This study will evaluate the safety and effectiveness of adefovir plus lamivudine for
chronic hepatitis B infection in people with and without HIV infection. Lamuvidine, an
FDA-approved treatment for hepatitis B infection, also works against HIV. In some patients,
the hepatitis B virus (HBV) continues to reproduce despite lamivudine treatment. Adefovir is
an experimental drug that inhibits HBV replication and may work against some strains of the
virus that have become resistant to lamivudine.
Patients 21 years of age or older with active hepatitis B infection despite treatment with
lamivudine for at least 1 year may be eligible for this 48-week study. Patients both with or
without HIV infection may participate. Candidates will be screened with a medical history,
blood and urine tests, liver ultrasound exam, electrocardiogram (EKG) and chest X-ray.
Participants will have a physical examination, review of their medical history, blood tests,
and a 24-hour urine collection. They will be admitted to the hospital for a liver biopsy to
determine if they can receive the study drug. For this procedure, the patient is given a
sedative for relaxation. The skin over the biopsy is numbed with an anesthetic and the
biopsy needle is passed rapidly into and out of the liver to collect a tissue specimen.
Patients are monitored in the hospital overnight for possible complications. After
discharge, they return home and begin taking the study medications.
Patients will be randomized to two treatment groups. One group will take 10 milligrams/day
of adefovir by mouth, and the other will take a placebo-a lookalike pill with no active
ingredient. Both groups will also take 150 mg lamivudine by mouth and L-carnitine pills or
liquid. Patients with HIV infection will continue to take antiretroviral therapy as well.
Patients will be followed in the clinic at study weeks 2, 4, 8, 12, 16, 20, 24, 28, 32, 36,
40 and 44 for blood and urine tests to determine the safety of the drug and to evaluate the
response to treatment. On week 48, a repeat 24-hour urine test and repeat liver biopsy will
be done. At the end of the 48 weeks, patients may continue to receive adefovir for another
48 weeks and possibly longer. All those who participate in this extension phase will receive
active adefovir, regardless of whether they had previously taken adefovir or placebo.
All patients will have the option to enroll in a separate study to examine the levels of HBV
(and levels of HIV in HIV-infected patients) in the blood immediately after starting
treatment and to determine if these initial levels can predict later outcome. This involves
seven additional visits, for which participants will be compensated. At these visits, blood
will be drawn on study days 0 (before starting drug treatment), 1, 3, 5, 7, 10 and 21 for
HIV and HBV viral loads and specialized immunology tests.
This clinical trial examines the addition of adefovir dipivoxil to a lamivudine regimen for
treating chronic hepatitis B infection. Two patient populations will be separately
recruited: HIV-infected (40 subjects) and HIV-uninfected (20 subjects). HIV-infected
patients will be enrolled in a randomized, placebo controlled study of the safety and
efficacy of the addition of adefovir to lamivudine for the treatment of chronic hepatitis B
in subjects with a hepatitis B virus (HBV) viral load of at least one million copies/mL
despite at least one year of lamivudine therapy. A similar population of HIV-uninfected
subjects will be treated with open-label adefovir 10 mg daily for one year. These
HIV-negative subjects will serve as a control group for immunological comparisons to the
HIV-positive group treated with adefovir. HIV-infected subjects will be randomly allocated
to receive adefovir 10 mg daily for one year or matching placebo. At the end of one year,
HIV-infected patients may choose to receive open-label adefovir, and HIV-uninfected patients
will have the option of continuing open-label drug if they are responding to treatment.
Patients may not have decompensated cirrhosis or other causes of liver disease such as
hepatitis C. Liver biopsies are performed prior to study and at the end of one year.
HIV-positive subjects whose liver biopsy demonstrates cirrhosis will not be randomized but
will be treated with open-label adefovir 10 mg daily. The purpose of the study is to
evaluate the safety and efficacy of lamivudine plus adefovir as compared with continued
lamivudine in HIV-infected patients, to compare responses between HIV-uninfected and
HIV-infected subjects, and to obtain specimens for studies of immune responses to HBV.
HIV-infected patients will receive lamivudine 150 mg bid plus adefovir 10 mg qd (or placebo)
and HIV-uninfected subjects will receive lamivudine 100 mg qd plus adefovir 10 mg qd.
L-carnitine supplementation will be used only if low serum carnitine levels are documented.
Additionally, patients will have the option of enrolling in a sub-study assessing the
kinetics of viral load response to study drug. Specimens will be stored for possible future
determination of adefovir levels and use in evaluating HBV and HIV resistance to adefovir.
