Summary of 1 Day Conference Held at NIH in December 1999 entitled "Hepatitis C in African-Americans"
    (excerpted from Gastroenterology 2000; 119: 1385-1396)

pdf version of entire article

On February 18, 2000 NATAP held a 1 day conference on HCV and Charles Howell from the University of Maryland summarized the NIH meeting. A free CD of the NATAP conference can be obtained by contacting NATAP: 212 2190106; 888-26-natap or info@natap.org

Introduction
In the 10 years since its discovery, the hepatitis C virus (HCV) has become recognized as a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma (HCC) in most countries of the world. In the United States, HCV affects 1%-2% of the general population, is the most common newly diagnosed cause of liver disease, and is the most frequent reason for liver transplantation in adults.

1-3 Recent findings indicate that there are large racial and ethnic differences in the prevalence of HCV infection. Antibody to hepatitis C (anti-HCV) is 2-3 times more common among African Americans than whites in the United States,1 and the complications of chronic hepatitis C, such as end-stage liver disease, death from cirrhosis, and liver cancer appear to be more common among African Americans than whites.4,5 African Americans are also far less likely than whites to respond to standard therapy of HCV with interferon, and are seriously underrepresented in clinical trials of new antiviral therapies.6  

To evaluate these issues and to develop strategies to address the health discrepancies related to HCV in African Americans, the National Institutes of Health (NIH) held a 1-day research workshop on December 2, 1999, entitled "Hepatitis C in African Americans." This conference was organized by the National Institute of Diabetes and Digestive and Kidney Diseases and cosponsored by the National Cancer Institute, the National Institute on Drug Abuse, the National Institute of Allergy and Infectious Diseases, and the Office for Research on Minority Health. This review provides a summary of the conference.

Epidemiology of HCV

Miriam Alter, M.D. (Epidemiology Section, Hepatitis Branch, Centers for Disease Control and Prevention, Atlanta, Georgia) reported that the prevalence of HCV infection in the United States has recently been estimated based on testing of stored serum samples from the third National Health and Nutrition Evaluation Survey (NHANES III), conducted from 1988 to 1994. In this survey, 1.8% of the adult, civilian, noninstitutionalized U.S. population had anti-HCV. 

Strikingly, rates of anti-HCV were higher among African American (3.2%) than white populations (1.8%) (Figure 1), a difference that was found in all age groups. After adjusting for socioeconomic status and prevalence of high-risk behaviors, the racial differences were not significant.

 The peak prevalence of anti-HCV was found in the 4th and 5th decades in African Americans, but peaked in the 4th decade in whites, declining thereafter. African American men between 40 and 49 years of age had the highest prevalence of anti-HCV (9.8%).

Testing for HCV RNA by polymerase chain reaction (PCR) showed that 76% of anti-HCV-positive samples had detectable viremia.1  The rate of viremia varied by gender and racial groups. Thus, 86% of African Americans with anti-HCV had HCV RNA compared with only 68% of whites (P < 0.05), and rates of viremia were higher in African American men (98%) than African American women (70%)

These findings suggest that African Americans, and particularly African American men, have a lower rate of viral clearance after acute infection. Extrapolations from these rates of anti-HCV and HCV RNA positivity indicate that 1.5 million whites and 588,000 African Americans in the United States have chronic HCV. African Americans, who represent 12%-13% of the population, account for 22% of the estimated 2.7 million people in the United States with chronic HCV.

Data from the Centers for Disease Control Sentinel County Study have documented a marked decline in acute HCV in the United States since 1989, from an estimated 242,000 per year between 1985 and 1989 to 36,000 per year in 1996.7  This 80% decrease in acute HCV cases was mostly caused by a general decrease in cases of HCV among injection drug users. The decrease in acute HCV occurred in all racial and ethnic groups. 

Overall, 12% of acute hepatitis cases between 1991 and 1996 were attributable to HCV. African Americans accounted for 12% of the United States population and 10% of acute HCV cases. African Americans and whites with acute HCV had similar clinical features, including rates of jaundice (73% and 73%), alanine aminotransferase (ALT) levels increasing above 600 IU/L (65% vs. 65%), hospitalization (9% vs. 16%), and death (2% vs. 2%).

