Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5

Antaki, Nabil; Hermes, A.; Hadad, M.; Ftayeh, M.; Antaki, Fadi; Abdo, Nour; Kebbewar, Kamel

doi:10.1111/j.1365-2893.2007.00946.x

Cited by 23 publications

(17 citation statements)

References 19 publications

(31 reference statements)

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“…Antaki and colleagues have published a retrospective study of genotype 5 infected patients treated with PEG-IFN/RBV. By this retrospective analysis, genotype 5 infected patients have an SVR rate of 67% [58], exactly as our tree predicts.…”

Section: Resultssupporting

confidence: 79%

“…Such a correlation suggests the intriguing forecast that prospective clinical trials for genotypes 5 and 6 will show intermediate response rates, between genotypes 4 and 2, to interferon-based regimens. This prediction is notably in line with current retrospective data regarding the SVR for genotype 5 [58]. It also highlights the need for more molecular studies that explore the genotype-specificity of HCV-immune interactions.…”

Section: Discussionsupporting

confidence: 83%

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The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

2009

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BackgroundPatients chronically infected with hepatitis C virus (HCV) require significantly different durations of therapy and achieve substantially different sustained virologic response rates to interferon-based therapies, depending on the HCV genotype with which they are infected. There currently exists no systematic framework that explains these genotype-specific response rates. Since humans are the only known natural hosts for HCV–a virus that is at least hundreds of years old–one possibility is that over the time frame of this relationship, HCV accumulated adaptive mutations that confer increasing resistance to the human immune system. Given that interferon therapy functions by triggering an immune response, we hypothesized that clinical response rates are a reflection of viral evolutionary adaptations to the immune system.Methods and FindingsWe have performed the first phylogenetic analysis to include all available full-length HCV genomic sequences (n = 345). This resulted in a new cladogram of HCV. This tree establishes for the first time the relative evolutionary ages of the major HCV genotypes. The outcome data from prospective clinical trials that studied interferon and ribavirin therapy was then mapped onto this new tree. This mapping revealed a correlation between genotype-specific responses to therapy and respective genotype age. This correlation allows us to predict that genotypes 5 and 6, for which there currently are no published prospective trials, will likely have intermediate response rates, similar to genotype 3. Ancestral protein sequence reconstruction was also performed, which identified the HCV proteins E2 and NS5A as potential determinants of genotype-specific clinical outcome. Biochemical studies have independently identified these same two proteins as having genotype-specific abilities to inhibit the innate immune factor double-stranded RNA-dependent protein kinase (PKR).ConclusionAn evolutionary analysis of all available HCV genomes supports the hypothesis that immune selection was a significant driving force in the divergence of the major HCV genotypes and that viral factors that acquired the ability to inhibit the immune response may play a role in determining genotype-specific response rates to interferon therapy.

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Section: Resultssupporting

confidence: 79%

Section: Discussionsupporting

confidence: 83%

The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

2009

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“…Patients with genotype 5a have been shown to respond better to pegylated-IFN and ribavirin therapy when compared to genotypes 1a and 1b, with response rates ranging from 48% to 67% (D'Heygere et al, 2011;Antaki et al,2008, Legrand-Abravanel et al, 2004, Bonny et al, 2006, Prabdial-Sing et al, 2009.…”

Section: Discussionmentioning

confidence: 99%

“…The standard of care (SOC) for treating hepatitis C in South Africa is combination therapy with pegylated interferon (PEG-IFN) and ribavirin (Botha et al, 2010). Individuals with genotype 5a, the predominant genotype in South Africa, have response rates to combination therapy ranging from 47-67% (Antaki et al, 2008;Devaki et al, 2015). However, many South Africans: typically present with advanced diseases for them to benefit from therapy, have poor access or cannot afford the treatment.…”

Section: Introductionmentioning

confidence: 99%

Naturally occurring resistance mutations within the core and NS5B regions in hepatitis C genotypes, particularly genotype 5a, in South Africa

et al. 2016

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Approximately 1 million South Africans are infected with Hepatitis C virus (HCV). The standard of care (SOC) in South Africa is combination therapy (pegylated interferon and ribavirin). HCV genotypes and/or mutations in the core/ non-structural regions have been associated with response to therapy and/or disease progression. This study examines mutations in the core (29-280 amino acids, including ~90 E1 amino acids) and NS5B (241-306 amino acids) regions on pre-treatment isolates from patients attending Johannesburg hospitals or asymptomatic South African blood donors. Diversity within known CD4+ and CD8+ T-cell epitopes was also explored. Samples grouped into subtypes 1a (N=10) 1b (N=12), 3a(N=5), 4a (N=3) and 5a(N=61). Two mutations, associated with interferon resistance-R70Q and T110N-were present in 29 genotype 5a core sequences. No resistance mutation to NS5B nucleotide inhibitors, sofosbuvir was found. Six putative CD8+ and one CD4+ T-cell epitope sequence in the core region showed binding scores of <300 IC 50 nM to HLA alleles frequently observed in the South African population. No known CD8+ and CD4+ T-cell epitopes were mapped in the NS5B region. The analysis begs the question whether those infected with genotype 5a will benefit better on interferon-free combination therapies. This study provides new insight into one of the lesser studied HCV genotypes and compares the diversity seen in a large pre-treatment cohort with other subtypes. KeywordsHepatitis C, genotype 5, interferon, mutations, therapy Highlights  We examined mutational changes of hepatitis C in the core/E1 and NS5B genes. Phylogenetic analyses were performed using Bayesian inferences. Diversity within known CD4+ and CD8+ T-cell epitopes was also explored. Mutations, associated with interferon resistance, were present in genotype 5a samples at baseline. 2

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“…8 Antaki et al reported data suggesting that a 24 week course of pegylated interferon and ribavirin could suffice for infected patients with HCV genotype 5. 9 These data might suggest that HCV genotype 5 is intrinsically sensitive to the current antiviral treatment.…”

Section: Introductionmentioning

confidence: 99%

Early Viral Kinetics and Response to Treatment in a Hepatitis C Virus Genotype 5 Infected Patient

Durante‐Mangoni

Iossa

Malgeri

2011

Clinics and Practice

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Genotype 5 hepatitis C has been poorly studied despite its worldwide spread. We have analyzed the early kinetics of genotype 5 hepatitis C virus RNA during pegylated interferon/ribavirin treatment in a 59-year-old man with active liver necroinflammatory changes and advanced liver fibrosis. The patient had a high viral load but a small serum level of hepatitis C core antigen. On combination antiviral treatment with pegylated-interferon alpha 2a, 180 µg/week, and ribavirin, 1200 mg/day, the patient experienced an impressive reduction in serum HCV RNA as early as day 2 of treatment and eventually became a sustained virological responder. Our viral kinetics data support previous clinical studies showing HCV genotype 5 could be as intrinsically sensitive to interferon as HCV genotypes 2 and 3.

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Efficacy of interferon plus ribavirin in the treatment of hepatitis C virus genotype 5

Cited by 23 publications

References 19 publications

The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

The Evolution of the Major Hepatitis C Genotypes Correlates with Clinical Response to Interferon Therapy

Naturally occurring resistance mutations within the core and NS5B regions in hepatitis C genotypes, particularly genotype 5a, in South Africa

Early Viral Kinetics and Response to Treatment in a Hepatitis C Virus Genotype 5 Infected Patient

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