Peginterferon Plus Adefovir Versus Either Drug Alone for Hepatitis Delta

T h e new england journal o f medicine

original article

Peginterferon plus Adefovir versus Either Drug Alone for Hepatitis Delta

Heiner Wedemeyer, M.D., Cihan Yurdaydìn, M.D., George N. Dalekos, M.D., Andreas 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., Thomas Bock, M.D., Hans Peter Dienes, M.D., and Michael P. Manns, M.D., for the HIDIT Study Group*

Abstr act

Background From Hannover Medical School, Han Chronic infection with hepatitis B virus and hepatitis delta virus (HDV) results in nover (H.W., A.K., M.P.M.); Heinrich Heine University, Düsseldorf (A.E.); Johann the most severe form of viral hepatitis. There is no currently approved treatment. We Wolfgang Goethe University, Frankfurt investigated the safety and efficacy of 48 weeks of treatment with peginterferon alfa- (S.Z.); Robert Koch Institute, Berlin (T.B.); 2a plus adefovir dipivoxil, peginterferon alfa-2a alone, and adefovir dipivoxil alone. and University Köln, Cologne (H.P.D.) — all in Germany; the University of Ankara Methods Medical School (C.Y., H.B.) and Ufuk Uni We conducted a randomized trial in which 31 patients with HDV infection received versity Medical School (H.D.), Ankara; Memorial Hospital Istanbul, Istanbul treatment with 180 μg of peginterferon alfa-2a weekly plus 10 mg of adefovir daily, (Y.C.); and University of Uludağ Medical 29 received 180 μg of peginterferon alfa-2a weekly plus placebo, and 30 received 10 mg School, Bursa (S.G.) — all in Turkey; and of adefovir alone weekly for 48 weeks. Follow-up was conducted for an additional University Larissa, Larissa, Greece (G.N.D., K.Z.). Address reprint requests to Dr. Manns 24 weeks. Efficacy end points included clearance of HDV RNA, normalization of at the Department of Gastroenterology, alanine aminotransferase levels, and a decline in levels of hepatitis B surface antigen Hepatology, and Endocrinology, Medizi (HBsAg). nische Hochschule Hannover, Carl-Neu berg Str. 1., D-30625 Hannover, Germany, Results or at [email protected]. The primary end point — normalization of alanine aminotransferase levels and clear- Drs. Wedemeyer and Yurdaydìn contrib ance of HDV RNA at week 48 — was achieved in two patients in the group receiving uted equally to this work. 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 ad- *The Hep-Net–International Delta Hepati tis Intervention Trial (HIDIT) Study Group efovir alone. At week 48, the test for HDV RNA was negative in 23% of patients in collaborators are listed in the Supplemen the first group, 24% of patients in the second, and none of those in the third tary Appendix, available at NEJM.org. (P = 0.006 for the comparison of the first and third groups; P = 0.004 for the com- N Engl J Med 2011;364:322-31. parison of the second and third). The efficacy of peginterferon alfa-2a was sus- Copyright © 2011 Massachusetts Medical Society. tained 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.)

