By Liz Highleyman

At the recent 58th Annual Meeting of the American Association for the Study of Liver Diseases in Boston (November 2-6, 2007), 2 research groups presented data on hepatitis C virus (HCV) genotype 5, while a third group announced the apparent discovery of a new seventh HCV genotype.

HCV genotypes 1, 2, and 3 are most common in North America and Western Europe. Genotype 4 is most common in Africa, including Egypt, and the Middle East, but is increasingly seen in some parts of Europe such as Spain. Genotype 5 also has been reported most often in Africa and the Middle East. Genotype 6 predominates in Southeast Asia.

Genotype plays an important role in response to interferon-based therapy. Genotypes 2 and 3 are comparatively easy to treat, while genotype 1 responds less well to interferon. Data are mixed concerning genotype 4, though it seems to be intermediate between genotypes 2/3 and genotype 1; many treatment studies group people with genotypes 1 and 4 together.

Genotype 5 in Syria

In the first study, researchers reported that about 10% of hepatitis C cases in Syria involve genotype 5. Previously, only 3 case series have described treatment of patients with this genotype.

At AASLD, the investigators presented retrospective epidemiological data and treatment outcomes for all genotype 5 patients evaluated at 3 medical centers in Syria between 2004 and 2006. Treatment consisted of 3 MU thrice-weekly conventional interferon alfa-2a or 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day ribavirin; patients were followed for 6 months after the completion of therapy.

Results

·    During the study period, 81 patients were diagnosed with HCV genotype 5.

·    The male/female ratio was 2 to 1, and the mean age was 53 years.

·    91% of the cases originated from 1 district in the northern part of Syria, of which 40% were from a single small city of 30,000 inhabitants.

·    The mode of transmission (transfusion, tattooing, and injection drug use) was determined for only 20% of cases.

·    Infection of multiple members of a family was observed (a mother, 2 sons, and 2 daughters), indicating that intra-familial transmission may occur.

·    At the time of the report, 26 treatment-naive patients had completed anti-HCV therapy.

·    Among these, 88% achieved early virological response, 88% achieved end-of-treatment response, and 54% achieved sustained virological  response (SVR).

·    The SVR rate was higher with pegylated interferon (67%) versus conventional interferon (47%).

·    SVR was also more likely in patients with minimal versus advanced fibrosis (75% vs 38%), and in those with low versus high HCV viral load (69% vs 38%).

·    SVR rates were similar in patients treated for 24 or 48 weeks.

In discussing these findings, the investigators stated, “There is no obvious cause for the high prevalence rate of HCV genotype 5 in northern Syria.”

They added that, “Compared to genotype 4, the SVR of genotype 5 appears to be better for patients treated with interferon (47% vs 28%) and comparable with pegylated interferon (66% vs 61%).”

They noted that the only 3 published studies on the treatment of HCV genotype 5 reported SVR rates of 67%, 48%, and 60% in series of 12, 21, and 87 patients.

“Similar to genotype 4, the response to treatment [of genotype 5] is intermediate between genotypes 2/3 and 1,” they concluded. “More epidemiological and clinical studies are needed to determine the reason for the high prevalence rate in a small area and the optimal duration of therapy.”

Genotype 5 in Belgium

In the second study, researchers conducted a meta-analysis of 2 large Phase III prospective, randomized clinical trials conducted in Belgium to compare the efficacy of antiviral therapy for HCV genotype 5 versus other genotypes.

Both trials were designed to evaluate the safety and efficacy of various interferon-based therapies in a large population of patients with chronic hepatitis C. Participants were treatment-naive in one study and relapsers in the other. In total, 1139 patients were recruited between October 2000 and May 2005 in both studies, of whom 48 (4.2%) had genotype 5.

The meta-analysis compared demographic characteristics, early virological response, end-of-treatment responses, SVR, and relapse rates between patients with genotype 5 and other genotypes. A subset of genotype 1 patients was then selected from the study database to match the genotype 5 patients according to sex, age (above or below 40 years), baseline HCV viral load (above or below 800,000 IU/mL), cirrhosis status, prior therapy, and type of treatment received.

In the matched patient groups, the “intrinsic sensitivity” of HCV genotype 5 was comparable to that of genotype 1, with an SVR rate of 56% in both groups. The observed SVR in the genotype 5 patients was close to that reported in a recently published study.

“This is the first comparative analysis of HCV [genotype] 5 response to interferon-based therapy derived from large prospective randomized clinical trials,” the researchers wrote. “The study allows better characterization of the Belgian HCV [genotype] 5 population and its response to treatment. It suggests that HCV [genotype] 5 patients should be treated with the same treatment regimen as HCV [genotype] 1 patients.”

Genotype 7

Finally, a third group of researchers reported on the identification of a new HCV genotype originating in Central Africa.

As background, they noted HCV genotypes 1, 2, and 4 display significant genetic diversity in Africa, while genotypes 3 and 6 show high genetic diversity in southern Asia. On the other hand, genotype 5 is comprised of only 1 subtype, and its origin has not yet been established.

The investigators identified 3 HCV variants (QC69, CS101285, and CS101300) that clustered together, but did not fall within the classification of the 6 known genotypes. QC69 was isolated from a patient residing in Canada, while CS101285 and CS101300 were obtained from patients in Belgium. However, all 3 patients came from the Democratic Republic of Congo, where they were presumably infected.

In order to better characterize these variants and study their evolutionary relationships with the other genotypes, the researchers determined the entire coding region sequence of QC69 and partial coding region sequences of CS101285 and CS101300.

QC69 contained an open reading frame of 3013 amino acids. It showed 33.4% to 35.5% nucleotide and 28.1% to 31.0% amino acid divergence compared with genotypes 1a-H77, 2a-HCJ6, 3a-NZL1, 4a-ED43, 5a-EUH1480, and 6a-EUHK2.

Phylogenetic analysis showed that QC69 forms a branch distinct from other HCV genotypes, confirming that it constitutes a novel genotype. Additional analysis indicated a closer relationship between QC69 and genotype 2 variants, analogous to the relationship between genotype 1 and 4 variants. The analysis also showed that QC69 was not a result of recombination between known genotypes.

“The finding of a new genotype in Central Africa will contribute in elucidating the origin of the worldwide HCV epidemic,” the researchers concluded. “We propose that these 3 isolates be classified as genotype 7 of HCV.”

11/27/07

References

N Antaki, A Hermes, M Hadad, and others. Hepatitis C Virus Genotype 5: Epidemiological Data and Response to Treatment. 58th Annual Meeting of the American Association for the Study of Liver Diseases (AASLD 2007). Boston, MA, November 2-6, 2007. Abstract 289.  

F D'Heygere, C George, and H Van Vlierberghe. Efficacy of interferon-based antiviral therapy in patients with Chronic Hepatitis C infected with Hepatitis C Virus genotype 5: a meta-analysis of two large prospective Belgian clinical trials. AASLD 2007. Abstract 339.  

D Murphy, J Chamberland, R Dandavino, and others. A New Genotype of Hepatitis C Virus Originating from Central Africa, AASLD 2007. Abstract
872.