The prevalence and etiology of chronic liver disease has been estimated in a population-based surveillance study performed in Jefferson County, Alabama, in 1988-1989 (in which most patients were white), and a retrospective hospital record review done in Harlem, New York, in 1991-1992 (in which most patients were African American).8 Chronic HCV represented 40% of newly diagnosed cases of chronic liver disease identified in Jefferson County (26% related to HCV alone, 14% related to HCV and alcohol) and 59% of cases in Harlem Hospital (11% HCV alone; 46% HCV and alcohol; 2% HBV, HCV, and alcohol). 

Thus, chronic but not acute hepatitis appears to be more common among African American than white populations in the United States. Furthermore, African Americans with anti-HCV are more likely to be viremic and to have genotype 1 than whites. The reasons for these differences remain to be defined.

HCV Kinetics During Antiviral Therapy in African Americans

Thomas Layden, M.D. (Professor of Medicine, Digestive and Liver Diseases, University of Illinois at Chicago, Chicago, Illinois) discussed HCV viral kinetics after single and multiple injections of IFN-, comparing African American and white patients.35-37  Following the first injection of IFN-, there is an initial delay followed by a 2-phase decline in HCV RNA levels. The initial 8-10 hours probably represents the time required for interferon to induce gene expression and the intracellular antiviral state. 

The first decline in HCV levels (phase 1) occurs between 8 and 24 hours after the first injection, is dependent on interferon dose, and probably represents decrease in virion production by hepatocytes under the influence of the interferon-induced antiviral state. Thereafter, there is a slower decline in HCV levels (phase 2) between days 2 and 14, which is not dose-related, and which probably reflects the gradual death or clearance of HCV-infected hepatocytes. The phase 2 decline continues for weeks to months and is the best predictor of complete HCV RNA clearance.

Although the viral kinetics of HCV clearance can be expressed mathematically using average HCV RNA levels, there is actually a heterogeneity of response, particularly in the second phase decline. The pattern of change in HCV RNA levels varies from patient to patient, some patients having a rapid reduction in HCV RNA and clearing virus within a month of therapy, and others having a slow decline clearing virus at a later point or never becoming HCV RNA negative. Other patients have no further decline in HCV RNA levels after the first phase despite daily interferon administration. The reasons for these differences in viral response in the second phase are unknown.

Recent studies have shown that the pattern of viral kinetics varies by viral genotype and other viral and host factors.35,37 The viral kinetics during IFN- therapy (15 MU daily) in 3 African Americans was compared with that in 4 whites with similar genotype and initial viral load. The phase 1 decline was similar in both groups, suggesting similar drug effectiveness in inhibiting viral production. In contrast, the phase 2 decline rate was significantly faster in the whites than in the African Americans.

Two African American subjects had no decline (<0.5 log) in HCV RNA levels over the month of therapy. Although the number of patients studied was small, these findings provide support to the clinical observations of low rates of response to IFN- among African American patients and provide a means of early assessment and clinical investigation of the reason for the differences in responses.

In a poster session, Sherman et al.38 analyzed HCV quasispecies complexity and diversity by race and ethnicity. Quasispecies analysis was based on heteroduplex assays combined with sequencing of the hypervariable region of the HCV E2 domain. The complexity of HCV quasispecies in 26 African Americans was greater than in 14 whites, matched for genotype, gender, age, and alcohol use. In previous studies, quasispecies complexity has correlated with severity of liver disease and lack of response to interferon. These results promise to provide insights into the relative resistance to interferon among African Americans with HCV.

HCV Among Injection Drug Users

David Thomas, M.D. (Division of Infectious Diseases, Johns Hopkins University School of Medicine, Baltimore, Maryland) described the outcomes of HCV infection in a cohort of 1667 persons infected by injection drug use (ALIVE Cohort). Patients were followed up at 6-month intervals since 1989, and data were available through 1997 (average follow-up of 8.8 years per patient). The mean age of the HCV-infected subjects was 34 years, 78% were men, 94% were African American, and 33% were coinfected with HIV.

