Ignite Creation Date:
2024-05-05 @ 11:37 PM
Last Modification Date:
2024-10-26 @ 10:36 AM
Study NCT ID:
NCT01373684
Status:
COMPLETED
Last Update Posted:
2019-11-08
First Post:
2011-06-14
Brief Title:
PEG-interferon Alfa-2a add-on Study in HBeAg Negative Chronic Hepatitis B Patients
Sponsor:
Foundation for Liver Research
Organization:
Foundation for Liver Research
Study Overview
Official Title:
Induction of HBsAg Decline Using an add-on Treatment of Peginterferon Alfa-2a in HBeAg-negative Chronic Hepatitis B Patients Treated With NucleostIde Analogous PAS
Status:
COMPLETED
Status Verified Date:
2019-11
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
PAS
Brief Summary:
This study intends to investigate whether addition of PEG-IFN alfa-2a in HBeAg-negative chronic hepatitis B patients who are pretreated with nucleostide analogues enhances the degree of HBsAg decline
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 nucleostide 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 n36 compared to those receiving placebo for 4 weeks n27 36 vs 15 p005 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 IUmL 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 08 15 and 21 log IUmL 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
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 n36 compared to those receiving placebo for 4 weeks n27 36 vs 15 p005 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 IUmL 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 08 15 and 21 log IUmL 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None