Download Efficacy of peginterferon alpha-2b in chronic hepatitis delta

Efficacy of Peginterferon alpha-2b in Chronic Hepatitis
delta: Relevance of Quantitative RT-PCR for Follow-Up
Corinne Castelnau,1 Frédéric Le Gal,2 Marie-Pierre Ripault,1 Emmanuel Gordien,2 Michelle Martinot-Peignoux,1
Nathalie Boyer,1 Bach-Nga Pham,3 Sarah Maylin,3 Pierre Bedossa,4 Paul Dény,2 Patrick Marcellin,1 and Elyanne Gault2
Hepatitis delta virus (HDV) can cause severe acute and chronic liver disease in patients infected
by hepatitis B virus. Interferon alpha at high doses, although poorly efficient, is the only treatment reported to provide some benefit in chronic hepatitis delta. Pegylated interferon alpha
(PEG-IFN) has not yet been evaluated. Treatment is usually monitored by the qualitative detection of HDV-RNA in serum. In this study, safety and efficacy of PEG-IFN were assessed in
chronic hepatitis delta, and serum HDV-RNA kinetics were determined using quantitative RTPCR. Fourteen patients with chronic hepatitis delta received subcutaneous PEG-IFN alpha-2b
during 12 months (1.5 ␮g/kg per week). Serum HDV-RNA was quantified at initiation and
during the course of therapy, and during the posttreatment follow-up period, which ranged from
6 to 42 months (median 16 months). PEG-IFN alpha-2b was well tolerated, inducing no serious
adverse effect. Sustained biochemical response was obtained in 8 patients (57%). At the end of
treatment, 8 patients (57%) had achieved virological response (undetectable HDV-RNA). Sustained virological response throughout the posttreatment follow-up period was observed in 6
patients (43%). HDV-RNA kinetics were predictive of the response: after 3 months of PEG-IFN,
HDV-RNA levels were significantly lower in the responders than in the nonresponders group
(P ⴝ .018). After 6 months of therapy, a negative HDV-RNA was predictive of sustained response
(P ⴝ .021). In conclusion, this preliminary study indicates that PEG-IFN alpha-2b is safe and
efficient for treatment of chronic hepatitis delta. The follow-up of HDV-RNA levels during
therapy, which allows the differentiation of various profiles of virological responses, improves
treatment monitoring. (HEPATOLOGY 2006;44:728-735.)
See Editorial on Page 536
H
epatitis delta virus (HDV) is a satellite RNA
virus, which depends on the hepatitis B virus
(HBV) for virion assembly and propagation.1
HDV infection can cause severe acute and chronic liver
Abbreviations: HDV, hepatitis delta virus; HBV, hepatitis B virus; IFN, interferon alpha; PEG-IFN, pegylated interferon alpha; ALT, alanine aminotransferase;
HbsAg, hepatitis B virus surface antigen.
From the 1Service d’Hépatologie, Hôpital Beaujon, AP-HP; INSERM U773
CRB3, Clichy, France; 2Service de Bactériologie-Virologie-Hygiène, Laboratoire
associé au Centre National de Référence des Hépatites B et C, Hôpital Avicenne,
AP-HP; Université Paris 13, EA3604, Bobigny, France; 3Département
d’Immunologie Microbiologie des Pathologies Infectieuses, Hôpital Beaujon, APHP; INSERM U773 CRB3, Clichy, France; and 4Service d’Anatomie
pathologique, Hôpital Beaujon, AP-HP, Clichy; CNRS UMR 8149, Faculté de
Pharmacie Paris V, France.
Received May 3, 2006; accepted June 22, 2006.
Supported by grants from the Assistance Publique Hôpitaux de Paris: Progrès
Médical et Innovation Thérapeutique, and by the French Ministère de la Santé.
Address reprint requests to: Dr. Elyanne Gault, Laboratoire de BactériologieVirologie-Hygiène, Hôpital Avicenne, 125 ave de Stalingrad, 93009 Bobigny Cedex, France. E-mail: [email protected]; fax number: (33) 1 4895 5911.
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.21325
Potential conflict of interest: Nothing to report.