Forty-three subjects were anti-HCV negative and subsequently developed antibody.16 HCV RNA was detectable in 42 of 43 subjects, and 37 became persistently viremic. Thus, the chronicity rate after seroconversion was 86% overall, yet 95% (35 of 37) of the African Americans developed chronic infection compared with only 33% (2 of 6) among whites. The patients who cleared HCV RNA had lower quasispecies complexity and a higher rate of HCV genetic mutations that altered the amino acid sequences of viral peptides.17 However, these factors did not explain the higher rate of persistent infection among African Americans. 

Viral clearance was also assessed in a subset of 919 subjects who were already anti-HCV positive when they enrolled. Ninety-five patients had cleared HCV RNA. Factors associated with viral clearance in multivariate analysis were race not African American (odds ratio, 4.8), age <45 years (odds ratio, 1.7), and HIV infection, particularly in those with CD4 lymphocyte counts of <500 cells/mL. Female gender did not correlate with viral clearance. 

Between 1988 and 1997, 40 of 1667 (2.4%) anti-HCV-positive patients developed end-stage liver disease (3.1 per 1000 patient-years). This rate of end-stage liver disease is similar to that reported among German children9  and young Irish women10  in recent cohort studies, but is less than the 7%-8% rates of cirrhosis per decade reported among predominantly white adults with posttransfusion hepatitis.9  The development of end-stage liver disease was associated with patient age (>38 vs. 38 years) and excessive alcohol intake (>250 g per week). Although there was a trend toward less end-stage liver disease among African Americans (relative incidence, 0.43), this was not statistically significance. Gender, moderate alcohol intake, HCV genotype, hepatitis B surface antigen (HBsAg), and HIV status did not correlate with development of end-stage liver disease. 

These findings suggest that African Americans are more likely to develop chronic infection after exposure to HCV, but that the disease tends to progress slowly in the majority of patients.

HCC in African Americans

Hashem El-Serag, M.D. (Assistant Professor of Medicine, Baylor College of Medicine, Houston, Texas) reported that HCC is an uncommon form of cancer in the general population but is common among patients with liver disease, particularly hepatitis B and C. In recent years, HCC, unlike most malignancies, has been increasing in incidence in the United States. Between 1976 and 1995, the incidence of HCC increased by 71% and overall mortality from HCC by 45%.5  Analysis of demographics of patients with HCC shows marked age, gender, and racial-related differences in rates. HCC is 2-3 times more common among men than women, and twice as common among African Americans than whites. The incidence of HCC increases with age, it rarely occurred before the age of 40 years, and peak incidence occurred in the 1970s (Figure 2). The recent increase in incidence of HCC has occurred in both men and women, African Americans and whites. There appears to be a shift in the age-related incidence of HCC to younger persons.

Several observations suggest that the increase in HCC is caused by an increase in the prevalence of HCV. At present, the bulk of patients with HCC were born between 1940 and 1955. This cohort of patients were young adults in the 1960s and 1970s when peak rates of HCV transmission occurred, probably as a result of the spread of injection drug use.1  This association is supported by recent information on the proportion of cases of liver cancer among hospitalized U.S. veterans caused by HCV, hepatitis B, and alcohol. 

Nevertheless, other factors may account for the rising incidence of HCC, including improved imaging and diagnostic tests for HCC, the availability of serologic tests for HCV, and an increased awareness of HCV and its complications. Furthermore, the recent increase in rates of HCC may also reflect the increased emigration of persons from areas of the world where HCC is common, such as Asia and Africa. Nevertheless, the rising incidence of HCC is disturbing. The fact that HCV is twice as common among African Americans than whites also suggests that African Americans will continue to experience twice the rate of HCC as whites.

Liver Transplantation for HCV in African Americans

Andrea E. Reid, M.D. (Associate Professor of Medicine, Massachusetts General Hospital, Boston, Massachusetts) reported that although African Americans represent 12.8% of the U.S. population and are more likely to have chronic liver disease than whites, they are less likely to undergo liver transplantation.

Thus, analysis of data from the United Network for Organ Sharing (UNOS) indicates that only 7% of patients currently on the waiting list for liver transplantation are African American.3  Once on the waiting list, however, African Americans appear to be as likely to receive a liver transplant as persons of other ethnic background. Thus, between 1994 and 1998, 34,845 persons were placed on the liver transplant waiting list and 17,968 (51%) underwent transplantation.3 The rate of transplantation was similar for African Americans (49.6%) as for whites (52.4%). Yet in every UNOS region analyzed, African Americans represented a lower proportion of transplants than their percentage of the population.

