Interferon therapy is efficient in eradicating HCV among 40% patients. The factors affecting therapeutic responses are not well elucidated.

The aim of the current study was to investigate the influence of viral factors on combination therapy (peginterferon and ribavirin) in patients with chronic HCV infection.

29 patients (HCV 1a 25 and 1b 4) were enrolled in this study. Each patient was treated with Pegasys (peginterferon alfa-2a) and ribavirin for 12 months. Serum samples were collected at days -30, -7, 0, 1, 3, 7, 8, 9, 15, 22, 29 and subsequently once a month up to 6 months after therapy. Time zero was designated as the starting day of therapy.

HCV RNA level was quantitated by Cobas Amplicor HCV Monitor v2.0 (Roche) at each time point. For each patient, the researchers examined HCV quasi-species profiles in a pretreatment sample (day -30) by sequencing 10 ~ 14 clones derived from PCR product covering almost entire HCV E1 and E2 domains (1380 bp).

The viral diversity and nucleotide substitution rates at E1, HVR1 and E2 without HVR1 were calculated using MEGA program, respectively. Phylogenetic analysis was performed over entire sequence domain.

Longitudinal changes of HCV quasi-species profiles in each patient during therapy were monitored by using heteroduplex mobility assay (HMA) of a 494 bp PCR fragment that covered HVR1. HCV quasi-species variants of up 5% in the total viral population could be detected using HMA.

Based on the virological responses to the combinational therapy, patients were divided into three groups, non-response, sustained response and relapse. By multi-variate analysis, the investigators did not detect any relatedness between the therapeutic responses and patients' age, sex and pretreatment viral loads.

Genetic analysis of 345 clones (each 1380 bp) showed that different therapeutic responses could not be attributed to viral factors at the baseline, such as viral diversity, nucleotide substitution rates at HCV E1, HVR1 or E2 without HVR1, and the primary nucleotide sequence of any small domain within E1/E2 region.

However, in the group with sustained response, there were consistent quasi-species profiles detected by HMA remained unchanged while in the other two groups, the HCV quasi-species profiles changed either in number or position at least at one time point during the course of therapy and subsequent follow-up.

Conclusion: The outcome of antiviral therapy may be determined by the intrinsic capability of a given HCV strain to generate new quasi-species variants while on treatment.

05/21/03

Reference
A Fan and others.  HCV Quasispecies Dynamics During Combination Therapy of Peginterferon alfa-2a and ribavirin. Abstract T1257. Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Evaluation of the 24-hour Decline in HCV Genotype 1 Viral Load to Predict Response to Pegasys Plus Ribavirin Combination Therapy

The response to antiviral therapy in chronic hepatitis C can be measured at various time points. The 24h response to a single IFN dose (24hVR) identifies unresponsiveness to standard IFN/ribavirin therapy (a decrease in viral load of <0.8 log predicted nonresponse with 100 percent specificity (Jessner et al, Lancet 2001).

Early virologic response (EVR) after 12 weeks has a high predictive value to achieve a sustained response to 48 weeks of Pegasys (40kD-PEG-IFN alfa2a / ribavirin therapy. THe Aim of this study was to investigate the value of 24hVR prospectively.

In an ongoing prospective trial which compares amantadine and placebo in addition to treatment with 180 microgram PEGASYS week + 1-1.2g ribavirin /day in chronic hepatitis C (genotype 1), patients are stratified according to the 24hVR at randomization (stratum A: >1.5 log decrease in viral load within 24 hrs; stratum B: 0.8-1.49; stratum C: < 0.8).

All patients had a liver biopsy and none had received an antiviral therapy before signing an informed consent. Currently all planned 220 patients were recruited, and 131, 101, and 35 completed 12,24, and 48 weeks of treatment, respectively.

In these patients the 24hVR was compared with the 12 week EVR, the 24-week and end of treatment response (each defined as HCV-RNA neg). Analysis was done without knowing to which treatment group a patient was assigned.

The 24hVR was performed 2 weeks prior randomization and was calculated from the decrease in viral load 24 hours following a single dose of 9 MU IFNalfa2a (Roche, Basel, CH).

Viral load was determined by the Cobas Amplicor Monitor HCV Test, v2.0 (Roche Diagnostic Systems, USA).

The table below summarizes the data.

Conclusion: The 24hVR is a good predictor of the response to Pegasys/ribavirin therapy. Patients with predicted poor response to standard-IFN/ribavirin therapy may still achieve a virologic response on Pegasys/ribavirin therapy.

