J. Rasenack

Peginterferon Alfa-2a in Patients with Chronic Hepatitis C

BACKGROUND Covalent attachment of a 40-kd branched-chain polyethylene glycol moiety to interferon alfa-2a results in a compound (peginterferon alfa-2a) that has sustained absorption, a slower rate of clearance, and a longer half-life than unmodified interferon alfa-2a. We compared the clinical effects of a regimen of peginterferon alfa-2a with those of a regimen of interferon alfa-2a in the initial treatment of patients with chronic hepatitis C. METHODS We randomly assigned 531 patients with chronic hepatitis C to receive either 180 microg of peginterferon alfa-2a subcutaneously once per week for 48 weeks (267 patients) or 6 million units of interferon alfa-2a subcutaneously three times per week for 12 weeks, followed by 3 million units three times per week for 36 weeks (264 patients). All the patients were assessed at week 72 for a sustained virologic response, defined as an undetectable level of hepatitis C virus RNA (<100 copies per milliliter). RESULTS In the peginterferon group, 223 of the 267 patients completed treatment and 206 completed follow-up. In the interferon group, 161 of the 264 patients completed treatment and 154 completed follow-up. In an intention-to-treat analysis in which patients who missed the examination at the end of treatment or follow-up were considered not to have had a response at that point, peginterferon alfa-2a was associated with a higher rate of virologic response than was interferon alfa-2a at week 48 (69 percent vs. 28 percent, P=0.001) and at week 72 (39 percent vs. 19 percent, P=0.001). Sustained normalization of serum alanine aminotransferase concentrations at week 72 was also more common in the peginterferon group than in the interferon group (45 percent vs. 25 percent, P=0.001). The two groups were similar with respect to the frequency and severity of adverse events, which were typical of those associated with interferon alfa. CONCLUSIONS In patients with chronic hepatitis C, a regimen of peginterferon alfa-2a given once weekly is more effective than a regimen of interferon alfa-2a given three times weekly.

Baseline characteristics and early on-treatment response predict the outcomes of 2 years of telbivudine treatment of chronic hepatitis B.

BACKGROUND/AIMS In the GLOBE trial, telbivudine treatment was identified as a significant, independent predictor of better outcomes at 2 years. We analyzed all telbivudine recipients in this trial to determine the predictors of optimal outcomes. METHODS The intent-to-treat population comprised 458 HBeAg-positive and 222 HBeAg-negative telbivudine-treated patients. Multivariate logistic regression analyses were employed to evaluate baseline and/or early on-treatment variables. RESULTS Baseline HBV DNA<9 log(10)copies/mL, or ALT levels > or = 2x above normal were strong pretreatment predictors for HBeAg-positive, but not for HBeAg-negative patients. However, non-detectable serum HBV DNA at treatment week 24 (TW24) was the strongest predictor for better outcomes for both groups. A combination of pretreatment characteristics plus TW24 response identified subgroups with the best outcomes: (1) HBeAg-positive patients with baseline HBV DNA<9 log(10)copies/mL, ALT > or = 2x above normal and non-detectable HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 89%, HBeAg seroconversion in 52%, telbivudine resistance in 1.8%; and (2) HBeAg-negative patients with baseline HBV DNA<7 log(10)copies/mL and non-detectable serum HBV DNA at TW24 achieved at 2 years: non-detectable HBV DNA in 91%, telbivudine resistance in 2.3%. CONCLUSION During telbivudine treatment, non-detectable serum HBV DNA at treatment week 24 is the strongest predictor for optimal outcomes at 2 years.

Peginterferon α-2b and ribavirin therapy in chronic hepatitis C genotype 4: impact of treatment duration and viral kinetics on sustained virological response

Background: The response rates and duration of peginterferon alpha (PEG-IFN-α) and ribavirin combination therapy in chronic hepatitis C genotype 4, the prevalent genotype in the Middle East and Africa, are poorly documented. Aims: To compare the efficacy and safety of 24, 36, or 48 weeks of PEG-IFN-α-2b and ribavirin therapy in chronic hepatitis C genotype 4. Methods: In this prospective, randomised, double blind study, 287 patients with chronic hepatitis C genotype 4 were randomly assigned to PEG-IFN-α-2b (1.5 μg/kg) once weekly plus daily ribavirin (1000–1200 mg) for 24 weeks (group A, n = 95), 36 weeks (group B, n = 96), or 48 weeks (group C, n = 96) and followed for 48 weeks after completion of treatment. Early viral kinetics and histopathological evaluation of pre- and post treatment liver biopsies were performed. The primary end point was viral clearance 48 weeks after completion of treatment. Results: Sustained virological response was achieved in 29%, 66%, and 69% of patients treated with PEG-IFN-α-2b and ribavirin for 24, 36, and 48 weeks, respectively, by intention to treat analysis. No statistically significant difference in sustained virological response rates was detected between 36 and 48 weeks of therapy (p = 0.3). Subjects with sustained virological response showed greater antiviral efficacy (ε) and rapid viral load decline from baseline to treatment week 4 compared with non-responders and improvement in liver histology. The incidence of adverse events was higher in the group treated for 48 weeks. Conclusion: PEG-IFN-α-2b and ribavirin for 36 or 48 weeks was more effective in the treatment of chronic hepatitis C genotype 4 than treatment for 24 weeks. Thirty six week therapy was well tolerated and produced sustained virological and histological response rates similar to the 48 week regimen.

