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Treating HCV with Normal ALT with Pegasys plus Ribavirin
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Reported by Jules Levin
"International, Multicenter, Randomized, Controlled Study for the Treatment of Patients With Chronic Hepatitis C and Persistently Normal ALT Levels With Peginterferon alfa-2a (40KD) (PEGASTS) and Ribavirin (COPEGUS)"
Stefan Zeuzem (Saarland University Hospital, Hamburg Germany) and colleagues reported on this study at AASLD (Oct 25-29, 2003), which examines treatment of individuals with chronic hepatitis C who have normal ALT.
Zeuzem provided this background. 25-45% of patients with chronic hepatitis C have "normal" ALT levels. Significant liver disease is possible. Patients with normal ALT were excluded from previous pivotol trials. There has been a concern about a risk for ALT flares in patients who are treated and have normal ALT. Current guidelines recommend against treatment in this subgroup until data from large multicenter trials become available.
Summary
The authors concluded that this study showed similar efficacy and safety in patients with chronic HCV and persistently normal or elevated ALT. Pegasys plus RBV therapy is not associated with ALT flares. Treatment duration shown in previous studies was shown here –24 weeks for genotyope 1 and 48 wks for genotyoe 2. There were further reductions below baseline levels in ALT for sustained responders. The authors stated that the treatment for patients with chronic hepatitis C should rely on the probability of viral eradication, symptoms, histology, anticipated progression of disease, and/or the risk of transmission (eg, health care workers) rather than on a biochemical parameter.
STUDY POPULATION
Patients had chronic HCV and persistently normal ALT on 3 occassions within 6-18 months before baseline.
The primary study endpoint is the sustained viral response (SVR) of Pegasys (180 ug/once weekly) plus ribavirin (800 mg per day) for 24 weeks or 48 weeks. The secondary endpoints are comparing efficacy by genotype, monitor ALT during & after treatment, and evaluate safety.
514 patients were randomized (3:3:1) to group A (PEG+RBV), n=220 for 24 weeks, group B (PEG-RBV), n=221 for 48 weeks, and Group C, n=73, were untreated. There is a 24 weeksfollowup period after the end of treatment.
PATIENT CHARACTERISTICS
40% male. 85% Caucasian. 44 yrs old. 73 kg. Baseline ALT 20.5 to 21.0. Necroimflammation (Ishak Score) -- 3.7 for group A, 3.5 for group B, and 3.3 for Group C. Fibrosis (Ishak Score) – 1.2 for Group A, 1.9 for Group B, 1.0 for untreated.
Viral load: 1.2 million IU/mL) for Group A, 1.1 million IU/mL Group B, 1.3 million IU/mL Group C. 67-68% across all 3 arms were genotype 1; 32-33% were non-1 genotype—18-20% were genotype 2, 9% genotype 3, 3-4% genotype 4.
RESULTS
SVR Sustained Viral Response
All genotypes
--30% (n=212) Group A -24 weeks treatment
--52% (n=210) Group B 48 wks treatment
--0% n=69 Group C untreated
SVR Genotype 1
--13% Group A (24 wks) n=144
--40% Group B (48 wks) n=141
SVR Genotype 2/3
--72% Group A (24 wks) n=144
--78% Group B (48 wks) n=141
Serum ALT According to Response
All patients showed some decline in ALT levels, which was sustained and increased for SVRs with median ALT levels as half that seen at baseline. Relapse patients saw increased ALT after treatment stopped that did not exceed baseline ALT levels. Viral nonresponders saw ALT increase on average 4-8 weeks after starting therapy following an initial ALT decline, and the increase also did not exceed baseline ALT levels. These patterns of response were similar for patients treated for either 24 or 48 weeks.
Adverse events were as expected with the most common being: fatigue 51%, headache 44-56%, mylagia 38-44%, pyrexia (fever) 30-43%, insomnia 32-40%, nausea 32-40%, depression 26-27%, irritability 26-27%, alopecia (hair loss) 20-28%, asthenia (waekness) 22-23%, pruritis (severe itching) 18-20%.
Premature Withdrawals
Group A (24 wks): 6% due to AE, 1% due to lab abnormality, 2% for non-safety reasons Group B (48 wks): 16% due to AE, 2% for labs, 10% for non safety reasons.
ALT elevations On Study
Percent of patients who had ALT elevation over the upper limit of normal (ULN)
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| Group |
1-2xULn |
2-4xULN |
5-10xULN |
>10xULN |
| A |
40% |
14% |
1% |
1% |
| B |
38% |
11% |
<1% |
0 |
| C |
45% |
6% |
0 |
1% |
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The Authors Summarized:
--this study showed similar efficacy and safety in patients with chronic HCV and persistently normal or elevated ALT
--Pegasys plus RBV therapy is not associated with ALT flares
--Treatment duration shown in previous studies was shown here –24 weeks for genotyope 1 and 48 wks for genotyoe 2
--there were further reductions in ALT for sustained responders
The authors concluded that the treatment for patients with chronic hepatitis C should rely on the probability of viral eradication, symptoms, histology, anticipated progression of disease, and/or the risk of transmission (eg, health care workers) rather than on a biochemical parameter.
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