African Americans and Hepatitis C Virus Infection

As the most common cause of liver-related deaths, hepatitis C virus (HCV) is now regarded as a major health problem in the US. HCV is thought to cause approximately 10,000 deaths annually in the US. [1] Unfortunately, that number is expected to increase threefold by 2020. [2]

In the US, people of all races are adversely affected by HCV infection. However, for reasons that are not yet understood, African Americans have disparate clinical features (e.g., response to therapy) and more complications from HCV infection than Caucasians.

The source of the present summary text is a Review Article by Brian Pearlman, MD, “Hepatitis C Virus Infection in African Americans,” published in the January 1, 2006 issue of Clinical Infectious Diseases. Dr Pearlman is affiliated with the Center for Hepatitis C, Atlanta Medical Center, Medical College of Georgia, and Emory University School of Medicine, Atlanta, Georgia.

“The aim of this review is to highlight the discrepancies in HCV infection characteristics and treatment responses between African American and white persons in the United States,” writes Dr. Pearlman.

Epidemiology, Genotype, and Natural History

The most recent US census data records that 12% of the population is African American, whereas 75% is white [3]. HCV infection is more prevalent in the African American population than in any other racial group in the United States. Although African Americans represent only 12% of the US population, they represent approximately 22% of the estimated Americans with chronic HCV infection [1].

The mode of transmission of HCV appears to be similar for white and African American individuals. In a large, prospective, controlled trial involving >400 patients, injection drug use was identified as the primary transmission route among both whites and African Americans. [4]

While 70% of all HCV-infected individuals in the US have genotype 1, African Americans have the highest prevalence of genotype 1 than any other racial group. The reason for this is not known.

In addition, it is well recognized that the chronic HCV infection rate is higher among African American than among white individuals. Despite higher rates of chronic infection, HCV positive African American persons may have a slower rate of fibrosis progression, compared to whites. [5] Results of several studies

suggest that histologic progression of HCV infection occurs less rapidly among African American patients than among white patients.

The mechanism for these and other possible discrepancies in the natural history of hepatitis C in African Americans is unknown. The answer may lie in the differing HCV-specific CD4 T cell responses between African American and white persons.

Although African Americans may experience slower progression of fibrosis, their rate of progression to hepatocellular carcinoma is faster. In addition, the rate of progression to hepatocellular carcinoma among African American persons is 2-fold higher than among white persons [6]. The rate of deaths from liver cancer is 2–3 times higher among African American patients than among whites [7]. More recent data confirm that the risk of hepatocellular carcinoma is twice as high among African American men as it is among white men [8].

Treatment

African Americans are usually underrepresented in clinical trials of treatment for acute and chronic HCV infection, even though their prevalence of chronic HCV infection is higher than among whites. Also concerning is the fact that despite the improved benefits from the pegylated interferons, the rates of sustained virologic response (SVR) among African Americans is significantly lower than in whites.

In the registration trials of treatment with pegylated IFN and ribavirin, too few African American subjects were enrolled to make outcome assessments. Fortunately, two recent prospective trials have examined the effect of pegylated IFN treatment in a large number of African Americans.

The first trial [9] compared a group of 100 African American patients with a control group of 100 non-Hispanic white patients, both of which were treated with pegylated IFN alfa-2b (PegIntron) 1.5 mcg/kg per week and ribavirin (1000 mg per day for 3 months, followed by 800 mg per day until week 48). Both groups were equally matched with regard to age, HCV viral load, genotype, and other attributes.

Treatment was well tolerated in both groups; 81% of African American and 79% of white patients completed therapy. Rates of adherence to treatment and of adverse events were also similar in both groups, and depression was the most common reason for discontinuation of therapy, regardless of ethnicity.

Compared with non-Hispanic white subjects, African American subjects had substantially poorer rates of sustained virologic response (19% vs. 52%; P < .001). The only predictor of sustained virologic response in multivariate analysis was race.

Also analyzed was the predictive value of an early virologic response, defined as a >/= 2-log10 reduction in HCV RNA level at week 12 of therapy. None of the subjects who did not achieve an early virologic response at week 12 reached a sustained virologic response, irrespective of ethnicity. Thus, the negative predictive value of early virologic response was 100%.

Study limitations included differences in sex, body weight, and diabetes status, some of which may have impacted response rates. Furthermore, alcohol use and abstinence were not documented in the study. Because alcohol affects response to IFN-based therapy [10], discrepancies in the 2 groups' rates of alcohol consumption may have influenced results.

The second study [11] enrolled 78 African American subjects and 28 white subjects who were infected with HCV genotype 1 and were treatment-naive. All subjects received pegylated IFN alfa-2a (Pegasys) 180 mcg per week and ribavirin (1000–1200 mg per day, dosed on the basis of weight) for 48 weeks. Unlike the study mentioned above, this trial allowed the use of growth factors.

