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Hepatitis C Virus Among African-American Persons
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Current Hepatitis Reports Jan 12, 2004, 3:129-135
Doris B. Strader, MD
Fletcher Allen Health Care, University of Vermont, College of Medicine, Department of Gastroenterology/Hepatology, 111 Colchester Avenue, Burgess 414, Burlington, VT 05401, USA.
Introduction
Epidemiology and Natural History
Racial Differences in Response to Anti-HCV Therapy
Factors that May Predict Racial Differences in Anti-HCV Therapy
• Genotype
• Viral kinetics
• Interferon resistance and racial differences in immune response to HCV
• Obesity, insulin resistance, and diabetes
• Iron stores
Conclusions
References and Recommended Reading
INTRODUCTION
Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC). In the United States, approximately 2% of the general population has serum antibodies to HCV. Although African-American persons make up only 12% of the US population, they account for 22% of the estimated 2.7 million persons infected with chronic HCV. In addition, African-American persons with HCV appear to be at greater risk for cirrhosis and HCC, and are less likely to respond to current anti-HCV therapy. Although the explanation for the observed racial differences in HCV prevalence, complications, and response to therapy is unclear, it has been speculated that ethnic variations in viral kinetics, immunogenetics, hepatic steatosis, and hepatic iron concentration may be partly responsible. Unfortunately, limited data are currently available. Adequately powered and sized prospective trials are needed to further investigate these provocative hypotheses.
CONCLUSIONS BY AUTHORS
Data show that hepatitis C is twofold more common among African-American persons than among white persons, and that once infected, African-American persons are more likely to develop chronic HCV. Despite the increased rate of chronicity, the rate of progression of liver disease to cirrhosis appears to be slower. Preliminary evaluation of large trials of HCV reveals a decreased response among African-American persons. Provocative hypotheses to explain these differences include racial differences in viral kinetics or immunogenetics, the high prevalence of concomitant obesity and insulin resistance among African-American patients with HCV, and possibly, higher hepatic iron concentrations among African-American patients with HCV. It is possible that the paucity of African-American patients included in large trials may have affected interpretation of results. A large-scale trial is currently ongoing, and hopefully other trials of HCV among minorities will help clarify some of these issues.
EPIDEMIOLOGY
Approximately 3.9 million Americans have anti-HCV, and among those 2.7 million have circulating HCV RNA, indicating chronic infection [1]. HCV accounts for 20% of acute viral hepatitis and progresses to chronic hepatitis in 65% to 85% of instances [1, 5, 6, 7]. It has been estimated that 20% of patients with chronic HCV infection will develop cirrhosis, some of whom will progress to end-stage liver disease and HCC [8, 9]. In the United States, HCV causes an estimated 10,000 deaths annually and is the most common indication for orthotopic liver transplantation. The NHANES III (Third National Health and Nutrition Examination Survey) data indicate that 86% of African-American patients with anti-HCV also have detectable serum HCV RNA, as compared with 68% of anti-HCV-positive white patients (P < 0.05) [1]. This suggests that African-American persons have a lower rate of hepatitis C viral clearance after acute infection. African-American men between the ages of 40 and 49 years have the highest prevalence of chronic HCV in the United States [1]. In addition, genotype 1 is overrepresented among African-Americans persons (91%) compared with white persons (67%), and this difference is particularly conspicuous with respect to the prevalence of genotype 1b (36% vs 18%).
Efforts to assess the natural history of HCV infection among African-American persons 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-American persons 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 [10]. A total of 288 cases were identified (195 white persons, 93 African-American persons). The sources of HCV infection, mean alanine aminotransferase level, average body weight, HCV-RNA level, and baseline histologic activity index were similar among African-American patients and white patients. By contrast, African-American patients were older, had a slightly longer duration of infection (27 vs 23 years), and a higher prevalence of genotype 1 (88% vs 65%). Interestingly, when patients were characterized by decade of infection, cirrhosis was less common among African-American patients, being present in 0% of African-American patients compared with 26% of white patients 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 [11]. 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 white patients, notwithstanding similar clinical and biochemical features at onset of infection.
