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In This Issue:
• Response to Hepatitis C Treatment
• Liver Genes and Treatment Response
• Insulin Resistance and Treatment Response
• Response in Coinfected Patients with HCV Genotypes 2 or 3
• Substance Use and HCV
• Liver Cancer
Response to Hepatitis C Treatment
Two recent studies looked at factors predicting response to pegylated interferon plus ribavirin for chronic hepatitis C. In the first, published in the April 2008 Journal of Viral Hepatitis, B.J. Thomas and colleagues looked at sustained virological response (SVR) rates in real-world clinical practice in the U.K. It is not unusual for outcomes in real-world settings to be inferior to those seen in the more controlled environment of a clinical trial. Out of 347 patients treated according to current guidelines, 37% with HCV genotype 1 and 70% with non-1 genotypes achieved SVR. About 10% stopped treatment early. Besides genotype, other factors that predicted sustained response were patient age and stage of liver disease at the start of therapy. After controlling for multiple factors, however, age only made a difference for genotype 1 patients. “Our study demonstrates that results comparable with those of randomized clinical trials can be achieved in clinical practice,” the investigators concluded.
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Liver Genes and Treatment Response
In the second study, French researchers assessed whether liver gene expression patterns could predict SVR. As reported in the April 2008 issue of Gut, T. Asselah and colleagues reviewed prior research to select 58 genes associated with dysregulation in people with chronic hepatitis C. They used PCR testing to analyze messenger RNA expression of these genes in pretreatment liver biopsy specimens. Looking first at a “training set” of 40 patients (26 with SVR and 14 nonresponders), they identified three genes (IFI-6-16/G1P3, IFI27, and ISG15/G1P2) with significantly increased expression in nonresponders compared with sustained responders. The same genes were then analyzed in a second “validation set” of 20 patients with SVR, nine nonresponders, and 11 relapsers. The researchers found that a two-gene “signature” of IFI27 and CXCL9 accurately predicted outcomes for 100% of nonresponders and 70% of sustained responders. Relapsers, however, did not have a distinct gene expression profile, and usually were incorrectly predicted to be responders. In the future, genetic testing may help identify which individuals are most likely to benefit from hepatitis C treatment.
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Insulin Resistance and Treatment Response
Prior studies have shown that insulin resistance (a condition in which the body’s cells do not respond normally to insulin) predicts poor response to interferon-based therapy in individuals with HCV monoinfection. The same also appears to be true for HIV/HCV coinfected patients, according to a study in the April 23, 2008 issue of AIDS. P. Nasta and colleagues from Italy studied 74 coinfected individuals treated with pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin. About half had advanced fibrosis and half were infected with HCV genotypes 1 or 4. After 4 weeks of therapy, 41% of patients achieved rapid virological response (RVR), or undetectable HCV RNA. Independent predictors of failure to achieve RVR were HCV genotype 1 or 4 (versus 2 or 3), high baseline HCV viral load (greater than 400,000 IU/mL), and insulin resistance (indicated by a HOMA-IR score greater than 3.00). The researchers recommended that insulin resistance should be “evaluated and possibly corrected” before coinfected patients start hepatitis C treatment to improve the likelihood of response.
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Response in Coinfected Patients with HCV Genotypes 2 or 3
Numerous studies have indicated that HIV/HCV coinfected individuals tend to respond less well to interferon-based therapy than those with HCV alone, but a variety of factors can influence response rates. As described in another report in the same issue of AIDS, O. Karlstrom and colleagues studied early HCV viral kinetics and SVR rates in 13 coinfected and 26 HCV monoinfected individuals with HCV genotypes 2 or 3 who were treated with 135 mcg/week Pegasys (lower than the standard 150 mcg/week dose) plus 11 mg/kg daily ribavirin for 24 weeks. There was no significant difference in the speed of HCV RNA decline in the coinfected and monoinfected patients at any time point during the first 12 weeks of therapy. Six months after completion of treatment, 69% of the coinfected patients and 77% of the HCV monoinfected patients achieved SVR. The investigators concluded that coinfected and monoinfected individuals with HCV genotypes 2 or 3 respond similarly to treatment, and that a lower dose of pegylated interferon “offered high compliance and reasonable sustained virological response rates” for patients with these genotypes.
