Is There Anything I Can Do to Improve the Chance That an African American With Chronic Hepatitis C Will Respond to Peginterferon and Ribavirin?
Mitchell L.
Shiffman,
MD
The spectrum of chronic hepatitis C virus (HCV) and its response to treatment appear to be somewhat different in African Americans compared to the general population of patients with this disease.1 The prevalence of chronic HCV in the African American community is significantly greater than in Caucasians. Over 3% of all African Americans have chronic HCV, compared to only 2% of Hispanics and 1.5% of Caucasians. In addition, African Americans have a significantly higher percentage of HCV genotype 1 than is observed in other races; 97% of African Americans have HCV genotype 1 compared to 70% for all other persons in this country. Even the distribution of genotypes 2 and 3 appear to be altered in African Americans. In the general population, 30% of HCV patients have genotypes 2 and 3 and the distribution among these genotypes is roughly equal. In contrast, only 3% of African Americans with chronic HCV have genotypes 2 and 3 and nearly all African Americans with a non-1 genotype have HCV genotype 2. Genotype 3 accounts for only 0.5% of all HCV infections in African Americans.2 The reason for the alteration in the distribution of genotypes in African Americans remains speculative. Clearly, African Americans are exposed to HCV through the same risk behaviors as persons of other races and must therefore be exposed to the same distribution of genotypes. It has therefore been hypothesized that the alteration in the distribution of HCV genotypes in African Americans is because persons in this racial group are able to spontaneously resolve nearly all acute exposures to genotype 3 and the majority of genotype 2 infections.
The natural history of chronic HCV also appears to be different in African Americans than in Caucasians. Although some studies have suggested that African Americans with chronic HCV have less severe inflammation and a lower prevalence of cirrhosis compared to the general US population with chronic HCV, this is not a universal finding. However, what is clear is that African Americans with chronic HCV and cirrhosis are at significantly increased risk for developing hepatocellular carcinoma (HCC). Large population-based studies have demonstrated that the risk of developing HCC is approximately 2-fold higher in African Americans compared with Caucasians for both men and women.3 Furthermore, the survival of African Americans with HCC is significantly lower than in Caucasians. It is currently unclear whether this latter finding is secondary to delayed or lack of access to health care in the African American population or because African Americans have more aggressive and less curable HCC.
African Americans also respond far less well to interferon therapy than persons of other races. This observation was initially noted nearly a decade ago when standard interferon was administered 3 times weekly for treatment of chronic HCV. The SVR rate in African Americans with this treatment was only 2%, compared to 12% in Caucasians. The rate of SVR increased significantly when ribavirin was utilized along with standard interferon. However, this remained significantly lower in African Americans, only 11% when compared to Caucasians. Initially, this lower rate of SVR was attributed to the much higher percentage of genotype 1 in the African American population. However, 3 controlled clinical trials utilizing peginterferon and ribavirin have now documented that the SVR rates in African Americans with HCV genotype 1 are approximately 40% to 50% lower than observed in Caucasians of the same genotype.4-6 The range in SVR observed for African Americans treated in these studies was 19% to 28% compared to 39% to 52% for Caucasians. In addition, a recent retrospective analysis has demonstrated that the SVRs in African Americans with genotypes 2 and 3 were only 52%, compared to 81% for Caucasian patients matched for genotype and various other parameters.2
The lower SVR observed in African Americans results from both an overall lower rate of virologic response and a higher rate of relapse. The patterns of virologic response were reviewed in Question 4. African Americans have a lower overall rate of early virologic response (EVR) and higher rate of null response. Within the category of EVR, the percentage of African Americans who do become HCV RNA undetectable at weeks 4, 12, and 24 is reduced compared to response rates observed in Caucasians (Figure 6-1). African Americans who do become HCV RNA undetectable tend to do so later during the course of treatment, and this slower rate of virologic response is associated with a higher relapse rate (see Question 4).
Figure 6-1. The percentage of African Americans and Caucasians who become HCV RNA undetectable at various time points during treatment, and those with partial and null response. (Adapted from Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470-477).
Several observations may help explain the slower and lower virologic response observed in African Americans. The ability of interferon to inhibit viral replication and increase HCV clearance is significantly reduced in African Americans. African Americans with chronic HCV have alterations in their cytokine profiles, less efficient T-cell responses to HCV antigens, and clear acute HCV infection less frequently than do Caucasians. Various aberrations in the immune response and differences in HLA alleles are also present in African Americans compared to Caucasians. Alternatively, recent data from several randomized controlled trials have demonstrated that the reduced SVR rate in African Americans is not secondary to differences in body weight, economic or environmental factors, or serum HCV RNA level. Interferon binds to its cell surface receptor equally well in African Americans as in Caucasians.
Based upon these data there are basically two strategies that can be utilized to enhance the effectiveness of interferon therapy in African Americans. One approach is to enhance the percentage of patients who respond to treatment and the second is to reduce the relapse rate. These strategies are summarized in Table 6-1.
Several studies have suggested that utilizing more interferon can enhance virologic response, but this benefit is likely confined to those patients with partial virologic response. Patients with partial response achieve a 2 log or greater decline in HCV RNA from pretreatment baseline but do not become HCV RNA undetectable. Partial responders as a group are somewhat responsive to interferon and may therefore become HCV RNA undetectable when higher doses of interferon are utilized. In contrast, it is unlikely that higher doses of interferon will affect virologic response in patients with null response. African Americans do have a higher percentage of null response. However, approximately 25% of African Americans exhibit a partial response and these patients may become HCV RNA undetectable when higher doses of interferon are utilized.
Another approach to enhancing SVR in African Americans is to reduce relapse. This can be accomplished in two ways: by utilizing more ribavirin and by treating patients for a longer duration. Two recent studies have demonstrated that utilizing a slightly higher dose of ribavirin, only 200 mg/day, can reduce relapse in both Caucasians and African Americans. Relapse is most common in those patients who become HCV RNA undetectable late during the course of treatment (see Question 4), and 2 studies have demonstrated that prolonging the duration of therapy from 48 to 72 weeks in these patients can reduce relapse. As a group, African Americans have a delayed response to treatment; therefore, continuing the duration of treatment from 48 to 72 weeks in those African Americans who become HCV RNA undetectable after week 4 would likely reduce relapse and enhance SVR.
At the present time none of these strategies has proven to be effective in enhancing SVR in African Americans with chronic HCV. However, based upon our current understanding of viral kinetics, response, and relapse, these strategies seem logical and worth implementing in motivated patients who have already demonstrated a virologic response to current treatment. In contrast, it is unlikely that African Americans with a null response would benefit from these strategies.
References
1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562.
2. Shiffman ML, Mihas AA, Millwala F, et al. Treatment of chronic hepatitis C virus in African Americans with genotypes 2 and 3. Am J Gastroenterol. 2007;102:1-6.
3. Leykum LK, El-Serag HB, Cornell J, Papadopoulos KP. Screening for hepatocellular carcinoma among veterans with hepatitis C on disease stage, treatment received, and survival. Clin Gastroenterol Hepatol. 2007;5:508-512.
4. 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;350:2265-2271.
5. Jeffers LJ, 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;39:1702-1708.
6. Conjeevaram HS, Fried MW, Jeffers LJ, et al. Peginterferon and ribavirin treatment in African American and Caucasian American patients with hepatitis C genotype 1. Gastroenterology. 2006;131:470-477.