Treating hepatitis C in African Americans

Authors



Lennox J. Jeffers, MD, Department of Medicine, Center for Liver Diseases, Division of Hepatology, Room D1011, Veterans Affairs Medical Center, 1201 N.W. 16th Street, Miami, FL 33125.
Tel: +305 243 5787
Fax: +305 346 3253
e-mail: l.jeffers@miami.edu

Abstract

Background: The epidemiology, natural history and response to therapy of chronic hepatitis C differs significantly between African Americans and other ethnic populations. The reasons for these differences are not entirely clear but include mode of transmission, viral kinetics, immune responsiveness, and demographics.

Objective: Review of the peer-reviewed literature and expert opinion from 1990 to 2005 regarding features of hepatitis C virus (HCV) infection in African Americans, differences in presentation and response to therapy, and treatment recommendations.

Results: The epidemiology of HCV infection in African Americans appears to be predominantly associated with socio-economic status and high-risk behaviors. However, disease course, response to treatment, and virologic outcome may be a function of race. African Americans may clear HCV less efficiently than other ethnic groups, although impaired immune responsivity may also lead to decreased necro-inflammatory activity and progression to cirrhosis. Therapy-naive African Americans have lower sustained virologic response rates to this treatment than other populations.

Conclusions: Strategies to improve outcomes in African Americans include higher doses of current medications, medications with fewer adverse events, and new experimental molecular therapies.

Chronic hepatitis C is a global epidemic, with more than 170 million people infected worldwide (1). In the United States, almost 4 million patients have been infected by the hepatitis C virus (HCV), and approximately 3 million have chronic hepatitis C (2). Although the initial stages of infection are often silent, chronic hepatitis C is a major cause of chronic liver disease, cirrhosis, end-stage liver disease (ESLD), and hepatocellular carcinoma (HCC). In the United States, chronic hepatitis C is the most common cause of newly diagnosed liver disease (2).

The epidemiology of chronic hepatitis C, the natural history of HCV infection, and response to therapy differ greatly between racial and ethnic groups. The reasons for these differences are not entirely clear but appear to involve mode of transmission, viral kinetics, variability in immune responsiveness, and other demographic factors. In the United States, anti-HCV seropositivity is two to three times more prevalent in African Americans than it is in whites (3). In addition, African Americans are at greater risk for the complications of chronic hepatitis C, including ESLD, HCC, and death (4, 5). African Americans are also less likely to respond to current HCV therapies than are whites, which can complicate interpretation of clinical trial data. This article examines the likely reasons for the additional disease burden and therapeutic difficulties in African Americans with chronic hepatitis C. The peer-reviewed literature was assessed along with expert opinion from 1990 to 2005 regarding features of HCV infection in this ethnic group, mechanisms associated with differences in presentation and response to therapy, and recommendations for treatment.

Epidemiology of hepatitis C in African Americans

The historically low rate of HCV seropositivity has increased in the United States since the mid-1900s. In frozen blood samples from 8568 military recruits from 1948 to 1954, the seroprevalence of anti-HCV antibodies was 0.2% (6). The Third National Health and Nutrition Examination Survey (NHANES III) from 1988 to 1994 reported that 1.8% of Americans were seropositive (3). This nine-fold increase occurred in concert with increases in parenteral drug use and high-risk sexual activities, starting primarily in the 1960s.

The trend in HCV seropositivity in African Americans mirrors that in the white population, although the figures are higher (Fig. 1) (7). In the study of military recruits, HCV antibody (anti-HCV) was identified in 0.07% of whites and 1.8% of blacks (6). NHANES III data show that the prevalence of HCV infection continued to vary by race (3). The prevalence in whites in the late 1990s was 1.5%. At the same time, the seropositivity in non-Hispanic blacks was 3.2%. Thus, although African Americans are only approximately 12–13% of the population, they account for almost 20% of HCV-infected Americans (8). Of the estimated 3.9 million Americans infected with HCV, approximately 780 000 are African American.

Figure 1.

 Prevalence of hepatitis C virus (HCV) infection by age and race in the United States, 1988–1994 (7).

Subgroup analysis of the NHANES III data reveals some interesting statistics. In the United States, the highest prevalence of anti-HCV was 9.8%, occurring in African-American men 40–49 years of age (3). The second highest prevalences were 6% in African Americans 30–39 years of age and Hispanics 20 years of age and older. Importantly, in the statistical analysis of the NHANES III data, the epidemiologic association between HCV and African-American race was more a function of socioeconomic status and high-risk behavior than race (3).

