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In This Issue:
• New HCV Cell Entry Molecule Identified
• Boceprevir for Genotype 1 Nonresponders
• Treatment of African Americans with Genotype 2/3
• Quality of Life in Patients with Advanced Fibrosis
• Treatment of HIV/HCV Coinfected Patients
• Early HAART Reduces Liver-Related Mortality
• Effect of HCV Treatment on Liver Disease Progression
New HCV Cell Entry Molecule Identified
Researchers do not fully understand how the hepatitis C virus (HCV) enters human host cells, which is important for the development of new therapies. In the April 12, 2007 issue of Nature, M.J. Evans and colleagues identified a new protein required for HCV entry known as claudin-1. In a laboratory study, claudin-1 was required for HCV infection of human hepatoma cell lines, and also conferred susceptibility in nonhepatic cells. Further, antibodies directed against a piece of claudin-1 blocked HCV infection. Claudin-1 appears to play a role late in the entry process, after viral binding and interaction with the CD81 cell-surface coreceptor. The researchers concluded that claudin-1 represents a “novel key factor for HCV entry and a new target for antiviral drug development,” but noted that additional, not-yet-identified factors may be required for efficient HCV infection of cells.
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Boceprevir for Genotype 1 Nonresponders
Boceprevir (formerly SCH 503034) is an experimental oral HCV protease inhibitor being developed by Schering-Plough. In the April 2007 issue of Gastroenterology, C. Sarrazin and colleagues reported data from a Phase Ib study of boceprevir plus pegylated interferon alpha-2b (PegIntron) in 26 patients with chronic genotype 1 HCV infection who did not respond to prior treatment with PegIntron plus ribavirin. Participants received boceprevir monotherapy (half at 200 mg and half at 400 mg thrice-daily) for one week, then PegIntron as monotherapy for two weeks, then combination therapy for two more weeks. Combination therapy led to mean HCV RNA decreases of 2.45 and 2.88 logs, respectively, for the 200 mg and 400 mg boceprevir doses, which was about twice the decreases seen with either boceprevir or PegIntron alone. The combination was well tolerated, with no clinically significant adverse events. Researchers also presented data at the 42nd Annual Meeting of the European Association for the Study of the Liver in Barcelona in April showing that boceprevir had good pharmocokinetic and safety profiles in patients with various degrees of liver impairment. Phase II studies are currently underway.
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Treatment of African Americans with Genotype 2/3
African Americans as a group do not respond as well as Caucasians to interferon-based therapy, but less research has been done in black patients with genotype 2 or 3 HCV. In the April 2007 American Journal of Gastroenterology, M.L. Schiffman and colleagues reported data from a retrospective analysis of virological response in this population. From a database review, they identified 42 African Americans and 334 Caucasians with genotype 2 or 3 chronic hepatitis C; 30 interferon-naive African Americans patients treated with either conventional or pegylated interferon plus ribavirin were matched with 90 Caucasians for sex, age, body weight, presence of cirrhosis, and treatment regimen. The proportion of patients with genotype 2 was significantly greater among African Americans compared with Caucasians (81% vs 52%). End-of-treatment virological response was observed in 94% of Caucasians and 80% of African Americans, while sustained virological response (SVR) occurred in 82% and 57%, respectively. These results, the researchers concluded, suggest that African Americans have a “global defect in their ability to eradicate HCV infection following treatment with interferon and ribavirin,” which holds across all genotypes.
