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.

Conflict of interest statement

Potential conflicts of interest: Dr. Hughes is a paid member of Data and Safety Monitoring Boards for Boehringer-Ingelheim, Medicines Development Ltd, Pfizer and Tibotec. These companies are all manufacturers or developers of antiretroviral therapy or other therapy for HIV infection. In the past year and currently, Dr. Benson has served on advisory boards for GlaxoSmithKline and Merck, and served on a Data and Safety Monitoring Board for Achillion, Dr. Collier receives research support from Merck & Co. and Schering-Plough, has served on advisory boards for GlaxoSmithKline and Pfizer, is a member of a Data and Safety Monitoring Board for Merck & Co., and owns stock in Abbott Laboratories and Bristol Myers Squibb. In the past year, Dr. Robbins was a consultant for Johnson and Johnson.

Figures

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.