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,Matthias Egger,Michael Schomaker,Bryan E Shepherd,Daniela Garone,Olivia Keiser,Peter Reiss,Janet Giddy,Heidi M Crane,Kathrin Ehren,Colin Campbell,Robert S Hogg,Antonella Castagna,Amy C Justice,Dominique Costagliola,James Ndirangu,Susana Monge,Margaret T May ,Michael S Saag ,Jodie L Guest ,M John Gill ,Fiona Lampe ,Suzanne M Ingle ,François Dabis ,Matthew P Fox ,Jonathan A C Sterne

doi:10.1371/journal.pmed.1001718

Abstract

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. 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. 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.

Highlights

Antiretroviral therapy (ART) for HIV-infected patients has been routinely available in some Sub-Saharan African settings for more than a decade
After accounting for under-ascertainment of mortality, with increasing duration on antiretroviral therapy (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
Acquisition of HIV was attributed to heterosexual contact in 15,045 (51%) patients in Europe and 672 (9%) in North America; data on mode of sexual transmission were not available for South African patients

Summary

Introduction

Antiretroviral therapy (ART) for HIV-infected patients has been routinely available in some Sub-Saharan African settings for more than a decade. Most data on long-term prognosis of patients started on ART continue to be derived from Europe and North America [7], in part because of concerns about mortality ascertainment in high burden settings [8]. Measured early mortality on ART has been higher in resource-limited settings including Southern Africa [9], with explanations for these differences focussing on demographic, socio-economic, biological, and health service factors [12]. 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. In 1996, effective antiretroviral therapy (ART) became available and, for people living in high-income countries, HIV infection became a chronic condition. By the end of 2012, nearly two-thirds of HIV-positive people (nearly 10 million individuals) living in low- and middle-income countries who were eligible for treatment because their CD4 cell count had fallen below 350/mm blood or because they had developed an AIDSdefining condition were receiving treatment

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