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Rates and Predictors of Failure of First-line Antiretroviral Therapy and Switch to Second-line ART in South Africa

Fox, Matthew P. DSc, MPH; Cutsem, Gilles Van MD, DTM&H, MPH; Giddy, Janet MBChB, MFamMed; Maskew, Mhairi MBChB, MSc; Keiser, Olivia PhD; Prozesky, Hans MD; Wood, Robin MMed, FCP(SA), BSc, BM; Hernán, Miguel A. MD, DrPH; Sterne, Jonathan A. C. PhD, MA, MSc; Egger, Matthias MD, MSc, FFPHM; Boulle, Andrew MBChC, MSc, FCPHM(SA), PhDfor the IeDEA-SA collaboration

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 1st, 2012 - Volume 60 - Issue 4 - p 428–437
doi: 10.1097/QAI.0b013e3182557785
Epidemiology and Prevention

Objectives: To measure rates and predictors of virologic failure and switch to second-line antiretroviral therapy (ART) in South Africa.

Design: Observational cohort study.

Methods: We included ART-naive adult patients initiated on public sector ART (January 2000 to July 2008) at 5 sites in South Africa who completed ≥6 months of follow-up. We estimated cumulative risk of virologic failure (viral load ≥400 copies/mL with confirmation above varying thresholds) and switching to second-line ART.

Results: Nineteen thousand six hundred forty-five patients (29,935 person-years) had a median of 1.3 years of study follow-up (1.8 years on ART) and a median CD4 count of 93 (IQR: 39–155) cells per microliter at ART initiation. About 9.9% (4.5 per 100 person-years) failed ART in median 16 (IQR: 12–23) months since ART initiation, with median 2.7 months (IQR: 1.6–4.7) months between first elevated and confirmatory viral loads. By survival analysis, using a confirmatory threshold of 400 copies per milliliter, 16.9% [95% confidence interval (CI): 15.4% to 18.6%] failed by 5 years on ART, but only 7.8% (95% CI: 6.6% to 9.3%) using a threshold of 10,000. CD4 <25 versus 100–199 (adjusted HR: 1.60; 95% CI: 1.37 to 1.87), ART initiation viral load ≥1,000,000 versus <10,000, (1.32; 0.91 to 1.93), and 2+ gaps in care versus 0 (95% CI: 7.25; 4.95 to 10.6) were predictive of failure. Overall, 10.1% (95% CI: 9.0% to 11.4%) switched to second-line by 5 years on ART. Lower CD4 at failure and higher rate of CD4 decline were predictive of switch (decline 100% to 51% versus 25% to –25%, adjusted HR: 1.96; 95% CI: 1.35 to 2.85).

Conclusions: In resource-limited settings with viral load monitoring, virologic failure rates are highly sensitive to thresholds for confirmation. Despite clear guidelines there is considerable variability in switching failing patients, partially in response to immunologic status and postfailure evolution.

*Center for Global Health and Development, Boston University, Boston, MA

Department of Epidemiology, Boston University School of Public Health, Boston University, Boston, MA

Medicines Sans Frontier, Cape Town, South Africa

§McCord Hospital, Durban, South Africa

Clinical HIV Research Unit, University of the Witwatersrand, Johannesburg, South Africa

Institute of Social and Preventive Medicine, University of Bern, Bern, Switzerland

#Department of Medicine, University of Stellenbosch and Tygerberg Academic Hospital, Cape Town, South Africa

**Desmond Tutu HIV Centre, University of Cape Town, Cape Town, South Africa

††Department of Epidemiology, Harvard School of Public Health, Boston, MA

‡‡Harvard-MIT Division of Health Sciences and Technology, Boston, MA

§§Department of Social Medicine, School of Social and Community Medicine, University of Bristol, Bristol, United Kingdom

‖‖Centre for Infectious Disease Epidemiology and Research, School of Public Health and Family Medicine, University of Cape Town, Cape Town, South Africa.

Correspondence to: Matthew P. Fox, DSc, MPH, Crosstown Center, 3rd Floor, 801 Massachusetts Ave, Boston, MA 02118 (e-mail:

Supported by Grant Number U01AI069924 from NIH (NIAID, NICHD, NCI, Principal Investigators Egger and Davies). Dr Fox was funded by Award Number K01AI083097 from the National Institute of Allergy And Infectious Diseases. Dr Hernán was funded by NIH R01 AI073127. Professor Sterne was supported by UK MRC grant G0700820. Dr Keiser was funded by a PROSPER fellowship by the Swiss National Science Foundation (Grant 32333B_131629). The findings are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

The authors have no conflicts of interest to disclose.

The Members of the IeDEA Southern Africa steering group and site principal investigators are listed in Appendix 3.

Received November 28, 2011

Accepted February 17, 2012

Copyright © 2012 Wolters Kluwer Health, Inc. All rights reserved.