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


Therapeutics

Combination nucleoside therapy or ddI alone delayed the progression of HIV infection compared with zidovudine alone

ACP J Club. 1997 May-Jun;126:64. doi:10.7326/ACPJC-1997-126-3-064

Related Content in this Issue
• Companion Abstract and Commentary: Combination nucleoside therapy was no better than zidovudine alone for advanced HIV infection


Source Citation

Hammer SM, Katzenstein DA, Hughes MD, et al., for the AIDS Clinical Trials Group Study 175 Study Team. A trial comparing nucleoside monotherapy with combination therapy in HIV-infected adults with CD4 cell counts from 200 to 500 per cubic millimeter. N Engl J Med. 1996 Oct 10;335:1081-90.


Abstract

Objective

To compare monotherapy with zidovudine or didanosine (ddI) with combination therapy (zidovudine plus ddI or zidovudine plus zalcitabine [ddC]) for disease progression in adults with HIV-1 infection and CD4+ cell counts of 200 to 500 cells/mm3.

Design

Randomized, double-blind, placebo-controlled trial with median follow-up of 143 weeks (AIDS Clinical Trials Group Study 175 [ACTG 175]).

Setting

43 AIDS Clinical Trials Units and 9 National Hemophilia Foundation sites in the United States and Puerto Rico.

Patients

2467 patients with HIV infection who were ≥ 12 years old (mean age 34.9 y, 82% men, 70% white, 57% with previous antiretroviral treatment, 65% homosexual men) and had a mean CD4+ cell count of 352 cells/mm3 and no history of an AIDS-defining illness.

Intervention

Patients were assigned to zidovudine alone (n = 619), zidovudine plus ddI (n = 613), zidovudine plus ddC (n = 615), or ddI alone (n = 620). Drug dosages were 200 mg 3 times/d for zidovudine, 200 mg 2 times/d for ddI, and 0.75 mg 3 times/d for ddC.

Main outcome measures

Disease progression (≥ 50% reduction in CD4+ cell counts, development of AIDS, or death).

Main results

Patients receiving zidovudine alone had a higher rate of disease progression than did patients in all other groups: 32% for zidovudine alone, 18% for zidovudine plus ddI, 20% for zidovudine plus ddC, and 22% for ddI alone (P < 0.001 for zidovudine alone vs other groups). For patients receiving zidovudine alone compared with patients receiving zidovudine plus ddI, {the absolute risk reduction (ARR) of 14% means that 8 patients would need to be treated (NNT) with zidovudine plus DDI (rather than zidovudine alone) for a median of 118 weeks to prevent 1 additional patient from reaching an end point (95% CI 6 to 12); the relative risk reduction (RRR) was 42%, CI 29% to 53%}*. For patients receiving zidovudine alone compared with patients receiving zidovudine plus ddC, {the ARR was 12%, the NNT was 9 (CI 6 to 14), and the RRR was 38% (CI 25% to 49%)}*. For patients receiving zidovudine compared with patients receiving ddI alone, {the ARR was 10%, the NNT was 11 (CI 7 to 21), and the RRR was 31% (CI 16% to 43%)}*. For patients receiving zidovudine plus ddC, the benefits were limited to patients without previous antiretroviral treatment. The groups did not differ for adverse events.

Conclusion

Zidovudine monotherapy was not as effective as combination therapy with didanosine or zalcitabine or didanosine monotherapy for delaying disease progression in patients with HIV infection.

Source of funding: National Institutes of Health.

For article reprint: Dr. S.M. Hammer, Division of Infectious Diseases, New England Deaconess Hospital, One Deaconess Road, Kennedy-6, Boston, MA 02215, USA. FAX 617-632-0766.

*Numbers calculated from data in article.


Commentary

The results of the trials by Hammer and Saravolatz and their colleagues should be considered with those of the recently published trial by the Delta Coordinating Committee (1). The overall results found by ACTG 175 are in general agreement with those found by the Delta Coordinating Committee and show that treatment with a combination of 2 nucleoside-analogue reverse-transcriptase inhibitors is more beneficial in decreasing disease progression and death than is treatment with zidovudine alone. These results have had a major effect on clinical practice; it is now a standard practice to treat patients with a combination of at least 2 nucleoside analogues.

The results of the study by Saravolatz and colleagues would seem to be at odds with those of ACTG 175. Major differences, however, are found in the patient population; this may have affected the overall results. As Corey and Holmes (2) state in an accompanying commentary, the study population in the trial by Saravolatz and colleagues included patients who had more advanced disease, received study treatment for a shorter period, had greater intolerance of study drugs, and were more likely to have taken zidovudine previously. When these differences are taken into account, the results of the 2 trials are comparable: In the trial by Saravolatz and colleagues, treatment with zidovudine and ddI consistently delayed disease progression compared with treatment with zidovudine alone throughout the study period, and the incidence of certain opportunistic infections was significantly lower. In a subgroup analysis of patients who previously had limited anti-retroviral experience or were inexperienced at entry, a benefit from combination therapy compared with zidovudine monotherapy was shown.

Both trials make it clear that the addition of ddC to zidovudine in patients with extensive previous use of zidovudine is not an appropriate treatment strategy. The addition of ddI to current zidovudine therapy was, however, beneficial in zidovudine-experienced patients. The results of recent trials suggest that a more appropriate clinical strategy might include the more potent protease inhibitors, especially in patients with advanced disease (3). Preliminary evidence shows that the addition of (or switching to) a potent protease inhibitor combined with a new nucleoside analogue may be effective (4).

One outcome of ACTG 175 that clinicians will find difficult to explain and that differs from the results of a previous trial (5) is the similar benefits seen with ddI monotherapy compared with zidovudine plus ddI. The relatively high incidence of zidovudine mutations present at baseline in the antiretroviral-inexperienced patients reported in a subset of patients in this study (6) may help to explain this result and account for the lower-than-expected rise in CD4+ cell count in patients in the zidovudine monotherapy group. Because of the greater effect that combination therapies have on surrogate markers and the general agreement from the results of other trials of the clinical benefit of combination therapies, most clinicians would not accept using ddI monotherapy as standard therapy when starting treatment for HIV infection.

It was not the intention of these trials to ascertain the optimum time to start anti-retroviral treatment. This remains uncertain with the treatments that are currently available. Limited efficacy of therapies (although clearly improved), drug intolerance, and poor compliance remain important issues in deciding when to start treatment. Little doubt exists, however, that the results of trials of combination therapies have given both the patient and physician more confidence about initiating treatment. I hope that the results from clinical trials of more potent combination regimens will further improve clinical effectiveness.

Ian G. Williams, MB, ChB
University College London Medical SchoolLondon, England, UK

Ian G. Williams, MB, ChB
University College London Medical School
London, England, UK


References

1. The Delta Coordinating Committee. Lancet. 1996;348:283-91.

2. Corey L, Holmes K. N Engl J Med. 1996; 335:142-4.

3. Cameron DW, Heath-Chiozzi M, Kravcik S, et al. Abstracts of the 11th International Conference on AIDS, Vancouver, BC, July 7-12, 1996:24.

4. Gulick R, Mellors J, Havlir D, et al. Abstracts of the 11th International Conference on AIDS, program supplement, Vancouver, BC, July 7-12, 1996:19.

5. Dolin R, Amatod DA, Fischl MA, et al. Arch Intern Med. 1995;155:961-74.

6. Rey D, Pi T, Diehl LJ, et al. In 5th International Workshop on HIV Drug Resistance, Whistler, BC, July 3-6, 1996:38.