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Strader, DB. Washington VA Medical Center
- African-Americans are more likely to have HCV genotype 1 and more likely to have complications of HCV compared with Caucasians.
- African-Americans are less likely to respond to anti-HCV therapy than Caucasians.
- Genotype, viral kinetics, interferon resistance and BMI have been suggested as factors that may be responsible for racial differences in response to anti-HCV therapy.
The hepatitis C virus (HCV) is a major public health problem and one of the most important causes of chronic liver disease in the United States. Approximately 3.9 million Americans, or 1.8% of the U.S. population, have antibody to HCV, indicating ongoing or previous infection. HCV accounts for 20% of acute viral hepatitis and progresses to chronic hepatitis in 75% to 85% of instances. Approximately 20% of patients with chronic HCV infection develop cirrhosis, some of whom progress to end-stage liver disease and hepatocellular carcinoma. In the U.S., HCV causes an estimated 10,000 deaths annually and is the most common indication for orthotopic liver transplantation.
Of interest are tile large racial and ethnic differences in the prevalence and characteristics of HCV infection in the United States. Antibody to HCV (anti-HCV) is almost twice as common among African-Americans as compared with whites (3.2% and 1.8%, respectively), as are the complications of chronic HCV infection, including death from cirrhosis and hepatocellular carcinoma. NHANES III data indicate that 86% of African-American patients with anti-HCV have detectable serum HCV RNA as compared with 68% of anti-HCV-positive white patients (P<0.05). This suggests that African-Americans have a lower rate of hepatitis C viral clearance after acute infection. In addition, genotype 1 is over represented among the African-Americans (91%) compared with whites (67%), and this difference is particularly conspicuous with respect to the prevalence of genotype 1b (36% versus 18%).
Efforts to assess the natural history of HCV infection among African-Americans have been hampered by the paucity of African-American patients included in prospective trials, and possibly by selection bias. An attempt to better define the clinical course and outcome of HCV infection among African-Americans was made at the University of Illinois Medical Center by means of a retrospective chart review of all patients undergoing liver biopsy at that institution between 1996 and 1999. Two hundred eighty-eight cases were identified (195 whites, 93 African-Americans). The source of HCV infection, mean ALT levels, average body weight, HCV RNA levels and baseline histologic activity index (HAl) were similar among African-Americans and whites.
By contrast, African-American patients were older, had a slightly longer duration of infection (27 versus 23 years) and a higher prevalence of genotype 1 (88% versus 65%). Interestingly, when patients were characterized by decade of infection, cirrhosis was less common among African-American patients, being present in 0% of African-Americans compared with 26% of whites in the second decade, 18% versus 31 % in the third decade and 33% versus 47% in the fourth decade of infection. Similar data were reported from the University of Southern California, Los Angeles. Despite the drawbacks intrinsic to a retrospective study, specifically the difficulty in accurately assessing the time of exposure, these data suggest that histologic progression of HCV infection among African-American patients is less rapid than among whites, not withstanding similar clinical and biochemical features at onset of infection.
Racial differences in response to anti-HCV therapy
Of particular concern is the accumulating data documenting the lower rate of response to therapy of chronic HCV infection among African-American patients as compared with whites. In a review of the five largest studies of HCV treatment in which racial comparisons can be made, the disparity in response persisted despite the choice of anti-HCV therapy. Escalating doses of interferon (IFN) a2b, consensus IFN (9 µg), and varying doses of PEG-IFN a2a (Pegasys) (two studies) achieved sustained viral response (SVR) rates among African-Americans of 0%, 2%, 8% and 9%, respectively, compared with higher SVR's among whites 26%,12%, 25%, and 17% respectively. A well-known study of 1744 HCV infected individuals (1600 whites, 53 African-Americans, 32 Asians and 27 Hispanics) randomized patients to receive either interferon monotherapy or combination therapy with standard IFN plus ribavirin. An SVR to either therapy was achieved in 27% of whites, 11 % of African-Americans, 44% of Asians and 16% of Hispanics.
Subgroup analysis confined to comparing response among genotype-l-infected whites and African-Americans only, revealed 16% (169 of 1041) of whites and 12% (6 of 51 ) of African-Americans achieved SVR irrespective of treatment (P = 0.4). However, further analysis evaluating the type of treatment in genotype-l-infected white and African-American subjects demonstrated no difference in SVR when subjects were treated with combination therapy (23% vs. 22%). Two recent international trials (one unpublished) evaluating the efficacy of pegylated IFN plus ribavirin combination reveal a 54%-56% overall SVR and a 42%-46% SVR in patients with genotype 1. Unfortunately, no information is available regarding the response among African-Americans in either of these trials. In fact, all three studies are hampered by the paucity of African-Americans included such that estimable data in this patient population is sorely missing. At present, the NIH is conducting a trial of pegylated IFN a2a, (Pegasys) plus ribavirin treatment among African-Americans infected with HCV -genotype 1 and the findings are awaited with great anticipation.
