Pegylated Interferon Alpha-2b as Monotherapy or in
Combination With Ribavirin in Chronic Hepatitis Delta
Grazia Anna Niro,1 Alessia Ciancio,2 Giovanni Battista Gaeta,3 Antonina Smedile,2 Aldo Marrone,4 Antonella Olivero,2
Maria Stanzione,3 Ezio David,5 Giuseppina Brancaccio,3 Rosanna Fontana,1 Francesco Perri,1
Angelo Andriulli,1 and Mario Rizzetto2
Therapy of chronic hepatitis delta with standard interferon therapy has met with limited
efficacy. This study was designed to examine the efficacy and safety of peginterferon with or
without ribavirin. Thirty-eight serum hepatitis B surface antigen- and HDV RNA-positive
patients with alanine aminotransferase (ALT) more than 1.5 times the upper normal limit
received peginterferon alpha-2b (1.5 ␮g/kg) alone as monotherapy (n ⴝ 16) or in combination with ribavirin (n ⴝ 22), for 48 weeks. Thereafter, all the patients were maintained on
peginterferon for 24 weeks and followed for 24 weeks off therapy. The primary end point
studied was the virological and biochemical response at the end of follow-up. HDV RNA was
determined by single or nested polymerase chain reaction assays. Twenty-seven patients
(71%), 11 receiving monotherapy and 16 receiving the combination treatment, completed
the follow-up. At the end of treatment, a virological response was observed in 3 of the
patients treated with peginterferon (19%) and in 2 of the patients treated with combination
therapy (9%), and a biochemical response was observed in 6 (37.5%) and 9 patients (41%),
respectively. In nonresponders, ALT diminished from a mean of 174 ⴞ 53 to 86 ⴞ 41 IU/L.
At the end of follow-up, serum HDV RNA was negative in 8 patients (21%), and a biochemical response was detected in 10 patients (26%). Treatment was discontinued in 25% of the
patients, and dosing was modified in 58%. In conclusion, a prolonged course of peginterferon alpha-2b resulted in clearance of serum HDV RNA and ALT normalization in a fifth of
patients with chronic hepatitis D, while ribavirin had no effect on the viral clearance rate.
Overall tolerance of therapy was poor. (HEPATOLOGY 2006;44:713-720.)
See Editorial on Page 536
H
epatitis delta virus (HDV) infection has a broad
spectrum of clinical manifestations but generally develops into a chronic, severe disease.1
Though the last 2 decades have seen a substantial decline
Abbreviations: HDV, hepatitis delta virus; ALT, alanine aminotransferase;
HBV, hepatitis B virus; IFN, interferon; RBV, ribavirin; PEG-IFN, pegylated
interferon; anti-HD, antibody to hepatitis delta antigen; HBsAg, hepatitis B surface
antigen; anti-HBe, antibody to hepatitis B e antigen.
From the1Gastroenterology CSS Hospital, S.Giovanni Rotondo, Italy; 2Gastroenterology Molinette Hospital and University, Turin, Italy; 3Department of Infectious Diseases, Second University of Naples, Italy; 4Department of Internal
Medicine and Hepatology, Second University of Naples, Italy; and 5Department of
Pathology, Molinette Hospital, Turin, Italy.
Received April 9, 2006; accepted June 7, 2006.
Address reprint requests to: Grazia Anna Niro, M.D., Division of Gastroenterology, Casa Sollievo della Sofferenza Hospital, Viale Cappuccini, 71013 San Giovanni Rotondo (FG), Italy. E-mail: [email protected]; fax: (39) 411879.
Copyright © 2006 by the American Association for the Study of Liver Diseases.
Published online in Wiley InterScience (www.interscience.wiley.com).
DOI 10.1002/hep.21296
Potential conflict of interest: Nothing to report.
in the circulation of HDV and the incidence of new forms
of the disease in southern Europe,2,3 there is still residual
manifestation of the disease in patients infected years ago
when HDV was endemic; these patients pose a difficult
therapeutic challenge, as most have advanced disease and
cirrhosis.
