Has the rate of CD4 cell count decline before initiation of antiretroviral therapy changed over the course of the Dutch HIV epidemic among MSM?

Abstract

Introduction: Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. Analysis of CD4 cell count decline before antiretroviral therapy (ART) initiation, a surrogate marker for disease progression, may be hampered by informative censoring as ART initiation is more likely with a steeper CD4 cell count decline.

Methods: Development of CD4 cell count from 9 to 48 months after seroconversion was analyzed using a mixed-effects model and 2 models that jointly modeled CD4 cell counts and time to censoring event (start ART, <100 CD4 cells/mm³, or AIDS) among therapy-naïve MSM HIV-1 seroconverters in the Netherlands. These models make different assumptions about the censoring process.

Results: All 3 models estimated lower median CD4 cell counts 9 months after seroconversion in later calendar years (623, 582, and 541 cells/mm³ for 1984-1995 [n = 111], 1996-2002 [n = 139], and 2003-2007 seroconverters [n = 356], respectively, shared-parameter model). Only the 2 joint-models found a trend for a steeper decline of CD4 cell counts with seroconversion in later calendar years (overall p-values 0.002 and 0.06 for the pattern-mixture and the shared-parameter model, respectively). In the shared-parameter model the median decline from 9 to 48 months was 276 cellsmm³ for 1984-1995 seroconverters and 308 cells/mm³ for 2003-2007 seroconverters (difference in slope, p = 0.045).

Conclusion: Mixed-effects models underestimate the CD4 cell decline prior to starting ART. Joint-models suggest that CD4 cell count declines more rapidly in patients infected between 2003 and 2007 compared to patients infected before 1996.

Figure 1. CD4 cell count for a typical patient (36 years of age), backtransformed to original scale by method of estimation.

Dashed lines and shaded regions are 95% confidence intervals.

Figure 2. Mean slope (fat line) of CD4 cell count and 95% CI (dashed thin lines) in /mm³/year according to calendar year of seroconversion estimated using a mixed-effects model and shared-parameter model.