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A Bi-Monthly Publication of the Hepatitis Support Project

June 25 , 2007
Volume 4, Issue 12

Liz Highleyman

To download pdf version click here

In This Issue:

Hepatitis C

• Resistance to Telaprevir

• Ribavirin and HCV Mutation

• Noninvasive Fibrosis Diagnosis

• Metabolic Changes in HIV/HCV Coinfected Patients

Resistance to Telaprevir
Telaprevir (VX-950) is an HCV protease inhibitor that has demonstrated strong antiviral activity in ongoing clinical trials. As reported in the May 2007 issue of Gastroenterology, C. Sarrazin and colleagues analyzed mutations in the NS3 protease domain of approximately 80 clones per sample from patients with genotype 1 HCV treated with telaprevir (450 or 750 mg every 8 hours or 1250 every 12 hours) for 14 days. They detected mutations conferring low-level (V36A/M, T54A, R155K/T, A156S) and high-level (A156V/T, 36+155, 36+156) resistance to telaprevir, which were correlated with levels of telaprevir exposure and virological response. After telaprevir was discontinued, a majority of telaprevir-resistant variants were replaced by wild-type HCV within 3-7 months. The authors concluded that, “Combination therapy with pegylated interferon alfa or other direct antiviral drugs seem[s] mandatory to avoid developing resistance [to telaprevir].”

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Ribavirin and HCV Mutation
It is not clear how ribavirin works against hepatitis C, but one theory is that it increases the rate of HCV mutation, thereby rendering the virus less fit. Two recent studies, however, suggest that this hypothesis is incorrect. As reported in the May 2007 issue of Gastroenterology, G. Lutchman and colleagues evaluated the mutagenic potential of ribavirin in 31 patients with genotype 1 chronic hepatitis C randomly assigned to receive ribavirin or placebo; after 48 weeks, those on placebo were given open-label ribavirin for an additional 48 weeks. During the randomization phase, there was no difference in the number of HCV NS5B mutations or mutation rates at week 24 between the ribavirin- and placebo-treated patients, and no mutations were observed in conserved regions of NS5B. While an increase in the mutation rate was observed at week 4 in patients who crossed over to ribavirin, this was no longer apparent at week 24. The authors concluded that, “Lethal mutagenesis and error catastrophe is unlikely to be the sole mechanism of action of ribavirin during therapy for chronic hepatitis C.

In the second study, reported in the May 9, 2007 advance online edition of the Journal of Virology, S. Chevaliez and colleagues performed a sequence-based analysis of two independent genomic regions of HCV in patients receiving ribavirin monotherapy and those treated with ribavirin plus conventional interferon either daily or thrice-weekly. Use of ribavirin monotherapy did not increase the variation rate, mutation frequency, error-generation rate, or between-sample genetic distance. Further, the accumulation of mutations did not accelerate during combination therapy with ribavirin plus interferon, even when viral replication was strongly inhibited. These authors, too, concluded that their study “strongly undermines the hypothesis whereby ribavirin acts as an HCV mutagen in vivo.”

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Noninvasive Fibrosis Diagnosis
In the May 2007 Journal of Hepatology, V. Leroy and colleagues reported on a comparison of the diagnostic performance of six noninvasive liver fibrosis biomarker scores – APRI, Fibrometer, Fibrotest, Forns’ index, Hepascore, and MP3 – in 180 patients with chronic hepatitis C. For distinguishing between absent or mild (stage F0-F1) fibrosis and moderate to severe (F2-F4) fibrosis, the overall diagnostic performance of the indices (as determined by areas under the receiver operating characteristic curves, or AUROCs) ranged from 0.86 for Fibrometer to 0.78 for Forns’ index. For discriminating between stage F0-F2 fibrosis and stage F3-F4, AUROCs ranged from 0.91 for Fibrometer to 0.78 for Forns’ index. The tests accurately predicted “significant or extensive” fibrosis in 10%-86% of patients, with positive predictive values ranging from 55% to 94%. In an evaluation of the performance of paired-combination scores, the best combinations accurately identified one-third of patients for whom either absence of significant fibrosis or presence of extensive fibrosis could be predicted with better than 90% certainty. The researchers concluded that, “Current non-invasive scores give reliable information on liver fibrosis in one-third of chronic hepatitis C patients, especially when used in combination.”

In a related study reported in the June 13, 2007 advance online edition of Hepatology, A. Vallet-Pichard and colleagues compared the results of a noninvasive test called FIB-4 – which combines patient age, platelet count, and ALT and AST levels – with liver biopsies from 847 hepatitis C patients. They also compared results from FIB-4 and Fibrotest measurements from 592 patients. The FIB-4 index correctly identified patients with severe (F3-F4) fibrosis or cirrhosis, with AUROCs of 0.85 and 0.91, respectively. A FIB-4 score less than 1.45 had a negative predictive value of 94.7% and a sensitivity of 74.3% for excluding severe fibrosis, while a score above 3.25 had a positive predictive value of 82.1% and a specificity of 98.2% for confirming the existence of significant fibrosis. Using these score cut-offs, 72.8% of the liver biopsies were correctly classified, and the FIB-4 index was also strongly correlated with Fibrotest results. The researchers concluded that for score below 1.45 or above 3.25, “the FIB-4 index is a simple, accurate, and inexpensive method for assessing liver fibrosis.” Taken together, these studies confirm past research showing that noninvasive methods perform well in distinguishing between absent/mild fibrosis and extensive fibrosis or cirrhosis, but do less well at distinguishing between intermediate stages.

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Metabolic Changes in HIV/HCV Coinfected Patients
Many HIV positive individuals experience metabolic complications including body fat changes, elevated blood fats, and insulin resistance or diabetes. Some past studies suggest that HIV/HCV coinfected patients may be at higher risk for such manifestations, though data are inconsistent. In the May 1, 2007 issue of AIDS, P. Tien and colleagues described a study examining the association between HCV infection and fat volume in 792 HIV positive men (20% coinfected) and 329 women (26% coinfected). HIV monoinfected and HIV/HCV coinfected women had similar amounts of subcutaneous and visceral adipose tissue at all sites measured. HIV monoinfected and coinfected men had similar fat volume in most areas, but the coinfected men had more leg fat. Reduced leg fat was associated with use of stavudine (d4T; Zerit) and indinavir (Crixivan). Overall, the researchers concluded that, “HIV/HCV coinfection is not associated with less subcutaneous adipose tissue in men and women,” adding that “HCV infection seems to mitigate the loss of leg fat seen in HIV-infected men on stavudine.”

In a related study reported in the May 2007 Journal of Acquired Immune Deficiency Syndromes, I. Brar and colleagues assessed the prevalence and predictors of diabetes mellitus in antiretroviral therapy-naive HIV positive adults in three CPCRA studies, comparing the results with those from an ongoing study of nutrition and health in the HIV negative population (NHANES). The overall prevalence of diabetes was 3.3% among the CPCRA subjects, compared with 4.8% in NHANES. While HCV coinfection was associated with diabetes in a univariate analysis, a multivariate analysis controlling for multiple factors found that only age, body mass index, and race/ethnicity were significant risk factors for diabetes in both the CPCRA and NHANES cohorts. They concluded that, “Although there was a trend toward increased prevalence of diabetes mellitus in HIV/HCV coinfected patients, dominant risk factors associated with diabetes mellitus among antiretroviral therapy-naive HIV-infected adults mirrored those of the general population.”

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