Safety and efficacy of lamivudine-zidovudine combination therapy in antiretroviral-naive patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group

Objective. -To compare safety and efficacy of lamivudine-zidovudine combination therapy with zidovudine monotherapy in treating human immunodeficiency virus type 1 (HIV-1) -infected, antiretroviral therapy-naive patients. . -Double-blind, randomized, multicenter, comparative trial of 129 patients throughout 24 weeks followed by 24 weeks of open-label lamivudine in combination with zidovudine. . -Outpatients from 14 hospitals in Belgium, France, Germany, Spain, and the United Kingdom were enrolled within 6 months. . -HIV-1-positive, antiretroviral-naive (less than or equal to 4 weeks prior zidovudine use) patients aged at least 18 years with CD4 (+) cell counts between 0. 10 x 10 (9) /L and 0. 40 x 10 (9) /L (100-400/mu L). . -Patients received either 300 mg of lamivudine every 12 hours in combination with 200 mg of zidovudine every 8 hours for 24 weeks or zidovudine monotherapy for 24 weeks. All patients were then allowed to receive zidovudine in combination with open-label lamivudine (300 mg every 12 hours). Outcome Measures. -Efficacy was assessed by changes in CD4 (+) cell counts, beta (2) -microglobulin, neopterin, HIV-1 immune-complex dissociated (ICD) p24 antigenemia, and HIV-1 viral load. Safety was assessed by incidence of adverse clinical events and defined laboratory-measured toxic effects. . -Combination therapy showed superior treatment effects compared with monotherapy during the first 24 weeks as documented by changes in CD4 (+) cell counts (increase of 0. 08 x 10 (9) /L vs 0. 02 x 10 (9) /L, P<. 001), ICD p24 (-88% vs -49%; P=. 04), cellular viremia (-1. 27 vs -0. 20 log (10) median tissue-culture infected dose TCID50 per 10 (6) peripheral blood mononuclear cells; P=. 001), and viral load measured by HIV-1 RNA polymerase chain reaction using a Roche method (-1. 33 vs -0. 57 log (10) copies/mL; P=. 001) or an immune-capture method (-0. 6 vs -0. 14 log, , copies/mL; P=. 008). Observed changes were sustained to 48 weeks for patients continuing to receive combination therapy. Patients switching to receive combination therapy at week 24 showed improvements in CD4 (+) cell count and viral load to week 48. Mutation results suggested that mutations associated with zidovudine resistance may have developed more slowly over the first 24 weeks in patients receiving combination therapy. In contrast, mutations associated with lamivudine resistance appeared to develop rapidly, despite sustained antiviral treatment effect. However, the number of patients evaluated for genotypic changes was small, and confirmation of these results is needed in larger studies. No statistically significant differences in incidence or severity of clinically manifested or laboratory-measured toxic effects were noted between treatment groups. . -The combination of lamivudine and zidovudine results in a potent and sustained antiviral effect in antiretroviral-naive patients that is superior to that observed with zidovudine monotherapy.