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epatitis delta virus (HDV) is a defec- titis C25 and hepatitis B.26 Three pilot studies tive RNA virus that requires coinfection using peginterferon alfa-2b (1.5 μg per kilogram Hwith hepatitis B virus (HBV) to replicate. of body weight per week) showed a sustained The HDV genome is encapsidated by hepatitis B response to treatment (defined as undetectable surface antigen (HBsAg), which forms the viral levels of HDV RNA 6 months after the end of envelope. The virus was first identified in 1977 in treatment) in 17 to 43% of patients treated for the serum of long-term carriers of HBsAg and periods of 48 to 72 weeks.27-29 Adefovir dipivoxil was noted to have an increased prevalence among has been reported to have an effect on levels of patients with liver damage.1 covalently closed circular DNA (cccDNA) within In long-term carriers of HBV, HDV infection infected hepatocytes in HBV infection; cccDNA can result in fulminant acute hepatitis or severe acts as a template for HBsAg production.30 A de- chronic hepatitis, often progressing to cirrhosis crease in the HBsAg level may deprive HDV of the and hepatocellular carcinoma.2-6 Eight HDV ge helper function of the HBV envelope protein and notypes have been suggested,7,8 and both HDV may therefore provide a benefit. The aim of the and HBV genotypes affect the clinical outcome.9,10 current study was to investigate the safety and Infection with HDV genotype 1, the most preva- efficacy of peginterferon alfa-2a plus adefovir lent genotype in Europe, the Middle East, North dipivoxil, as compared with either drug alone, in America, and North Africa, is associated with patients with chronic HDV infection. more severe disease than infection with genotype 2.9,11 Although the prevalence of HDV in- Methods fection in southern Europe has declined since the introduction of vaccination against HBV,3,12 Study Protocol and Oversight HDV infection — and HDV-related disease — con- The Hep-Net–International Delta Hepatitis Inter- tinues to be a major health problem in several vention Trial (HIDIT) was an investigator-initiat- regions of the world.13 Immigration to central ed, randomized, controlled trial that was ap- Europe from areas where HDV is highly endemic proved by the German Network of Excellence on has put a substantial burden on that part of the Viral Hepatitis (Hep-Net) and operated under its continent, where 8 to 14% of patients infected auspices.31 F. Hoffmann–La Roche and Gilead with HBV are reported to be positive for anti- Sciences provided financial support for the study HDV antibodies.13-15 and approved the study design proposed by the There is currently no approved therapy for investigators. The authors vouch for the veracity infection with HDV. Oral antiviral agents, in- and completeness of the data and data analyses. cluding ribavirin, lamivudine, and famciclovir, The manuscript was written by the first, second, are ineffective against it.16-19 Clinical data for and last authors with the assistance of a repre- the more potent oral antiviral agents widely used sentative of Elements Communication. Writing for the treatment of chronic HBV infection, such assistance was funded by F. Hoffmann–La Roche. as adefovir dipivoxil, entecavir, telbivudine, and Patients were recruited between March 2004 tenofovir, are currently lacking. The effective- and September 2006, and data collection and ness of treatment of HDV infection with inter- analysis were completed in August 2009. The feron alfa is limited by the need for prolonged study was approved by the ethics committee at administration and high doses that are poorly each participating institution. Written informed tolerated. However, high-dose interferon alfa-2a consent was obtained from each patient. therapy has been shown to reduce levels of alanine aminotransferase and HDV RNA20 and to Study Population be associated with improved long-term clinical Patients between 18 and 70 years of age who had outcomes and survival.21 The addition of lamivu- HDV infection were eligible for inclusion if they dine or ribavirin to interferon-based therapy has had compensated liver disease, had been positive not improved efficacy, as compared with the use for HBsAg for at least 6 months and positive for of interferon alone.19,22-24 anti-HDV antibodies for at least 3 months, and Pegylated interferon (peginterferon) has been were positive for HDV RNA on polymerase-chain- shown to be more beneficial than conventional reaction assay. A description of the eligibility cri- interferon in the treatment of both chronic hepa- teria can be found in the Supplementary Appen-