At present, interferon alpha is the only option for treating chronic hepatitis D; however, the response is limited
and variable depending on the different schedules of treatment.4-6 Up to 70% of patients may reach a normal aminotransferase level while on therapy, but the relapse rate is
high after discontinuation. Therapeutic efficacy increases
when higher doses of interferon alpha (9 MU t.i.w.) are
administered for prolonged periods (12-24 months).3,4
Twelve years of treatment with a high dose of interferon
alpha achieved complete resolution of the infection in a
single HDV patient, with remission of liver fibrosis and
disappearance of the HDV and hepatitis B virus (HBV)
from serum.7 Improvement in clinical outcome and survival has been reported even in patients with cirrhosis at
baseline.8 Unfortunately, compliance with an intensive
713
714
NIRO ET AL.
interferon (IFN) regimen has been poor because of the
dose-dependent development of side effects.9 Other antiviral agents, whether given as monotherapy or in combination, have not proven to be beneficial.10-12 Ribavirin
(RBV), a guanosine analogue, was able to inhibit HDV
replication in primary woodchuck hepatocyte cultures infected with HDV13; its mechanism of action against
HDV is not fully understood, although the mechanism
may involve inhibition of viral mRNA formation. However, the in vitro results were not reproduced in vivo in a
pilot study of 9 patients with chronic hepatitis D given
RBV monotherapy.14 In a recent study, the association of
RBV with interferon alpha-2a in chronic hepatitis delta
was found to provide no additional benefit than treatment
with interferon alone.15
Pegylated IFN (PEG-IFN), the product of conjugation of interferon with poly(ethylene glycol), could be
more effective than conventional interferon because of its
improved pharmacodynamics and pharmacokinetics. By
prolonging the plasma half-life and providing protracted
activity of the cytokine, PEG-IFN allows for once-weekly
dosing and stable therapeutic levels. The new formulation
of long-acting interferon is also likely to provide better
compliance if the drug has to be administered for a protracted time, as is required in chronic hepatitis D. The
current study was designed to compare the efficacy and
safety of PEG-IFN alpha-2b monotherapy given for 72
weeks versus therapy with a combination of PEG-IFN
alpha-2b with RBV given for 48 weeks, followed by PEGIFN monotherapy for 24 additional weeks.
Patients and Methods
Patients. Thirty-eight patients with chronic hepatitis
delta who had been referred to 3 Italian medical centers
(in Torino, San Giovanni Rotondo, and Naples) were
enrolled. Inclusion criteria were the presence of antibodies to hepatitis delta antigen (anti-HDV) and hepatitis B
surface antigen (HBsAg) in serum for at least 6 months
prior to screening, detectable serum HDV RNA at enrollment, and alanine aminotransferase (ALT) ⱖ 1.5 and ⱕ
10 times the normal value. Patients with compensated
cirrhosis were eligible if their hemoglobin was ⱖ 12 g/dL,
their WBC ⬎ 3.000/mm3, and their platelets ⬎ 80.000/
mm3. Patients were excluded if they were hepatitis C virus
(HCV) or HIV positive, had received antiviral, cytotoxic,
corticosteroid, or immunomodulatory treatment within 6
months of inclusion, or had a history of psychiatric disorders. Hospital ethics committees approved the study;
written informed consent was obtained from all patients
prior to enrollment.
HEPATOLOGY, September 2006
The patients were randomly assigned on the basis of a
computer-generated list to one arm of a 2-arm study: in
one arm, patients were given PEG-IFN alpha-2b (1.5
␮g/kg of body weight subcutaneously weekly) and RBV
(800 mg orally daily) for 48 weeks followed by PEG-IFN
alpha-2b monotherapy for 24 additional weeks; in the
other arm, patients were treated with PEG-IFN alpha-2b
monotherapy for 72 weeks at the same dosage. After completing treatment, all patients were followed up for 24
weeks.
