Viral dynamics and response differences in HCV-infected African American and white patients treated with IFN and ribavirin

Abstract

Studies have suggested that African American patients infected with hepatitis C virus (HCV) do not respond as well to treatment with interferon (IFN) as white patients. Here we analyzed the difference in the viral kinetic response between genotype 1 HCV-infected African American patients (n ‫؍‬ 19) and white patients (n ‫؍‬ 16). Patients were treated with 10 mIU IFN-␣2b daily with or without ribavirin for 1 month followed by 3 mIU IFN-␣2b 3 times a week with ribavirin. The kinetic parameters (⑀, treatment effectiveness at inhibiting virion production; ␦, loss rate of virus-producing cells; c, clearance rate of free virions; , delay until viral decline starts) were estimated from the viral load decay profiles using a previously described mathematical model. Differences in early kinetic parameters and viral negativity frequencies at weeks 4, 12, and 48 were compared. Ribavirin did not appear to enhance any of the viral kinetic parameters, although this may have been due to the high dose of IFN used. African American patients exhibited significantly (P ‫؍‬ .005) lower drug effectiveness (88.6% vs. 98.2%) compared with white patients, accounting for a 0.8 log lower HCV RNA decrease in the first 24 hours of treatment. Significant differences (P ‫؍‬ .006) were also noted for ␦. There was no correlation between any of the viral kinetic parameters and either age, body mass index (BMI), or genotype 1 subtype. No patient achieved viral negativity at weeks 4, 12, or 48 without an ⑀ greater than 90%. The mean viral decline and viral negativity rates were statistically different between the two races; however, when controlling for treatment effectiveness, these differences were no longer apparent. In conclusion, the failure of IFN response in African American patients infected with genotype 1 HCV is in part due to an impaired ability to inhibit viral production. ( H epatitis C virus (HCV) infects 1.0% to 1.5% of the white population and 2.5% to 3.5% of the African American population in the United States. 1,2 In infected white patients, 65% to 75% have genotype 1 virus; in infected African American patients, 90% to 95% are infected with this subtype. [2][3][4] In 1999, Reddy et al. reported that African American patients failed to respond as well to consensus interferon (IFN) and IFN-␣2b treatment as white patients, in part due to a greater rate of genotype 1 infection in African American patients. 4 These lower response rates have been confirmed by others for African American patients treated with IFN monotherapy. [5][6][7] McHutchison et al. reported that combination therapy with IFN plus ribavirin partly overcame these impaired response rates, 5 although preliminary results from other sites have not shown consistently improved results with combination therapy. [7][8][9] The kinetics of HCV RNA decline following the initiation of IFN therapy have recently been described. [10][11][12][13][14] Following an initial dose of IFN, there is a rapid dosedependent decline in HCV RNA levels of 0.5 to 2.0 logs over the first 24 hours...

New kinetic models for the hepatitis C virus

“…This effect is predicted to be entirely in the second-phase decay of HCV RNA. These predictions are in agreement with recent experiments, 6,14,36 such as those observing that with high daily dosing of IFN, ribavirin addition does not affect first-phase decay (⑀), 14 and the observation by Hermann et al 6 of an increased infected cell loss rate in patients treated with PEG-IFN ␣-2a in combination with ribavirin, compared with patients treated with pegylated interferon ␣-2a alone. Thus, the model reconciles the seemingly conflicting observations that ribavirin addition enhances viral load decline in some cases but not in others.…”

“…35 An immune modulatory effect would enhance the second-phase slope regardless of interferon effectiveness, contrary to these observations. 6,14,36 Lastly, the model predicted long-term response rates that are in good agreement with experiments. This model thus provides a picture of how ribavirin enhances HCV RNA decline and improves the long-term outcome of interferon-based therapy.…”

“…In nonresponders, there may be no first-or second-phase decline (null response) or a first phase followed by little or no second-phase decline (flat response). In responders, the biphasic HCV RNA decline pattern tends to be seen when high daily doses of IFN are used, 1,3,10,14 and more complex patterns tend to be seen when standard thrice-weekly doses or pegylated forms of IFN are used. 4,6,11,15,16 When daily doses of IFN are given to chronically infected patients, the magnitude of the first-phase decline depends on the dose of IFN given, with 10-MU and 15-MU doses leading to larger declines than a 5-MU dose.…”

“…[17][18][19] The effectiveness of therapy in blocking virion production depends not only on treatment regimens but also on further factors, such as ethnicity and HCV genotype. 10,13,14 Results on the effectiveness in blocking virion production in patients co-infected with HCV and HIV from recent viral kinetic studies are problematic because of small sample sizes and complex patterns leading to a lack of model fit in several patients. [20][21][22] Nevertheless, no large differences have been found in the effectiveness of therapy in blocking virion production in patients with HCV and HIV coinfection compared with those in patients with HCV monoinfection.…”

Viral kinetics during antiviral therapy in patients with chronic hepatitis C and persistently normal ALT levels

“…[15][16][17]23,25,26 Here, viral kinetics in 20 patients with chronic hepatitis C and persistently normal ALT levels and 19 patients with elevated ALT levels were analyzed. The first-phase decline of the viral load is mainly determined by the clearance rate of free viral particles c and the effectiveness of blocking virus production ⑀.…”