Long-term increase in CD4+ T-cell counts during combination antiretroviral therapy for HIV-1 infection

Abstract

Objective: To inform guidelines concerning when to initiate combination antiretroviral therapy (ART), we investigated whether CD4(+) T-cell counts (CD4 cell counts) continue to increase over long periods of time on ART. Losses-to-follow-up and some patients discontinuing ART at higher CD4 cell counts hamper such evaluation, but novel statistical methods can help address these issues. We estimated the long-term CD4 cell count trajectory accounting for losses-to-follow-up and treatment discontinuations.

Design: The study population included 898 US patients first initiating ART in a randomized trial (AIDS Clinical Trials Group 384); 575 were subsequently prospectively followed in an observational study (AIDS Clinical Trials Group Longitudinal Linked Randomized Trials).

Methods: Inverse probability of censoring weighting statistical methods were used to estimate the CD4 cell count trajectory accounting for losses-to-follow-up and ART discontinuations, overall and for pretreatment CD4 cell count categories (<or=200, 201-350, 351-500, and >500 cells/microl).

Results: Median CD4 cell count increased from 270 cells/microl pre-ART to an estimated 556 cells/microl at 3 and 532 cells/microl at 7 years after starting ART in analyses ignoring treatment discontinuations, and to 570 and 640 cells/microl, respectively, had all patients continued ART. However, even had ART been continued, an estimated 25, 9, 3, and 2% of patients with pretreatment CD4 cell counts of 200 or less, 201-350, 351-500, and more than 500 cells/microl would have had CD4 cell counts of 350 cells/microl or less after 7 years.

Conclusion: If patients remain on ART, CD4 cell counts increase in most patients for at least 7 years. However, the substantial percentage of patients starting therapy at low CD4 cell counts who still had low CD4 cell counts after 7 years provides support for ART initiation at higher CD4 cell counts.

Trial registration: ClinicalTrials.gov NCT00000919 NCT00001137.

Figure 1

Estimated median CD4 count (cells/mm³) over time since starting antiretroviral therapy by initial antiretroviral therapy received in ACTG 384 had all patients been followed for 7 years. Dashed lines are for non-weighted estimates (based on available data at each year of follow-up); solid lines are estimates obtained using inverse probability of censoring weighting (IPCW). N=898 patients starting antiretroviral therapy. efavirenz (EFV); zidovudine (ZDV); lamivudine (3TC).

Figure 2

Estimated median CD4 count (cells/mm³) over time since starting antiretroviral therapy by category of pre-treatment CD4 count: (a) had all patients been followed for 7 years, and (b) had all patients received ART throughout seven years. Dashed lines are for non-weighted estimates (based on available data at each year of follow-up); solid lines are estimates obtained using inverse probability of censoring weighting (IPCW). N=898 patients starting antiretroviral therapy. Horizontal lines are shown at 350, 500 and 800 cells/mm³.

Figure 3

Median CD4 count (cells/mm³) over time among patients who remained in follow-up for seven years according to whether they maintained virologic suppression to <400 copies/ml after starting ART and throughout the seven years (solid lines; N=224 (63%); by pre-treatment CD4 count category: ≤ 200: N=107 (72%); 201–350: N= 52 (70%); 351–500: N= 34 (50%); >500: N= 31 (48%)) or did not maintain virologic suppression (dashed-dotted lines; N=132 (37%); by pre-treatment CD4 count category: ≤ 200: 42 (28%); 201–350: 22 (30%); 351–500: 34 (50%); >500: 34 (52%)). Of those not virologically suppressed for 7 years, N=33 (25%) were on ART without interruptions for 7 years of more than 60 days; by pre-treatment CD4 count category: ≤ 200: 16 (38%); 201–350: 6 (27%); 351–500: 6 (18%); >500: 5 (15%). Horizontal lines are shown at 350, 500 and 800 cells/mm³.