Immune modulators and treatment interruption

Current Opinion in HIV and AIDS

Volumn 3, Issue 2, 2008, Pages 124-130

  García, Felipe ^a,b,c   Fumero, Emilio ^a   Gatell, José María ^a,b  

^a UNIVERSITY OF BARCELONA   (Spain)

^b UNIVERSITY OF BARCELONA   (Spain)

^c HOSPITAL CLÍNIC   (Spain)

Author keywords

Hydroxyurea; Immune activation; Mycophenolate mofetil; Structured treatment interruptions

Indexed keywords

ABACAVIR; ANTIRETROVIRUS AGENT; CORTICOSTEROID; CYCLOSPORIN A; CYTOSTATIC AGENT; DIDANOSINE; HYDROXYUREA; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; THALIDOMIDE;

ADJUVANT THERAPY; BACTERIAL TRANSLOCATION; CD4 LYMPHOCYTE COUNT; CELL FUNCTION; CLINICAL TRIAL; COMBINATION CHEMOTHERAPY; DRUG INHIBITION; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS INFECTION; IMMUNOMODULATION; MONOTHERAPY; MULTIPLE CYCLE TREATMENT; PRIORITY JOURNAL; REVIEW; THERAPY DELAY; VIRUS REPLICATION;

EID: 40049095702     PISSN: 1746630X     EISSN: 17466318     Source Type: Journal    
DOI: 10.1097/COH.0b013e3282f52413     Document Type: Review

References (42)