Hepatocellular carcinoma is a common malignancy among patients with liver disease, and appears to be increasing in the United States. Epidemiologic studies in the United States show that the incidence of HCC increased by 71% between 1976 and 1995, and the mortality increased by 45% during that same period [2]. It has been suggested that the increase in HCC is related, in part, to an increase in liver disease caused by HCV [2]. Likewise, it is felt that hepatocellular carcinogenesis secondary to hepatitis C proceeds through the development of chronic hepatitis and, subsequently, cirrhosis [2]. Despite data indicating a relatively slow progression to fibrosis and cirrhosis among African-American persons infected with hepatitis C, the incidence of HCC among African-American persons is relatively high. Information gathered from the Surveillance, Epidemiology, and End Results database in 1999 revealed the incidence rate of HCC among African-American men between 1991 and 1995 was 6.1 per 100,000, compared with 2.4 per 100,000 among white persons [2]. The mortality rates mirrored the incidence rates with death rates secondary to HCC among African-American men estimated at 6.0 per 100,000, compared with mortality rates among white persons of 2.3 per 100,000 [2].
A recent report attempted to define the influence of race on the incidence of HCV-related HCC in the United States [12*]. In this study, 852 patients from 13 centers with proven HCC were evaluated. Fifty-nine percent were white, 14% African American, 16% Asian, and 11% of "unknown ethnicity." Hepatitis B surface antigen (HBsAg) was identified in 107 patients (15.4%), anti-HCV in 322 (46.5%), both HBsAg and anti-HCV in 33 (4.7%), and neither marker in 229 (33.1%). Hepatitis C infection was associated with HCC at a significantly higher rate among white persons and African-American persons than among Asian persons (51.7%, 53.6%, and 30%, respectively), whereas hepatitis B infection was more associated with HCC among persons of Asian descent (Asian persons-49.5%, white persons -5.8%, and African-American persons -15.7%) [12*]. These data imply that hepatitis C is the leading risk factor for HCC in the United States, and appears to be the most common risk factor among both white persons and African-American persons. Unfortunately, the study did not investigate ethnic and regional variability in the pathogenesis of HCC (eg, the impact of other risk factors such as obesity, alcohol abuse, or iron overload, and ethnicity in the development of HCC).
Racial Differences in Response to Anti-HCV Therapy
Current data suggest that the sustained viral response (SVR) achieved with pegylated interferon (IFN) plus ribavirin in the treatment of hepatitis C is 54% to 56% overall, and 42% to 46% among patients with genotype 1 [13, 14]. 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 white patients.
In a review of five early studies of HCV treatment in which racial comparisons can be made, the disparity in response persisted, despite the choice of anti-HCV therapy [15*]. Escalating doses of IFN alfa-2b, consensus IFN (9 mg), and varying doses of pegylated IFN alfa-2a (two studies) achieved SVR rates among African-American persons of 0%, 2%, 8%, and 9%, respectively, compared with higher SVRs among white persons (26%, 12%, 25%, and 17%, respectively). A well-known study of 1744 HCV-infected individuals (1600 white persons, 53 African-American persons, 32 Asian persons, and 27 Hispanic persons) randomized patients to receive either IFN monotherapy or combination therapy with standard IFN plus ribavirin [16]. An SVR to either therapy was achieved in 27% of white persons, 11% of African-American persons, 44% of Asian persons, and 16% of Hispanic persons. Subgroup analysis confined to comparing response among genotype 1-infected white persons and African-American persons only revealed 16% (169/1041) of white persons and 12% (6/51) of African-American persons achieved SVR irrespective of treatment (P = 0.4) [16]. However, further analysis evaluating the type of treatment in genotype 1-infected white and African-American subjects demonstrated no difference in SVR when subjects were treated with combination therapy (23% vs 22%) [16]. It should be noted that these results were based on a relatively small number of African-American patients included in this study.
