Massimo Puoti

Ledipasvir and Sofosbuvir for Untreated HCV Genotype 1 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% confidence interval [CI], 96 to 100) in the group that received 12 weeks of ledipasvir-sofosbuvir; 97% (95% CI, 94 to 99) in the group that received 12 weeks of ledipasvir-sofosbuvir plus ribavirin; 98% (95% CI, 95 to 99) in the group that received 24 weeks of ledipasvir-sofosbuvir; and 99% (95% CI, 97 to 100) in the group that received 24 weeks of ledipasvir-sofosbuvir plus ribavirin. No patient in either 12-week group discontinued ledipasvir-sofosbuvir owing to an adverse event. The most common adverse events were fatigue, headache, insomnia, and nausea. CONCLUSIONS Once-daily ledipasvir-sofosbuvir with or without ribavirin for 12 or 24 weeks was highly effective in previously untreated patients with HCV genotype 1 infection. (Funded by Gilead Sciences; ION-1 ClinicalTrials.gov number NCT01701401.).

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.

STATEMENTS FROM THE TAORMINA EXPERT MEETING ON OCCULT HEPATITIS B VIRUS INFECTION

Giovanni Raimondo*, Jean-Pierre Allain, Maurizia R. Brunetto, Marie-Annick Buendia, Ding-Shinn Chen, Massimo Colombo, Antonio Craxi, Francesco Donato, Carlo Ferrari, Giovanni B. Gaeta, Wolfram H. Gerlich, Massimo Levrero, Stephen Locarnini, Thomas Michalak, Mario U. Mondelli, Jean-Michel Pawlotsky, Teresa Pollicino, Daniele Prati, Massimo Puoti, Didier Samuel, Daniel Shouval, Antonina Smedile, Giovanni Squadrito, Christian Trepo, Erica Villa, Hans Will, Alessandro R. Zanetti, Fabien Zoulim

A meta-analysis of epidemiological studies on the combined effect of hepatitis B and C virus infections in causing hepatocellular carcinoma

The aim of the study was to assess whether co‐infection by hepatitis‐B virus (HBV) and hepatitis‐C virus (HCV) is associated with a higher risk of developing hepatocellular carcinoma (HCC) than each infection alone. A meta‐analysis of data published up to June 1997 was performed. HBsAg and anti‐HCV antibodies or HCV RNA (anti‐HCV/HCV RNA) were considered as serological markers of current HBV and HCV infection respectively. A total of 32 case‐control studies were suitable for a quantitative overview. The summary odds ratios (OR) were 13.7 for HBsAg positivity and 11.5 for anti‐HCV/HCV RNA positivity. The OR for anti‐HCV was lower among studies using second‐ or third‐generation anti‐HCV or HCV RNA (OR, 8.2) with respect to studies with first‐generation anti‐HCV test (OR, 19.1). When combining data from the studies with second‐ or third‐generation anti‐HCV or HCV RNA, the OR for HBsAg positivity and anti‐HCV/HCV RNA negativity was 22.5 (95% confidence interval (CI), 19.5–26.0), the OR for anti‐HCV/HCV RNA positivity and HBsAg negativity was 17.3 (95% CI, 13.9–21.6), and the OR for both markers positivity was 165 (95% CI: 81.2–374, based on 191 cases and 8 controls exposed). A synergism was found between HBV and HCV infections, the OR for co‐infection being greater than the sum and lower than the product of those for each infection alone. The interaction was therefore negative according to the multiplicative model, providing epidemiological evidence both of an independent effect and of interference between the 2 viruses in the carcinogenic process. Int. J. Cancer 75:347–354, 1998.

A systematic review of hepatitis C virus epidemiology in Europe, Canada and Israel

Background and Aim: Decisions on public health issues are dependent on reliable epidemiological data. A comprehensive review of the literature was used to gather country‐specific data on risk factors, prevalence, number of diagnosed individuals and genotype distribution of the hepatitis C virus (HCV) infection in selected European countries, Canada and Israel.

Incidence and Predictors of Severe Liver Fibrosis in Human Immunodeficiency Virus—Infected Patients with Chronic Hepatitis C: A European Collaborative Study

A study was performed in 10 European health care centers in which 914 patients coinfected with hepatitis C virus (HCV) and human immunodeficiency virus (HIV) who had elevated serum alanine aminotransferase (ALT) levels underwent liver biopsy during the period of 1992 through 2002. Overall, the METAVIR liver fibrosis stage was F0 in 10% of patients, F1 in 33%, F2 in 22%, F3 in 22%, and F4 in 13%. Predictors of severe liver fibrosis (METAVIR stage, F3 or F4) in multivariate analysis were age of >35 years (odds ratio [OR], 2.95; 95% confidence interval [CI], 2.08-4.18), alcohol consumption of >50 g/day (OR, 1.61; 95% CI, 1.1-2.35), and CD4+ T cell count of <500 cells/mm3 (OR, 1.43; 95% CI, 1.03-1.98). Forty-six percent of patients aged >40 years had severe liver fibrosis, compared with 15% of subjects aged <30 years. The use of antiretroviral therapy was not associated with the severity of liver fibrosis. In summary, severe liver fibrosis is frequently found in HCV-HIV-coinfected patients with elevated serum ALT levels, and its severity increases significantly with age. The rate of complications due to end-stage liver disease will inevitably increase in this population, for whom anti-HCV therapy should be considered a priority.