The prevalence of HCV infection has also been studied in military and institutionalized African-American populations. In a study of 10 000 randomly selected active-duty military personnel (including 1000 oversampled non-white, non-black personnel) who provided serum that has been frozen since 1997, the prevalence of anti-HCV in African Americans was twice that of whites (0.8% vs. 0.4%) (9). The lower incidence of hepatitis C in African Americans and other racial or ethnic groups in this study compared with the general population was attributed to mandatory pre-induction testing for illicit drugs and regular drug screening throughout military service. In a correctional setting, which has a high proportion of African Americans, the reported prevalence of anti-HCV is 15–40% (10–12).

Natural history of hepatitis C infection

Genotype 1 is the most common HCV strain in the United States and among African Americans (2, 13). In the Western world, approximately 74% of infections are HCV genotype 1 (1a, 56.7%; 1b, 17%). The prevalence of genotype 1 is 67% in whites but 91% in blacks. In addition, blacks are twice as likely to be infected by genotype 1b as whites (2, 13). The high prevalence of genotype 1 is a major prognostic factor for adverse events in this group.

African Americans may be unable to clear HCV efficiently (7). A study of 43 patients who seroconverted to HCV positivity while under observation showed that white patients were significantly more likely to clear the virus than African Americans (14). Although 37 (86%) of the 43 HCV-infected patients developed chronic hepatitis, chronicity was significantly associated with African-American ethnicity: chronic infection developed in 95% of the African Americans but in only 33% of the white patients (P=0.04).

Differences in viral clearances may be a function of racial differences in immunologic reactivity. A study of HCV-specific CD4+ cell response indicated that African Americans had a significantly greater proliferative response to HCV NS3–NS5 antigens than did white Americans (22% vs. 0%; P=0.007) (15). Although this response suggests the potential to clear the virus more effectively, the HCV-specific CD4+ T-cell proliferative response in African Americans was dysfunctional: most showed no increase in interferon-γ (IFNγ) production. IFNγ is a cytokine that inhibits protein synthesis and RNA replication of subgenomic and genomic HCV replicons (16). Thus, African-American ethnicity may be a risk factor for chronicity of HCV infection.

Despite the prevalence of genotype 1 infection and some degree of immune dysfunction in black patients, African-American ethnicity may be associated with some positive prognostic features. Although alanine aminotransferase (ALT) levels may not always accurately reflect the stage of chronic hepatitis C, as they are only weakly associated with disease activity (2), several studies have reported that African Americans are significantly more likely to have lower ALT levels than other populations (17). A study of 302 consecutive inmates with chronic hepatitis C at a correctional facility reported that African Americans had significantly lower mean ALT levels (79 vs. 106 U/l; P=0.01) and were more likely to have normal enzyme levels than white patients (57% vs. 46%; P=0.06) (12).

While the histologic activity index did not differ significantly between the African American and white inmates, the former had significantly lower piecemeal necrosis scores, a finding that may correlate with lower ALT levels (12). Similar histologic features were identified in a retrospective review of 355 patients with hepatitis C (17). African Americans may also have less fibrosis than whites. In the inmate study, African Americans had significantly lower mean fibrosis scores than whites (1.12 vs. 1.14; P=0.047) (12). This observation was consistent for the prevalence of all types of fibrosis: portal (42% vs. 48%), bridging (17% vs. 20%), and cirrhosis (5% vs. 8%). In the retrospective review just mentioned, African Americans also had fewer cases of cirrhosis (22% vs. 30%) (17).

These observations suggest that genetically mediated immunologic features may have both negative and positive effects on the course and prognosis of chronic hepatitis C in African Americans. Although impaired CD4 cell cytokine response may increase the risk of disease persistence, the impaired immunologic reaction may produce less necro-inflammatory activity and progression to cirrhosis. However, these beneficial features may be negated by impaired access to health care, resulting in higher overall mortality (6).