Three abstracts presented at a recent international meeting evaluated the response of African-American patients with HCV genotype 1 to pegylated IFN alone or in combination with ribavirin (Shiffman et al., Unpublished data; Lindsay et al., Unpublished data) [17]. In the two trials evaluating pegylated IFN monotherapy, African-American persons represented less than 5% of the participants and had an SVR rate of 8% and 15% (Shiffman et al., Unpublished data; Lindsay et al., Unpublished data). A recent trial evaluating combination therapy compared the response of 78 non-Hispanic black persons with 28 non-Hispanic white persons [17]. All patients were infected with HCV genotype 1 and were treated with pegylated IFN alfa-2a plus ribavirin for 48 weeks [17]. The SVR rate among white patients was 39%, whereas that among African-American patients was 26%. Despite the low SVR rates, when biopsy specimens were examined, one quarter of African-American patients had improvement in fibrosis scores. In a second study, African-American and white patients with HCV genotype 1 were treated with 48 weeks of IFN alfa-2b plus ribavirin [18]. The SVR rate was 52% among non-Hispanic whites compared with only 19% among African-American patients. In addition, the African-American patients had significantly lower rates of early virologic and end-of-treatment response. In this study, African-American race was the only variable significantly associated with decrease in response rate. Despite the small size of these two studies, a significantly lower SVR rate among African-American patients infected with HCV is noted, which cannot be explained on the basis of viral genotype. In response to this shortcoming, the National Institutes of Health (NIH) is conducting a trial of pegylated IFN plus ribavirin treatment among 200 African-American persons and 200 white persons infected with HCV genotype 1. The findings of this trial are awaited with great anticipation.
Factors that May Predict Racial Differences in Anti-HCV Therapy
Genotype
Data show that although the prevalence of HCV genotype 1 in the general population is approximately 67%, the prevalence of genotype 1 among African-American persons is greater than 90% [1]. The reason for the overrepresentation of genotype 1 among this subset of the US population is unclear. Risk factors for the acquisition of HCV infection do not differ substantially between African-American persons and white persons, and are unlikely to be the explanation for the racial differences in genotype predominance. Studies have clearly shown that patients with genotypes 1a or 1b 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 [13, 14, 16]. 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-American persons and white persons infected with genotype 1, 23% versus 22%, respectively [16]. Likewise, a more recent study of treatment of chronic HCV in the Virginia Department of Corrections revealed an increased SVR among white prisoners compared with African-American prisoners (70% vs 40%), but no difference in response when comparing those with genotype 1 (33% among white persons, 29% among African-American persons) [19]. By contrast, a study of 61 African-American persons and 49 white persons with HCV revealed a 2% end-of-treatment response (ETR) among African-American persons with genotype 1 compared with a 15% ETR among white persons with the same genotype [20]. All of these studies used therapy with standard IFN and ribavirin for the treatment of HCV. Whether response rates among African-American persons will improve with the use of pegylated IFN should be answered in the ongoing NIH trial.
Viral kinetics
A number of studies have described the kinetics of HCV-RNA decline after initiation of IFN therapy [21, 22, 23, 24, 25]. The initial HCV-RNA decline, termed phase 1, occurs between 8 to 24 hours after the first injection, is dose dependent, and represents inhibition of viral production by IFN. Phase 2 occurs between 2 to 14 days, is not dose dependent, and is felt to represent both the effectiveness of IFN in blocking viral production and the death or disappearance of HCV-infected hepatocytes. This second phase is highly dependent upon the hosts' response to virus-infected cells, presumably orchestrated by cytotoxic T-lymphocyte recognition, and therefore, the rate of decline of phase 2 is the best predictor of early HCV clearance. 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 rate of viral decline in phase 2 can be highly variable among subjects. Initial studies showed that race influenced the pattern of decline. McHutchison et al. [16] reported that the decline in HCV RNA among 53 African-American patients at each time point measured was significantly lower than that of 1600 white patients, and that this difference could not be accounted for by genotype alone. Thirty percent to 40% of white patients and less than 20% of African-American patients had undetectable HCV RNA by week 12 of therapy. However, on further evaluation of their data using analysis of variance, the authors suggested that the statistically significant differences in HCV-RNA decline were confined to African-American patients receiving IFN monotherapy. Patients in the study receiving IFN plus ribavirin had similar phase 1 and 2 viral kinetics, regardless of race.
