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Pegasys plus Ribavirin for African-Americans with Genotype 1
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"Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1"
Hepatology
June 2004, Volume 39, Issue 6
Lennox J. Jeffers 1 *, William Cassidy 2, Charles D. Howell 3, Sylvia Hu 4, K. Rajender Reddy 51Miami Veterans Affairs Medical Center, Miami, FL
2Louisiana State University Health Sciences Center, Baton Rouge, LA
3University of Maryland School of Medicine, Baltimore, MD
4Roche Laboratories, Inc., Nutley, NJ
5University of Pennsylvania, Philadelphia, PA
Note from Jules Levin: this week results from two studies in African-Americans were reported. The response to HCV therapy by African-Americans is less than by Caucasians and this is not new information. These published studies were conducted previously and for several years this information has been known. One study reported on the use of PegIntron plus ribavirin in 100 African-Americans and the other reported on the use of Pegasys plus ribavirin in African-Americans. In reports over the internet regarding the low response of 19% by African-Americans in the PegIntron study it appears that they discouraged treatment for African-Americans. In the Pegasys study response rates for African-Americans were 26% (ITT) and 32% (On-Treatment). It's important to bear in mind that it is impossible to predict who will respond to treatment until the 12 week point on therapy is reached. After 12 weeks of therapy if you do not have what is called an early viral response (defined as a 2-log reduction in viral load or undetectable viral load) it is unlikely that you will achieve a sustained viral response. The only way to see if a person will be a responder to therapy is to try therapy and evaluate at week 12. To reject consideration of therapy may increase risk for progression of disease. Liver biopsy is the most reliable diagnostic test to evaluate the stage of hepatitis C disease. If you have very early disease stage perhaps you can delay therapy. If you have later stage disease (stage 2, 3 or 4) delaying therapy increases risk for disease progression. HIV accelerates hepatitis disease progression. Studies show HIV may accelerate disease progression twice as fast for HCV/HIV coinfected patients compared to HCV monoinfected. So, it's very important to have a clear and serious discussion with a good hepatitis specialist regarding consideration of whether or not you should delay therapy. There are many research programs ongoing to discover & develop new orally administered drugs for HCV. Hopefully, these drugs will be tolerable and improve response rates, particularly for patients with genotype 1. It appears that these drugs, if successfully developed, are at least several years away. Several HCV protease inhibitors are entering phase I studies in 2004. several polymerase inhibitors are in early stages of development. A polymerase inhibitor called NM283 is being studied in HCV+ patients and the first study showed the drug reduced HCV viral load by 1 log, which is encouraging. This drug is expected to enter the next phase of study in combination with peginterferon plus ribavirin. It appears that peginterferon and perhaps ribavirin as well will be used in combination with new HCV drugs. So the possibility that peginterferon will not be used after these new drugs are available does not seem high, but perhaps lower doses of peginterferon may be possible. We don't have an answer yet to this question.
This week the results from a study in African-Americans receiving PegIntron (peginterferon Alfa-2b) plus ribavirin was reported in the New England Journal of Medicine. In this study 100 whites and 100 blacks were treated. The results were as stated in the NEJM: "The rate of sustained virologic response was higher among non-Hispanic white patients than among black patients (52 percent vs.19 percent, P<0.001). The black patients also had significantly lower rates of virologic response at 12 weeks and at the end of treatment. Multivariable analyses examining sociodemographic and clinical characteristics found that black race was the only variable significantly associated with the difference in response rate". Ninety-eight percent of the patients in each group had HCV genotype 1infection. Compliance was similar in the groups, and the similar education levels of our groups suggested that there was no difference in socioeconomic status.
