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July 10, 1996, Vol 276, No. 2 >
ARTICLE | July 10, 1996

Surrogate Markers in AIDS Research: Title and subTitle BreakIs There Truth in Numbers? FREE

Jay A. Levy, MD
[+] Author Affiliations

Edited by Phil B. Fontanarosa, MD, Senior Editor.

Reprints not available.


JAMA. 1996;276(2):161-162. doi:10.1001/jama.1996.03540020083035
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References

MATHEMATICAL models and statistical evaluations are often used to explain biologic phenomena. The acquired immunodeficiency syndrome (AIDS) is no exception. Through the years of studying the human immunodeficiency virus (HIV) and its effect on the immune system, investigators have emphasized counting CD4+ cells and CD8+ cells and/or measuring p24 antigen levels or, more recently, the viral RNA content of the plasma. What is known, but not always appreciated, is the limited information that may be reflected by these parameters when measured in the blood. Peripheral blood lymphocyte numbers represent only a small percentage (3%) of the total white blood cells in the body,1 and plasma virion content is just a portion of the total HIV virions, which are concentrated primarily in lymphoid organs.2 Thus, in several experimental systems, plasma viral RNA may not reflect the actual viral load. Moreover, although CD4+ cell numbers may be helpful in predicting

REFERENCES

1 +
Westermann J, Pabst R.  Lymphocyte subsets in the blood: a diagnostic window on the lymphoid system? Immunol Today . 1990;;11:406-410.
2 +
Embretson J, Zupancic M, Ribas JL, et al.  Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS . Nature . 1993;;362:359-362.
3 +
Phillips AN, Lee CA, Elford J, et al.  Serial CD4 lymphocyte counts and development of AIDS . Lancet . 1991;;337:389-392.
4 +
Choi S, Lagakos SW, Schooley RT, Volberding PA.  CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine . Ann Intern Med . 1993;;118:674-680.
5 +
Volberding PA, Lagakos SW, Grimes JM, et al.  A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter . N Engl J Med . 1995;;333:401-407.
6 +
Stein DS, Korvick JA, Vermund SH.  CD4+ lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease: a review . J Infect Dis . 1992;;165:352-363.
7 +
Mellors JW, Kingsley LA, Rinaldo CR Jr, et al.  Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion . Ann Intern Med . 1995;;122:573-579.
8 +
Mayaux M-J, Burgard M, Teglas J-P, et al.  Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease . JAMA . 1996;;275:606-610.
9 +
Mackewicz CE, Yang LC, Lifson JD, Levy JA.  Non-cytolytic CD8 T-cell anti-HIV responses in primary infection . Lancet . 1994;;344:1671-1673.
10 +
Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MBA.  Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection . J Virol . 1994;;68:6103-6110.
11 +
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.
12 +
Henrard DR, Phillips JF, Muenz LR, et al.  Natural history of HIV-1 cell-free viremia . JAMA . 1995;;274:554-558.
13 +
Levy JA.  HIV research: a need to focus on the right target . Lancet . 1995;;345:1619-1621.
14 +
Kinloch-de Loes S, Hirschel BJ, Hoen B, et al.  A controlled trial of zidovudine in primary human immunodeficiency virus infection . N Engl J Med . 1995;;333:408-413.
15 +
Levy JA, Ramachandran B, Barker E, Guthrie J, Elbeik T.  Plasma viral load, CD4+ cell counts, and HIV-1 production by cells . Science . 1996;;271:670-671.
16 +
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection . Nature . 1995;; 373:123-125.
17 +
Wei X, Ghosh SK, Taylor ME, et al.  Viral dynamics in human immunodeficiency virus type 1 infection . Nature . 1995;;373:117-122.
18 +
D'Aquila RT.  HIV-1 drug resistance: molecular pathogenesis and laboratory monitoring . Clin Lab Med . 1994;;14:393-422.
19 +
Richman DD.  HIV drug resistance . AIDS Res Hum Retroviruses . 1992;;8:1065-1071.
20 +
Lech WJ, Wang G, Yang YL, et al.  In vivo sequence diversity of the protease of human immunodeficiency virus type 1 . J Virol . 1996;;70:2038-2043.
21 +
Pantaleo G, Cohen RJ, Schwartzentruber DJ, Graziosi C, Vaccarezza M, Fauci AS.  Pathogenic insights from studies of lymphoid tissue from HIV-infected individuals . J Acquir Immune Defic Syndr Hum Retrovirol . 1995;;10( (suppl 1) ):S6-S14.
22 +
Lee TH, Sheppard HW, Reis M, Dondero D, Osmond D, Busch MP.  Circulating HIV-1-infected cell burden from seroconversion to AIDS: importance of postseroconversion viral load on disease course . J Acquir Immune Defic Syndr . 1994;;7:381-388.
23 +
Raboud JM, Montaner JSG, Thorne A, Singer J, Schechter MT.  Impact of missing data due to dropouts on estimates of the treatment effect in a randomized trial of antiretroviral therapy for HIV-infected individuals . J Acquir Immune Defic Syndr Hum Retrovirol . 1996;;12:46-55.
24 +
Cameron B, Heath-Chiozzi M, Kravciki S, Mills R, Potthoff A, Henry D. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. Presented at the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1, 1996; Washington, DC.
25 +
Mackewicz CE, Landay A, Hollander H, Levy JA.  Effect of zidovudine therapy on CD8+ T cell anti-HIV activity . Clin Immunol Immunopathol . 1994;;73:80-87.
26 +
Volberding PA.  Caring for the patient with AIDS . In: Sande MA, ed. The Medical Management of AIDS . Philadelphia, Pa: WB Saunders Co; 1988;:353-361.
27 +
Eron JJ, Benoit SL, Jemsek J, et al.  Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter . N Engl J Med . 1995;;333:1662-1669.
28 +
Kovacs JA, Baseler M, Dewar RJ, et al.  Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection: a preliminary study . N Engl J Med . 1995;;332:567-575.
29 +
Clerici M, Lucey DR, Berzofsky JA, et al.  Restoration of HIV-specific cellmediated immune responses by interleukin-12 in vitro . Science . 1993;;262:1721-1724.
30 +
Barker E, Mackewicz CE, Levy JA.  Effects of TH1 and TH2 cytokines on CD8+ cell response against human immunodeficiency virus: implications for long-term survival . Proc Natl Acad Sci USA . 1995;;92:11135-11139.
31 +
Levy JA, Mackewicz CE, Barker E.  Controlling HIV pathogenesis: the role of noncytotoxic anti-HIV activity of CD8+ cells . Immunol Today . 1996;;17:217-224.