Laboratory and Virological Testing. Assessment of
the efficacy and safety of the treatments was carried out at
baseline, at weeks 2, 4, 6, 8, and 12, and then every 6
weeks until week 72. Off treatment, follow-up assessments were carried out at 4, 12, and 24 weeks. At each
clinical visit, routine laboratory tests performed included
serum ALT and aspartate aminotransferase, serum direct
and total bilirubin, albumin, and complete blood counts.
Serologic markers of HBV, HDV, HCV, and HIV were
tested by commercial enzyme immunoassays (Abbott
Laboratories, North Chicago, IL; Sorin Biomedica, Saluggia, Italy; Ortho Diagnostic Systems, Raritan, NJ).
IgM anti-HD was measured using a previously described
capture immunoassay.16 Serum samples were tested for
HDV RNA as previously reported17 by semiquantitative
single and nested polymerase chain reaction (PCR) assays,
with a sensitivity of approximately 1,000 and 1-10 genomes/mL respectively. Serum HBV DNA levels were
determined with a commercial quantitative PCR assay
(Amplicor HBV Monitor Test, Roche Diagnostics,
GmbH Mannheim, Germany) with a sensitivity threshold of about 400 copies/mL.
Liver Histology. A liver biopsy was performed within
24 months prior to screening and at the end of treatment.
A single pathologist, blinded to study treatment, assessed
all biopsies. Changes in histological activity were evaluated by the modified Ishak score.18
End Points. The primary efficacy end point was the
ability of PEG-IFN, as monotherapy or in combination
with RBV, to clear HDV viremia or to suppress HDV
RNA levels below 1,000 copies/mL. Secondary efficacy
objectives included biochemical response, improvement
of histological score in paired pre- and post-treatment
liver biopsies and loss of HBsAg with seroconversion to
antibodies to hepatitis B surface antigen (anti-HBs). As in
previous investigations5,6 the virological response was defined as the loss of serum HDV RNA at the end of treatment (end-of-therapy virological response) or during the
6-month post-therapy follow-up period (sustained virological response). Relapse was defined as the reappearance
of serum HDV RNA after treatment. A biochemical response was defined as a normal serum alanine aminotrans-
HEPATOLOGY, Vol. 44, No. 3, 2006
NIRO ET AL.
715
Table 1. Demographic Characteristics of the 38 Patients With Chronic Hepatitis D Enrolled in the 2 Treatment Arms
Age, years (mean ⫾ SD)
Sex, male (no., %)
Known risk factors of transmission* (no., %)
Duration of HDV, years (mean ⫾ SD)
Previous antiviral therapy (no ., %)
ALT (mean ⫾ SD)
IgM anti-HDV positive (no., %)
HDV RNA ⫹ ve, first PCR (no., %)
HBV DNA ⬎ 1,000 copies/mL (no., %)
Grading, median score (range)
Fibrosis, median score (range)
All Patients
(n ⴝ 38)
Patients Who Received
PEG-IFN
(n ⴝ 16)
Patients Who Received
PEG-IFN ⴙ RBV
(n ⴝ 22)
44 ⫾ 9.2
23 (61%)
13 (34%)
11 ⫾ 6.7
30 (79%)
144 ⫾ 82
38 (100%)
35 (92%)
7 (18%)
4.5 (1-9)
4.0 (1-6)
45.4 ⫾ 8.8
8 (50)
5 (31%)
9.6 ⫾ 6.8
10 (62.5%)
147 ⫾ 110
16 (100%)
13 (81%)
2 (13%)
4.4 (1-6)
4.7 (2-6)
43 ⫾ 9.6
15 (68)
8 (36%)
11.6 ⫾ 6.7
20 (91%)
139 ⫾ 61
22 (100%)
22 (100%)
5 (23%)
4.8 (1-9)
3.6 (1-6)
*Familial history of HDV infection, blood transfusion, drug addiction.
ferase level at the end of treatment (end-of-therapy
biochemical response) or after 6 months of follow-up
(sustained biochemical response). A relapse was defined as
an increase in the serum alanine aminotransferase level to
more than 1.5 times the upper limit of normal after a
biochemical response.