You are not supposed to compare results from one study to another for several good reasons including that the patient populations in the studies can be different and you need to consider dosing regimens. In the PegIntron study all patients received 1.5 µg of peginterferon alfa-2b (PEG-Intron, Schering-Plough) per kilogram of body weight subcutaneously once weekly for 48 weeks and1000 mg of ribavirin (Rebetol, Schering-Plough) orally twice daily for the first 12 weeks and then 800 mg per day for weeks 13 to 48. The dosing regimen of ribavirin was lower in the PegIntron study compared to the Pegasys study where patients received 1000 or 1200 mg per day of ribavirin. This alone could suggest a reason for differences in response between these two studies. Ribavirin is dosed differently bed on your weight and patients receive 800 mg per day when weight is lower and 1000 or 1200 mg as weight increases. Some would consider a dose of 800 mg to be too low.Growth factors were not used in the PegIntron study. This is another difference with the Pegasys study where growth factors were used to treat anemia & neutropenia.
The authors said: The two groups had similar types and severities of adverse events, with similar numbers of episodes of anemia and neutropenia, rates of dose reduction, and discontinuation rates. Ten black patients were excluded because of neutropenia. Recent data indicate that neutropenia related to interferon alfa therapy is not associated with an increased risk of infection, and black patients have minimal decreases in neutrophil counts during therapy. Neutropenia in blacks should thus not be an absolute contraindication to interferon alfa therapy. The reason for the differences in response between black patients and non-Hispanic white patients with chronic hepatitis C remains unclear. In addition to thediscrepancy in treatment responses, blacks also appear less likely to clear acute HCV infection. Recent analyses have noted differences in viral kinetics andincreased iron stores among black patients with HCV infection. Differences in the immune response among racial and ethnic groups, however, have repeatedlybeen implicated as a potential explanation for the disparity in response rates. The presence of the HLA-DQB1*0301 allele has been associated with viral clearance,and work in an ethnically diverse cohort found that this association was strongest in black patients. Another study reported that black patients with HCV infectionhad higher levels of tumor necrosis factor and interleukin-2 than white patients. One study examined the response to HCV antigens and found that black patientshad a greater CD4 proliferative T-cell response but surprisingly, did not have increased interferon- production. These findings suggest that the dysregulation of a CD4 T-cell effect or function may be related to HCV infection.21 Our findings demonstrate a limitation of current HCV therapy.
ARTICLE REPORTING PEGASYS STUDY IN JOURNAL OF HEPTAOLOGY
This study was conducted in whites & blacks with genotype 1, 90% of blacks and 67% of whites in USA have genotype 1. The authors say: "...In summary, we have shown that 48 weeks of therapy with peginterferon alfa-2a (Pegasys, Roche) plus ribavirin (Copegus, Roche) 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..."
"...the limited data from retrospective analyses indicate that the response to interferon, alone and in combination with ribavirin, is lower among blacks than among whites...Two recent large clinical studies of treatment with pegylated interferons plus ribavirin showed overall sustained virological response (SVR) rates of 54% and 56%. For patients with HCV genotype 1, the SVR rates were 42% and 46% in the respective studies... We have shown in this prospective study that treatment with Pegasys plus ribavirin was modestly effective in black Americans chronically infected with HCV genotype 1 (26% vs 39% for whites in the USA... 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, 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. In this study, the number of patients with high viral load is too small to permit interpretation...
... 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 reference 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. In addition, response rates in nonregistration trials or clinical practice settings are often lower overall...
... A recent report measured the effectiveness of interferon therapy, defined as the percent inhibition of virus production during the first 24 hours of therapy, in blacks and whites. Racial differences in therapeutic outcomes with standard interferon were attributed to differences in the effectiveness, estimated at 98% for white patients and 87% for black patients (P = .005). Only 7 of 19 blacks (37%) exhibited effectiveness greater than 90%, compared with 13 of 15 whites (87%; P = .003). These differences in viral clearance may be due to variations in interferon pharmacokinetics, signal transduction pathways, or immunologic factors...