Chronic hepatitis B and C and alcoholism are risk factors for HCC (18). The incidence of HCC is increasing in the United States, in a greater proportion of African Americans than whites (19, 20). In 1991, the incidence of histologically documented HCC in African Americans and whites was 6.1 and 2.8 per 100 000 people, respectively (19). Although other factors may contribute, the epidemic of HCV in the 1960s and 1970s is believed to account for the increase in HCC (4). Because the prevalence of HCV in African Americans is double that of whites, it is reasonable to assume that African Americans will continue to experience HCC at twice the rate of whites. Despite improvements in diagnosis, the 5-year survival rate for HCC is only about 6%. In addition, blacks have an HCC-associated mortality rate that is twice that of whites (21). Thus, African Americans remain at substantial risk for both morbidity and mortality from non-neoplastic and neoplastic liver disease.

Treatment for hepatitis C

Interferon monotherapy

Before investigators established the safety and efficacy of combination therapy with IFN plus ribavirin, IFN monotherapy was the treatment of choice for chronic hepatitis C. However, several studies noted that African-American patients did not respond as well as white patients.

In 420 patients with chronic hepatitis C treated with either IFN α-2b (3 million units) or consensus IFN (9 μg) three times per week for 24 weeks, response rates were lower in the 40 African-American patients than in other groups (22). Although patients were matched for age and baseline HCV RNA levels, African Americans had significantly lower end-of-treatment rates (5% vs. 33%; P=0.04) and sustained virologic response (SVR) rates (2% vs. 12%; P=0.07). The racial disparity was not significant in Hispanics or Asian Americans. Stepwise regression analysis suggested that this difference reflected higher HCV RNA levels (3.6 vs. 3.0 million copies/ml) and a higher prevalence of genotype 1 (88% vs. 66%; P=0.004) among African Americans. The effect of genotype 1 on the response to IFN therapy of African Americans was supported by a subsequent retrospective analysis of 61 African Americans and 49 whites (23). However, subsequent analysis of the 420 patients indicated that the racial difference, rather than the prevalence of genotype 1, was a major contributor to outcomes (13). When matched for genotype 1, African Americans were less likely to attain SVRs than whites (1% vs. 17%).

Impaired response to therapy is also evident in African Americans treated with dose-intensive IFN monotherapy. In a retrospective analysis, 31 African American and 62 white patients were matched according to genotype, sex, presence or absence of cirrhosis, age, and histologic score, and were treated with high-dose IFN α (5 million units) daily for 12 months (24). Virologic responses were evaluated after 6 and 12 months of treatment 6 months after cessation of therapy. Race-related impairments were observed in the African American subgroup at all time points. On-therapy and end-of-therapy virologic response rates were 26% vs. 60% (P<0.01) and 10% vs. 53% (P<0.001) for African American and matched patients, respectively (24). A second retrospective analysis supported these observations and noted that HCV RNA declined more slowly in African Americans than in whites (25).

Interferon plus ribavirin combination therapy

Although ribavirin is ineffective in lowering HCV RNA levels by itself, it significantly improves outcomes when administered in combination with IFN (26, 27). Pegylation of IFN improves the molecule's pharmacokinetics, and the combination of pegylated IFN (PegIFN) plus ribavirin is now the standard of care for patients with chronic hepatitis C (28, 29).

Recent studies comparing the efficacy of combination therapy in African Americans and white patients challenged the assertion that the racial disparity in SVRs is related to the higher prevalence of genotype 1 among blacks (Table 1) (30–34). The results of a prospective, multicenter, open-label trial of 78 African and 28 white Americans with genotype 1 infections found that a racial disparity in outcomes persists; however, the improvements seen with combination therapy were apparent (32). Patients were treated with PegIFN α-2a (180 μg/week) plus ribavirin (1000/1200 mg/day) for 48 weeks. In the intent-to-treat analysis, SVR rates (HCV RNA <50 IU/ml) were 26% in African Americans and 39% in whites. These rates were better than those reported in smaller studies of black patients but indicate a continuing need for substantial improvements in both populations. For patients who completed the full 48-week therapeutic course, SVRs were attained in 48% of African Americans and 50% of whites. Importantly, combination therapy improved fibrosis in 25% of African-American patients. Adverse event rates were generally higher in whites. However, neutropenia was observed in approximately twice as many African Americans (37%). Ribavirin dose reductions for anemia were required in 24% of African Americans and 32% of whites. These data show that combination therapy is safe and offers antiviral and histologic benefits to African Americans (32).