Factors that may predict racial differences in anti-HCV therapy
Data show that while the prevalence of HCV genotype in the general population is approximately 75%, the prevalence of genotype 1 among African-Americans is > 90%. The reason for the overrepresentation of genotype I among this subset of the US population is unclear. Risk factors for the acquisition of HCV infection do not differ substantially between African-Americans and whites, and are unlikely to be the explanation for the racial differences in genotype predominance. Studies have clearly shown that patients with genotypes 1 a or 1 b have poorer responses to treatment with either IFN monotherapy or standard or pegylated IFN plus ribavirin combination therapy than patients with genotypes 2 or 3. Whether there are racial differences in response to therapy among patients infected with genotype 1 is controversial. One study suggests no difference in response rate among African-Americans and whites infected with genotype 1, while other unpublished data refute these findings. An ongoing trial at the NIH should answer this question.
HCV viral kinetics during IFN antiviral therapy has received much attention in the past few years as a means of predicting response to therapy. The initial HCV RNA decline. termed Phase 1, occurs between 8-24 hours after the first injection, is dose dependent and represents inhibition of viral production. Phase 2 occurs between 2 - 14 days, is not dose-dependent and is felt to represent the death and/or disappearance of HCV infected hepatocytes. This second phase is highly dependent upon the hosts’ response to virus-infected cells, presumably orchestrated by CTL recognition and therefore, the rate of decline of Phase 2 is the best predictor of early HCV clearance. The rate of viral decline in Phase 2 can be highly variable among subjects and recent studies have shown that race may influence the pattern of decline. A small study comparing HCV viral kinetics during IFN therapy noted no difference in the Phase 1 decline between African-American and white patients. By contrast, the rate of decline of Phase 2 was significantly faster among whites than among African-Americans, with 2 of the 4 African-American patients showing no decline (<0.5 log) in HCV RNA over a month of therapy. McHutchinson et al reported that the decline in HCV RNA among 53 African-American patients at each time point measured was significantly lower than that of 1600 whites and that this difference could not be accounted for by genotype alone. 30% to 40% of whites and < 20% of African-Americans had undetectable HCV RNA by week 12 of therapy. However, on further evaluation of their data using analysis of variance (ANOVA), the authors suggested that the statistically significant differences in HCV RNA decline were confined to African-American patients receiving interferon monotherapy. Patients in the study receiving interferon plus ribavirin had similar Phase 1 and 2 viral kinetics, regardless of race. These data must be interpreted cautiously as it is possible that the lack of early viral measurements in these trials concealed a Phase 2 effect. Studies evaluating the effects of viral kinetics on response to therapy are ongoing.
The differences in viral kinetics noted between responders and non responders of HCV antiviral therapy may be due, in part, to HCV virus strategies which have evolved to evade the antiviral effects of interferon. Studies in Japan identified an IFN sensitivity-determining region (ISDR) in the NS5A region of the HCV genome. Efforts to determine whether this region contributes to IFN-resistance in the clinical setting have produced conflicting results. The presence of this ISDR among Japanese patients with HCV genotype 1b was associated with lack of response, while mutations within the ISDR predicted response to therapy. By contrast studies of patients with HCV genotypes 1a and 1b performed in the US and Europe, respectively, failed to show a correlation between the presence of ISDR and IFN response. Despite this, a small study of 17 African-American and 15 white patients with HCV genotype 1 revealed an association between 3 or more ISDR mutations and clearance of HCV RNA within 1 month of therapy. Eight of 15 white patients, but only 2 of 17 African-Americans had> 3 ISDR mutations. In addition, all white patients had at least one ISDR mutation, while 7 African-American patients had no ISDR mutation at all. While most investigators are skeptical that the ISDR plays a significant role in determining response to anti-HCV therapy, its effects are being assessed in some trials.
Obesity and Body Mass Index:
It has been suggested that increased body weight and body mass index (BMI) may adversely affect response to HCV anti-viral therapy. This hypothesis stems from the observation that steatosis is a common histologic finding among patients with HCV, and that the prevalence of hepatic steatosis increases with increasing BMI. In fact mean BMI correlated with focal or extensive subsinusoidal fibrosis in one trial and another study of 7 patients with chronic HCV infection demonstrated a decrease in hepatic steatosis resulting from a 12-week intensive weight loss and exercise program. Interferon has been demonstrated to influence the progression of steatosis in patients who achieve a SVR, and one small study suggests that increased IFN dose/kg together with progressive decrease in BMI in the first three months of treatment is associated with improved end of treatment viral response. A recently published trial of pegylated IFN a 2b plus ribavirin therapy suggests that response rate increased as the ribavirin dose increased (to maximum of 13mg/kg). These data imply that the histologic effects of obesity may augment those of HCV and indirectly hamper response to therapy, necessitating elevated doses of interferon and/or ribavirin. Controversy in this area underscores the need for further evaluation of the effect of weight and body mass index on steatosis and response to therapy among patients infected with HCV.
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