The National Institute of Diabetes and Digestive and Kidney Diseases Liver Transplantation Database is a study of 916 patients who underwent liver transplantation at 1 of 3 medical centers in the United States between 1991 and 1994.27 In that study, only 44 patients (5%) were African American. Overall, there was no difference in survival after liver transplantation for African Americans vs. whites. However, survival among 42 non-whites (heterogeneous ethnic background) with HCV was lower than the 124 whites. The cause of death was recurrent HCV in 19% of whites compared with 44% of non-whites.

There were too few African Americans in this study for meaningful further analyses. Thus, the complete explanation for poorer survival is unknown.

Racial and Ethnic Issues in HCV Research

Claudia R. Baquet (Associate Professor of Epidemiology, Preventive Medicine Director, Cancer Prevention and Control Research, University of Maryland, Greenebaum Cancer Center, Baltimore, Maryland) discussed the racial and ethnic barriers to participation of African Americans in clinical research. In the United States, African Americans account for at least 22% of patients with HCV1 but are usually underrepresented in clinical trials of antiviral therapy, comprising <5% of patients in the 5 large clinical trials discussed in this meeting (Table 1). The small participation of African Americans in these trials prevent meaningful assessment of the efficacy, safety, and utility of antiviral agents in African- Americans.

The reasons for a lack of participation of African Americans in clinical research are multiple and interrelated.39 There is a low awareness of the significance of liver disease and HCV among African Americans. Multiple socioeconomic limitations complicate participation in research, including low income, education level, and inability to lose the time from work to participate in medical research. Also, minority individuals have a general distrust of medical institutions and research, arising out of a long history of racial bias in academic medicine and clinical research.

The barriers to participation in clinical research can be categorized into 6 areas: patient, community, health care professionals, investigator, research institution, and health system. Patient barriers are personal attitudes toward such participation, mistrust of the research and the institution, fear of the consequences of research or what might be discovered, and cultural issues. There may be little administrative support for persons from lower socioeconomic conditions and lack of reimbursement for travel, loss of work, or per diem costs.

Community barriers include fear of exploitation and poor relationships between the African American and the academic communities. For many African American communities, other priorities are more important, such as providing a safe environment, adequate housing, better education, and basic medical care. The community health care professional barriers include a lack of information on availability of clinical studies, negative personal views regarding research benefits and risks, and lack of understanding of research design. Community physicians may also be concerned about losing patients and reimbursement. Research investigator barriers include the failure to use culturally sensitive approaches and lack of awareness of fears and areas of distress of minority patients. Investigators also often fail to reach out to community groups and depend largely on referral from physicians who serve middle- or upper-socioeconomic communities. Research institutional barriers to wider minority participation in clinical research include rigidity in scheduling of visits, isolation, and lack of involvement in the community, and an inability to fund outreach efforts or provide reimbursement to patients in lower socioeconomic groups.

Approaches to overcoming barriers to wider involvement of minority individuals in clinical research can be classified into 4 strategies or models. In the medical-system participation model, health care professionals from underserved communities are active partners, recruiting and treating patients, gathering data, and providing results to the established research organization. This model is best used for diseases that are common and for therapies that are easily applied. In the medical-system referral model, health care professionals from underserved areas are actively recruited to help in the referral process. Patients are referred to a central research center and the investigators and support staff operate from these established research institutions. This model is best for the relatively uncommon disease and therapy that is complex or likely to have problematic adverse events. In the general community-direct model, the central research organization appeals directly to patients, not depending on referral from health care professionals. Typically, familiar media and community contacts such as churches, community centers, and radio talk shows are used. This model is best used for diseases or conditions that are common and generally understood by the patient. In the general community-indirect model, research organizations use intermediaries or brokers to reach patients. The intermediaries act as agents for recruitment between community residents and the established research organization. An excellent intermediary to reach African American patients are churches and ministers.

Recognition of the barriers to participation in clinical research is needed to lay the groundwork to overcome these barriers. A community outreach strategy can be helpful in correcting the lack of participation of minority individuals in clinical research.

