Skip to main content

Advertisement

SpringerLink
Log in

Structured treatment interruption: Approaches and risks

  • Published:
Current Infectious Disease Reports Aims and scope Submit manuscript

Abstract

Although highly active antiretroviral therapy suppresses HIV replication resulting in extraordinary clinical benefits, toxicity, adherence difficulties, and the monetary cost of medications limit the long-term effectiveness and availability of therapy for many HIV-infected individuals. Strategies to interrupt therapy have been proposed as a means to enhance the sustainability of antiretroviral treatment. Widely different approaches with varied patient populations, theoretical concepts, and clinical designs are frequently lumped together as "structured treatment interruptions." This review summarizes the approaches and risks of treatment interruptions in HIV infection. Currently, none of these strategies can be recommended in standard clinical practice.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References and Recommended Reading

  1. Chun TW, Stuyver L, Mizell SB, et al.: Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy. Proc Natl Acad Sci U S A 1997, 94:13193–13197.

    Article  PubMed  CAS  Google Scholar 

  2. Natarajan V, Bosche M, Metcalf JA, et al.: HIV-1 replication in patients with undetectable plasma virus receiving HAART. Highly active antiretroviral therapy. Lancet 1999, 353:119–120.

    Article  PubMed  CAS  Google Scholar 

  3. Furtado MR, Callaway DS, Phair JP, et al.: Persistence of HIV-1 transcription in peripheral-blood mononuclear cells in patients receiving potent antiretroviral therapy. N Engl J Med 1999, 340:1614–1622.

    Article  PubMed  CAS  Google Scholar 

  4. Zhang L, Ramratnam B, Tenner-Racz K, et al.: Quantifying residual HIV-1 replication in patients receiving combination antiretroviral therapy. N Engl J Med 1999, 340:1605–1613.

    Article  PubMed  CAS  Google Scholar 

  5. Davey RT, Bhat N, Yoder C, et al.: HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression. Proc Natl Acad Sci U S A 1999, 96:15109–15114. To understand and rationally design treatment interruption strategies in chronic HIV infection it is essential to be familiar with the kinetics of HIV rebound following interruption of HAART, as well as the rate at which one would predict a return to suppression of plasma viremia in many patients. It is also important to know the likely decline in CD4+ T-cell counts. These authors provide a comprehensive analysis of virologic and immunologic parameters following a single interruption and resumption of HAART in individuals with chronic HIV infection with less than 50 copies/mL of plasma HIV RNA prior to interrupting antiretroviral therapy.

    Article  PubMed  CAS  Google Scholar 

  6. Garcia F, Plana M, Vidal C, et al.: Dynamics of viral load rebound and immunological changes after stopping effective antiretroviral therapy. AIDS 1999, 13:F79-F86.

    Article  PubMed  CAS  Google Scholar 

  7. Neumann AU, Tubiana R, Calvez V, et al.: HIV-1 rebound during interruption of highly active antiretroviral therapy has no deleterious effect on reinitiated treatment. Comet Study Group. AIDS 1999, 13:677–683.

    Article  PubMed  CAS  Google Scholar 

  8. Hatano H, Vogel S, Yoder C, et al.: Pre-HAART HIV burden approximates post-HAART viral levels following interruption of therapy in patients with sustained viral suppression. AIDS 2000, 14:1357–1363.

    Article  PubMed  CAS  Google Scholar 

  9. Behrens G, Dejam A, Schmidt H, et al.: Impaired glucose tolerance, beta cell function and lipid metabolism in HIV patients under treatment with protease inhibitors. AIDS 1999, 13:F63-F70.

    Article  PubMed  CAS  Google Scholar 

  10. Heath KV, Hogg RS, Chan KJ, et al.: Lipodystrophy-associated morphological, cholesterol and triglyceride abnormalities in a population-based HIV/AIDS treatment database. AIDS 2001, 15:231–239.

    Article  PubMed  CAS  Google Scholar 

  11. Fortgang IS, Belitsos PC, Chaisson RE, Moore RD: Hepatomegaly and steatosis in HIV-infected patients receiving nucleoside analog antiretroviral therapy. Am J Gastroenterol 1995, 90:1433–1436.

