A Comparison of Adefovir and Tenofovir for the Treatment of Lamivudine-Resistant Hepatitis B Virus in People With HIV

A Randomized, Phase II, Controlled Trial Comparing the Efficacy of Adefovir Dipivoxil and Tenofovir Disoproxil Fumarate for the Treatment of Lamivudine-Resistant Hepatitis B Virus in Subjects Who Are Co-Infected With HIV

Control of hepatitis B virus (HBV) infection can be difficult in HIV infected people who have taken the antiviral lamivudine (3TC). These people may have HBV that has become resistant to 3TC. Adefovir dipivoxil (ADV) has shown promising anti-HBV activity in clinical trials; tenofovir disoproxil fumarate (TDF) is used to treat HIV and may also be effective against HBV. The purpose of this study is to find out if adding ADV or TDF to a highly active antiretroviral therapy (HAART) regimen that includes 3TC has an effect on HBV infection in patients coinfected with HIV and HBV. The tolerability and safety of these drugs will be examined.

HBV presents a worldwide health crisis and is difficult to treat when a patient's HBV strain is no longer responsive to 3TC. Given the significant incidence of 3TC-resistant HBV in patients receiving this drug as part of an antiretroviral regimen, other agents with anti-HBV activity are needed. ADV has shown promising anti-HBV activity in preclinical assessments and in Phase I, II, and III clinical trials. TDF, developed for the treatment of HIV infection, has in vitro activity against HBV. This study will compare TDF/3TC combination therapy with ADV/3TC combination therapy to determine which treatment regimen is more effective in patients coinfected with HBV and HIV.

This study will include two populations of patients. Patients in Population A are on stable HAART that includes TDF and will either be in Group I (compensated liver disease) or Group II (decompensated liver disease). All patients in Population A will be randomly assigned to one of two arms: Arm 1 patients will receive 10 mg ADV daily and TDF placebo; Arm 2 patients will receive ADV placebo and 300 mg TDF. Patients in Population B are on stable HAART and have never taken TDF as part of their HAART. Population B patients will receive 300 mg TDF daily during the course of the study.

Study visits will occur every 4 weeks for the 96-week study period. Targeted clinical and medication assessments and blood work assessing clotting time, liver function, and blood chemistry will be conducted at each study visit. HIV and HBV DNA viral load will be tested every 12 weeks. CD4 cell counts will be tested at Weeks 24, 48, 72, and 96.

Inclusion Criteria for All Participants:

• HIV infected
• HBV infected
• Serum HBV DNA of 100,000 copies/ml or greater
• Positive for serum hepatitis B surface antigen (HBsAg) within 12 weeks prior to study entry
• Agree to use acceptable methods of contraception
• Serum alpha-fetoprotein (AFP) of 50 ng/ml or less within 30 days of study entry. If AFP is greater than 50 ng/ml, the patient must have an imaging study of the liver showing no tumor within 30 days prior to study entry

Inclusion Criteria for Population A:

• Uninterrupted stable HAART regimen at study entry for at least 12 continuous weeks prior to study entry
• HIV viral load of 10,000 copies/ml or less within 12 weeks of study entry

Inclusion Criteria for Population A, Group I:

• Compensated liver disease
• Child-Pugh-Turcotte (CPT) score of less than 7

Exclusion Criteria for Population A, Group I:

• Excess fluid in the space between the membranes lining the abdomen and abdominal organs (ascites)
• Gastrointestinal (variceal) bleeding
• Brain and nervous system damage as a result of liver disease
• Abnormal blood clotting time

Inclusion Criteria for Population A, Group II:

• Decompensated liver disease
• CPT score of 7-12

Inclusion Criteria for Population B:

• Prior HAART regimen
• Never taken TDF as part of HAART regimen
• Serum HBV DNA of 100,000 copies/ml or greater within 12 weeks of study entry
• HIV viral load of greater than 10,000 copies/ml within 12 weeks of study entry
• CPT score less than 13

Exclusion Criteria

• Serious kidney problems within the last 12 months
• Allergic or sensitive to ADV or TDF
• Active hepatitis C virus (HCV) disease or unknown HCV status within 24 weeks of study entry
• Any medical or mental illness that, in the opinion of the investigator, would interfere with the protocol
• Past or current alcohol or drug abuse that would affect the protocol
• Malignancy that, in the opinion of the investigator, would make the patient unsuitable for the study
• Certain anti-HBV drugs within 90 days of study entry or expected use of these agents during the course of the study
• Drugs that may damage the kidneys within 8 weeks prior to study screening or expected use of these agents during the course of the study
• Systemic corticosteroids within 90 days of study entry
• Current use of drugs containing pivalic acid
• Certain investigational anti-HIV agents
• Pregnant or breastfeeding