728
disease, with a chronicity rate reaching 70% to 90% in
cases of super-infection,1-3 and a common progression to
cirrhosis (60%-70%) accounting for frequent evolution
to end-stage liver disease and hepatocellular carcinoma.4,5
To date, treatment of chronic hepatitis delta relies on
interferon alpha (IFN), but the efficacy is limited.6 Antiviral drugs such as ribavirin, acyclovir, or famcyclovir are
inefficient,7,8 and anti-HBV drugs such as lamivudine,
which efficiently reduce HBV viremia but not HBsAg
levels have no effect on hepatitis delta,9 even when associated to IFN.10 Clevudine, which induces a reduction in
the covalently closed circular DNA replication template
levels could be useful in the treatment of chronic hepatitis
delta but has only been evaluated in the woodchuck
model for this indication.11 The pegylated form of IFN
(PEG-IFN), which has been proved to be more efficient
than standard IFN in chronic hepatitis B and C, might
improve the outcome of chronic hepatitis delta, but such
treatment has not yet been evaluated.12,13
The diagnosis of HDV infection usually relies on the
detection of specific anti-HDV antibodies, with the presence of anti-HDV IgM reflecting ongoing viral replication. However, serological approach for the detection of
virus replication lacks sensitivity and HDV-RNA detec-
HEPATOLOGY, Vol. 44, No. 3, 2006
tion in serum appears to be the most suitable means to
assess active HDV infection.10,14,15 As for other chronic
viral infections, quantification of HDV-RNA levels in
serum might improve the monitoring of treatment efficacy, but the relevance of viral load determination in the
management of hepatitis delta remains to be established.
However, HDV-RNA quantification might help with the
understanding of the physiopathology of HDV infection,
contribute to the evaluation of the severity of the liver
disease and improve treatment monitoring.16,17
The aims of our study were (1) to evaluate the efficacy
and safety of PEG-IFN alpha-2b therapy in patients with
chronic hepatitis delta and (2) to assess the usefulness of
HDV-RNA quantification to follow the response to treatment. For this purpose, fourteen patients with chronic
hepatitis delta received PEG-IFN alpha-2b during 12
months. Treatment efficacy and HDV-RNA kinetics
were evaluated during the course of the treatment and the
posttreatment follow-up.
Patients and Methods
Patients. Patients with chronic hepatitis delta, aged
28 to 52 years, were included in the study between December 2000 and December 2003. Chronic hepatitis
delta was defined by the following criteria over a period of
6 months: histological evidence of chronic hepatitis, serum alanine aminotransferase (ALT) levels ⬎1.3 fold the
upper limit of normal (normal range 5 to 40 IU/L), detectable hepatitis B virus surface antigen (HBsAg), HDV
total antibody and HDV-RNA in serum.
Patients with another cause of chronic liver disease
were excluded, as well as patients with HIV infection,
serious medical illness, hepatocellular carcinoma, decompensated liver disease, platelet count ⬍50 000/mm3 and
pregnant or breastfeeding women.
Treatment Schedule. All patients received 1.5 ␮g/kg
subcutaneous PEG-IFN alpha-2b (Viraferon Peg, Schering Plough) weekly for 12 months.
Assessment of Treatment Efficacy. Treatment was
monitored with biochemical, histological and virological
markers, namely serum ALT levels, METAVIR scoring of
the necroinflammatory activity and fibrosis of the liver,18
anti-HDV IgM and HDV-RNA. Biochemical and virological responses were evaluated every 3 months during
the course of the treatment (M3, M6, M9 and M12), at
the end of therapy, and every 3 months during the posttreatment follow-up period. The primary efficacy parameter of the study was virological response, which was
assessed at the end of therapy by undetectable HDV-RNA
in the serum. Sustained virological response was defined
by undetectable HDV-RNA in the serum 6 months after
CASTELNAU ET AL.
729
the end of therapy and throughout the posttreatment follow-up period. Patients were considered nonresponders
when HDV-RNA was still detected in serum at the end of
therapy. Biochemical response was assessed at the end of
therapy by normal ALT levels.
Liver biopsies were performed before initiation of therapy in all patients, and at the end of therapy for some of
them. Each biopsy was anonymously re-analyzed by a
single pathologist.
