Ef®cacy, safety, and adherence with a twice-daily combination lamivudine/zidovudine tablet formulation, plus a protease inhibitor, in HIV infection Joseph J. Eron a , Ellen S. Yetzer b , Peter J. Ruane c , Stephen Becker d , Gosford A. Sawyerr e , Robin L. Fisher e , Jerry M. Tolson e and Mark S. Shaefer e Objective: A randomized, open-label, multicenter study to establish clinical equiva- lence (non-inferiority) of a regimen employing a lamivudine 150 mg/zidovudine 300 mg combination tablet, administered twice daily, plus a marketed protease inhibitor, compared with a conventional regimen of 150 mg lamivudine twice daily, 600 mg zidovudine daily, and a protease inhibitor, in antiretroviral-experienced pa- tients infected with HIV-1. Patients: Adults who were seropositive for HIV-1 infection with plasma HIV-1 RNA levels , 10 000 copies/ml (Roche Amplicor polymerase chain reaction assay, lower limit of quantitation (LLOQ) 400 copies/ml) and CD4 cell counts > 300 3 10 6 /l). All patients had been receiving the conventional lamivudine/zidovudine/protease inhibi- tor regimen for > 10 weeks immediately prior to the study. Intervention: Patients were randomized to the conventional regimen (n  113) or combination tablet regimen (n  110) for 16 weeks. The primary study endpoint was treatment failure, de®ned as an increase in HIV-1 RNA > 0.5 log 10 above baseline in patients with viral load . LLOQ at randomization and as HIV-1 RNA increasing to > 1250 copies/ml in patients with viral load , LLOQ at randomization. Results: The combination tablet regimen was associated with a 3.5% greater success rate than the conventional regimen (96.4 versus 92.9%), with four and eight patients failing treatment due to increases in HIV-1 RNA levels, respectively. The lower limit of the associated con®dence interval for the difference was 2.4%, which was well within the 10% margin prede®ned as clinically unimportant. This establishes the clinical equivalence (non-inferiority) of the combination tablet regimen to the conven- tional regimens regarding virologic response. The combination tablet and conven- tional regimens were similar with respect to percentage of patients maintaining HIV-1 RNA levels , LLOQ at the end of study or improving from baseline to undetectability (94 versus 91%; P  0.063), overall incidence of drug-related adverse events (21 versus 19%) ( P  0.868), and mean area under the curve for CD4 cell counts [treatment difference, 5.9 cells (95% con®dence interval, 15.8 to 27.6 3 10 6 cells/ l)]. A self-reported adherence questionnaire indicated that patients in the combination tablet group were less likely to miss doses of nucleoside analogue medication at weeks 8 ( P  0.007) and 16 ( P  0.046). From the a University of North Carolina, Chapel Hill, North Carolina, b Paci®c Oaks Research, Beverly Hills, c Tower Infectious Diseases, Los Angeles, d Paci®c Horizons Medical Group, San Francisco, California and e Glaxo Wellcome Inc., Research Triangle Park, North Carolina, USA. Note: ,The results of this study were presented in part in Abstract I-240 at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, California, 24±27 September 1998; in Abstract 387c at the 5th Conference on Retroviruses and Opportunistic Infections, Chicago, Illinois, 1±5 February 1998; and in Abstract 12220 at the XIIth World AIDS Conference, Geneva, Switzerland, 28 June ± 3 July 1998.. Correspondence to Joseph J. Eron, Jr., MD, Associate Director, General Clinical Research Center, Infectious Disease Division, Campus Box 7030, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599-7030, USA. Tel: 1 919 966 2536; fax: 1 919 966 6714; e-mail: jeron@med.unc.edu Received: 11 May 1999; revised: 15 December 1999; accepted: 22 December 1999. ISSN 0269-9370 & 2000 Lippincott Williams & Wilkins 671