Efficacy of interferon dose and prediction of response in chronic hepatitis C: Benelux study in 336 patients.
OBJECTIVE
In an attempt to improve the limited efficacy of treatment of chronic hepatitis C with interferon-alpha 3 MU tiw, we studied the effects of double-dose therapy followed by downward titration, and analyzed the pre- and pertreatment factors associated with response or non-response.


METHODS
Three hundred and fifty-four consecutive patients in 19 centers were randomized to interferon-alpha 3 MU tiw for 6 months or 6 MU tiw for 8 weeks followed by down-titration (3,1 MU tiw) till alanine aminotransferase remained normal and plasma HCV RNA was repeatedly undetectable. The primary outcome measure was sustained alanine aminotransferase and HCV RNA response 6 months after treatment.


RESULTS
Three hundred and thirty-six patients received treatment. The sustained response rate for patients receiving 3 MU tiw for 6 months was 14% (9-21%,) and for patients receiving double dose tiw for 8 weeks and thereafter titrated therapy 15% (10-21%) (p=0.8). Pretreatment factors associated with a sustained alanine aminotransferase plus HCV RNA response were the absence of cirrhosis, presence of genotype 2 or 3, a low viral load and, in addition, a low alanine aminotransferase/aspartate aminotransferase ratio; a model was developed to allow estimation of the chance of response for the individual patient. The most powerful predictor of sustained response, however, was plasma HCV RNA at week 4; a positive test virtually precluded a sustained response (1.7%, 0.4-5.0%). If week 4 HCV RNA was not detectable, the chance of a sustained response was 21% (12-34%) for genotype 1 versus 40% (28-54%) for the others (p=0.02). Six MU tiw led to a significantly higher week 4 HCV RNA response (47% not detectable) than 3 MU (37%) (p=0.02). During down-titration this difference in viral on-treatment response was lost.


CONCLUSIONS
In the treatment of hepatitis C, an early HCV RNA response is a prerequisite for long-term efficacy. Doubling the initial interferon dose increases this early response, but subsequent downward titration negates this effect, especially in genotype 1.
Erasmus University Hospital-Dijkzigt, Rotterdam, The Netherlands. brouwer@inw2.azr.nl
J T
JT
Brouwer
F
F
Nevens
B
B
Kleter
A
A
Elewaut
M
M
Adler
R
R
Brenard
R A
RA
Chamuleau
P P
PP
Michielsen
J
J
Pirotte
M L
ML
Hautekeete
J
J
Weber
N
N
Bourgeois
B E
BE
Hansen
C M
CM
Bronkhorst
F J
FJ
ten Kate
R A
RA
Heijtink
J
J
Fevery
S W
SW
Schalm
D000328:Adult; D000368:Aged; D000410:Alanine Transaminase / Q000097:blood; D000998:Antiviral Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D001219:Aspartate Aminotransferases / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics / Q000302:isolation & purification; D019698:Hepatitis C, Chronic / Q000097:blood / Q000473:pathology / Q000628:therapy*; D006801:Humans; D007279:Injections, Subcutaneous; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000627:therapeutic use*; D008103:Liver Cirrhosis / Q000473:pathology; D008297:Male; D008875:Middle Aged; D011336:Probability; D012367:RNA, Viral / Q000097:blood; D011994:Recombinant Proteins; D013997:Time Factors
D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D012367:RNA, Viral; D011994:Recombinant Proteins; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase