Safety and efficacy of lamivudine-zidovudine combination therapy in zidovudine-experienced patients. A randomized controlled comparison with zidovudine monotherapy. Lamivudine European HIV Working Group
S. Staszewski, C. Loveday, J. J. Picazo, P. Dellarnonica, P. Skinhoj, M. A. Johnson, S. A. Danner, P. R. Harrigan, A. M. Hill, L. Verity and H. McDade
Klinikum der Johann Wolfgang Goethe Universitat, Frankturt, Germany.
OBJECTIVE--To compare the safety and efficacy of 2 doses of lamivudine
given in combination with zidovudine with continued zidovudine monotherapy.
DESIGN--Double-blind, randomized, multicenter, comparative trial of 223
patients treated for 24 weeks. SETTING--Patients from 32 hospitals in
Europe were enrolled throughout a 1-year period. PATIENTS--Adult human
immunodeficiency virus type 1 (HIV-1)-positive, zidovudine-experienced (
> or = 24 weeks prior zidovudine) patients with CD4+ cell counts between
0.10 and 0.40 x 10(9)/L (100-400 cells/microL). INTERVENTION--Patients
received either 200 mg of zidovudine every 8 hours, 150 mg of lamivudine
every 12 hours plus zidovudine, or 300 mg of lamivudine every 12 hours plus
zidovudine for 24 weeks. All patients were then allowed to receive
zidovudine and open-label lamivudine combination therapy. Twelve patients
withdrew because of adverse events during the 24-week treatment period.
MAIN OUTCOME MEASURES--Efficacy was measured by evaluating immunological
and viral load changes, and safety was assessed by evaluating clinical
manifestations and laboratory indexes of toxic effects. RESULTS--Patients
receiving low- or high-dose combination therapy had greater treatment
effects compared with patients receiving continued zidovudine monotherapy
during the first 24 weeks as documented by changes in CD4+ cell counts
(+0.04 vs +0.03 vs -0.02 x 10(9)/L, respectively; P < .001); log10 HIV-1
RNA as measured by the Roche assay (-0.96 vs -0.77 vs +0.07 copies/mL,
respectively; P < .001) or log10 HIV-1 RNA measured by the quantitative
nucleic acid sequence-based amplification assay (-0.59 vs -1.06 vs -0.02
copies/mL, respectively; P < .011); and immune-complex dissociated (ICD)
p24 antigen (-74% vs -68% vs +27%, respectively; P < .001). There were
no statistically significant differences in viral measurements, in CD4+
cell counts, or in safety profile between the groups receiving 2 doses of
lamivudine in combination with zidovudine. The effects on CD4+ cell counts
and ICD p24 antigen were sustained throughout 48 weeks for patients
continuing combination therapy. Patients switching to combination therapy
at week 24 showed improvement. CONCLUSION--In zidovudine-experienced
HIV-1-infected patients, combination treatment with lamivudine and
zidovudine is well tolerated and provides greater and more sustained
increases in CD4+ cell counts and decreases in viral load than continued
zidovudine monotherapy.
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Zhou et al.
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Metabolism of 2',3'-Dideoxy-2',3'-Didehydro-beta -L(-)-5-Fluorocytidine and Its Activity in Combination with Clinically Approved Anti-Human Immunodeficiency Virus beta -D(+) Nucleoside Analogs In Vitro
Dutschman et al.
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A Novel Polymorphism at Codon 333 of Human Immunodeficiency Virus Type 1 Reverse Transcriptase Can Facilitate Dual Resistance to Zidovudine and L-2',3'-Dideoxy-3'-Thiacytidine
Kemp et al.
J. Virol. 1998;72:5093-5098.
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Hammer et al.
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Recent advances: hiv infection–I
Cohn
BMJ 1997;314:487-487.
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A Trial Comparing Nucleoside Monotherapy with Combination Therapy in HIV-Infected Adults with CD4 Cell Counts from 200 to 500 per Cubic Millimeter
Hammer et al.
NEJM 1996;335:1081-1090.
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