Abstract Body

Background: Measures of CD4 T-cell count (CD4) and HIV-1 plasma viral load (pVL) are proxies for HIV-1 virulence. Whether these proxies are changing over time has serious implications for prevention and treatment. The aim of this study is to investigate these trends. Methodology: Data were derived from the CASCADE collaboration (updated in 2011) excluding African cohorts, recent seroconverters (≥2009) and children <15 years old at seroconversion (SC). Follow-up was censored at the time of antiretroviral initiation or clinical AIDS onset. CD4 at SC, CD4 rate of decline and pVL measurements were analyzed using linear or fractional polynomials mixed models adjusting for all available potential confounders. Calendar time effects were modelled through natural cubic splines. Results: 15,875 individuals seroconverting from 1979-2008 fulfilled the inclusion criteria. Estimated (95% CI) CD4 at SC for a typical individual declined from ~770 (750-800) in the early `80s to a plateau of ~570 (560-580) cells/μL after 2000. Rates of CD4 loss were relatively stable up to 1996 becoming faster between 1996 and 2004. Estimated (95% CI) pVL set-point increased from 4.05 (3.98-4.12) in 1980 to 4.50 (4.45-4.54) log10 copies/mL in 2002 with a tendency of returning to lower levels thereafter. Estimated (95% CI) CD4 at SC and pVL set-point for white men, infected through sex between men (MSM), aged 30-39 years at seroconversion are shown in Figure (a and b, respectively). Results were similar when restricting the analyses to various subsets (e.g. those with a ‘midpoint’ method of seroconversion determination and a test interval <180 days; white MSM etc.), adjusting for pVL assay, censoring follow-up at 3 years or using variations of the main statistical approach. Conclusions: Our results provide strong indications of an increased HIV-1 virulence and transmissibility during the course of the epidemic and a potential plateau effect after ~2000. Continued monitoring and basic science studies are needed to detect further virulence changes and to assess the consistency of our findings.