Skip to main content

Combination Antiretroviral Therapy

Back to the Future

Summary

HIV causes chronic infection and is associated with persistent viral replication and a high viral mutation rate. It is an illusion to think that monotherapy with any antiretroviral agent will have a major and lasting impact on this disease. Monotherapy with antitubercular agents led to dramatic improvements in treatment, but the development of drug resistance meant that these improvements were of only short duration, and hence it was concluded that drugs should be combined. The response to the limited efficacy of nucleoside analogue monotherapy in HIV infection has in many instances been the stance that ‘currently available antiretrovirals are no good; it is better not to treat’.

In addition, regulatory insistence on clinical end-points has also hampered antiretroviral drug development. It is implied that antiretrovirals must be tested in populations with fairly advanced HIV infection, in whom the least success may be expected. The regulatory bind has also resulted in artificial and counterproductive treatment guidelines.

Common sense and experience in infectious diseases dictate that treatment should hit hard and early. No study published thus far undermines the concept that early therapy is better than late therapy or that a tolerable combination of drugs with additive or synergistic anti-HIV activity is better than nucleoside monotherapy.

Promising data have been generated in trials on combinations of zidovudine plus didanosine or zalcitabine; a combination of zidovudine and lamivudine (3TC) may be even more promising. However, with 2-drug combinations there still is suboptimal suppression of HIV virus load. In vitro findings indicate that most 3-drug combinations are more effective at suppressing virus production than 2-drug combinations, and a good number of antiretroviral agents that could have a place in triple-drug regimens are available. Thus, we should proceed expeditiously with the clinical testing of triple-drug combinations. This can only be done efficiently in a systematic manner, in trials of limited size but with intensive virological and immunological monitoring and of sufficiently long duration. Only regimens that give the most profound and durable suppression of HIV virus load in such exploratory studies may be taken forward to be studied in large, clinical-end-point trials.

This is a preview of subscription content, access via your institution.

References

  1. 1.

    Mitsuya H, Broder S. Strategies for antiviral therapies in AIDS. Nature 1987; 325: 773–8.

    PubMed  Article  CAS  Google Scholar 

  2. 2.

    Meng T-C, Fischl MA, Boota AM, et al. Combination therapy with zidovudine and dideoxycytidine in patients with advanced human immunodeficiency virus infection. Ann Intern Med 1992; 116: 13–20.

    PubMed  CAS  Google Scholar 

  3. 3.

    Collier AC, Coombs RW, Fischl MA, et al. Combination therapy with zidovudine and didanosine compared to zidovudine alone in human immunodeficiency virus type one infection. Ann Intern Med 1993; 119: 786–93.

    PubMed  CAS  Google Scholar 

  4. 4.

    Yarchoan R, Lietzau JA, Nguyen B-Y, et al. A randomized pilot study of alternating or simultaneous zidovudine and didanosine therapy in patients with symptomatic human immunodeficiency virus infection. J Infect Dis 1994; 169: 9–17.

    PubMed  Article  CAS  Google Scholar 

  5. 5.

    Ragni M, Dafni R, Amato DA, et al. Combination zidovudine and dideoxyinosine in asymptomatic HIV(+) patients [abstract MoB 0055]. VIIIth International Conference on AIDS; 1992 July 19–24; Amsterdam.

    Google Scholar 

  6. 6.

    Schooley RT, Cooper DA, Lange JMA, et al. IVth European Conference on Clinical Aspects and Treatment of HIV Infection; 1994 Mar 16–18; Milan

  7. 7.

    Fischl MA, Richman DD, Grieco MH, et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex: a double-blind, placebo-controlled trial. N Eng J Med 1987; 317: 185–91.

    Article  CAS  Google Scholar 

  8. 8.

    Fischl MA, Richman DD, Causey DM, et al. Prolonged zidovudine therapy in patients with AIDS and advanced AIDS-related complex. JAMA 1989; 262: 2405–10.

    PubMed  Article  CAS  Google Scholar 

  9. 9.

    Fischl MA, Richman DD, Hansen N, et al. The safety and efficacy of zidovudine (AZT) in the treatment of patients with mildly symptomatic human immunodeficiency virus type 1 (HIV) infection: a double-blind, placebo-controlled trial. Ann Intern Med 1990; 112: 727–37.

    PubMed  CAS  Google Scholar 

  10. 10.

    Volberding PA, Lagakos SW, Koch MA, et al. Zidovudine in asymptomatic human immunodeficiency virus infection: a controlled trial in persons with fewer than 500 CD4-positive cells per cubic millimeter. N Engl J Med 1990; 322: 941–9.

    PubMed  Article  CAS  Google Scholar 

  11. 11.

    Hamilton JD, Hartigan PM, Simberkoff MS, et al. A controlled trial of early versus late treatment with zidovudine in symptomatic human immunodeficiency virus infection: results of the Veterans Affairs Cooperative Study. N Engl J Med 1992; 326: 437–43.

    PubMed  Article  CAS  Google Scholar 

  12. 12.

    Concorde Coordinating Committee. Concorde: MRC/ANRS randomised double-blind controlled trial of immediate and deferred zidovudine in symptom-free HIV infection. Lancet 1994; 343: 871–81.

    Article  Google Scholar 

  13. 13.

    Graham NMH, Zeger SL, Park LP, et al. Effect of zidovudine and Pneumocystis carinii pneumonia prophylaxis on progression of HIV-1 infection to AIDS. Lancet 1991; 338: 265–9.

    PubMed  Article  CAS  Google Scholar 

  14. 14.

    Graham NMH, Zeger SL, Park LP, et al. The effects on survival of early treatment of human immunodeficiency virus infection. N Engl J Med 1992; 326: 1037–42.

