randomized, phase 3 trial, we evaluated the addition of telaprevir to peginter feron alfa-2a plus ribavirin in patients with HCV genotype 1 infection who had no response or a partial response to previous therapy or who had a relapse after an initial response. A total of 663 patients were assigned to one of three groups: the T12PR48 group, which received telaprevir for 12 weeks and peginterferon plus ribavirin for a total of 48 weeks; the lead-in T12PR48 group, which received 4 weeks of peginterferon plus ribavirin followed by 12 weeks of telaprevir and peginterferon plus ribavirin for a total of 48 weeks; and the control group (PR48), which received peginterferon plus ribavirin for 48 weeks. The primary end point was the rate of sustained virologic response, which was defined as undetectable HCV RNA 24 weeks after the last planned dose of a study drug. Results Rates of sustained virologic response were significantly higher in the two telaprevir groups than in the control group among patients who had a previous relapse (83% in the T12PR48 group, 88% in the lead-in T12PR48 group, and 24% in the PR48 group), a partial response (59%, 54%, and 15%, respectively), and no response (29%, 33%, and 5%, respectively) (P<0.001 for all comparisons). Grade 3 adverse events (mainly anemia, neutropenia, and leukopenia) were more frequent in the telaprevir groups than in the control group (37% vs. 22%). Conclusions Telaprevir combined with peginterferon plus ribavirin significantly improved rates of sustained virologic response in patients with previously treated HCV infection, re gardless of whether there was a lead-in phase. (Funded by Tibotec and Vertex Phar maceuticals; REALIZE ClinicalTrials.gov number, NCT00703118.)

/pdf/telaprevir-for-retreatment-of-hcv-infection-4zxboxpirq.pdf

Telaprevir for retreatment of HCV infection.

A B S T R AC T Background In phase 2 trials, telaprevir, a hepatitis C virus (HCV) genotype 1 protease inhibitor, in combination with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, has shown improved efficacy, with potential for shortening the duration of treatment in a majority of patients. Methods In this international, phase 3, randomized, double-blind, placebo-controlled trial, we assigned 1088 patients with HCV genotype 1 infection who had not received previous treatment for the infection to one of three groups: a group receiving telaprevir combined with peginterferon alfa-2a and ribavirin for 12 weeks (T12PR group), followed by peginterferon–ribavirin alone for 12 weeks if HCV RNA was undetectable at weeks 4 and 12 or for 36 weeks if HCV RNA was detectable at either time point; a group receiving telaprevir with peginterferon–ribavirin for 8 weeks and placebo with peginterferon–ribavirin for 4 weeks (T8PR group), followed by 12 or 36 weeks of peginterferon–ribavirin on the basis of the same HCV RNA criteria; or a group receiving placebo with peginterferon–ribavirin for 12 weeks, followed by 36 weeks of peginterferon–ribavirin (PR group). The primary end point was the proportion of patients who had undetectable plasma HCV RNA 24 weeks after the last planned dose of study treatment (sustained virologic response). Results Significantly more patients in the T12PR or T8PR group than in the PR group had a sustained virologic response (75% and 69%, respectively, vs. 44%; P<0.001 for the comparison of the T12PR or T8PR group with the PR group). A total of 58% of the patients treated with telaprevir were eligible to receive 24 weeks of total treatment. Anemia, gastrointestinal side effects, and skin rashes occurred at a higher incidence among patients receiving telaprevir than among those receiving peginterferon–ribavirin alone. The overall rate of discontinuation of the treatment regimen owing to adverse events was 10% in the T12PR and T8PR groups and 7% in the PR group. Conclusions Telaprevir with peginterferon–ribavirin, as compared with peginterferon–ribavirin alone, was associated with significantly improved rates of sustained virologic response in patients with HCV genotype 1 infection who had not received previous treatment, with only 24 weeks of therapy administered in the majority of patients. (Funded by Vertex Pharmaceuticals and Tibotec; ADVANCE ClinicalTrials.gov number, NCT00627926.)

