Geoffrey Dusheiko

Telaprevir for Previously Untreated Chronic Hepatitis C Virus Infection

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.).

EASL Clinical Practice Guidelines: Management of chronic hepatitis B

Our understanding of the natural history of hepatitis B virus (HBV) infection and the potential for therapy of the resultant disease has improved. Several new and effective antiviral agents have been evaluated and licensed since the EASL International Consensus Conference on hepatitis B held in 2002 [1]. The objective of these EASL Clinical Practice Guidelines (CPGs) is to update recommendations for the optimal management of chronic hepatitis B (CHB). The CPGs do not focus on prevention and vaccination. Several difficulties remain in formulating treatments for CHB; thus areas of uncertainty exist. At the present time clinicians, patients and public health authorities must continue to make choices on the basis of evidence that is not fully matured.

Telaprevir and Peginterferon with or without Ribavirin for Chronic HCV Infection

BACKGROUND In patients with chronic infection with hepatitis C virus (HCV) genotype 1, treatment with peginterferon alfa and ribavirin for 48 weeks results in rates of sustained virologic response of 40 to 50%. Telaprevir is a specific inhibitor of the HCV serine protease and could be of value in HCV treatment. METHODS A total of 334 patients who had chronic infection with HCV genotype 1 and had not been treated previously were randomly assigned to receive one of four treatments involving various combinations of telaprevir (1250 mg on day 1, then 750 mg every 8 hours), peginterferon alfa-2a (180 microg weekly), and ribavirin (dose according to body weight). The T12PR24 group (81 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks, followed by peginterferon alfa-2a and ribavirin for 12 more weeks. The T12PR12 group (82 patients) received telaprevir, peginterferon alfa-2a, and ribavirin for 12 weeks. The T12P12 group (78 patients) received telaprevir and peginterferon alfa-2a without ribavirin for 12 weeks. The PR48 (control) group (82 patients) received peginterferon alfa-2a and ribavirin for 48 weeks. The primary end point, a sustained virologic response (an undetectable HCV RNA level 24 weeks after the end of therapy), was compared between the control group and the combined T12P12 and T12PR12 groups. RESULTS The rate of sustained virologic response for the T12PR12 and T12P12 groups combined was 48% (77 of 160 patients), as compared with 46% (38 of 82) in the PR48 (control) group (P=0.89). The rate was 60% (49 of 82 patients) in the T12PR12 group (P=0.12 for the comparison with the PR48 group), as compared with 36% (28 of 78 patients) in the T12P12 group (P=0.003; P=0.20 for the comparison with the PR48 group). The rate was significantly higher in the T12PR24 group (69% [56 of 81 patients]) than in the PR48 group (P=0.004). The adverse events with increased frequency in the telaprevir-based groups were pruritus, rash, and anemia. CONCLUSIONS In this phase 2 study of patients infected with HCV genotype 1 who had not been treated previously, one of the three telaprevir groups had a significantly higher rate of sustained virologic response than that with standard therapy. Response rates were lowest with the regimen that did not include ribavirin. (ClinicalTrials.gov number, NCT00372385.)

Peginterferon Alfa-2a in Patients with Chronic Hepatitis C and Cirrhosis

BACKGROUND Chronic hepatitis C virus (HCV) infection in patients with cirrhosis is difficult to treat. In patients with chronic hepatitis C but without cirrhosis, once-weekly administration of interferon modified by the attachment of a 40-kd branched-chain polyethylene glycol moiety (peginterferon alfa-2a) is more efficacious than a regimen of unmodified interferon. We examined the efficacy and safety of peginterferon alfa-2a in patients with HCV-related cirrhosis or bridging fibrosis. METHODS We randomly assigned 271 patients with cirrhosis or bridging fibrosis to receive subcutaneous treatment with 3 million units of interferon alfa-2a three times weekly (88 patients), 90 microg of peginterferon alfa-2a once weekly (96), or 180 microg of peginterferon alfa-2a once weekly (87). Treatment lasted 48 weeks and was followed by a 24-week follow-up period. We assessed efficacy by measuring HCV RNA and alanine aminotransferase and by evaluating liver-biopsy specimens. A histologic response was defined as a decrease of at least 2 points on the 22-point Histological Activity Index. RESULTS In an intention-to-treat analysis, HCV RNA was undetectable at week 72 in 8 percent, 15 percent, and 30 percent of the patients treated with interferon alfa-2a and with 90 microg and 180 microg of peginterferon alfa-2a, respectively (P=0.001 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). At week 72, alanine aminotransferase concentrations had normalized in 15 percent, 20 percent, and 34 percent of patients, respectively (P=0.004 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). In the subgroup of 184 patients with paired liver-biopsy specimens, the rates of histologic response at week 72 were 31 percent, 44 percent, and 54 percent, respectively (P=0.02 for the comparison between 180 microg of peginterferon alfa-2a and interferon alfa-2a). All three treatments were similarly tolerated. CONCLUSIONS In patients with chronic hepatitis C and cirrhosis or bridging fibrosis, 180 microg of peginterferon alfa-2a administered once weekly is significantly more effective than 3 million units of standard interferon alfa-2a administered three times weekly.