1. Kahn JO, Walker BD. Current concepts: acute human immunodeficiency virus type 1 infection. N Engl J MEd 1998; 339:33-39.
2. Mocroft A, Bofill M, Lipman M, et al. Cd8+, Cd38+ lymphocyte percentage: a useful immunological marker for monitoring HIV-1-infected patients. J Acquir Immune Defic Syndr Hum Retrovirol 1997; 14:158-162.
3. Bofill M, Mocroft A, Lipman M, et al. Increased numbers of primed activated CD8+CD38+CD45RO+ T cells predict the decline of CD4+ T cells in HIV-1-infected patients. AIDS 1996; 10:827-834.
4. Douek DC, Brenchley J, Betts M, et al. HIV preferentially infects HIV-specific CD4+ T cells. Nature 2002; 417:95-98.
5. Chougnet CA, Shearer GM. Regulatory T cells (Treg) and HIV/AIDS: summary of the September 7-8, 2006 workshop. AIDS Res Hum Retroviruses 2007; 23:945-952. This paper is a comprehensive summary of the knowledge in the field of regulatory T cells and their role HIV infection. It includes many questions that remain to be answered.
6. Belkaid Y. Regulatory T cells and infection: a dangerous necessity. Nat Rev Immunol 2007; 7:875-888. This paper is an excellent review of the state of the art in this complicated field of regulatory T cells and their influence in infections.
7. Brenchley JM, Price DA, Schacker TW, et al.Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 2006; 12:1365-1371. This paper is an important study supporting the hypothesis of bacterial translocation as the main cause of immune activation in HIV infection.
8. Plana M, Garcia F, Gallart MT, et al. Lack of T-cell proliferative response to HIV-1 antigens after one year of HAART in very early HIV-1 disease. Lancet 1998; 352:1194-1195.
9. Plana M, García F, Gallart MT, et al. Immunological benefits of antiretroviral therapy in very early stages of asymptomatic chronic HIV-1 infection. AIDS 2000; 14:1921-1933.
10. Weiss L, Donkova-Petrini V, Caccavelli L, et al. Human immunodeficiency virus-driven expansion of CD4+CD25+ regulatory T cells, which suppress HIV-specific CD4 T-cell responses in HIV-infected patients. Blood 2004; 104:3249-3256.
11. + HIV-specific T cell immune responses in vitro and are associated with favorable clinical markers of disease status. J Exp Med 2004; 200:331-343.
12. Mozos A, Garrido M, Carreras J, et al. Redistribution of FOXP3-positive regulatory T cells from lymphoid tissues to peripheral blood in HIV-infected patients. J Acquir Immune Defic Syndr 2007; 46:529-537.
13. Mattapallil JJ, Douek DC, Hill B, et al. Massive infection and loss of memory CD4+ T cells in multiple tissues during acute SIV infection. Nature 2005; 434:1093-1097.
14. Lisziewicz J, Rosenberg E, Lieberman J, et al. Control of HIV despite the discontinuation of antiretroviral therapy [letter]. N Engl J Med 1999; 340:1683-1684.
15. Ortiz GM, Nixon DF, Trkola A, et al. HIV-1 specific immune response in subjects who temporarily contain virus replication after discontinuation of HAART. J Clin Invest 1999; 104:R13-R18.
16. Autran B, Carcelain G. AIDS. Boosting immunity to HIV: can the virus help? Science 2000; 290:946-949.
17. Jacobson JM, Pat BR, Spritzler J, et al. Evidence that intermittent structured treatment interruption, but not immunization with ALVAC-HIV vCP1452, promotes host control of HIV replication: the results of AIDS Clinical Trials Group 5068. J Infect Dis 2006; 194:623-632. This randomized study suggested that structured treatment interruption could induce a control of HIV replication in about 20% of patients.
18. Fagard C, Oxenius A, Gunthard H, et al. A prospective trial of structured treatment interruptions in HIV infection. Arch Intern Med 2003; 163:1220-1226.
19. García 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.
20. Papasavvas E, Kostman JR, Mounzer K, et al. Randomized, controlled trial of therapy interruption in chronic HIV-1 infection. Plos Med 2004; 1:e64.
21. Oxenius A, Price D, Gunthard HF, et al. Stimulation of HIV specific cellular immunity by structured treatment interruption fails to enhance viral control in chronic HIV-infection. Proc Natl Acad Sci U S A 2002; 99:13747-13752.
22. 3. J Acquir Immune Defic Syndr 2004; 36:791-799.
23. Autran B, Costagliola D, Murphy R, et al. ORVACS Study Group. Time to ART resumption following treatment interruption is shorter for individuals immunized with HIV-recombinant canarypox vaccine (Vcp1452) compared to placebo: The Manon-02 Trial [abstract]. In: 14th Conference on Retroviruses and Opportunistic Infections; 25-28 February 2007; Los Angeles. Alexandria: CROI; 2007. Abstract 126LB.
24. Ledford H. HIV vaccine may raise risk. Nature 2007; 450:325.
25. Nuesch R, Hirschel B. Treatment interruption for convenience, cost cutting and toxicity sparing. Curr Opin HIV AIDS 2007; 2:31-38.
26. Taylor S, Boffito M, Khoo S, et al. Stopping antiretroviral therapy. AIDS 2007; 21:1673-1682. This article summarizes the current knowledge about antiretroviral therapy interruption discussing the pros and cons of this strategy.
27. SMART Study Group. CD4+ Count-guided interruption of antiretroviral treatment. N Engl J MEd 2006, 355:2283-2296. The SMART trial is the largest randomized controlled trial ever performed in the field of HIV infections. It showed an increase in morbidity and mortality in patients who discontinued antiretroviral therapy. It has been suggested that immune activation due to viral load rebound after ART interruption could play a critical role in these events.
28. Jacobson JM. The rationale for immunosuppressive therapy for HIV infection. Curr Opin HIV AIDS 2007; 2:207-212.
29. Lori F, Lewis M, Xu J, et al. Control of SIV rebound through structured treatment interruptions during early infection. Science 2000; 290:1591-1593.
30. Lori F, Malykh A, Cara A, et al. Hydroxyurea as an inhibitor of human immunodeficiency virus-type 1 replication. Science 1994; 266:801-804.
31. Hellinger J, Iwane M, Smith J, et al. A randomized study of the safety and antiretroviral activity of hydroxyurea combined with didanosine in persons infected with human immunodeficiency virus type 1. American Foundation for AIDS Research Community-Based Clinical Trials Network. J Infect Dis 2000; 181:540-547.
32. García F, Plana M, Arnedo M, et al. A cytostatic drug improves control of HIV-1 replication during structured treatment interruptions. A randomized study. AIDS 2003; 17:43-51.
33. Bloch MT, Smith DE, Quan D, et al. The role of hydroxyurea in enhancing the virologic control achieved through structured treatment interruption in primary HIV infection: final results from a randomized clinical trial (Pulse). J Acquir Immune Defic Syndr 2006; 42:192-202. This study is the largest trial of use of hydroxyurea in structured therapy interruption during primary HIV-1 infection. No benefits seem to offer this strategy in this setting.
34. Benito JM, Lopez M, Ballesteros C, et al. Immunological and virological effects of structured treatment interruptions following exposure to hydroxyurea plus didanosine. AIDS Res Hum Retroviruses 2006; 22:734-743.
35. Lori F, Foli A, Groff A, et al. Optimal suppression of HIV replication by low-dose hydroxyurea through the combination of antiviral and cytostatic ('virostatic') mechanisms. AIDS 2005; 19:1173-1181.
36. Margolis D, Heredia A, Gaywee J, et al. Abacavir and mycophenolic acid, an inhibitor of inosine monophosphate dehydrogenase have profound and synergistic anti-HIV activity. J Acquir Immune Defic Syndr 1999; 21:362-370.
37. Chapuis A, Rizzardi P, D'Agostini C, et al. Effects of mycophenolic acid on human immunodeficiency virus infection in vitro and in vivo. Nat Med 2000; 6:762-768.
38. Vrisekoop N, Sankatsing SU, Jansen CA, et al. Short communication: No detrimental immunological effects of mycophenolate mofetil and HAART in treatment-naive acute and chronic HIV-1-infected patients. AIDS Res Hum Retroviruses 2005; 21:991-996.
39. García F, Plana M, Arnedo M, et al. Effect of mycophenolate mophetil on immune response and on plasma and lymphatic tissue viral load during and after interruption of HAART in chronic HIV-1 infected patients. A pilot randomized study. J Acquir Immune Defic Syndr 2004; 36:823-830.
40. Margolis D, Kewn S, Coull J, et al. The addition of mycophenolate mofetil to antiretroviral therapy including abacavir is associated with depletion of intracellular deoxyguanosine triphosphate and a decrease in plasma HIV-1 RNA [abstract]. J Acquir Immune Defic Syndr 2002; 31:45-49.
41. Rizzardi GP, Harari A, Capiluppi B, et al. Treatment of primary HIV-1 infection with cyclosporin A coupled with highly active antiretroviral therapy. J Clin Invest 2002; 109:681-688.
42. Lederman MM, Smeaton L, Smith KY, et al. Cyclosporin A provides no sustained immunologic benefit to persons with chronic HIV-1 infection starting suppressive antiretroviral therapy: results of a randomized, controlled trial of the AIDS Clinical Trials Group A5138. J Infect Dis 2006; 194:1677-1685. This paper describes well designed trial to assess the role of the use of cyclosporin A in chronic HIV-1 infection.