Poor Response to Treatment with Peg-IFN Containing Regimens in Patients Coinfected with Hepatitis B and Hepatitis C Virus

Abstract

Background and Aims: To investigate the clinical charcteristics and treatment response of patients with chronic coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV). .Methods: The study included nine consecutive patients with chronic HBV/HCV coinfection. Diagnosis was performed by liver biopsy and/or clinical and laboratory evaluation. Six patients received 48 weeks of pegylated interferon (Peg-IFN) monotherapy or combination therapy with Peg-IFN plus ribavirin according to the dominant virus..Results: The dominant infection was hepatitis C in six cases. Of the four patients who completed the treatment and follow-up period, only one had a sustained viral response (SVR) to HCV, but unfortunately, this was accompanied by a reactivation of HBV-DNA without flaring of hepatitis. No patient had an HBV-DNA response. Another two patients are still in the follow-up period. One of these patients had an undetectable level of HCV-RNA, and the other had an undetectable level of HBV-DNA at baseline. At the end of treatment, both HBV-DNA and HCV-RNA were negative in these patients. The HBV-DNA-negative patient showed a transient HBV-DNA positivity after clearance of HCV-RNA..Conclusions: In the majority of HBV/HCV coinfected cases in our sample, HCV was the dominant virus. Currently, the standard treatment regimens are not effective for clearance of HBV and/or HCV. HCV clearance may induce HBV reactivation without flaring of hepatitis.

Full text

Page 1

Introduction
H
their combined infection is not uncommon in high-
endemic areas (1-3). In general, anti-HCV prevalence
is around 10-20% in patients with chronic HBV
infection, and 2-10% of anti-HCV-positive patients
have markers of HBV infection (4). Although several
studies have suggested that HBV/HCV coinfection
may be associated with more severe forms of chronic
liver disease, there are inconsistent reports about the
interaction between the two viruses in influencing
the severity and nature of liver disease (5, 6).
epatitis B virus (HBV) and hepatitis C virus
(HCV) share modes of transmission, and
Despite its considerable clinical importance, scant
Poor Response to Treatment with Peg-IFN Containing Regimens in
Patients Coinfected with Hepatitis B and Hepatitis C Virus
* Correspondence:
Serpil Erol, M.D.
Medical School, Ataturk University, Aziziye Hospital,
Department of Infectious Diseases and Clinical Microbiology,
25100 Erzurum, Turkey.
Tel: +90 442 3166333
Fax: +90 442 3166340
E-mail: sererol@gmail.com
Received: 29 Apr 2009 Revised: 3 Jun 2009
Accepted: 3 Jul 2009
Hepat Mon 2009; 9 (3): 224-228
Serpil Erol 1*, Zulal Ozkurt 1, Ahmet Ozbek 2, Mehmet Parlak 1
1Department of Infectious Diseases and Clinical Microbiology, Medical School, Ataturk University, Erzurum, Turkey
2 Department of Microbiology and Clinical Microbiology, Medical School, Ataturk University, Erzurum, Turkey
Hepatitis Monthly 2009; 9(3): 224-228
Background and Aims: To investigate the clinical charcteristics and treatment response of patients with chronic
coinfection of hepatitis B virus (HBV) and hepatitis C virus (HCV).
Methods: The study included nine consecutive patients with chronic HBV/ HCV coinfection. Diagnosis was performed by
liver biopsy and/ or clinical and laboratory evaluation. Six patients received 48 weeks of pegylated interferon (Peg-IFN)
monotherapy or combination therapy with Peg-IFN plus ribavirin according to the dominant virus.
Results: The dominant infection was hepatitis C in six cases. Of the four patients who completed the treatment and
follow-up period, only one had a sustained viral response (SVR) to HCV, but unfortunately, this was accompanied by a
reactivation of HBV-DNA without flaring of hepatitis. No patient had an HBV-DNA response. Another two patients are
still in the follow-up period. One of these patients had an undetectable level of HCV-RNA, and the other had an
undetectable level of HBV-DNA at baseline. At the end of treatment, both HBV-DNA and HCV-RNA were negative in
these patients. The HBV-DNA-negative patient showed a transient HBV-DNA positivity after clearance of HCV-RNA.
Conclusions: In the majority of HBV/ HCV coinfected cases in our sample, HCV was the dominant virus. Currently, the
standard treatment regimens are not effective for clearance of HBV and/ or HCV. HCV clearance may induce HBV
reactivation without flaring of hepatitis.
Keywords: Coinfection, Hepatitis B, Hepatitis C, Treatment
BRIEF
REPORT
Archive of SID
www.SID.ir

