Decreasing CD4 + T-cell Count During Suppressed or Low-Level Viraemia in Patients with HIV Infection

Abstract

Background

Suboptimal improvement in CD4⁺ T-cell count is not uncommon in HIV-infected patients with suppressed plasma HIV RNA levels, and a decrease in CD4⁺T-cell count in patients with suppressed or low-level viraemia has been observed.

Methods

Our objectives were to identify the prevalence of decreasing CD4⁺ T-cell counts during suppressed or low-level viraemia, to determine the frequency of clinical events during and immediately after such decreases, and to examine for associations with individual variables. A matched case-control study was undertaken using the Duke Infectious Diseases Clinic database (n=3,949). Cases had at least two consecutive significant decreases in either CD4⁺ absolute count or CD4⁺ percentage, while also having plasma HIV RNA levels <1,000 copies/ml.

Results

The prevalence of decreasing CD4⁺ T-cell counts during suppressed or low-level viraemia was 1.22%. Only three HIV-associated clinical events occurred. The majority of cases had an increase in the CD4⁺ T-cell count immediately following the study period. The use of either zidovudine or stavudine was weakly associated with decreasing CD4⁺ T-cell counts in a multivariable analysis, but this association was not present in cases with only a decrease in CD4⁺ T-cell percentage.

Conclusions

Decreasing CD4⁺ T-cell counts during suppressed or low-level viraemia are rare, typically transient, and not associated with an increase in HIV-associated clinical events.

References

Bartlett

J.A.

, DeMasi

, Quinn

, Moxham

, Rousseau

Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1 infected adults.

AIDS 2001; 15: 1369–1377.

Wood

, Yip

, Hogg

R.S.

Full suppression of viral load is needed to achieve an optimal CD4 cell count response among patients on triple drug antiretroviral therapy.

AIDS 2000; 14: 1955–1960.

Wood

, Hogg

R.S.

, Yip

‘Discordant’ increases in CD4 cell count relative to plasma viral load in a closely followed cohort of patients initiating antiretroviral therapy.

J Acquir Immune Defic Syndr 2002; 30: 159–166.

Smith

C.J.

, Sabin

C.A.

, Youle

M.S.

Factors influencing increases in CD4 cell counts of HIV-positive persons receiving long-term highly active antiretroviral therapy.

J Infect Dis 2004; 190: 1860–1868.

Hunt

P.W.

, Deeks

S.G.

, Rodriguez

Continued CD4 cell count increases in HIV-infected adults experiencing 4 years of viral suppression on antiretroviral therapy.

AIDS 2003; 17: 1907–1915.

Grabar

, Le Moing

, Goujard

Clinical outcome of patients with HIV-1 infection according to immunologic and virologic response after 6 months of highly active antiretroviral therapy.

Ann Intern Med 2000; 133: 401–410.

Piketty

, Weiss

, Thomas

, Mohamed

A.S.

, Belec

, Kazatchkine

M.D.

Long-term clinical outcome of human immunodeficiency virus-infected patients with discordant immunologic and virologic responses to a protease inhibitor-containing regimen.

J Infect Dis 2001; 183: 1328–1335.

Florence

, Lundgren

, Dreezen

Factors associated with a reduced CD4 lymphocyte count response to HAART despite full viral suppression in the EuroSIDA study.

HIV Med 2003; 4: 255–262.

Viard

J.P.

, Mocroft

, Chiesi

Influence of age on CD4 cell recovery in human immunodeficiency virus-infected patients receiving highly active antiretroviral therapy: evidence from the EuroSIDA study.

J Infect Dis 2001; 183: 1290–1294.

10.

Yamashita

T.E.

, Phair

J.P.

, Munoz

Immunologic and virologic response to highly active antiretroviral therapy in the Multicenter AIDS Cohort Study.

AIDS 2001; 15: 735–746.

11.

Rutschmann

O.T.

, Opravil

, Iten

A placebo-controlled trial of didanosine plus stavudine, with and without hydroxyurea, for HIV infection. The Swiss HIV Cohort Study.

AIDS 1998; 12: F71–F77.

12.

Barrios

, Rendon

, Negredo

Paradoxical CD4⁺ T-cell decline in HIV-infected patients with complete virus suppression taking tenofovir and didanosine.

AIDS 2005; 19: 569–575.

13.

Negredo

, Molto

, Burger

Unexpected CD4 cell count decline in patients receiving didanosine and tenofovir-based regimens despite undetectable viral load.

AIDS 2004; 18: 459–463.

14.

Soriano

, Bravo

, Samaniego

J.G.

CD4⁺ T-lymphocytopenia in HIV-infected patients receiving interferon therapy for chronic hepatitis C. HIV-Hepatitis Spanish Study Group.

AIDS 1994; 8: 1621–1622.