...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. During acute infection with HCV, men have been shown to have a less robust response than women, and heavier individuals a less vigorous response than lighter individuals. The low SVR rate for the black patients in this trial may be related to the higher proportion of males and the greater average weight of patients in the black group. A larger clinical trial, the ViraHep-C Study (National Institute of Diabetes & Digestive & Kidney Diseases), designed to compare the effectiveness of peginterferon alfa-2a plus ribavirin in black and white American patients infected with hepatitis C genotype 1 is currently addressing the basis of ethnic differences in response rates...
... We found that patients who did not experience an EVR at week 12 uniformly failed to achieve SVR at week 72. These findings are in agreement with those of previous studies, showing that, in white patients with chronic HCV, the lack of an EVR predicts failure to achieve SVR. In contrast, the positive predictive value of an EVR at week 12 for SVR was only 43% in the black group. As in other analyses, undetectable HCV RNA at week 12 was superior as a positive predictor, with a 73% likelihood of achieving SVR. Nonetheless, there were a few patients who achieved SVR (16%) despite having detectable HCV RNA at week 12. Thus, while the positive predictive value is higher for patients with undetectable HCV RNA, these data support current practice that all genotype 1 patients with EVR, regardless of race, should continue to receive 48 weeks of treatment with peginterferon alfa-2a plus ribavirin.
ABSTRACT/SUMMARY
Black Americans (blacks) have a high prevalence of chronic hepatitis C virus (HCV) infection and respond poorly to therapy with interferon alfa-based regimens, but they have been underrepresented in clinical trials.
The aim of this study was to assess the rate of sustained virological response (SVR) to peginterferon alfa-2a (40 kd) (Pegasys) in combination with ribavirin in black patients chronically infected with HCV genotype 1.
In a prospective, multicenter, open-label trial, 78 black and 28 white American interferon-naïve patients were enrolled to receive once weekly subcutaneous injections of 180 g peginterferon alfa-2a plus oral ribavirin (1000 mg/d for patients weighing less than 75 kg and 1200 mg/d for patients weighing 75 kg or more) for 48 weeks.
Pre- and post-treatment liver biopsies were evaluated for necroinflammation and fibrosis.
SVR, defined as undetectable (<50 IU/mL) HCV RNA, was 26% in the black group and 39% in the white group. Although the SVR rate was 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.
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.
EVR was 60% (47/78) for black patients, and the negative predictive value of the week-12 virological response was 100% for both blacks and whites. 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.
We also observed improvement in fibrosis in 25% of the black patients. No unexpected adverse events occurred. A fibrosis response was defined as a decrease of greater than or equal to 1 point and worsening was defined as an increase of greater than or equal to 1 point on the fibrosis component of the Histology Activity Index (HAI) scale.
When combined virological and fibrosis responses were evaluated, a substantial group of black patients (8/36, 22%) showed fibrosis improvement without achieving SVR. These included 5 of 14 (36%) patients who relapsed and 3 of 22 (14%) nonresponders. In contrast, 5 of 17 (29%) black patients who achieved SVR also demonstrated fibrosis improvement.
Author commentary on fibrosis response: Although response to therapy of chronic hepatitis C is evaluated primarily by virological criteria, the effect on fibrosis is also important in assessing efficacy of treatment. Several studies in HCV-infected patients have shown that interferon-based therapy improved the degree of fibrosis, although this effect has been most prominent in patients who achieved a virological response. 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 SVRs, 5 were relapsers, and 3 were nonresponders. We recognize that any improvement that occurs in virological relapsers or nonresponders may be transient, and fibrosis progression may resume after cessation of treatment. Although intriguing, these histological results did not reach statistical significance due to the small number of patients with paired biopsies. Furthermore, because the number of patients is small, sampling error may have contributed importantly to the observed differences. Future larger studies to evaluate the effect of treatment on fibrosis in the black American population will be important in understanding the overall benefit of treatment.
Incidence rates for most AEs were generally higher among whites than among blacks, with injection-site erythema, vomiting, alopecia, dry skin, and sinusitis having a threefold greater frequency in whites than in blacks.