Virological Assays. Virological assays were performed
at inclusion, during the course of therapy and during the
posttreatment follow-up period. HBsAg and HBeAg, as well
as anti-HBs and anti-HBe antibodies were detected using the
AxSYM system (ABBOTT, Rungis, France). HBV-DNA
was quantified by quantitative PCR, with COBAS TaqMan
HBV (Roche Diagnostics Systems, Meylan, France), sensitivity threshold, 50 copies/mL.
Anti-HCV antibodies were detected using the AxSYM
HCV system V3.0 (ABBOTT). Serum HCV-RNA was
detected by the use of the VERSANT HCV-RNA Qualitative Assay (TMA) (Bayer HealthCare, Puteaux,
France), sensitivity threshold, 50 copies/mL.
Total antibodies to HDV were detected with ETI-ABDELTA-2 (DiaSorin S. A, Antony, France), and specific
anti-HDV IgM were detected with ETI-DELTAIGMK-2 (DiaSorin). In this ELISA-format test, the presence or absence of IgM is determined by comparing the
absorbance value of the unknown sample to that of the
cutoff value. Samples with absorbance values repeatedly
within ⫾10% of the cutoff value were considered “indeterminate” for anti-HDV IgM detection.
Qualitative detection of HDV-RNA in serum was performed as previously described by the use of a sensitive
RT-PCR assay (sensitivity threshold ⬇100 copies/mL).19
HDV-RNA quantification was performed simultaneously for each patient, from serum aliquots kept frozen
at ⫺80°C, using a recently described real-time quantitative PCR assay (sensitivity threshold ⬇100 copies/mL).17
HDV genotype was determined by phylogenetic analysis
of the amplified R0 region of the genome (nucleotides
885 to 1285) as previously described.20
Statistical Analysis. The nonparametric Mann Whitney U test and Willcoxon Rank test (StatView 4.02), and the
exact Fisher t-test were used for statistical comparisons. Differences were considered significant at P values less than .05.
Results
Characteristics of the Patients at Baseline (Table
1). Fourteen patients chronically infected with HBV
and HDV were enrolled in this study. Patients consisted
of 12 men and 2 women, aging from 28 to 52 (median age
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CASTELNAU ET AL.
HEPATOLOGY, September 2006
Table 1. Baseline Characteristics of 14 Patients With
Chronic Hepatitis delta
n (%)
Median (Range)
Male sex
12 (86)
—
Age, years
—
42 (28-52)
African origin
6 (43)
—
French origin
8 (57)
—
Unknown source of infection
6 (43)
—
Intravenous drug use
7 (50)
—
Previous treatment with
standard IFN
12 (86)
—
ALT level, x ⫻ the normal value
—
1.95 (1.3-7.5)
Necroinflammatory activitya
—
2 (1-3)
Fibrosis stagea
—
3 (1-4)
HDV genotype 1/5b
12/2 (86/14)
—
Positive anti-HDV IgM
11 (78)
—
Positive HBV-DNA
4 (28)
HBV-DNA level, copies/mL
—
⬍50 (⬍50-1.9x106)
Positive HBeAg
0
—
Positive anti-HBe
14 (100)
—
Positive anti-HCV
8 (57)
—
Follow-up duration,months
—
16 (6-42)
HDV-RNA level, copies/mL
—
9x105 (4.8⫻104 - 1.1⫻107)
aMETAVIR
bgenotype
score.
1 or 5, as defined by the analysis of the R0 region of the genome.
42). Six patients were of African origin and were considered to have been infected during childhood, as no other
risk factor was identified. The eight remaining patients
were of French origin, and for 7 of them, past intravenous
drug use was assumed to be the cause of the infection.
Twelve patients (85%) had previously been treated with
standard IFN (9 MU, 3 times a week) during 6 to 22
months (median treatment duration: 12 months). In all
cases, this former treatment had been interrupted at least
1 year before enrollment in the present study.
All patients had abnormal ALT levels, comprised between 1.3 to 7.5 times (median 1.95) the upper limit of
normal. Liver histology, assessed with METAVIR (18)
scoring system, indicated that most patients had moderate
necroinflammatory activity (median METAVIR score: 2,
ranging from 1 to 3) associated to severe fibrosis (median
score: 3, ranging from 1 to 4). Cirrhosis was evident in 4
patients.