EASL Recommendations on Treatment of Hepatitis C

Summary Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, with approximately 71 million chronically infected individuals worldwide. Clinical care for patients with HCV-related liver disease has advanced considerably thanks to an enhanced understanding of the pathophysiology of the disease, and because of developments in diagnostic procedures and improvements in therapy and prevention. These European Association for the Study of the Liver Recommendations on Treatment of Hepatitis C describe the optimal management of patients with acute and chronic HCV infections in 2018 and onwards.

Mortality from liver cancer and liver disease in haemophilic men and boys in UK given blood products contaminated with hepatitis C

BACKGROUND Most people with haemophilia who were treated with blood products before the introduction of virus-inactivation procedures were infected with the hepatitis-C virus (HCV). However, there is little quantitative information about the long-term effects on mortality of such infection. METHODS We carried out a cohort study of mortality from liver cancer and liver disease in 4865 haemophilic men and boys in the UK. They were treated between 1969 and 1985 with blood products carrying a high risk of HCV infection, and were followed up from first recorded exposure to Jan 1, 1993. FINDINGS Based on death-certificate information, mortality was 16.7 times higher than in the general population for liver disease (95% CI 12.5-22.0; 51 deaths), and 5.6 times higher (1.8-13.0; five deaths) for liver cancer. For men and boys with severe haemophilia who were not infected with HIV-1, the cumulative risks of death from chronic or unspecified liver disease or from liver cancer in the 25 years since first recorded exposure to high HCV-risk products were 1.4% (0.7-3.0) at all ages, and 0.10% (0.01-0.7), 2.2% (0.8-6.1), and 14.3% (4.5-40.9) for those with first recorded exposure at ages under 25, 25-44, and 45 or older. For those with haemophilia and HIV-1 infection, the corresponding risks were 6.5% (4.5-9.5) at all ages, and 3.8% (2.1-6.8), 17.1% (10.0-28.5), and 18.7% (6.4-47.6) in the three age-groups. In those with severe haemophilia, age-standardised all-cause mortality was stable during 1969-84 but increased during 1985-92 in both HIV-1-infected and HIV-1-uninfected groups. Among those not infected with HIV-1, the increase in all-cause mortality resulted largely from deaths attributed to chronic or unspecified liver disease or liver cancer in men aged over 45. INTERPRETATION There is an emerging risk of mortality from liver disease and liver cancer in the UK haemophilia population in individuals both infected and uninfected with HIV-1, which probably results from infection with hepatitis C.

Recent epidemic of acute hepatitis C Virus in HIV-positive men who have sex with men linked to high-risk sexual behaviours.

Objective:To characterize the mode of hepatitis C virus (HCV) transmission in a recent epidemic of acute HCV in HIV-infected individuals using linked molecular and clinical epidemiological studies. Design:Individuals diagnosed with acute HCV between 1999 and 2005 at three urban HIV units in the UK were enrolled into a phylogenetic and case–control study. Phylogenetic trees were constructed from the amplified sequences of the E1/E2 region of the HCV genome and were used to compare cases with unrelated sequences. A questionnaire-based, case–control study using matched controls recruited from each HIV unit identified putative transmission factors. Results:One hundred and eleven HIV-positive men who have sex with men with acute HCV (genotype 1: 84%) were enrolled. Phylogenetic analysis of 93 E1/E2 sequences revealed seven monophyletic clusters signifying multiple independent HCV lineages co-circulating in the HIV-positive population. Permucosal rather than percutaneous transmission factors were associated with case/control status. Cases (n = 60) had more sexual partners, increased levels of high-risk sexual behaviour and were more likely to have shared drugs via a nasal or anal route in the preceding year in comparison with controls (n = 130). Sex in a group of more than two people was the strongest predictor of case/control status; odds ratios associated with participation in two or at least three types of high-risk sexual behaviour in a group were 9.16 (95% confidence interval, 3.51–23.90) and 23.50 (95% confidence interval, 9.47–58.33), respectively. Conclusion:The identified co-circulating HCV lineages belong to different subtypes and genotypes, implying that rather than viral change, the epidemic is due to permucosal transmission factors that should be the focus of public health interventions.