Statistical Analysis. The SPSS statistical package
(version 6.1.3; SPSS Inc., Chicago, IL) was used to analyze the data. Continuous variables are expressed as means
and standard deviations (SDs). Categorical variables are
reported as percentages. Baseline characteristics of the 2
treatment groups were compared with the Student t test if
continuous variables or the ␹2 test (or Fisher’s exact test,
when needed) if categorical variables. A P value of ⬍ .05
was considered statistically significant. Predictors of response to therapy were analyzed by univariate and multivariate analyses. The intention-to-treat approach was
taken by including all patients and per protocol analysis at
24, 48, and 72 weeks by including all patients who completed treatment.
Results
Sixteen patients were randomized to PEG-IFN alpha-2b monotherapy, 22 to treatment with PEG-IFN
alpha-2b in combination with RBV. The baseline clinical,
demographic, and histological features of patients are
given in Table 1: the patients in the 2 treatment arms had
similar features at baseline. Thirty patients had previously
received treatment, 17 with interferon, 2 with lamivudine, and 11 with both lamivudine and interferon. Of the
28 patients treated with IFN, 25 patients had previously
received a 48-week course of interferon alpha-2a, 5 of
whom received a dose of 9 million units 3 times a week
and 20 of whom received 5 million units. Intolerance
caused the remaining 3 patients to stop therapy after 3
months of treatment with interferon alpha at a dose of 5
million units 3 times a week. By the end of their previous
treatments, 19 patients had not responded, 7 patients had
normalized serum ALT levels but remained viremic, and
2 patients exhibited both biochemical and virological responses. A virological relapse occurred in both responders
1 to 10 months after cessation of therapy.
Twenty-eight of the 38 patients had cirrhosis; 12 of
these patients were assigned to receive the monotherapy
(75%) and 16 to receive the combination therapy (73%).
Eleven of the 38 patients (29%) did not complete
treatment, 5 (31%) in the monotherapy group and 6
(27%) in the combination group; they dropped out of
the study after an average of 29 weeks (range 4-54
weeks; Fig 1). Nine of the 11 patients stopped treatment because of poor compliance or for personal reasons; the remaining 2 ceased treatment because of
adverse events, which is discussed in the Safety section.
Because this was an intention-to-treat analysis, dropouts were included as nonresponders in therapy outcomes.
Biochemical Response. By the end of treatment a
biochemical response was achieved in 15 patients
(39%), 6 who had been in the monotherapy group
(37%) and 9 in the combination therapy group (41%);
the difference was not significant (P ⫽ .83) . In the 23
nonresponders, mean ALT level diminished from
174 ⫾ 53 IU/L (range 74-185) to 86 ⫾ 41 IU/L (range
49-184). At the end of follow-up, the biochemical response was maintained in 6 of the 15 patients with
end-of-therapy response (3 in each treatment arm),
whereas the remaining 9 patients relapsed, 3 who had
received the monotherapy and 6 who had received the
combination therapy. In the 9 relapsers, ALT level
started to increase again 1-3 months after stopping
therapy; in 3 patients aminotransferase showed as
much as 5- to 10-fold increase above the upper normal
limit, an elevation that persisted up to the 16th month
716
NIRO ET AL.
Fig. 1.
HEPATOLOGY, September 2006
Flow of participants through the study, including patients who withdrew prematurely from treatment.
of follow-up. In 4 nonresponders ALT values dropped
to normal during follow-up. At the end of follow-up,
10 patients had normal ALT values.
