Disease progression and mortality with untreated HIV infection: evidence synthesis of HIV seroconverter cohorts, antiretroviral treatment clinical cohorts and population-based survey data

Abstract

Introduction: Model-based estimates of key HIV indicators depend on past epidemic trends that are derived based on assumptions about HIV disease progression and mortality in the absence of antiretroviral treatment (ART). Population-based HIV Impact Assessment (PHIA) household surveys conducted between 2015 and 2018 found substantial numbers of respondents living with untreated HIV infection. CD4 cell counts measured in these individuals provide novel information to estimate HIV disease progression and mortality rates off ART.

Methods: We used Bayesian multi-parameter evidence synthesis to combine data on (1) cross-sectional CD4 cell counts among untreated adults living with HIV from 10 PHIA surveys, (2) survival after HIV seroconversion in East African seroconverter cohorts, (3) post-seroconversion CD4 counts and (4) mortality rates by CD4 count predominantly from European, North American and Australian seroconverter cohorts. We used incremental mixture importance sampling to estimate HIV natural history and ART uptake parameters used in the Spectrum software. We validated modelled trends in CD4 count at ART initiation against ART initiator cohorts in sub-Saharan Africa.

Results: Median untreated HIV survival decreased with increasing age at seroconversion, from 12.5 years [95% credible interval (CrI): 12.1-12.7] at ages 15-24 to 7.2 years (95% CrI: 7.1-7.7) at ages 45-54. Older age was associated with lower initial CD4 counts, faster CD4 count decline and higher HIV-related mortality rates. Our estimates suggested a weaker association between ART uptake and HIV-related mortality rates than previously assumed in Spectrum. Modelled CD4 counts in untreated people living with HIV matched recent household survey data well, though some intercountry variation in frequencies of CD4 counts above 500 cells/mm³ was not explained. Trends in CD4 counts at ART initiation were comparable to data from ART initiator cohorts. An alternate model that stratified progression and mortality rates by sex did not improve model fit appreciably.

Conclusions: Synthesis of multiple data sources results in similar overall survival as previous Spectrum parameter assumptions but implies more rapid progression and longer survival in lower CD4 categories. New natural history parameter values improve consistency of model estimates with recent cross-sectional CD4 data and trends in CD4 counts at ART initiation.

Keywords: CD4; HIV; adults; cell counts; disease progression; statistical model; survival.