Although some individuals maintain that treatment with zidovudine (AZT) has compounded the AIDS epidemic (Duesberg, 1992), published reports of both placebo-controlled clinical trials and observational studies provide data to the contrary (Table 4).

Table 4. Major placebo-controlled trials of zidovudine (AZT) monotherapy in HIV-infected patients without AIDS

Asymptomatic HIV infection
Study	Reference	CD4+ T cell count at study entry (cells/mm3)	Daily dose zidovudine (milligrams)	Avg. Duration of follow-up (months)	Number in analysis ZDV/imm/ P/def	No. progressing to AIDS or death ZDV/imm/ P/def
ACTG 019‡	Volberding, 1990	<500	1500 500	13	457,453/428	14,11/33
-	Volberding, 1994 (extended follow-up)	<500	1500 500	31	530,542/493	75,79/78
EACG 020	Cooper, 1993	<400	1000	21	495/489	6/9
ACTG 036	Merigan, 1991	<=500	1500	10	92/101	3/6
EA hemophilia	Mannucci, 1994	100-400†	1000	21	69/71	5/4
EACG 017	Mulder, 1994	200-400†	1000	14	167/162	11/12
Concorde	Concorde, 1994	any	1000	36	877/872	176/171

The Concorde trial and VA 298 compared immediate (imm) and deferred (def) use of zidovudine (ZDV); the other trials compared zidovudine (ZDV) and placebo (P).
† Or p24 antigenemia.
‡ In ACTG 019, original treatment group included placebo, 500 mg. ZDV/day or 1500 mg. ZDV/day.
After the unblinding of the original randomized trial in 1989, subjects in each original arm were offered a daily dose of 500 mg. open-label zidovudine.

Modified from Concorde Coordinating Committee, 1994.

In patients with symptomatic HIV disease, for whom a beneficial effect is measured in months, AZT appears to slow disease progression and prolong life, according to double-blind, placebo-controlled clinical studies (reviewed in Sande et al., 1993; McLeod and Hammer, 1992; Volberding and Graham, 1994). A clinical trial known as BW 002 compared AZT with placebo in 282 patients with AIDS or advanced signs or symptoms of HIV disease. In this study, which led to the approval of AZT by the FDA, only one of 145 patients treated with AZT died compared with 19 of 137 placebo recipients in a six month period. Opportunistic infections occurred in 24 AZT recipients and 45 placebo recipients. In addition to reducing mortality, AZT was shown to have reduced the frequency and severity of AIDS-associated opportunistic infections, improved body weight, prevented deterioration in Karnofsky performance score, and increased counts of CD4+ T lymphocytes in the peripheral blood (Fischl et al., 1987; Richman et al., 1987). Continued follow-up in 229 of these patients showed that the survival benefit of AZT extended to at least 21 months after the initiation of therapy; survival in the original treatment group was 57.6 percent at that time, whereas survival among members of the original placebo group was 51.5 percent at nine months (Richman and Andrews, 1988; Fischl et al., 1989).

In another placebo-controlled study known as ACTG 016, which enrolled 711 symptomatic HIV-infected patients with CD4+ T cell counts between 200 and 500 cells/mm3, those taking AZT were less likely to experience disease progression than those on placebo during a median study period of 11 months (Fischl et al., 1990). In this study, no difference in disease progression was noted among participants who began the trial with CD4+ T cell counts greater than 500/mm3.

A Veteran's Administration study of 338 individuals with early symptoms of HIV disease and CD4+ T cell counts between 200 and 500 cells/mm3 found that immediate therapy significantly delayed disease progression compared with deferred therapy, but did not lengthen (or shorten) survival after an average study period of more than two years (Hamilton et al., 1992).

Among asymptomatic HIV-infected individuals, several placebo-controlled clinical trials suggest that AZT can delay disease progression for 12 to 24 months but ultimately does not increase survival. Significantly, long-term follow-up of persons participating in these trials, although not showing prolonged benefit of AZT, has never indicated that the drug increases disease progression or mortality (reviewed in McLeod and Hammer, 1992; Sande et al., 1993; Volberding and Graham, 1994). The lack of excess AIDS cases and death in the AZT arms of these large trials effectively rebuts the argument that AZT causes AIDS.

During a 4.5 year follow-up period (mean 2.6 years) of a trial known as ACTG 019, no differences were seen in overall survival between AZT and placebo groups among 1,565 asymptomatic patients entering the study with fewer than 500 CD4+ T cells/mm3 (Volberding et al., 1994). In that study, AZT was superior to placebo in delaying progression to AIDS or advanced ARC for approximately one year, and a more prolonged benefit was seen among a subset of patients.

The Concorde study in Europe enrolled 1,749 asymptomatic patients with CD4+ T cell counts less than 500/mm3. In that study, no statistically significant differences in progression to advanced disease were observed after three years between individuals taking AZT immediately and those who deferred AZT therapy or did not take the drug (Concorde Coordinating Committee, 1994). However, the rate of progression to death, AIDS or severe ARC was slower among the "immediate" AZT group during the first year of therapy. Although the Concorde study did not show a significant benefit over time with the early use of AZT, it clearly demonstrated that AZT was not harmful to the patients in the "immediate" AZT group as compared to the "deferred" AZT group.

A European-Australian study (EACG 020) of 993 patients with CD4+ T cell counts greater than 400/mm3 showed no differences between AZT and placebo arms of the trial during a median study period of 94 weeks, although AZT did delay progression to certain clinical and immunological endpoints for up to three years (Cooper et al., 1993). Both this study and the Concorde study reported little severe AZT-related hematologic toxicity at doses of 1,000 mg/day, which is twice the recommended daily dose in the United States.

Uncontrolled studies have found increased survival and/or reduced frequency of opportunistic infections in patients with HIV disease and AIDS who were treated with AZT or other anti-retrovirals (Creagh-Kirk et al., 1988; Moore et al., 1991a,b; Ragni et al., 1992; Schinaia et al., 1991; Koblin et al., 1992; Graham et al., 1991, 1992, 1993; Longini, 1993; Vella et al., 1992, 1994; Saah et al., 1994; Bacellar et al., 1994). In the Multicenter AIDS Cohort Study, for example, HIV-infected individuals treated with AZT had significantly reduced mortality and progression to AIDS for follow-up intervals of six, 12, 18 and 24 months compared to those not taking AZT, even after adjusting for health status, CD4+ T cell counts and PCP prophylaxis (Graham et al., 1991, 1992).

In addition, several cohort studies show that life expectancy of individuals with AIDS has increased since the use of AZT became common in 1986-87. Among 362 homosexual men in hepatitis B vaccine trial cohorts in New York City, San Francisco and Amsterdam, the time from seroconversion to death, a period not influenced by variations in diagnosing AIDS, has lengthened slightly in recent years (Hessol et al., 1994). In a Dutch study of 975 males and females with HIV infection, median survival with AIDS increased from nine months in 1982-1985, to 26 months in 1990 (Bindels et al., 1994). Even taking into consideration the benefits of improved PCP prophylaxis and treatment, if AZT were contributing to or causing disease, one would expect a decrease in survival figures, rather than an increase that parallels the use of AZT.

In an analysis from the San Francisco Men's Health Study, the investigators note that 169 (73 percent) of 233 AIDS patients had been treated with AZT at one time or another. However, 90 (53 percent of the 169) were diagnosed with clinical AIDS before beginning AZT treatment, and another 51 (30 percent of the 169) had CD4+ T cell counts lower than 200/mm3 before initiation of AZT treatment (Ascher et al., 1995). The authors conclude, "These data are not consistent with the hypothesis of a causal role for AZT in AIDS."