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A Bi-Monthly Publication of the Hepatitis Support Project

July 15 , 2008
Volume 5, Issue 7

Liz Highleyman

To download pdf version click here

In This Issue:


Shorter Therapy for HCV Genotype 1
In an effort to reduce the side effects and cost of hepatitis C treatment, researchers have explored shorter durations of therapy for selected patients. In the June 2008 issue of Hepatology, M.L. Yu and colleagues reported on a study comparing 24 weeks of combination therapy versus the standard 48 weeks in 200 Taiwanese patients with hard-to-treat HCV genotype 1. All participants received 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin.

Overall, patients in the 24-week arm had a significantly lower sustained virological response (SVR) rate than those in the 48-week arm (59% vs 79%). This was also true for the 87 participants who achieved rapid virological response (RVR) or undetectable HCV RNA after 4 weeks of therapy – with SVR rates of 89% and 100%, respectively. However, among the 52 patients with both RVR and low baseline HCV viral load (< 400,000 IU/mL), the 96% SVR rate in the 24-week arm was comparable to the 100% rate in the standard duration arm.

The researchers concluded that genotype 1 patients “derive a significantly better SVR from 48 weeks versus 24 weeks of peginterferon/ribavirin even if they attain an RVR,” but acknowledged that the shorter duration produces a high likelihood of sustained response for carefully selected individuals. For an overview of individualized treatment duration, see the February 2008 HCV Advocate. An article in the August issueof the HCV Advocate will look at tailored treatment duration and doses for patients with easier-to-treat HCV genotypes 2 or 3.

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Importance of Adequate Ribavirin
A study published in the May 2008 issue of Hepatology confirmed the importance of ribavirin in interferon-based therapy for chronic hepatitis C. Previous studies have shown that ribavirin concentrations in the body can vary widely among individuals despite weight-adjusted dosing. V. Loustaud-Ratti and colleagues performed a pharmacokinetic-pharmacodynamic analysis of 28 genotype 1 chronic hepatitis C patients in France treated with Pegasys plus weight-based ribavirin for 12 weeks; amantadine was then added for an additional 36 weeks.

Individuals who achieved SVR had significantly higher ribavirin concentrations at day 0, and those whose total ribavirin concentrations over time exceeded specific cut-off values had a better chance of achieving a sustained response (1755 microg/hr/L for area under the curve [AUC] from 0-4 hours and 3014 microg/hr/L for AUC from 0-12 hours). These findings indicate that ribavirin exposure is an important predictor of response that does not always correlate with actual dosages administered. Adjusting doses to reach a target concentration in the body may improve treatment outcomes.

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Anti-HCV Activity of Fluvastatin
In 2006, Japanese researchers demonstrated that statin drugs, used to manage high blood cholesterol, inhibited HCV replication in cell cultures. At the 2007 Digestive Disease Week conference, T. Bader and colleagues reported that statins also inhibited HCV replication in chronic hepatitis C patients treated with pegylated interferon plus ribavirin. As described in the June 2008 American Journal of Gastroenterology, this team then conducted a prospective trial to assess the safety and antiviral activity of fluvastatin (Lescol) – which demonstrated the most potent anti-HCV effect in the laboratory – in 31 U.S. veterans not receiving interferon-based therapy.

Participants received fluvastatin doses ranging from 20 to 320 mg/day for two to 12 weeks. Half the patients who received 80 mg/day or less experienced a significant reduction in HCV RNA, usually within the first four weeks; the largest weekly decrease was 1.75 logs. About three-quarters of responders had stable reductions in HCV RNA for two to five weeks, and about one-quarter had continued viral load reduction at the end of the study. There was no evidence of liver toxicity, a potential concern with statin drugs. The researchers concluded that fluvastatin monotherapy demonstrated a “modest, variable, and often short-lived” suppressive effect on HCV, and recommended further trials combining fluvastatin with pegylated interferon and ribavirin.

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Chronic Hepatitis C in Children
While chronic hepatitis C has been extensively studied in adults, less is known about its natural history and outcomes in children. As reported in the June 2008 issue of Gastroenterology, F. Bortolotti and colleagues examined the long-term course of the disease in 504 children at 12 centers in Italy. Just over half were presumably exposed via perinatal transmission and about one-third via parenteral exposure. All children were positive for HCV antibodies and 95% had detectable HCV RNA.

Of the 118 children treated with conventional interferon, 33 (28%) achieved SVR. Among the 359 untreated children, 27 (8%) had undetectable viral load 10 years after the presumed time of infection, and genotype 3 was a predictor of spontaneous viral clearance. Among the 332 children with persistent chronic HCV after 10 years, six (1.8%) progressed to decompensated cirrhosis; four of them had been infected perinatally with genotype 1a and had mothers who were injection drug users. “Persistent viral replication led to end-stage liver disease in a small subgroup characterized by perinatal exposure, maternal drug use, and infection with HCV genotype 1a,” the researchers concluded. “Children with such features should be considered for early treatment.” For more on chronic hepatitis C in children, see the June 2008 HCV Advocate.

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Coinfected People Have Worse Fibrosis
A study in the June 2008 Journal of Viral Hepatitis added to the evidence that HIV/HCV coinfected individuals tend to experience more advanced liver fibrosis than people with HCV alone. V. De Ledinghen and colleagues assessed fibrosis in 287 HIV positive and 656 HIV negative chronic hepatitis C patients in Europe using the noninvasive transient elastography (FibroScan) method and biochemical markers. The researchers detected advanced fibrosis or cirrhosis in 39% of the HIV/HCV coinfected patients compared with 18% of the HIV negative participants. Based on these findings, they concluded that coinfected patients have more advanced liver fibrosis than HCV monoinfected patients, despite the immunological benefits of treating HIV with effective combination antiretroviral therapy.

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Immune Response to HCV in Coinfected Patients
About one-quarter of HIV negative people spontaneously clear HCV without treatment, but this is less likely in HIV/HCV coinfected individuals. In the past few years, researchers have reported several outbreaks of apparently sexually transmitted acute hepatitis C in European cities, mostly among HIV positive gay and bisexual men. In the June 1, 2008 Journal of Infectious Diseases, M. Danta and colleagues reported on a study of immune response to HCV in 55 HIV positive and 8 HIV negative men with recent infection. Just 5% of the HIV positive participants spontaneously cleared HCV; 95% developed persistent chronic infection, compared with 65% of the HIV negative men. The HIV positive individuals also had significantly higher HCV RNA levels.

The researchers analyzed blood samples from 14 of the HIV positive men and all of the HIV negative men, looking for specific T-cell responses against a range of HCV antigens. HIV negative participants had weaker immune activity against HCV, with significantly reduced interferon gamma responses. “HIV coinfection is associated with increased rates of HCV persistence and a lack of critical CD4 T-cell responses,” the researchers concluded. “Loss of key cellular immune responses against HCV during acute disease may contribute to the failure of early host control of HCV” in coinfected patients.

In a related study described in the May 2008 Journal of Viral Hepatitis, S. Gonzalez and colleagues looked at changes in inflammatory cytokines in the livers of HIV positive individuals with chronic hepatitis C. Coinfected patients had decreased levels of interferon gamma, interleukin 4 (IL-4), and IL-12p35 compared with HCV monoinfected people, but had elevated IL-10. Interferon gamma levels fell along with CD4 cell counts as immune function declined. The researchers concluded that HIV-induced T-cell loss may lead to inflammatory cytokine suppression in the liver, and that further studies are needed to determine whether this might explain accelerated fibrosis progression in coinfected patients.

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