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Quality of Life in Patients with Advanced Fibrosis
Although the virological and histological benefits of hepatitis C treatment are well known, the effects on health-related quality of life (HRQoL) are less clear. As reported in the March 2007 Journal of Hepatology, H.L. Bonkovsky and colleagues assessed HRQoL (using the SF-36 questionnaire) and sexual health in 1,144 patients with advanced liver fibrosis or cirrhosis undergoing treatment with pegylated interferon alpha-2a (Pegasys) plus ribavirin in the HALT-C Trial. After 72 weeks of follow-up, 70% achieved SVR. At baseline, HCV positive patients had poorer scores for all eight SF-36 domains compared with healthy HCV negative control subjects, and patients with cirrhosis had lower HRQoL scores than those with bridging fibrosis. Patients with higher depression scores also had lower HRQoL scores. Subjects who achieved SVR experienced significant improvement in 7of the SF-36 domains, while relapsers experienced worsening in at least 1 domain. Similarly, sexual health scores improved in sustained responders but declined in relapsers. The researchers concluded that, “Achievement of SVR after pegylated interferon/ribavirin therapy improves HRQoL and sexual health in chronic hepatitis C patients with advanced fibrosis or cirrhosis.”
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Treatment of HIV/HCV Coinfected Patients
Studies to date have produced varying rates of sustained response to interferon-based therapy in HIV/HCV coinfected patients. As reported in the April 2007 Journal of Viral Hepatitis, N.J. Shire and colleagues sought determine a pooled response rate and sources of variability between studies. A literature search yielded seven randomized and/or prospective trials evaluating treatment with pegylated interferon (Pegasys or PegIntron) plus ribavirin, with a combined total of 784 patients. In the various studies, intention-to-treat SVR rates ranged from 27.3% to 44.2%, for a pooled estimate of 33.3%. Response rates were lowest for patients with genotype 1 HCV, high pre-treatment HCV viral loads, and low CD4 cell counts. Overall, the researchers concluded, SVR rates in coinfected patients were poor compared with those of HCV monoinfected individuals.
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Early HAART Reduces Liver-Related Mortality
As HAART has reduced AIDS-related mortality, liver disease has become an increasingly important cause of death among people with HIV, especially those with HCV coinfection. While coinfected patients respond less well to hepatitis C treatment and experience more rapid liver disease progression, the difference is less pronounced in those with well controlled HIV and higher CD4 cell counts. In the April 15, 2007 issue of AIDS, S.D. Shafran discussed the outcome of anti-HCV therapy in coinfected individuals. To date, 11 cohort studies have shown that antiretroviral therapy for HIV is associated with a reduced rate of HCV-related liver disease progression, and four of these studies also demonstrated a reduction in liver-related mortality. While treatment with pegylated interferon/ribavirin produces sustained response in up to 40% of treated coinfected patients, only about 10% of such individuals are considered good candidates for anti-HCV therapy, and thus only about 4% of the total coinfected population is successfully treated. “Although offering HCV therapy to the few eligible HIV/HCV coinfected patients is important, early initiation of HAART in coinfected patients has a greater public health impact in reducing liver-related mortality than in curing HCV infection in approximately 4% of these patients” Shafran concluded.
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Effect of HCV Treatment on Liver Disease Progression
While successful hepatitis C treatment is less likely in coinfected patients, those who do achieve sustained response can derive substantial benefit, according to a study in the April 2007 Journal of Hepatology. M. Rodriguez-Torres and colleagues compared liver fibrosis progression rates and time to development of cirrhosis in coinfected patients receiving or not receiving interferon-based therapy; among treated patients, they compared responders versus nonresponders. The study included 74 participants with paired liver biopsies, categorized by type of treatment (conventional interferon, Pegasys/ribavirin, or no therapy). Patients treated with Pegasys/ribavirin experienced a decrease in fibrosis progression rate and stabilization of time-to-cirrhosis. The untreated group had twice the fibrosis progression rate and a time-to-cirrhosis of 9.09 years, compared with 22.7 years for Pegasys/ribavirin-treated patients. However, among subjects treated with Pegasys/ribavirin, sustained responders and nonresponders had similar fibrosis progression rates and staging. The authors concluded that, “In patients with HIV/HCV coinfection [Pegasys] based treatment produced regression or stable fibrosis in contrast to accelerated progression in those without treatment.”
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