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Country-Specific Mortality and Growth Failure in Infancy and Yound Children and Association With Material Stature

Use interactive graphics and maps to view and sort country-specific infant and early dhildhood mortality and growth failure data and their association with maternal

1 +
Westermann J, Pabst R.  Lymphocyte subsets in the blood: a diagnostic window on the lymphoid system? Immunol Today . 1990;;11:406-410.
2 +
Embretson J, Zupancic M, Ribas JL, et al.  Massive covert infection of helper T lymphocytes and macrophages by HIV during the incubation period of AIDS . Nature . 1993;;362:359-362.
3 +
Phillips AN, Lee CA, Elford J, et al.  Serial CD4 lymphocyte counts and development of AIDS . Lancet . 1991;;337:389-392.
4 +
Choi S, Lagakos SW, Schooley RT, Volberding PA.  CD4+ lymphocytes are an incomplete surrogate marker for clinical progression in persons with asymptomatic HIV infection taking zidovudine . Ann Intern Med . 1993;;118:674-680.
5 +
Volberding PA, Lagakos SW, Grimes JM, et al.  A comparison of immediate with deferred zidovudine therapy for asymptomatic HIV-infected adults with CD4 cell counts of 500 or more per cubic millimeter . N Engl J Med . 1995;;333:401-407.
6 +
Stein DS, Korvick JA, Vermund SH.  CD4+ lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease: a review . J Infect Dis . 1992;;165:352-363.
7 +
Mellors JW, Kingsley LA, Rinaldo CR Jr, et al.  Quantitation of HIV-1 RNA in plasma predicts outcome after seroconversion . Ann Intern Med . 1995;;122:573-579.
8 +
Mayaux M-J, Burgard M, Teglas J-P, et al.  Neonatal characteristics in rapidly progressive perinatally acquired HIV-1 disease . JAMA . 1996;;275:606-610.
9 +
Mackewicz CE, Yang LC, Lifson JD, Levy JA.  Non-cytolytic CD8 T-cell anti-HIV responses in primary infection . Lancet . 1994;;344:1671-1673.
10 +
Borrow P, Lewicki H, Hahn BH, Shaw GM, Oldstone MBA.  Virus-specific CD8+ cytotoxic T-lymphocyte activity associated with control of viremia in primary human immunodeficiency virus type 1 infection . J Virol . 1994;;68:6103-6110.
11 +
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.
12 +
Henrard DR, Phillips JF, Muenz LR, et al.  Natural history of HIV-1 cell-free viremia . JAMA . 1995;;274:554-558.
13 +
Levy JA.  HIV research: a need to focus on the right target . Lancet . 1995;;345:1619-1621.
14 +
Kinloch-de Loes S, Hirschel BJ, Hoen B, et al.  A controlled trial of zidovudine in primary human immunodeficiency virus infection . N Engl J Med . 1995;;333:408-413.
15 +
Levy JA, Ramachandran B, Barker E, Guthrie J, Elbeik T.  Plasma viral load, CD4+ cell counts, and HIV-1 production by cells . Science . 1996;;271:670-671.
16 +
Ho DD, Neumann AU, Perelson AS, Chen W, Leonard JM, Markowitz M.  Rapid turnover of plasma virions and CD4 lymphocytes in HIV-1 infection . Nature . 1995;; 373:123-125.
17 +