Patients discontinuing study drug and not initiating a commerically available anti-HBV
medication (including adefovir) will be monitored for safety for at least an additional 24
weeks. The primary study endpoint will be a comparison of the absolute HBV viral load at
Week 48 between the placebo and adefovir HIV-positive patient groups, and for the
HIV-negative population, the comparison of absolute HBV viral at Week 48 versus baseline.
Secondary endpoints include safety, liver pathology, and transaminase level. Adefovir will
be discontinued for toxicity; there will be no dose reduction. A DSMB will oversee the
trial for toxicity.
Age greater than or equal to 18 years
Infection with HBV with HBV viral load greater than 1.0 x 10 (6) copies/mL by Roche assay
HIV infected or uninfected
If HIV infected: CD4 greater than or equal to 100 and VL less than or equal to 10,000 at
screen; No antiretroviral changes 12 weeks prior to entry and no anticipated changes 12
weeks into study.
Have a physician(s) outside of NIH who will provide routine, as well as HIV (if
applicable) and liver specific, care.
Able to return to NIH for study visits
Receiving lamivudine at a dose of at least 100 mg qd for greater than or equal to one year
prior to enrollment (with no dosing interruptions of greater than 1 month total in the
previous year and no interruption in the 3 months prior to study entry)
Serum creatinine less than 1.5 mg/dL
1.2 less than or equal to ALT (SGPT) less than or equal to 7 X ULN (current NIH lab values
49-287 U/L inclusive) at screen
Direct bilirubin less than or equal to 1.0 mg/dL
Serum phosphorus greater than or equal to 2.2 mg/dL (normal range NIH 2.3-4.3 mg/dL)
Neutrophil count greater than or equal to 750 cells/mm(3)
Platelets greater than or equal to 70,000/mm(3)
INR less than or equal to 1.5
Hemoglobin greater than or equal to 10 mg/dL
If capable of pregnancy: use of effective contraception during study: effective
contraception methods include abstinence, surgical sterilization of either partner,
barrier methods such as diaphragm, condom, cap or sponge, or use of hormonal
contraception. If HIV infected using hormonal contraception, must be receiving an
anti-HIV regimen that will not alter the metabolism of hormonal contraception.
Willing and able to provide written informed consent
Willing to undergo hepatic biopsy at the start and end of study. The initial protocol
biopsy will not be required if the subject can provide pathologic slides from a biopsy
performed within six months of the History and Physical visit that are found by the Liver
Disease Section and the NIH's pathologist to be adequate for this study.
Prior use of ADV, tenofovir, or cidofovir
Child-Pugh Class B or C cirrhosis;
Class A Score = 5 acceptable; Class A Score = 6 acceptable as long as not secondary to
encephalopathy or ascites
Active serious systemic infections other than HIV or HBV
Liver disease caused by reasons other than hepatitis B e.g., HCV, HDV, Wilson's,
hemochromatosis, autoimmune hepatitis (ANA greater than or equal to 3 EU) except history
of drug-associated hepatitis with discontinuation of causative agent
History of encephalopathy, varices, heart failure, or ascites
Current history of clinical pancreatitis
New AIDS-defining event other than esophageal candidiasis diagnosed within 1 month prior
Treatment with immunomodulator drugs (interleukins, corticosteriods for indications other
than the treatment of adrenal insufficiency) in the 4 weeks prior to baseline. G-CSF and
epoetin use are permitted.
Anti-HBV therapy other than lamivudine (such as emtricitabine, lobucavir, entecavir, HBIG,
clevudine, MCC-478) with the exception of interferon alpha, famciclovir or foscarnet that
ended more than 12 weeks prior to screen.
Hepatic mass suggestive of hepatocellular carcinoma
Alpha fetoprotein greater than 200 ng/ml
Evidence of gastrointestinal malabsorption or chronic nausea or vomiting
Current alcohol or substance abuse that potentially could interfere with patient
Malignancy other than cutaneous Kaposi's sarcoma, skin cancer treated by resection or
HPV-associated carcinoma in situ or Bowen's disease in the 5 years prior to enrollment
History of clinically significant renal dysfunction within the previous 12 months prior to
Concomitant therapy with aminoglycosides, amphotericin B, cisplatinum, IV pentamidine,
vancomycin, systemic chemotherapeutic agents, probenecid or other nephrotoxic agents
Proteinuria (greater than or equal to 3+)
Positive PCR test for hepatitis C
Antibodies to hepatitis D (delta hepatitis)
Pregnancy or breast-feeding. Pregnancy test must be negative within two weeks prior to
dosing with adefovir or placebo.
History of organ or bone marrow transplantation
Any systemic illness that will make it unlikely that the subject will be able to return to
NIH for the required study visits