Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta

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http://www.nejm.org/doi/full/10.1056/NEJMoa0912696

Original Article

Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta

Heiner Wedemeyer, M.D., Cihan Yurdaydìn, M.D., N. Dalekos, M.D., s

Erhardt, M.D., Yilmaz Çakaloğlu, M.D., Halil Değertekin, M.D., Selim Gürel,

M.D., Stefan Zeuzem, M.D., Kalliopi Zachou, M.D., Hakan Bozkaya, M.D., Armin

Koch, M.D., Bock, M.D., Hans Dienes, M.D., and P. Manns,

M.D. for the HIDIT Study Group

N Engl J Med 2011; 364:322-331January 27, 2011

Background

Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results

in the most severe form of viral hepatitis. There is no currently approved

treatment. We investigated the safety and efficacy of 48 weeks of treatment with

peginterferon alfa-2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and

adefovir dipivoxil alone.

Methods

We conducted a randomized trial in which 31 patients with HDV infection received

treatment with 180 μg of peginterferon alfa-2a weekly plus 10 mg of adefovir

daily, 29 received 180 μg of peginterferon alfa-2a weekly plus placebo, and 30

received 10 mg of adefovir alone weekly for 48 weeks. Follow-up was conducted

for an additional 24 weeks. Efficacy end points included clearance of HDV RNA,

normalization of alanine aminotransferase levels, and a decline in levels of

hepatitis B surface antigen (HBsAg).

Results

The primary end point — normalization of alanine aminotransferase levels and

clearance of HDV RNA at week 48 — was achieved in two patients in the group

receiving peginterferon alfa-2a plus adefovir and two patients in the group

receiving peginterferon alfa-2a plus placebo but in none of the patients in the

group receiving adefovir alone. At week 48, the test for HDV RNA was negative in

23% of patients in the first group, 24% of patients in the second, and none of

those in the third (P=0.006 for the comparison of the first and third groups;

P=0.004 for the comparison of the second and third). The efficacy of

peginterferon alfa-2a was sustained for 24 weeks after treatment, with 28% of

the patients receiving peginterferon alfa-2a plus adefovir or peginterferon

alfa-2a alone having negative results on HDV-RNA tests; none of the patients

receiving adefovir alone had negative results. A decline in HBsAg levels of more

than 1 log10 IU per milliliter from baseline to week 48 was observed in 10

patients in the first group, 2 in the second, and none in the third (P<0.001 for

the comparison of the first and third groups and P=0.01 for the comparison of

the first and second).

Conclusions

Treatment with peginterferon alfa-2a for 48 weeks, with or without adefovir,

resulted in sustained HDV RNA clearance in about one quarter of patients with

HDV infection. (Funded by Hep-Net [the German Network of Excellence on Viral

Hepatitis] and others; Current Controlled Trials number, ISRCTN83587695.)

Drs. Wedemeyer and Yurdaydìn contributed equally to this work.

Supported by Hep-Net (a national network sponsored by the German Ministry for

Education and Research, BMBF-Förderkennzeichen), F. Hoffmann–La Roche, and

Gilead Sciences.

Disclosure forms provided by the authors are available with the full text of

this article at NEJM.org.

Source Information

From Hannover Medical School, Hannover (H.W., A.K., M.P.M.); Heinrich Heine

University, Düsseldorf (A.E.); Johann Wolfgang Goethe University, furt

(S.Z.); Koch Institute, Berlin (T.B.); and University Köln, Cologne

(H.P.D.) — all in Germany; the University of Ankara Medical School (C.Y.,

H.B.) and Ufuk University Medical School (H.D.), Ankara; Memorial Hospital

Istanbul, Istanbul (Y.C.); and University of UludaÄŸ Medical School, Bursa

(S.G.) — all in Turkey; and University Larissa, Larissa, Greece (G.N.D.,

K.Z.).

Address reprint requests to Dr. Manns at the Department of Gastroenterology,

Hepatology, and Endocrinology, Medizinische Hochschule Hannover, Carl-Neuberg

Str. 1., D-30625 Hannover, Germany, or at manns.michael@....

We thank Hep-Net members U. Drebber (pathology), B. Bremer, P. Magerstedt, and

R. Raupach (virology), T. Müller and K. (study management team), U.

Alshuth of F. Hoffmann–La Roche, and C. Fischer of Gilead Sciences for their

contributions to the study; and K. Searle for support in writing and editing an

earlier version of the manuscript.