15.

Rai

K.R.

, Freter

C.E.

, Mercier

R.J.

Alemtuzumab in previously treated chronic lymphocytic leukemia patients who also had received fludarabine.

J Clin Oncol 2002; 20: 3891–3897.

16.

Gajewski

T.F.

Temozolomide for melanoma: new toxicities and new opportunities.

J Clin Oncol 2004; 22: 580–581.

17.

Leng

, Borkow

, Weisman

, Stein

, Kalinkovich

, Bentwich

Immune activation correlates better than HIV plasma viral load with CD4 T-cell decline during HIV infection.

J Acquir Immune Defic Syndr 2001; 27: 389–397.

18.

Dybul

, Nies-Kraske

, Condoluci

Evaluation of the pathogenesis of declining CD4⁺ T cell counts in HIV-1-infected patients receiving successfully suppressive antiretroviral therapy. 3rd International AIDS Society Conference on HIV Pathogenesis and Treatment, 24–27 July 2005, Rio de Janeiro, Brazil. Abstract WePe8.1B01.

19.

Greub

, Ledergerber

, Battegay

Clinical progression, survival, and immune recovery during antiretroviral therapy in patients with HIV-1 and hepatitis C virus coinfection: the Swiss HIV Cohort Study.

Lancet 2000; 356: 1800–1805.

20.

Braitstein

, Zala

, Yip

Immunologic response to antiretroviral therapy in hepatitis C virus-coinfected adults in a population-based HIV/AIDS treatment program.

J Infect Dis 2006; 193: 259–268.

21.

Centers for Disease Control and Prevention.

U.S. HIV and AIDS cases reported through December 2001.

HIV/AIDS Surveillance Reports 2001; 13: 1–41.

22.

Richman

D.D.

, Fischl

M.A.

, Grieco

M.H.

The toxicity 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: 192–197.

23.

Koduri

P.R.

, Parekh

Zidovudine-related anemia with reticulocytosis.

Ann Hematol 2003; 82: 184–185.

24.

Viora

, Di Genova

, Rivabene

, Malorni

, Fattorossi

Interference with cell cycle progression and induction of apoptosis by dideoxynucleoside analogs.

Int J Immunopharmacol 1997; 19: 311–321.

25.

Barreiro

, Soriano

, Casas

, Gonzalez-Lahoz

Different degree of immune recovery using antiretroviral regimens with protease inhibitors or non-nucleosides.

AIDS 2002; 16: 245–249.

26.

Hosmer

D.W.

, Lemeshow

Applied Logistic Regression. 2nd edn. New York: John Wiley and Sons 2005.

27.

Phillips

A.N.

, Youle

, Lampe

CD4 cell count changes in individuals with counts above 500 cells/mm and viral loads below 50 copies/ml on antiretroviral therapy.

AIDS 2002; 16: 1073–1075.

28.

Kline

M.W.

, Van Dyke

R.B.

, Lindsey

J.C.

A randomized comparative trial of stavudine (d4T) versus zidovudine (ZDV, AZT) in children with human immunodeficiency virus infection. AIDS Clinical Trials Group 240 Team.

Pediatrics 1998; 101: 214–220.

29.

Gebo

K.A.

, Gallant

J.E.

, Keruly

J.C.

, Moore

R.D.

Absolute CD4 vs. CD4 percentage for predicting the risk of opportunistic illness in HIV infection.

J Acquir Immune Defic Syndr 2004; 36: 1028–1033.

30.

Hughes

M.D.

, Stein

D.S.

, Gundacker

H.M.

, Valentine

F.T.

, Phair

J.P.

, Volberding

P.A.

Within-subject variation in CD4 lymphocyte count in asymptomatic human immunodeficiency virus infection: implications for patient monitoring.

J Infect Dis 1994; 169: 28–36.

31.

Giorgi

J.V.

, Cheng

H.L.

, Margolick

J.B.

Quality control in the flow cytometric measurement of T-lymphocyte subsets: the multicenter AIDS cohort study experience. The Multicenter AIDS Cohort Study Group.

Clin Immunol Immunopathol 1990; 55: 173–186.

32.

Stein

D.S.

, Korvick

J.A.

, Vermund

S.H.

CD4⁺ lymphocyte cell enumeration for prediction of clinical course of human immunodeficiency virus disease: a review.

J Infect Dis 1992; 165: 352–363.

33.

The DHHS Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1 infected adults and adolescents. Department of Health and Human Services. 10 October 2006; 1–122. Available at http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentsGL.pdf. Accessed November 2006.

34.

Carpenter

C.C.

, Fischl

M.A.

, Hammer

S.M.

Antiretroviral therapy for HIV infection in 1997. Updated recommendations of the International AIDS Society-USA panel.

JAMA 1997; 277: 1962–1969.