Hepatitis C Treatment and Recipients

Hepatitis C Treatment in Liver Transplant Recipients

In the June 2007 Journal of Hepatology, M. Angelico and colleagues reported data from a randomized trial of pegylated interferon alfa-2a (Pegasys) monotherapy versus Pegasys plus ribavirin in 42 non-cirrhotic liver transplant recipients with recurrent hepatitis C; participants were treated for 48 weeks. In an intention-to-treat analysis, early virological response (EVR, defined as an HCV RNA decrease of at least 2 logs at week 12) occurred in 76% of the monotherapy patients and 71% of those in the combination therapy group. Sustained virological response (SVR, defined as undetectable HCV RNA 24 weeks after completion of therapy) was achieved in 38% and 33%, respectively. EVR had positive predictive values for SVR of 50% and 47%, respectively, and none of the patients who failed to achieve EVR went on to become sustained responders. Six patients in the monotherapy group and seven in the combination therapy group discontinued treatment prematurely, while seven and eight subjects, respectively, required Pegasys dose reduction. The researchers concluded that Pegasys, with or without ribavirin, led to sustained response in one-third of transplant recipients with recurrent hepatitis C, adding that, “The low SVR rate is mainly due to inability to sustain full doses of antivirals and lack of the booster effect of ribavirin.”

Ursodeoxycholic Acid for Liver Inflammation
Many patients with hepatitis C – especially those with genotype 1 – fail to achieve SVR with interferon-based therapy, and could thus benefit from treatments that reduce liver inflammation and fibrosis. As reported in the June 25, 2007 advance online edition of Gut, M. Omata and colleagues assessed the effect of oral ursodeoxycholic acid (UDCA) on serum biomarkers in nearly 600 prior non-responders with elevated ALT levels; participants were randomly assigned to receive UDCA at doses of 150, 600, or 900 mg/day for 24 weeks. Levels of the liver enzymes ALT, AST, and GGT decreased by week 4, then remained constant for the remainder of the drug-administration period. All three biomarkers decreased significantly less in the 150 mg/day arm compared with the two higher dose groups. While overall changes in ALT and AST did not differ between the 600 and 900 mg/day groups, GGT was significantly lower in the 900 mg/day group; however, ALT decreased significantly more in the 900 mg/day group among patients whose baseline GGT level exceeded 80 IU/L. Adverse events were reported by 19% of the patients in all three dose groups, and serum HCV RNA levels did not change in any group. “A 600 mg/day UDCA dose was optimal to decrease ALT and AST levels in chronic hepatitis C patients,” the researchers concluded. “The 900 mg/day dose decreased GGT levels further, and may be preferable in patients with prevailing biliary injuries.”

Chronic Liver Disease and Cardiovascular Risk
Past studies have produced conflicting evidence regarding the prevalence of cardiovascular disease risk factors in people with chronic hepatitis C. As reported in the June 2007 Journal of Hepatology, G. Targher and colleagues analyzed carotid intima-media thickness (IMT) – a measure of the health of the carotid arteries in the neck, and an early indicator of atherosclerosis – in 35 patients with chronic hepatitis B, 60 with chronic hepatitis C, 60 with nonalcoholic steatohepatitis (NASH), and 60 healthy control subjects. Carotid IMT measurements were lowest in the healthy controls, intermediate in patients with HBV or HCV, and highest in those with NASH. These differences were minimally affected by adjustment for age, sex, body mass index, smoking, low-density lipoprotein (LDL) cholesterol levels, insulin resistance, and presence of the metabolic syndrome. “These data suggest that NASH, HCV, and HBV are strongly associated with early atherosclerosis independent of classical risk factors,” the investigators concluded.


Treatment in HIV/HCV Coinfected Patients
Two recent studies assessed response to hepatitis C treatment in patients with HIV/HCV coinfection, a population that typically does not respond as well to interferon-based therapy. As reported in the May 15, 2007 issue of Clinical Infectious Diseases, C.M. Behler and colleagues assessed whether interferon and/or ribavirin dose modification due to side effects, or the use of hematopoietic growth factors, influenced treatment outcomes in the ACTG A5071 study. A total of 133 coinfected participants were randomly assigned to receive ribavirin plus either conventional interferon or Pegasys for 48 weeks. Doses were modified in patients with adverse events including hematological toxicity (e.g., anemia or neutropenia), and growth factors were administered as needed (e.g., erythropoietin for anemia, G-CSF for neutropenia). Patients treated with Pegasys were more likely to require dose reduction or treatment discontinuation than those treated with conventional interferon. The majority of interferon dose reductions were due to neutropenia, while most ribavirin dose reductions were due to anemia. The incidence of side effects did not differ with regard to CD4 cell count or the use of antiretroviral therapy – including AZT (Retrovir), which is known to cause anemia. Participants who underwent dose modification for any reason were significantly less likely to achieve SVR and/or histological response. Hematological toxicity itself was not directly linked with clinical outcomes, but use of hematopoietic growth factors was associated with increased SVR and histological response rates. “Dose modifications for anti-HCV therapy may adversely affect the outcome of treatment of HCV in individuals who are coinfected with HIV,” the investigators concluded, adding that, “The use of hematopoietic growth factor support may be associated with an improved clinical response to therapy.”

Importance of Adequate Ribavirin
In the second study, reported in the June 2007 Journal of Viral Hepatitis, B. Ramos and colleagues analyzed the relationship between ribavirin dose and treatment outcomes among HIV/HCV coinfected patients in three trials. In the Spanish PRESCO study, coinfected patients received Pegasys plus 1000-1200 mg/day weight-based ribavirin. In the PISG trial, HIV negative subjects were treated with the same regimen. In the Pegasys combination therapy arm of the pivotal APRICOT trial, coinfected patients received a fixed dose of 800 mg/day ribavirin. Among genotype 1 patients, rates of rapid virological response (RVR, defined as undetectable HCV RNA at week 4) were 33.3% in PRESCO, 31.2% in PISG, and 13% in APRICOT. For patients with genotypes 2 or 3, the corresponding RVR rates were 83.7%, 84.2%, and 37%. Both RVR and EVR rates were similar in the two studies that used the higher weight-based ribavirin dose, but lower in the trial that used the lower fixed dose, leading the researchers to conclude that, “Prescription of high ribavirin doses enhances the early virological response to HCV therapy in HCV/HIV coinfected patients, with results approaching those seen in HCV-monoinfected patients.”



By: Liz Highleyman