A more recent, detailed study of viral kinetics sheds more light on racial differences in response to IFN therapy [26*]. In this study, 19 African-American and 16 white patients with HCV genotype 1 were evaluated. All were treated with high-dose IFN alfa-2b daily with or without ribavirin for 1 month, followed by 3 MU of IFN alfa-2b plus ribavirin three times a week. The addition of ribavirin to IFN therapy did not appear to enhance early viral kinetic parameters in either race. No difference in virion half-lives was noted between races. However, African-American patients had a significantly increased delay in the initial response compared with white patients (8.7 vs 6.6 hours). In addition, African-American patients had a significantly lower median IFN effectiveness of 88.6% (representing a 0.94 log first-phase decline), compared with a 98.2% IFN effectiveness among white patients (1.74 log first-phase decline). A significant difference also existed between the rate of loss of infected cells between the races, with white patients exhibiting a higher rate than among African-American patients (0.20 per day vs 0.13 per day, respectively) [26*]. No appreciable second-phase decline was observed in 53% of African-American patients compared with only 7% of white persons. When evaluating treatment response, ribavirin use in the first month appeared to enhance the viral negativity rates at weeks 12 and 48 among white patients, but not among African-American patients. Of interest, when controlling for an IFN effectiveness of 90% (> 1 log decrease in HCV RNA), the viral negativity rates at week 48 were not different between the races; eight of 13 white persons and three of seven African-American patients cleared virus. No patient of either race cleared the virus at week 48 without an effectiveness of greater than 90%.
The mechanism explaining these differences in response among the two races is unclear. It has been suggested that signal transduction pathways, host immunologic factors, and differences in the viral genome may be responsible. Recently, a great deal of interest has been paid to evaluating portions of the HCV genome, as well as racial differences in immunologic response to HCV infection. Studies are ongoing.
Interferon resistance and racial differences in immune response to HCV
The differences in viral kinetics noted between responders and nonresponders of HCV antiviral therapy have been suggested to be due, in part, to HCV virus strategies, which have evolved to evade the antiviral effects of IFN. Studies in Japan identified an interferon sensitivity-determining region (ISDR) in the NS5A region of the HCV genome [27, 28, 29, 30]. 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, whereas mutations within the ISDR predicted response to therapy [31, 32]. By contrast, studies of patients with HCV genotypes 1a and 1b performed in the United States and Europe, respectively, failed to show a correlation between the presence of ISDR and IFN response [33, 34, 35, 36]. Despite this, a small study of 17 African-American and 15 white patients with HCV genotype 1 revealed an association between three or more ISDR mutations and clearance of HCV RNA within 1 month of therapy. Eight of 15 white patients, but only two of 17 African-American patients had greater than three ISDR mutations [37]. In addition, all white patients had at least one ISDR mutation, whereas seven African-American patients had no ISDR mutation at all. Although 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.
Immunogenetic data from transplant studies have suggested that African-American persons may have a more robust immunologic response and thus require more aggressive immunotherapy [38, 39, 40, 41, 42]. A study by Kimball et al. [43] attempted to establish normal levels of cytokine production among a small cohort of healthy African-American and white patients, and determine whether racial differences in pretherapy cytokine production could be used to predict response to HCV therapy. Healthy African-American patients appeared to produce more proinflammatory TH1 cytokines (eg, interleukin [IL]-2, tumor necrosis factor-a [TNF-a]) and underproduce downregulatory TH2 cytokines (eg, IL-10) when compared with the healthy white cohort, suggesting that "normal" levels of immune parameters may differ between these two races [43]. Taking these racial differences in cytokine production into account, no differences were found in pretherapy cytokine production between African-American and white nonresponders and healthy members of both races [43]. No African-American patient in this study responded to therapy and, therefore, using pretherapy cytokine production to predict response among African-American patients infected with HCV was not possible. However, pretherapy production of TH2 cytokines predicted clinical outcome among white patients. White responders to anti-HCV therapy produced less IL-10 and more transforming growth factor-b than white nonresponders, predicting nonresponse with an 83% sensitivity and 96% specificity [43]. Due to the small number of patients in this study, further investigation into this provocative area is required.