Page 2

Hepatitis Monthly, Summer 2009; 9(3): 224-228
information is currently available on the treatment of
the HBV/HCV-coinfected population. Moreover,
most of the studies evaluating treatment for
coinfection are related to monotherapy or a
combination of therapy of conventional interferon
(IFN) and ribavirin.
We performed a retrospective analysis to evaluate
the frequency, clinical characteristics, and efficacy of
pegylated IFN (Peg-IFN) plus ribavirin therapy in
patients with HBV/HCV coinfection.
Materials and Methods
This study included nine consecutive patients
with chronic HCV/HBV coinfection, recruited
between 2003 and 2008 at the Department of
Infectious Diseases and Clinical Microbiology at the
Ataturk University Medical School. They were all
seropositive for HCV antibody (anti-HCV) and
hepatitis B surface antigen (HBsAg) for more than 6
months. HCV-RNA was positive in all but one
patient, and HBV-DNA was positive in five patients
at baseline. No patient
immunodeficiency virus (HIV) infection; active
alcohol abuse or drug addiction; or evidence of
metabolic, autoimmune, or genetic causes of liver
disease. The diagnosis was performed by liver biopsy
in five cases and by clinical/laboratory evaluation in
four cases.
Both HBV-DNA and HCV-RNA quantification
were performed using a real-time polymerase chain
reaction (RT-PCR) method (BioRad, iCycler,
Hercules, CA, USA) with a sensitivity of 200
copies/ml for HBV-DNA and 10 copies/ml for
HCV-RNA.
Levels of serum HBV-DNA and HCV-RNA are
commonly used as surrogate markers of viral activity.
As described previously
conventional--and arbitrary--level of 104copies/mL
of serum HBV-DNA as the cutoff for distinguishing
between active and inactive HBV infection.
Similarly, active HCV infection was arbitrarily
defined on the basis of virus RNA values above 10
copies /ml, which is the detection limit of the kits
used for quantifying HCV viremia.
Six patients received 48 weeks of monotherapy
with Peg-IFN or combination therapy with Peg-IFN
plus ribavirin according to the dominant virus.
Patients were followed for an additional 24 weeks
after the end of therapy. The patients had biweekly
outpatient visits during the first 4 weeks of treatment
and monthly thereafter for 68 weeks. HBV
serological markers, HCV-RNA, and HBV-DNA
were tested for at 12, 24, and 48 weeks of treatment,
had human
(7), we used the
as well as at 12 and 24 weeks after the end of
treatment.
For HCV and HBV infections, sustained viral
response (SVR) was defined as having no detectable
HCV-RNA or HBV-DNA at the end of treatment
and after 24 weeks of follow-up. The patients who
failed to achieve SVR were classified as non-
responders. An increase of HBV-DNA was defined
as greater than two logs elevation of serum HBV-
DNA from the baseline level on at least one occasion.
Sustained biochemical response was defined as the
persistence of normal
aminotransferase (ALT) values up to 24 weeks after
the end of treatment.
serum alanine
Results
Of the 83 patients with chronic HCV infection,
9 (10.8%) were coinfected with HBV (7 were male,
2 were female; mean age 43.9 ± 11.5 years), and 4
had known risk factors for parenterally transmitted
viruses (3 had history of blood transfusion, and 1 had
history of dental-care procedures). Two patients were
hepatitis B e antigen (HBeAg) positive and 7 were
hepatitis B e antibody (anti-HBe) positive. The
baseline characteristics and treatment responses for
patients who were coinfected with HBV and HCV
are shown in Table 1.
Of the nine coinfected patients, four were both
HBV-DNA and HCV-RNA positive, four were only
HCV-RNA positive, and one was only HBV-DNA
positive. The dominant infection was hepatitis C in
six (66.6%) cases.
A liver biopsy was performed in five patients, and
specimens were evaluated by Knodell’s scoring
system. The results are shown in the Table 1. No
patient had previously received antiviral therapy.
One patient did not receive antiviral treatment
because a liver biopsy revealed a mild liver disease,
and another two patients refused treatment. Finally,
six patients received antiviral treatment as shown in
Table 1.
Of the six treated patients, four (Patients 1, 3, 6,
and 8) completed the treatment and a 24-week
follow-up period. Two of these patients (Patients 3
and 6) had detectable serum HBV-DNA levels at
baseline. One patient did not achieve a virological
response for HBV or HCV. The other patient had an
SVR to HCV but no response to HBV infection.
Furthermore, that patient had an increase of HBV-
DNA level after the clearance of HCV, without an
outbreak of hepatitis. Two other patients who
completed the treatment and follow-up (Patients 1
and 8) already had undetectable HBV-DNA levels at
Archive of SID
www.SID.ir

