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Efficacy and Safety of PegIFN +/- FTC / TDF to Treat Chronic Hepatitis B in HIV-Coinfected Patients


Trial Overview

StatusConditionSponsor/Collaborator(s)First ReceivedLast ChangedVerification Date
Terminated Chronic Hepatitis B; HIV Infections University Hospital, Bonn Other
collaborator(s): Hoffmann-La Roche
September 14, 2005 February 17, 2009 February 2009

Study TypeStudy DesignPhaseEnrollmentStart DateEnd Date
Interventional Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Factorial Assignment, Masking: Open Label, Primary Purpose: Treatment Phase 3 2 September 2004 -

Locations

FacilityAddressContactPhoneEmailStatus
Abteilung Klinische Immunologie Zentrum Innere Medizin der Medizinischen Hochschule Hannover Hannover Lower Saxony 30625 Germany - - - -
Immunologische Ambulanz, Medizinische Klinik und Poliklinik I, Bonn University Bonn North-Rhine Westfalia 53127 Germany - - - -
Praxiszentrum Kaiserdamm Berlin 14057 Germany - - - -
ifi Institut für Interdisziplinäre Medizin Hamburg 20099 Germany - - - -
Praxis St. Georg Hamburg 20099 Germany - - - -

Intervention

TypeInterventionDescription
Drug pegylated interferon alfa-2a -
Drug tenofovir DF / emtricitabine combination therapy -
Drug pegIFN / TDF / FTC combination therapy -

Outcome

TypeMeasureTime FrameSafety Issue
Primary Efficacy: HBeAg seroconversion (HBeAg loss and presence of anti HBe) ; intent to treat analysis. week 48 and 72 No
Primary Safety: study discontinuation due to adverse events; intent to treat analysis. week 48 Yes
Secondary Efficacy: loss of HBe-Ag,HBV-DNA < 5x10³ copies/ml(COBAS TaqMan HBV Test),decrease of HBV-DNA > 2xlog10 compared to baseline week 48 and 72 No
Secondary normalization of ALT,intent to treat and as treated analysis; Viral kinetics of HBV-DNA; Paired liver biopsy comparison according to METAVIR-activity and fibrosis score. week 48 and 72 No
Secondary for Arm B (B1 and B2): HIV-RNA < 50 copies/ml and CD4-cell increase intent to treat and as treated analysis Weeks 4, 12, 24, 48 and 72 No
Secondary Safety: number of adverse events, according to type and severity. Throughout study Yes

Official Title

Pegylated Interferon Alfa-2a Versus Emtricitabine / Tenofovir +/- Pegylated Interferon Alfa-2a for the Treatment of Chronic HBe-Ag Positive Hepatitis B Infection in HIV-Coinfected Patients - the PEGPLUS Trial

Description

Even though the generated data on standard interferon for the treatment of chronic
HBV-infection in HIV-coinfected patients appears not promising at the moment, it is however
the only treatment with a curative intention. Trials with pegylated interferon in the
treatment of chronic HBV-infection in monoinfected patients with pegylated interferons
showed higher efficacy than standard of care and when compared to historic data higher
efficacy compared to non-pegylated interferon. This suggests in parallel a higher efficacy
in the treatment of chronic hepatitis B in HIV-coinfected as well. At the same time,
analysis suggested a further benefit when pegylated interferon therapy was prolonged beyond
24 weeks to 48 weeks as the elimination of HBV-DNA from serum appeared to continue beyond 24
weeks. Looking again at data from chronic hepatitis C infection, it is well known that the
elimination kinetics of HCV-RNA in HIV-coinfected patients is slower compared to
HCV-monoinfected patients, clearly suggesting rationale to offer 48 weeks pegylated
interferon for the treatment of chronic hepatitis B to HIV-coinfected patients as well.

Parallel to the above said there are several other factors suggesting a positive effect of a
combination treatment with nucleoside / nucleotide analogues active against HBV and
interferon. Therefore patients in need for antiretroviral therapy with CD4-cells above
200/µl will be randomized to either PegIFN as part of a combination treatment with FTC and
TDF or to FTC / TDF combination therapy alone. Patients receiving HAART will also receive a
third active antiretroviral HIV-drug, either a non-nucleoside analogue (NNRTI) or a protease
inhibitor (PI), at the choice of the investigator. A non-divergent antiretroviral therapy
solely based on nucleoside analogues will not be allowed in this trial.

The objective of this study is to assess the efficacy (HBV-DNA < 5x10³ copies/ml, loss of
HBe-Ag, HBe-seroconversion) and safety (adverse events, serious adverse events) of PegIFN
for 48 weeks, to that of PegIFN for 48 weeks plus TDF and FTC containing HAART, to that of
TDF and FTC containing HAART for 72 weeks.

