Twenty-six percent (26%) of black Americans (BA) with chronic hepatitis C who received treatment with Pegasys plus Copegus (peginterferon alfa-2a plus ribavirin) achieved a sustained virological response (SVR), according to study results published in the June 2004 issue of Hepatology. Preliminary results of this study were first presented at the 54th annual AASLD meeting in Boston in October 2003.

In this study, SVR is defined as continued undetectable serum hepatitis C RNA levels 24 weeks after the individual concludes a course of treatment.

“We have shown that 48 weeks of therapy with peginterferon alfa-2a [Pegasys] and ribavirin [Copegus] results in an SVR in 26 percent of blacks chronically infected with HCV genotype 1 [intent to treat analysis]. To date, this is the highest response rate to treatment observed in a black population,” write the authors. The SVR rate among the Caucasian American (CA) patients was 39 percent.

Background
Limited data from prior studies show that conventional interferon alfa therapy, alone or in combination with ribavirin (RBV), is less effective for chronic hepatitis C genotype 1 infections in BA compared with CA. Combination therapy with pegylated interferon and ribavirin are now the standard of care for chronic hepatitis, at least in the developed world.

Two recent large clinical studies of treatment with pegylated interferons plus ribavirin showed overall sustained virological response (SVR) rates of 54% and 56% (Mann. Lancet. 2001) (Fried. NEJM. 2002). For patients with HCV genotype 1, the SVR rates were 42% and 46% in the respective studies.

The primary objective of the present study was to investigate the efficacy and safety of peginterferon alfa-2a plus ribavirin in a population of non-Hispanic black patients with HCV genotype-1 infection.

Patient Population
Eligible patients included male and female outpatients aged 18 years or older with documented chronic hepatitis C as evidenced by anti-HCV and by a polymerase chain reaction assay for HCV RNA. In addition, patients had to be non-Hispanic black or white, naïve to treatment with interferon or ribavirin and to have genotype 1 HCV.

This open label study took place in 11 medical sites in the US. A total of 108 patients received at least one dose of study medication. Of patients completing treatment, 62 of 78 (80%) were BA and 22 of 28 (79%) were CA.

Participants received 180 micrograms subcutaneously of Pegasys once weekly and either 1000 or 1200 mg/day of ribavirin (Copegus), depending on weight, for 48 weeks, with 24 weeks of treatment-free follow up.

Early virologic response (EVR) was assessed at 12 weeks of therapy and SVR at week 72. SVR was defined as an undetectable level (<50 IU/mL) of serum HCV RNA at the end of the follow-up period (week 72). EVR was defined as either an undetectable HCV RNA (<50 IU/ mL) or a minimum 2-log10 decrease from baseline in HCV RNA at week 12.

Results

Virological Responses
ITT analysis revealed that 20 of 78 black patients (26%) and 11 of 28 white patients (39%) achieved SVR. When only patients who completed 48 weeks of treatment were analyzed, 20 of 62 blacks (32%) and 11 of 22 whites (50%) achieved SVR. Thus, there was a trend toward a lower SVR rate for the black patients.

Only 20 of 47 (43%) black patients with EVR went on to SVR. Further analysis showed that 22 black patients had undetectable levels of HCV RNA at week 12 and that 16 (73%) of these patients went on to SVR.

Histological Responses
Paired biopsies from 53 of 78 (68%) patients in the black group and from 16 of 28 (57%) patients in the white group were obtained and reviewed. Evaluation of the paired biopsies from black patients revealed that improvements in fibrosis score occurred in 13 of 53 (25%) patients.

Adverse Events
Incidence rates for most AEs were generally higher among whites than among blacks. Injection site erythema, vomiting, alopecia, dry skin, and sinusitis had a threefold greater frequency in whites than in blacks.

Dose modifications of Pegasys (withheld or reduced) occurred among 46% of black patients and 29% of white patients. The most common cause was neutropenia: 37% of black and 29% of white patients.