HDV genotype determination indicated that 12 patients (86%) were infected by HDV-1, and 2 by HDV-5.
Specific anti-HDV IgM were positive in 11 patients, negative in 1 and indeterminate in 2. HBV replication level
was evaluated with a sensitive quantitative PCR assay.
HBV-DNA was below the sensitivity threshold (50 copies/mL) in 10 (71%) patients, was comprised between
3.3⫻102 and 5.2⫻104 copies/mL in 3 patients, and was
1.9x106 copies/mL in one. In all patients, HBeAg was
negative, while anti-HBe was positive.
Past and resolved HCV infection was evidenced in
eight patients, who were positive for anti-HCV antibod-
ies, but negative for the detection of HCV-RNA during at
least the past 3 to 9 years.
Safety. Safety profile was similar to that usually observed with PEG-IFN alpha-2b in patients with chronic
hepatitis C. Mild adverse effects such as flu-like symptoms and asthenia were observed in most patients during
the first weeks of treatment but attenuated with time.
Dose reduction from 1.5 to 1␮g/kg was required in five
patients because of leucopoenia, but no other severe side
effect was noted, and no treatment withdrawal was
needed.
Treatment Efficacy. The median posttreatment follow-up duration was 16 months, ranging from 6 to 42
months (Table 1). Eight patients (57%) were virological
responders at the end of therapy (undetectable HDVRNA), but 2 of them relapsed during posttreatment follow-up. Thus, 6 patients (43%) were sustained virological
responders and 6 were nonresponders (43%).
Five patients (36%) were biochemical responders at
the end of therapy, but 1 of them relapsed during posttreatment follow-up. However, 4 patients, who were considered biochemical nonresponders at the end of therapy
achieved ALT level normalization during posttreatment
follow-up. Thus, 8 patients (57%) presented a biochemical sustained response. Among them, 6 were sustained
virological responders and 2 were nonresponders.
In the virological responders group, 6 patients of 8 had
previously been unsuccessfully treated 12 months with
standard IFN, indicating that PEG-IFN may be effective
in patients with chronic hepatitis delta, even as a second
line treatment. In the nonresponders group, 4 patients
out of 6 required a dose reduction from 1.5 ␮g/kg to 1
␮g/kg because of leucopoenia, while in the responders
group, 7 patients out of 8 received the full dose of 1.5
␮g/kg.
Eight patients (3 nonresponders, 3 sustained responders and 2 responders-relapsers) underwent a second liver
biopsy at the end of the treatment. METAVIR scoring
indicated no significant short-term histological improvement, neither for necroinflammatory activity, nor for fibrosis.
Tests to detect specific anti-HDV IgM were performed
at initiation of therapy, during the course of the treatment
and during follow-up. As illustrated in Table 2, the results
of IgM detection did not strictly correlate those of HDVRNA, with, for example, negative or indeterminate IgM
at initiation of therapy (3 patients), or positive IgM at the
end of follow-up in 2 sustained responders.
HBsAg remained positive throughout treatment and
follow-up periods in all patients except one from the sustained responders group, who lost HBsAg and developed
anti-HBs antibodies at month 9 of therapy. Serum HBV-
HEPATOLOGY, Vol. 44, No. 3, 2006
CASTELNAU ET AL.
Table 2. Comparative Detection of Specific Anti-HDV IgM
and HDV-RNA in Serum
Patients (n ⴝ 14)
Sustained responders (n ⫽ 6)
Responder-relapsers (n ⫽ 2)
Nonresponders (n ⫽ 6)
a
b
Number
of
patients
3
1
1
1
1
1
5
1
IgM / HDV-RNA detection at:
T0a
⫹b
/⫹
⫹/⫹
⫺/⫹
⫹/⫹
⫹/⫹
I/⫹
⫹/⫹
I/⫹
EOT
FU
⫹/⫺
⫺/⫺
⫺/⫺
⫺/⫺
⫺/⫺
I/⫺
⫹/⫹
⫹/⫹
⫹/⫺
⫺/⫺
⫺/⫺
⫹/⫺
⫹/⫹
I/⫹
⫹/⫹
⫹/⫹
T0: initiation of therapy, EOT: end of treatment, FU: end of follow-up
⫹: Positive, ⫺: Negative, I: indeterminate
DNA was undetectable at the end of the treatment and
during the posttreatment follow-up period in all patients
(responders and nonresponders) but one, who developed
a symptomatic acute hepatitis (ALT level 22 folds over the
normal value) 10 months after initiation of PEG-IFN.