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dix and in the study protocol, both available with ues were categorized as not having had a re- the full text of this article at NEJM.org. The study sponse. Comparisons of specific variables were was conducted in accordance with the protocol. made with the use of analysis of variance or the Kruskal–Wallis test when appropriate, with P val- Study Design ues of less than 0.05 considered to indicate sta- Patients were stratified according to country and tistical significance. Continuous variables were presence or absence of a history of interferon evaluated with the use of a t-test or a nonpara- treatment before undergoing randomization to metric test. one of three treatment groups, and they received the assigned medication for 48 weeks. The first Results group included a total of 31 patients who received peginterferon alfa-2a (180 μg once week- Characteristics of the Patients ly) plus adefovir (10 mg daily), the second group Demographic and baseline clinical characteris- included a total of 29 patients who received peg tics of the patients in the three treatment groups interferon alfa-2a (180 μg once weekly) plus pla- are shown in Table 1 and are described in further cebo, and the third had a total of 30 patients who detail in the Supplementary Appendix. received adefovir (10 mg daily) alone. Assess- ments for virologic end points were made at a Adverse Events central laboratory at weeks 24 and 48 (end of Of the 90 patients included in the study, 10 with- treatment), with a final clinic visit at week 72 (24 drew (5 in the group receiving peginterferon alfa- weeks after the end of treatment). At each clinic 2a plus adefovir dipivoxil, 3 in the group receiv- visit, all patients underwent a complete physical ing peginterferon alfa-2a plus placebo, and 2 in examination and safety assessment, and blood the group receiving adefovir alone). Six of the was taken for biochemical and virologic analysis. withdrawals were due to disease progression (including 1 death from intraperitoneal bleeding as Safety and Efficacy a result of hepatocellular carcinoma, 1 case of Safety was assessed by the study investigators on hepatic decompensation [with the patient placed the basis of adverse events reported spontane- on the waiting list for liver transplantation], and ously by study participants. In addition, plasma 1 hospitalization because of suspected hepato- samples were routinely assessed for hematologic cellular carcinoma); 2 patients left the country, 1 variables (e.g., leukocyte and platelet counts and patient did not comply with the treatment regi- levels of creatinine, alanine aminotransferase, as- men, and 1 patient decided to withdraw because partate aminotransferase, γ-glutamyl transferase, of severe malaise from interferon alfa–related ad- and bilirubin). verse events. The primary end point was the achievement The remaining 80 patients (89%) completed the of undetectable levels of HDV RNA and normal study. Overall, 66 patients (73%) reported a total levels of alanine aminotransferase at week 48. of 318 adverse events, which were more common Secondary end points were based on HDV RNA in patients treated with peginterferon alfa-2a than levels and alanine aminotransferase levels at in patients receiving adefovir (Table 2). The ad- week 48 and week 72; levels of HBV DNA, ala- verse events were those typically associated with nine aminotransferase, and HBsAg through week interferon alfa or adefovir treatment, and no un- 72; and histologic analysis (evaluation of biopsy expected adverse events occurred. The 17 serious specimens for fibrosis and histologic activity). adverse events that occurred in the study are de- Outcome measures are described in detail in the scribed in detail in the Supplementary Appendix. Supplementary Appendix. Outcomes Statistical Analysis The primary outcome of the intention-to-treat Detailed information on the procedures used for analysis (normal serum levels of alanine amino- the statistical analysis is available in the Supple- transferase and undetectable levels of HDV RNA mentary Appendix. In brief, an intention-to-treat at week 48) occurred in two patients (7%) receiv- efficacy analysis was performed for all patients ing peginterferon alfa-2a plus adefovir, two (7%) receiving at least one dose of the study medica- receiving peginterferon alfa-2a plus placebo, and tion (i.e., 90 patients). Patients with missing val- none receiving adefovir alone (P = 0.16 for pegin-

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Table 1. Baseline Characteristics of the Study Participants.*

Peginterferon Alfa-2a Peginterferon Alfa-2a plus Adefovir Dipivoxil plus Placebo Adefovir Dipivoxil Characteristic (N = 31) (N = 29) (N = 30)

Age — yr Median 42 38 33 Range 23–59 17–62 21–55 Male sex — no. (%) 20 (65) 17 (59) 19 (63) HBeAg-positive — no. (%) 5 (16) 5 (17) 4 (13) HBV DNA

Median — log10 IU/ml 1.4‡ 2.6 2.1 ≥100 IU/ml — no./total no. (%) 13/31 (42) 17/27 (63) 15/28 (54) HDV RNA

