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In This Issue:
• Targets for New Anti-HCV Therapies
• Resistance to Telaprevir
• Milk Thistle for Hepatitis C
• Reasons HCV Patients Decline Treatment
• Sexual Transmission of HCV
Targets for New Anti-HCV Therapies
Interferon-based therapy for hepatitis C works by stimulating the body’s natural immune response, but several newer agents directly inhibit HCV replication. In the May 2007 issue of Gastroenterology, J.M. Pawlotsky and colleagues reviewed the HCV lifecycle and the various steps targeted by novel therapies. These steps include viral attachment, fusion, and entry into host cells, translation of viral RNA, post-translation processing, replication of viral components, and assembly and release of new virus particles. Novel agents targeting these steps include HCV polymerase and protease inhibitors. For an overview of the HCV lifecycle and new targets for therapy, see the June 2005 issue of HCV Advocate.
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Resistance to Telaprevir
One such directly targeted agent is the HCV NS34A protease inhibitor telaprevir (VX-950). Telaprevir demonstrates strong antiviral activity, but can lead to the emergence of drug-resistant virus, especially when used as monotherapy. As described in the May 2007 issue of Gastroenterology, C. Sarrazin and colleagues used a highly sensitive sequencing method to assess mutations in the NS3 protease catalytic domain in genotype 1 patients receiving various doses of telaprevir for 14 days. They identified several mutations that conferred low-level resistance (V36A/M, T54A, R155K/T, A156S) and high-level resistance (A156V/T, 36+155, 36+156) to the drug. After telaprevir was discontinued, most resistant variants were replaced by wild-type virus within 3-7 months. “Resistant HCV isolates are selected rapidly during therapy with the highly active protease inhibitor telaprevir,” the investigators concluded. “Combination therapy with pegylated interferon-alfa or other direct antiviral drugs seems mandatory to avoid developing resistance.”
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Milk Thistle for Hepatitis C
Many patients use alternative and complementary therapies to manage hepatitis C and resulting liver fibrosis, but most such agents have not been studied in Western clinical trials. Again in the May 2007 issue of Gastroenterology, S.J. Polyak and colleagues reported data from a laboratory study of the anti-inflammatory and antiviral properties of a standardized milk thistle (Silybum marianum) silymarin extract known as MK-001. They found that MK-001 inhibited expression of tumor necrosis factor-alpha in human peripheral blood mononuclear cells and inhibited nuclear factor kappa B-dependent transcription in human hepatoma cells. MK-001 also demonstrated both preventive and therapeutic effects against HCV infection of cells. When combined with interferon alpha, MK-001 inhibited HCV replication more than interferon alone. The compounds silybin A, silybin B, isosilybin A, and isosilybin B produced the strongest anti-HCV activity. These antiviral effects were found to be independent of MK-001-induced cytotoxicity. The authors concluded that, “The data indicate that silymarin exerts anti-inflammatory and antiviral effects, and suggest that complementary and alternative medicine-based approaches may assist in the management of patients with chronic hepatitis C.”
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Reasons HCV Patients Decline Treatment
As reported in the May 2007 issue of Digestive Diseases and Sciences, O.S. Khokhar and colleagues conducted a retrospective study to assess why some patients with chronic hepatitis C decline treatment. Of 446 patient charts reviewed, 280 treatment-naive individuals had no contraindications to interferon-based therapy. Of these, 41% declined treatment, with women outnumbering men by about 3 to 2. Older and younger patients were more likely to decline treatment than middle-aged individuals (45-55 years), and African-Americans were more likely to do so than people of other races (48% vs 36%). The two most common reasons for declining therapy – cited by nearly 66% of patients – were asymptomatic disease and concern about side effects. In addition, about 10% mentioned lack of health insurance or social support. However, only 4.3% cited doubts about treatment efficacy.
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Sexual Transmission of HCV
Sexual transmission of HCV remains poorly understood. While the risk of transmission among monogamous heterosexual couples is low (3% or less in most studies), outbreaks of apparently sexually transmitted acute HCV infection have been reported among mostly HIV positive men who have sex with men (MSM) in the U.K. and Europe.
In the May 2007 issue of HIV Medicine, M. Ruf and colleagues provided further data on one such outbreak in London. The investigators surveyed genitourinary medicine and HIV clinics to assess the incidence of recent HCV infection (defined as a positive HCV RNA or antibody test in individuals who had a negative test within the previous three years) in MSM seen between 2002 and 2006. A total of 352 cases of recently acquired HCV were reported, for an incidence rate of 9.0 cases per 1000 person years. Over the study period, the estimated incidence of recently acquired HCV infection increased by 20%.
In another study, reported in the May 11, 2007 issue of AIDS, researchers following the U.K. outbreak further characterized the modes of HCV transmission. M. Danta and colleagues studied 111 HIV positive MSM with acute HCV infection at three urban HIV clinics in the U.K. between 1999 and 2005. Using blood samples, they constructed phylogenetic trees to determine whether patients’ HCV strains were related. Analysis of 93 HCV E1/E2 sequences revealed seven clusters, signifying multiple independent HCV lineages circulating within the HIV positive population. Acute HCV infection was associated with mucosal risk factors (suggesting sexual transmission) rather than percutaneous risk factors (suggested transmission via injection drug use). Compared with uninfected controls, men with acute HCV had more sex partners, higher levels of risky sexual behavior, and were more likely to have shared drugs via the nasal or anal route. Group sex was found to be the strongest predictor of HCV infection, with the odds increasing as men participated in more types of high-risk sexual behavior in a group setting.
In contrast with the U.K. and Europe, outbreaks of apparently sexually transmitted HCV infection have not been observed in the U.S. As reported in the June 2007 issue of Sexually Transmitted Diseases, S. Bollepalli and colleagues conducted a retrospective analysis of factors associated with HCV infection in 242 HIV positive American subjects (168 with HIV monoinfection and 74 with HIV/HCV coinfection). Risk factors that differed significantly between HIV monoinfected and coinfected individuals included intravenous drug use, sex with an intravenous drug user, snorting drugs, sharing razors or toothbrushes, spending time in prison, having tattoos, exchanging sex for money or drugs, and being a man who has sex with men. In a multivariate regression model, however, only intravenous drug use remained a significant predictor of HIV/HCV coinfection. Further, a history of sexually transmitted diseases and having 11 or more sex partners were more common among HIV monoinfected compared with coinfected MSM, leading the researchers to conclude that, “HIV/HCV coinfection was associated with intravenous drug use but not with sexual risk factors.”
Finally, as reported in the June 1, 2007 Journal of Infectious Diseases, J.M. McMahon and colleagues used a novel modeling technique to assess risk factors for HCV infection among 265 drug-using couples in East Harlem in New York City. They found that significant individual risk factors for HCV included a history of injection drug use, tattooing, and older age. HCV infection tended to cluster within couples, and was accounted for by drug-injection behavior. In contrast, sexual behavior was not associated with HCV infection in this model. The researchers concluded that, “Our results are consistent with prior research indicating that sexual contact plays little role in HCV transmission.”
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