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Substance Use and HCV
Use of tobacco, drugs, and alcohol can influence liver disease progression and response to treatment in people with chronic hepatitis C, according to three recently published studies. In the April 2008 Journal of Hepatology, A. Mallat, C. Hezode, and S. Lotersztajn reviewed environmental factors associated with accelerated liver fibrosis progression. It is well known that heavy alcohol use accelerates liver disease progression, but more recent studies indicate that even light alcohol consumption may also worsen fibrosis. Tobacco smoking, according to some studies, may promote histological activity, thereby contributing to fibrosis progression. Cannabis, too, is emerging as a risk factor for liver disease, and a prior study by Hezode’s team found that regular cannabis smoking was an independent predictor of both fibrosis and liver steatosis (fat accumulation) in hepatitis C patients. The authors concluded that, “[P]atients should be informed of the deleterious impact of alcohol, tobacco, and cannabis use, and should be offered appropriate support to achieve abstinence.”
As reported in the April 2008 Journal of Viral Hepatitis, L. Ye and colleagues performed a laboratory study to asses the effect of methamphetamine on HCV replication in cultured human hepatocytes. They found that methamphetamine inhibited natural interferon alfa expression in hepatocytes, which was associated with increased HCV replication. Exposure to methamphetamine also reduced the antiviral effect of recombinant interferon alfa used as anti-HCV therapy. Adding methamphetamine to cell cultures inhibited expression of STAT-1, a protein that plays a key role in interferon-mediated biological response, and reduced expression of IRF-5, a factor that activates the interferon pathway. These in vitro findings, the investigators concluded, suggest that methamphetamine use may impair natural immune control of HCV as well as response to interferon-based therapy.
Finally, as reported in the April 2008 Journal of Clinical Virology, E.A. Operskalski and colleagues analyzed risk factors associated with elevated HCV viral load among 882 HIV positive and 167 HIV negative participants in the Women’s Interagency HIV Study who had hepatitis C. About 80% of the women had detectable HCV RNA. Women with detectable HCV viral load were more likely to have a high HIV viral load, to be black, and to smoke tobacco. Current tobacco smoking and a history of drug use (cocaine, marijuana, amphetamine, or heroin) were associated with both a greater likelihood of detectable HCV RNA and higher HCV viral load, leading the investigators to recommended that effective substance abuse counseling might “reduce clinical progression, improve response to treatment, and decrease HCV transmission by lowering levels of HCV viremia in women.”
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Hepatocellular carcinoma (HCC), a potential outcome of chronic HCV infection, is difficult to treat, in part because it is usually not detected until later stages. But regular HCC screening of high-risk patients can lead to more successful surgical management of liver cancer, according to a study in the April 2008 Annals of Surgery. A. Chan and colleagues from Hong Kongreviewed data from 1366 patients with chronic hepatitis B or C who were diagnosed with HCC either through screening or based on symptoms between January 1991 and December 2004. Long-term survival was significantly greater in the screened group compared with the symptomatic group (median survival 62 versus 12 months). Among screened patients, the likelihood of curative treatment rose from 51% during 1991-1997 to 68% during 1998-2004, and median survival increased from 39 to 69 months. There was no significant improvement over time, however, in the patients identified based on symptoms.
In another recent study, reported in the April 9, 2008 Journal of the American Medical Association, B. Cheng and colleagues from China compared the benefits of two HCC treatment methods alone or in combination. In transarterial chemoembolization (TACE), the blood supply to the hepatic artery is blocked and chemotherapy drugs are directly administered. Radiofrequency ablation (RFA) destroys tumors with heat using a high frequency current delivered through a needle electrode. In a randomized, controlled trial, 291 patients with HCC tumors larger than 3 cm underwent TACE only, RFA only, or both procedures in combination. The median survival time was 37 months in the TACE plus RFA group, compared with 24 months for TACE alone and 22 months for RFA alone. The researchers suggested that blocking blood flow to the tumor using TACE might allow for more prolonged heating using RFA, and therefore more thorough tumor destruction.
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