The pattern of ALT fluctuation during and off therapy is
shown in Fig. 2. During therapy ALT was higher than base-
Fig. 2.
line in 9 patients (7 of them treated with combination therapy) and reached peak values by week 24; in 2 patients the
enzyme levels were more than 10-fold higher than the upper
normal limit. Hepatic flares were not associated with jaundice or symptoms of hepatic decompensation. Because of a
Mean serum alanine aminotransferase levels during the 96-week study period.
HEPATOLOGY, Vol. 44, No. 3, 2006
NIRO ET AL.
717
Table 2. Rates of Biochemical and Virological Responses in Patients Treated With Peginterferon Alpha-2b as Monotherapy
or in Combination With Ribavirin
Response at End of Therapy
Biochemical response
Normal ALT (N %)
Virological response
HDV RNA ⱕ 1,000 cp/mL
HDV RNA -ve
PEG-IFNAlpha-2b
(N ⴝ 16)
PEG-IFN Alpha-2b
ⴙ RBV (N ⴝ 22)
All Patients
(N ⴝ 38)
PEG-IFN Alpha-2b
(N ⴝ 16)
PEG-IFN Alpha-2b
ⴙ RBV (N ⴝ 22)
15 (39%)
6 (37%)
9 (41%)
10 (26%)
4 (25%)
6 (27%)
8 (21%)
5 (13%)
3 (19%)
3 (19%)
5 (23%)
2 (9%)
4 (10%)
8 (21%)
1 (6%)
4 (25%)
3 (14%)
4 (18%)
concomitant increase in gammaglutamyltransferase, treatment was discontinued in 1 patient. No association was
found by univariate analysis between biochemical response
with treatment regimen, duration of disease, age, sex, risk
factors for HDV transmission (familial history, blood transfusion, drug addiction), histology, body weight, or previous
therapy with lamivudine and/or interferon.
Virological Response. After 72 weeks of therapy, serum
HDV RNA was undetectable in 5 patients (13%), 3 of them
in the monotherapy arm. More patients who received peginterferon alpha-2b monotherapy achieved an end-of-therapy
response than did those who received the combination therapy (19% vs. 9%), but the difference did not reach statistically significance because of the small sample size. In 8 other
patients (21%) viremia diminished to less than 1,000 copies/mL by the end of treatment; 3 had received monotherapy
(19%) and 5 had received the combination regimen (23%);
this difference was not significant (P ⫽ 1). Altogether, 13
patients had undetectable or very low HDV RNA levels at
the end of therapy (Table 2).
A sustained virological response was obtained in 5 patients who showed end-of-treatment response; an additional
Fig. 3.
Response at End of Follow-Up
All Patients
(N ⴝ 38)
3 patients whose tested HDV RNA level was less than 1,000
copies/mL at the end of therapy had undetectable HDV
RNA at the end of follow-up. The rates of patients with
negative, low (⬍1,000 copies/mL), and high (ⱖ1,000 copies/mL) viremia levels during treatment and at the end of
follow-up are shown in Fig. 3. At the end of follow-up, 8
patients (21%) were HDV RNA negative, 4 in each treatment arm. The virological response was 88.2% in patients
with no risk factor versus 11.8% in patients with risk factors
for viral transmission (P ⫽ .009; OR ⫽ 4.5; 95% CI ⫽
1.1-17.6). The 87.5% rate of virological response in previously untreated patients was significantly higher than the
35.7% rate in patients previously treated with standard interferon and/or lamivudine (P ⫽ .09; OR ⫽ 1.6; 95% CI ⫽
1.1-2.4). In the multivariate analysis, not having risk factors
for viral transmission and being treatment naive were independent predictors of a sustained virological response. There
was no significant association between HDV viremia variations with treatment regimen, duration of disease, age, sex,
liver histology, or body weight.
