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Perdita
Wietzke-Braun,
Volker Meier, Felix Braun, Giuliano Ramadori
Abteilung
für Gastroenterologie und Endokrinologie, Georg-August-Universit-t,
G-ttingen, Germany
Correspondence to: Professor Dr. Dr. G. Ramadori, Abteilung für
Gastroenterologie und Endokrinologie, Georg-August-Universit-t,
Robert-Koch-Strasse 40, 37075 G-ttingen, Germany
Telephone:
+49-551-39-6301, Fax. +49-551-39-8596
Received: 2001-02-06 Accepted: 2001-03-01
Subject
headings:
hepatitis C, chronic/drug therapy; interferon alpha-2a/therapeutic
use; interferon alpha-2a/ administration & dosage; ribavirin/administration
& dosage; ribavirin/therapeutic use
Wietzke
Braun P, Meier V, Braun F, Ramadori G. Combination of
“low-dose”ribavirin and interferon alfa- 2a therapy followed by
interferon alfa -2a monotherapy in chronic HCV infected non
responders and relapsers after interferon alfa- 2a monotherapy.
World J Gastroenterol,2001;7(2):222-227
Abstract
AIM: To report on the efficacy, safety and tolerability of
interferon alfa -2a combined with a “low dose” of ribavirin for
relapsers and non-responders to alpha interferon monotherapy.
METHODS: Thirty four chronic hepatitis C virus infected non
responders to interferon alfa 2a monotherapy (a course of at least 3
months treatment) and 13 relapsers to interferon alfa 2a monotherapy
(a dose of 3 to 6 million units three times per week for at least 20
weeks but not more than 18 months) were treated with the same dose
of interferon alfa-2a used before (3 to 6 million units three times
per week) and ribavirin (10mg/kg daily) for 6 months. In complete
responders, interferon alfa-2a was administered for further 6 months
at the same dose used before as monotherapy.
RESULTS: Seven (20.6%) of 34 non responders stopped the
combined therapy due to adverse events, including two patients with
histological and clinical Child A cirrhosis. In 17/27 (63%) non
responders, the combined therapy was stopped after three months
because of non response. Ten of the 27 non responders completed the
12 month treatment course. At a mean follow up of 28 months (16-37
months) after the treatment, 4/10 (15%) previous non responders
still remained complete responders. All 13 previous relapsers
completed the 12-month treatment course. At a mean follow up of 22
months (9-36 months) after treatment, 6/13 (46%) the previous
relapsers were still sustained complete responders.
CONCLUSION: Our treatment schedule of the combined therapy
for 6 months of interferon alfa-2a with a low dose of ribavirin
(10mg/kg/day) followed by 6 months of interferon alfa-2a monotherapy
is able to induce a sustained complete response rate in 15% of non
responders and 46% of relapsers with chronic hepatitis C virus
related liver diseases comparable to those obtained with the
standard doses of ribavirin 1000-1200 mg/day. Randomized prospective
controlled trials using lower total amounts of ribavirin in
combination with interferon should be performed.
INTRODUCTION
The hepatitis C virus (HCV) is the most common infectious agent
associated with post-transfusion and community-acquired non-A-non-B
hepatitis and cryptogenic cirrhosis[1]. Up to 85% of
patients with acute HCV infection will develop chronic liver disease
and spontaneous viral elimination is rare[2]. In studies
with a follow up of 10-20 years, cirrhosis secondary to chronic HCV
infection develops in 20%-30%[2,3] and is the most common
indication for liver transplantation worldwide[4].
Patients with cirrhosis secondary to chronic HCV infection also have
an increased risk for development of hepatocellular carcinoma,
estimated to be between 1%-4% per year[5]. The
introduction of alpha interferon (IFNα) for the treatment of
HCV infection is an outstanding revolution in antiviral therapy[6].
However, alpha interferon monotherapy strategies can only induce a
sustained response in 8%-21% of the patients with chronic HCV-related
liver disease[7]. Thus, new therapeutic strategies were
needed for chronic HCV infection in order to increase the sustained
response rate in naive patients and patients in whom the response to
standard alpha interferon monotherapy was ineffective, in particular
the relapsers and non-responders.