Wei X, Ghosh SK, Taylor ME, et al.  Viral dynamics in human immunodeficiency virus type 1 infection . Nature . 1995;;373:117-122.
18 +
D'Aquila RT.  HIV-1 drug resistance: molecular pathogenesis and laboratory monitoring . Clin Lab Med . 1994;;14:393-422.
19 +
Richman DD.  HIV drug resistance . AIDS Res Hum Retroviruses . 1992;;8:1065-1071.
20 +
Lech WJ, Wang G, Yang YL, et al.  In vivo sequence diversity of the protease of human immunodeficiency virus type 1 . J Virol . 1996;;70:2038-2043.
21 +
Pantaleo G, Cohen RJ, Schwartzentruber DJ, Graziosi C, Vaccarezza M, Fauci AS.  Pathogenic insights from studies of lymphoid tissue from HIV-infected individuals . J Acquir Immune Defic Syndr Hum Retrovirol . 1995;;10( (suppl 1) ):S6-S14.
22 +
Lee TH, Sheppard HW, Reis M, Dondero D, Osmond D, Busch MP.  Circulating HIV-1-infected cell burden from seroconversion to AIDS: importance of postseroconversion viral load on disease course . J Acquir Immune Defic Syndr . 1994;;7:381-388.
23 +
Raboud JM, Montaner JSG, Thorne A, Singer J, Schechter MT.  Impact of missing data due to dropouts on estimates of the treatment effect in a randomized trial of antiretroviral therapy for HIV-infected individuals . J Acquir Immune Defic Syndr Hum Retrovirol . 1996;;12:46-55.
24 +
Cameron B, Heath-Chiozzi M, Kravciki S, Mills R, Potthoff A, Henry D. Prolongation of life and prevention of AIDS in advanced HIV immunodeficiency with ritonavir. Presented at the Third Conference on Retroviruses and Opportunistic Infections; January 28-February 1, 1996; Washington, DC.
25 +
Mackewicz CE, Landay A, Hollander H, Levy JA.  Effect of zidovudine therapy on CD8+ T cell anti-HIV activity . Clin Immunol Immunopathol . 1994;;73:80-87.
26 +
Volberding PA.  Caring for the patient with AIDS . In: Sande MA, ed. The Medical Management of AIDS . Philadelphia, Pa: WB Saunders Co; 1988;:353-361.
27 +
Eron JJ, Benoit SL, Jemsek J, et al.  Treatment with lamivudine, zidovudine, or both in HIV-positive patients with 200 to 500 CD4+ cells per cubic millimeter . N Engl J Med . 1995;;333:1662-1669.
28 +
Kovacs JA, Baseler M, Dewar RJ, et al.  Increases in CD4 T lymphocytes with intermittent courses of interleukin-2 in patients with human immunodeficiency virus infection: a preliminary study . N Engl J Med . 1995;;332:567-575.
29 +
Clerici M, Lucey DR, Berzofsky JA, et al.  Restoration of HIV-specific cellmediated immune responses by interleukin-12 in vitro . Science . 1993;;262:1721-1724.
30 +
Barker E, Mackewicz CE, Levy JA.  Effects of TH1 and TH2 cytokines on CD8+ cell response against human immunodeficiency virus: implications for long-term survival . Proc Natl Acad Sci USA . 1995;;92:11135-11139.
31 +
Levy JA, Mackewicz CE, Barker E.  Controlling HIV pathogenesis: the role of noncytotoxic anti-HIV activity of CD8+ cells . Immunol Today . 1996;;17:217-224.

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