Pegylated interferon α therapy in acute hepatitis C: Relation to hepatitis C virus–specific T cell response kinetics

Pegylated interferon α (PEG IFN‐α) improves sustained virological response rates in chronic hepatitis C, but neither its role in acute hepatitis C nor the biologic basis for its action has been defined. This prospective study assessed the efficacy of PEG IFN‐α treatment in acute hepatitis C in relation to the kinetics of hepatitis C virus (HCV)‐specific CD4+ T cell responses during therapy and follow‐up. Forty subjects with proven acute hepatitis C who received either PEG IFN‐α plus ribavirin (n = 20) or PEG IFN‐α monotherapy (n = 20) for 24 weeks in addition to 14 untreated subjects with acute hepatitis C were prospectively followed. Serum HCV RNA, HCV‐specific CD4+ T cell responses, and cytokine production were measured before and during therapy and at follow‐up and correlated to the outcome. The sustained virological response rate was 85% with PEG IFN‐α/ribavirin combination and 80% with PEG IFN‐α monotherapy. Five untreated subjects had spontaneous recovery. The frequency, magnitude, and breadth of HCV‐specific CD4+ T helper 1 responses were significantly higher in treated subjects compared with untreated subjects with self‐limited disease or subjects with chronic evolution. The CD4+ T cell responses were maintained in subjects with sustained virological responses and self‐limited disease but fluctuated in those who developed chronic infection. In conclusion, PEG IFN‐α therapy in acute hepatitis induces high rates of sustained virological response and prevents choronicity, probably through efficient early stimulation of multispecific HCV‐specific CD4+ T helper 1 responses. (HEPATOLOGY 2004;39:1721–1731.)

Duration of peginterferon therapy in acute hepatitis C: A randomized trial

Spontaneous resolution of acute hepatitis C virus infection cannot be predicted, and chronic evolution of the disease occurs in a majority of cases. To assess the efficacy and safety of peginterferon alpha‐2b administered for 8, 12, or 24 weeks in patients with acute hepatitis C virus infection a total of 161 patients were identified with acute hepatitis C virus infection. Of these, 30 patients refused treatment but were retained in the study as a nonrandomized comparison group. Of the 131 patients who consented to treatment, 29 patients spontaneously resolved, leaving 102 patients randomly assigned to peginterferon alpha‐2b (1.5 μg/kg) for 8 weeks (group A; n = 34), 12 weeks (group B; n = 34), and 24 weeks (group C; n = 34). The primary end point was sustained virologic response. An intent‐to‐treat analysis was used for efficacy and safety end points. Sustained virologic response was achieved in 23/34 (67.6%), 28/34 (82.4%), and 31/34 (91.2%) of patients in groups A, B, and C, respectively; all had undetectable hepatitis C virus RNA 48 weeks after the end of therapy. Treatment for 8 or 12 weeks was effective in genotypes 2, 3, and 4, whereas genotype 1 required 24 weeks of therapy. The 8‐ and 12‐week regimens were associated with fewer adverse events compared with the 24‐week regimen. In conclusion, peginterferon alpha‐2b effectively induces high sustained virologic response rates in patients with acute hepatitis C virus infection, thus preventing development of chronic hepatitis C. Duration of treatment should be further optimized based on genotype and rapid virologic response at week 4. (HEPATOLOGY 2006;43:923–931.)

Progression of fibrosis in hepatitis C with and without schistosomiasis: correlation with serum markers of fibrosis.

Serial liver biopsies are the gold standard by which the progression of fibrosis is evaluated. This longitudinal cohort study assessed the different rates in the progression of fibrosis using serial liver biopsies and serum fibrosis markers YKL‐40 and PIIINP and the cytokines, transforming growth factor beta (TGF‐β) and tumor necrosis factor alpha (TNF−α). A 10‐year cohort study was performed in patients with hepatitis C virus (HCV) alone or HCV and schistosomiasis. Patients were enrolled at the time of acute HCV infection and prospectively evaluated with two liver biopsies (at entry and end of follow‐up), and true rates in the progression of fibrosis were calculated per year. Serum YKL‐40, N‐terminal propeptide of collagen III (PIIINP), TGF‐β, and TNF‐α were measured, as well as the expression of TGF‐β, TNF‐α, and YKL‐40 mRNA in liver tissue. A significant increase in the progression rates of fibrosis occurred in the coinfected group (0.61 ± 0.13) compared with the HCV monoinfection group (0.1 ± 0.06; P < .001)). The progression of fibrosis rate/year had a direct linear correlation for YKL‐40 (r = 0.892, P < .001) and for PIIINP (r = 0.577, P < .01). YKL‐40 showed a linear correlation with TGF‐β (r = 0.897, P < .001). Hepatic mRNA levels of YKL‐40 and TGF‐β correlated with the serum levels, confirming a hepatic source for the elevated serum levels. In conclusion, serial cytokine and fibrosis markers can accurately determine the rate at which fibrosis is progressing, identifying both those with rapid fibrosis and those with stable disease. (HEPATOLOGY 2006;43:771–779.)