Combination therapy with peginterferon alfa-2a plus ribavirin was reasonably well tolerated by both groups of patients. Severe neutropenia was more frequent in blacks, with neutrophil counts below 0.5 x 109/L during treatment observed only among blacks, and more blacks (37%) than whites (18%) had their doses of peginterferon alfa-2a reduced for neutropenia. Healthy blacks have been observed to have lower neutrophil counts than healthy whites, suggesting an increased prevalence of constitutional neutropenia among blacks chronically infected with HCV. Constitutional neutropenia in HCV-infected blacks, however, does not appear to increase the risk for serious infections. Our findings suggest that peginterferon alfa-2a can be used to treat blacks, even those with constitutional neutropenia, and that it may be reasonable to lower thresholds for dose modification due to neutropenia. The 5 serious infections that did occur in this study are a matter of concern. However, 2 of these occurred at weeks 70 and 72, well after treatment completion, and their relationship to treatment is doubtful. Furthermore, of the remaining 3 infections, 1 occurred in a patient with a history of recurrent cellulitis and 1 as a result of an animal bite. Only 1 serious infection (appendicitis) was considered possibly related to treatment.
Premature discontinuation by the investigators for laboratory abnormalities or AEs occurred in 4 (5%) black and 5 (18%) white patients. (see below for details for dose modifications, discontinuations, use of growth factors). Black patients in this study were as compliant as patients in a previous trial with the same regimen, in which 22% of patients discontinued therapy. 39% of whites discontinued therapy, authors did nopt comment if difference was significant.
In conclusion, 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 such individuals with reasonable antiviral and histological benefit.
INTRODUCTION
Large racial disparities in the prevalence of hepatitis C virus (HCV) infection exist in the United States. Antibodies to HCV are 2 to 3 times more common among black Americans (blacks) than among white Americans (whites), as is hepatocellular carcinoma, a serious complication of chronic HCV infection. In addition, the distribution of HCV genotypes differs among racial groups, with genotype 1 virus responsible for approximately 90% of HCV infections in blacks, compared with only 67% in whites.
Meaningful assessment of the efficacy and safety of antiviral therapy in blacks has been hampered by the underrepresentation of these patients in prospective clinical trials. Nevertheless, the limited data from retrospective analyses indicate that the response to interferon, alone and in combination with ribavirin, is lower among blacks than among whites. Pegylated interferons plus ribavirin are now the standard of care for the treatment of patients with chronic hepatitis C. Two recent large clinical studies of treatment with pegylated interferons plus ribavirin showed overall sustained virological response (SVR) rates of 54% and 56%. 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 (40 kd) plus ribavirin in a population of non-Hispanic black patients with HCV genotype-1 infection.
Results
Patient Characteristics
A total of 108 patients, 80 blacks and 28 whites, were enrolled in the study. Two patients, both blacks, did not receive any study drug, leaving 78 black and 28 white patients in the ITT and safety populations. The characteristics of the black and white groups were generally similar, except that the mean weight of the black group was about 6 kg greater than that of the white group, and the proportion of males was higher in the black group (72%) than in the white group (61%). Due to the small number of whites in this study, none of these differences was statistically significant. Mean baseline HAI activity and fibrosis scores were comparable for the 2 groups. Only 1 patient in each group had cirrhosis (fibrosis score of F4), as reported by the study pathologist upon review of the submitted material. Age: 44-46; sex: 61-72% men, 28-39% female; weight: 84-09 kg; serum HCV RNA, >8 x 105 IU/ml: 65% Blacks, 61% whites; ALT: 62 U/L Blacks, 64 U/L whites; baseline fibrosis scores-- F0: 2.6% blacks, 3.6% whites; F1: 56% blacks, 57% whites, F3: 38% blacks, 35% whites; F4: 1.3% blacks, 3.6% whites.
