Current issues of ACP Journal Club are published in Annals of Internal Medicine


Therapeutics

Didanosine benefited HIV-infected patients failing on zidovudine

ACP J Club. 1994 July-Aug;121:2. doi:10.7326/ACPJC-1994-121-1-002


Source Citation

Spruance SL, Pavia AT, Peterson D, et al. Didanosine compared with continuation of zidovudine in HIV-infected patients with signs of clinical deterioration while receiving zidovudine. A randomized, double-blind clinical trial. Ann Intern Med. 1994 Mar 1;120;360-8.


Abstract

Objective

To determine the benefits of switching to didanosine compared with continuing zidovudine in patients infected with the human immunodeficiency virus (HIV) who have previously used zidovudine and have signs of clinical deterioration.

Design

Randomized, double-blind, clinical trial with a median follow-up of 47 weeks.

Setting

Outpatient clinics at 19 tertiary care medical centers.

Patients

312 patients (mean age, 37 y; 96% men) who were seropositive for HIV, had the acquired immunodeficiency syndrome (AIDS) or AIDS-related complex, had received zidovudine for ≥ 6 months, had CD4+ cell counts ≤ 300/mL, and had signs of clinical deterioration within 12 weeks of study entry or a 50% decrease in CD4+ cells from the time of initiation of zidovudine therapy. Exclusion criteria were acute or chronic pancreatitis in the past 2 years, moderate-to-severe peripheral neuropathy, seizures requiring medication, or other serious complications.

Intervention

160 patients were allocated to receive zidovudine capsules, 600 mg/d, and 152 patients were allocated to receive didanosine buffered tablets, 600 mg/d, adjusted for weight. Patients also received placebo capsules or placebo tablets.

Main Outcome Measures

The primary study end points were death, a new AIDS-defining event, and the combination or 2 new or recurrent HIV-related diagnoses with a 50% decrease in CD4+ cells.

Main Results

Patients who continued to receive zidovudine had more primary study end points than those who switched to didanosine (82 [54%] vs. 67 [42%]; {95% CI for the 12% difference, 1% to 23%}[numbers calculated from data in article]). This benefit of switching to didanosine was consistent across subgroups of patients with either AIDS-related complex or AIDS and was most apparent in patients with a CD4+ cell count of ≥ 100/µL or those on zidovudine for > 12 months. The study groups did not differ when the end point was either the development of a new AIDS-defining diagnosis or death, or death alone.

Conclusion

Patients with HIV infection who showed clinical deterioration while receiving zidovudine had fewer HIV-related clinical events when treatment was changed to didanosine compared with those who continued to receive zidovudine.

Source of funding: In part, Bristol-Myers Squibb.

For article reprint: Dr. S.L. Spruance, University of Utah Health Sciences AIDS Center, MC 4B322, 50 North Medical Drive, Salt Lake City, UT 84132. FAX 801-585-3377.


Commentary

Zalcitabine was as effective as didanosine for zidovudine nonresponders

Previous studies have shown that patients who are clinically stable on zidovudine for at least 16 weeks have fewer AIDS-defining events or deaths if they are switched to didanosine (1). Spruance and colleagues studied patients taking zidovudine for at least 6 months with clinical deterioration in the final 12 weeks. Switching to didanosine decreased disease progression, with the greatest benefit seen in those with less advanced disease (CD4+ ≥ 100/mL) and a longer duration of zidovudine therapy (> 12 mo). This is consistent with the understanding that antiretroviral agents work less well in patients who are severely immunodeficient and that zidovudine-resistant HIV strains are detected within months of initiating zidovudine.

Zalcitabine has been shown to be beneficial in combination with zidovudine for patients with CD4+ counts < 300/mL (2). The study by Abrams and colleagues also lends support to zalcitabine use as monotherapy. In patients who are intolerant to or show disease progession while on zidovudine, zalcitabine was at least as effective as didanosine in preventing disease progression or death. The possibly lower death rate in the zalcitabine groups remains to be confirmed.

These studies assist us in many ways. First, they make us more comfortable switching from zidovudine to other antiretroviral agents in patients with adverse reactions or clinical progression. Second, the toxicity profiles shown by Abrams and colleagues help us choose between didanosine and zalcitabine as a second-line agent. Patients with preexisting neuropathies or poor oral hygiene may do better on didanosine. Zalcitabine may be a better choice in persons who have preexisting diarrhea. Previous episodes of pancreatitis, heavy alcohol ingestion, or concomitant intravenous pentamidine should also favor zalcitabine use because of the absence of cases of pancreatitis in the group receiving this drug.

Lastly, it is important to temper our optimism by noting that although the patients in both studies benefited from didanosine or zalcitabine, the rates of disease progression or death were 42% at a median of 47 weeks and 66% at a median of 64 weeks.

The finite benefits to reverse transcriptase monotherapy are becoming clearer. Although more studies will clarify the roles of these agents, giant steps in the control of HIV disease progression will probably be made through the use of agents that interfere at other stages in the HIV replicative cycle, such as protease inhibitors. In addition, the combined or alternating use of 2 or 3 reverse transcriptase inhibitors may prove more beneficial than monotherapy alone. Meanwhile, a cautious and organized use of reverse transcriptase inhibitors remains our only Food and Drug Administration-approved approach to the patient infected with HIV. Recently published guidelines that take into account the patient's clinical status and CD4 count are consistent with the 2 studies presented here (3). For now, the reverse transcriptase inhibitors provide a temporizing effect on disease progression and future research will define how best to improve our approach.

Fred A. Zar, MD
St. Francis Hospital Evanston, Illinois, USA