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


Therapeutics

Dual maintenance therapy did not sustain suppression of viral replication in HIV-1 infection compared with prolonged reduction therapy

ACP J Club. 1999 Jan-Feb;130:14. doi:10.7326/ACPJC-1999-130-1-014


Source Citation

Reijers MH, Weverling GJ, Jurriaans S, et al. Maintenance therapy after quadruple induction therapy in HIV-1 infected individuals: Amsterdam Duration of Antiretroviral Medication (ADAM) study. Lancet. 1998 Jul 18;352:185-90.


Abstract

Question

After treatment with a quadruple induction regimen, can maintenance therapy with a dual antiretroviral regimen sustain suppression of viral replication in patients with HIV-1 infection?

Design

Randomized controlled trial with 36-week follow-up.

Setting

Outpatient clinics of tertiary care centers in the Netherlands.

Patients

31 patients with HIV-1 infection who were ≥ 18 years of age (mean age about 40 y, about 93% men); who had completed 26 weeks of induction therapy with stavudine, 40 mg 2 times/d or 30 mg 2 times/d if body weight was < 60 kg; lamivudine, 150 mg 2 times/d; saquinavir, 800 mg 3 times/d; and nelfinavir, 750 mg 3 times/d; and who had a plasma HIV-1 RNA level < 50 copies/mL at 24 and 25 weeks. Patients were eligible to receive induction therapy if they had CD4+ cell counts ≥ 200 cells/µL, plasma HIV-1 RNA levels ≥ 1000 copies/mL, and no previous exposure to antiretroviral drugs. Exclusion criteria included active opportunistic infection, active hepatitis C, or presence of hepatitis B surface antigen. Follow-up was 81%.

Intervention

After 26 weeks of induction therapy, 15 patients were allocated to prolonged induction therapy and 16 were allocated to maintenance regimens: stavudine and nelfinavir (n = 8) or saquinavir and nelfinavir (n = 8).

Main outcome measure

Detectable plasma HIV-1 RNA level ≥ 50 copies/mL at 36 weeks.

Main results

25 patients were followed for at least 36 weeks. More patients who received maintenance therapy (9 of 14, 64%) than patients who received prolonged induction therapy (1 of 11, 9%) had higher detectable plasma HIV-1 RNA levels { P = 0.012}* (Table); no difference existed between the 2 maintenance therapy groups { P = 1}*.

Conclusion

Compared with prolonged induction therapy, maintenance therapy with 2 drugs after a quadruple induction regimen did not sustain suppression of viral replication in patients with HIV-1 infection.

Sources of funding: Stichting AIDS Fonds and Dutch Ministry of Welfare, Public Health, and Sport.

For correspondence: Professor J.M. Lange, Department of Internal Medicine, National AIDS Therapy Evaluation Centre, Academic Medical Centre, University of Amsterdam, 1105 AZ Amsterdam, The Netherlands. FAX 31-20-691-8821.

*Calculated from data in article.


Table. Prolonged induction vs maintenance therapy in HIV-1 infection†

Outcome at 36 wk Induction Maintenance RRR (95% CI) NNT (CI)
Detectable HIV-1 RNA 9% 64% 86% (35 to 98) 2 (1 to 6)

†Abbreviations defined in Glossary; RRR, NNT, and CI calculated from data in article.


Commentary

The ADAM study provides timely information on an important clinical question in the management of HIV disease. Induction maintenance strategies need to be tested because of the difficulty most patients have in coping with combination therapy for prolonged periods. The ADAM study gives us both bad and good news. The bad news is that in most patients, a reduction from 4 to 2 antiretroviral agents was not adequate to suppress plasma HIV-1 RNA levels compared with maintenance of quadruple drug therapy. The good news is that if circulating HIV-1 RNA levels decrease rapidly, such a maintenance strategy is more likely to succeed. Although patients in both the induction and maintenance therapy groups had similar viral load measurements at baseline, the rate of decrease in viral load was important in predicting which patients would rebound when switched to maintenance therapy. Because drug-resistance assays were not done on patients in whom plasma HIV-1 RNA levels became detectable, it is premature to say whether the development of resistance, as opposed to inadequate suppression, was the reason for virologic rebound.

This study is the third induction maintenance trial to show the inadequacy of this approach (1, 2). However, the outcomes seen in these studies may not negate the effectiveness of other induction main-tenance approaches, such as reducing the number of drugs and switching to drugs of different classes at the time of reduction. Given the ongoing complexity of continuous use of 3 or 4 antiretroviral agents, further studies are needed to evaluate more subtle ways of improving long-term efficacy by reducing toxicity and adherence problems.

Don E. Smith, MB, CHB
University of New South WalesSydney, New South Wales, Australia


References

1. Raffi F, Pialoux G, Brun-Vezinet F, et al. Results of TRILEGE trial, a comparison of three maintenance regimens for HIV infected adults receiving induction therapy with zidovudine (ZDV), lamivudine (3TC) and indinavir (IDV). Fifth National Conference on Retroviruses and Opportunistic Infections, Chicago, USA, February 1-5, 1998:LB15 (abstract).

2. Havlir DV, Marschner IC, Hirsch M, et al. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. N Engl J Med. 1998;339:1261-8.