Zidovudine twice daily in asymptomatic subjects with HIV infection and a high risk of progression to AIDS: a randomized, double-blind placebo-controlled study. The European-Australian Collaborative Group (Study 017)
OBJECTIVE
To evaluate the efficacy of zidovudine given twice daily in subjects with asymptomatic HIV-1 infection and a high risk of progression to AIDS.


METHODS
Randomized, double-blind placebo-controlled trial.


METHODS
Multicentre study in five European countries and Australia.


METHODS
Asymptomatic subjects (n = 329) with CD4 cell counts between 200 and 400 x 10(6)/l, or if > 400 x 10(6)/l, subjects with HIV p24 antigenaemia (> 10 pg/ml).


METHODS
Patients were randomly assigned to receive zidovudine 500 mg or placebo twice daily for 104 weeks, following a 250 mg four times daily dose regimen for the first 4 weeks.


METHODS
The primary end-point was the development of AIDS or severe AIDS-related complex (ARC). Before unblinding the study other end-points were defined: the development of Centers for Disease Control and Prevention (CDC) group IV disease (AIDS, severe ARC and other CDC stage IV disease) and the development of symptomatic HIV disease (AIDS, severe ARC, other CDC stage IV disease and minor HIV disease). Changes in CD4+ cell counts, p24 antigenaemia and toxicity were also reviewed.


RESULTS
Median treatment duration was 57 weeks for the placebo and 60 weeks for the zidovudine group, respectively. Progression to AIDS or severe ARC occurred in 17 placebo and 12 zidovudine recipients (log-rank P = 0.26). However, in the first of the 2 study years the rate of progression to AIDS or severe ARC was significantly higher in the placebo than in the zidovudine group. Zidovudine delayed progression to symptomatic HIV disease (P = 0.01); a trend in a delay in progression to CDC stage IV disease was observed (P = 0.08). Zidovudine recipients maintained CD4+ cell counts at or above baseline levels for longer than placebo recipients (P = 0.04). HIV p24-antigen levels decreased in the zidovudine group and returned to pretreatment levels by week 36. Substantial toxicity was not observed.


CONCLUSIONS
Zidovudine twice daily is effective in delaying progression to symptomatic HIV disease in high-risk, asymptomatic HIV-infected subjects. Modified definitions of clinical end-points may be useful for evaluating Phase III trials in comparable patient groups in the light of changes in the definition of AIDS and the increasing use of primary prophylaxis against opportunistic infections.
Mulder
J W
JW
Slotervaatziekenhuis, Department of Internal Medicine, Amsterdam, The Netherlands.
Cooper
D A
DA
Mathiesen
L
L
Sandström
E
E
Clumeck
N
N
Gatell
J M
JM
French
M
M
Donovan
B
B
Gray
F
F
Yeo
J M
JM
D000386:AIDS-Related Complex / Q000517:prevention & control; D000163:Acquired Immunodeficiency Syndrome / Q000517:prevention & control; D015496:CD4-Positive T-Lymphocytes; D004311:Double-Blind Method; D005060:Europe; D005260:Female; D016655:HIV Core Protein p24 / Q000097:blood; D015658:HIV Infections / Q000097:blood / Q000188:drug therapy* / Q000382:microbiology; D015497:HIV-1; D006801:Humans; D007958:Leukocyte Count; D008297:Male; D010349:Patient Compliance; D012307:Risk Factors; D012449:Safety; D013997:Time Factors; D015215:Zidovudine / Q000008:administration & dosage* / Q000009:adverse effects
D016655:HIV Core Protein p24; D015215:Zidovudine