Treating chronic hepatitis delta: The need for surrogate markers of treatment efficacy.

Chronic hepatitis delta represents the most severe form of chronic viral hepatitis. The current treatment of hepatitis delta virus (HDV) infection consists of the use of interferons and is largely unsatisfactory. Several new compounds are currently in development for the treatment of HDV infection. However, surrogate markers that can be used to develop clinical endpoints in HDV infection are not well defined. In the current manuscript, we aimed to evaluate the existing data on treatment of HDV infection and to suggest treatment goals (possible "trial endpoints") that could be used across different clinical trials.

Safety and efficacy of viramidine versus ribavirin in ViSER2: randomized, double-blind study in therapy-naive hepatitis C patients.

BACKGROUND & AIMS: Pegylated interferon (peg-IFN) plus ribavirin (standard of care for chronic hepatitis C virus [HCV]), can cause dose-limiting anemia in up to 22% of patients. Viramidine is associated with a lower incidence of anemia because of its liver-targeting properties. METHODS: The efficacy and safety of viramidine versus ribavirin plus peg-IFN alfa-2a was assessed in patients with HCV. Randomized patients received peg-IFN alfa-2a 180 mcg with viramidine 600 mg twice daily or weight-based doses of ribavirin 1000 or 1200 mg/day. Treatment duration was based on HCV ribonucleic acid (RNA) genotype: genotype 2/3 and non-2/3 patients were treated for 24 and 48 weeks, respectively. The primary efficacy end point was the non-inferiority of viramidine versus ribavirin (proportion of patients achieving sustained virologic response at week 24). The primary safety end point was the proportion of patients experiencing a hemoglobin event. RESULTS: In total, 962 patients received peg-IFN alfa-2a with viramidine (n=644) or ribavirin (n=318). Sustained virologic response was achieved in 40% of viramidine-treated patients and 55% of ribavirin-treated patients (difference of proportions 0.150 [95% CI, 0.09, 0.21]). Improved efficacy was seen with higher viramidine exposure on a mg/kg basis. Viramidine was significantly superior to ribavirin in hemoglobin event rates (54% vs. 80%; p<0.001). Adverse event rates were similar between groups except for diarrhea (viramidine 29.5%; ribavirin 15.7%; p<0.0001). CONCLUSIONS: Viramidine 600 mg BID did not meet the primary efficacy non-inferiority end point but met the safety end point. Determination of a viramidine dosage that would yield superior efficacy over ribavirin is needed.

Improving outcomes for patients with chronic hepatitis B.

The ultimate goal in managing patients with chronic hepatitis B (CHB) is to improve long-term outcomes by decreasing deaths and liver transplantation procedures due to hepatitis B virus (HBV)-related cirrhosis and hepatocellular carcinoma. Active intervention and vaccination of individuals susceptible to HBV infection are key steps to decrease the risk of this global public health problem. Large studies have demonstrated that long-term outcomes of CHB are tied to serum levels of HBV DNA. New oral treatments, characterized by potent antiviral effects, good tolerability, improved histology, stable seroconversion, and minimal resistance, are available. Long-term data with oral medications have shown decreased rates of liver cancer development, liver disease reversal, and progression to liver failure. Pegylated interferon trials have demonstrated modest rates of hepatitis B e antigen seroconversion and improved histology after treatment. This paper describes ways to improve outcomes of CHB using vaccines, interferon, lamivudine, adefovir, and newer agents.

A pilot study of extended duration peginterferon alfa-2a for patients with hepatitis B e antigen-negative chronic hepatitis B.