This episode occurred as HDV-RNA was becoming undetectable and was accompanied by an increase of HBVDNA load, which exceeded 109 copies/mL (Fig. 1). In
this particular case, HBV-DNA load was 1.9⫻106 copies/mL at baseline and had initially been reduced by PEGIFN therapy. PEG-IFN therapy was interrupted and was
replaced by lamivudine. During the following months,
HBV-DNA level decreased under lamivudine while
HDV-RNA re-increased. The patient was thus considered responder-relapser to PEG-IFN for HDV infection.
Taken together, these results tend to indicate that although HBV replication was low at baseline in most patients (possibly because of an inhibitory effect of HDV on
HBV) the clearance of HDV-RNA under PEG-IFN therapy did not lead to the reactivation of HBV, except in one
particular case, where HBV-DNA was unusually high at
baseline.
Serum HCV-RNA remained undetectable in the 8 patients with anti-HCV antibodies, throughout the treatment and follow-up periods. The role of HDV on HCV
replication is not well known, but previous studies have
indicated a possible inhibition of HCV by HDV.21 The
absence of HCV re-activation in the sustained responders
group is probably indicative of a favorable outcome of a
past HCV infection in these patients.
Serum HDV-RNA Levels During Therapy. At
baseline, HDV-RNA levels ranged from 4.8⫻104 to
1.1⫻107 copies/mL (Table 1). Median HDV-RNA levels
are shown in Fig. 2A. In the responders group (including
sustained responders and relapsers), HDV-RNA levels
significantly decreased during the first 3 and 6 months of
treatment (P ⫽ .028, using the nonparametric Wilcoxon
731
Rank test). Median viral load loss was of 2.28 log10 after 3
months of treatment, and 3.95 log10 after 6 months
(HDV-RNA being undetectable in 6 of 8 responders at
M6 of treatment). In the nonresponders group, although
median HDV-RNA levels decreased during therapy (0.67
log10 during the first 3 months, 1.84 log10 throughout the
treatment) the reduction was not significant, and viral
loads re-increased after the end of the treatment. None of
the nonresponders had undetectable HDV-RNA at M6
of treatment.
Median ALT levels roughly followed those of the viral
loads in the responders group, but not in the group of
nonresponders (Fig. 2B). Moreover, the decrease in ALT
levels was never significant, even in the responders group.
These results indicate that although ALT levels follow
HDV viral loads during PEG-IFN therapy, they are not
sufficiently accurate to monitor treatment efficiency. Individual HDV-RNA and ALT levels are represented on
Fig. 3, except for 2 patients for whom the number of
available frozen samples was insufficient to allow a kinetic
follow-up. Figure 3 represents the four profiles of HDVRNA and ALT levels observed during PEG-IFN therapy.
Fig. 3A-B represent the typical profiles observed for the
sustained responders and the nonresponders, respectively.
Fig. 3C represents the profile observed for the respondersrelapsers. For 2 nonresponders, a distinct profile was observed (Fig. 3D): HDV-RNA significantly decreased
Fig. 1. Evolution of HDV-RNA, HBV-DNA and ALT levels in a case of
acute HBV reactivation during the treatment. Viral load kinetics are
represented on the upper part of the panel, ALT levels on the middle part,
and treatment schedule on the lower part. Viral loads are represented by
circles (black circles for HDV, white circles for HBV) and ALT levels are
represented by white triangles. Treatment schedule is represented by a
box along a scale of time starting at initiation of therapy (T0: initiation of
PEG-IFN, which was replaced after 10 months by lamivudine) until the
end of follow-up (in months).
732
CASTELNAU ET AL.