Ribavirin treatment for patients with chronic hepatitis C: results of a placebo-controlled study

BACKGROUND/AIMS Small, uncontrolled studies of ribavirin for patients with chronic hepatitis C have reported efficacy in chronic hepatitis C. We have evaluated the efficacy and safety of a 24-week course of oral ribavirin in patients with chronic hepatitis C, compared to placebo. METHODS A total of 114 patients were randomised to ribavirin or placebo. Ribavirin was administered in doses of 1000 or 1200 mg/day for 24 weeks. Efficacy was determined in the intention-to-treat population: 76 received ribavirin and 38 placebo. RESULTS Ribavirin was significantly more effective than placebo in reducing and normalising serum ALT levels: 42/76 (55%) of ribavirin-treated patients vs 2/38 (5%) placebo recipients had either normalisation of the ALT levels or a reduction from baseline of at least 50% (p < 0.001). ALT levels were normal in 22/76 (29%) of ribavirin-treated patients vs 0/38 placebo recipients (p < 0.001). Twenty-four weeks after stopping ribavirin, the majority of patients had abnormal ALT levels. There was no difference between the treatment groups in reduction or disappearance of HCV-RNA levels. HCV RNA disappeared during treatment in 3% of ribavirin-treated patients and 3% of placebo recipients. More ribavirin than placebo patients showed improvement in total Knodell score (45% vs 31%), but these differences were not statistically significant. Analysis of each component of a histology activity index revealed no statistically significant differences between treatment groups. Ribavirin patients had fewer lymphoid aggregates than did placebo recipients at the post-treatment assessment (p = 0.05). Ribavirin was associated with reversible haemolytic anaemia: a fall in haemoglobin occurred in 3% of placebo- and 32% (25/78) of ribavirin-treated patients, respectively (p < 0.001). CONCLUSIONS These data indicate that ribavirin was no more effective than placebo in reducing or eliminating HCV-RNA levels, and was not significantly more effective than placebo in improving hepatic histology after 6 months of treatment. The role of a 6-month treatment of chronic hepatitis C with ribavirin alone, without a significant effect on HCV RNA, is therefore limited.

The progression of HCV-associated liver disease in a cohort of haemophilic patients

We have studied morbidity and mortality related to hepatitis C virus infection in haemophilic patients treated at our centre. 11/255 HCV seropositive patients have developed hepatic decompensation. 20 years after first exposure to lyophilized clotting factor concentrate the risk of hepatic decompensation is estimated to be 10.8% (95% CI 3.8‐17.8%). There is a significantly increased risk associated with HIV infection, and also with increased age. For HIV seropositive patients the rates of decline in CD4 lymphocyte count and the development of p24 antigenaemia are significant risk factors for hepatic decompensation. Cirrhosis was seen in 9/19 HIV seropositive patients at post mortem. There was an association of cirrhosis with increased age but not with CD4 count, p24 antigenaemia or AIDS. In conclusion, HCV infection is associated with serious liver disease in haemophilic patients, but so far this has been restricted to a minority of those at risk. HIV coinfection accelerates progression to hepatic decompensation, and we speculate that this is probably due to enhanced HCV replication in the presence of immune deficiency.

Natural history of hepatitis C

There has long been evidence that hepatitis C can lead to persistent infection in a high proportion of infected individuals, and can progress to chronic liver disease, cirrhosis and hepatocellular carcinoma (HCC). The transition from acute to chronic hepatitis C is usually sub-clinical. Accurate studies of the time course for clearance of acute hepatitis C are difficult to carry out because of the silent onset of the acute disease. The likelihood of spontaneous HCV resolution is associated with several genetic factors, including IL28B inheritance and the DQB1*0301 allele of the major histocompatibility complex class II. Most data suggest that resolution in the acute phase without progression to chronic disease is not accompanied by significant disease, but minor histological lesions have been observed in anti-HCV positive, HCV RNA negative individuals. The risk of reinfection remains a possibility after clearance of acute hepatitis C. High rates of sexually-transmitted infection are being reported in HIV positive men who have sex with men (MSM). Chronic infection with HCV is the leading cause of end-stage liver disease, hepatocellular carcinoma (HCC) and liver related death in the Western world. The natural history of the chronic disease remains incompletely defined. It is generally a slowly progressive disease characterized by persistent hepatic inflammation, leading to the development of cirrhosis in approximately 10-20% of patients over 20-30 years of HCV infection. However, the published data indicate varying progression rates to cirrhosis. Overall, once cirrhosis has developed there is a 1-5% annual risk of HCC and a 3-6% annual risk of hepatic decompensation. Following an episode of decompensation the risk of death in the following year is between 15% and 20%. The high number of chronically infected individuals, the burden of disease, and the absence of a vaccine indicates that treatment will form part of the disease control but the impact, effectiveness and outcomes of treatment in various groups remain uncertain. Several studies and meta-analysis have concluded that eradication of HCV with antiviral therapy reduces the risk of HCC in patients with chronic hepatitis C, independent of fibrosis stage, but the risk is not eliminated.