Anti-HDV Antibodies and HBV Markers. All patients were positive for IgM antibodies to hepatitis delta
HDV RNA levels during therapy and after 24 weeks of follow-up in patients treated with PEG-IFN or PEG-IFN plus RBV.
718
NIRO ET AL.
HEPATOLOGY, September 2006
Table 3. Histologic Changes in Necroinflammatory Activity
and Fibrosis Score From Baseline to Week 72
Number of subjects with pre- and
post- treatment biopsy
Necroinflammation
Better than baseline
No change from baseline
Fibrosis
Better than baseline
No change from baseline
PEG-IFN no.
(%)
PEG-IFN ⴙ RBV
no. (%)
3 (19)
3 (14)
2 (66)
1 (33)
1 (33)
2 (66)
2 (66)
1 (33)
0
3 (100)
antigen (IgM anti-HD) at baseline, with a mean titer of
10⫺4. The IgM titer remained unchanged in nonresponder patients, in biochemical but not virological
responders, and in those who experienced a decrease in
HDV RNA levels on therapy. In the 5 virological responders, the mean IgM anti-HD titer decreased by 1
log. Anti-HD IgM antibodies disappeared in 2 sustained responders after they had been off therapy for 6
months.
During follow-up no patient lost HBsAg or seroconverted to anti-HBs. All but one patient were positive for
antibodies to hepatitis B e antigen at baseline and
throughout the study. Two of the 7 patients with a baseline HBV DNA level higher than 1,000 copies/mL had
levels of at least 105 copies/mL: in both patients HBV
DNA viremia declined from baseline but rebounded
when treatment was stopped.
Liver Histology. Only 6 patients, 3 with an end-oftherapy biochemical response, 1 with a sustained biochemical and virological response, and 2 nonresponders,
consented to a second biopsy at the end of the 72 weeks of
therapy. No worsening was documented in paired preand post-treatment biopsy specimens. Necroinflammatory activity improved in 2 patients(ⱖ2 points), fibrosis
in 1 patient, and both in another patient (Table 3). Histology also improved in 2 patients who did not achieve a
biochemical or virological response.
Safety. Two patients, one of whom was with treated
with the combination treatment, discontinued therapy
for safety reasons. In one patient ALT increased at week
24 in association with an increase in gammaglutamyltransferase to a level 8.5 times the upper normal limit.
The other patient withdrew at week 4 because of being in
a prolonged lethargic state, secondary to the assumption
of antidepressants. Nine patients, 4 of them treated with
monotherapy and 5 with combination therapy, withdrew
consent while on therapy.
Adverse events were typical of interferon alpha treatment.
They included fatigue (n ⫽ 14), headache (n ⫽ 12), insomnia and irritability (n ⫽ 11), arthralgia (n ⫽ 9), cellulitis,
urinary and respiratory infections (n ⫽ 8), generalized itching (n ⫽ 6), nausea (n ⫽ 5), injection site reactions (n ⫽ 2 ),
and depression (n ⫽ 1). Itching prevailed in patients treated
with RBV; the other side effects were similarly distributed in
the 2 treatment arms. Dose modifications of PEG-IFN
and/or RBV were required for 22 patients (58%), 8 (50%) of
whom were treated with PEG-IFN monotherapy and 14
(63%) of whom received combination therapy (P ⫽ .6).
Reasons for dose modification were thrombocytopenia
(n ⫽ 13 patients, 6 treated with PEG-IFN and 7 with combination therapy), neutropenia (n ⫽ 8 patients, 2 treated
with monotherapy and 6 with PEG-IFN and RBV), anemia
(n ⫽ 4 cases, all treated with PEG-IFN and RBV), and
gammaglutamyltransferase elevation (in a single patient
treated with combination therapy).