Page 3

Hepatitis Monthly, Summer 2009; 9(3): 224-228
baseline. These two patients became HCV-RNA
negative at the 12th week of treatment and reached
end of treatment response. However, the
reappearance of HCV-RNA was detected in both
patients in the follow-up period. Finally, only one of
the four patients who completed the treatment and
follow-up had an SVR to HCV, and unfortunately,
this was accompanied by a reactivation of HBV-
DNA.
Another two patients (Patients 2 and 7)
completed the treatment, but they are still in the
follow-up period as of this writing. One of these
patients (Patient 2) was the only patient who had an
undetecable HCV-RNA at baseline and whose HBV-
DNA and HCV-RNA levels were negative at the end
of treatment. The second patient (Patient 7) had an
undetectable HBV-DNA level at baseline, but after
the clearance of the HCV-RNA, the HBV-DNA
level became detectable for three months (during the
6th, 7th, and 8th months of treatment). However,
this patient tested negative for both HBV-DNA and
HCV-RNA at the end of the treatment. Hepatitis
flare was not observed in that patient.
No patient achieved loss of HBsAg or HBeAg by
the end of treatment or follow-up period. Three
patients had sustained biochemical response.
Discussion
Our present study, which revealed a prevalence
rate of 10.8% among patients with chronic HCV
infection, agrees with the findings of previous studies
(4). A multicenter prospective study from Italy
showed that being more than 42 years old, having a
history of intravenous drug use and/or blood
transfusion, and residing in the south of the country
were independent factors
HBV/HCV coinfection (8). In our study, five
patients had no known risk factors. Male
circumcision, which is an almost universal surgical
procedure among Muslim men, may contribute to
coinfection with HBV and HCV.
Several studies have suggested an interplay
between the two viruses in cases of dual infection
with a prevalent negative influence of HCV on HBV
activity (5, 6, 9). All clinical studies, however, do not
uniformly report a dominant role of HCV. Some
findings suggest a reciprocal interference, or even a
dominant effect of HBV (10-12). Although most
patients appear to have active HCV and inactive
HBV infection, some patients have high HBV
viremia levels and undetectable HCV-RNA (13). In
our series, HCV was dominant in six patients, and
associated with
148/M HAI 11, FS3 67/38-/ 7 000 000 -/+
Peg-IFN 120µgr/week
+ ribavirin 1000 mg/day
* HBV-DNA(-)
HCV NR
&HBV-DNA(-)
HCV-RNA (-)
*HCV NR HBV
NR
240/M HAI 11, FS3 66/324 000 000/ --/+Peg-IFN 180µgr/week
364/MNA54/397800/ 200 000-/+
Peg-IFN 180µgr/week
+ribavirin 1000 mg/day
420/MNA36/2410 000 000/1000 000+/- no-
5 39/FNA248/206-/100 000 000-/+no-
645/FNA75/58100 000/2 000 000 +/-
Peg-IFN 180µgr/week
+ribavirin 800mg/day
Peg-IFN120µgr/week
+ ribavirin1000mg/day
Peg-IFN 180µgr/week +
ribavirin 1200 mg/day
*HCV SVR HBV-
DNA reactivation
&HBV-DNA(-)
HCV-RNA(-)
*HCV NR HBV
DNA (-)
747/MHAI 11, FS1 250/194-/600 000 000 -/+
846/MHAI 7, FS165/48-/ 700 000-/+
9 46/MHAI 3, FS174/41 3000/1 000 000-/+no-
M: male, F: female, HAI: histological activity index, FS: fibrosis score, ALT: alanine aminotransferase, AST: aspartate aminotransferase, SVR:
sustained virological response, NR: non responder, NA: not available.
*End of follow-up response
&End of treatment response
Archive of SID
www.SID.ir