Median — log10 copies/ml 6.3 5.9 5.7 Above median — no./total no. (%) 16/28 (57) 12/23 (52) 11/26 (42) Alanine aminotransferase Median — IU/liter 88 73 111 Above median — no./total no. (%) 12/31 (39) 11/27 (41) 19/29 (66) Cirrhosis — no./total no. (%) 4/29 (14) 5/25 (20) 7/29 (24) HDV genotype 1 — % 100 100 100 Previous interferon treatment — no. (%) 12 (38) 15 (52) 12 (40)

* HBeAg denotes hepatitis B e antigen, HBV hepatitis B virus, and HDV hepatitis delta virus. † P = 0.01 for the comparison of adefovir dipivoxil with peginterferon alfa-2a plus adefovir, and P = 0.04 for the compari son of adefovir with peginterferon alfa-2a plus placebo. ‡ P<0.05 for the comparison of peginterferon alfa-2a plus adefovir with peginterferon alfa-2a plus placebo. terferon alfa-2a plus adefovir vs. adefovir dipivox plus placebo vs. adefovir dipivoxil) (Fig. 1A). Over- il, P = 0.14 for peginterferon alfa-2a plus placebo all, the proportion of patients treated with pegin- vs. adefovir dipivoxil, and P = 0.95 for peginter- terferon alfa-2a (with or without adefovir dipiv- feron alfa-2a plus adefovir vs. peginterferon alfa- oxil) who had HDV-RNA clearance was 23% (14 2a plus placebo). of 60) at week 48 and 28% (17 of 60) at week 72. There was a reduction from baseline in me- HDV RNA dian HDV RNA levels in both of the groups re- At week 48, test results for HDV RNA were nega- ceiving peginterferon alfa-2a (P<0.001 for weeks tive in 7 of the 31 patients (23%) treated with 24 and 48, and P = 0.02 and 0.03, respectively, for peginterferon alfa-2a plus adefovir dipivoxil, 7 of week 72) (Fig. 1B). A reduction in median HDV the 29 patients (24%) treated with peginterferon RNA levels of more than 2 log10 copies per mil- alfa-2a plus placebo, and none of the 30 patients liliter from baseline to week 72 was observed in treated with adefovir alone (P = 0.006 for pegin- 8 (26%) of the patients treated with peginter- terferon alfa-2a plus adefovir vs. adefovir dipivox feron alfa-2a plus adefovir dipivoxil, 9 (31%) of il, and P = 0.004 for peginterferon alfa-2a plus pla- those treated with peginterferon alfa-2a plus cebo vs. adefovir dipivoxil) (Fig. 1A). At week 72, placebo, and none of those treated with adefovir tests for HDV RNA were negative in 8 (26%) of alone (P = 0.003 for peginterferon alfa-2a plus the patients treated with peginterferon alfa-2a adefovir vs. adefovir dipivoxil, and P = 0.001 for plus adefovir dipivoxil, 9 (31%) of those treated peginterferon alfa-2a plus placebo vs. adefovir with peginterferon alfa-2a plus placebo, and none dipivoxil). Only 2 patients had a virologic relapse, of those treated with adefovir alone (P = 0.006 for with the reappearance of HDV RNA, after the peginterferon alfa-2a plus adefovir vs. adefovir end of treatment (1 patient in each peginterferon dipivoxil, and P = 0.004 for peginterferon alfa-2a alfa-2a group), whereas 9 patients (4 treated with