Virologic on treatment response (N HCV RNA neg/N total)

 05/21/03

Reference
P Ferenci and others. Prospective Evaluation of The 24-hour Interferon-Induced Decline in Hepatitis C Virus Genotype 1 Load to Predict Response to Peginterferon-Alfa2a/Ribavirin Combination Therapy. Abstract T1211 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Early Viral Kinetics in Chronic Hepatitis C Virus Genotype 4

Only few data on viral kinetics in hepatitis C virus genotype 4 infection are currently available. The initial sensitivity to IFN in genotype 1 identifies patients resistant to standard IFN/ribavirin (Jessner et al., Lancet 2001) or unlikely to achieve a sustained response to Pegasys (peginterferon alfa-2a / PEG-IFNa2a) plus ribavirin therapy. The researchers aimed to examine IFN sensitivity in genotype 4 infection.

Viral load was measured using the Cobas Amplicor Monitor HCV Assay v2.0 before and 24h after 10 MU PEG-Intron (IFNalfa2b) (days 0, 1), and before and during daily 5 MU IFNalfa2b (days 7, 8, 14, 20) administration. Thereafter, combination therapy (1-1.2g ribavirin daily) with either 5MU IFNalfa2b every other day (n=5), 1.5 mg/kg PEG-IFNalfa2b weekly (n=7) or 180mg PEG-IFNalfa2a weekly (n=10) was given.

24h log change after 10 MU IFNalfa (24lc10) was 1.34 (0.25-2.48; median-range) and after 5 MU IFNalfa was 0.99 (0.13-2.22, p<0.001). 24lc10 was 1.47 (0.40-2.48) for month 6 responder (n=18), 0.36 (0.25-0.57; p=0.006) for nonresponder (n=4) and highly predictive on ROC analysis (AUC=0.867; p=0.007).

Currently 6 responder have completed follow-up, one relapsed after stopping treatment at month 8 (24lc10=1.88), one relapsed after the full 12 month course (24lc10=0.44), and 4 became sustained responder (24lc10=1.59 [1.26-1.91])

Conclusion: Primary interferon resistance as in genotype 1 occurs in genotype 4 as well although at a lower rate. Overall response to IFN is therefore significantly better than in genotype 1. A 24h response to standard interferon has high predictive power for on treatment response as in genotype 1.

05/21/03

Reference 
W Jessner and others. Early Viral Kinetics in Chronic Hepatitis C Virus Genotype 4 Infection. Abstract T1220 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Racial Differences in Risk for Liver Cancer in Patients with HCV-related Cirrhosis

The incidence of hepatocellular carcinoma (HCC) is rising in the US with HCV infection accounting for one-third of the cases. Early detection with screening may offer the best hope for treatment and improved survival.

Identifying high-risk patients is an essential requirement for a cost-effective screening program. No study to date has examined race as a potential risk factor for HCC in a diverse U.S. population with HCV cirrhosis.

In this multi-center study, researchers performed a hospital-based, clinic-based case-control study of 507 patients with HCV cirrhosis at four study centers using pathology records, ICD-9 diagnosis, and patient visits to the study centers.

Hepatitis B carriers and patients with chronic hepatitis B, HIV or other malignancies were not included in this study.

Cases were confirmed by cytology, histology and/or by the presence of focal hypervascular hepatic mass (on biphasic CT, MRI and/or angiogram) and elevated AFP. HCC was ruled out in controls by negative AFP and imaging studies. Multivariate logistic regression was employed to examine associations between HCC and race.

Adjustment was made for age, gender, severity of liver disease (MELD score, Child class), moderate-to-heavy alcohol use, and study centers. For all variables, values at diagnosis were obtained for HCC cases and at first negative AFP and x-ray for controls.

The investigators identified 205 HCC cases and 264 controls without HCC. Thirty-eight patients could not be classified as cases or controls based on above criteria and were excluded.

HCC patients were significantly older (median age=59 vs. 52, p < 0.001), more likely to be male (84% vs. 71%, p=0.001), more likely to be Child class C (57% vs. 43%, p=0.001), and had slightly higher MELD score (median MELD=11 versus 10, p=0.05).

There was no significant association between alcohol use or Hispanic race (n=66) and HCC compared with Caucasian (n=274). After adjustment was made for age, gender, MELD score, Child class, moderate-to-heavy alcohol use, and study centers, multivariate OR was 3.0 for African Americans (n=38, p=0.003) and 5.7 for Asians (n=83, p<0.0001) as predictors for HCC.

Conclusions: African Americans and Asians with HCV cirrhosis may have 3 and 6 times higher risk for HCC as compared to their Caucasian counterparts - independent of age, gender, severity of liver disease, and alcohol use.

Genetic study of liver cancer in a racially diverse population should be carried out, and high-risk ethnic patients may be among those with HCV cirrhosis who would benefit the most from HCC screening.

05/21/03

Reference
MH Nguyen and others. Racial Differences in Risk for Liver Cancer in Patients with Hepatitis C Cirrhosis: A Multicenter Case-Control Study. Abstract 121 (oral). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Racial Differences in Treatment Response to Hepatitis C Virus in a Large Urban Health System

Minority populations in the US are disproportionately affected by hepatitis C virus (HCV), with estimated seroprevalences of 2.1% in Hispanics, 3.2% in African-Americans, and 1.5% in whites.

