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In This Issue:
Shorter Therapy for HCV Genotypes 1/4
Researchers continue to explore shorter treatment durations for chronic hepatitis C patients who respond rapidly to interferon-based therapy. As reported in the August 2008 issue of Gastroenterology, P. Ferenci and colleagues from Austria studied more than 500 genotype 1 and 4 patients treated with 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-based ribavirin. Among 143 patients who achieved rapid virological response (RVR) – undetectable HCV RNA at week 4 – and completed 24 weeks of therapy, the overall sustained virological response (SVR) rate 24 weeks after treatment completion was 80.4% (78.8% for genotype 1; 86.7% for genotype 4). Younger age, lower body fat, low baseline HCV viral load (≤ 400,000 IU/mL), and genotype 4 were significant predictors of RVR. Once a patient achieved RVR, however, no additional baseline factors significantly predicted sustained response. “This prospective study confirms that a 24-week regimen of peginterferon alfa-2a plus ribavirin 1000-1200 mg/day is appropriate in genotype 1 and 4 patients with a low baseline HCV RNA level who achieve an RVR by week 4 of therapy,” the researchers concluded.
Other recent studies of tailored treatment duration based on early response were reviewed in the February 2008 HCV Advocate, and shorter therapy for genotype 2/3 was discussed in the August 2008 issue.
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Directly Targeted Therapy
Targeted antiviral drugs that interfere with specific steps of the HCV lifecycle continue to progress through the development pipeline. Furthest along is telaprevir (VX-950), an HCV NS34A protease inhibitor. While promising findings from the ongoing Phase 2 PROVE trials have been reported at recent conferences, results from a smaller, earlier trial of telaprevir combination therapy were reported in the August 2008 Journal of Hepatology. E. Lawitz and colleagues assessed the safety and activity of 750 mg thrice-daily telaprevir plus 180 mcg/week Pegasys and 1000-1200 mg/day ribavirin for 28 days in 12 treatment-naive genotype 1 patients; participants could then continue on Pegasys plus ribavirin without telaprevir for 44 more weeks. All 12 treated patients experienced RVR. All eight who completed the full course of Pegasys plus ribavirin achieved SVR, as did one person treated for only 22 weeks. Telaprevir combination therapy was well-tolerated, with no serious adverse events or treatment discontinuations; 42% experienced pruritus (itching), which resolved during or after telaprevir treatment.
Two recently published studies looked at R1626, an oral prodrug metabolized in the body to R1479, an HCV NS5B polymerase inhibitor. In the August 2008 issue of Hepatology, S. Roberts and colleagues described a Phase 1b study in which 47 treatment-naive genotype 1 chronic hepatitis C patients were randomly assigned to receive R1626 at doses of 500 mg, 1500 mg, 3000 mg, or 4500 mg, or else placebo, twice daily for 14 days. R1626 was efficiently converted to R1479, and it produced dose-dependent and time-dependent reductions in HCV viral load. After 14 days, mean HCV RNA decreased by 0.32, 1.2, 2.6, and 3.7 log10, respectively, in the four ascending dose arms. Doses of 3000 mg or less were generally well-tolerated, but adverse side effects – notably hematological (blood cell) toxicities – increased at the 4500 mg dose. No resistance mutations were detected.
In another study reported in the same issue, P. Pockros and colleagues randomly assigned 104 previously untreated genotype 1 patients to receive 1500 or 3000 mg twice-daily R1626 in combination with Pegasys, with or without ribavirin, for 28 days. At week 4, HCV RNA was undetectable in 29% of patients in the 1500 mg R1626/Pegasys arm, 69% in the 1500 mg R1626/Pegasys arm, 74% in the 1500 mg R1626/Pegasys/ribavirin arm, and only 5% in the standard therapy (Pegasys/ribavirin without R1626) arm. Mean HCV RNA decreases were 3.6, 4.5, 5.2, and 2.4 log10, respectively. The researchers reported synergistic activity between R1626 and both pegylated interferon and ribavirin. Most adverse events were mild or moderate and no resistance was observed. However, serious (grade 4) neutropenia (low white blood cell count) was common – 48%, 78%, and 39%, respectively, in the R1626 arms, versus 10% in the standard therapy arm – and was the main reason for dose reduction.