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peginterferon alfa-2a plus adefovir and 5 treated cebo, and 2 of 30 (7%) receiving adefovir alone with peginterferon alfa-2a plus placebo) became (P = 0.01 for peginterferon alfa-2a plus adefovir negative for HDV RNA during follow-up. No vs. adefovir dipivoxil, and P = 0.03 for peginter- follow-up data on HDV RNA were available for 4 feron alfa-2a plus placebo vs. adefovir dipivoxil) patients who were negative for HDV RNA at the (Fig. 2A). At week 72, a total of 11 patients (35%) end of treatment. receiving peginterferon alfa-2a plus adefovir and 13 patients (45%) receiving peginterferon alfa-2a Alanine Aminotransferase plus placebo had normal alanine aminotransfer- At week 48, the level of alanine aminotransferase ase levels, as compared with 3 patients (10%) re- was normal in 10 of 31 patients (32%) receiving ceiving adefovir alone (P = 0.02 for peginterferon peginterferon alfa-2a plus adefovir dipivoxil, 8 of alfa-2a plus adefovir vs. adefovir dipivoxil, and 29 (28%) receiving peginterferon alfa-2a plus pla- P = 0.003 for peginterferon alfa-2a plus placebo

Table 2. Summary of Adverse Events and Incidence of Most Common Adverse Events.*

Peginterferon Alfa-2a Peginterferon Alfa-2a plus Adefovir Dipivoxil plus Placebo Adefovir Dipivoxil Adverse Eve nt (N = 31) (N = 29) (N = 30) Total adverse events — no. 116 121 81 Patients with adverse events — no. (%) 25 (81) 23 (79) 18 (60) Total serious adverse events — no. 3 8 6 Patients with serious adverse events — no. (%) 2 (6) 7 (24) 6 (20) Type of adverse event — no. (%) General Any 18 (58) 13 (45) 9 (30) Loss of appetite 3 (10) 3 (10) 3 (10) Influenza-like symptoms 6 (19) 2 (7) 3 (10) Fatigue 8 (26) 8 (26) 4 (13) Pyrexia† 6 (20) 2 (7) 0 Dry mouth† 0 6 (21) 0 Sexual 2 (6) 1 (3) 0 Nervous system Any 9 (29) 11 (38) 8 (27) Headache 8 (26) 9 (31) 5 (17) Dizziness 0 1 (3) 3 (10) Respiratory Any 4 (13) 3 (10) 4 (13) Cough 3 (10) 3 (10) 2 (7) Gastrointestinal Any 10 (32) 13 (45) 9 (30) Nausea 3 (10) 4 (14) 2 (7) Abdominal pain 7 (23) 7 (24) 5 (17) Skin Any 10 (32) 9 (31) 5 (17) Pruritus 2 (6) 4 (14) 2 (7) Rash or rashlike event 8 (26) 3 (10) 4 (13) Hair loss 6 (19) 2 (7) 1 (3)

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Table 2. (Continued.)

Peginterferon Alfa-2a Peginterferon Alfa-2a plus Adefovir Dipivoxil plus Placebo Adefovir Dipivoxil Adverse Eve nt (N = 31) (N = 29) (N = 30) Psychiatric 2 (6) 5 (17) 1 (3) Insomnia 2 (6) 4 (14) 1 (3) Musculoskeletal Any‡ 11 (35) 16 (55) 1 (3) Myalgia 7 (23) 8 (26) 1 (3) Arthralgia 4 (13) 6 (21) 0 Circulatory Any 8 (26) 3 (10) 3 (10) Neutropenia 3 (10) 2 (7) 0 Thrombocytopenia 5 (16) 2 (7) 0