Of the 78 black patients, 62 (80%) completed 48 weeks of treatment and 60 (77%) returned at week 72. In comparison, 22 of the 28 white patients (79%) completed 48 weeks of treatment and 17 (61%) returned at week 72.
Virological Responses
ITT analysis revealed that 20 of 78 black patients (26%; 95% CI, 16%-35%) and 11 of 28 white patients (39%; 95% CI, 21%-57%) achieved SVR. When only patients who completed 48 weeks of treatment were analyzed, 20 of 62 blacks (32%; 95% CI, 21%-44%) and 11 of 22 whites (50%; 95% CI, 30%-71%) achieved SVR. Thus, there was a trend toward a lower SVR rate for the black patients.
Virological response rates in both groups peaked at week 24, although the response rate was lower in the black group than in the white group at all study visits. EVR was 60% (47/78) for black patients, and the negative predictive value of the week-12 virological response was 100% for both blacks and whites. 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. Use of the HCV RNA cutoff of 30,000 IU/mL instead of a minimum 2-log10 decrease in viral load as a criterion for EVR did not increase the positive predictive value of EVR; in fact, it decreased the number of patients who could be excluded from treatment with a 100% negative predictive value (data not shown). Positive Predictive Value of EVR at week 12: 43% for blacks, 58% for whites. EVR at week 12 was 20 individuals among blacks (n=78) who achieved SVR and 27 individuals who did not achieve SVR. Among whites (n=28) with EVR at week 12, 11 individuals achieved SVR and 8 did not achieve SVR. For blacks with no EVR at week 12, 0 had SVR & 31 had no SVR. For whites with no SVR at week 12, 0 had SVR & 9 had no SVR.
EVR at week 12 is defined as undetectable (<50 IU/mL) HCV RNA or a decrease in viral load from baseline of >2-log10; SVR is defined as undetectable HCV RNA at week 72.
Positive predictive value is the frequency with which patients achieve SVR if they have an EVR; negative predictive value is the frequency with which patients fail to achieve SVR if they fail to achieve EVR.
Of the 45 black patients with high baseline HCV RNA (>8 million IU/ml), 9 (20%) had SVR.
Independent Factors Associated With SVR
Both univariate and multivariate analyses to identify predictors of SVR in the black patient group were performed. Factors entered into the final stepwise regression analysis included age (>40 vs. 40), sex (female vs. male), weight (>85 kg vs. 85 kg), baseline ALT (>3 times ULN vs. 3 times ULN), baseline HCV RNA (>800,000 IU/mL vs. 800,000 IU/mL), and baseline total HAI score.
Univariate analysis identified baseline HCV RNA less than 800,000 IU/mL as the only significant predictor of SVR (odds ratio [OR] 0.31; 95% CI, 0.11-0.89; P = .03). On multivariate analysis, age less than or equal to 40 (OR 0.13; 95% CI, 0.02-0.82; P = .03), HCV RNA less than 800,000 IU/mL (OR 0.21; 95% CI, 0.06-0.66; P = .008), and ALT less than or equal to 3 times ULN (OR 0.06; 95% CI, 0.00--0.84; P = .037) were significant baseline predictors of SVR. Weight (85 kg) was not a significant predictor in the multivariate analysis (OR 0.50; 95% CI, 0.18-1.40; P = 0.186).
Histological Response
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. Although the difference was not statistically significant (P = .16), only 1 of 16 (6%) in the white group showed improvement. Over 90% of the patients in both groups showed either improvement or stabilization of fibrosis.
CHANGE IN FIBROSIS SCORE
| Fibrosis Score | | | | (Knodell - Part IV) | Black (n=53) | White (n=16) | | Improved | 25% | 6% | | Stable | 68% | 88% | | Worsened | 8% | 6% |
When combined virological and fibrosis responses were evaluated, a substantial group of black patients (8/36, 22%) showed fibrosis improvement without achieving SVR. These included 5 of 14 (36%) patients who relapsed and 3 of 22 (14%) nonresponders. In contrast, 5 of 17 (29%) black patients who achieved SVR also demonstrated fibrosis improvement.
