The Safety and Effectiveness of Adefovir Dipivoxil Plus Indinavir Combined With Zidovudine or Lamivudine or Stavudine in HIV-Infected Patients Who Have Not Taken Anti-HIV Drugs

A Phase II, Stratified, Randomized, Open-Label, Multi-Center Study of the Safety and Efficacy of Adefovir Dipivoxil and Indinavir in Combination With Zidovudine, Lamivudine, or Stavudine for the Treatment of Therapy Naive HIV-Infected Patients With CD4 Cell Counts >= 100 Cells/mm3 and HIV-1 RNA Copy Numbers >= 5,000 Copies/Ml

To evaluate the safety and tolerance of adefovir dipivoxil and indinavir administered orally in combination with zidovudine, lamivudine, or stavudine in HIV-infected patients with CD4 cell counts >= 100 cells/mm3 and an HIV-1 RNA baseline copy number >= 5000 copies/ml. To determine the proportion of patients whose plasma HIV-1 RNA level falls below the level of detection (500 copies/ml) by 20 weeks of study therapy and the average reduction in HIV-1 RNA from baseline through study week 20. To evaluate the durability of the antiviral response through 48 weeks of study in patients who continue on study therapy after week 24.

This protocol is a stratified, randomized, open-label study of the safety and efficacy of adefovir dipivoxil with indinavir as quadruple therapy in combination with zidovudine and lamivudine, or as triple combination administered with either zidovudine or lamivudine or stavudine for 48 weeks in the treatment of HIV-infected patients with CD4 cell counts >= 100/mm3 and an HIV-1 RNA baseline copy number >= 5000 copies/ml. Patients will be randomized to adefovir dipivoxil, indinavir, zidovudine, and lamivudine or adefovir dipivoxil, indinavir, and a nucleoside inhibitor (randomly assigned to receive zidovudine, lamivudine, or stavudine) or to indinavir, zidovudine, and lamivudine. Additionally, a daily dose of L-carnitine will be administered to all patients randomized to an arm containing adefovir dipivoxil.

Inclusion Criteria

Patients must have:

• Laboratory diagnosis of HIV infection (positive HIV antibody test confirmed by Western blot, p24 antigen assay, HIV-1 RNA, or HIV-1 culture).
• An HIV-1 RNA plasma titer >= 5000 copies/ml within 14-21 days prior to the baseline visit.
• CD4 cell count >= 100 cells/mm3 within 14-21 days prior to the baseline visit.
• A minimum life expectancy of at least 1 year.
• Signed, informed consent from parent or legal guardian for those patients < 18 years of age.

Exclusion Criteria

Co-existing Condition:

Patients with any of the following symptoms and conditions are excluded:

• Active, serious infections (other than HIV infection) requiring parenteral antibiotic or antiviral therapy. Patients will be considered recovered from such infectious episodes if at least 2 weeks elapsed following the cessation of parenteral therapy before the baseline visit.
• Exhibiting evidence of a gastrointestinal malabsorption syndrome or chronic nausea or vomiting which may confer an inability to receive an orally administered medication.
• Malignancy other than cutaneous Kaposi's sarcoma (KS) or basal cell carcinoma. Patients with biopsy-confirmed cutaneous KS are eligible, but must not have received any systemic therapy for KS within 4 weeks prior to baseline and are not anticipated to require systemic therapy during the study.
• Any other clinical condition that in the opinion of the investigator would make the patient unsuitable for study or unable to comply with the dosing requirements.

Patients with any of the following prior conditions are excluded:

• A new AIDS-defining event diagnosed within 1 month prior to baseline.

• Any patient who has previously been discontinued from zidovudine, lamivudine, and/or stavudine due to a drug-related toxicity.

• Significant history of peripheral neuropathy.

  1. Treatment with immunomodulating agents such as systemic corticosteroids, IL-2, or interferons.

• Saquinavir, ritonavir, nelfinavir, nevirapine, delavirdine, didanosine, dideoxycytidine, interferon alpha, interferon beta, isoniazid, rifampin, investigational agents (except upon Sponsor approval), chemotherapeutic agents (systemic), terfenadine, astemizole, cisapride, triazolam, and midazolam.

  1. Prior use of adefovir dipivoxil.

• Prior non-protease antiretroviral therapy (other than antiretroviral vaccines) for greater than 4 cumulative weeks.

• Prior use of any antiretroviral protease inhibitor.

• Immunizations within 30 days of baseline.

• Antiretroviral vaccine therapy within 60 days of baseline.

• Treatment in the 4 weeks prior to baseline, with immunomodulating agents such as systemic corticosteroids, IL-2, or interferons.

• Any other investigational drug within 30 days prior to baseline.

• Any prior therapy that, in the opinion of the investigator, would make the patient unsuitable for study or unable to comply with the dosing requirements.

Patients with current alcohol or substance abuse judged by the investigator to potentially interfere with patient compliance.