Patient characteristics were similar in the 2 groups. Rates of adverse events were higher among white patients. Thirty-nine percent of white subjects discontinued therapy, compared with 23% of African American subjects. At week 72, in the African American group, the rate of sustained virologic response was 26%,  significantly lower than the 39% rate for the white group.

Interestingly, of the 36 African American patients who did not achieve sustained virologic response and who underwent both liver biopsies, 22% achieved fibrosis improvement. These data may support the concept that some patients may achieve reversal in fibrosis, irrespective of whether they achieve a sustained virologic response. Like the previous study, this study did not indicate differences in alcohol use between patient groups.

Despite the fact that early virologic response had an inferior positive predictive value for African American patients, patients of both ethnicities should be treated for 48 weeks if early virologic response is achieved.

WIN-R Trial

Preliminary findings from the weight-based dosing of Peg-Intron and Rebetrol (WIN-R) trial demonstrate that weight-based dosing of ribavirin confers a significant advantage in the treatment of African American persons infected with genotype 1, compared with fixed dosing of ribavirin [12]. WIN-R is a prospective trial of 5000 treatment-naive HCV-infected patients from >200 US study centers designed to study weight-based versus fixed-dose ribavirin therapy.

Three hundred eight-seven genotype 1–infected African American patients were among those treated. Of the 362 African American subjects who weighed >/= 65 kg, those who received weight-based ribavirin dosing had better end-of-treatment and sustained virologic response rates than did those who received flat dosing. VR rates were more than doubled (sustained virologic response rate, 21% vs. 10%; P = .004). However, even though African American patients achieved higher response rates with weight-based doses of ribavirin, rates of sustained virologic response were still inferior to the rates for white patients.

Of the 3 recent large trials that have focused on HCV treatment in HCV-HIV coinfected persons, only 2 enrolled a significant percentage of African American subjects. However, race was not predictive for sustained response [13,14].

Conclusions

With few exceptions, African Americans have been significantly

Under-represented in clinical trials of HCV infection. More clinical studies are needed that seek answers for why African Americans have much lower treatment responses than whites, particularly those studies that investigate the mechanisms for different treatment responses in African Americans compared to whites.

In 2006, final results are expected from a multicenter trial, the Viral Resistance to Antiviral Therapy for Chronic Hepatitis C (VIRAHEP-C) Study. Approximately 200 African American subjects and 200 white subjects in this study are receiving treatment with pegylated IFN and ribavirin. The objectives are to assess response rates to therapy, and to analyze both viral factors and host factors, including genetic and immunologic variables, that may influence treatment results.

01/13/06

Source

B L Pearlman. Hepatitis C Virus Infection in African Americans. Clinical Infectious Diseases 42(1): 82-91. January 1, 2006.

References

1. Alter MJ. Epidemiology of hepatitis C. Hepatology 1997; 26(3 Suppl 1):62S–5S.

2. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States. N Engl J Med 1999; 341:556–62.

3. Hobbs F, Stoops N. Demographic trends in the 20th century. US Census Bureau, census 2000. Special reports series CENSR-4. Washington, DC: US Government, 2002. Available at http://www.census.gov/prod/2002pubs/censr-4.pdf.

4. Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Hepatology 1999; 30:787–93.

5. Wiley TE, Brown J, Chan J. Hepatitis C infection in African Americans: its natural history and histological progression. Am J Gastroenterol 2002; 97:700–6.

6. El-Serag HB. Hepatocellular carcinoma: recent trends in the United States. Gastroenterology 2004; 127:S27–34.

7. El-Serag HB, Mason AC. Rising incidence of hepatocellular carcinoma in the United States. N Engl J Med 1999; 340:745–50.

8. Nguyen MH, Whittemore AS, Garcia RT, et al. Role of ethnicity in risk for hepatocellular carcinoma in patients with chronic hepatitis C and cirrhosis. Clin Gastroenterol Hepatol 2004; 2:820–4.

9. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-hispanic whites. N Engl J Med 2004; 350:2265–71.

10. Ohnishi K, Matsuo S, Matsutani K, et al. Interferon therapy for chronic hepatitis C in habitual drinkers: comparison with chronic hepatitis C in infrequent drinkers. Am J Gastroenterol 1996; 91:1374–9.

11. Jeffers L, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 2004; 39:1702–8.

12. Jacobson I, Brown R, McCone J, et al. Weight based ribavirin dosing improves virologic response in HCV-infected genotype 1 African Americans compared to flat dose ribavirin with peginterferon alfa-2b combination therapy. Hepatology 2004; 40(4 Suppl 1):217A.

13. Toriani FJ, Rodriguez-Torres M, Rockstroh JK, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection in HIV-infected patients. N Engl J Med 2004; 351:438–50.

14. Chung RY, Andersen J, Volberding P, Robbins GK, et al. Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis in HIV-coinfected persons. N Engl J Med 2004; 351:451–9.