Eligibility

GenderMinimum AgeMaximum AgeHealthy Volunteers
Both - 65 Years No

Inclusion Criteria:

- Documented chronic hepatitis B infection (> 6 months) with detectable HBV DNA >
5x100000 copies/ml (PCR-Assay) on two separate occasions

- HBe-Ag positive, anti-HBe negative

- HBs-Ag positive, anti-HBs negative

- a liver biopsy within the last 12 months prior to screening consistent with chronic
hepatitis B

- Documented HIV-infection

- CD4-cell count > 200 cells/µl

- Elevated serum ALT > ULN but £ 10X ULN as determined by two abnormal values taken >14
days apart during the six months before the first dose of study drug with at least
one of the determinations obtained during the screening period

- Serum-creatinine clearance > 70 ml/min, according to Cockcroft-Gault

- Anorganic phosphate > 0,65 mmol/l (2,0 mg/dl)

- Neutrophils above 1.5 G/l, Hb above 11.5 g/dl (females) or 12.5 g/dl(males),
thrombocytes above 90 G/l

- Ability to understand and sign a written consent form

Exclusion Criteria:

- Older than 65 years of age, younger than 18 years of age

- Pregnancy, lactating women

- Concomitant / prior medication / hypersensitivity to study medication

- Prior use of antiretroviral therapy in particular adefovir dipivoxil, tenofovir DF,
lamivudine, emtricitabine, or interferon

- Treatment with interleukin 2 or corticosteroids less than 6 months prior to the first
dose of study drug or the expectation that such treatment will be needed at any time
during the study.

- Currently receiving investigational agents unless approved by the study coordinator

- History of having received any systemic anti-neoplastic (including radiation < 6
months prior to the first dose of study drug or the expectation that such treatment
will be needed at any time during the study.

- Patients not receiving HAART (Arm A) must be expected not be in need for
antiretroviral therapy for HIV-infection at any time during the study 72 weeks, as
judged by the investigator.

- Hypersensitivity to any of the components of the study drugs (tenofovir,
emtricitabine, pegylated interferon alfa-2a)

Concurrent liver disease:

- Ongoing hepatitis A, C or Delta infection: positive testing for anti HAV-IgM,
HCV-RNA, anti-HDV, HDV-Ag

- Ongoing EBV or CMV infection: positive testing for anti EBV-IgM, CMV-eAg

- Autoimmune hepatitis

- Patients with a value of alpha-fetoprotein >100 ng/mL are excluded, unless stability
(less than 10% increase) has been documented over at least the previous 3 months and
magnetic resonance tomography of the liver shows no evidence of hepatocellular
carcinoma.

- Liver cirrhosis, CHILD-Pugh Score B or C; history or other evidence of bleeding from
esophageal varices or other conditions consistent with decompensated liver disease

- History or other evidence of a medical condition associated with chronic liver
disease other than HBV (e.g., hemochromatosis, autoimmune hepatitis, metabolic liver
diseases including Wilson's and alpha1-antitrypsin deficiency, alcoholic liver
disease, toxin exposures, thalassemia).

- Alcohol abuse (> 30g ethanol/d for males, > 20 g ethanol/d for females) or use of
other recreational drug substances)

- Serum total bilirubin above twice the upper limit of normal

- ALT > 10 times the upper limit of normal

Neurological / psychiatric disorders:

- History of severe psychiatric conditions(ICD F30 - 33), graded by the consulting
psychiatrist, in particular severe depression. Severe psychiatric disease is defined
as major depression or psychosis, a period of treatment with an antidepressant
medication or tranquilizer at therapeutic doses for depression or psychosis for at
least 3 months, a suicidal attempt, hospitalization for psychiatric disease, or a
period of disability due to a psychiatric disease.

- History of a severe seizure disorder or current anticonvulsant use.

Cardiovascular disorders:

- History or other evidence of chronic pulmonary disease associated with functional
limitation.

- Severe cardiac disease (e.g., NYHA Functional Class III or IV, myocardial infarction
within 6 months, ventricular tachyarrhythmias requiring ongoing treatment, unstable
angina or other significant cardiovascular diseases).

Immunological disorders:

- Elevated auto-antibody findings

- History of immunologically mediated disease (e.g. inflammatory bowel disease,
idiopathic thrombocytopenic purpura, lupus erythematosus, autoimmune hemolytic
anemia, scleroderma, severe psoriasis, rheumatoid arthritis).

- Thyroid disease with thyroid function poorly controlled on prescribed medications.
Patients with elevated thyroid stimulating hormone or T4 concentrations, with
elevation of antibodies to thyroid peroxidase and any clinical manifestations of
thyroid disease are excluded.

Other:

- Gastrointestinal malabsorption

- Evidence of an active or suspected cancer or a history of malignancy where the risk
of recurrence is ³20% within 2 years. Patients with a lesion suspicious of hepatic
malignancy on a screening imaging study will only be eligible if the likelihood of
carcinoma is £10% following an appropriate evaluation.

- History of organ transplantation

- History or other evidence of severe retinopathy (e.g. CMV retinitis, macula
degeneration) or clinically relevant ophthalmological disorder due to diabetes
mellitus or hypertension