(Editorial comment from Jules Levin: Another point not addressed above is the role that treatment education can play. Education from properly trained persons can help alleviate fears. As well, such education can help patients better understand the treatment issues relevant to the study and to themselves and the community).

HCV in African Americans: Summary and Conclusions

Charles Howell, M.D. (Director, Division of Hepatology, University of Maryland School of Medicine, Baltimore, Maryland) provided an analysis of large databases on the epidemiology, natural history, complications, and therapy of HCV for racial differences have provided several common themes that offer research challenges to understanding this important liver disease.

Clearly, chronic HCV is 2-3-fold more common among African American than white populations.1 The higher rate correlates with the lower socioeconomic status among African Americans. Most studies have also shown that African Americans, once infected with HCV, are more likely to develop chronic

infection.1,16 In particular, African American men have a 90%-95% rate of chronicity, far higher than the 65%-75% rate for whites. The reasons for the higher chronicity rate are not known, but may be virological (genotype, stain, quasispecies diversity) or host-related (genetic, immunologic, behavioral).

Interestingly, genotype 1 appears to be more common in African Americans than whites, and genotype 3 is less common. The high rate of genotype 1 is a major reason why African Americans have a low response to current therapy. Whether the differences in genotypes are also responsible for differences in chronicity is not clear.

Although chronicity is more common, the rate of progression of liver disease to cirrhosis may be slower in African Americans than in whites. Yet because of the higher rate of infection, African Americans have a higher rate of cirrhosis, HCC, and death from HCV-related liver diseases than whites.3-5 The apparent discrepancy between the estimated progression rate of liver fibrosis and morbidity among African Americans with HCV may be explained by the limited size, retrospective nature, and patient-selection bias of current studies. The issue of rate of progression can be addressed adequately only by prospective studies of African American and white cohorts with HCV.

Of enormous importance is the finding of a poor rate of virological response to IFN- therapy among African Americans.6 This low rate of response is partially attributable to the high prevalence of HCV genotype 1. However, one is still left with a dismally low rate of response to interferon among African Americans compared with whites. Indeed, in the 5 trials of IFN- therapy for HCV reviewed here, the total number of African American patients with genotype 1 who had an SVR to IFN- monotherapy was one. It is doubtful that IFN- would have been approved for use in HCV, had the initial clinical trials used a predominantly African American population. Furthermore, it is doubtful that any physician would recommend interferon monotherapy for an African American patient with HCV outside of the 5%-10% who have non-1 genotype infections.

Preliminary evaluation of 2 large clinical trials has shown that the combination of interferon and ribavirin yields a higher rate of response in both African Americans and whites, but the overall rate is still somewhat low.13 The low response rate may be caused by viral genotype, rather than actual racial differences.

 However, it should be stressed that <5% of the participants in these trials were African Americans. Thus, 9 years after IFN- was approved for use in chronic HCV and 2 years after approval of combination therapy in the United States, there remains inadequate information on the response rate of African Americans to licensed therapies for this disease. These findings emphasize the need for active outreach to achieve adequate representation of all ethnic groups in clinical trials.

The analysis of kinetics of HCV RNA clearance during therapy with interferon has provided important clues to the basis of racial differences in response

to therapy in HCV. African Americans are more likely to have an interferon-resistant phenotype, with either no response or a flat response of HCV RNA levels during treatment. These findings suggest a host-related defect in interferon signal transduction or a viral-related interference with interferon action.

An important priority is for further research on the biological basis for this lack of response to interferon, evaluating all steps in interferon receptor occupancy, signal transduction, and gene expression, as well as cytokine production and activity during therapy, serum and intrahepatic HCV RNA levels, HCV strain differences, HCV sequence variations such as in the interferon-sensitivity determining region, immune responsiveness to HCV antigens, antibody levels to HCV epitopes, iron and antioxidant status, and other biomarkers.37, 38, 40  

What also is clearly needed is a greater participation of African Americans in both clinical investigation and clinical trials in HCV. The use of community outreach models and direct approaches to decreasing barriers to patient participation should be the first priority in approaching the issue of HCV in African Americans and decreasing the health disparities for this important and common form of liver disease. 

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