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Early Versus Delayed Treatment of HIV Infection

Zidovudine Should be Given Before Symptoms Develop

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Summary

An understanding of the virology and pathogenesis of HIV infection provides a rationale for initiating early intervention with antiretroviral drugs. Even at the earliest stages of infection when HIV-infected patients are asymptomatic, viral replication is ongoing, particularly in lymphoid tissues. Initiation of antiretroviral therapy can reduce viral replication and delay disease progression. A possible objection to early intervention therapy with zidovudine is the risk of selecting out resistant isolates of HIV, which would be difficult to treat. In practice, zidovudine-resistant isolates occur significantly less frequently in patients with early-stage disease compared with those with late-stage HIV infection, thus supporting the early use of zidovudine; in addition, alternative therapies, active against zidovudine-resistant isolates, are available.

Clinical trials with zidovudine in asymptomatic patients have differed in terms of length of follow-up, patient inclusion criteria, dosages and end-points. However, a number of conclusions are possible based on the results obtained: early intervention delays the progression to AIDS, delays the onset of symptomatic disease, has a favourable effect on surrogate markers of HIV infection and is well tolerated; it does not, however, seem to produce any benefit in terms of survival. It is this last point that has given rise to much of the controversy regarding early intervention with zidovudine in asymptomatic patients.

Since the disease is progressive in nature with persistent and high levels of viral replication and as prolonging the period of relative health and quality of life when the patient is asymptomatic is desirable, the choice to treat before symptoms develop would appear to be the optimal therapeutic strategy.

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References

  1. 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 Engl J Med 1987; 317: 185–91.

    Article  PubMed  CAS  Google Scholar 

  2. Richman DD, Fischl MA, Grieco MH, et al. The toxicity of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. N Engl J Med 1987; 317: 192–7.

    Article  PubMed  CAS  Google Scholar 

  3. 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: 437–43.

    Google Scholar 

  4. Fischl MA, Parker CB, Pettinelli C, et al. A randomized controlled trial of a reduced daily dose of zidovudine in patients with the acquired immunodeficiency syndrome. N Engl J Med 1990; 323: 1009–14.

    Article  PubMed  CAS  Google Scholar 

  5. 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.

    Article  PubMed  CAS  Google Scholar 

  6. 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.

    Article  PubMed  CAS  Google Scholar 

  7. 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 

  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.

    Article  PubMed  CAS  Google Scholar 

  9. Richman DD, Andrews J. Results of continued monitoring of participants in the placebo-controlled trial of zidovudine for serious human immunodeficiency virus infection. Am J Med 1988; 85: 208–13.

    PubMed  CAS  Google Scholar 

  10. Doumon E, Matheron S, Rozenbaum W, et al. Effects of zidovudine in 365 consecutive patients with AIDS or AIDS-related complex. Lancet 1988; 2: 1297–302.

    Google Scholar 

  11. Jackson GG, Paul DA, Falk LA, et al. Human immunodeficiency virus (HIV) antigenemia (p24) in the acquired immunodeficiency syndrome (AIDS) and the effect of treatment with zidovudine (AZT). Ann Intern Med 1988; 108: 175–80.

    PubMed  CAS  Google Scholar 

  12. Reiss P, Lange JM, Boucher CA, et al. Resumption of HIV antigen production during continuous zidovudine treatment Lancet 1988; 1: 421.

    Article  PubMed  CAS  Google Scholar 

  13. Larder BA, Darby G, Richman DD. HIV with reduced sensitivity to zidovudine (AZT) isolated during prolonged therapy. Science 1989; 243: 1731–4.

    Article  PubMed  CAS  Google Scholar 

  14. Boucher CA, Tersmette M, Lange JM, et al. Zidovudine sensitivity of human immunodeficiency viruses from high-risk symptom-free individuals during therapy. Lancet 1990; 336: 585–90.

    Article  PubMed  CAS  Google Scholar 

  15. Richman DD, Grimes JM, Lagakos SW. Effect 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 

  16. Embretson J, Zupanic M, Ribas JL, et al. Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS. Nature 1993; 362: 359–62.

