PEG-interferon Alfa-2a add-on Study in HBeAg Negative Chronic Hepatitis B Patients
Information source: Foundation for Liver Research
ClinicalTrials.gov processed this data on August 23, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Chronic Hepatitis B
Intervention: Peginterferon alfa-2a (Drug); Nucleos(t)ide analogue (Drug)
Phase: Phase 4
Status: Recruiting
Sponsored by: Foundation for Liver Research Official(s) and/or principal investigator(s): H.L.A. Janssen, MD PhD, Principal Investigator, Affiliation: Erasmus Medical Center
Overall contact: H.L.A. Janssen, MD PhD, Phone: +14166035800, Ext: 2776, Email: harry.janssen@uhn.ca
Summary
This study intends to investigate whether addition of PEG-IFN alfa-2a in HBeAg-negative
chronic hepatitis B patients who are pretreated with nucleos(t)ide analogues enhances the
degree of HBsAg decline.
Clinical Details
Official title: Induction of HBsAg Decline Using an add-on Treatment of Peginterferon Alfa-2a in HBeAg-negative Chronic Hepatitis B Patients Treated With Nucleos(t)Ide Analogous (PAS)
Study design: Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment
Primary outcome: HBsAg decline
Secondary outcome: HBsAg declineHBsAg decline HBsAg loss
Detailed description:
Chronic hepatitis B (CHB) is one of the most serious health problems affecting more than 350
million people worldwide, accounting for one million deaths every year. Hepatitis B e
antigen (HBeAg)-negative chronic hepatitis B represents a late phase in the course of the
infection, which is recognized worldwide with increasing prevalence. Therapeutic
intervention is often indicated for HBeAg-negative patients because spontaneous remission
rarely occurs and patients usually have more advanced liver disease in comparison with
HBeAg-positive patients. With the introduction of nucleos(t)ide analogues (NA), an important
progress has been made regarding antiviral therapy of CHB, but the management of the
HBeAg-negative type remains difficult. NA target the reverse transcriptase of hepatitis B
virus (HBV) and are potent inhibitors of viral replication. Initiation of treatment in
HBeAg-negative CHB usually results in a rapid decline of serum HBV DNA levels, which is
often accompanied by normalization of serum aminotransferases. However, response to
treatment may not be durable in a large proportion of patients after discontinuation of
therapy, indicating the necessity of long-term, and maybe indefinite, treatment. Although NA
are well-tolerated during the first years of treatment, little is known about long-term
safety and resistance. In contrast, the antiviral potency of peginterferon (PEG-IFN) is
inferior to nucleoside analogues, but response to PEG-IFN probably is more durable in the
majority of patients due to its immunomodulatory effects. Sustained off-treatment responses
can be achieved in about 25% of patients treated with PEG-IFN for 1 year.
Natural killer (NK) cells are innate immune cells that not only represent the first line of
defense against viral infections but play also an important role in controlling adaptive
responses. The numerous mechanisms evolved by viruses to inhibit NK cell activity, as
already demonstrated for HIV and HCV, may not be directed at the innate immune response, but
may represent a strategy to prevent effective induction of adaptive immune responses.
Defective T cell activity observed in viral infection may therefore represent a bystander
effect of viral NK cell inhibition.
Recent findings of our group demonstrate that NK cells derived from the peripheral blood of
chronic HBV patients display an impaired capacity to produce IFNgamma, an important cytokine
for the skewing of virus-specific Th-1 responses, compared to healthy controls. Since HBV
has been shown to be able to directly interfere with immune cells as well as
IFNalpha-induced intracellular signalling, viral load reduction may not only improve the
function of immune cells, it may also facilitate the response to PEG-IFNalpha therapy and
subsequently the induction of an effective HBV-specific immune response. Treatment with a
nucleoside analogue and subsequent viral decline has already shown to restore helper T-cell
(TH-cell) and cytotoxic T-cell (CTL) responsiveness in chronic HBV infected patients.
Add-on treatment with PEG-IFN can be expected to further stimulate adaptive immune
reactivity and may therefore result in higher rates of response.
Previous studies investigating the effect of lowering viral load with NA therapy in
HBeAg-positive CHB prior to the initiation of PEG-IFN showed promising response rates to
treatment. A study by Sarin et al. showed a significantly higher rate of sustained HBeAg
loss in patients who received 4 weeks of lamivudine before PEG-IFN therapy (n=36) compared
to those receiving placebo for 4 weeks (n=27) (36% vs. 15%, p=0. 05). This treatment strategy
has however not yet been applied to HBeAg-negative patients. Current guidelines recommend
continuation of NA therapy for HBeAg-negative CHB until hepatitis B surface antigen (HBsAg)
is cleared from serum. However, HBsAg loss rarely occurs during NA therapy in HBeAg-negative
patients. In contrast, PEG-IFN therapy is associated with increasing rates of HBsAg loss
every year after discontinuation of therapy.