Several studies have reported that African-Americans do not respond to treatment of chronic HCV infection with the same efficacy as whites. To our knowledge no published study has evaluated the response rate of Hispanics to HCV treatment. Because our institution serves a predominantly minority population - 52% Hispanic, 13% African-American and 25% white - we are uniquely positioned to investigate this question.

The researchers retrospectively reviewed all patients who completed treatment for HCV in our institution from January 1, 2000 until October 31, 2002. Data regarding self-reported demographics and virologic response were obtained via retrospective electronic chart review.

HIV-positive patients and those with Childs class B or C were either not treated or excluded from analysis. Patients received several different regimens of interferon and ribavirin for either 24 weeks (non-genotype 1) or 48 weeks (genotype 1). Those with an end treatment sustained virologic response (SVR) returned at 6 months for follow-up viral load.

50 of 68 patients who began treatment finished the intended duration of therapy. The racial distribution of this group was 54% white, 36% Hispanic, 6% African-American, and 4% Asian. White and Hispanic groups had similar age and genotype 1 distribution (63% v. 61.1%).

Gender distribution revealed a male:female ratio of 2:1 in whites and 1:2 in Hispanics. In an intention-to-treat analysis, overall SVR was 48.7% for white patients and 45.4% for Hispanic patients (p = 0.86).

The SVR of patients who completed therapy was 70.4% white and 55.6% Hispanic (p = 0.30). No African-American patient responded to treatment.

Conclusion: These preliminary data suggest that, in our patient population, Hispanic and white patients have similar response rates to HCV treatment.

05/21/03

Reference
J Riopelle and others. Racial Differences in Treatment Response to Hepatitis C Virus in a Large Urban Health System. Abstract M1622 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.

Interaction of Steatosis and Non-Alcoholic Steatohepatitis (NASH) in Chronic Hepatitis C

Hepatic steatosis or superimposed non-alcoholic steatohepatitis (NASH) may affect HCV-related fibrosis and the efficacy of anti-viral therapy.

The objective of this study was to determine the relationship of hepatic steatosis and NASH with chronic hepatitis C (CHC).

Patients with chronic hepatitis C (CHC) and available liver biopsies who completed a regimen of PEG-Intron (peginterferon alfa-2b/ PEG-IFN, ribavirin (RIBA) and amantadine (AMANT) were included [PEG-IFN 1.5 mcg/kg weekly, RIBA 1000-1200 mg/d and AMANT 200 mg/d for 4 weeks, followed by PEG-IFN 0.5 mcg/kg weekly, RIBA 1000-1200 mg/d and AMANT 200 mg/d for another 20 weeks].

Patients with undetectable HCV RNA at week 24 continued this regimen for 48 weeks and were followed for another 24 weeks. Patients with undetectable virus (<50 IU/mL) after 24 weeks of follow up were considered to have SVR.

All biopsies were read by one hepatopathologist using METAVIR, modified HAI as well as a Fatty Liver Pathologic protocol. Patients' baseline clinico-demographic data as well as virologic response were associated with the extent of steatosis (>33% vs. <33%) and the type of fatty liver (No Fatty Liver vs. Steatosis vs. NASH) seen on the biopsy.

Of 119 patients, 69% were male, age 47.48±5.68, BMI 29.0±4.99, waist/hip ratio (W/H) 0.90±0.08, 79% being white, 84.2% with genotype 1, 6.7% with genotype 2, 7.5% with genotype 3, 0.8% with genotype 4, and 40% with advanced fibrosis (METAVIR F3 and 4).

Patients with higher grade of steatosis (>33%, n=14) were more obese (BMI 32.83±1.67 vs. 28.49±0.45, p=0.034), more likely to have HCV genotype 3 (21.4% vs. 5.7%, p=0.037) and advanced fibrosis (64.3% vs. 37.1%, p=0.048) than those patients with lower grade of steatosis (<33%, n=105).

Furthermore, in comparing patients with superimposed NASH (n=22) to those with Steatosis (n=49) and those without steatosis (n=48), patients with NASH had more evidence of obesity and advanced fibrosis (68.2% vs. 44.9% vs. 22.9%, p=0.001).

Neither the extent of steatosis nor the presence of superimposed NASH had an impact on SVR. Race, gender and age did not affect extent of steatosis or presence of superimposed NASH.

Conclusions: Markers of obesity (BMI and W/H) and HCV genotype 3 are associated with extent of steatosis and type of fatty liver. Higher grade of steatosis and superimposed NASH were associated with advanced fibrosis but not the efficacy of the antiviral regimen.

05/21/03

Reference
ZM Younossi and others.  Interaction of Steatosis and Non-Alcoholic Steatohepatitis (NASH) with Chronic Hepatitis C. M1388 (poster). Abstract M1625 (poster). Abstracts of Digestive Disease Week 2003. May 17-22, 2003. Orlando, FL.