Discussion
Hepatitits D virus infection has considerably diminished in southern Italy in the last 2 decades; in Italy, the
prevalence of anti-HD in chronic HBsAg carriers with
chronic liver disease has declined from 25% at the beginning of 19852 to less than 10% in recent years.3 Despite
the diminished epidemiological burden, the clinical impact of residual disease in the cohorts of patients infected
when HDV was endemic remains appalling, as there as
yet no efficacious therapy for hepatitis D, and for most
patients the disease has now progressed to cirrhosis.2 The
present study, one of the first to evaluate the efficacy and
tolerability of treatment with PEG-IFN alpha-2b with or
without RBV in these difficult-to-treat patients, has
shown that a prolonged, 72-week course of PEG-IFN
induced the sustained clearance of HDV in a fifth of those
treated. There was also decreased necroinflammation in 2
of 4 patients for whom paired biopsies were available;
however, this number was too limited to draw conclusions on the efficacy of PEG-IFN on liver histology.
Consistent with the results of a recent study,15 adding
RBV to IFN did not result in greater benefit for any
biochemical, virological, or histological end points considered. These results were achieved at the expense of
relatively important side effects; treatment needed to be
interrupted in 29% of the patients, mostly because of
poor compliance. Two patients had a severe flare of hepatitis while on a full dose of PEG-IFN alpha-2b, both
during week 2 of therapy; fortunately the increase in aminotransferase levels was transient and not accompanied by
symptoms of hepatic decompensation or cholestasis. Hepatic flares also were reported during standard interferon
alpha treatment.19,20 In contrast to the frequent and severe psychiatric side effects observed during standard interferon therapy,9,21 our patients reported insomnia,
HEPATOLOGY, Vol. 44, No. 3, 2006
irritability, and depression of moderate intensity and usually did not require pharmacological support.
Of the 38 patients evaluated, 28 had a histological cirrhosis, and 30 had undergone previous courses of standard IFN
therapy; both factors diminished the response to IFN in both
HCV- and HBV-related liver disease22,24 and possibly explain, at least in part, the relatively low rate of HDV clearance achieved by our patients. Naive patients without
cirrhosis might respond better25; in the post hoc analysis of
the 8 patients in this study who were naive for previous
therapy, HDV infection cleared in 3 cases (37.5%). In a
recent study of 31 patients with chronic hepatitis D, including many (75%) without cirrhosis, 20% cleared HDV after
2 years of treatment with standard IFN.15
Consistent with the superior results achieved in therapy of chronic HBV and HCV diseases using pegylated
rather than standard IFN, the results of our study would
also support the use of PEG-IFN as a first-line therapy
and the recommendation to initiate therapy as early as
possible for those with chronic hepatitis D. In fact, the
efficacy of standard IFN-␣ in the treatment of chronic
delta hepatitis (CHD) remains controversial; the few controlled and the many small uncontrolled trials of the use
of standard IFN as a treatment for CHD found that HDV
synthesis was suppressed in a fraction of patients while on
therapy, but treatment failed to induce sustained clearance of the virus post-therapy; transient and occasionally
even permanent clearance of HDV can also occur spontaneously in untreated patients.26 At variance with the
delayed clearance of HBsAg after spontaneous or standard
IFN-induced clearance of HDV RNA from serum,21-27 in
the present study none of the patients treated with PEGIFN who achieved a sustained response cleared this antigen, possibly because of the relatively short posttreatment follow-up.
Of note, the administration of PEG-IFN for 72 weeks
made HDV undetectable in 5 patients while on therapy,
but 3 patients cleared HDV only after therapy was discontinued. A similar pattern of delayed response has been
observed in chronic hepatitis D also after discontinuation
of conventional interferon.8
In conclusion, our study has provided evidence that a
72-week course of therapy with PEG-IFN alpha-2b may
result in sustained clearance of HDV in about a fifth of
patients with chronic hepatitis D, even though most of
our patients had cirrhosis and had been unresponsive to a
previous course of monotherapy with standard IFN.
Acknowledgment:
The authors thank ScheringPlough for providing PEG-IFN alpha-2b and ribavirin.
NIRO ET AL.
719
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