HEPATOLOGY, September 2006
statistical analysis. However, our results indicate that
HDV-RNA kinetics might provide predictive information concerning the response to PEG-IFN. Indeed, after 3
months of PEG-IFN, HDV-RNA levels were significantly lower in the responders than in the group of nonresponders (P ⫽ .018 by the use of the nonparametric
Mann-Whitney U test). This trend was confirmed after 6
months of PEG-IFN (P ⫽ .006), with 75% of the responders being undetectable for HDV-RNA, versus none
in the nonresponders group. Moreover, negative HDVRNA at M6 was predictive of sustained response (P ⫽
.021). At baseline, neither HDV-RNA levels, nor ALT
levels, IgM detection or histological grade were predictive
of treatment response.
Discussion
Fig. 2. Median HDV-RNA and ALT levels in virological responders
versus nonresponders to PEG-IFN. Median HDV-RNA levels are represented on the upper panel, median ALT levels on the lower panel.
Medians obtained from the responders group are represented in black,
those from the nonresponders group in white. The virological responders
group includes sustained responders and responder-relapsers. Medians
were calculated from the values obtained at initiation of therapy (T0),
after 3 and 6 months of treatment (M3 and M6, respectively), at the end
of therapy (M12) and at the end of follow-up (FU). Upper and lower bars
indicate upper and lower quartiles, respectively.
during the course of the treatment (3 log10 copies/mL)
but remained ⬎2 log10 copies/mL at the end of therapy,
and increased again after its ending. For all profiles, ALT
levels, expressed as a multiple number of the normal upper limit value, roughly followed HDV viral kinetics.
However, in some cases, moderate ALT flares were observed (Fig. 3A,D). In these examples, peaks of ALT
could be explained neither by HDV nor by HBV replication rebounds.
Predictive Factors of Response. The limited number of patients included in this study did not allow us to
determine accurate predictive factors of response to PEGIFN treatment. In particular, epidemiological data such as
the geographic origin (France or Africa), the HDV genotype (HDV-1 or HDV-5), the mode of contamination
(unknown or use of intravenous drugs), or the age at the
initiation of treatment could not be taken into account for
In this study, 14 patients with chronic hepatitis delta
received 12 months of PEG-IFN alpha-2b, and a sustained virological response was achieved in 6 patients
(43%). In 2 recent studies evaluating the virological response to standard IFN therapy by the means of qualitative RT-PCR assays with sensitivity thresholds similar to
the one we describe,22,23 a sustained virological response
was obtained after two years of IFN monotherapy (9 MU
three times weekly) in 20% of the patients. Thus, our
results seem to indicate that PEG-IFN is probably at least
as effective as standard IFN for treatment of chronic hepatitis delta, with sustained responses obtained after one
year of treatment. Moreover, we observed that the tolerance profile was not different from that described during
the treatment of chronic hepatitis C although 5 (36%)
patients required a dose reduction because of leucopoenia. Interestingly, 4 of these patients were nonresponders,
suggesting that virological response might be related to
the dose (P ⫽ .036). As previously suggested by a single
case of an HIV positive patient with chronic hepatitis
delta,24 we believe that the use of PEG-IFN could be
extended to the treatment of hepatitis delta, and that its
efficacy should be compared to that of standard IFN by
the means of large scale comparative studies.
We monitored the efficacy of PEG-IFN by the means
of biochemical, serological and molecular analyses.
HDV-RNA was detected by the means of a very sensitive
qualitative RT-PCR,19 quantification being secondarily
performed from frozen aliquots of the sera. We found that
the most reliable biological marker for treatment monitoring was HDV-RNA quantification in serum. Indeed,
we detected flares of cytolysis that were independent of
HDV replication (as illustrated in Fig. 3A,C-D), but
might have been generated by the treatment itself, as previously described in chronic hepatitis B.25-27 Moreover,
like others,6 we observed that anti-HDV IgM could re-
HEPATOLOGY, Vol. 44, No. 3, 2006
CASTELNAU ET AL.
