Study of Once Daily Elvucitabine Versus Lamivudine in Subjects With a Documented M184V Mutation (Resistance)

HIV-1 infected patients receiving long-term therapy with lamivudine or emtricitabine (nucleoside reverse transcriptase inhibitors [NRTIs]) are at risk for the development of a mutation at position M184 on the HIV reverse transcriptase gene. This mutation confers resistance to both drugs (> 100 fold increase in IC50).

In-vitro studies with elvucitabine have shown that HIV-1 isolates with the M184V mutation show only a 10-fold increase in IC50 as compared to wild type HIV-1. Achillion Pharmaceutical's intention is to demonstrate that 10 mg of elvucitabine, administered once per day for 14 days with continued background anti-HIV-1 medications, will demonstrate a fall in HIV-1 RNA plasma levels, as compared to baseline. The data from this study will guide dosing in future long-term studies in HIV-1 infected patients with the M184V mutation.

Protocol Title: A 14-Day, Randomized, Double-Blind, Comparative Viral Kinetic Study of Elvucitabine Versus Lamivudine Administered Once Daily to HIV-1 Infected Subjects With a Documented M184V Variant Protocol Number: ACH443-014A Clinical Phase: 2a Primary Objectives: • To assess the viral kinetics of 10 mg of elvucitabine administered once daily (QD) for 14 days in combination with background antiretroviral therapy in HIV-1-infected subjects with a documented M184V variant

• To demonstrate the antiviral activity of 10 mg of elvucitabine administered QD for 14 days in combination with background antiretroviral therapy as compared with lamivudine in combination with background antiretroviral therapy in HIV-1 infected subjects with a documented M184V variant
• To assess the safety of elvucitabine therapy in HIV-1 infected subjects with a documented M184V variant Number of Subjects: 20 Number of Study Centers: Multi-center study Study Population: HIV-1 infected subjects who are presently failing an antiretroviral therapy regimen containing lamivudine or emtricitabine, genotypically demonstrate a MI84V variant, and have an HIV RNA plasma level ≥ 2,000 and ≤ 150,000 copies/mL. Study Design: HIV-1 infected subjects, with a documented M184V variant, will be randomized to receive elvucitabine 10 mg QD or lamivudine 300 mg QD for 14 days. Subjects must be receiving a stable antiretroviral regimen (defined as no change in antiretroviral therapy for at least 4 weeks prior to randomization) that includes lamivudine or emtricitabine. At 72 hours prior to randomization, only lamivudine or emtricitabine will be stopped for washout; subjects will continue to receive the other drugs in their prescribed regimen (background antiretroviral therapy) during the 72-hour washout period. Subjects will then be randomized to receive blinded elvucitabine or lamivudine in a 1:1 ratio and continue to receive their prescribed background antiretroviral therapy for 14 days on an outpatient basis. Subjects will be followed for an additional 14 days post-treatment for safety, unless they enroll into the ACH443-018 extension study where they will continue to be treated and followed for safety.

• Drug: elvucitabine
  Elvucitabine 10 mg QD for 14days
• Drug: Lamivudine
  Lamivudine 300 mg QD for 14 days

• Experimental: A
  Intervention: Drug: elvucitabine
• Active Comparator: B
  Intervention: Drug: Lamivudine

Inclusion Criteria:

• Clinically stable HIV-1 infected patients
• Ages > 18 and < 65 years
• Documented M184V mutation
• CD4 cell count > 100 cells/mL
• Plasma HIV-1 RNA levels > 5000 and < 150,000 copies/mL
• Currently receiving lamivudine or emtricitabine
• Other hematologic and metabolic parameters must be met.
• Provide written informed consent
• Other inclusion criteria apply.

Exclusion Criteria:

• Hepatitis B antigen positive
• HIV-1 genotype positive for more than or equal to 4 protease mutations
• HIV-1 genotype positive for more than or equal to 2 non-nucleoside reverse transcriptase inhibitor (NNRTI) mutations
• Previous therapy with cytotoxic or myelosuppressive drugs in the past 3 months
• Evidence or history of cirrhosis
• Women who are pregnant or breast feeding
• Other exclusion criteria apply.