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Therapeutics

Combination therapy was better than zidovudine alone for HIV infection

ACP J Club. 1997 Jan-Feb;126:6. doi:10.7326/ACPJC-1997-126-1-006


Source Citation

Delta Coordinating Committee. Delta: a randomised double-blind controlled trial comparing combinations of zidovudine plus didanosine or zalcitabine with zidovudine alone in HIV-infected individuals. Lancet. 1996 Aug 3;348:283-91.


Abstract

Objective

To determine whether zidovudine combined with didanosine (ddI) or zalcitabine (ddC) is more effective than zidovudine alone for reducing mortality and disease progression in patients with HIV infection.

Design

Randomized, double-blind, controlled trial with interim analyses.

Setting

175 centers in Europe and Australasia.

Patients

3207 adults (mean age 36.5 y, 85% men) with confirmed HIV infection were included if they had never taken zidovudine (n = 2124) or had taken it for ≥ 3 months (n = 1083). Exclusion criteria were AIDS with a CD4+ count ≥ 350/mm3, history of pancreatitis or peripheral neuropathy, combination chemotherapy for cancer, abnormal laboratory results, or previous use of antiretroviral drugs other than zidovudine. Follow-up was 99%.

Intervention

Patients were allocated to zidovudine alone, 600 mg/d (n = 1055; no previous zidovudine use, n = 700; previous use, n = 355); zidovudine and ddI, 400 mg/d (n = 1080; no previous zidovudine use, n = 718; previous use, n = 362); or zidovudine and ddC, 2.25 mg/d (n = 1072; no previous zidovudine use, n = 706; previous use, n = 366). Therapy was changed using a defined protocol if disease progressed or serious adverse events occurred.

Main outcome measures

Death and, in patients who did not have AIDS at entry, progression to AIDS or death.

Main results

The study was stopped early. After a median follow-up of 30 months, 74% of the patients had stopped blinded trial treatment, 699 patients (22%) had died, and 936 of 2765 (34%) who were free of AIDS at enrollment had either developed AIDS or died. Intention-to-treat analyses were done. Overall, both drug combinations improved survival when compared with zidovudine alone (hazard ratio [HR] for death for ddI combination vs zidovudine alone 0.67, 95% CI 0.56 to 0.80, and HR for ddC combination vs zidovudine alone 0.79, CI 0.66 to 0.94). For patients without previous zidovudine use, both drug combinations reduced the combined end point (death plus progression to AIDS), but when all patients were included, death and progression to AIDS were reduced only in the ddI combination group (HR 0.76, CI 0.65 to 0.89).

Conclusions

Combination therapy with zidovudine and either didanosine or zalcitabine reduced the death rate and progression to AIDS in patients with HIV infection better than zidovudine alone. The benefit was greatest in patients without previous zidovudine use.

Sources of funding: Australian National Council on AIDS; Agence Nationale de Recherches sur le SIDA (France); National Antiviral AIDS Project (Italy); Stichting AIDS Fonds (the Netherlands); Swiss Federal Office of Public Health; Medical Research Council (UK); Bristol-Myers Squibb; Roche; Glaxo-Wellcome.

For article reprint: Dr. J.H. Darbyshire, MRC HIV Clinical Trials Centre, UCLMS, Mortimer Market Centre, London WC1E 6AU, England, UK.


Commentary

The results of the Delta study and 2 similar studies from the AIDS Clinical Trials Group (ACTG175) (1) and the Community Programs for Clinical Research on AIDS (CPCRA007) (2) support the superiority of combination therapy over zidovudine monotherapy in the treatment of HIV infection. In all 3 studies, the benefit of combination therapy on survival was most obvious in patients without previous zidovudine use; less benefit was seen in patients previously treated. In the Delta trial, greater improvement in CD4+ counts and less disease progression occurred with the ddI combination than with the ddC combination.

No serious side effects occurred in the Delta study. It and the other studies of combination therapies had a high drug discon-tinuation rate for nonprotocol reasons.

Eleven antiretroviral agents are now available in the United States and Europe: nucleoside reverse transcriptase inhibitors (zidovudine, ddI, ddC, 3TC, d4T), nonnucleoside reverse transcriptase inhibitors (nevirapine, delavirdine, and loviride), and protease inhibitors (saquinavir, ritonavir, and indinavir). Clinical studies of combination regimens with protease inhibitors in advanced HIV disease have shown survival benefits and marked effects on the CD4+ cell count and viral load. The role of these combinations in initial therapy, however, has not been established; resistance may also develop, and important drug interactions complicate their use.

Timing of initiation of therapy, optimal drug combinations, duration of benefit, and when and how to switch drugs need further study. The clinical message, however, is clear: When a decision is made to initiate therapy, combination therapy should be started.

Philippa J. Easterbrook, MD
Chelsea and Westminster HospitalLondon, England, UK

Philippa J. Easterbrook, MD
Chelsea and Westminster Hospital
London, England, UK


References

1. Hammer SC, Katzenstein DA, Hughes MD, et al. N Engl J Med. 1996;335:1081-90.

2. Saravolatz LD, Winslow DL, Collins G, et al. N Engl J Med. 1996;335:1099-106.