In the United States the rate of HCV infection among blacks is estimated at 2-3 times higher than the rate seen in whites, and blacks appear less likely to naturally clear the virus. Several retrospective studies with small numbers of black participants have shown that blacks do not respond as well as whites to interferon-based therapy. Two new prospective studies confirm this finding.
In the May 27th edition of the New England Journal of Medicine, Andrew Muir and colleagues reported on an open-label study of 100 black and 100 non-Hispanic white participants. Ninety-eight percent of patients in both groups had HCV genotype 1, which is most common in the United States and responds poorly to treatment. Most subjects were men (67% of blacks, 53% of whites).
Baseline characteristics of the two groups were generally similar, although blacks were on average slightly older (47.5 vs 44.2 years of age), somewhat heavier (89.0 vs 81.6 kg), and had been infected slightly longer (19.3 vs 18.8 years). Participants were not coinfected with HIV or hepatitis B virus (HBV). Treatment adherence was similar in the two groups.
Subjects were treated for 48 weeks with 1.5 mcg/kg weekly pegylated interferon alfa-2b (Peg-Intron, manufactured by Schering Corporation) plus ribavirin. After 72 weeks, 19% of black subjects achieved a sustained virological response (SVR) using an intent-to-treat analysis, compared with 52% of whites (p < .001). The corresponding as-treated SVR rates were 23% and 66% (p < .001). Black patients also had lower 12-week early virological response (EVR; 40% vs 69%) and end-of-treatment response (ETR; 20% vs 58%) rates. Among those who achieved EVR, 48% of blacks and 74% of whites went on to achieve SVR; among those with undetectable HCV viral loads at week 12, SVR rates were 64% and 83%, respectively. No patients in either group who failed to achieve early virological response later achieved sustained virological response.
Rates and types of adverse events were similar in both groups, as were the rates of dose reduction (22% black vs 24% white) and treatment discontinuation (19% black vs 21% white). Rates of Peg-Intron dose reduction (13 black and 14 white subjects) or discontinuation (4 black and 3 white) due to neutropenia were similar. However, 10 black patients were initially excluded because of neutropenia. (Healthy blacks normally have lower neutrophil counts than healthy whites.)
A comparison of pre- and post-treatment liver biopsies in about half of the patients in both groups who did not achieve SVR revealed that white subjects experienced a greater reduction in disease activity scores than blacks.
In a multivariate analysis, black race was the only variable significantly associated with the difference in response rates (p < .001); a correlation was not seen for other factors including age, sex, weight, baseline HCV RNA level, duration of infection, or presence of cirrhosis or steatosis (fatty liver).
In the June 2004 edition of Hepatology, Lennox Jeffers and colleagues reported on an open-label study of 78 blacks and 28 non-Hispanic whites receiving HCV treatment for the first time. All participants had genotype 1 HCV and elevated ALT. Again, most participants were men (72% of blacks, 61% of whites). Baseline characteristics of the two groups were generally similar, although black subjects were slightly older (mean 46.3 vs 44.7 years) and somewhat heavier (mean 90.7 vs 84.7 kg). Participants did not have HIV or HBV. Only 1 patient in each group had cirrhosis.
Because blacks have been under-represented in past HCV research, this study was designed to focus on treatment response in blacks. A small number of white subjects was included as a reference group to ensure that SVR values were consistent with previous studies; because this number was small, p-values were not reported for intergroup comparisons.
Participants received 180 mcg weekly pegylated interferon alpha-2a (Pegasys, produced by Hoffmann-LaRoche) plus ribavirin for 48 weeks. After 72 weeks, SVR rates were 26% among blacks and 39% among whites in an intent-to-treat analysis. About 80% of subjects in both groups completed therapy; corresponding as-treated rates were 32% and 50%. EVR at week 12 was observed in 60% of blacks; 43% who achieved EVR later went on to achieve SVR. Among the 22 black patients with undetectable HCV viral load at week 12, 73% achieved SVR. (This analysis was not reported for the small group of white subjects.)
In contrast to Muir’s study, side effects were considerably more common in whites than blacks, and more whites (18% vs 5%) discontinued due to adverse events. However, about twice as many blacks (37% vs 18%) had their Pegasys doses reduced due to neutropenia. Unlike Muir, Jeffers’ team did not exclude patients with neutropenia at the outset.
Paired pre- and post-treatment biopsies from 53 black and 16 white patients revealed that more than 90% in both groups showed improved or stabilised fibrosis progression. Overall, 25% of black patients had evidence of improvement (22% with SVR, 29% without SVR).
In a multivariate analysis, HCV RNA below 800,000 IU/mL, age less than 40 years, and ALT less than three times the upper limit of normal – but not sex or weight - significantly predicted SVR.
Although Jeffers’ study found “the highest response rate to treatment observed in a black population” to date, the SVR rate is still lower than that seen in whites. Blacks are more likely to have hard-to-treat genotype 1 HCV (90% of blacks vs 67% of whites), but these studies controlled for that difference. Men and older individuals respond less well to HCV therapy than women and younger individuals, and heavier people respond less well those of lighter weight. While the proportions of males, older individuals, and heavier individuals were higher among blacks than whites in both studies, these factors did not play a significant role in the multivariate analyses.
Recent research shows that interferon does not produce as much HCV suppression within the first 24-48 hours of treatment in black patients compared with whites. “These differences in viral clearance,” Jeffers and colleagues suggested, “may be due to variations in interferon pharmacokinetics, signal transduction pathways, or immunologic factors.” Other possible factors include higher testosterone levels and different HLA (human antigens that affect immune response) patterns in blacks compared with whites. A large National Institutes of Health study (VIRAHEP-C) is currently underway to further study treatment response in black patients with chronic hepatitis C.
References
Jeffers LJ et al. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology 39: 1702-1708, 2004.
Muir A et al. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. NEJM 350: 2265-2271, 2004.