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. 2014 Sep 9;11(9):e1001718.
doi: 10.1371/journal.pmed.1001718. eCollection 2014 Sep.

Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies

Andrew Boulle  1 , Michael Schomaker  2 , Margaret T May  3 , Robert S Hogg  4 , Bryan E Shepherd  5 , Susana Monge  6 , Olivia Keiser  7 , Fiona C Lampe  8 , Janet Giddy  9 , James Ndirangu  10 , Daniela Garone  11 , Matthew Fox  12 , Suzanne M Ingle  3 , Peter Reiss  13 , Francois Dabis  14 , Dominique Costagliola  15 , Antonella Castagna  16 , Kathrin Ehren  17 , Colin Campbell  18 , M John Gill  19 , Michael Saag  20 , Amy C Justice  21 , Jodie Guest  22 , Heidi M Crane  23 , Matthias Egger  24 , Jonathan A C Sterne  3
Affiliations

Mortality in patients with HIV-1 infection starting antiretroviral therapy in South Africa, Europe, or North America: a collaborative analysis of prospective studies

Andrew Boulle et al. PLoS Med. .

Abstract

Background: High early mortality in patients with HIV-1 starting antiretroviral therapy (ART) in sub-Saharan Africa, compared to Europe and North America, is well documented. Longer-term comparisons between settings have been limited by poor ascertainment of mortality in high burden African settings. This study aimed to compare mortality up to four years on ART between South Africa, Europe, and North America.

Methods and findings: Data from four South African cohorts in which patients lost to follow-up (LTF) could be linked to the national population register to determine vital status were combined with data from Europe and North America. Cumulative mortality, crude and adjusted (for characteristics at ART initiation) mortality rate ratios (relative to South Africa), and predicted mortality rates were described by region at 0-3, 3-6, 6-12, 12-24, and 24-48 months on ART for the period 2001-2010. Of the adults included (30,467 [South Africa], 29,727 [Europe], and 7,160 [North America]), 20,306 (67%), 9,961 (34%), and 824 (12%) were women. Patients began treatment with markedly more advanced disease in South Africa (median CD4 count 102, 213, and 172 cells/µl in South Africa, Europe, and North America, respectively). High early mortality after starting ART in South Africa occurred mainly in patients starting ART with CD4 count <50 cells/µl. Cumulative mortality at 4 years was 16.6%, 4.7%, and 15.3% in South Africa, Europe, and North America, respectively. Mortality was initially much lower in Europe and North America than South Africa, but the differences were reduced or reversed (North America) at longer durations on ART (adjusted rate ratios 0.46, 95% CI 0.37-0.58, and 1.62, 95% CI 1.27-2.05 between 24 and 48 months on ART comparing Europe and North America to South Africa). While bias due to under-ascertainment of mortality was minimised through death registry linkage, residual bias could still be present due to differing approaches to and frequency of linkage.

Conclusions: After accounting for under-ascertainment of mortality, with increasing duration on ART, the mortality rate on HIV treatment in South Africa declines to levels comparable to or below those described in participating North American cohorts, while substantially narrowing the differential with the European cohorts. Please see later in the article for the Editors' Summary.

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Conflict of interest statement

MSS is the local principal investigator on studies sponsored by Abbvie, Gilead, BMS, Merck, BI, ViiV, and Jannsen, where funding goes directly to the institution but not to MSS. PR, through his institution, has received independent scientific grant support from Gilead Sciences, Janssen Pharmaceutica N.V., Merck&Co, Bristol-Myers Squibb, and ViiV Healthcare, and travel support through his institution from Gilead Sciences and Janssen Pharmaceutica N.V. In addition, PR has served on a scientific advisory board for Gilead Sciences and serves on a data safety monitoring committee for Janssen Pharmaceutica N.V., for which his institution has received remuneration. KE has received honoraria from Abbott for educational lectures. JS has received research grants from the UK Medical Research Council. JS has received payment from Gilead Sciences, Inc for educational presentations.

Figures

Figure 1
Figure 1. Cumulative incidence of mortality up to four years after start of ART by region, corrected in South Africa for mortality under-ascertainment.
Figure 2
Figure 2. Cumulative incidence of mortality up to four years after start of ART by region and CD4 count at ART initiation, corrected in South Africa for mortality under-ascertainment.
Figure 3
Figure 3. Relative mortality by region and duration on ART comparing European and North American cohorts to South Africa. (A) Crude rates, (B) adjusted for baseline covariates*, (C) corrected for cohort-assessed mortality under-ascertainment** and adjusted for baseline covariates, and (D) limited in Europe and North America to patients with sexual acquisition of HIV, adjusted for baseline covariates.
*Adjusted for baseline gender, CD4 count, clinical stage, viral load, and calendar period. **In order to correct for cohort-assessed completeness of mortality ascertainment, mortality was predicted for each region and duration from a multivariable model for each cohort for women aged 30–45 starting ART with a CD4 count 100–199 cells/µl in 2004–2007, with advanced clinical stage and viral load 4–5 log copies/ml. Each mortality rate in Europe and North America was multiplied by the inverse of the cohort-assessed proportion of deaths ascertained (weighted estimate from participating cohorts), prior to converting to rate ratios relative to South Africa.
Figure 4
Figure 4. Predicted mortality by cohort and region.
Predicted for women aged 30–45, starting ART with a CD4 count 100–199 cells/µl in 2004–2007, advanced clinical stage, and viral load 4–5 log copies/ml. The squares are scaled to the square root of cohort size, the horizontal lines represent 95% CIs, and the dotted vertical lines represent regional estimates for each duration. A mortality rate could not be estimated for one European cohort between 6 and 12 months on ART due to the absence of events. RSA, South Africa; NA, North America; EUR, Europe.
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