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In This Issue:
• Sustained Response Reduces HCC and Liver-Related Death
• Interferon Gamma Does Not Reverse Fibrosis
• Treatment of Nonresponders
• Early Response in HIV/HCV Coinfected Patients
• Does HAART Increase Liver Enzymes?
Sustained Response Reduces HCC and Liver-Related Death
Sustained suppression of hepatitis C virus (HCV) is used as a measure of treatment success, but the ultimate goal is reducing liver disease progression and death. As reported in the March 2007 issue of Hepatology, S. Bruno and colleagues assessed the long-term risk of liver-related complications, hepatocellular carcinoma (HCC), and liver-related mortality in 920 patients with cirrhosis who were treated with conventional interferon monotherapy between January 1992 and December 1997; 124 subjects (13.5%) achieved sustained virological response (SVR). Over a mean 96 months of follow-up, patients who achieved SVR had significantly lower incidence rates of liver-related complications (0 vs 1.88 per 100 person-years [PY]), HCC (0.66 vs 2.10 per 100 PY), and liver-related death (0.19 vs 1.44 per 100 PY) compared with nonresponders. Those who did not achieve SVR were nearly three times more likely to develop HCC, and about seven times more likely to die from liver disease. Pegylated interferon plus ribavirin has not been in use long enough to assess long-term clinical outcomes, but given that this regimen increases the likelihood of SVR, it may be expected to reduce rates of liver-related complications and death even more than conventional interferon monotherapy.
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Interferon Gamma Does Not Reverse Fibrosis
Along with HCV suppression, researchers have also studied therapies to slow or reverse liver fibrosis in patients with chronic hepatitis C; one such agent is interferon gamma-1b, a cytokine with antifibrotic and antiproliferative activity. In the March 2007 issue of Hepatology, P.J. Pockros and colleagues reported on a study in which nearly 500 participants with compensated liver disease (Ishak fibrosis scores of 4-6) were randomly assigned to receive 100 mcg interferon gamma, 200 mcg interferon gamma, or placebo three times weekly for 48 weeks. Among 420 patients with available pre- and post-treatment liver biopsy results, there was no significant difference after treatment in the proportions with improved fibrosis scores (12.1%, 12.4%, and 16%, respectively). The rates of death were also similar in all three treatment arms. The researchers concluded that, “Interferon gamma-1b therapy was not able to reverse fibrosis in patients with advanced liver disease for 1 year.” However, they noted that individuals who achieved increased levels of the chemokine interferon-inducible T-cell-alpha chemoattractant (I-TAC) did show fibrosis improvement, suggesting that the drug may be useful for a subset of patients.
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Treatment of Nonresponders
Chronic hepatitis C patients who do not respond or relapse after an initial attempt at treatment have limited options, one of which is a second course of therapy. As reported in the March 2007 issue of Digestive Diseases and Sciences, R. Cheruvattath and colleagues evaluated outcomes in 20 subjects who were retreated with pegylated interferon (PegIntron or Pegasys) plus ribavirin after failing to achieve sustained response with an initial course of the same regimen. Twelve subjects had received no prior treatment before their first course of pegylated interferon plus ribavirin, while the rest had tried previous regimens. After the second course of pegylated interferon plus ribavirin, just 2 of 20 patients (10%) achieved SVR. “These results suggest marginal benefit of retreatment of patients with chronic HCV with another course of pegylated interferon plus ribavirin,” the researchers concluded. Other studies have shown that retreatment response rates are higher for patients who previously received suboptimal regimens, such as the older conventional form of interferon or interferon monotherapy without ribavirin.
In a related study reported in the April 2007 Journal of Hepatology, R. Moucari and colleagues assessed the efficacy of PegIntron plus 1000-1200 mg/day ribavirin in 53 prior relapsers and 101 previous nonresponders to interferon/ribavirin combination therapy. Overall, 28.6% achieved SVR. Prior relapsers were significantly more likely to attain SVR than prior nonresponders (59% vs 13%). Patients with non-1 HCV genotypes, mild-to-moderate (as opposed to severe) fibrosis, and HCV viral load less that 2 million copies/mL were also more likely to achieve sustained response. Rapid virological response (RVR) at week 4 and early virological response (EVR) at week 12 had high negative predictive values for SVR (94% and 97%, respectively), but relatively low positive predictive values (52% and 49%, respectively).
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Early Response in HIV/HCV Coinfected Patients
Predicting early in the course of therapy which patients will achieve sustained response can allow the rest to avoid the side effects and expense of additional treatment that is unlikely to be successful. Two recent studies looked at the predictive value of early and rapid response in HIV/HCV coinfected individuals. As reported in the February 1, 2007 Journal of Acquired Immune Deficiency Syndromes, M. Laguno and colleagues studied 95 coinfected patients treated with PegIntron or conventional interferon, both with ribavirin. Overall, 69% achieved early virological response at week 12 (80% with PegIntron and 56% with conventional interferon), and 43% went on to achieve SVR (56% and 30%, respectively), giving a positive predictive value of 64% (70% with PegIntron and 55% with conventional interferon). In contrast, no patients who experienced less than a 2-log reduction in HCV RNA by week 12 achieved SVR, giving a negative predictive value of 100%.
A second study, reported in the February 19, 2007 issue of AIDS, looked at any even earlier cut-off point: rapid virological response at 4 weeks. M. Crespo and colleagues assessed 35 coinfected patients with genotype 3 HCV enrolled in a trial of PegIntron versus conventional interferon, both with ribavirin. Overall, 78% of patients receiving PegIntron and 53% receiving conventional interferon achieved SVR. At 4 weeks, 49% overall had HCV RNA below 50 IU/mL and 63% had viral loads below 600 IU/mL. Among these rapid responders, 88% and 86%, respectively, achieved SVR. In contrast, just 44% of subjects who still had HCV RNA levels of at least 50 IU/mL and 31% with at least 600 IU/mL at week 4 achieved SVR; relapse rates in these groups were 33% and 50%. The researchers concluded that monitoring early response may be used to tailor duration of therapy in HIV/HCV coinfected as well as HCV monoinfected individuals.
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Does HAART Increase Liver Enzymes?
Liver toxicity is a potential concern for individuals receiving antiretroviral therapy (HAART), especially patients with chronic hepatitis B or C. As reported in the March 12, 2007 issue of AIDS, P. Cicconi and colleagues studied the association between liver enzyme elevation and HAART use among more than 5000 participants in the ICoNA study; about half (47.6%) were coinfected with HBV and/or HCV. Overall, 275 episodes of ALT elevation (greater than 5 x baseline, or greater than 3.5 x baseline if the initial level was above 40 IU/L) occurred during 18,259 person-years of follow-up. Coinfected subjects were about five times more likely than HIV monoinfected patients to experience ALT elevation. However, the use of HAART did not significantly increase the risk of liver enzyme elevation for either coinfected or HIV monoinfected patients. The researchers concluded that HIV/HCV and HIV/HBV coinfection are associated an with increased risk of liver enzyme elevation, but that there is no added risk associated with the use of HAART.
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