OBJECTIVES: Forty-eight weeks of peginterferon alfa-2a is the approved regimen for chronic hepatitis B (CHB). Standard interferon is more effective for hepatitis B e antigen (HBeAg)-negative CHB when given for longer than 1 yr. This study evaluated peginterferon alfa-2a for 60 wk, alone or in combination with lamivudine. METHODS: Thirteen patients with HBeAg-negative CHB received peginterferon alfa-2a (180 microg/week) for 60 wk or peginterferon alfa-2a (180 microg/week) for 12 wk followed by 48 wk of peginterferon alfa-2a plus lamivudine. The primary end point, sustained virologic response (SVR), was defined as a reduction in hepatitis B virus deoxyribonucleic acid (HBV DNA) of >or=2 log10 copies/mL and HBV DNA<20,000 copies/mL at 24 wk of follow-up (week 84). Hepatitis B surface antigen (HBsAg) concentrations were analyzed and compared to changes in HBV DNA. RESULTS: SVR was achieved by 9/13 patients (69%). At week 84, HBV DNA was undetectable by polymerase chain reaction in 5/13 (38%) patients, and 3 additional patients had a sustained 2-3 log reduction in HBV DNA. Five patients demonstrated a >90% decrease in HBsAg concentration at week 60, including 3 with undetectable HBV DNA at week 84 and a fourth who met criteria for SVR. CONCLUSIONS: Sixty weeks of peginterferon alfa-2a with or without lamivudine resulted in a higher rate of SVR compared to historical controls with HBeAg-negative CHB treated with 48 wk of pegylated interferon. Larger studies are necessary to assess if longer duration therapy is more effective than the standard regimen and results in a greater decline in HBsAg concentration.

Virological response and safety outcomes in therapy-nai ve patients treated for chronic hepatitis C with taribavirin or ribavirin in combination with pegylated interferon alfa-2a: a randomized, phase 2 study.

BACKGROUND/AIMS: Pegylated interferon plus ribavirin can cause dose-limiting anemia. Taribavirin, a ribavirin prodrug, has shown a lower incidence of anemia. We sought to determine the efficacy and safety of taribavirin vs. ribavirin combined with pegylated interferon in patients with chronic hepatitis C (CHC). METHODS: This phase 2 open-label study randomized 180 patients with CHC to receive pegylated interferon alfa-2a 180 microg/week plus taribavirin 800, 1200 or 1600 mg QD or ribavirin 1000 or 1200 mg QD. Efficacy variables included proportions of patients with undetectable serum HCV RNA levels at end of treatment and after a 24-week follow-up. RESULTS: The proportions of patients with undetectable HCV RNA at 12 weeks did not differ significantly between taribavirin (38%, 42%, and 49% for the 800, 1200, and 1600 mg groups) and ribavirin (49%). The highest proportion of patients with undetectable HCV RNA at end of treatment and at follow-up occurred in both the taribavirin 1200mg QD (63% and 37%) and ribavirin groups (62% and 44%). SVR rates were 23%, 37% and 29% for taribavirin and 44% for ribavirin. Fewer patients on any dose of taribavirin had severe anemia (hemoglobin <10 g/dL) than on ribavirin (6/135 [4%] vs. 12/45 [27%]). CONCLUSIONS: Given with interferon, taribavirin produced SVR rates comparable to those of ribavirin, with a lower occurrence of anemia.

Efficacy of interferon alpha-2b induction therapy before retreatment for chronic hepatitis C.