    Article  PubMed  CAS  Google Scholar 

  17. Pantaleo G, Graziosi C, Demarest JF, et al. HIV infection is active and progressive in lymphoid tissue during the clinically latent stage of disease. Nature 1993; 362: 355–8.

    Article  PubMed  CAS  Google Scholar 

  18. Piatak M, Saag MS, Yang LC, et al. High levels of HIV-1 in plasma during all stages of infection determined by competitive PCR. Science 1993; 259: 1749–54.

    Article  PubMed  CAS  Google Scholar 

  19. Bagasra O, Pomerantz RJ. Human immunodeficiency virus type 1 provirus is demonstrated in peripheral blood monocytes in vivo: a study utilizing an in situ polymerase chain reaction. AIDS Res Hum Retroviruses 1993; 9: 69–76.

    Article  PubMed  CAS  Google Scholar 

  20. Patterson BK, Till M, Otto P, et al. Detection of HIV-1 DNA and messenger RNA in individual cells by PCR-driven in situ hybridization and flow cytometry. Science 1993; 259: 1749–54.

    Article  Google Scholar 

  21. Ho DD, Moudgil T, Alam M. Quantitation of human immunodeficiency virus type 1 in the blood of infected persons. N Engl J Med 1989; 321: 1621–5.

    Article  PubMed  CAS  Google Scholar 

  22. Coombs RW, Collier AC, Allain JP, et al. Plasma viremia in human immunodeficiency virus infection. N Engl J Med 1989; 321: 1626–31.

    Article  PubMed  CAS  Google Scholar 

  23. Pantaleo G, Graziosi C, Fauci A. The immunopathogenesis of human immunodeficiency virus infection. N Engl J Med 1993; 328: 327–35.

    Article  PubMed  CAS  Google Scholar 

  24. Fischl M, 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 

  25. Bartlett JA. Early versus delayed zidovudine in the management of HIV infection. Exp Opin Invest Drugs 1994; 3(8): 809–19.

    Article  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  27. Ho DD, Neumann AU, Perelson AS, et al. Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection. Nature 1995; 373: 123–6.

    Article  PubMed  CAS  Google Scholar 

  28. Choi S, Lagakos SW, Schooley RT, et al. CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine. Ann Intern Med 1993; 118: 674–80.

    PubMed  CAS  Google Scholar 

  29. 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 

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

    Article  PubMed  CAS  Google Scholar 

  31. Volberding PA, Lagakos SW, Grimes JM, et al. The effect of disease stage on the duration of zidovudine’s effect [abstract WS-B24-6]. IXth International Conference on AIDS; 1993 June 6–11; Berlin.

    Google Scholar 

  32. Sande MA, Carpenter CCJ, Cobbs CG, et al. Antiretroviral therapy for adult HIV-infected patients: recommendations from a state-of-the-art conference. JAMA 1993; 270: 2583–9.

    Article  PubMed  CAS  Google Scholar 

  33. Lambert JS, Seidlin M, Reichman RC, et al. 2’,3’-dideoxyinosine (ddl) in patients with the acquired immunodeficiency syndrome or AIDS-related complex: a phase I trial. N Engl J Med 1990; 322: 1333–40.

    Article  PubMed  CAS  Google Scholar 

  34. Yarchoan R, Perno CF, Thomas RV, et al. Phase I studies of 2’,3’-dideoxycytidine in severe human immunodeficiency virus infection as a single agent and alternating with zidovudine. Lancet 1988; 1: 76–81.

    Article  PubMed  CAS  Google Scholar 

  35. Browne MJ, Mayer KH, Chafee SBD, et al. 2’,3’-didehydro-3’ deoxythymidine (d4T) in patients with AIDS or AIDS-related complex: a phase I trial. J Infect Dis 1993; 167: 21–9.

    Article  PubMed  CAS  Google Scholar 

  36. 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: 581–7.

    Article  PubMed  CAS  Google Scholar 

  37. 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; 120: 360–8.

    PubMed  CAS  Google Scholar 

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Richman, D.D., Havlir, D. Early Versus Delayed Treatment of HIV Infection. Drugs 49 (Suppl 1), 9–16 (1995). https://doi.org/10.2165/00003495-199500491-00005

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