Systemic ribavirin (1-β-D-ribofuranosyl-1, 2,
4-triazole-3-carboxamide), a broad-spectrum oral purine nucleoside
analogue, has been used for the treatment of a variety of viral
diseases[8]. In children with viral diseases, ribavirin
is usually given orally at a dosage of 10mg/kg daily[8].
In adult human immunodeficiency virus (HIV)-infected patients,
ribavirin plasma levels between 6 and 12μmol/L are required to
achieve viral inhibition with acceptable toxicity[9].
Daily oral doses of 600 (1200) mg ribavirin resulted in a mean peak
plasma concentration of 5.0 (11.1) μmol/L at the end of the
first week. Clinical and hematologic toxicities were not noted at a
ribavirin dosage of 600mg/d for 2 weeks, but a dosage of 1200mg/d
for 2 weeks resulted in moderate to severe clinical and
hematological adverse events (hematocrit decrease)[9].
Furthermore Glue et al. reported similar ribavirin
pharmacokinetics comparing pediatric and adult patients[10].
In patients with chronic HCV infection, ribavirin monotherapy
has been found to improve serum levels of hepatic transaminases and
liver histology by decreasing hepatic inflammation and necrosis[11-13].
In 1991, oral ribavirin treatment in a dosage of 1000mg/d for
chronic HCV-infected patients weighing less than 75kg and 1200mg/d
weighing more than 75kg for 12 weeks was evaluated in a pilot study[14].
In 1994 and 1995, the first promising reports[15-18] on
the combined therapy with alpha interferon and ribavirin in a dosage
of 1000-1200 mg/d orally according to Reichard et al[14]
were obtained in relapsers and non-responders as well in naive
patients with chronic HCV infection. Therefore, we started a
combination treatment with interferon alfa-2a (IFN) in
non-responders and relapsers to IFN monotherapy. However, we used a
lower dosage of oral ribavirin (10mg/kg body weight daily) according
to that used in child[8] and adult[9] HIV-infected
patients and to pharmacokinetic studies performed in healthy
volunteer and patient populations[10]. Duration of the
combined therapy was 6 months, followed by a 6-month treatment with
IFN monotherapy for responders to combined therapy in chronic HCV-infected
patients who were previous non-responders or non-sustained
responders (relapsers) to IFN alone. The results of safety,
tolerability and virological efficacy during and after treatment are
reported.
PATIENTS AND METHODS
Patients
Fourty-seven chronic HCV-infected patients (15 female, 32 male, mean
age 48 years) with histological mild chronic hepatitis (n=17),
moderate chronic hepatitis (n=18), severe chronic hepatitis (n=5),
cirrhosis (n=5) and unknown histology (n=2) received antiviral
therapy. HCV genotypes were classified in 10 patients as Ⅰ
(1a), in 30 as Ⅱ
(1b), in 2 as Ⅳ
(2b), in 4 as Ⅴ
(3a), and one was unclassifiable according to Okamoto[19]
and Simmonds[20]. The cause for HCV transmission could be
identified as lood-transfusions (n=13), injection drug use (n=3),
occupational (n=2), sexual/household (n=1) and unknown (n=28). All
patients had been previously treated with IFN. Thirty-four patients
had not responded. Non-response to the first IFN therapy was defined
as the persistence of at least 3 abnormal aminotransferase
activities during a course of at least 3 months of IFN treatment
with monthly control and after IFN discontinuation, and by PCR which
remained positive[21]. Thirteen patients had an initial
response to a dose of 3-6 million units three times per week for at
least 20 weeks but not more than 18 months[22], followed
by relapse. The IFN treatment was discontinued for at least 3 months
before the combination therapy was started. All patients had
persistent elevations of serum alanine aminotransferase (ALT) and
aspartate aminotransferase (AST), a positive third-generation anti-HCV
test using an immunoblot procedure (CHIRON RIBA HCV 3.0 SIA, Ortho
Diagnostic Systems Inc., Raritan, USA) and positive serum HCV RNA by
reverse transcriptase/polymerase chain reaction (RT/PCR). Patients
with decompensated liver disease, autoimmune disorders, thyroid
gland alterations, active alcohol or injection drug abuse, history
of major psychiatric disease, pregnancy, significant anemia
(hemoglobin ＜12g/dL)
, leukocytopenia (＜3000μL)
or thrombocytopenia (＜50000μL)
were not included. Active hepatitis A virus, HIV, hepatitis B virus,
cytomegalovirus or Ebstein-Barr virus infections were excluded by
convential laboratory tests. Informed consent was obtained in all
treated patients.