Table 1.   Trials comparing sustained viral response rates in African Americans and whites with chronic hepatitis C treated with interferon plus ribavirin combination therapy
TrialNAfrican Americans (n)TreatmentSVR rateComments
  1. ALT, alanine aminotransferase; BMI, body mass index; Hb, hemoglobin; PegIFN, pegylated interferon; RBV, ribavirin; SVR, sustained virologic response.

Conjeevaram et al. (30)401196PegIFN α-2a+weight-based RBV for 48 wkWhite: 50%
African American: 28%
1. The differences in virologic response between the two ethnic groups were apparent at 4 wk and persisted thereafter
2. The African Americans had higher BMIs and lower ALT, neutrophil, and Hb levels (P<0.001)
Jacobson et al. (31)5000387 with genotype 1PegIFN α-2b+RBV (standard or weight based)African American: 21% (weight-based) or 10% (standard)1. Anemia (Hb<11 g/dl) occurred in 47% of weight-based group
2. Weight-based RBV offers a significant advantage in African Americans
Jeffers et al. (32)106, all with genotype 178PegIFN α-2a+RBV (weight based) for 48 wkWhite: 39%
African American: 26%
1. SVR was 48% in African American patients who completed all 48 wk
2. Study was not powered to evaluate racial differences
3. Mean weight of African American patients was 6 kg greater than that of whites
Muir et al. (33)200, 98% genotype 1100, matched to white patientsPegIFN α-2b+RBV for 48 wkWhite: 52%
African American: 19%
1. African American patients had significantly lower 12-wk and end-of-treatment responses

A second US study evaluated the efficacy and safety of combination therapy in 200 matched African Americans and whites distributed equally into two groups; 98% of patients had HCV genotype 1 infection (33). Patients were treated for 48 weeks with PegIFN α-2b (1.5 mg/kg/week) plus ribavirin (1000 mg/day for 12 weeks, followed by 800 mg/day for the remainder of the active treatment). Compared with whites, African-American patients had significantly (P<0.001 for all) lower SVR rates (19% vs. 52%) and early (40% vs. 69%) and end-of-treatment (20% vs. 58%) virologic response rates. Multivariate analysis indicated that African-American ethnicity was the only variable significantly associated with the differences in response rates (P<0.001) (33).

These results were confirmed by a third study of 196 African-American and 205 white treatment-naïve patients with chronic hepatitis C who were treated with pegIFN α-2a and ribavirin for up to 48 weeks (30). As with the earlier studies, SVR rates were lower in the African American than in the white group (28% vs. 52%; P<0.0001). African-American ethnicity was again an independent predictor of not achieving an SVR in the multivariate analysis (P<0.001). This difference was not explained by disease characteristics, baseline viral levels, or amount of medication taken.

Liver transplantation

Live or cadaveric liver transplantation is the therapy of choice for patients with chronic hepatitis C and ESLD. Surgical excision and liver transplantation may also be curative in patients with small HCC (18). In the United States, HCV-associated liver disease is the most common indication for liver transplantation (2). However, African Americans are underrepresented on waiting lists for the procedure. In a study of the United Network for Organ Sharing database, only 7% of patients were black (35). Yet, once on the waiting list, their likelihood of receiving a transplant is similar to that of other ethnic groups. Between 1994 and 1998, 34 845 patients were placed on the list and 17 968 (51%) received a transplant; African Americans had the same rate of transplantation as whites (49.6% vs. 52.4%) (18). Thus, barriers to transplantation in African Americans appear to come before the referral process and are most likely related to health care access and economic factors (4).

African Americans may also have a lower long-term survival after liver transplantation. In 345 patients with chronic hepatitis C in the United Network for Organ Sharing database, African-American ethnicity was independently associated with an increased risk of death, identified within 2 years after transplantation (35). At 4 years, survival was 71% among blacks and 77% among whites (<0.001 for ethnicity). The negative effect of African American ethnicity on survival of patients with chronic hepatitis C after transplantation was confirmed in another study of 345 patients, 17 (5%) of whom were African Americans (36). Although 1-year survival was similar in the various ethnic groups, it was 6% less at 3 years and 7% less at 5 years for African Americans than it was for whites. The differences in long-term survival are not fully explained. However, potential factors include severity of disease recurrence, comorbidities, and duration of disease before seeking medical treatment.

Response to treatment in African Americans

Ethnic differences in response to treatment for HCV are clear (Fig. 2) (37). Although several potential explanations for these differences have been proposed, the basis remains uncertain.