Impact of hepatitis B and C on graft loss and mortality of patients after kidney transplantation.

Background: Mortality or graft loss after renal transplantation might be influenced by hepatitis virus infection.

Cellular Immune Responses in Seronegative Sexual Contacts of Acute Hepatitis C Patients

ABSTRACT Acute hepatitis C virus (HCV) is typically defined as new viremia and antibody seroconversion. Rates and immunologic correlates of hepatitis C clearance have therefore been based on clearance of viremia only in individuals who initially had an antibody response. We sought to characterize the immunological correlates of clearance in patients with acute hepatitis C and their sexual contacts. We prospectively determined CD4+ and CD8+ cytotoxic T-lymphocyte responses in index patients with acute HCV and their sexual contacts who developed acute infection, either with or without spontaneous clearance, as well as those contacts who never developed viremia. Responses were measured using proliferation and ELISpot assays for CD4+ and CD8+ responses. We demonstrate in this prospective study that cellular immune responses can develop in exposed but persistently aviremic and antibody-negative individuals as well as those individuals with spontaneous clearance of acute HCV. These findings lend further credence to the importance of cellular immune responses in recovery from HCV and suggest that low exposure to HCV may lead to development of HCV-specific immune responses without ongoing HCV replication. This finding has important implications for HCV vaccine and therapeutic development.

Telbivudine Improves Renal Function in Patients With Chronic Hepatitis B

BACKGROUND & AIMS There is a close relationship between chronic hepatitis B virus infection and chronic renal disease. We analyzed changes in renal function using different markers of glomerular filtration rate (GFR) in multiple studies of telbivudine treatment of patients with chronic hepatitis B virus infection. METHODS We used serum creatinine-based equations (ie, Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration) to estimate GFR (eGFR) in adults with chronic hepatitis B virus infection and compensated liver disease who participated in a phase III, randomized, double-blind study comparing the efficacy and safety of telbivudine (600 mg/d) and lamivudine (100 mg/d) for 2 years (the GLOBE study) and in long-term extension studies (4-6 years), as well as in patients with decompensated cirrhosis (2 years). RESULTS eGFRs calculated using the Cockcroft-Gault, Modification of Diet in Renal Disease, and Chronic Kidney Disease Epidemiology Collaboration equations were concordant, indicating improved renal function in telbivudine-treated patients during the 2-year GLOBE study (there was an 8.5% increase in mean eGFR, based on the Modification of Diet in Renal Disease equation). Improved renal function was maintained for 4-6 years. Increased eGFR with telbivudine treatment was also observed in patients at increased risk for renal impairment: patients with baseline eGFRs of 60-89 mL/min/1.73 m(2) (+17.2%), older than 50 years (+11.4%), and with liver fibrosis/cirrhosis (+7.2% for patients with Ishak fibrosis score at 5-6). In decompensated patients with high renal risk, eGFR was also improved on telbivudine (+2.0%). CONCLUSIONS In global trials of patients with compensated and decompensated cirrhosis, long-term telbivudine therapy was associated with a sustained improvement of renal function-particularly among patients with increased risk of renal impairment. The mechanisms of this renal protective effect remain to be determined.

Kinetics of Intrahepatic Hepatitis C Virus (HCV)-Specific CD4+ T Cell Responses in HCV and Schistosoma mansoni Coinfection: Relation to Progression of Liver Fibrosis

The kinetics of intrahepatic hepatitis C virus (HCV)-specific CD4(+) T cell responses and their role in progression of fibrosis have not previously been characterized. Subjects with HCV/Schistosoma mansoni coinfection have a more rapid progression of HCV liver fibrosis than do those with HCV infection alone. The present prospective longitudinal study compared the liver histology, HCV-specific intrahepatic and peripheral CD4(+) T cell proliferative responses, and cytokines (enzyme-linked immunospot) in 48 subjects with unresolved acute HCV infection with or without S. mansoni coinfection, at 6-10 months after acute infection and at the end of follow-up (96+/-8.7 months), and the findings were correlated to the rate of progression of fibrosis per year. Coinfected subjects had significant worsening of fibrosis, compared with subjects with HCV infection alone. At baseline, subjects with HCV infection alone had stronger multispecific intrahepatic HCV-specific CD4(+) T helper 1 responses than did coinfected subjects, who had either no responses or weak, narrowly focused responses, and, over time, these T cell responses were maintained only in the liver. The rate of progression of fibrosis and virus load inversely correlated with intrahepatic HCV-specific CD4(+) T cell response. The present prospective analysis indicates that enhancement of progression of liver fibrosis is associated with failure to develop early, multispecific, HCV-specific CD4(+) Th1 responses, suggesting that novel therapeutic approaches inducing strong cellular immune responses might limit subsequent liver damage in individuals with chronic hepatitis C.