In a study by Chan et al. HBsAg remained stable in HBeAg-positive patients and tended to
reduce slowly in HBeAg-negative patients. They concluded that reduction of HBsAg for >1 log
IU/mL could reflect improved immune control. It was previously shown in a study of our group
that 14% of HBeAg-negative CHB patients had an HBsAg concentration decline of > 1 log after
24 weeks of therapy with PEG-IFN. Moucari et al. found an HBsAg decline of > 1 log in 25% of
their patients at week 24, with mean decreases of 0. 8, 1. 5, and 2. 1 log IU/mL at weeks 12,
24, and 48, respectively. Another study showed that 22% of patients had an HBsAg
concentration decline of > 1 log after 48 weeks of treatment, which was significantly
associated with HBsAg clearance three years after treatment with PEG-IFN. However, recent
studies also showed that HBsAg levels do not decrease during prolonged NA therapy of
HBeAg-negative CHB. Addition of PEG-IFN to NA therapy in HBeAg-negative patients may
therefore be necessary to induce a decline in HBsAg levels, a first step towards subsequent
HBsAg loss.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
Inclusion Criteria:
- Chronic hepatitis B (HBsAg positive > 6 months)
- HBeAg negative and anti-HBe positive within six months prior to initiation of
peginterferon alfa-2a
- HBV DNA < 200 IU/ml during nucleos(t)ide analogue (except Telbivudine) treatment
within one month prior to initiation of peginterferon alfa-2a
- Compensated liver disease
- Age > 18 years
- Written informed consent
Exclusion Criteria:
- Treatment with any investigational drug within 30 days of entry to this protocol
- Current treatment with Telbivudine
- Severe hepatitis activity as documented by ALT>10 x ULN
- History of decompensated cirrhosis (defined as jaundice in the presence of cirrhosis,
ascites, bleeding gastric or esophageal varices or encephalopathy)
- Pre-existent neutropenia (neutrophils <1,500/mm3) or thrombocytopenia (platelets <
90,000/mm3)
- Co-infection with hepatitis C virus, hepatitis D virus or human immunodeficiency
virus (HIV)
- Other acquired or inherited causes of liver disease: alcoholic liver disease, obesity
induced liver disease, drug related liver disease, auto-immune hepatitis,
hemochromatosis, Wilson's disease or alpha-1 antitrypsin deficiency
- Alpha fetoprotein > 50 ng/ml
- Hyper- or hypothyroidism (subjects requiring medication to maintain TSH levels in the
normal range are eligible if all other inclusion/exclusion criteria are met)
- Immune suppressive treatment within the previous 6 months
- Contra-indications for alfa-interferon therapy like suspected hypersensitivity to
interferon or Peginterferon or any known pre-existing medical condition that could
interfere with the patient's participation in and completion of the study.
- Pregnancy, breast-feeding
- Other significant medical illness that might interfere with this study: significant
pulmonary dysfunction in the previous 6 months, malignancy other than skin
basocellular carcinoma in previous 5 years, immunodeficiency syndromes (e. g. HIV
positivity, auto-immune diseases, organ transplants other than cornea and hair
transplant)
- Any medical condition requiring, or likely to require chronic systemic administration
of steroids, during the course of the study
- Substance abuse, such as alcohol (>80 g/day), I. V. drugs and inhaled drugs in the
past 2 years.
- Any other condition which in the opinion of the investigator would make the patient
unsuitable for enrollment, or could interfere with the patient participating in and
completing the study
Locations and Contacts
H.L.A. Janssen, MD PhD, Phone: +14166035800, Ext: 2776, Email: harry.janssen@uhn.ca
Onze Lieve Vrouwen Gasthuis, Amsterdam, Netherlands; Recruiting
VU university medical center, Amsterdam, Netherlands; Recruiting
Rijnstate Hospital, Arnhem, Netherlands; Recruiting
Reinier de Graaf Gasthuis, Delft, Netherlands; Recruiting
Atrium Medical Center, Heerlen, Netherlands; Recruiting
Radboud University Medical Center, Nijmegen, Netherlands; Recruiting
University Medical Center Utrecht, Utrecht, Netherlands; Recruiting
Erasmus Medical Center, Rotterdam, Zuid Holland 3015 CE, Netherlands; Recruiting M.J.H. van Campenhout, MD, Phone: +31107034513, Email: m.vancampenhout@erasmusmc.nl H.L.A. Janssen, MD PhD, Principal Investigator M.J.H. van Campenhout, MD, Sub-Investigator
Additional Information
Starting date: March 2012
Last updated: March 12, 2015
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