    PubMed  CAS  Google Scholar 

  12. Kopp JB, Miller KD, Mican JA, et al.: Crystalluria and urinary tract abnormalities associated with indinavir. Ann Intern Med 1997, 127:119–125.

    PubMed  CAS  Google Scholar 

  13. Miller KD, Jones E, Yanovski JA, et al.: Visceral abdominal-fat accumulation associated with use of indinavir. Lancet 1998, 351:871–875.

    Article  PubMed  CAS  Google Scholar 

  14. Mulligan K, Grunfeld C, Tai VW, et al.: Hyperlipidemia and insulin resistance are induced by protease inhibitors independent of changes in body composition in patients with HIV infection. J Acquir Immune Defic Syndr 2000, 23:35–43.

    PubMed  CAS  Google Scholar 

  15. Periard D, Telenti A, Sudre P, et al.: Atherogenic dyslipidemia in HIV-infected individuals treated with protease inhibitors. The Swiss HIV Cohort Study. Circulation 1999, 100:700–705.

    PubMed  CAS  Google Scholar 

  16. Thiebaut R, Daucourt V, Mercie P, et al.: Lipodystrophy, metabolic disorders, and human immunodeficiency virus infection: Aquitaine Cohort, France, 1999. Groupe d’Epidemiologie Clinique du Syndrome d’Immunodeficience Acquise en Aquitaine. Clin Infect Dis 2000, 31:1482–1487.

    Article  PubMed  CAS  Google Scholar 

  17. Aboulafia DM: Acute pancreatitis. A fatal complication of AIDS therapy. J Clin Gastroenterol 1997, 25:640–645.

    Article  PubMed  CAS  Google Scholar 

  18. ter Hofstede HJ, de Marie S, Foudraine NA, et al.: Clinical features and risk factors of lactic acidosis following longterm antiretroviral therapy: 4 fatal cases. Int J STD AIDS 2000, 11:611–616.

    Article  PubMed  Google Scholar 

  19. Ickovics JR, Meisler AW: Adherence in AIDS clinical trials: a framework for clinical research and clinical care. J Clin Epidemiol 1997, 50:385–391.

    Article  PubMed  CAS  Google Scholar 

  20. Binswanger HP: Public health. HIV/AIDS treatment for millions. Science 2001, 292:221–223.

    Article  PubMed  CAS  Google Scholar 

  21. Miller V, Sabin C, Hertogs K, et al.: Virological and immunological effects of treatment interruptions in HIV-1 infected patients with treatment failure. AIDS 2000, 14:2857–2867.

    Article  PubMed  CAS  Google Scholar 

  22. Deeks SG, Wrin T, Liegler T, et al.: Virologic and immunologic consequences of discontinuing combination antiretroviraldrug therapy in HIV-infected patients with detectable viremia. N Engl J Med 2001, 344:472–480. These authors provide an important evaluation of the likely increase in plasma HIV RNA and decrease in CD4+ T-cell counts following treatment interruption in salvage therapy. They also demonstrate the shift in plasma HIV RNA from drug-resistant HIV to drug-sensitive HIV. However, they show also that drug-resistant HIV remains archived in peripheral blood mononuclear cells.

    Article  PubMed  CAS  Google Scholar 

  23. Deeks SG, Wrin T, Hoh R, et al.: Response to salvage therapy in patients undergoing a structured treatment interruption [abstract 292]. In 8th Conference on Retroviruses and Opportunistic Infections. Chicago. February 4–8, 2001.

  24. Delaugerre C, Valantin MA, Mouroux M, et al.: Re-occurrence of HIV-1 drug mutations after treatment re-initiation following interruption in patients with multiple treatment failure. AIDS 2001, 15:2189–2191.

    Article  PubMed  CAS  Google Scholar 

  25. Koup RA, Safrit JT, Cao Y, et al.: Temporal association of cellular immune responses with the initial control of viremia in primary human immunodeficiency virus type 1 syndrome. J Virol 1994, 68:4650–4655.

    PubMed  CAS  Google Scholar 

  26. Schmitz JE, Kuroda MJ, Santra S, et al.: Control of viremia in simian immunodeficiency virus infection by CD8+ lymphocytes. Science 1999, 283:857–860.

