CD4 Cell Count
- Number of CD4 cells (T-helper lymphocytes with CD4 cell surface marker), used to assess immune status, susceptibility to OIs, urgency of ART, need for OI prophylaxis, and for defining AIDS (CD4 < 200).
Facts about CD4
- Normal adult CD4 count reference ranges vary by laboratory; however, ranges are generally in 500-1500 range.
- Large individual variability in measurement reflecting method of determining CD4 count by calculation from 3 measured variables: WBC, % lymphocytes, and % lymphocytes that are CD4+ (CD4%). CD4% less variable than absolute count; within-subject coefficient of variation is 18% for CD4% vs 25% for CD4 count.
- Approximate corresponding values for CD4 count and CD4% are: >500 ~ >29%, 200-500 ~ 14-28%, < 200 ~ < 14%.
- CD4 count usually determined by flow cytometry; specimens must be processed within 18 hrs of collection for optimal accuracy when assayed by flow cytometry.
Factors that Affect CD4 Count
- Seasonal and diurnal variation (lowest at 12:30 PM, highest at 8:30 PM), surgery, viral infections, tuberculosis.
- Decreases with some medications (e.g. corticosteroids, especially with acute use, less pronounced with chronic use; PEG-IFN, IFN; cancer chemotherapy).
- Acute changes in CD4 more often due to redistribution of CD4 in lymphatics, spleen and bone marrow.
- Splenectomy causes abrupt, prolonged increase in CD4. In asplenic pts, CD4% provides more accurate assessment of immune status.
- HTLV-I can increase CD4 (may have low CD4% with disproportionately high CD4 count). HTLV-I common in Brazil, Caribbean, and Japan.
- Sex, race, psychologic stress, and physical stress have minimal effect on CD4. Pregnancy leads to hemodilution and a small decline in CD4 count, but no decline in CD4%.
CD4 in HIV Infection
- Abrupt decline in CD4 after acute HIV infection followed by rise. CD4 count after recovery from acute infection can return to normal range (close to pre-infection baseline) or can remain low.
- Without ART, annual CD4 decline correlated with viral load (VL) only on population level. VL is poor predictor of 1-2 yr CD4 decline on individual level, accounting for less then 10% of individual variation.
- On ART, biphasic increase in CD4, 50-120 in first 3 mos (thought to be due to redistribution of memory CD4 cells from lymphoid tissue) followed by avg. increase of 2-7 cells/mo via expansion of naïve CD4 cell population; CD4 increase can continue years after ART initiation (>6 yrs). Normalization of CD4 count more likely in pts who start therapy with higher CD4 counts.
- CD4 response generally correlates with VL suppression, but discordant results can occur; 10% have VL suppression but no CD4 rise. Lack of CD4 response is not evidence of treatment failure if VL suppressed. Older age and lower CD4 nadir are predictors of poorer CD4 increase.
- Bone marrow suppression from AZT and TMP/SMX can blunt CD4 response. Evidence for better CD4 response with boosted PIs, integrase inhibitors, and CCR5 antagonsts than NNRTIs.
- Abrupt decrease in CD4 towards nadir level may occur after discontinuing ART (100-150 in 3-4 mos).
Idiopathic CD4 Lymphopenia (ICL)
- ICL characterized by low CD4 not explained by HIV or other medical conditions
- Defined as: (1) CD4 < 300 or CD4% < 20% on >2 measurements; (2) lack of HIV infection; and (3) absence of alternative explanation
- Lower risk of OIs than with HIV infection; CD4 tends to remain stable; prognosis relatively good. PCP prophylaxis recommended for CD4 < 200.
- DHHS Guidelines (3/25/2022):
- Untreated patients: CD4 at initiation of care and q3-6 mos
- After initiation of ART: 3 mos
- First 2 years of ART: q3-6 mos
- After 2 years of ART with consistently suppressed VL:
- CD4 300-500: q12 mos
- CD4 >500 for more than 2 years: CD4 monitoring optional
- After modifying ART because of drug toxicity or for regimen simplification in patient with virologic suppression: monitor according to prior CD4 count and duration on ART (as above)
- After modifying ART because of virologic failure: q3-6 mos
- IAS-USA Guidelines (10/14/2020):
- After ART initiation: monitor CD4 q3 mos, especially if CD4 < 200, to determine need for initiation or discontinuation of OI prophylaxis
- After VL suppression for 1 year with stable CD4 >250; further CD4 count monitoring is optional
- CD4% less variable than absolute count, but less predictive of risk of OI. Can be used in cases of discrepant CD4 count results (e.g., to determine whether an apparent decline is likely to be real).
- CD4 count is most important lab result for untreated patients as measure of urgency of ART and need for OI prophylaxis; VL is most important measure of ART efficacy in treated patients.
CD4 Response to ART
- If VL suppression but poor CD4 rise, assess for concomitant infections and use of drugs that suppress bone marrow. Assess concordance of CD4 percent trends. Consider switch from AZT to other NRTI (e.g. TDF or ABC). Consider alternatives to TMP/SMX for PCP prophylaxis, and note very low risk of PCP in patients with undetectable VL and CD4 between 100 and 200 (discontinuation of prophylaxis may be considered)
- No evidence of CD4 improvement with switching or intensifying ART
- IL-2 increases CD4 count, but no clinical benefit in 2 large clinical trials (SILCAAT, ESPRIT) and is not appropriate for use in this setting.
- Worse clinical outcomes with poor CD4 response on ART
- CD4 decline on ART is associated with increased mortality, especially from malignancy and cardiovascular disease. Decline with undetectable viral load should prompt assessment for comorbidities.
