Hepatitis C Management:
Management of Special Groups:
|Print Monograph (pdf)|
African Americans have a higher rate of HCV infection.
African Americans are more likely to be infected with HCV genotype 1.
African Americans—males in particular—have a higher incidence of hepatocellular carcinoma.
African Americans are more resistant to IFN-based treatments.
African Americans with HCV infection should be offered antiviral treatment with PEG-IFN and ribavirin.
The role of maintenance therapy to prevent fibrotic progression in African American nonresponders is under active investigation.
African Americans have the highest observed rate of HCV infection among all racial and ethnic groups. At 3.2%, this rate is nearly twice that reported for non-Hispanic whites. Among men aged 40 to 49 years, the rate is nearly 10%. African Americans are more likely to be infected with genotype 1 virus (88%) than are non-African Americans (67%). HCV-infected African Americans have lower baseline ALT levels, are significantly older at presentation, and have less cirrhosis and piecemeal necrosis, but they have a higher incidence of hepatocellular carcinoma, particularly among men.
African Americans have historically been underrepresented in HCV treatment trials. To remedy this situation and to better understand how to manage this population, the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDKD) has launched the Viral Resistance to Antiviral Therapy of Chronic Hepatitis C (VIRAHEP-C) study, which is being conducted at eight medical centers in the United States. In addition to gaining a better understanding of treatment response in African Americans, the NIDDKD is also endeavoring to better define immune responses, viral kinetics, and genetic factors specific to this population.
It has been noted that African Americans have a relative constitutive neutropenia. This finding has caused concern, particularly with the use of PEG-IFNs, because neutropenia is the most common bone marrow toxicity caused by these new compounds. A recent report from the NIH suggests that African Americans did not experience more severe neutropenia when they were exposed to nonpegylated IFN, and the infections seen in this trial did not occur in the neutropenic patients.
African Americans appear to be more resistant to IFN-based treatments for HCV than are other racial groups. Layden-Almer et al conducted an intense viral kinetic study to compare treatment response, early viral kinetics, and viral factors that affect response in 19 whites and 19 African Americans with HCV infection.65 Baseline demographic characteristics, including body mass index, in the two groups were similar with the exception of age—the African Americans were significantly older, a finding that has been described in other studies. Patients were randomized to receive IFN alfa-2b at 10 million IU daily with or without ribavirin for 1 month, followed by IFN alfa-2b at 3 million IU daily with or without ribavirin for 11 months. The addition of ribavirin resulted in no intragroup differences in the inhibition of viral production, the loss rate of virus-producing cells, intrinsic free virion clearance, or the onset of early viral decline in either whites or African Americans.
With respect to intergroup differences, African Americans experienced significantly longer delays before viral levels declined. Moreover, IFN was not as effective in blocking viral production in African Americans. The loss rate of virus-producing cells was also significantly lower. Of interest, no measurable second-phase viral decline was observed in 8 of 15 African Americans; only one white patient experienced a lack of second-phase decline. At 28 days, the total viral decline was 2.5 log smaller in the African Americans (Figure 7, top panel). Intention-to-treat analysis revealed that 50% of whites experienced a sustained virologic response, compared with only 16% of African Americans (p < 0.03). Viral negativity per protocol was 62% in whites and 23% in African Americans (p < 0.05). There was no difference in serum viral half-life between the two groups. The three African American patients who cleared virus had an initial viral load of less than 106 copies/mL.
Both the first and second phases of viral decline were slower in African Americans. However, after correcting for the degree of effectiveness, similarities were seen in the second-phase decline (Figure 7, bottom panel). The seven African American patients who exhibited an IFN effectiveness of greater than 90% experienced a second-phase decline that was similar to that in the white patients. Only two of 15 whites showed an effectiveness of less than 90%, and they experienced an impaired or flat second-phase decline. Of 15 patients overall in whom effectiveness was less than 90%, none cleared virus. In contrast, 11 of 20 patients with greater than 90% effectiveness did achieve a sustained virologic response. The researchers concluded that African American patients are less likely to respond to IFN-based therapy than whites, and that clearly lower IFN effectiveness is a major factor in their poor response.
In a retrospective analysis of a study that compared consensus IFN with IFN alfa-2b, Reddy et al looked at response rates among 40 African Americans and 380 non-Hispanic whites.66 At baseline, the African Americans tended to have higher serum HCV RNA levels than did the whites, a higher prevalence of genotype 1 HCV infection (88% vs. 66%; p = 0.004), and a trend toward less cirrhosis (5% vs. 12%; p = 0.1). Rates of end-of-treatment response and sustained virologic response were lower in the African American cohort (5% and 2%, respectively, in African Americans vs. 33% and 12% in whites).
A subsequent report by McHutchison et al looked at response rates in African Americans and whites with genotype 1 HCV infection who had been treated with a combination of IFN alfa-2b and ribavirin.67They found that the sustained virologic response rates were similar: 23% among the African Americans and 22% among the whites. However, in patients treated with IFN alfa-2b alone, the rate of sustained virologic response was significantly lower in African Americans. These findings suggest that the poorer response rates seen in African Americans in other studies were attributable to the higher prevalence of genotype 1 HCV in African Americans.
Two more recently published well-designed prospective studies68,69 examined whether factors other than genotype 1 may play a role in the differential response to therapy between African Americans and other racial groups. Both studies evaluated 48 weeks of therapy with standard doses of PEG-IFN alfa-2a or -2b plus ribavirin among African American or non-Hispanic white patients, all or virtually all 98%) of whom were infected with HCV genotype 1.
The study by Jeffers et al found a 26% rate of sustained virologic response (95% confidence interval, 21% to 35%) in its 78-patient African American treatment arm.68 Although this was lower than the 39% rate among the study's 28 white patients, it demonstrated that a meaningful number of African Americans with genotype 1 do respond to PEG-IFN and ribavirin therapy. No unexpected adverse events occurred in the African American patients. Notably, this study clarified previous questions about whether early virologic response has the same predictive value in African Americans as in other patients. The absence of a virologic response at 12 weeks of therapy had a 100% negative predictive value for a sustained virologic response among African Americans in this study (Figure 8), confirming that the 12-week stopping rule does indeed apply to African Americans when sustained virologic response is the treatment goal. Improvements in fibrosis score were seen in 25% of the 53 African American patients who underwent paired liver biopsies.
Muir et al reported sustained virologic response in 19% of the 100 African Americans in their prospective study, compared with 52% of white patients. Although the African American patients weighed significantly more than their white counterparts and were significantly more likely to have diabetes mellitus and hypertension, multivariate analysis showed that race was the only variable significantly associated with the difference in response rates between the two groups. Virologic, immunologic, genetic, or IFN-signaling mechanisms may contribute to these racial differences in response to IFN-based therapy.
African Americans with HCV infection should be offered antiviral therapy. Their regimen should be the same as for patients in other racial groups, even though the response rate in African Americans is not as high. As in other patient groups, treatment discontinuation should be considered in the absence of an early virologic response after 12 weeks of therapy.
The potential role of maintenance therapy with PEG-IFN to prevent fibrotic progression in African Americans who do not achieve virologic response is a question under active investigation. The high incidence of hepatocellular carcinoma among HCV-infected African American men makes this issue particularly urgent. While histologic improvement may be a valuable secondary goal of IFN-based therapy in these patients, there is currently no good evidence that such an approach yields an overall benefit for patients. Results from the ongoing HALT-C and VIRAHEP-C studies are expected to clarify this question.