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Predictors of Rapid and Early Virological Response to Pegylated Interferon plus Ribavirin in Genotype 1 Hepatitis C Patients

SUMMARY: Low pre-treatment HCV viral load, elevated ALT, normal body weight, less severe liver damage, white race/ethnicity, and adequate ribavirin dosage predicted favorable response to treatment with pegylated interferon plus ribavirin in an analysis of participants in 5 American clinical trials that reflect the general chronic hepatitis C patient population in the U.S., according to a report published in the February 2010 Journal of Viral Hepatitis.

By Liz Highleyman

Maribel Rodriguez-Torres and colleagues performed a retrospective analysis of data from prior studies of generally difficult-to-treat patients, looking for baseline and on-treatment factors associated with treatment response.

The researchers looked at rates of rapid virological response (RVR), or HCV RNA viral load clearance at week 4 after starting therapy, and complete early virological response (EVR), or undetectable viral load at week 12. Both of these early responses predict sustained virological response (SVR), or continued undetectable HCV RNA 24 weeks after completing of treatment.

The analysis included a total of 1550 HCV genotype 1 patients who had been randomly assigned to receive 180 mcg/week pegylated interferon alfa-2a (Pegasys) plus 1000-1200 mg/day weight-adjusted ribavirin for 48 weeks in 5 clinical trials. Among these trials, 3 were "enriched" with harder-to-treat populations, including 1 study in which all 189 patients had high baseline HCV viral load (> 800 000 IU/mL), 1 in which 74% of participants were black (a group known to respond less well to interferon), and 1 in which 47% were Latino, another group with poorer response rates compared with whites and Asians.


Overall, 15.6% of participants across studies achieved RVR and 54.0% achieved complete EVR.
Baseline factors that were significant predictors of RVR included:
Serum HCV RNA 400 000 IU/mL (odds ratio [OR] 7.34);
Alanine aminotransferase (ALT) level > 3 x upper limit of normal (OR 2.01);
Not having liver cirrhosis (OR 1.92);
Age 40 years (OR 1.56);
White, non-Latino race/ethnicity (OR 1.41);
These factors, along with body mass index 27 kg/m2, also predicted complete EVR.
In a multivariate analysis adjusting for these factors, a mean on-treatment ribavirin dose > 13 mg/kg/day independently predicted both RVR and complete EVR (OR 1.69 and 1.24, respectively).
Pegylated interferon dose, however, was not a significant predictive factor.
Blood cell measures were also associated with early response (possibly an indicator of drug doses, since ribavirin can cause anemia and interferon can cause neutropenia, or low neutrophil count).
A larger decrease in neutrophils was a significant predictor of complete EVR but not RVR.
A larger decrease in mean hemoglobin concentration (an indicator of anemia) also predicted complete EVR but not RVR.

In conclusion, the investigators wrote, "several baseline and on-treatment factors were associated with RVR and complete EVR to peginterferon alfa-2a plus ribavirin in difficult-to-treat HCV genotype-1 patients, providing important prognostic information on the antiviral response in a patient cohort that is reflective of the general chronic hepatitis C population."

"The response to antiviral therapy in HCV-infected patients is heterogeneous and, despite increases in SVR rates, treatment outcomes with peginterferon alfa-2a plus ribavirin are not optimal in certain patient populations and might still be improved," the researchers elaborated in their discussion. "Monitoring the early antiviral response to therapy can help identify those patients who are less likely to achieve SVR and therefore provide critical information for the overall management of patients with chronic hepatitis C."

"Optimizing the antiviral response is crucial for accomplishing these goals," they continued. "Since ribavirin dose is one of the only modifiable factors identified in this analysis that is associated with an increase in RVR and complete EVR, physicians may be advised to maintain a higher ribavirin dose to increase the likelihood of achieving SVR."

Fundación de Investigación de Diego, San Juan, Puerto Rico; Johns Hopkins University, Baltimore, MD; Gastrointestinal Unit, Massachusetts General Hospital, Boston, MA; Roche, Nutley, NJ; University of Chicago, Chicago, IL.


M Rodriguez-Torres, MS Sulkowski, RT Chung, and others. Factors associated with rapid and early virologic response to peginterferon alfa-2a/ribavirin treatment in HCV genotype 1 patients representative of the general chronic hepatitis C population. Journal of Viral Hepatitis 17(2): 139-147 (Free full text). February 1, 2010.






















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