Sanaa M. Kamal, Qi He, Camilla S. Graham, Alaa M. Ismail, Khalifa El Sayed, Mahmoud Massoud, Jens W. Rasenack, Margaret J. Koziel
Pegylated interferon alfa (PEG IFNa (Pegasys)) improves sustained virological response 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 IFNa treatment in acute hepatitis C in relation to HCV-specific CD4+ T-cell responses and viral kinetics during therapy and follow-up.
Forty subjects with proven acute hepatitis C who did not achieve spontaneous resolution after 12 weeks received either PEG IFNa plus ribavirin (n=20) or PEG IFNa monotherapy (n=20) for 24 weeks. Fourteen untreated subjects with acute hepatitis C served as control group. All treated and untreated subjects were prospectively followed for 48 weeks. Serum HCV RNA, HCV-specific CD4+ T-cell responses and cytokine production (ELISPOT) were measured before, during therapy and follow-up and correlated to the outcome.
The sustained virological response (SVR) was 85% in PEG IFNa/ribavirin combination and 80% in PEG IFNa monotherapy. Five untreated subjects had spontaneous recovery. The frequency, magnitude and breadth of HCV-specific CD4+ T helper 1 responses were significantly enhanced in treated subjects compared to untreated subjects with self-limited disease or subjects with chronic evolution. The CD4+ T cell responses were maintained in subjects with sustained response and self-limited disease, but were fluctuating and rapidly lost in those who developed chronic infection.
PEG IFNa therapy in acute hepatitis induces high rates of sustained virological response and prevents choronicity probably through efficient early stimulation and maintenance of multi-specific HCV-specific CD4+ T helper-1 responses
The authors further noted that:
a) This was a study of injection drug users only to keep other co-factors absent so that the results could be interpreted more precisely
b) Consistent with other studies, all patients who cleared the virus on their own were symptomatic
c) Treated patients that were symptomatic were more likely to achieve SVR
Vikas Khurana, Tejinder Singh, John King, Lamar T. Jones
HCV infection is one of the commonest causes of cirrhosis in the US. The risk of developing hepatocellular cancer is 1-4% per year in cirrhotics. Interferon and Ribavirin in various formulations form the basis for the standard therapy of this infection. Attempts are being made to identify various pretreatment characteristics by which better success rates can be predicted, thereby helping select patients to whom this expensive and arduous therapy with serious side effects should be offered. Of those studied, with the exception of HCV genotype (non-1), the rest are proving to be of uncertain significance.
To search for a more reliable predictor to treatment response by evaluating the role of hepatocyte regeneration as a predictor for successful therapy of chronic hepatitis C virus (HCV) infection.
Hepatocyte regeneration in normal liver is negligible but it increases with active inflammation as the disease progresses. Increased hepatocyte regeneration in HCV infection in relation to the severity of the underlying histology of the diseased liver may identify the patient with a greater likelihood to respond to therapy.
In this small study, 23 patients were evaluated for inclusion in this pilot study. 5 were excluded due to technical reasons, 2 were non-compliant with guidelines and 2 were excluded after developing side-effects from therapy. 14 patients with chronic HCV infection with pre-treatment liver biopsy who successfully completed therapy and had HCV RNA quantification by PCR 24 weeks after completion of therapy were included in the study. All patients were treated with the same regimen consisting of Interferon alpha-2b and Ribavirin for 48 weeks. Hepatocyte regeneration analysis on biopsy specimens was done via immunohistological identification of proliferating cell nuclear antigen (PCNA) quantification by Automated Cell Imaging System (ACIS). Histological grading and staging were obtained. A composite score was then generated for each patient by dividing the PCNA positive cell percentage by the sum of the grade and stage of their liver biopsy.
All failures (3/3) were found to have a composite score of less than one, whereas 72% (8/11) patients negative for HCV viral RNA at 18 months had a score of more than 1.
Hepatocyte regeneration in combination with grade and stage of liver biopsy is a predictor of response to standard therapy for HCV infection in our pilot study.
Kenneth E. Sherman, Norah J. Shire, Susan D. Rouster, Sandra D. Dericks, James P. Steinberg, Cindy Leissinger, M. E. Eyster
Hepatitis C virus (HCV) quasispecies emergence has been linked to disease progression in patients with inherited bleeding disorders. Quasispecies selection in the setting of treatment intervention in HCV/HIV coinfected patients with PEG-IFN + ribavirin has not been described.
Patients with inherited bleeding disorders infected with HCV or HCV/HIV from 4 tertiary centers were enrolled in a NIH-sponsored treatment trial. All were given PEG-IFN alfa 2a (180mcg qw) + ribavirin (800mg qd). HCV viral loads (VL) were measured at baseline and weeks 2 and 4 (Roche COBAS Amplicor Monitor). Quasispecies emergence was determined at the same timepoints via a heteroduplex complexity assay. Generalized estimating equations (GEE) were used for the analysis of repeated measures.
Nineteen patients with inherited bleeding disorders were evaluated (17 male, 2 female). 42% (8/19) had HIV. Mean age was 38 years. 63% of patients were HCV genotype 1. Six coinfected pts had baseline HIV RNA <75 copies/mL. Median log HCV VL at baseline were 5.84 and 6.37 IU/mL, for monoinfected vs. coinfected, respectively (p = n.s.). Median baseline CD4+ counts were 819 and 720 cells/mm3, respectively (p = n.s.). The mean numbers of quasispecies at baseline were 1.8 (SE 0.29) and 2.8 (SE 0.22), respectively (p = 0.01). 50% of monoinfected patients achieved HCV VL below detectable limits (<600 IU/mL) during the 4-week period in contrast to 12.5% of the coinfected patients (p = 0.15). Quasispecies number in both groups decreased with time, trending toward statistical significance (p = 0.07). Multivariate analysis determined that a lower quasispecies count at baseline (1-2) was significantly associated with the probability of clearance (p < .0001) after controlling for genotype, HIV infection, age, gender, and CD4+ count.
Coinfected patients had greater HCV quasispecies complexity than monoinfected patients at baseline. Treatment reduces quasispecies complexity over time. These data suggest that failure to clear virus may be associated with increased baseline quasispecies complexity in patients with inherited bleeding disorders. The final results of this study will look at the SVR in relationship to quasi-species complexities.