    Article  PubMed  CAS  Google Scholar 

  27. Matano T, Shibata R, Siemon C, et al.: Administration of an anti-CD8 monoclonal antibody interferes with the clearance of chimeric simian/human immunodeficiency virus during primary infections of rhesus macaques. J Virol 1998, 72:164–169.

    PubMed  CAS  Google Scholar 

  28. Rosenberg ES, Billingsley JM, Caliendo AM, et al.: Vigorous HIV-1-specific CD4+ T cell responses associated with control of viremia. Science 1997, 278:1447–1450.

    Article  PubMed  CAS  Google Scholar 

  29. Rosenberg ES, Altfeld M, Poon SH, et al.: Immune control of HIV-1 after early treatment of acute infection. Nature 2000, 407:523–526. This important proof-of-concept study provides insight into potential mechanisms of the immune control of HIV infection in individuals who initiated HAART during HIV infection who subsequently control plasma viremia following one or more treatment interruptions.

    Article  PubMed  CAS  Google Scholar 

  30. Pitcher CJ, Quittner C, Peterson DM, et al.: HIV-1-specific CD4+ T cells are detectable in most individuals with active HIV-1 infection, but decline with prolonged viral suppression. Nat Med 1999, 5:518–525.

    Article  PubMed  CAS  Google Scholar 

  31. Betts MR, Ambrozak DR, Douek DC, et al.: Analysis of total human immunodeficiency virus (HIV)-specific CD4(+) and CD8(+) T-cell responses: relationship to viral load in untreated HIV infection. J Virol 2001, 75:11983–11991.

    Article  PubMed  CAS  Google Scholar 

  32. Ortiz GM, Nixon DF, Trkola A, et al.: HIV-1-specific immune responses in subjects who temporarily contain virus replication after discontinuation of highly active antiretroviral therapy. J Clin Invest 1999, 104:R13-R18.

    Article  PubMed  CAS  Google Scholar 

  33. Kalams SA, Goulder PJ, Shea AK, et al.: Levels of human immunodeficiency virus type 1-specific cytotoxic T-lymphocyte effector and memory responses decline after suppression of viremia with highly active antiretroviral therapy. J Virol 1999, 73:6721–6728.

    PubMed  CAS  Google Scholar 

  34. Dybul M, Mercier G, Belson M, et al.: CD40 ligand trimer and IL-12 enhance peripheral blood mononuclear cells and CD4+ T cell proliferation and production of IFN-gamma in response to p24 antigen in HIV-infected individuals: potential contribution of anergy to HIV-specific unresponsiveness. J Immunol 2000, 165:1685–1691.

    PubMed  CAS  Google Scholar 

  35. Ruiz L, Carcelain G, Martinez-Picado J, et al.: HIV dynamics and T-cell immunity after three structured treatment interruptions in chronic HIV-1 infection. AIDS 2001, 15:F19-F27.

    Article  PubMed  CAS  Google Scholar 

  36. Garcia F, Plana M, Ortiz GM, et al.: The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS 2001, 15:F29-F40.

    Article  PubMed  CAS  Google Scholar 

  37. Ortiz GM, Wellons M, Brancato J, et al.: Structured antiretroviral treatment interruptions in chronically HIV-1-infected subjects. Proc Natl Acad Sci U S A 2001, 98:13288–13293.

    Article  PubMed  CAS  Google Scholar 

  38. Fagard C, Lebraz M, Gunthard H, et al.: SSITT: A prospective trial of strategic treatment interruptions in 128 patients [abstract 357]. In 8th Congress on Retroviruses and Opportunistic Infections. Chicago. February 4–8, 2001.

  39. Dybul M, Yoder C, Belson M, et al.: A randomized, controlled trial of intermittent versus continuous HAART [abstract 364]. In 8th Congress on Retroviruses and Opportunistic Infections. Chicago. February 4–8, 2001.

  40. Lisziewicz J, Rosenberg E, Lieberman J, et al.: Control of HIV despite the discontinuation of antiretroviral therapy. N Engl J Med 1999, 340:1683–1684.

    Article  PubMed  CAS  Google Scholar 

  41. Walker B: Immune control of HIV infection [abstract 139]. In 1st IAS Conference on HIV Pathogenesis. Buenos Aires. July 8–11, 2001.

