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Therapeutics

Ditiocarb sodium for reduction of opportunistic infections in AIDS

ACP J Club. 1991 July-Aug;115:5. doi:10.7326/ACPJC-1991-115-1-005


Source Citation

Hersh EM, Brewton G, Abrams D, et al. Ditiocarb sodium (diethyldithiocarbamate) therapy in patients with symptomatic HIV infection and AIDS. A randomized, double-blind, placebo-controlled, multicenter study. JAMA. Mar


Abstract

Objective

To evaluate the safety and efficacy of ditiocarb sodium for reduction of opportunistic infections in patients with symptomatic human immunodeficiency virus (HIV) infection and the acquired immunodeficiency syndrome (AIDS).

Design

Randomized, double-blind, placebo-controlled study of 24 weeks duration.

Setting

Ambulatory patients were treated at 8 medical centers.

Patients

HIV-positive patients without child-bearing potential were included if they had ≥ 3 of lymphadenopathy, fever, night sweats, weight loss, diarrhea, fatigue, thrush, hairy leukoplakia, or if they had AIDS with opportunistic infections or Kaposi sarcoma; and if they had ≥ 2 of the following: CD4+ count < 0.5 x 109/L, CD4+:CD8 + ratio < 0.5, hypergammaglobulinemia, or skin test anergy. There were 375 men and 12 women (age range, 18 to 63 years).

Intervention

Patients were randomized according to severity. After clinical and serologic evaluation, patients received 125-mg oral ditiocarb capsules, to be taken once weekly at a dose of 400 mg/m 2 of body surface area, or equivalent placebo. 191 patients were assigned to ditiocarb and 196 to placebo. Patients were required to stop other AIDS drugs except zidovudine for at least 4 weeks. Patients were evaluated every 4 weeks, with the exception of 9 patients (2%) who were not evaluated before 24 weeks.

Main outcome measures

Occurrences of new AIDS-defined opportunistic infections; occurrence or progression of Kaposi sarcoma; survival; effects on immune system responses; and adverse effects.

Main results

10 patients (5.2%) assigned to ditiocarb and 21 patients (11%) assigned to placebo developed new opportunistic infections (relative risk, 0.44 COLOR=GREEN>, P COLOR=RED>; P = 0.032). 21 of these were Pneumocystis carinii pneumonia infections (9 in the ditiocarb group and 12 in the placebo group). 4 patients in each group developed Kaposi sarcoma. Of patients with pre-existing Kaposi sarcoma, 4 of 10 on ditiocarb and 7 of 16 on placebo developed exacerbations. 8 patients in each treatment group died. There were no differences in immunologic measurements (CD4 + cell numbers, CD4+:CD8+ ratio, and skin test reactivity). There were no adverse reactions that could be clearly attributed to ditiocarb.

Conclusion

Ditiocarb sodium reduces the rate of opportunistic infections for at least 24 weeks in patients with symptomatic HIV infection and AIDS, without major adverse effects.

Sources of funding: Mérieux Institute and Pasteur Mérieux Sérums et Vaccins.

Address for article reprint: Dr. E.M. Hersh, Arizona Cancer Center, 1501 North Campbell Avenue, Tucson, AZ 85724.


Commentary

This intriguing trial purports to show that ditiocarb sodium lowers the rate of opportunistic infections in symptomatic HIV infection and in AIDS. The possibility of a relatively inexpensive, nontoxic agent with such effects that can be used in combination with existing antiretroviral agents is exciting and would represent an important advance in the treatment of HIV disease.

As the authors acknowledge, there is inadequate power to draw conclusions about important subgroups such as those with symptomatic HIV infection without AIDS and those receiving zidovudine. Moreover, the follow-up of only 6 months does not allow determination of whether the short-term reduction in infections translates into any survival benefit; it is not clear how many of the 16 deaths were preceded by opportunistic infections. Compliance was measured but not reported, and a number of patients were entered and analyzed who did not meet all the eligibility criteria (including some with active disease at entry).

It is of note that no significant effects on CD4+ counts were observed. This could be due to lack of a biologic effect or simply to inherent variability. In either case, if ditiocarb turns out to be an effective drug without such measurable effects, this would underscore the dangers implicit in the use of surrogate markers alone to evaluate promising new therapies.

Despite these shortcomings, this study suggests that ditiocarb may have a role in the treatment of AIDS. A longer-term study with a more clearly defined group of patients on current conventional therapy would add credibility to the adjunctive value of this drug, particularly for less advanced stages of HIV infection.

Martin T. Schechter, MD, PhD
The University of British Columbia Vancouver, British Columbia