Figure 2.

 Sustained virologic response for different interferon doses by ethnicity. Reprinted with permission from Hepburn et al. (37).

Non-adherence to treatment

Adherence to treatment is important to maximize outcomes but is challenging, particularly when treatment is for a chronic and largely silent disease. For example, after 3 months of therapy, only 60% of a cohort of Medicaid patients was at least 80% adherent to statin therapy for primary or secondary prevention of coronary heart disease (38). In patients with chronic hepatitis C, an adherence rate above 80% has clinically and statistically significant advantages. One study found that genotype 1-infected patients who were maintained on more than 80% of their IFN or PegIFN α-2b and ribavirin dosages for the duration of treatment in a clinical trial had enhanced SVR rates (39).

Adherence to pharmacotherapy has also been inversely linked to adverse event rates (40), and this relationship is particularly important for combination therapy with PegIFN plus ribavirin. Both medications have potentially serious adverse effects. Although no evidence suggests that African Americans are less adherent to combination therapy than whites, the black race has been associated with a 57% decreased adherence to immunosuppressive medications, as measured using microelectronic cap monitors on medication bottles provided after renal transplantation (41).

Body weight and weight-based dosing

Obesity is increasing in prevalence in all age and ethnic groups in the United States; however, it is increasing disproportionately among African Americans (42). Racial disparities in body weight can have substantial effects on pharmacokinetics, therapeutic outcomes, and the interpretation of clinical trials. The dose of ribavirin, expressed per kilogram of body weight, is independently associated with SVR (28). When SVRs were assessed according to the amount of ribavirin received relative to body weight (mg/kg), SVR rates were higher than those observed in the randomized analysis. This result is relevant to African Americans treated for chronic hepatitis C because they weigh an average of 6–7 kg more than whites (32, 33).

Given ribavirin pharmacokinetics and the importance of dose, heavier patients will have lower SVR rates when treated with the same amount of ribavirin used for lighter-weight patients. The weight-based dosing of interferon and ribavirin (WIN-R) trial compared PegIFN α-2b plus either fixed or weight-based ribavirin dosing of patients with chronic hepatitis C (31). The preliminary results support the importance of optimizing ribavirin dose in African Americans with genotype 1 infections. The multicenter study evaluated the response to Peg-IFN α-2b plus a standard ribavirin dose of 800 mg/day or one of four weight-based ribavirin regimens: (1)<65 kg: 800 mg/day; (2) 65–85 kg: 1000 mg/day; (3) 86–104 kg: 1200 mg/day; and (4) 105–124 kg: 1400 mg/day (31). Of the approximately 5000 patients randomized, 387 were African Americans with genotype 1 infections who received at least one dose of the study drugs. The demographic makeup of the African-American enrollees was male sex, 64%; mean body weight, 89 kg; HCV RNA>600 000 IU/ml, 64%; and Metavir stages 3 or 4, 31%. On an intent-to-treat basis, weight-based dosing was clearly superior: of 362 enrollees with body weight of at least 65 kg, the end-of-treatment response rate was 29% in the weight-based dosing group and 10% in the standard dose group. However, SVR rates were similar: 21% for weight-based dosing and 10% for standard dosing. Patients who received weight-based ribavirin doses were less likely to relapse than those who received standard doses (22% vs. 31%). In fact, as patient weight increased, the efficacy of ribavirin in weight-based doses also increased. Importantly, however, weight-based dosing was much more likely to result in ribavirin-associated anemia than standard dosing (29% vs. 47%) (31).

Weight-based dosing may also be important for the PegIFN component of combination therapy. The preliminary results of the Re-treatment of Non-responders with Escalating Weight-based Therapy (RENEW) trial suggest that African Americans who fail to respond to standard IFN plus ribavirin will have higher rates of SVR if the dose of PegIFN is doubled (16% vs. 4%) (43).

Dose reduction or premature discontinuation

Adverse events secondary to either of the drugs used in combination therapy can result in dose reductions or discontinuations. The most common adverse events reported during clinical trials of PegIFN α-2a were neuropsychiatric: fatigue or asthenia (56%); headache (54%); myalgias (37%); irritability, anxiety, or insomnia (19%); depression (18%); and anorexia (17%) (44). In 500 consecutive patients with chronic hepatitis C in a tertiary medical center, depression was reported in 85 (24%) of 359 untreated patients and required treatment in nearly two-thirds (45). Depression has been reported to prompt discontinuation 4% of African Americans and 6% of white Americans treated with combination therapy for chronic hepatitis C (33). Although it may require dose reduction or drug discontinuation, depression in patients receiving IFN can generally be treated with a selective serotonin re-uptake inhibitor (46, 47).