Safety
Incidence rates for most AEs were generally higher among whites than among blacks, with injection-site erythema, vomiting, alopecia, dry skin, and sinusitis having a threefold greater frequency in whites than in blacks.There were no unexpected AEs or unusual patterns of AEs reported during this study. One black patient died as a result of an acute anterior myocardial infarction about 180 days after the last dose of study drug, but this was not considered drug-related.
| ADVERSE EVENT | Black | White | | Fatigue | 60% | 71% | | Headache | 54% | 82% | | Rigors | 35% | 32% | | Insomnia | 27% | 50% | | Rash | 26% | 18% | | Nausea | 23% | 54% | | Arthralgia | 23% | 21% | | Myalgia | 22% | 32% | | Pyrexia | 19% | 25% | | Anorexia | 19% | 11% | | Pain | 18% | 21% | | Pruritis | 18% | 21% | | Back pain | 18% | 18% | | Depression | 17% | 29% | | Influenza-like Illness | 17% | 7% | | Cough | 15% | 11% | | Dizziness (excluding vertigo) | 13% | 29% | | Dry mouth | 6% | 18% | | Injection site Erythema | 5% | 29% | | Dry skin | 4% | 25% | | Vomiting | 4% | 21% | | Sinusitis | 3% | 18% |
DOSE MODIFICATIONS- TREATMENT DISCONTINUATIONS-GROWTH FACTORS USE
Dose modifications, growth factor administration, and treatment discontinuations are summarized. Decreases in hemoglobin levels to less than 8.5 g/dL were observed in 4 black (5%) and 2 white (7%) patients, but there were no discontinuations for anemia. Neutropenia was the most common reason for modifying peginterferon alfa-2a dose, occurring in 29 of 78 blacks (37%) and 5 of 28 whites (18%); anemia was the most frequent reason for modifying ribavirin dose, occurring in 19 of 78 blacks (24%) and 9 of 28 whites (32%). Thrombocytopenia, defined as platelet counts less than 50 x 109/L was evident in 3 black (4%) patients and 1 white (4%) patient. There were no clear patterns of dose reduction relative to any clinical parameter, and most dose reductions were transient, with patients returning to their assigned doses later in the course of treatment. No relationship between administration of erythropoietin and granulocyte colony stimulating factor and virological response was evident.
| Dose Modifications | Growth Factor Use | Treatment Discont. | | Pegasys | RBV | EPO | GCSF | | | Blacks | 40% | 40% | 4% | 4% | 23% | | Whites | 29% | 46% | 14% | 7% | 39% |
Premature discontinuation by the investigators for laboratory abnormalities or AEs occurred in 4 (5%) black and 5 (18%) white patients. Of the 4 black patients in this group, 2 had neutropenia, and 2 had serious infections (1 cellulitis, 1 appendicitis). The cellulitis occurred in a patient with a history of recurrent cellulitis, and the event was at week 70. Of the 5 white patients in the group, 1 had thrombocytopenia, 1 had abnormal liver function tests, and 3 had serious infections (1 cellulitis, 1 appendicitis, and 1 gram-positive sepsis). The appendicitis was diagnosed in a patient who related a history of epigastric pain, the cellulitis in a veterinary worker as a result of an animal bite, and the sepsis occurred at week 72 after an auto accident. None of the serious infections were associated with severe (grade 3/4) neutropenia, defined as less than 0.75 x 109 neutrophils/L, at any point during the study. Most of the patients that withdrew from this study either failed to return for follow-up or withdrew consent. In addition, black patients in this study were as compliant as patients in a previous trial with the same regimen, in which 22% of patients discontinued therapy.
