Antiviral Activity of and Resistance to Lamivudine in Combination With Zidovudine, Stavudine, or Didanosine

A Phase II, Randomized Study of the Antiviral Activity and Resistance Interactions of Lamivudine (3TC) in Combination With Zidovudine (AZT), Stavudine (d4T), or Didanosine (ddI) Versus Monotherapy With ddI or d4T in HIV-Infected Individuals With 200 - 600 CD4+ Cells/mm3 and No Previous Nucleoside Experience

To evaluate the efficacy, safety, and pharmacokinetics of lamivudine (3TC) combined with zidovudine (AZT), stavudine (d4T), or didanosine (ddI) in comparison with d4T or ddI monotherapy in HIV-infected patients with no prior nucleoside therapy.

3TC may be uniquely effective in combination with AZT due to the interaction of AZT and 3TC resistance mutations. One explanation is that the M184V mutation, which confers resistance to 3TC, suppresses AZT resistance. This benefit of 3TC may not extend to combination therapy with other nucleoside analogs.

3TC may be uniquely effective in combination with AZT due to the interaction of AZT and 3TC resistance mutations. One explanation is that the M184V mutation, which confers resistance to 3TC, suppresses AZT resistance. This benefit of 3TC may not extend to combination therapy with other nucleoside analogs.

Patients are randomized to either a ddI limb or d4T limb, then randomized a second time to one of six treatment arms, as follows: ddI alone, d4T alone, 3TC/AZT (on both ddI and d4T limbs), 3TC/ddI, and 3TC/d4T. Treatment is given for 48 weeks. At study week 24, patients on monotherapy will have 3TC added to their regimen (in a blinded fashion).

PER AMENDMENT 10/18/96: A treatment extension phase has been added to the study design in order to allow subjects who complete 48 weeks of therapy to remain on their same blinded treatment until approximately 2 months after the last enrolled subject completes 48 weeks on the study.

Inclusion Criteria

Concurrent Medication:

Allowed:

• PCP prophylaxis.

Patients must have:

• HIV infection.
• CD4 count 200 - 600 cells/mm3.
• Life expectancy of at least 24 weeks.
• Consent of parent or guardian if less than 18 years old.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Unexplained temperature >= 38.5 C for 7 consecutive days within 30 days prior to study entry.

PER AMENDMENT 1/25/96:

• A malignancy that requires systemic chemotherapies other than Kaposi's sarcoma.

Concurrent Medication:

Excluded:

• Concurrent other antiretroviral or immunologic agents.
• Other experimental therapies.
• Systemic corticosteroids (except as adjuvant therapy for acute PCP) and other immunosuppressive drugs.
• Systemic cytotoxic chemotherapy.
• Induction or maintenance with foscarnet or ganciclovir (oral or IV).

Patients with the following prior conditions are excluded:

• History of acute or chronic pancreatitis.
• History of grade 2 or higher peripheral neuropathy.

Prior Medication:

Excluded:

• Antiretrovirals within 90 days prior to study entry.
• More than 7 days total lifetime use of any antiretroviral nucleoside.