Anemia is a common side effect of combination therapy and is reported in approximately equal numbers of African American and white patients. In one study that included both populations, dose reductions for anemia were required in 24% of blacks and 32% of whites. Importantly, decreases in ribavirin dose for anemia can lower SVR rates (48, 49). Anemia is currently treated with recombinant human erythropoietin (rHuEPO), a growth factor that restores the patient's hemoglobin and improves quality of life. In 185 patients with chronic hepatitis C, ribavirin dose was maintained in 88% of patients receiving rHuEPO and in only 60% of those receiving placebo (P<0.001) (50).

Neutropenia is also common in African-American patients undergoing combination therapy, occurring in 37% in one study (32). In a more recent study of chronic hepatitis C in African-American patients, dose reductions of pegIFN α-2a owing to anemia were required in 46% of patients (51). Importantly, the same study showed that no patient who received less than 60% of their planned pegIFN dose achieved an SVR, highlighting the need to manage treatment-treated adverse events effectively. IFN-mediated neutropenia may be successfully managed with filgrastim. A study in 39 patients with pegIFN-related neutropenia receiving filgrastim demonstrated significant improvement in 89% of patients (32, 52).

Viral dynamics

Mathematical modeling of HCV viral dynamics reveals that after a dose of IFN, HCV RNA levels decline in a biphasic pattern (53–55). The first phase of the decline is caused by IFN blocking virus production and a rapid rate of clearance of free virions (56). The second phase appears to result from the ability of IFN to continue to block viral production plus a net loss of virus-producing cells.

A comparison of viral dynamics in 19 African American and 16 white patients found significant differences between the two groups that were associated with African Americans' inability to eliminate the virus (57). All patients were treated with IFN α-2b 10 million units with or without ribavirin for 1 month, followed by 3 million units plus ribavirin. African-American patients had significantly lower drug effectiveness measured by viral kinetics (treatment effectiveness at inhibiting virion production; loss rate of virus-producing cells; clearance rate of free virions; and delay until viral decline begins) than white patients (88.6% vs. 98.2%; P=0.005); their first-phase decline in HCV RNA was 0.8 logs lower during the first 24 h of treatment. The clearance of virus-infected cells, as reflected in the second-phase curves, was also significantly slower (P=0.006). No correlation was identified between any of the viral kinetic variables and either age, body mass index, or genotype 1 virus infection. Thus, IFN appears to be less effective in clearing HCV in African Americans than it is in whites. The cause of the difference is unknown.

Improving outcomes in African Americans

Potential explanations for the higher prevalence of chronic hepatitis C and poorer response to HCV therapy among African American vs. white patients can generally be divided into two categories: (1) patient-related factors and (2) disease-related factors.

Patient-related factors

Hepatitis C is predominantly transmitted parenterally. African Americans are disproportionately affected by intravenous drug abuse, chronic hepatitis C, HIV, and AIDS (58). Therefore, additional and continuous efforts should be made to reduce these risk factors in this population. African Americans are often underserved medically (59). Educational efforts should be made to increase awareness of the prevalence and outcomes of untreated chronic hepatitis C in the African-American community. Such efforts have the potential to lower the age of diagnosis, decrease the transmission of the disease, and expand the pool of African Americans with ESLD on the transplant list.

More common among African Americans, obesity can greatly reduce the effect of ribavirin in treating chronic hepatitis C. Efforts to decrease the prevalence of obesity in this group can improve outcomes after combination therapy as well as substantially decrease cardiovascular morbidity and mortality. Lastly, because adherence to pharmacotherapy is significantly associated with virologic clearance, the importance of maintaining the prescribed dose and schedule should be emphasized.

Treatment-related factors

African Americans with chronic hepatitis C need better therapies to overcome an increased prevalence of genotype 1 infections and an inability to clear HCV efficiently. Several new medications that may improve outcomes are in various stages of development. Future therapies for African Americans and others with difficult-to-eradicate HCV infections may combine an IFN and a ribavirin analog plus other medications in a manner similar to highly active antiretroviral therapy for advanced HIV disease.