Treatment
Combination therapy was given for 6 months with IFN and ribavirin.
The IFN dose was adjusted to the previous IFN treatment. Twenty-two
of 34 previous non-responders were treated with 6 MU subcutaneous (s.c.)
t.i.w . and 12/34 with 3 MU t.i.w. Eleven of 13 previous relapsers
were treated with 6 MU t.i.w. and 2/13 with 3 MU t.i.w. . To improve
virological efficacy and tolerability instead of using ribavirin at
a dose of 1000-1200 mg/day, we administered ribavirin at 10mg/kg
body weight daily in three divided doses orally. This dose was
chosen in accordance to the tolerability data obtained in
HIV-infected children[8] whose pharmacokinetic data are
similar to those obtained in adults[10] and in
HIV-infected adults[9]. Patients who responded to the
combination therapy were treated for another 6 months with IFN
monotherapy with the same preceeded dose (3 or 6 MU s.c. t.i.w.).
After 12 months of treatment, the patients were followed up for at
least 9 months.
Monitoring
Clinical examination, total blood cell counts, routine biochemical
tests and detection of serum HCV RNA by RT/PCR were performed before
and at monthly intervals during and after 6 months treatment,
thereafter every 3 months.
Detection of serum HCV-specific RNA by RT/PCR
RNA was extracted from serum samples (140μL) using the QIAamp
viral RNA KIT (Qiagen, Hilden, Germany) according to the
manufacturer’s protocol. One-fifth of the extracted material from
serum was subjected to a nested RT/PCR procedure essentially as
described[23].
Determination of HCV genotypes
HCV genotypes were determined according to Okamoto et al[19]
using RT/PCR with a type-specific primer of the core region.
Genotypes determination was then confirmed by restriction enzyme
digestion analysis as described previously[24].
RESULTS
Response to previous IFN monotherapy, combination therapy with IFN
and ribavirin, subsequent IFN monotherapy for responders to
combination therapy and outcome during follow-up for previous
non-responders is depicted in Figure 1 and for previous relapsers in
Figure 2.
Drop-outs
Seven of 34 non-responders to previous IFN monotherapy (20.6%)
stopped the combination therapy because of insulin dependent
diabetes mellitus (n=1), sarcoidosis (n=1), lichen ruber oris
mucosae (n=1), severe fatigue (n=1) or depression and fatigue (n=3).
Two of seven drop-out patients had a histological and clinical Child
A cirrhosis. During combination therapy and after withdrawal,
transaminases remained unchanged at elevated levels and serum HCV
RNA was still positive in all patients. There were no drop-outs in
the 13 relapsers to the previous IFN monotherapy.
Outcome of combination treatment (6 months)
Twenty-seven non-responders to previous IFN monotherapy continued on
the 6-month course of combination therapy. At the end of the 3
months, 17/27 (63%) patients did not respond to the combination
therapy with unchanged elevated transaminases and positive serum HCV-RNA,
so therapy was stopped. Ten of 27 (37%) had a complete response with
transaminases in the reference ranges and negative serum HCV RNA.
All 13 relapsers to previous IFN monotherapy completed the 6-month
course of combination therapy. At the end of 6 months, 13/13 (100%)
patients had a complete response with transaminases in the reference
ranges and negative serum HCV RNA.
