Once-Daily Quadruple-Drug Therapy With Adefovir Dipivoxil, Lamivudine, Didanosine, and Efavirenz in Treatment-Naive HIV Type 1-Infected Patients

Highly active antiretroviral therapy (HAART) has proved to be very effective in suppressing viral load, boosting immunologic function, and improving clinical outcome in HIV infection. However, because many regimens are complicated, disruptive, and involve high pill burdens, adherence is often challenging. The purpose of the Intercompany Collaboration for AIDS Drug Development Protocol 604 was to evaluate the efficacy, safety, and pharmacokinetics and adherence to a once-daily quadruple-drug antiretroviral regimen of adefovir dipivoxil, lamivudine, didanosine, and efavirenz in the treatment of antiretroviral-naive HIV-1-infected patients.

This 48-week, phase II, open-label, single-arm clinical trial was conducted between October 1998 and November 2000 at three US study centers. Eligible patients received once-daily doses of adefovir dipivoxil (one 60-mg tablet), lamivudine (two 150-mg tablets), didanosine (two 200-mg tablets; dose adjusted by weight), efavirenz (three 200-mg capsules), and L-carnitine (one 500-mg tablet to prevent adefovir-associated L-carnitine deficiency). Eleven patients (10 men, 1 woman) enrolled and completed the study. Eight were white; 2 were black; 1 was Native American. At baseline, the median plasma HIV-1 RNA level was 4.99 log10 copies/mL, and the median CD4 cell count was 471 cells/mm³.

At 24 and 48 weeks after initiation of treatment, median HIV-1 RNA levels decreased from baseline by 4.77 and 4.99 log10 copies/mL, respectively, and median CD4 cell counts increased by 135 and 177 cells/mm³, respectively.

A meta-analysis of 22 antiretroviral clinical efficacy trials showed that fewer than 50 percent of patients achieved HIV-1 RNA levels of less than 50 copies/mL at 48 weeks with triple-drug HAART. In contrast, the current study indicated that a once-daily quadruple-drug HAART regimen of adefovir dipivoxil, lamivudine, didanosine, and efavirenz provided better virologic suppression, with more than 90 percent of patients achieving HIV-1 RNA levels of less than 50 copies/mL by week 48. The consistently high overall adherence -- 85 percent -- may have accounted for this. Interestingly, 85 percent adherence with a protease inhibitor-containing triple-drug HAART regimen would be expected to result in poorer virologic response. Patients in the current study cited low pill burden and convenient dosing as enhancing adherence.

Other than adefovir nephrotoxicity in 7 patients, the quadruple-drug regimen was generally well-tolerated. This problem resolved without sequelae after adefovir was discontinued. No patient discontinued the study because of drug-related adverse events. This was expected, because the four drugs have no overlapping toxicities. Adefovir is no longer being developed as an anti-HIV agent; tenofovir disoproxil fumarate, a related once-daily nucleotide not associated with nephrotoxicity, has recently been approved for this indication. In future studies of once-daily quadruple-drug HAART with efavirenz, didanosine and lamivudine, replacement of adefovir with tenofovir disoproxil fumarate should be considered, the researchers recommended.

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