  42. Fauci AS: Host factors in the pathogenesis of HIV disease: implications for therapeutic strategies [abstract PL-4]. In 1st IAS Conference of HIV Pathogenesis. Buenos Aires. July 8–11, 2001.

  43. Altfeld M, Rosenberg ES, Shankarappa R, et al.: Cellular immune responses and viral diversity in individuals treated during acute and early HIV-1 infection. J Exp Med 2001, 193:169–180.

    Article  PubMed  CAS  Google Scholar 

  44. Dybul M, Chun TW, Yoder C, et al.: Short-cycle structured intermittent treatment of chronic HIV infection with highly active antiretroviral therapy: effects on virologic, immunologic, and toxicity parameters. Proc Natl Acad Sci U S A 2001, 98:15161–15166. This proof-of-concept study demonstrates that it is possible to maintain suppression of HIV in the periphery and lymph nodes while preserving CD4+ T-cell counts and decreasing serum lipid levels by strictly adhering to a regimen of 7 days on HAART followed by 7 days off HAART. The clinical applicability of this approach requires an evaluation in randomized, controlled clinical trials.

    Article  PubMed  CAS  Google Scholar 

  45. Mellors JW, Munoz A, Giorgi JV, et al.: Plasma viral load and CD4+ lymphocytes as prognostic markers of HIV-1 infection. Ann Intern Med 1997, 126:946–954.

    PubMed  CAS  Google Scholar 

  46. Department of Health and Human Services/Henry J. Kaiser Family Foundation Panel on Clinical Practices for Treatment of HIV Infection: Guidelines for the use of antiretroviral agents in HIV-infected adults and adolescents. Accessible at www.hivatis.org.

  47. Parish MA, Raines C, Higgins M, Gallant JE: Treatment discontinuation in patients with marginal indications for HAART[abstract 673]. In 41st Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago. December 16–19, 2001.

  48. Kilby JM, Goepfert PA, Miller AP, et al.: Recurrence of the acute HIV syndrome after interruption of antiretroviral therapy in a patient with chronic HIV infection: a case report. Ann Intern Med 2000, 133:435–438.

    PubMed  CAS  Google Scholar 

  49. Zala C, Salomon H, Ochoa C, et al.: Supervised treatment interruption following D4T/DDI/Nevirapine initiated within 6 months of HIV seroconversion [abstract 442]. In 1st IAS Conference on HIV Pathogenesis. Buenos Aires. July 8–11, 2001.

  50. McNeil AC, Shupert WL, Iyasere CA, et al.: High-level HIV-1 viremia suppresses viral antigen-specific CD4(+) T cell proliferation. Proc Natl Acad Sci U S A 2001, 98:13878–13883.

    Article  PubMed  CAS  Google Scholar 

  51. Moir S, Malaspina A, Ogwaro KM, et al.: HIV-1 induces phenotypic and functional perturbations of B cells in chronically infected individuals. Proc Natl Acad Sci U S A 2001, 98:10362–10367.

    Article  PubMed  CAS  Google Scholar 

  52. Gray RH, Wawer MJ, Brookmeyer R, et al.: Probability of HIV-1 transmission per coital act in monogamous, heterosexual, HIV-1-discordant couples in Rakai, Uganda. Lancet 2001, 357:1149–1153.

    Article  PubMed  CAS  Google Scholar 

  53. Quinn TC, Wawer MJ, Sewankambo N, et al.: Viral load and heterosexual transmission of human immunodeficiency virus type 1. Rakai Project Study Group. N Engl J Med 2000, 342:921–929.

    Article  PubMed  CAS  Google Scholar 

  54. Havlir D: Structured intermittent treatment for HIV disease: necessary concession or premature compromise? Proc Natl Acad Sci U S A 2002, 99:4–6. A comprehensive and insightful review of the field.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 31/Rm 7A-03, 20892, Bethesda, MD, USA

    Mark Dybul MD

Authors
  1. Mark Dybul MD
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Dybul, M. Structured treatment interruption: Approaches and risks. Curr Infect Dis Rep 4, 175–180 (2002). https://doi.org/10.1007/s11908-002-0059-2

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11908-002-0059-2

Keywords

Search

Navigation