DRUG-RESISTANCE AND VIROLOGICAL RESPONSE IN NUCA-3001, A RANDOMIZED TRIAL OF LAMIVUDINE (3TC) VERSUS ZIDOVUDINE (ZDV) VERSUS ZDV PLUS 3TC IN PREVIOUSLY UNTREATED PATIENTS

Objective: To study the effect of HIV-1 resistance to lamivudine (3TC) and zidovudine (ZDV), and syncytium-inducing (SI) phenotype on virolo gic response to treatment with ZDV, 3TC, or ZDV plus 3TC in previously untreated individuals with HIV-1 infection. Design: A prospective vir ologic substudy of GlaxoWellcome protocol NUCA 3001. Methods: HIV-1 is olates obtained at study entry and at week 12 were expanded in periphe ral blood mononuclear cell (PBMC) culture, titered, and assayed for ph enotypic and genotypic evidence of resistance to ZDV and 3TC, and for syncytium formation on MT-2 cells. Results: Phenotypic and genotypic r esistance to 3TC was detected in the majority of HIV-1 isolates from p atients who received 3TC alone or in combination with ZDV. Despite sho wing 3TC resistance, subjects who received 3TC in combination with ZDV had significantly greater decreases in plasma HIV-1 RNA levels compar ed with those who received ZDV alone. Occurrence of the K70R ZDV resis tance mutation was significantly reduced in patients who received the 3TC/ZDV combination as compared with patients on ZDV monotherapy. Plas ma HIV-1 RNA returned to near-baseline levels more quickly in patients with SI isolates at study entry. Conclusions: Despite the rapid emerg ence of 3TC resistance, combination therapy with 3TC plus ZDV resulted in greater reduction in plasma HIV-1 RNA levels over 24 weeks as comp ared to ZDV monotherapy. Prevention of ZDV resistance may contribute t o the sustained activity of the combination therapy.