Treatment of Chronic Hepatitis C Virus Infection: Response At Four Weeks Predicts Sustained Response
ABSTRACT & COMMENTARY
Synopsis: The strongest predictor of a virological sustained response to interferon-a therapy in patients with chronic HCV infection was a decrease in serum HCV RNA of at least 3 log10 after four weeks of drug administration.
Source: Zeuzem S, et al. Quantification of the initial decline of serum hepatitis C virus RNA and response to interferon alfa. Hepatology 1998;27:1149-1156.
Zeuzem and colleagues in frankfurt evaluated 70 patients with chronic hepatitis C virus (HCV) infection in order to determine the predictive value of the quantitative change in serum HCV RNA after one month of therapy with interferon a. Thirteen patients (19%) were infected with genotype 1a, 30 (43%) with genotype 1b, 10 (14%) with genotypes 2a-c, 13 (19%) with genotype 3a, and four (6%) with genotype 4. The mean age was 45.8 ± 12.5 years; 67% were male. Hepatitis B virus infection, as well as HIV infection, were reasons for exclusion.
Patients received 3 million units recombinant IFN-a2a (rIFN-a2a; Roferon; Hoffman-la Roche) subcutaneously three times each week for 12 months and were then followed for an additional six months. After four weeks of therapy, 42 (60%) patients had a less than 1 log10 change in HCV RNA. Of the remaining patients, nine (13%) had a decrease of 1-3 log10, while 19 (27%) had a decrease of serum HCV RNA of greater than 3 log10. The response rates at three months were almost identical to those at one month. After three months, 40 nonresponders were then given 6 million units of IFN-a2a three times weekly for the next nine months; a subsequent decrease in serum HCV RNA greater than 3 log was observed in eight (20%).
HCV RNA was undetectable at the end of treatment in 21 (30%) patients, but remained undetectable six months later in only nine (13%) of the 70 patients. Eight of the 40 patients who underwent dose escalation had undetectable HCV RNA at 12 months, but viral copies were again detectable at 18 months in four of these. Seven of the nine patients with a sustained response were infected with HCV subtypes 2a-c or 3a. All patients with a sustained response had a decreased viral load of at least 3 log10 at four weeks of treatment.
The only factor independently associated with end-of-treatment outcome by multivariate analysis was the change in serum HCV RNA after one month of therapy, accounting, by stepwise discriminant-function analysis, for 37% of the variance in prediction of a sustained virological response (P < 0.0001). The latter analysis found that HCV genotype accounted for only 7% of the predictive variance (P = 0.03).
COMMENT BY STAN DERESINSKI, MD, FACP
Previous studies have consistently reported that HCV genotype and the degree of pretreatment viremia are important predictors of response to therapy with IFN-a. In addition, some studies have reported that a negative test for serum HCV RNA after one or three months of therapy is predictive of a response at the end of therapy. The variable (and often low) sensitivity of viral detection by the individual test systems used, however, makes this observation assay-specific. Furthermore, it does not take into account the likelihood that the time required to eliminate viremia is dependent upon the pretreatment serum HCV RNA concentration.
Assuming almost immediate and complete interference with HCV replication, and taking into account the reported serum half-life of the virus of approximately two days, the quantity of virus in the blood would decrease by a factor of 214 during the first 28 days (14 viral half-lives) of therapy (Zeuzem S, et al. Hepatology 1996;23:366-371). As Zeuzem and colleagues point out, with an assay with a sensitivity of 100 copies/mL, a patient with pretreatment serum HCV RNA in excess of 2 million copies/mL with complete inhibition of viral replication will still have detectable virus after four weeks of therapy.
This study found that the most important predictor of a sustained suppression of viremia was the quantitative decrease in serum HCV RNA after four weeks of therapy. This observation largely eliminates the need for an ultrasensitive assay in predicting the end of therapy response. It also supports the authors' conclusion that consideration be given to discontinuation of treatment with IFN-a at four weeks in patients who fail to achieve a decrease in serum of HCV RNA of at least 3 log10. Doubling the dose of IFN-a does not appear to be an effective alternative for those patients.
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