Interferon-antibodies and the breakthrough phenomenon during ribavirin/interferon-alpha combination therapy and interferon-alpha monotherapy of patients with chronic hepatitis C.
OBJECTIVE
The significance of interferon antibodies with respect to response to treatment in patients with chronic hepatitis C treated with interferon-alpha (INF-alpha) remains a matter of debate. The influence of ribavirin on IFN-antibody formation in combination therapy with IFN-alpha has not yet been studied. Therefore we evaluated the relationship between IFN-antibodies and response to ribavirin/IFN-alpha combination therapy and IFN-alpha monotherapy.


METHODS
We studied 169 patients with chronic hepatitis C who were treated either with IFN alpha 2a (6 MU, thrice weekly) alone or in combination with ribavirin (14 mg/kg per day) for twelve weeks. Thereafter, patients who achieved a virological response (HCV-RNA-negative) were treated with 3 MU IFN-alpha thrice weekly for another 40 weeks. IFN antibodies were analyzed and quantified by a double-antigen sandwich enzyme immunoassay (EIA). In 86 patients two neutralization assays--an antiviral neutralization assay as well as an antiproliferative neutralization assay--were performed in addition. The relationship of the development of IFN-antibodies with the virologically defined response to treatment was analyzed.


RESULTS
Ribavirin did neither influence the prevalence nor the level of IFN-antibodies. The frequencies of IFN-antibody formation did not differ in the response groups. However, patients with breakthrough showed significantly higher IFN-antibody titers as compared to responder at end of treatment (median 1,336 BU/ml vs. 148 BU/ml; p = 0.018). Among the breakthrough patients those with IFN-antibodies showed the reappearance of HCV-RNA during therapy significantly earlier (median week 24) than those without IFN-antibodies (median week 32; p = 0.03).


CONCLUSIONS
The addition of ribavirin to IFN-alpha does not influence the formation of IFN-antibodies. The development of high-titer IFN-antibodies during IFN-alpha or ribavirin/IFN-alpha therapy of patients with chronic hepatitis C may account for the early occurrence of breakthrough in some patients, while other mechanisms seem to be responsible for this phenomenon in the majority of the afflicted patients.
Hoffmann
R M
RM
Medizinische Klinik II, Klinikum Grosshadern, Ludwig-Maximilians-Universität, München.
Berg
T
T
Teuber
G
G
Prümmer
O
O
Leifeld
L
L
Jung
M C
MC
Spengler
U
U
Zeuzem
S
S
Hopf
U
U
Pape
G R
GR
D000328:Adult; D000906:Antibodies / Q000097:blood*; D000998:Antiviral Agents / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000628:therapy*; D006801:Humans; D000077190:Interferon alpha-2; D016898:Interferon-alpha / Q000008:administration & dosage / Q000009:adverse effects* / Q000276:immunology; D007372:Interferons / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D011994:Recombinant Proteins; D012254:Ribavirin / Q000008:administration & dosage / Q000009:adverse effects*; D016896:Treatment Outcome
D000906:Antibodies; D000998:Antiviral Agents; D000077190:Interferon alpha-2; D016898:Interferon-alpha; D011994:Recombinant Proteins; D012254:Ribavirin; D007372:Interferons