HIV ePharmacotherapy Network - Immune Restoration after Treatment of Chronic HIV-1 Infection

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University at Buffalo, the State University of New York School of Pharmacy and Pharmaceutical Sciences

Immune Restoration after Treatment of Chronic HIV-1 Infection

Dr. Hernan Valdez, Case Western Reserve University.

Treatment of HIV-1 infection with highly active antiretroviral therapy (HAART) is associated with partial immune restoration. A few weeks after initiation of HAART there is an increase in the total number of circulating CD4+, CD8+, and B-lymphocytes^2-4. This initial increase in circulating lymphocytes appears to be due to redistribution of lymphocytes trapped in lymph nodes into the peripheral circulation^5,6. This simple redistribution of lymphocytes is associated with improvements in immune function and clinical benefit. Most of the increase in CD4+ lymphocytes a patients will experience during the first year of therapy will be seen during the initial 12 weeks⁷.

Beyond the first 12 weeks of therapy there is a more gradual increase in circulating CD4+ lymphocytes that is mainly comprised of naïve CD4+ cells^3,7. This second phase increase in CD4+ lymphocytes may reflect normalization of lymphopoiesis, since there is evidence of thymopoiesis^8,9 and improved bone marrow function¹⁰. Patients who start on HAART during moderately advanced HIV infection increase in average 150 CD4+ lymphocytes during the first year of treatment, but this increase is highly variable¹¹.

After the first year of therapy, the increase in CD4+ lymphocytes is even slower, if at all significant^12-14. A large proportion of patients who start HAART during moderately advanced HIV infection will not achieve "normal" (> 500) circulating CD4 + lymphocytes after 3 years of therapy. In contrast, it has been shown that patients who start HAART earlier during the course of HIV infection experience a more complete immune restoration¹⁵. It is unknown whether "subclinical" immune deficiency will be associated with long-term adverse clinical outcomes and whether the benefit of more complete immune restoration with early treatment will outweigh the risk of toxicity due to long-term antiretroviral administration.

REVIEW

1. Lederman MM, Valdez H. Immune restoration with antiretroviral therapies: implications for clinical management [see comments]. Jama 2000;284:223-8 [PubMed]

ADDITIONAL READING

2. Lederman MM, Connick E, Landay A, et al. Immunologic responses associated with 12 weeks of combination antiretroviral therapy consisting of zidovudine, lamivudine, and ritonavir: results of AIDS Clinical Trials Group Protocol 315. J Infect Dis 1998;178:70-9 [PubMed]

3. Li TS, Tubiana R, Katlama C, Calvez V, Ait Mohand H, Autran B. Long-lasting recovery in CD4 T-cell function and viral-load reduction after highly active antiretroviral therapy in advanced HIV-1 disease [see comments]. Lancet 1998;351:1682-6 [PubMed]

4. Autran B, Carcelain G, Li TS, et al. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease [see comments]. Science 1997;277:112-6 [PubMed]

5. Bucy RP, Hockett RD, Derdeyn CA, et al. Initial increase in blood CD4(+) lymphocytes after HIV antiretroviral therapy reflects redistribution from lymphoid tissues. J Clin Invest 1999;103:1391-8 [PubMed]

6. Pakker NG, Notermans DW, de Boer RJ, et al. Biphasic kinetics of peripheral blood T cells after triple combination therapy in HIV-1 infection: a composite of redistribution and proliferation [see comments]. Nat Med 1998;4:208-14 [PubMed]

7. Connick E, Lederman MM, Kotzin BL, et al. Immune reconstitution in the first year of potent antiretroviral therapy and its relationship to virologic response. J Infect Dis 2000;181:358-63 [PubMed]

8. Douek DC, McFarland RD, Keiser PH, et al. Changes in thymic function with age and during the treatment of HIV infection [see comments]. Nature 1998;396:690-5 [PubMed]

9. Smith KY, Valdez H, Landay A, et al. Thymic size and lymphocyte restoration in patients with human immunodeficiency virus infection after 48 weeks of zidovudine, lamivudine, and ritonavir therapy. J Infect Dis 2000;181:141-7 [PubMed]

10. Isgro A, Mezzaroma I, Aiuti A, et al. Recovery of hematopoietic activity in bone marrow from human immunodeficiency virus type 1-infected patients during highly active antiretroviral therapy. AIDS Res Hum Retroviruses 2000;16:1471-9. [PubMed]

11. Teixeira L, Valdez H, McCune JM, et al. Poor CD4 T cell restoration after suppression of HIV-1 replication may reflect lower thymic function. Aids 2001;15:1749-56. [PubMed]

12. Notermans DW, Pakker NG, Hamann D, et al. Immune reconstitution after 2 years of successful potent antiretroviral therapy in previously untreated human immunodeficiency virus type 1-infected adults. J Infect Dis 1999;180:1050-6. [PubMed]

13. Angel JB, Parato KG, Kumar A, et al. Progressive human immunodeficiency virus-specific immune recovery with prolonged viral suppression. J Infect Dis 2001;183:546-54. [PubMed]

14. Tarwater PM, Margolick JB, Jin J, et al. Increase and plateau of CD4 T-cell counts in the 3(1/2) years after initiation of potent antiretroviral therapy. J Acquir Immune Defic Syndr 2001;27:168-75. [PubMed]

15. Kaufman GR, Zaunders JJ, Cunningham P, et al. Rapid restoration of CD4 T cell subsets in subjects receiving antiretroviral therapy during primary HIV-1 infection. Aids 2000;14:2643-51. [PubMed]