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In This Issue:
• Factors that Predict SVR
• Relapse in HIV/HCV Coinfected Patients
• Race/Ethnicity and Treatment Response
• Taribavirin Comparable to Ribavirin
• Early Ribavirin Pharmacokinetics in Coinfected Patients
Factors that Predict SVR
Various factors affect response to treatment for chronic hepatitis C, and these may differ by HCV genotype. As reported in the July 2007 issue of Hepatology, L.I. Backus and colleagues performed a retrospective analysis to identify predictors of sustained virological response (SVR) to pegylated interferon plus ribavirin among 5944 patients (80% with genotype 1) treated at 121 Department of Veterans Affairs facilities. Overall SVR rates were 20% for genotype 1, 52% for genotype 2, and 43% for genotype 3¾lower than the rates typically seen in clinical trials. Further, a large proportion of patients discontinued treatment prematurely: 68%, 34%, and 41%, respectively.
Among genotype 1 patients, factors that decreased the likelihood of SVR were being African-American; having clinical liver disease or diabetes; low cholesterol, hemoglobin, or platelet levels; and treatment at a facility that saw fewer patients. Factors that increased the likelihood of SVR were low pre-treatment HCV viral load, elevated ALT, and use of pegylated interferon alfa-2a (Pegasys) rather than pegylated interferon alfa-2b (PegIntron). Among genotype 2 patients, high body mass index, prior use of interferon, and low platelet count predicted non-response, while only low viral load predicted SVR. For genotype 3 patients, the only factor that seemed to affect the likelihood of sustained response was use of Pegasys. Across all genotypes, those taking Pegasys were about 40% more likely to achieve SVR compared with those taking PegIntron. The researchers concluded that for patients treated in a routine medical care setting, “multiple factors including form of pegylated interferon received affect the SVR rate for genotype 1 patients.” But, they added, “Few of these factors affect the rate for genotype 2 patients, and even fewer do so for genotype 3 patients.”
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Relapse in HIV/HCV Coinfected Patients
Spanish researchers evaluated factors that predict SVR in HIV/HCV coinfected patients, who tend to have lower sustained response rates than people with HCV alone; results were published in the August 1, 2007 Journal of Acquired Immune Deficiency Syndromes. M. Nunez and colleagues studied 389 coinfected participants in the PRESCO trial (about half with genotype 1) who were treated with 180 mcg/week Pegasys plus 1000-1200 mg/day ribavirin. Patients who experienced early virological response at week 12 continued treatment for either 48 or 72 weeks if they had genotype 1 or 4, and either 24 or 48 weeks if they had genotype 2 or 3. Overall, about two-thirds achieved an end-of-treatment response: 55% with genotype 1, 90% with genotype 2 or 3, and 41% with genotype 4. During the post-treatment follow-up period, 33% with genotype 1, 18% with genotype 2 or 3, and 21% with genotype 4 experienced HCV relapse. The factors that best predicted relapse were high pre-treatment HCV viral load (≥ 500,000 IU/mL) and lack of rapid virological response (undetectable HCV RNA at week 4). Use of antiretroviral therapy for HIV predicted relapse less strongly. There was a trend toward a higher relapse rate in patients with genotype 1 or 4 compared with 2 or 3, but the difference did not reach statistical significance. Extended treatment duration also did not appear to reduce the risk of relapse.
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Race/Ethnicity and Treatment Response
Studies consistently show that African-Americans do not respond as well as whites to interferon-based therapy, but other racial/ethnic groups have been less well studied. In the July 19, 2007 online edition of the American Journal of Gastroenterology, S. Missiha and colleagues with the Canadian Pegasys Expanded Access Group reported data from a study to assess response rates in Asian patients. They collected retrospective data on treatment-naive patients starting therapy with 180 mcg/week Pegasys plus 800 mg/day ribavirin. SVR occurred in 65% of the 52 Asian patients, compared with 45% of the 384 white patients. After adjusting for other factors, being Asian remained an independent predictor of sustained response. Consistent with past studies, other factors predicting SVR were HCV genotype, body mass index, degree of fibrosis, and ribavirin adherence. The researchers concluded that these findings suggest “a genetic influence on the antiviral response.”
In another recent study, published in the August 2007 issue of Hepatology, H.R. Rosen and colleagues aimed to learn more about why African-Americans respond poorly to treatment. The researchers examined type 1 CD4 helper T-cell (Th1) immune responses to HCV proteins and cytomegalovirus (CMV) antigens in 187 white and 187 African-American patients with chronic genotype 1 hepatitis C using an interferon-gamma ELISPOT assay. Th1 immune responses specific to HCV core protein and combined HCV antigens were significantly lower in African-Americans compared with whites, even after adjusting for factors including sex, ALT level, fibrosis severity, and HCV viral load. In contrast, responses to CMV antigens were comparable in the two groups. Different prevalence of HLA class II alleles (which present antigens for recognition by T-cells) in black and white patients did not account for the differences in anti-HCV immune response. Further, they found that patients who had good pre-treatment HCV-specific CD4 T-cell responses were more likely to achieve SVR with pegylated interferon plus ribavirin.
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Taribavirin Comparable to Ribavirin
Ribavirin can cause hemolytic anemia that sometimes necessitates dose reduction or drug discontinuation, which increases the risk of HCV relapse after treatment. As reported in the July 2007 Journal of Hepatology, R. Gish and colleagues studied the efficacy and safety of taribavirin (Viramidine), a ribavirin pro-drug that appears to cause less red blood cell destruction. In this Phase 2 study, 180 patients were randomly assigned to receive 180 mcg/week Pegasys plus either taribavirin at doses of 800, 1200, or 1600 mg, or 1000-1200 mg ribavirin. At 12 weeks, similar proportions of patients had undetectable HCV RNA: 38% with 800 mg taribavirin, 42% with 1200 mg taribavirin, 49% with 1600 mg taribavirin, and 49% with ribavirin. The best end-of-treatment response and SVR rates were seen in the 1200 mg taribavirin and ribavirin arms (SVR 37% and 44%, respectively; not a statistically significant difference). However, only 4% of patients taking taribavirin developed severe anemia (hemoglobin < 10 g/dL) compared with 27% of those taking ribavirin. “Given with interferon, taribavirin produced SVR rates comparable to those of ribavirin, with a lower occurrence of anemia,” the researchers concluded.
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Early Ribavirin Pharmacokinetics in Coinfected Patients
In another study published in the July 2007 Journal of Hepatology, H. Dahari and colleagues assessed whether early ribavirin pharmacokinetics differed between HIV/HCV coinfected individuals who achieved SVR and nonresponders. The study included 24 treatment-naive coinfected patients who received 1.5 mcg/kg PegIntron plus 13.6 mg/kg ribavirin for up to 48 weeks. Six of 24 patients (25%) achieved SVR. During the first four weeks of treatment, median plasma ribavirin levels and areas under the curve (a measure of drug concentration over time) were significantly lower in sustained responders compared with nonresponders. However, compared with levels at weeks 2 and 4, ribavirin concentrations in sustained responders—but not nonresponders—continued to rise through week 8. Also, at week 4, declines in hemoglobin (an indication of anemia due to ribavirin) were greater in sustained responders compared with nonresponders. Changes in HCV RNA and ALT levels at week 1 identified likely sustained responders better than plasma ribavirin levels. “We conjecture that intracellular ribavirin accumulation may be enhanced early in treatment in coinfected sustained responders,” the researchers wrote.
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