European AIDS Clinical Society (EACS) guidelines for the clinical management and treatment of chronic hepatitis B and C coinfection in HIV-infected adults

With the decline in HIV‐associated morbidity and mortality following the introduction of highly active antiretroviral therapy (HAART), liver disease has emerged as a major cause of death in HIV/hepatitis B virus (HBV) and HIV/hepatitis C virus (HCV) coinfected persons. Therefore, screening for underlying viral hepatitis coinfection and the provision of management and treatment recommendations for patients with chronic viral hepatitis are of great importance in preventing, as far as possible, the development of liver disease. With the introduction of new agents for the treatment of hepatitis B and increased knowledge of how best to manage hepatitis C, an update of current guidelines for management of HBV and HCV coinfection with HIV is warranted.

Care of patients with hepatitis C and HIV co-infection.

Liver disease caused by chronic hepatitis C virus (HCV) infection is now a leading cause of morbidity and mortality among HIV-infected patients in the developed world, where classic opportunistic complications of severe immunodeficiency have declined dramatically as a result of the widespread use of potent antiretroviral therapies [1]. Over the past few years, several consensus reports have addressed the issue of viral hepatitis and HIV infection [2,3]. In 2000, a group of experts in the field were invited to join the HCV– HIV International Panel. The first consensus conference took place in Paris [4]. Two years later, the large amount of new information on HCV and HIV, as well as important changes made in the guidelines for using antiretroviral drugs [5], prompted us to organize another consensus conference, which was held in Barcelona in the summer of 2002. Following international recommendations for the development of clinical guidelines [6], the meeting was planned as a full oneday workshop in which nine experts in the field of HIV and viral hepatitis discussed a total of nine questions, which were selected in advance as the most relevant and currently conflicting topics in the management of chronic viral hepatitis in the setting of HIV infection. A draft was written and circulated among panel members during the following months. Finally, in a second meeting that took place in February 2003, a final consensus was reached, and is presented here. The statements are graded according to the Infectious Diseases Society of America scoring system [6], with minor changes (see Table 1).

Mortality for liver disease in patients with HIV infection : A cohort study

We undertook this study to assess the association between the various potential causes of liver disease in HIV-seropositive patients and mortality due to liver failure. Three hundred and eight in-hospital deaths were observed from 1987 to December 1995 in a prospectively followed cohort of 1894 HIV-seropositive patients. For each study subject, clinical data were evaluated to assess whether liver failure had substantially contributed to mortality. A case control study nested in the cohort was then performed, which compared demographic and clinical variables observed at enrollment and during follow-up between patients who died for liver disease as the main or concurrent cause of death (cases) and those who died as a result of illness related to AIDS or other causes (controls). Among 308 in-hospital deaths, liver failure was found the cause of death in 35 patients (12%); in 16 cases, it was the primary cause and in 19 cases it was concurrent. Multivariate analysis showed that in-hospital liver-disease-related mortality was independently associated with hepatitis B surface antigen reactivity (odds ratio [OR], 9; 95% confidence interval [CI], 3.8-21.7) and history of alcohol abuse (OR, 2.3; 95% CI, 1-5.2). Prevention and treatment of hepatitis B virus infection and alcohol intake are management priorities in HIV-seropositive patients.

Hepatocellular carcinoma in HIV-infected patients: epidemiological features, clinical presentation and outcome.

Objective: Hepatocellular carcinoma (HCC) is an increasing cause of mortality in HIV-seropositive individuals. The aim of the study was to compare the main features of HCC in HIV-seropositive individuals with those in to HIV-negative patients. Patients and methods: All HIV-infected subjects with a diagnosis of HCC included in three cancer registry databases were enrolled in the study as cases. HCC cases that occurred in the province of Brescia, North Italy, in the period 1995–1998 and all cases reported at the Italian Liver Cancer Project were enrolled as controls. All data were collected using a standardized case report form. The main clinical and epidemiological characteristics of patients with HCC and their survival were compared between HIV-positive and uninfected subjects. Results: Forty-one HIV-infected subjects with HCC were identified. Multivariate analysis adjusted for age and sex identified an association between HIV infection and HCV infection [odds ratio (OR), 11; P = 0.005], and infiltrating tumours and/or extranodal metastasis at presentation (OR = 11.8; P < 0.001). HIV infection was independently associated with shorter survival (hazard ratio, 1.63; P = 0.015). Conclusions: HCC in HIV-infected patients is mainly associated with underlying chronic hepatitis C and has a more aggressive clinical course. Thus, preventative strategies (including the treatment of hepatitis C) should be implemented in the management of HIV/HCV-coinfected patients.