Figure 1(PDF)
Outcome of 34 HCV infected non-responders to IFN monotherapy,
including response to combined therapy with IFN and “low-dose”
ribavirin for 6 months, response to followed IFN monotherapy for 6
months for complete responders to combined therapy and outcome
during follow up after 12 months treatment.
Figure 2(PDF)
Outcome of 13 HCV-infected relapsers to IFN monotherapy,
including response to combined therapy with IFN and“low-dose”
ribivirin for 6 months, response to followed IFN monotherapy for 6
months for complete responders to combined therapy and outcome
during follow-up after end of 12 months treatment.
Outcome of complete treatment (12 months)
The 10 non-responders to previous IFN monotherapy, who had a
complete response at the end of combination therapy were treated
with the same dose of IFN used before as monotherapy for a further 6
months. During the 6-month course of IFN monotherapy, 4/10 (40%)
patients had a relapse within 6- months after the end of ribavirin
treatment. Six of ten (60%) patients still had a complete response
at the end of 12-month treatment course with transaminases in the
reference ranges and undetectable serum HCV RNA. All 13 relapsers to
previous IFN monotherapy had a complete response at the end of
combination therapy and were treated with the same dose of IFN used
before as monotherapy for a further 6 months. During the 6-month
course of IFN monotherapy, 4/13 (31%) patients had a relapse within
6 months after ribavirin treatment. Nine of 13 (69%) patients still
had a complete response at the end of 12-month treatment with
transaminases in the reference ranges and undetectable serum HCV
RNA.
Follow-up (at least 9 months)
At the end of the 12-month treatment, 6 non-responders to previous
IFN monotherapy became complete responders. At a mean follow-up of
28 months (16-37 months), 2/6 (33%) patients relapsed, 4/6 (67%)
were sustained responders, including one patient with genotype Ⅱ
(1b) and cirrhosis.
At the end of 12-month treatment, 9 relapsers to previous IFN
monotherapy became complete responders. At a mean follow-up of 22
months (9-36 months), 3/9 (33%) patients relapsed, 6/9 (67%) were
sustained responders with transaminases in the normal range and
undetectable serum HCV-RNA.
In summery, 4/27 previous non-responders (15%) and 6/13
previous relapsers (46%) are sustained responders.
Side effects
Combination therapy with IFN (3-6 MU s.c. t.i.w.) and “low-dose”
ribavirin (10mg/kg body weight) was well tolerated. Monitoring of
side effects by questioning and clinical examination revealed
arthralgia in 77%, fatigue in 27% and loss of weight in 19% of the
patients. The most prominent side effects of combination therapy
were alterations in total blood cell counts. Mild leukocytopenia
(minimal 2000/μL in a patient without cirrhosis and 1400/μL
in a patient with cirrhosis) and thrombocytopenia (minimal 79000μL
in a patient without cirrhosis and 35000μL in a patient with
cirrhosis) were generally seen. Decreases in hemoglobin is shown in
Figure 3. Of 40 patients who continued on combination therapy 7
patients were withdrawn. There was no need of transfusion or drug
dose reduction. All side effects were completely reversible within
one month after treatment.
Figure 3(PDF)
Decrease of hemoglobin of 40 patients (34 non-responders and 13
relapsers to IFN monotherapy) who continued on combination therapy
with IFN and “low-dose” ribavirin.
DISCUSSION
In this retrospective uncontrolled analysis, we report on our
experience of 47 chronic HCV-infected patients who received a
combination treatment of IFN and “low-dose” ribavirin after
previous failure to IFN monotherapy. Of the 47 patients, 34 were
non-responders and 13 relapsers to the initial IFN monotherapy.
Seven of 34 (20.6%) non-responders to the previous IFN monotherapy
(two with histological cirrhosis), did not complete the 6 months
course of combination therapy due to various side effects, but none
of the 13 relapsers to previous IFN monotherapy. In comparison to
our results, a meta-analysis of individual patient data from
European centers revealed that about 10% of patients withdrawn from
treatment[25]. Although our results have the drawback of
being obtained under uncontrolled conditions, they have the
advantage of being more realistic as every day experience is often
different from that obtained under controlled study conditions.