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Resistance to HCV Protease Inhibitors
As reported in the September 12, 2008 Journal of Infectious Diseases, D.J. Bartels and colleagues analyzed the natural prevalence of HCV variants with pre-existing resistance to NS34A protease inhibitors in patients who had not received prior treatment. Out of 570 treatment-naive individuals studied, 98% had wild-type HCV1 without resistance mutations. The researchers detected four mutations that confer resistance to protease inhibitors: V36M (0.9%), R155K (0.7%), V170A (0.2%), and R109K (0.2%). V36M, R109K, and V170A all confer low-level resistance (< 7-fold) to protease inhibitors in cultured cells; R155K confers low-level resistance to telaprevir and boceprevir (SCH 503034), but high-level resistance (< 70-fold) to BILN 2061 and ITMN-191. Four of five patients with the V36M or R109K variants who were treated with telaprevir plus Pegasys, with or without ribavirin, for 8-24 weeks achieved SVR (the fifth was lost to follow-up). Among individuals with the R155K variant, telaprevir/Pegasys/ribavirin produced greater antiviral activity than Pegasys/ribavirin alone, though response was reduced compared to patients with wild-type virus. “High levels of naturally occurring protease inhibitor-resistant variants were uncommon (< 1% each) in HCV treatment-naive patients,” the researchers concluded. “As new HCV agents are evaluated in clinical trials, it will be important to monitor the effect of baseline variants on sensitivity.”
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Albumin interferon (albinterferon or Albuferon) consists of interferon alfa fused to the human protein albumin, enabling it to last longer in the body. As reported in the August 2008 issue of Hepatology, S. Zeuzem and an international team of colleagues conducted an open-label study in which 458 treatment-naive genotype 1 chronic hepatitis C patients were randomly assigned to receive subcutaneous albumin interferon alfa-2b at doses of 900 or 1200 mcg once every two weeks or 1200 mcg once every four weeks, or else 180 mcg once-weekly pegylated interferon (standard of care), all in combination with 1000-1200 mg/day weight-based ribavirin for 48 weeks. In an intent-to-treat analysis, SVR rates were 58.5%, 55.5%, and 50.9%, respectively, in the three albumin interferon arms, compared with 57.9% in the pegylated interferon arm. Rates of discontinuation due to adverse events were 9.3%, 18.2%, and 12.1%, respectively, in the albumin interferon arms versus 6.1% with pegylated interferon. At week 12, participants receiving 900 mcg albumin interferon once every two weeks missed significantly fewer workdays due to treatment-associated side effects than those taking pegylated interferon (1.1 vs 4.3 days). The investigators concluded that albumin interferon administered once every two or four weeks “may offer comparable efficacy, with an improved dosing schedule,” compared with pegylated interferon.
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Studies have produced widely varying estimates of liver fibrosis progression in people with hepatitis C. As reported in the August 2008 issue of Hepatology, H.H. Thein and colleagues conducted a systematic literature review and meta-analysis to estimate annual liver disease progression rates according to current fibrosis stage. Using a mathematical model, they analyzed data from 111 studies that included more than 33,000 total chronic hepatitis C patients. The estimated annual probability of progressing from F0 (absent) to F1 (mild) fibrosis was 11.7%, from F1 to F2 (moderate) was 8.5%, from F2 to F3 (advanced) was 12.0%, and from F3 to F4 (severe fibrosis or cirrhosis) was 11.6%. Duration of infection was the most consistent factor significantly associated with fibrosis progression. After 20 years of infection, the estimated prevalence of cirrhosis was 16% across all studies, though the rate was more than twice as high in studies conducted in clinical settings (18%) compared with non-clinical settings (7%). The researchers concluded that these findings support non-linear fibrosis progression, and noted that “Estimates of progression to cirrhosis from studies conducted in clinical settings were lower than previous estimates.”
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HCV Neutralizing Antibodies in Coinfected Patients
While approximately one-quarter of people initially infected with HCV spontaneously clear the virus without treatment, HIV positive people are more likely to develop chronic infection and tend to experience faster liver disease progression. As reported in the August 1, 2008 Journal of Infectious Diseases,S. Castelain and colleagues from France assessed HCV-specific neutralizing antibody responses in 37 HCV monoinfected individuals and 37 HIV/HCV coinfected people with well-controlled HIV disease, matched for age, sex, and HCV genotype. Coinfected patients had mean HCV neutralizing antibody titers significantly higher than those of HCV monoinfected individuals, which, the researchers suggested, “could help worsen the outcome of HCV infection” and “favor starting HCV therapy as soon as possible in coinfected patients.”
1 Wild type virus: that used as a standard for a given species or variety of organism, usually assumed to be the one found in nature.
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