* The adverse events listed are those that were reported by at least three patients in at least one of the three study groups. The term “serious adverse event” is defined in the protocol, available at NEJM.org. † For these events there was a significant difference in the number per study group (P = 0.03 for pyrexia and 0.01 for dry mouth, calculated with the use of chi-square analysis). ‡ P = 0.004 for the comparison of the groups receiving peginterferon alfa-2a, with or without adefovir dipivoxil, with the group receiving adefovir dipivoxil alone. vs. adefovir dipivoxil) (Fig. 2A). After the end of vs. adefovir, and P = 0.02 for peginterferon alfa-2a treatment, mean alanine aminotransferase levels plus adefovir vs. peginterferon alfa-2a plus pla- increased slightly in the two groups receiving ad- cebo). In total, 2 patients treated with peginter- efovir (Fig. 2B). feron alfa-2a plus adefovir had clearance of HBsAg by week 72; both had seroconversion to anti- HBV DNA HBsAg antibodies. Patients older than 38 years Median HBV DNA levels decreased until week (median age) were more likely to have a decline 48 and rebounded at week 72 in all three treat- in HBsAg of more than 1 log10 IU per milliliter at ment groups (for details, see the Supplementary week 72 if they had received treatment with peg Appendix). interferon alfa-2a (29% vs. 8%, P = 0.052), but no association was found between a decline in HBsAg HBsAg and sex, status with respect to alanine HBsAg levels showed a marked decline only in aminotransferase, HBV DNA, HDV RNA, HBeAg, patients receiving combination therapy, with a histologic grade, or stage. median decline of 0.89 log10 IU per milliliter from baseline to week 48 (P = 0.002) and 1.12 Histologic Analysis log10 IU per milliliter from baseline to week 72 Specimens from biopsies performed before and (P<0.001). In contrast, there was no substantial after treatment were available for a total of 59 effect on median HBsAg levels in patients treated patients (65% of all treated patients). Analysis of with peginterferon alfa-2a plus placebo or adefo- paired specimens revealed approximately equal vir alone, and levels remained largely stable in distributions of patients with deterioration, those these two groups throughout therapy and during with improvement, and those with no change in follow-up. A decline of more than 1 log10 IU per each treatment group (for details, see the Supple- milliliter in HBsAG levels from baseline to week mentary Appendix). 48 was observed in 10 patients treated with peg interferon alfa-2a plus adefovir dipivoxil, 2 pa- Discussion tients treated with peginterferon alfa-2a plus placebo, and none treated with adefovir (Fig. 3) Our study showed that a 48-week course of peg (P<0.001 for peginterferon alfa-2a plus adefovir interferon alfa-2a, alone or in combination with

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A HDV RNA B Median HDV RNA Levels over Time 60 7 Peginterferon alfa-2a Peginterferon alfa-2a Adefovir + adefovir + placebo Adefovir 50 6

5 40 copies/ml) Peginterferon alfa-2a 10 + adefovir 4 30 3

Patients (%) 20 Peginterferon alfa-2a 2 + placebo

10 Treatment Median HDV RNA (log 0 0 HDV RNA– HDV RNA HDV RNA– HDV RNA Baseline 24 48 72 negative >2 log decline, negative >2 log decline, 10 10 Week copies/ml copies/ml

Week 48, End of Treatment Week 72, End of Follow-up

Figure 1. Virologic Response to Treatment as Determined by Serum Level of HDV RNA, According to Treatment Group.

Panel A shows the percentage of patients with a decline in hepatitis delta virus (HDV) RNA of at least 2 log10 copies per milliliter or clearance of HDV RNA at the end of treatment (week 48) or follow-up (week 72). Panel B shows the change in median HDV RNA levels over time. In both groups receiving peginterferon alfa-2a, HDV RNA levels were significantly lower at week 48 than at baseline (P<0.001 for both groups). At week 72, HDV RNA levels were slightly reduced as compared with baseline in both these groups (P = 0.02 for the group receiving peginterferon alfa-2a plus adefovir dipivoxil, and P = 0.03 for the group receiving peginterferon alfa-2a plus placebo), but levels were increased in the group receiving adefovir dipivoxil alone (P = 0.02).