BACKGROUND/AIMS: Chronic hepatitis C (HCV) patients who have failed previous treatment have low sustained viral response (SVR) rates with repeat treatment. We evaluated whether interferon (IFN) induction during retreatment improves response rates. METHODS: Two randomized, controlled trials were conducted in chronic HCV patients who failed IFN. In Study 1, patients received IFN 3 MU daily plus ribavirin (RBV) 1000 mg/day for 4 weeks, followed by IFN 3 MU TIW plus RBV 1000 mg/day for 44 weeks (induction; n=232), or IFN 3 MU TIW plus RBV 1000 mg/day for 48 weeks (non-induction; n=237). In Study 2, patients received IFN 5 MU B.I.D. plus RBV 1000-1200 mg/day for 2 weeks, followed by pegylated IFN (PEG-IFN) 75-150 mug weekly plus RBV 1000-1200 mg/day for 46 weeks (induction; n=201), or PEG-IFN 75-150 mug weekly plus RBV 1000-1200 mg/day for 48 weeks (non-induction; n=206). The primary end point for both trials was SVR. RESULTS: Induction did not increase SVR compared with non-induction, but did increase the on-treatment response among genotype non-1 patients in Study 2. By intention-to-treat (ITT) analysis, SVR in Study 1 was 13% for induction vs. 9% for non-induction (P=NS). In Study 2 (ITT), SVR was 20% for induction vs. 24% for non-induction (P=NS). However, by non-ITT analysis of Study 2, genotype non-1-previous non-responders showed significantly higher response rates with induction than non-induction. CONCLUSION: For chronic HCV patients who have failed IFN, induction with retreatment does not improve SVR, but may be beneficial for patients with genotype non-1 HCV.

Chronic hepatitis B: a critical appraisal of current approaches to therapy.

BACKGROUND & AIMS: Treatment of chronic hepatitis B (CHB) involves a number of complex and controversial issues. Expert opinions may differ from those of practicing hepatologists and gastroenterologists. We aimed to explore this issue further after a critical review of the literature. METHODS: A panel of 14 international experts graded the strength of evidence for 16 statements addressing 3 content areas: patient selection, therapeutic end points, and treatment options. Available data relating to the statements were reviewed critically in 3 small work groups. After discussion of each statement with the entire panel, the experts voted anonymously to accept or reject statements based on the strength of evidence and their experience. A total of 241 members of the American Association for the Study of Liver Diseases (AASLD) responded to the same statements and their responses were compared with those of the experts. A discordant response was defined as a difference of more than 20% in any of the 5 graded levels of response (accept or reject) between the 2 groups. RESULTS: With the exception of 2 statements, the experts' responses were relatively uniform. However, the responses of the AASLD members were discordant from the experts in 12 statements, spanning all 3 content areas. CONCLUSIONS: Several areas of disagreement on the management of CHB exist between experts and AASLD members. Our results indicate a potential knowledge gap among practicing hepatologists. Better educational efforts are needed to meet the challenge of managing this complex disorder in which even expert opinion occasionally may disagree.

Eight genotypes (A-H) of hepatitis B virus infecting patients from San Francisco and their demographic, clinical, and virological characteristics.

Clinical lines of evidence have been accumulated that hepatitis B virus (HBV) genotypes have characteristic geographical distributions and distinct clinical impact on liver diseases. The distribution of HBV genotypes was determined with reference to hepatitis B e antigen (HBeAg) and alanine aminotransferase (ALT) levels in 165 patients with hepatitis B in San Francisco. HBV genotypes were determined by enzyme-linked immunosorbent assay (ELISA) and the unclassified samples were sequenced within the S region for phylogenetic analysis. Genotype A occurred in 60 (36%) patients, B in 16 (10%), C in 56 (34%), D in 19 (12%), E in 1 (1%), F in 1 (1%), G in 8 (5%), and H in 4 (2%). Caucasians were infected predominantly with HBV genotype A (HBV/A) (38 of 57 [67%]), Asians with HBV/C (45 of 63 [71%]), and Hispanics with HBV/F and HBV/H (4 of 9 [44%]). Serum ALT levels were higher in the patients infected with HBV/A (P = 0.03) or HBV/G (P = 0.02) than HBV/C. HBeAg was more frequent in patients infected with HBV/G than HBV/C or HBV/D (7 of 8 [88%] vs. 25 of 56 [45%] or 6 of 19 [32%], P = 0.03 or 0.01). In conclusion, eight genotypes (A-H) were identified in San Francisco in association with various ethnicities and then influenced ALT levels as well as the prevalence of serum HBeAg. HBV genotype H might be identified by combination of preS2 serotpe bksf and HBsAg serotype adw.