Zidovudine dosage for AIDS and advanced HIV infection
ACP J Club. 1992 May-June;116:75. doi:10.7326/ACPJC-1992-116-3-075
Nordic Medical Research Councils' HIV Therapy Group. Double blind dose-response study of zidovudine in AIDS and advanced HIV infection. BMJ. 1992 Jan 4;304:13-7.
To compare the efficacy and side effects of 400 mg, 800 mg, and 1200 mg of zidovudine daily in patients with AIDS or advanced HIV infection.
Randomized, double-blind, multicenter trial from February 1988 through June 1990. Survival to 1 July 1991 was ascertained.
Hospital departments of infectious diseases and dermatology in Scandinavia.
The 474 patients recruited were aged ≥ 18 years, had AIDS, or current or previous symptomatic HIV-related infection including ≥ 1 of severe oral candidiasis or hairy leucoplakia, herpes zoster, extensive mucocutaneous herpes simplex, unexplained fever or diarrhea and weight loss. Other HIV-infected patients were enrolled if the investigators considered zidovudine use was indicated. Patients were excluded if they had a life expectancy of < 3 months, were potential drug users, or were pregnant or lactating. Survival status after a mean follow-up of 19 months was known for 99.5% of patients.
Patients were randomized to zidovudine, 400 mg (n = 160); 800 mg (n = 158); or 1200 mg (n = 156); taken as 3 identical capsules (either active drug or placebo) 4 times daily.
Main outcome measures
Mortality; incidence of new AIDS-related events; decline in CD4+ cell count; quality of life assessed by visual analog scale and Karnofsky score; incidence of hematologic adverse events.
The 3 treatment groups did not differ in mortality: 36 deaths (23%) compared with 36 (23%) and 30 (19%) for the 400-mg, 800-mg, and 1200-mg groups, respectively (P = 0.49; 95% CI for the difference in mortality between the 400-mg and 1200-mg groups, -5.6% to 12.2%). The average number of new AIDS-defining events per patient (including Pneumocystis carinii pneumonia, candidiasis, and Kaposi sarcoma) tended to increase with lower doses (mean new events, 0.74, 0.59, and 0.53 for the 400-mg, 800-mg, and 1200-mg groups, respectively; CI for difference between 400-mg and 1200-mg groups, -0.02 to 0.43 events; P > 0.2). The groups did not differ in quality of life scores or in decline in CD4+ cell count. Zidovudine was withdrawn in 28% of patients, mainly because of side effects. The incidence of moderate or severe adverse reactions (including anemia and leucopenia) was dose-related (58%, 63%, and 71% of patients for the groups, respectively; P = 0.01).
Zidovudine in a dose of 400 mg daily had equivalent efficacy to higher doses with fewer side effects in patients with AIDS or advanced HIV infection.
Source of funding: Nordic Medical Research Councils.
Address for article reprint: Dr. P.C. Gøtzsche, Department of Infectious Diseases, Rigshospitalet, DK-2200 Copenhagen N, Denmark.
There appear to be 3 major trends in the use of antiretroviral drugs for HIV infection. The first is toward use of these drugs earlier in the natural history of the infection; the second is toward evaluation of these drugs in combination or in alternating schedules; and the third is toward far lower doses than were first studied just a few years ago. The initial starting dose of zidovudine was 1500 mg per day. Later randomized trials showed that daily doses in the range of 500 to 600 mg were clinically effective at varying stages of HIV disease (1, 2). The present study largely confirms the dose-related toxicity of zidovudine and the efficacy of lower daily doses. Clinicians can now confidently prescribe doses in the range of 400 to 600 mg per day; even so, toxicity remains a significant problem. Over half the patients randomized to the 400-mg dose in the present study had moderate to severe adverse reactions.
A small study has shown that a low daily dose of 300 mg can achieve short-term improvements in surrogate markers (CD4 count, levels of antigenemia, plasma virus titers) equivalent to those obtained with higher doses (3). However, until efficacy is shown with clinical end points in a larger, longer trial, a dose of 300 mg/d should be reserved for exceptional circumstances.
Martin T. Schechter, MD, PhD
The University of British Columbia Vancouver, British Columbia