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Pegasys plus Ribavirin (Copegus) for African-Americans with Hepatitis C Genotype 1
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Reported by Jules Levin
Lennox Jeffers (Miami VA Medical Center , Miami, FL) reported results a prospective, open-label study of Pegasys (peginterferon alfa-2a) and ribavirin (Copegys) for African Americans with chronic hepatitis C virus and genotype 1.
Black Americans have a higher prevalence of chronic hepatitisc C than whites, but have been underrepresented in clinical trials. Historically, blacks have had lower response rates to IFN-based therapy. There is an NIH study ongoing to examine why blacks don’t respond as well to interferon or IFN/RBV.
The objective of this study was to investigate the viral response and safety of Pegasys in combination with Copegus (ribavirin) in black americans with genotype 1 chronic hepatitis C virus (HCV). This is a prospective, open-label study conducted at 11 US centers. Patients received Pegasys 180 mcg/wk plus Copegus 1000/1200 mg/day. Patients received study drug for 48 weeks with a 24 week follow-up period. Non-Hispanic black and white patients with HCV genotype 1 with a 3:1 ratio were enrolled. Patients were treatment-naïve, had elevated ALT, no cirrhosis, and no significant concomitant systemic illness.
The primary efficacy study endpoint was sustained virologic response (SVR). The secondary study endpoints were virologic response over time, early virologic response and predictability of SVR at week 12, histologic response, and safety. The first two substudies on histologic response and safety were written by me yesterday and should be posted today to the NATAP website (www.natap.org).
PATIENT DEMOGRAPHICS
Black patients in this study had several differences than whites. Of note is that more blacks had high body mass and mean weight. We know that weight is a predictive factor in response to therapy. Response to therapy tends to be lower when a patient weighs more. We also knowthat higher BMI may predict the presence of fatty liver (steatosis) which may also predict less of a response to therapy. As well, higher viral load (>2 million) can also predict less of a response to therapy. Patients with high viral load may not respond as well to HCV therapy.
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Blacks |
Whites |
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N=78 |
n=28 |
| Mean age (yrs) |
46 |
44 |
| Mean weight* (kg) |
90.7 |
84.7 |
| Weight (kg, min-max) |
54-136 |
47-128 |
| Body mass index >27, n |
56 (72%) |
14 (50%) |
| Males, n(%) |
56 (72%) |
17 (61%) |
| HCV RNA >800,000 IU/ml n |
51 (65%) |
17 (61%) |
| Mean ALT |
62 |
64 |
| ALT quotient (ALT/ULN) |
2.1 |
2.1 |
| Mean HAI score |
7.2 |
6.9 |
| Mean fibrosis score |
1.8 |
1.9 |
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(*kg=2.2 lbs)
80 non-hispanic black americans enrolled vs 28 non-hispanic white americans. 78 blacks received Pegasys plus Copegus vs 28 whites. 62 blacks completed 48 weeks of treatment vs 22 whites. 60 blacks completed the 72 week study vs 17 whites. So although this is the largest study to date, the study is not very large.
RESULTS
- 39% of whites (n=11/28) had Sustained Viral Response (SVR)
- 26% of blacks (n=20/78) achieved SVR (95% CI 16-35%)
Of patients with high viral load:
- 18% of blacks (n=9/51) achieved an SVR
- 41% of whites (n=8/17) achieved an SVR
This is interesting in that blacks with high viral load were less likely than whites with high viral load to achieve an SVR. The numbers of patients were small so perhaps this needs further examination in another study.
VIRAL RESPONSE OVER TIME
At week 24 about 62% of whites had HCV RNA <50 IU/ml (undetectable) compared to 45% of blacks. By week 48 the viral response for whites fell to about 55% and to about 32% for blacks. The fall off in response (breakthrough) of about 30% was greater for blacks than whites, about 10%. This higher breakthrough rates for blacks received some attention at the study presentation. The ongoing NIH study is intended to try to understand this type of response to therapy for blacks.
PREDICTIVE VALUE of 12-WEEK EARLY VIROLOGIC RESPONSE in BLACK AMERICANS
47 blacks had EVR (early viral response), which is at least a 2 log reduction of HCV RNA by week 12, or an undetectable viral load. 20 blacks (43%) had a SVR, while 27 blacks (57%) did not achieve an SVR. However, of the 31 blacks who did not achieve an EVR 100% did not achieve an SVR. This means that if by week 12 HCV RNA (viral load) was not reduced by at least 2 logs no patients achieved an SVR. This suggests that if by week 12 a patient does not achieve at least a 2 log reduction in HCV RNA, they may want to consider stopping therapy. However, if the patient has stage 3 or 4 HCV disease they should consider Maintenance Therapy, which is ongoing half dose of interferon. Studies suggest that this may reduce risk for progression of disease to decompensated cirrhosis and death. In HCV/HIV co-infection the 12 week stop rule has not been established. Continuing until 24 weeks to evaluate viral response is preferable.
INCIDENCE OF DOSE MODIFICATIONS for LAB ABNORMALITIES
37% of blacks vs 18% of whites modified the dose of Pegasys for neuropenia (reduced neutropenia & white blood cell count). Taking a lower dose of interferon can have an effect of reducing response rate to therapy. The affect of reducing dose has not yet been examined so we do not know the effect on SVR.
24% of blacks and 32% of whites developed anemia (reduced hemoglobin). Jeffers noted that dose reductions were transient in most cases, with patients returning to their assigned doses later in the course of treatment. Jeffers was asked about the use of Procrit for anemia and GCSF for reduced WBC and I think he said they were generally not used much but I don’t recall for sure.
SERIOUS ADVERSE EVENTS (SAEs)
- 7 patients in each group experienced 20 SAEs
- 3 were judged possibly treatment-related (all in white patients): thrombocytopenia (reduced platelets), abdominal pain, hydronephrosis
- infectious AEs (not associated with neutropenia or lymphopenia; all resolved with no sequelae) -2 black patients cellulitis (day 508, wk 72) probably unrelated appendicituis (day 56, wk 72) - 3 white patients (none related to treatment) appendicitis (day 163, wk 23) dose modified cellulitis (day 270, wk 38) sepsis (day 270, wk 72)
- one death: myocardial infarction (day 516, wk 74)
PREMATURE TREATMENT DISCONTINUATION for ADVERSE EVENTS or LAB ABNORMALITIES
5% of blacks vs 18% of whites
Black
- anemia (1)
- neutropenia (2)
- pruritus
White
- fatigue (1)
- thrombocytopenis (1)
- abnormal liver function (1)
- uticaria (1)
Other reasons
- insufficient therapeutic response (1 black)
- failure/refusal to return (12 blacks, 6 whites)
- protocol violation (1 black)
Jeffers concluded: Fibrosis improvements occurred in 25% of black patients; no unexpected adverse events occurred in black patients, and infrequent infectious complications. My report on fibrosis improvements was emailed yesterday & will be posted today to NATAP website.
Jeffers commented this study was a good first step in studying treatment in blacks and more studies are needed.
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