Page 4

Hepatitis Monthly, Summer 2009; 9(3): 224-228
44.4% of the patients were HBV-DNA negative. In
contrast, in a recent study from Turkey, 70.6% of
coinfected patients were HBV-DNA negative (9).
There is no scientific evidence indicating the
most appropriate follow-up procedure for coinfected
patients, and no guidelines have been established for
their treatment. A key step to identifying this
category of patients is the behavior of the viruses
involved in the coinfection. Sustained response to
conventional IFN monotherapy is low in coinfected
patients (14). More recent studies have shown that
IFN- /ribavirin combination therapy is effective for
eradicating HCV infection in coinfected patients (15,
16). HBV eradication rates in these studies, however,
were lower. In a recent study, conventional IFN- 2a
plus ribavirin were evaluated in 21 coinfected
patients over a 24-week period (15), and the results
were compared with those of 30 HCV monoinfected
patients. The groups were similar with respect to age,
gender, serum ALT levels, and genotype distribution.
Serum HCV-RNA clearance rates were comparable
in both groups (43% vs. 60%, P > 0.05). Sustained
HBV-DNA clearance was obtained in 17.6% of the
HBV viremic patients but was not accompanied by
loss of HBsAg. Chung
chronicly coinfected patients and 84 HCV
monoinfected controls receiving conventional IFN-
plus ribavirin combination therapy. The SVRs of
the monoinfected and coinfected patients were
67.2% and 69%, respectively. Of 16 baseline HBV
viraemic patients, 31.3% achieved HBV SVR. Only
one patient had simultaneous seroclearance of HCV
and HBV. Anti-HBe developed in 11.9% of the
patients during the long-term follow-up. The
authors concluded that
combination therapy was effective in eradicating
HCV infection and might promote HBV
seroclearance for HCV/HBV-coinfected patients. In
contrast, Senturk
HCV clearance rates for coinfected patients with
either conventional or Peg-IFN-based regimens
(5.3% and 5.9%, respectively). All of their 36
patients had negative serum HBV-DNA levels at
baseline. The authors suggested that the reason for
the low clearance rate may have been due to the high
proportion of male patients and a unique genotype 1
virus infection among cases.
In fact, there are limited data regarding Peg-IFN
containing regimens. Two recent case reports have
suggested that Peg-IFN plus ribavirin treatment was
effective for HBV/HCV coinfection (18, 19). Rotou
(18) reported HCV eradication and HBeAg to
anti-HBe seroconversion after Peg-IFN- 2b plus
ribavirin treatment in a coinfected patient. The
second case tested negative for HBV-DNA and
(16)Evaluated 42
IFN- /ribavirin
(17)reported much lower
HBeAg at baseline (19). HBsAg levels showed a linear
decline during a 48-week treatment period. At this
point, the patient
immunization and another 4 weeks of Peg-IFN plus
ribavirin treatment. Forty-three weeks after the
treatment, the patient showed a robust HBsAg
seroconversion. Recently, in a large-scale prospective
study, coinfected patients were treated for 48 weeks
for HCV genotype 1 or 24 weeks for genotypes 2
and 3 (20). The results revealed high rates of SVR for
HCV in both genotype 1 (73%) and 2/3 (86%)
patients. Of the 68 patients who had detectable