/pdf/telaprevir-for-previously-untreated-chronic-hepatitis-c-3g65p85484.pdf

Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection

Current strategies for treating hepatitis B focus on clearance of active HBV infection through suppression of viral replication by interferon-alpha (IFN-alpha) and the nucleoside analogs (lamivudine and adefovir). Lamivudine therapy for 1 year leads to HBeAg seroconversion in 16-18% of patients compared to 4-6% of untreated controls, to histological improvement in 49-56% treated patients and in 23-25% controls. HBeAg seroconversion rates increase with the duration of lamivudine therapy from 17% at 1 year to 27, 40, 47 and 50% at 2, 3, 4 and 5 years, respectively. When prescribing lamivudine, drug resistance due to the emergence of tyrosine-methionine-aspartate-aspartate (YMDD) mutations that increases with duration of therapy and the potential risk of a severe flare of hepatitis with sudden cessation of therapy, probably greatest in patients with cirrhosis, are realistic concerns. After 48 weeks of treatment with 10 or 30 mg of adefovir dipivoxil per day, significantly more patients with HBeAg-positive chronic hepatitis B than those on placebo had histologic improvement (53, 59 and 25%, respectively), a reduction in serum HBV DNA levels (by a median of 3.52, 4.76 and 0.55 log copies/ml), undetectable levels of serum HBV DNA (21, 39 and 0%), normalisation of ALT levels (48, 55 and 16%) and HBeAg seroconversion (12, 14 and 6%). In HBeAg negative patients treated with adefovir dipivoxil (10mg/day) for 48 weeks, ALT levels had normalised in 72% (29% in the placebo group), serum HBV DNA levels were reduced to fewer than 400 copies/ml in 51% (none in the placebo group), liver histology improved in 64% (33% in the placebo group). No adefovir-associated resistance mutations of viral DNA were detected. Ongoing studies investigate combination therapy with lamivudine or IFN.

Treatment of chronic viral hepatitis

The number one choice for treatment of chronic hepatitis C is the combination of once weekly subcutaneous pegylated interferon plus daily oral ribavirin. The duration of treatment and dose of ribavirin must be tailored to the hepatitis C virus (HCV) genotype. Patients infected with HCV genotype 1 should be treated for 48 weeks with a standard dosage of ribavirin (1000 or 1200 mg/d). This ribavirin dosage regimen is 'off-label' when used in conjunction with pegylated interferon alfa-2b (12 kD). The approved dosage for use in combination with this agent is 800 mg daily. The appropriate duration of treatment and dosage of ribavirin for patients infected with HCV genotype 2 or 3 differs depending on the pegylated interferon that is chosen. It is important to note that the treatment paradigm for these individuals is quickly evolving. When using peginterferon alfa-2a (40 kD) in patients with HCV genotype 2 or 3, the duration of treatment should be 24 weeks in combination with a low dose of ribavirin (800 mg/d). When using pegylated interferon alfa-2b (12 kD) in patients infected with HCV genotype 2 or in patients infected with genotype 3 and hepatitis C virus RNA less than 600,000 IU/mL, the duration of treatment should be 24 weeks. However, recent data suggest such treatment may not be optimal for patients infected with HCV genotype 3 and hepatitis C virus RNA at levels greater than or equal to 600,000 IU/mL; treatment duration may need to be greater than 24 weeks. When using pegylated interferon alfa-2b (12 kD) in patients infected with HCV genotype 3 and high viral load, the optimal dosage of ribavirin appears to be 800 to 1400 mg/d based on bodyweight.

Current Treatment for Chronic Hepatitis C.

HCV-genotype 4 is the predominant genotype in patients in North-East (especially in Egypt and Lybia) and Sub-Saharan Africa and in most Middle Eastern countries and is spread by migration and IVDU to Europe in the last years. Current treatment consists of peginterferon-alfa2 plus ribavirin (Peg/RBV) combination therapy using a response guided approach with sustained virologic response (SVR) rates about 60 %. Combination of Peg/RBV with drugs like nitazoxanide or silibinin appear to improve SVR rates, but they were not systematically studied. The first generation protease inhibitors have no activity in genotype 4 patients. In contrast, the second wave protease inhibitors (simeprevir, faldaprevir, r-danoprevir) and the NS5B NUC polymerase inhibitor Sofosbuvir are potent inhibitors of HCV replication, but have not been explored in phase 3 trials. Hopefully these drugs will become available for these patients.

Treatment of Chronic Hepatitis C, Genotype 4

Chronic hepatitis C is the leading cause of cirrhosis and hepatocellular carcinoma. The first treatment attempt was interferon monotherapy, but it was not effective and was associated with substantial side effects. A major breakthrough was the licensing of direct acting antivirals (DAA) containing triple therapies in 2011. Like the dual combination, the triple combinations with first generation DAAs are associated with unpleasant, sometimes lethal, adverse effects. Therefore treatment regimens not needing a PegIFN/RBV backbone are a major unmet medical need. The first proof of concept study of an interferon-free therapy was presented in 2010. Today we have three different categories of DAAs which inhibit viral replication at different sites and can be combined for treatment of hepatitis C. These three categories are discussed in this chapter. Also treatment regimens for patients who have undergone liver transplantation are discussed. Fine-tuning of treatments with respect to drug selection, treatment duration, and the need for ribavirin (RBV) is urgently needed.

Peter Ferenci

Papers

Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection

Treatment of chronic viral hepatitis

Current Treatment for Chronic Hepatitis C.

Treatment of Chronic Hepatitis C, Genotype 4

Current Treatment of Chronic Hepatitis C