A more recent study suggests that although African-American persons have a more robust CD4 T-cell response to HCV infection, these T cells are dysfunctional and limited in their ability to control disease [44]. In this study, 99 patients with chronic HCV and 31 patients who spontaneously cleared HCV were subjected to clinical, virologic, and immunologic analysis. CD4-proliferative T-cell responses to genotype 1-derived HCV antigens among 82 patients with HCV genotype 1 were examined. HCV-specific CD4 T-cell responses were significantly greater (particularly against nonstructural antigens) among recovered subjects compared with those chronically infected. Although African-American persons showed a greater CD4 T-cell response to HCV than white persons, this response was not associated with the production of IFN-g, suggesting a dysregulation of CD4 T-cell effector function [44]. Among African-American patients who cleared the virus, a vigorous and multispecific response was noted against nonstructural, but not core antigens. By contrast, among white patients HCV clearance was associated with a significant CD4 T-cell response against HCV core antigens [44]. These data suggest that the immunologic requirements for response to HCV may differ among races, and further study on host-virus interaction should clarify this issue.
Obesity, insulin resistance, and diabetes
It has been suggested that increased body weight and body mass index (BMI) may adversely affect the course of HCV and the response to anti-HCV therapy. This hypothesis stems from the observation that steatosis is a common histologic finding among patients with HCV [45, 46]. Some data indicate that the prevalence of hepatic steatosis may increase with increasing BMI, and that steatosis is associated with accelerated necroinflammatory activity and fibrosis among patients with HCV [47, 48]. In addition, pharmacologic data show a weaker biologic response to standard IFN among patients with obesity [49]. A recent study revealed that the presence of hepatic steatosis alone was not an independent risk factor for response to treatment, but obesity, defined as a BMI greater than 30, was an independent negative predictor of response to anti-HCV therapy [50].
A mechanism by which obesity and steatosis may lead to increased hepatocyte injury was recently described [51]. In this study, 125 patients with HCV had liver biopsy tissue examined for grade of steatosis, apoptotic index (percent of total number of hepatocytes/high power field with apoptosis by TUNEL assay), expression of Bcl-2, Bcl-xL, Bax, TNF-a, and Bax/Bcl-2 ratio. Steatosis grade was 0 (< 5% of hepatocytes affected) in 55.2%, grade 1 (5% to 29% of hepatocytes affected) in 23.2%, and grade 2 (30% to 70% of hepatocytes affected) or grade 3 (> 71% of hepatocytes affected) in 21.6%. Forty-one percent of patients had stage 2 or greater fibrosis. Steatosis and previous heavy alcohol consumption (> 50 g/d) were independently associated with apoptotic index [51]. Steatosis was associated with decreased Bcl-2 and an increase in the proapoptotic Bax/Bcl-2 ratio. In addition, the apoptotic index was significantly correlated with the stage of fibrosis in the presence of steatosis [51]. Interestingly, in the absence of steatosis, there was no independent association between apoptosis and stage of fibrosis, suggesting that factors other than simple liver injury, such as hepatocyte lipid accumulation, are involved in liver cell death.
