Hepatitis delta and HIV infection.

Hepatitis delta is the most severe of all chronic viral infections of the liver. Its agent, the hepatitis delta virus (HDV), is unique in many aspects. Because of similar transmission pathways, triple infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV), and HDV occurs frequently in intravenous drug users. The addition of HDV to an HIV/HBV coinfection is associated with a particularly aggressive course of liver disease, frequently leading to cirrhosis, decompensation, and death. Thus, screening for antibodies against HDV should be mandatory in all HBsAg-positive/HIV-positive patients. There is no specific treatment for HDV. The only therapeutic options currently available are long-duration interferon regimens, which are effective in <30% of the patients. Additionally, long-term treatment with HBV polymerase inhibitors as part of antiretroviral treatment may lower HBsAg- and HDV-ribonucleic acid levels in some patients. Early initiation of anti-HIV therapy seems to be reasonable in patients with hepatitis delta - even though controlled studies are not available.

Phase III results of Boceprevir in treatment naïve patients with chronic hepatitis C genotype 1.

INTRODUCTION: Chronic hepatitis C virus infection affects approximately 2% of the world population and can result in cirrhosis and hepatocellular carcinoma. Until 2011, the standard of care (SOC) has been therapy with pegylated interferon alfa and ribavirin (PEG-IFN/RBV). Sustained virologic response rates (SVR) after SOC in patients infected with genotype 1 have been 40-50%. The development of new direct antiviral agents (DAA) is vital. The first drugs that specifically target the HCV protease have been approved in 2011. This review summarizes the results of SPRINT-2, a phase III double blind, placebo controlled study in which the efficacy and safety of Boceprevir, a new HCV protease inhibitor, was compared to SOC. DESIGN: A total of 1097 treatment-naïve, genotype 1, chronic hepatitis C patients were randomized into three different groups. All patients received a 4-week lead in phase with peginterferon alfa-2b and ribavirin. A total of 363 patients were randomized to the control group and received 44 additional weeks of PEG-IFN/RBV; of the 368 patients randomized to group 2, the response-guided treatment regimen (RGT), patients with undetectable HCV RNA through week 8 and 24 received 24 weeks of triple therapy (PEG-IFN/RBV/Boceprevir); patients whose HCV-RNA was detectable between weeks 8 and 24 but undetectable at week 24 received subsequently 20 weeks of (PEG-IFN/RBV); 366 patients in group 3 were treated with lead-in followed by triple therapy through week 48. RESULTS: Treatment with Boceprevir triple therapy increased SVR to 63-66% compared to 38% receiving PEG-IFN/RBV therapy. Non-Black patients achieved higher SVR rates compared to Black patients. Responsiveness to interferon in the lead-in phase was predictive for SVR. SVR rates did not differ between patients randomized to RGT with Boceprevir and those treated with a fixed duration. Anaemia was the most important adverse event leading to dose reduction of RBV in 13% of controls and 21% of Boceprevir recipients. CONCLUSION: Triple therapy of Boceprevir in combination with PEG-IFN 2b/RBV is more effective than SOC alone. RGT is possible without reducing the SVR rates. Management of anaemia has to be considered.

Hepatitis B surface antigen (HBsAg) levels in the natural history of hepatitis B virus (HBV)-infection: a European perspective.