adefovir dipivoxil, significantly reduced HDV Considerable decreases in HDV RNA levels have RNA levels, with 28% of patients receiving the been reported after 1 year of treatment with drug having clearance of HDV RNA 24 weeks af- high-dose interferon alfa (9 million units three ter the end of treatment. In contrast, treatment times a week),20 results that were associated with adefovir dipivoxil alone had no appreciable with long-term improvements in hepatic func- effect on HDV replication; none of the patients tion and histologic findings.21 A number of case who received this treatment had clearance of reports and reports on small studies have noted HDV RNA, and none had a decline from baseline reductions in or clearance of HDV RNA as a re- 27-29,32 HDV RNA levels of more than 2 log10 copies per sult of treatment with peginterferon. milliliter. The predefined primary end point of With regard to efficacy, the results of our larger the study, normal serum levels of alanine amino- study are in general accordance with these reports. transferase and undetectable HDV RNA at week In contrast with the findings for peginter- 48, was achieved in few patients — 7% of those feron in the treatment of HDV and HBV infec- treated with peginterferon alfa-2a, with or with- tion, we observed that in several patients, HDV out adefovir dipivoxil, and none of those treated RNA cleared between the end of treatment and with adefovir dipivoxil alone. Since alanine ami- follow-up 24 weeks later. Earlier studies also notransferase levels frequently remain elevated showed that a decrease in HDV RNA levels may during treatment with peginterferon alfa,25 this occur late in the course of therapy, and in some finding was not completely unexpected. On the cases even after the end of treatment, with both other hand, levels of alanine aminotransferase conventional interferon and peginterferon.27-29 normalized in several patients in our study, who Further studies are needed to determine whether nonetheless remained positive for HDV RNA, a patients with a slow response to treatment who finding also reported in the pilot studies of pe- have clinically significant declines in HDV RNA ginterferon alfa-2b.29 levels during treatment without becoming HDV Clearance of HDV RNA in patients treated RNA–negative would benefit from a longer pe- with interferon has been reported previously. riod of treatment.33

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A ALT Normalization B ALT Levels over Time 60 150 Peginterferon Peginterferon Adefovir Peginterferon alfa-2a alfa-2a + adefovir alfa-2a + placebo + placebo 50 120 Adefovir

40 90 30 60 20 Peginterferon alfa-2a + adefovir Mean ALT Levels (U/liter) 30 10 Treatment Patients with Normal Levels (%)

0 0 Week 48, Week 72, Baseline 24 48 72 End of Treatment End of Follow-up Week

Figure 2. Biochemical Response to Treatment as Determined by Serum Level of Alanine Aminotransferase, According to Treatment Group. Panel A shows the percentage of patients who had normal levels of alanine aminotransferase (ALT) at week 48 or week 72. Panel B shows the change in mean levels of ALT over time. ALT levels were significantly lower than base line values at week 48 in patients treated with peginterferon alfa-2a plus adefovir dipivoxil (P = 0.008) and in those treated with adefovir dipivoxil alone (P = 0.002). At week 72, ALT levels were not significantly different from baseline values in all three treatment groups.

In line with earlier studies of the use of oral alone; approximately one third of patients re- anti-HBV agents, monotherapy with adefovir ceiving combination therapy had a decline in the dipivoxil had no appreciable effect on HDV RNA HBsAg level of at least 1 log10 IU per milliliter. levels in our study, and none of the patients The apparently higher rate of HBsAg decline in treated with adefovir alone had clearance of patients receiving combination therapy may be HDV RNA. Currently, we would not recommend related to differences in patient characteristics the use of nucleoside or nucleotide monotherapy or to the mechanisms of action or the potency of for HDV infection in patients with suppressed or adefovir as compared with lamivudine. very low HBV replication.13 In the current study, the absence of any appar- The clearance of HBsAg is considered to be ent differences in histologic scores in analyses the closest outcome to a cure in chronic HBV of paired biopsy samples may reflect the shorter infection and is therefore recognized as the follow-up period in our study, as compared with ideal end point of therapy.34 Since the virus that in previous studies, or sample bias due to needs HBsAg to produce infectious viral parti- the small numbers of patients with paired biopsy cles, reducing HBsAg levels, or even achieving samples. More patients in the combination-therapy clearance of HBsAg, is of considerable relevance group had a worsening of fibrosis scores and a in the treatment of infection with HBV and HDV. higher number of patients receiving peginter- Patients with chronic HBV infection in whom a feron alfa-2a alone had a worsening of scores for sustained virologic response to interferon-based histologic activity. It is noteworthy that biopsies therapy is achieved have an increased likelihood were performed at the end of treatment, rather of HBsAg clearance during long-term follow than 24 weeks after the end of treatment, as has up.35,36 HBsAg clearance is not generally seen in been the case in most trials investigating the use HBeAg-negative patients treated with nucleoside of peginterferon alfa-2a for hepatitis B and C. or nucleotide analogues, including lamivudine, Thus, more data on the results of biopsies per- entecavir, and telbivudine.32,37,38 In our study, formed at follow-up after the completion of treat- the combination of peginterferon alfa-2a and ment would be needed to answer the question of adefovir resulted in a more pronounced decrease whether peginterferon alfa-2a worsens certain in serum HBsAg levels than did either agent histologic features of infection with HDV.