New interferons

Several α and non-α IFNs are being studied for treatment of chronic hepatitis C. They include albumin-linked IFN, consensus IFN, gene-shuffled IFNs, and non-α IFNs. Albumin-IFN α, an IFN α-2b linked to albumin (60), is well tolerated and has a prolonged half-life. Consensus IFN was created by assigning the most frequently observed amino acid of several natural α IFNs to a corresponding position in the recombinant molecule (61). Modification of the molecule to improve its pharmacokinetics may provide a therapeutic indication for this IFN variant. The results of a single-center trial suggest that African American non-responders to PegIFN plus ribavirin may respond to consensus IFN plus weight-based ribavirin (62). Interestingly, there were no significant statistical differences between African Americans and whites in virologic response at weeks 24, 48, and 72. DNA shuffling techniques can yield IFN molecules with improved antiviral and antiproliferative activities (63). A variety of IFNγ and IFNΩ species are also under development. However, their utility is yet to be demonstrated clinically.

Ribavirin analogs

Ribavirin, an inosine monophosphate dehydrogenase inhibitor, can significantly improve outcomes compared with standard or PegIFN alone (26–29). However, ribavirin-related hemolytic anemia has led to dose reductions and drug discontinuations that can be associated with an inability to achieve an SVR.

Taribavirin is a liver-targeting prodrug of ribavirin now in phase 3 clinical trials. In an open-label, multicenter, 48-week study of combination therapy with PegIFN α-2a plus taribavirin or ribavirin in 180 patients, the drug produced similar antiviral efficacy with significantly less anemia (64). The antiviral efficacy of taribavirin was similar to that of ribavirin across genotypes. However, the incidence of severe anemia was much lower in the ribavirin group (4% vs. 27%; P<0.0001) (Fig. 3). The subsequent VIramidine's (taribavirin's) Safety and Efficacy vs. Ribavirin (VISER I) study also demonstrated a lower incidence of drug-associated anemia in the taribavirin vs. ribavirin arm (5% vs. 24%, P<0.01). However, taribavirin failed to meet the non-inferiority efficacy end point in VISER 1 (65).

Figure 3.

 Incidence of anemia (hemoglobin <10 g/dl) at any time during therapy. Reprinted with permission from Gish (64).

Another inosine monophosphate dehydrogenase inhibitor, merimepodib, was dropped from development after disappointing results from a double-blind, placebo-controlled, randomized phase 2b study of this medication given in combination with PegIFN α-2a and ribavirin in non-responders.

Other medications

Like HIV, the HCV replication cycle provides a number of potential targets for antiviral therapy. They include the HCV internal ribosome entry site, the viral NS3 serine protease, helicase, and the viruses' RNA-dependent polymerase. Potential internal ribosome entry site inhibitors include antisense oligodeoxynucleotides, ribozymes, and small-interfering RNAs (66–68). VX-950 is a well-tolerated NS3 protease inhibitor. In a phase 1b study of VX-950 administered in three doses over 14 days to therapy-refractory patients with genotype 1 infection, all treatment groups achieved on average a three- to four-fold decline in HCV RNA shortly after therapy was initiated (69).

Hepatitis C virus replication depends on the activity of the viruses' RNA-dependent RNA polymerase. Double-blind, randomized, phase 1 studies of valopicitabine (NM283), a drug that targets the active site of HCV NS5B polymerase, have shown moderate antiviral efficacy and side effects that were generally minor, except nausea and vomiting in some patients (70). Interim results of a phase 2a randomized trial of valopicitabine plus PegIFN α-2b suggest that the drug rapidly reduces HCV RNA levels (71).

Conclusions

Hepatitis C is more prevalent in African Americans and responds differently to current therapies. Currently, SVR rates are in the 19–28% range. The only explanation at this time for the observed differences in outcomes is the African-American race. Data from ongoing and future studies may provide additional information about genetic factors, differences in immune response, and IFN signaling that may further clarify this issue. To improve outcomes in African Americans with chronic hepatitis C, steps should be taken to decrease disease prevalence. Newer medications may also improve outcomes in difficult-to-treat African-American patients.

Acknowledgement

I wish to thank Richert Goyette, MD, for writing and editorial assistance during the preparation of this manuscript.

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