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Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)

The treatment of antiretroviral-naive subjects with the 3TC/zidovudine combination: a review of North American (NUCA 3001) and European (NUCB 3001) trials.

OBJECTIVE: The compound (-)-2',3'-dideoxy-3'-thiacytidine (3TC, lamivudine) is a nucleoside analogue with potent in vitro antiretroviral activity, synergy with zidovudine, activity against zidovudine-resistant isolates and minimal cytotoxicity. In early-phase studies, 3TC had a favourable pharmacokinetic profile, was well tolerated by those with HIV infection, and had a modest effect on HIV-1 p24 antigen levels. Although resistance to 3TC monotherapy develops rapidly, the activity of the drug persists. However, zidovudine-resistant virus, in which the 3TC-resistance mutation is selected for, regains phenotypic sensitivity to zidovudine. Therefore, 3TC and zidovudine are a logical combination to evaluate as initial therapy in treatment-naive HIV-1 infected individuals. DESIGN: Two randomized controlled trials, one in Europe and one in North America, evaluated 3TC in combination with zidovudine and compared this combination to zidovudine monotherapy. In the North American study, 3TC monotherapy was also evaluated. In both studies, subjects entered having received less than 4 weeks of zidovudine therapy and no other previous antiretroviral treatments. In the European study, subjects had CD4 cell counts of 100-400/mm3 and received blinded therapy for 24 weeks; they were then offered open-label 3TC and zidovudine for a further 24-week period. In the North American study, initial patient CD4 cell counts were 200-500/mm3, and blinded treatment continued for 52 weeks. Endpoints measured included CD4 cell counts and HIV-1 RNA in plasma, in addition to clinical and laboratory adverse events. RESULTS: In both studies, the combination of 3TC and zidovudine resulted in rises in CD4 counts of 75-85 cells/mm3 that were sustained at 48-60 cells/mm3 above base-line at 48-52 weeks. Effects on HIV-1 RNA levels in plasma also persisted through 48 and 52 weeks at approximately a 90% reduction (1 log10 decrease) from baseline. In the European study, the combination was superior to zidovudine alone over the first 24 weeks, as measured by CD4 and HIV-1 RNA effects, and the addition of 3TC to zidovudine after 24 weeks resulted in a subsequent increase in the mean CD4 count of 39 cells/mm3. In the North American study, the combination of 3TC and zidovudine was better than zidovudine monotherapy when considering the effect on CD4 cells or HIV-1 RNA through 24 weeks. When these treatment groups were compared, using an average of the mean change from baseline of the CD4 counts and HIV-1 RNA levels over that last three study time points (44, 48 and 52 weeks), the combination treatments remained superior to zidovudine alone. In neither study did the addition of 3TC to zidovudine result in additional toxicity. SUMMARY: In two independent studies in patients with limited antiretroviral treatment experience, remarkably similar results were obtained when 3TC/zidovudine in combination was compared to zidovudine monotherapy, demonstrating sustained antiretroviral and immunological effects of the combination over the 48 and 52 weeks of study.[1]


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