In our patients, we found that a 6-month course of combined
therapy with “low-dose” ribavirin induced a complete response at
the end of treatment in 10 (37%)of 27 initial non-responders. In a
similar retrospective analysis, 2 (12.5%) of 16 non-responders to
IFN monotherapy were complete responders at the end of combination
therapy and both patients relapsed during the follow-up period[26].
From our initial 13 relapsers to IFN monotherapy, 13 (100%) were
complete responders at the end of 6-month combination treatment with
“low-dose” ribavirin, in contrast to the multicenter study from
Davis et al, who found 77% complete responders at the end of
6-month combination treatment with ribivarin in a dose of 1000-1200
mg per day depending on body weight[22].
Previous publications had suggested that duration of therapy
longer than 6 months may reduce the number of
relapsers[16,27]. Therefore, the 23 complete responders
(10 initial non-responders and 13 relapsers to IFN monotherapy) at
the end of 6-month combined therapy continued with IFN alone for
another 6 months. Eight of 23 (35%) complete responders at the end
of combined therapy with “low-dose” ribavirin (4 initial
non-responders and 4 relapsers to IFN monotherapy) relapsed under
IFN monotherapy within 3 months, suggesting that in a subgroup of
patients a longer course of combined therapy could leed to sustained
response.
During the follow-up period, 5 of 15 (33%) complete responders
at the end of 12 months treatment (2 initial non-responders and 3
relapsers to IFN monotherapy) relapsed within 3 months. Also, these
patients represent a subgroup who may benefit of a longer period of
combined therapy. However, 4/27 (15%) initial non-responders
(including one with histological cirrhosis and genotype Ⅰ
(1b) and 6/13 (46%) relapsers to IFN monotherapy were still complete
sustained responders (16-37 months follow-up for initial
non-responders and 9-36 months for initial relapsers to IFN
monotherapy) after 12 months treatment.
A combined therapy with IFN and “low-dose” ribavirin for 6
months followed by 6 months of IFN monotherapy in those patients who
responded to the combination therapy can induce sustained response
not only in relapsers to IFN monotherapy, but also in some
non-responders, among whom, one patient had histological sign of
cirrhosis and genotype Ⅰ
(1b). This result is noteworthy as the monotherapy course was
performed with a total amount of IFN which was previously shown to
be effective in a large number of patients[27]. This
suggests that retreatment with a higher dose of IFN for a longer
period[28-30] is less promising than the combination
therapy. Our experience also shows that a further 6 months of IFN
monotherapy after combination therapy may help reduce the number of
relapsers and that on the other hand the duration of the combination
therapy of 6 months may not be sufficient for some patients.The
results of this retrospective analysis are difficult to compare with
those recently published by Sostegni et al[31],
Davis et al[22], Pol et al[21]
and by Milella et al[32] obtained treating
patients who were non-responders to[21,31,32] or relapsed
after[22,32] interferon alfa monotherapy with a
combination therapy for 6 months, because the number of
non-responders and relapsers we treated is small. However, it is
also noteworthy that the lower dose of ribavirin we used seems to
allow response rate may similar to those recently published in
controlled studies[21,22,31,32]. This strategy received
support in a recently presented abstract[33] where a
ribavirin dose of 600mg/day was as effective as 1000mg/day as for as
week 12 HCV RNA levels concerns during alpha interferon and
ribavirin therapy in chronic HCV-infected patients. This is also of
economic relevance as the ribavirin released into the market
recently increases the costs of about 1000 Dollars per month. Our
results may stimulate a prospective study where complete responders
under combination therapy are treated for further 6 months with
alpha interferon alone as has been recently suggested by Perasso et
al [34].
In conclusion, combination therapy with “low-dose”
ribavirin may represent a therapeutic alternative for at least some
non-responders and relapsers.
ACKNOWLEDGMENT We like to thank Dr. S. Mihm for determination
of HCV genotypes and detection of serum HCV RNA, Mrs. Gogoll for
assistance in collecting the data, the colleagues of our department
for co-operation in treating patients, and Prof. V. W. Armstrong for
reading the manuscript.
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