n engl j med 364;4 nejm.org january 27, 2011 329 The New England Journal of Medicine Downloaded from nejm.org by Matthew Bys on January 26, 2011. For personal use only. No other uses without permission. Copyright © 2011 Massachusetts Medical Society. All rights reserved. T h e new england journal o f medicine

A HBsAg B HBsAg Levels over Time 60 5 Peginterferon alfa-2a Peginterferon alfa-2a Adefovir Peginterferon alfa-2a + adefovir + placebo + placebo 50 Adefovir 4 40 IU/ml) 10

30 3 Peginterferon alfa-2a Patients (%) 20 + adefovir

Treatment

10 Median HBsAg (log 2

0 0 HBsAg- HBsAg HBsAg- HBsAg Baseline 24 48 72 negative >1 log IU/µl negative >1 log IU/µl 10 10 Week decline decline

Week 48, End of Treatment Week 72, End of Follow-up

Figure 3. Change in Levels of Hepatitis B Surface Antigen According to Treatment Group. Panel A shows the percentage of patients in each treatment group who had levels of hepatitis B surface antigen (HBsAg) that declined by more than 1 log10 IU per milliliter or in whom HBsAg clearance was achieved at week 48 or week 72. Panel B shows the change from baseline in median levels of HBsAg over time. The decline in patients treated with peginterferon alfa-2a plus adefovir dipivoxil was sig nificant at week 48 and week 72 (P = 0.002 for week 48 and P<0.001 for week 72).

The withdrawal rate for the patients in our In conclusion, treatment with peginterferon study (all of whom had HDV infection) who were alfa-2a for 48 weeks resulted in sustained HDV treated with peginterferon alfa-2a was 11% — a RNA clearance in more than 25% of patients rate that is not dissimilar to that in large-scale and a sustained biochemical response in 40%. studies of peginterferon alfa-2a in the treatment 39 Supported by Hep-Net (a national network sponsored by the of chronic HBV monoinfection. The one patient German Ministry for Education and Research, BMBF-Förderkenn in our study who had hepatic decompensation zeichen), F. Hoffmann–La Roche, and Gilead Sciences. during treatment with peginterferon alfa-2a had Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. a baseline platelet count of 74,000 per cubic mil- We thank Hep-Net members U. Drebber (pathology), B. limeter after an initial screening count of 75,000 Bremer, P. Magerstedt, and R. Raupach (virology), T. Müller and per cubic millimeter, which was in line with the K. Peter (study management team), U. Alshuth of F. Hoffmann– La Roche, and C. Fischer of Gilead Sciences for their contribu- study inclusion criteria. Thus, we would recom- tions to the study; and K. Searle for support in writing and edit- mend caution in the use of peginterferon alfa-2a ing an earlier version of the manuscript. therapy for patients whose platelet counts are below 90,000 per cubic millimeter.

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