Anemia was the most frequent reason for modifying ribavirin dose, occurring in 24% of blacks and 32% of whites.

Conclusions

• SVR was 26% in the black group and 39% in the white group;
• Although lower in blacks than in whites, the SVR of 26% represents an improvement over previously reported SVR rates from smaller, retrospective studies of black patients;
• An improvement in fibrosis in 25% of the black patients was observed;
• No unexpected adverse events occurred; and
• All genotype 1 patients with EVR, regardless of race, should continue to receive 48 weeks of treatment with peginterferon alfa-2a plus ribavirin.

In conclusion, the authors write, “This prospective study evaluating responses of black patients with chronic hepatitis C to peginterferon alfa-2a/ribavirin has demonstrated that treatment can be safely offered to black patients with reasonable antiviral and histological benefit.”

Discussion
The study authors state, “We have shown in this prospective study that treatment with peginterferon alfa-2a plus ribavirin was modestly effective in black Americans chronically infected with HCV genotype 1.”

At the end of the follow-up period (week 72), the SVR rate was 26% in the black group, which was lower than the SVR rate (39%) in the white group. In a larger trial of peginterferon alfa-2a plus ribavirin, an SVR rate of 46% was reported for 298 predominantly white patients infected with HCV genotype 1.

The lower SVR rate for whites in this study may have been due to the relatively small cohort of patients, the relatively high rate of premature discontinuations, and failure to return for the 72-week follow-up visit, say the authors. In addition, they note, response rates in non-registration trials or clinical practice settings are often lower overall.

The finding of a lower SVR in blacks than in whites is consistent with previous findings that blacks have lower rates of response. For example, in a retrospective analysis, the SVR in response to interferon monotherapy or combination therapy with interferon plus ribavirin was 11% (5/53) in blacks, compared with 27% (432/1600) in whites.

The results presented of the current study also confirm those of 3 previous trials, in which it was shown that the SVR rates to interferon monotherapy were lower in blacks than in whites, even when the 2 groups were otherwise well matched in factors such as HCV genotype, markers of prior hepatitis B infection, and prevalence of diabetes.

Although the reasons for apparent racial differences in the virological response to interferon therapies for chronic HCV are not understood, HCV genotype 1, which has been consistently associated with a poorer response to interferon, is more prevalent among blacks than among whites.

“The genotype prevalence cannot explain the difference in this study,” say the authors, “since all patients in this trial were infected with HCV genotype 1. The presence of higher HCV RNA titers has also been associated with a poorer treatment response. But in this study, the authors note, “The number of patients with high viral load is too small to permit interpretation.”

The baseline factors identified by multivariate analysis as significant predictors of SVR were age (< 40 years), baseline viral load (<800,000 IU/mL), and ALT (< 3 times ULN), similar to those from a larger clinical trial of peginterferon alfa-2a plus ribavirin in which age of 40 or less, HCV genotype other than 1, and body weight of 75 kg or less were significant predictors of SVR.

Other factors that may lead to racial disparity are socioeconomic or environmental factors, including diet, and genetic factors, including the higher levels of serum testosterone and higher rates of aberrant immune response in blacks.

Of interest in this study is that 13 of 53 black patients, but only 1 of 16 white patients, showed improved fibrosis scores. Five of the black patients also had SVR, 5 were relapsers, and 3 were nonresponders.

“In summary,” write the authors, “we have shown that 48 weeks of therapy with peginterferon alfa-2a plus ribavirin results in an SVR in 26% of blacks chronically infected with HCV genotype 1. To date, this is the highest response rate to treatment observed in a black population.”

“Our observation of improvement in fibrosis score in the black population requires confirmation in a larger trial.”

LJ Jeffers. Peginterferon Alfa-2a (40 kd) and Ribavirin for Black American Patients with Chronic HCV Genotype 1. Hepatology 39(6). June 2004.