Sanaa M. Kamal

Hepatitis C genotype 4: What we know and what we don't yet know

Hepatitis C virus genotype 4 (HCV‐4) is the most common variant of the hepatitis C virus (HCV) in the Middle East and Africa, particularly Egypt. This region has the highest prevelance of HCV worldwide, with more than 90% of infections due to genotype 4. HCV‐4 has recently spread in several Western countries, particularly in Europe, due to variations in population structure, immigration, and routes of transmission. The features of HCV‐4 infection and the appropriate therapeutic regimen have not been well characterized. This review discusses the virology, epidemiology, natural history, histology, clinical data, and treatment options for patients with HCV‐4 infections. Early reports on the treatment of patients with chronic HCV‐4 with conventional interferon (IFN)‐α monotherapy indicated poor rates of sustained viral response (SVR), which improved slightly when combined with ribavirin. Pegylated IFN and ribavirin combination therapy has dramatically improved the response rates, with recent clinical trials showing rates that exceed 60%. These data can now be used as a platform for further research to define optimal treatment duration and predictors of SVR in patients with HCV‐4 infection. Conclusion: HCV‐4 infection is spreading beyond its strongholds in Africa and the Middle East. Recent clinical trials show that HCV‐4 is not difficult to treat, as the response to treatment may be at an intermediate level compared with genotype 1 and genotypes 2 or 3. Tailored treatment options that are comparable to the treatment approaches for genotype 1, 2, and 3 patients to optimize treatment for each patient are now being developed. (HEPATOLOGY 2008.)

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.)

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.

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.