HBV-DNA levels at baseline, 69% achieved HBV-
DNA negativity by the end of treatment. HBV-
DNA remained undetectable in 56% of the cases
during 24 weeks of follow-up. In addition, HBsAg
clearance occurred in 10% of the patients. However,
36% of the patients who were HBV-DNA negative
at baseline demonstrated HBV-DNA rebound
during the treatment period or follow-up. In our
series, despite our limited data, HBV viraemic and
non-viraemic coinfected patients had poor results for
HCV-RNA and HBV-DNA clearance with Peg-IFN
and ribavirin combination treatment. No patients
achieved loss of HBsAg or HBeAg. Interestingly,
three patients had a sustained biochemical response
at the end of the follow-up period. Our findings were
similar to the results of Senturk
reported very low response rates in patients
coinfected with genotype 1 virus. As in their study,
the majority of our cases were male, and HCV
clearance was seen only in one female patient.
Unfortunately, HCV genotypes were not specified in
our study. According to previous studies, the most
prevalent genotype of HCV in Turkey is genotype 1,
at 91% to 100% (21-23). It is probable that genotype
1 was also the most prevalent genotype in the present
study and caused a poor treatment response.
Successful treatment of HCV infection may
induce HBV reactivation and flaring of hepatitis in
patients who had an undetectable level of HBV-
DNA prior to treatment (20, 24). We did observe
HBV-DNA reactivation, but no clinical hepatitis
flare, in two cases. Unlike previous reports, one of
these cases had a detectable level of HBV-DNA at
baseline. That patient was also the only case who
reached an HCV SVR in this study.
It is generally agreed that it is important to
determine “the dominant virus” before initiation of
therapy to specify the most appropriate antiviral
regimen for HBV/HCV-coinfected patients (14, 25).
According to Chu
phenomenon of reciprocal viral interference can
develop during or after therapy and this may cause
exacerbation of liver disease, in coinfected patients
received active HBV
(17), who
(14), although the
Archive of SID
www.SID.ir

Page 5

Hepatitis Monthly, Summer 2009; 9(3): 224-228
with negative HBeAg and a low level of viremia
(<104IU/mL, which is approximately equivalent to
0.5´ 105copies/mL), Peg-IFN plus ribavirin is the
recommended regimen. For patients with dually-
active HBV/HCV coinfection (
positive, HBeAg positive, or HBV-DNA >104
IU/mL), very little relevant information is available.
The limited data indicate that IFN/ Peg-IFN plus
ribavirin might be inadequate. Adding one or more
nucleotide analogs to suppress HBV replication
might be feasible, but more studies are needed to
elucidate the problem (14).
In conclusion, this study found that HCV was
the dominant virus in the majority of HBV/HCV-
coinfected cases in the sample. Current standard
treatment regimens are not effective for clearance of
HBV and/or HCV. Sustained clearance of HCV
seems difficult in both viraemic and non-viraemic
HBV patients. Reactivation of HBV replication
without clinical hepatitis flaring may be observed in
HBV-DNA-positive or HBV-DNA-negative patients
who achieve SVR for their HCV infection. Improved
strategies for dealing with HBV/HCV coinfection
are required.
HCV-RNA
References
Archive of SID
www.SID.ir