Basis for recommendation
- Panel on Antiretroviral Guidelines for Adults and Adolescents; Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. March 25, 2022; https://clinicalinfo.hiv.gov/en/guidelines/adult-and-adolescent-arv/
Comment: DHHS guidelines now recommending less frequent CD4 count monitoring ( for clinically stable pts with suppressed viral loads.
- Saag MS, Gandhi RT, Hoy JF, et al. Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2020 Recommendations of the International Antiviral Society-USA Panel. JAMA. 2020;324(16):1651-1669. [PMID:33052386]
- Helleberg M, Kronborg G, Larsen CS, et al. CD4 Decline Is Associated With Increased Risk of Cardiovascular Disease, Cancer, and Death in Virally Suppressed Patients With HIV. Clin Infect Dis. 2013;57(2):314-21. [PMID:23575194]
Comment: Documented association between CD4 decline and later detection of malignancy and cardiovascular disease.
- Thompson MA, Aberg JA, Cahn P, et al. Antiretroviral treatment of adult HIV infection: 2010 recommendations of the International AIDS Society-USA panel. JAMA. 2010;304(3):321-33. [PMID:20639566]
Comment: IAS-USA guidelines for ART, including recommendations for laboratory monitoring.
- Novitsky V, Woldegabriel E, Kebaabetswe L, et al. Viral load and CD4+ T-cell dynamics in primary HIV-1 subtype C infection. J Acquir Immune Defic Syndr. 2009;50(1):65-76. [PMID:19295336]
Comment: Rate of CD4 decline in a small cohort acute seroconverters with subtype C HIV in Botswana
- Ding M, Tarwater P, Rodriguez M, et al. Estimation of the predictive role of plasma viral load on CD4 decline in HIV-1 subtype C-infected subjects in India. J Acquir Immune Defic Syndr. 2009;50(2):119-25. [PMID:19131898]
Comment: Rate of CD4 decline in a cohort of patients with subtype C HIV in India
- Riddler SA, Haubrich R, DiRienzo AG, et al. Class-sparing regimens for initial treatment of HIV-1 infection. N Engl J Med. 2008;358(20):2095-106. [PMID:18480202]
Comment: Better virologic response with EFV compared to LPV/r in naive pts, but better CD4 response with LPV/r.
- Moore RD, Keruly JC. CD4+ cell count 6 years after commencement of highly active antiretroviral therapy in persons with sustained virologic suppression. Clin Infect Dis. 2007;44(3):441-6. [PMID:17205456]
Comment: CD4 increase can continue 6 yrs after starting HAART, but pts with lower nadir CD4 counts may reach a lower plateau than those with higher CD4 counts, and this is clinically relevant, with greater risk of progression or death despite undetectable VL.
- Gallant JE, DeJesus E, Arribas JR, et al. Tenofovir DF, emtricitabine, and efavirenz vs. zidovudine, lamivudine, and efavirenz for HIV. N Engl J Med. 2006;354(3):251-60. [PMID:16421366]
Comment: TDF/FTC superior to AZT/3TC (in combination with EFV) in naive pts, with better CD4 response.
- DeJesus E, Herrera G, Teofilo E, et al. Abacavir versus zidovudine combined with lamivudine and efavirenz, for the treatment of antiretroviral-naive HIV-infected adults. Clin Infect Dis. 2004;39(7):1038-46. [PMID:15472858]
Comment: ABC/3TC associated with greater increase in absolute CD4 count and CD4 percent than AZT/3TC (combined with EFV) in naive pts.
- Gebo KA, Gallant JE, Keruly JC, et al. Absolute CD4 vs. CD4 percentage for predicting the risk of opportunistic illness in HIV infection. J Acquir Immune Defic Syndr. 2004;36(5):1028-33. [PMID:15247555]
Comment: New comparison of CD4 and CD4% in era of HAART. Demonstrates superiority of absolute CD4 as predictor of OI within 180 days.
- Graham NM, Park LP, Piantadosi S, et al. Prognostic value of combined response markers among human immunodeficiency virus-infected persons: possible aid in the decision to change zidovudine monotherapy. Clin Infect Dis. 1995;20(2):352-62. [PMID:7742442]
Comment: Affirms use of CD4 as marker for effectiveness of ART therapy
- Laurence J. T-cell subsets in health, infectious disease, and idiopathic CD4+ T lymphocytopenia. Ann Intern Med. 1993;119(1):55-62. [PMID:8098929]
Comment: Evaluates ranges for "normal" CD4 counts, and those in HIV-infected pts
- Margolick JB, Muñoz A, Vlahov D, et al. Changes in T-lymphocyte subsets in intravenous drug users with HIV-1 infection. JAMA. 1992;267(12):1631-6. [PMID:1347321]
Comment: CD4 falls by 50 cells/yr in HIV infection
- Taylor JM, Fahey JL, Detels R, et al. CD4 percentage, CD4 number, and CD4:CD8 ratio in HIV infection: which to choose and how to use. J Acquir Immune Defic Syndr. 1989;2(2):114-24. [PMID:2495346]
Comment: CD4% more reliable marker of immune suppression than absolute CD4
- Lazzarin A, Battegay M, Cooper DA, et al.; CD4+ cell increases at 48 weeks in the maraviroc (MVC) treatment-naive (TN) MERIT trial.; 48th Annual ICAAC/IDSA 46th Annual Meeting; 2008; pp. Abstract 1248;
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