study of once daily elvucitabine versus lamivudine in participants with a documented m184v mutation

Conditions: HIV Infections

Summary: human immunodeficiency virus (hiv)-1 infected participants 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 the concentration of drug producing 50% inhibition \[ic50\]). 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. alexion pharmaceuticals inc. intention is to demonstrate that 10 milligrams (mg) of elvucitabine, administered once per day for 14 days with continued background anti-hiv-1 medications, will demonstrate a fall in hiv-1 ribonucleic acid (rna) plasma levels, as compared to baseline. the data from this study will guide dosing in future long-term studies in hiv-1 infected participants with the m184v mutation.

this was a phase 2a, 14-day randomized, double-blind, comparative viral kinetic study of10 mg elvucitabine as compared to lamivudine that was administered once daily (qd) to hiv-1 infected participants with a documented m184v variant. this study also demonstrated the antiviral activity as well as the assessment of safety of the elvucitabine therapy participants 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; participants will continue to receive the other drugs in their prescribed regimen (background antiretroviral therapy) during the 72-hour washout period. participants 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. participants will be followed for an additional 14 days post-treatment for safety unless they enroll in the ach443-018 extension study where they will continue to be treated and followed for safety.

Eligibility criteria:
inclusion criteria: * clinically stable hiv-1 infected participants * ages \>18 and \<65 years * documented m184v mutation * cd4 cell count \>100 cells/ml * plasma hiv-1 rna levels \>5000 and \<150,000 copies/milliliter (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.

Keywords: hiv-1 treatment experienced