    PubMed  Article  CAS  Google Scholar 

  15. 15.

    Mulder JW, Cooper DA, Mathiesen L, et al. Zidovudine twice daily in asymptomatic subjects with HIV infection and a high risk of progression to AIDS 1994; 8: 313–21.

    CAS  Google Scholar 

  16. 16.

    Cooper DA, Gatell JM, Kroon S, et al. Zidovudine in persons with asymptomatic HIV infection and CD4+ cell/μl counts greater than 400 per cubic millimeter. N Engl J Med 1993; 329: 297–303.

    PubMed  Article  CAS  Google Scholar 

  17. 17.

    Kahn JO, Lagakos SW, Richman DD, et al. A controlled trial comparing continued zidovudine with didanosine in human immunodeficiency virus infection. N Engl J Med 1992; 327: 582–7.

    Article  Google Scholar 

  18. 18.

    Dolin R, Amato D, Fischl MA, et al. Zidovudine compared to didanosine in patients with advanced HIV-1 infection and little or no previous experience with zidovudine. Arch Intern Med. In press

  19. 19.

    Scott R, Follansbee S, Olson R, et al. Safety and tolerance of zalcitabine (ddc, HIV1D) in a double-blind, comparative trial (ACTG 114; N3300). IXth International Conference on AIDS; 1993 June 6–11; Berlin.

    Google Scholar 

  20. 20.

    Abrams DI, Goldman AI, Launer C, et al. A comparative trial of didanosine or zalcitabine after treatment with zidovudine in patients with human immunodeficiency virus infection. N Engl J Med 1994; 330: 657–62.

    PubMed  Article  CAS  Google Scholar 

  21. 21.

    Saah AJ, Hoover DR, He Y, et al. Factors influencing survival after AIDS; report from the Multicenter AIDS Cohort Study (MACS). J Acquir Immune Defic Syndr 1991; 4: 267–76.

    PubMed  Google Scholar 

  22. 22.

    Portegies P, de Gans J, Lange JMA, et al. Declining incidence of AIDS dementia complex after introduction of zidovudine treatment. Br Med J 1989; 299: 819–21.

    Article  CAS  Google Scholar 

  23. 23.

    Portegies P, Enting RH, de Gans J, et al. Presentation and course of AIDS dementia complex: 10 years of follow-up in Amsterdam, The Netherlands. AIDS 1993; 7: 669–75.

    PubMed  Article  CAS  Google Scholar 

  24. 24.

    Portegies P, Enting RH, de Jong MD, et al. AIDS dementia complex and didanosine Lancet 1994; 344: 759.

    PubMed  Article  CAS  Google Scholar 

  25. 25.

    Wu AW, Mathews WC, Brysk LT, et al. Quality of life in a placebo-controlled trial of zidovudine in patients with AIDs and AIDS-related complex. J Acquir Immune Defic Syndr 1990; 3: 683–90.

    PubMed  CAS  Google Scholar 

  26. 26.

    Lenderking WR, Gelber RD, Cotton DJ, et al. Evaluation of the quality of life associated with zidovudine treatment in asymptomatic human immunodeficiency virus infection. N Engl J Med 1994; 330: 738–43.

    PubMed  Article  CAS  Google Scholar 

  27. 27.

    Fischl MA, Stanley K, Collier AC, et al. Combination and monotherapy with zidovudine and zalcitabine in patients with advanced HIV disease. Ann Intern Med 1995; 122: 24–32.

    PubMed  CAS  Google Scholar 

  28. 28.

    Richman DO, Grimes JM, Lagakos SW. Effects of stage of disease and drug dose on zidovudine susceptibilities of isolates of human immunodeficiency virus. J Acquir Immune Defic Syndr 1990; 3: 743–6.

    PubMed  CAS  Google Scholar 

  29. 29.

    Vella S, Chiesi A, Dally, et al. Early increase in CD4+ count following AZT treatment predicts longer survival in symptomatic HIV disease [abstract PO-B26-2037]. IXth International Conference on AIDS; 1993 June 6–11; Berlin

    Google Scholar 

  30. 30.

    Katlama C, European Lamivudine Working Group. Combination 3TC (lamivudine)/ZDV (zidovudine) vs ZDV monotherapy in ZDV naïve HIV-1 positive patients with CD4 of 100–400 cells/mm3 [abstract no. 7.5]. AIDS 1994; 8 Suppl. 4: S6.

    Article  Google Scholar 

  31. 31.

    Staszewski S, European Lamivudine HIV Working Group. Combination 3TC (lamivudine)/ZDV (zidovudine) vs ZDV monotherapy in ZDV pre-treated HIV-1 positive patients with CD4 of 100–400 cells/mm3 [abstract no. 7.6]. AIDS 1994; 8 Suppl. 4: S7.

    Google Scholar 

  32. 32.

    Larder BA. The influence of combination therapy on HIV-1 viral load and drug resistance [abstract no. 5.1]. AIDS 1994; 8 Suppl. 4: S4.

    Article  Google Scholar 

  33. 33.

    Johnson VA, Barlow MA, Merrill DP, et al. Three-drug synergistic inhibition of HIV-1 replication in vitro by zidovudine, recombinant soluble CD4, and recombinant interferon-alpha A. J Infect Dis 1990; 161: 1059–67.

    PubMed  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Joep Lange.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Lange, J. Combination Antiretroviral Therapy. Drugs 49, 32–37 (1995). https://doi.org/10.2165/00003495-199500491-00008

Download citation

Keywords

  • Human Immunodeficiency Virus
  • Human Immunodeficiency Virus Type
  • Human Immunodeficiency Virus Infection
  • Lamivudine
  • Zidovudine