ASSESSMENTS. The primary efficacy variable in this study was the proportion of patients with SVR, defined as an undetectable (<50 IU/mL) level of serum HCV RNA, as measured by the AMPLICOR HCV Test (Roche Diagnostics, Branchburg, NJ, version 2.0), at the end of the follow-up period (week 72). All virological testing was done by the central lab (LabCorp, Raritan, NJ). SVR rates were calculated separately for black and white patients.
Secondary efficacy variables included virological response over time, defined as less than 50 IU/mL serum HCV RNA at each visit during the treatment and follow-up periods. The utility of early virological response (EVR) in predicting SVR was also assessed. 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. EVR was then cross-tabulated with SVR in order to assess its predictive value.
Slides of liver biopsy specimens obtained before the study and approximately 24 weeks after completion of treatment were coded and read by a central pathologist (Dr. Sugantha Govindarajan, Liver Research Laboratory, Downey, CA), who was blinded regarding patient identity and date of biopsy. A fibrosis response was defined as a decrease of greater than or equal to 1 point and worsening was defined as an increase of greater than or equal to 1 point on the fibrosis component of the Histology Activity Index (HAI) scale.
Safety was assessed by recording adverse events (AEs) as reported by patients, by clinical laboratory test results (including hematology, blood chemistry, thyroid function tests, and urinalysis), and by vital signs.
Data Analysis
The trial was designed to enroll a sufficient number of black patients to estimate SVR so that the width of the 95% CI would be less than 20%. A small number of white patients was enrolled as a reference group to ensure that SVR values for whites were consistent with historical controls in previous clinical studies. As such, the ratio of black to white patients was 3:1. Efficacy analyses were performed using an intent-to-treat (ITT) population, defined as all enrolled patients who received at least 1 dose of any study medication. Two-sided 95% CIs were calculated for each efficacy variable, expressed as percentages of patients. Continuous efficacy variables were summarized using descriptive statistics.
Statistical analyses of safety were performed on all enrolled patients who received at least 1 dose of study medication and had at least 1 postbaseline safety assessment. Safety variables were summarized using proportions, frequency distributions, and descriptive statistics as appropriate.
PATIENT SELECTION
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, be naïve to treatment with any form of interferon or ribavirin, and have HCV genotype 1 as determined by automated DNA sequencing. Other inclusion criteria were the same as those described previously; these included a liver biopsy within the previous 24 months consistent with chronic HCV infection but without evidence of cirrhosis; serum HCV RNA greater than or equal to 600 IU/mL; and serum alanine aminotransferase (ALT) above the upper limit of normal (ULN) on at least 2 occasions within the previous 12 months and at least once during the 6 months before initiation of study drug. Patients with clinically significant concomitant systemic illnesses were excluded. A negative pregnancy test for all women of childbearing age and effective contraception by all patients and their partners of childbearing age during the study period were also required, as described previously.
Study Design
This was an open-label, noncomparative, multicenter study investigating the efficacy of peginterferon alfa-2a plus ribavirin as initial treatment of non-Hispanic black patients with chronic HCV genotype 1 infection. The study was conducted at 11 clinical sites in the United States. Informed consent was obtained from each patient. The study protocol was reviewed and approved according to ethical guidelines of the 1975 Declaration of Helsinki by institutional review committees at the respective sites.
Patients were screened within 35 days of their first dose of peginterferon alfa-2a and ribavirin. Patients who fulfilled the inclusion and exclusion criteria received 180 g peginterferon alfa-2a subcutaneously once weekly. In addition, patients weighing less than 75 kg received 1,000 mg/d ribavirin (400 mg in the morning and 600 mg in the evening); patients weighing 75 kg or more received 1,200 mg/d ribavirin (600 mg each in the morning and evening). Patients were treated for 48 weeks and followed up for an additional 24 weeks. Stepwise reductions in peginterferon alfa-2a or ribavirin dose were allowed to manage adverse events or laboratory abnormalities.
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