Safety and Efficacy of Lamivudine-Zidovudine Combination Therapy in Antiretroviral-Naive Patients

A Randomized Controlled Comparison With Zidovudine Monotherapy

Katlama, Christine MD
Ingrand, Didier MD
Loveday, Clive PhD
Clumeck, Nathan MD
Mallolas, Jose MD
Staszewski, Schlomo MD
Johnson, Margaret MD
Hill, Andrew M.
Pearce, Gill PhD
McDade, Hugh FRCP

For the Lamivudine European HIV Working Group.
From the Hospitalier Pitie Salpetriere, Paris, France (Drs Katlama and Ingrand); University College London (England) Medical School (Dr Loveday); St Pierre University Hospital, Brussels, Belgium (Dr Clumeck); Hospital Clinico y Provincial, Barcelona, Spain (Dr Mallolas); Klinikum der Johann Wolfgang Goethe Universitat, Frankfurt, Germany (Dr Staszewski); The Royal Free Hospital, London (Dr Johnson); and the Divisions of Biostatistics and Reporting (Mr Hill), and European Anti-viral Clinical Research (Drs Pearce and McDade), Glaxo Wellcome Research and Development, Greenford, England.

JAMA: The Journal of the American Medical Association 276(2):p 118-125, July 10, 1996.

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.

Design

Double-blind, randomized, multicenter, comparative trial of 129 patients throughout 24 weeks followed by 24 weeks of open-label lamivudine in combination with zidovudine.

Setting

Outpatients from 14 hospitals in Belgium, France, Germany, Spain, and the United Kingdom were enrolled within 6 months.

Patients

HIV-1-positive, antiretroviral-naive (<or= to 4 weeks prior zidovudine use) patients aged at least 18 years with CD4⁺ cell counts between 0.10x10⁹/L and 0.40x10⁹/L (100-400/microliters).

Intervention

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).

Main Outcome Measures

Efficacy was assessed by changes in CD4⁺ cell counts, beta₂ -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.

Results

Combination therapy showed superior treatment effects compared with monotherapy during the first 24 weeks as documented by changes in CD4⁺ cell counts (increase of 0.08x10 (⁹)/L vs 0.02x10⁹/L; P<.001), ICD p24 (-88% vs -49%; P=.04), cellular viremia (-1.27 vs -0.20 log₁₀ median tissue-culture infected dose [TCID₅₀ ] per 10⁶ 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 log₁₀ 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.

Conclusions

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.

JAMA.1996;276:118-125