BACKGROUND & AIMS: The quantifiable level of HBsAg has been suggested as a predictor of treatment response in chronic hepatitis B. However, there is limited information on HBsAg levels considering the dynamic natural course of HBV-infection. This study aimed to determine HBsAg levels in the different phases of HBV-infection in European HBsAg-positive patients. METHODS: 226 HBV-monoinfected patients, not undergoing antiviral therapy, were analyzed in a cross-sectional study. Patients were categorized according to the phase of HBV-infection: HBeAg(+) immune tolerance phase (IT, n=30), immune clearance phase (IC, n=48), HBeAg(-) low-replicative phase (LR, n=68), HBeAg(-) hepatitis (ENH, n=68), and acute hepatitis B (n=12). HBsAg was quantified and correlated with HBV-DNA, HBV-genotypes and clinical parameters. In addition, 30 LR-patients were followed longitudinally. RESULTS: HBsAg levels were higher in IT-patients and IC-patients compared to LR-patients and ENH-patients (4.96/4.37/3.09/3.87-log(10)IU/ml, p<0.001). HBsAg showed a strong correlation with HBV-DNA during acute hepatitis B (R=0.79, p<0.01). Correlation of HBsAg and HBV-DNA was weak or missing when analyzing different phases of persistent HBV-infection separately. However, associations between HBsAg and HBV-DNA were observed in patients infected with HBV-genotype D but not with HBV-genotype A. LR-patients with HBV-reactivation during follow-up (increase of HBV-DNA >2000IU/ml) showed >3-fold higher baseline HBsAg levels with a NPV of 95% for an HBsAg cut-off of 3500IU/ml. CONCLUSIONS: HBsAg levels show significant differences during the natural course of HBV-infection and between HBV-genotypes. These findings may have important implications for understanding the natural history of HBV-infection and for using quantitative HBsAg as a diagnostic tool, i.e. as a marker for predicting HBV-reactivation.

Anti-HDV IgM as a marker of disease activity in hepatitis delta.

BACKGROUND: Hepatitis delta frequently leads to liver cirrhosis and hepatic decompensation. As treatment options are limited, there is a need for biomarkers to determine disease activity and to predict the risk of disease progression. We hypothesized that anti-HDV IgM could represent such a marker. METHODS: Samples of 120 HDV-infected patients recruited in an international multicenter treatment trial (HIDIT-2) were studied. Anti-HDV IgM testing was performed using ETI-DELTA-IGMK-2-assay (DiaSorin). In addition, fifty cytokines, chemokines and angiogenetic factors were measured using multiplex technology (Bio-Plex System). A second independent cohort of 78 patients was studied for the development of liver-related clinical endpoints (decompensation, HCC, liver transplantation or death; median follow up of 3.0 years, range 0.6-12). RESULTS: Anti-HDV IgM serum levels were negative in 18 (15%), low (OD<0.5) in 76 (63%), and high in 26 (22%) patients of the HIDIT-2 cohort. Anti-HDV IgM were significantly associated with histological inflammatory (p<0.01) and biochemical disease activity (ALT, AST p<0.01). HDV replication was independent from anti-HDV IgM, however, low HBV-DNA levels were observed in groups with higher anti-HDV IgM levels (p<0.01). While high IP-10 (CXCL10) levels were seen in greater groups of anti-HDV IgM levels, various other antiviral cytokines were negatively associated with anti-HDV IgM. Associations between anti-HDV IgM and ALT, AST, HBV-DNA were confirmed in the independent cohort. Clinical endpoints occurred in 26 anti-HDV IgM positive patients (39%) but in only one anti-HDV IgM negative individual (9%; p = 0.05). CONCLUSIONS: Serum anti-HDV IgM is a robust, easy-to-apply and relatively cheap marker to determine disease activity in hepatitis delta which has prognostic implications. High anti-HDV IgM levels may indicate an activated interferon system but exhausted antiviral immunity.

HCV's days are numbered: next-generation direct-acting antivirals and host-targeting agents.

Chronic hepatitis C affects approximately 170 million people worldwide and is one of the leading causes of liver-related morbidity and mortality. Until 2011, the only therapeutic option was combination therapy of pegylated interferon and ribavirin, with efficacy rates around 50% and plenty of side effects. In the past months, important steps have been made towards a more effective antiviral therapy. However, we are still far from both highly efficient and well-tolerable ideal therapy. The development of new drugs against HCV is a very dynamic field. This review summarizes the up-to-date knowledge of the most significant anti-HCV compounds in development.