Abstract

IntroductionStudies 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.MethodsDevelopment 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.ResultsAll 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).ConclusionMixed-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.

Highlights

  • Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated

  • The effect of higher viral load and lower CD4 T-cell count at set-point on progression to AIDS or death is difficult to study in the combination antiretroviral therapy era as these endpoints are hardly observed in effectively treated patients

  • Of all men having sex with men (MSM), 9 (8%) out of 120 with seroconversion between 1984 and 1995, 122 (47%) out of 261 with seroconversion between 1996 and 2002, and 165 (32%) out of 521 with seroconversion between 2003 and 2007, were excluded because either the date of antiretroviral therapy (ART) initiation, the date CD4 cell count had dropped below 100 cells/mm3, or the date 1 year prior to diagnosis of AIDS was before 9 months after seroconversion

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Summary

Introduction

Studies suggest that the HIV-1 epidemic in the Netherlands may have become more virulent, leading to faster disease progression if untreated. We found an increasing trend over time in plasma HIV-1 RNA concentration at set-point, i.e., 9 to 27 months after HIV-1 seroconversion and an accompanying decreasing trend of CD4 cell count measured at viral set-point [3]. Some cohorts have reported a similar increase in HIV-1 RNA concentration and decrease in CD4 cell count at viral set-point over time [5,6,7], whereas others found no evidence for such changes [8,9]. The effect of higher viral load and lower CD4 T-cell count at set-point on progression to AIDS or death is difficult to study in the combination antiretroviral therapy (cART) era as these endpoints are hardly observed in effectively treated patients. We investigated trends in CD4 cell count decline between 9 months and 4 years after HIV seroconversion, using regression models that make different assumptions about the censoring pattern

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