It is becoming increasingly clear that there is an association between type 2 diabetes and the presence of HCV. To determine whether persons who acquired type 2 diabetes were more likely to have antecedent HCV, 1084 adults from the Atherosclerosis Risk in Communities Study were evaluated [52]. A total of 548 patients developed diabetes over 9 years of follow-up. Although the overall prevalence of HCV in the population was only 0.8% (15/548), those with HCV who also had high risk factors for the development of diabetes were 11 times more likely to develop overt diabetes than those with high risk factors without HCV infection [52]. Mason et al. [53] found a twofold higher incidence of HCV among those with well-documented diabetes among 1117 patients screened. In a third study, the prevalence of HCV among 176 diabetic patients was 11.5%, compared with only 2.5% among control subjects without diabetes [54]. Direct involvement of HCV in the development of insulin resistance, as evidenced by abnormal insulin tolerance tests and elevated basal serum insulin levels, has been suggested in one study of HCV transgenic mice [55]. Feeding the HCV transgenic mice a high-fat diet led to the development of overt diabetes, as well as high levels of TNF-a, which leads to insulin resistance by affecting the tyrosine phosphorylation of insulin receptor substrate-1. These data suggest that in those with a predisposition to insulin resistance, the presence of HCV may accelerate the onset of diabetes and consequent steatosis.
Finally, in addition to obesity and type 2 diabetes, hepatic steatosis can be the result of viral steatosis associated with a presumed cytopathic effect of infection with HCV genotype 3. In one study of 131 patients with HCV, steatosis was detected in 48.1% (grade 2 or 3 in 38%) [56]. Eighty-one percent of patients infected with genotype 3 had steatosis on biopsy compared with only 35.2% of those with genotype 1, irrespective of BMI, percentage of body fat, leptin levels, or visceral obesity. In those with genotype 3, steatosis was directly correlated with liver HCV viral load. By contrast, steatosis among patients with genotype 1 was significantly associated with BMI, percent of body fat, leptin levels, and visceral obesity [56]. In another trial, moderate to severe steatosis was more prevalent in patients with HCV genotype 3 with injection drug use as a risk factor than among patients with similar risk factors infected with genotypes 1 or 2 [57]. There was no correlation between grade of steatosis in those with genotype 3 and BMI, fibrosis, necroinflammation, or hyperlipidemia.
Epidemiologic data suggest a disproportionate occurrence of obesity and diabetes among African-American persons in the United States [58, 59]. However, there are no data to suggest that genotype 3 is more common among African-American persons infected with HCV. The increased prevalence of obesity and diabetes among African-American persons, coupled with the high prevalence of HCV in the African-American community, may, in part, explain the observed decreases in response to therapy. Controversy in this area underscores the need for further evaluation of the effect of weight and BMI on steatosis and response to therapy among patients infected with HCV.
Iron stores
Recent data suggest that African-American persons may respond to HCV infection with an increase in iron stores, which may be partly responsible for the reduced efficacy of antiviral therapy. Using data from NHANES III, ferritin and transferrin-iron saturation was evaluated in 100 African-American and 126 non-African American persons with positive serum HCV RNA, and 4002 African-American and 10,943 non-African American persons without HCV RNA [60]. HCV-RNA-positive African-American persons were fivefold more likely to have increased iron stores than HCV-RNA-positive non-African American persons. Among HCV-RNA-positive African-American persons with abnormal aminotransferases, 16.4% had elevated iron stores compared with 2.8% of HCV-RNA-positive African-American persons with normal aminotransferases and 0.6% of black persons with negative HCV RNA [60]. By contrast, among non-African American persons with positive HCV RNA, 3.4% with abnormal aminotransferase levels had increased iron stores compared with 1.4% of those with normal aminotransferases. The increased risk of elevated iron stores among HCV-RNA-positive black persons persisted despite adjusting for age, alcohol intake, gender, socioeconomic status, and BMI (odds ratio 17.8; 95% confidence interval, 5.1 to 63). The study is limited by the fact that hepatic iron index, which is a better predictor of IFN response, was not available. However, ferritin and transferrin saturation are surrogate markers of hepatic iron concentration. Further study is required to determine the relationship between iron stores and the course of HCV, as well as the response to therapy.
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