733
Fig. 3. HDV-RNA and ALT levels during PEG-IFN therapy. Four profiles of response to PEG-IFN were observed. Viral load kinetics are represented
on the upper part of each panel and ALT levels on the lower part. In each panel, the same symbol is used for a given patient (in black for viral loads,
in white for ALT levels) and each curve corresponds to a single patient. The scale of time starts at initiation of therapy (T0) until the end of follow-up
(in months). End of treatment is M12. (A) 5 patients with sustained response: virological response was observed between 3 and 12 months of
treatment. (B) 3 patients showing no response to PEG-IFN. (C) Virological response at M12 and relapse during follow-up. (D) Incomplete virological
response at M12 but significant viral load decrease during the course of the treatment; relapse after the end of the treatment.
main undetected despite HDV replication, or, on the
contrary, could be detected while no HDV-RNA was
detected in the serum (Table 2). Therefore, as previously
suggested,28-30 and despite the usefulness of tests to detect
anti-HDV IgM, we recommend the use of a consensus
and sensitive RT-PCR approach for treatment monitoring of chronic hepatitis delta.
Besides qualitative detection, quantification of HDVRNA provides useful information regarding the individual viral load kinetics during treatment, and might be
taken into account for the adjustment of treatment duration. Indeed in most studies, interferon is administered
during 12 months15,31-34 although some authors adopt
longer regimens or adapt treatment length to individual
factors.22,23,35 In our study, most patients of the responder
group had achieved HDV-RNA clearance during the first
6 months of treatment. However, the fact that 2 of them
relapsed after the end of the treatment seems to indicate
that PEG-IFN might need to be continued for more than
12 months, if possible. Four patients of the nonresponders group kept a viral load decrease ⬍2 log10 copies/mL throughout the 12 months therapy. In such cases
of insignificant viral load decrease after a period of time
which remains to be defined (probably ranging between 9
and 12 months of treatment), we suggest that a change in
the treatment schedule might be considered, depending
on the tolerance and on the effect of the treatment upon
liver fibrosis. In 2 patients of the non responders group
(Fig. 3D), the kinetic profiles looked more like those of
the group of responder-relapsers (Fig. 3C) than like those
of the nonresponders (Fig. 3B), suggesting the existence
of slow responders among patients considered nonresponders after only 12 months of treatment.17 When slow
responders can be identified on the basis of HDV-RNA
kinetics, long-term treatment may need to be considered.
Further studies implying a greater number of patients are
734
CASTELNAU ET AL.
needed to specify these preliminary suggestions. Considering the small number of patients followed in most specialized care centers, large-scale multicenter studies are
required to define guidelines for optimal management of
patients with chronic hepatitis delta.
In this study, the course of HBV infection was also
considered because of the specific relationship between
HBV and HDV during chronic hepatitis delta. Indeed,
although HDV depends on HBV to produce infectious
viral particles, it also inhibits HBV replication in vitro as
well as in vivo.36-39 Moreover, PEG-IFN, which was used
to treat hepatitis delta is also efficient to treat HBV infection.12,40 PEG-IFN therapy led to HBsAg seroconversion
in only one of the sustained responders, and there was no
example of HBV reactivation during the posttreatment
follow-up period in the group of sustained responders.
However, in one case, an acute HBV reactivation occurred after 10 months of treatment, while HDV-RNA
was no longer detected (Fig. 1). The replacement of PEGIFN by lamivudine led to the disappearance of HBVDNA in serum, while HDV started to replicate again.
Although unclear, the mechanism of this dual balance of
viral replication might illustrate the role of HDV in HBV
inhibition during this dual infection. Thus, as previously
suggested by Yalcin et al., and despite previous studies
indicating that reverse-transcriptase inhibitors are inefficient to treat chronic HDV infection,9,10 antiviral therapy
combining PEG-IFN with an HBV replication inhibitor
may need to be considered when HDV infection is associated to active HBV replication.41
In conclusion, this preliminary study indicates that
PEG-IFN is well tolerated and effective in the treatment
of chronic hepatitis delta, even in the case of a previous
failure of standard IFN therapy. Controlled studies are
needed to evaluate the benefit of PEG-IFN against standard IFN, and to define the optimal treatment schedule.
The quantitative detection of HDV-RNA in serum improves treatment monitoring, and the analysis of the
HDV-RNA kinetic profiles might help to adjust the duration of therapy. Studies of larger scale are needed to
specify the predictive value of early virological response.
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