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  1. Improving adherence and survival in antiretroviral therapy programs Andrew Boulle Infectious Disease Epidemiology UnitSchool of Public Health and Family MedicineUniversity of Cape Town

  2. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Drivers of mortality on ART Lawn. AIDS 2008 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  3. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Distribution of excess mortality in population on ART - SSA Brinkhof. PLoS Med 2009 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  4. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Clinical outcomes on ART in Switzerland and South Africa Keiser, PLoS Medicine 2008 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  5. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Clinical outcomes on ART in Switzerland and South Africa South Africa Adjusted HR for mortality Months 1-3: 5.9 (1.8-19.2) Months 4-24: 1.8 (0.9 – 3.5) Switzerland Keiser, PLoS Medicine 2008 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  6. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Possible explanations for adjusted mortality differences on ART • Host and agent • Patients from sub-Saharan Africa treated in France and Switzerland have equivalent survival after adjustment for later initiation of ART* • Environment • Access to ART • Access to health care • Co-morbidities * Breton, HIV Med, 2007; Staehelin, AIDS, 2003. 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  7. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Later access to ART could result in selection bias Khayelitsha 2001 - 2005 20 CD4 = 200 cells/µl 15 10 5 0 Switzerland* 2001 - 2007 Percent 20 15 10 5 0 0 200 400 600 800 Baseline CD4 count (cells/µl) at ART initiation * Source: Matthias Egger for the SHCS 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  8. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Adjustment for clinical severity by WHO stage may be incomplete 160 160 2001/2 2003/4 2005/6 2007+ 140 140 120 120 100 100 Mean # adults started on ART per month 80 80 Median CD4 count at start of ART 60 60 40 40 20 20 250 0 0 Median baseline Oesophageal Extra-pulmonary New adults/month CD4 - all patients candidiasis tuberculosis 0 50 100 150 200 12 66 23 57 2001/2 60 93 42 61 2003/4 144 110 52 85 2005/6 130 130 96 93 2007+ 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  9. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Important not to lose sight of pre-ART mortality • Raise eligibility threshold • Expand VCT • Improve wellness programmes • Improve referral systems Pre-Care Pre-ART ART Enrolment Enrolment 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  10. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Mortality in HIV patients in care in the Free State Province • See update LBPED05. (Margaret May) • 80% of deaths still pre-ART • 12% in waiting times if CD4<25 vs. 100-200 cells/µl 87% of patients who died never received ART Source: Fairall, Arch Intern Med, 2008 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  11. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality 25% Deaths Losses to follow-up 20% 15% Proportion died or lost to followup at 6 months 10% 5% 0% 2001 2002 2003 2004 2005 Year starting ART n 80 248 524 4041 7694 CD4 < 50 cells/µl 51.3% 50.4% 36.8% 24.4% 19.7% 95% CI (39.8 - 62.6) (44.0 - 56.8) (32.7 - 41.1) (23.1 - 25.8) (18.8 - 20.6) Mortality 13.1% 11.1% 8.9% 6.1% 6.3% 95% CI (6.7 - 22.2) (7.6 - 15.3) (6.7 - 11.6) (5.5 - 6.9) (5.6 - 7.1) Loss to follow-up 0.0% 0.4% 1.8% 3.9% 4.3% 95% CI (0.0 - 4.3) (0.0 - 2.0) (0.9 - 3.3) (3.4 - 4.5) (3.7 - 5.0) Does increased enrolment reduce on-ART mortality? Boulle, B-WHO, 2008 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  12. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Mortality by year of starting ART post-linkage Corrected mortality by year, Khayelitsha cohort 2001/2 0.20 2003 logrank p=0.014 2004 2005 2006 0.15 2007 Cumulative mortality - corrected 0.10 2001-2007 Enrolment: from <100 to 2000 adults/year Median baseline CD4: 43 to 131 cells/µl Stage IV at start of ART: 55% to 29% 0.05 0.00 0 1 2 Duration on ART in years N (events) 2001/2 276 (40) 233 (7) 221 2003 365 (52) 307 (10) 287 2004 985 (95) 858 (24) 804 2005 1557 (127) 1349 (33) 576 2006 1969 (127) 920 (6) 2007 921 (32) WEPED211 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  13. Introduction Improving survival Improving adherence Summary Determinants of on-ART mortality Excess on-ART mortality in resource-limited settings Relationship between programme mortality and access to care Evidence for improved survival with increased access to ART Clinical challenges associated with averting on-ART mortality Clinical factors related to context • Tuberculosis • TB treatment when starting ART is not an independent risk for higher mortality • Lawn CROI 2007; Zachariah AIDS 2006; Stringer JAMA 2006; Boulle JAMA 2008 • But, undiagnosed TB a likely contributor based on pre-ART autopsy studies. • Effective TB screening pre-ART and on ART could dramatically reduce new TB disease early on ART (Gideon, TUPEB154) • Presumptive treatment where strongly suspected? (Saranchuk, SAMJ 2007) • IPT on HAART as well? • Undiagnosed drug resistance in hospitalised patients is an important consideration in patients deteriorating on TB treatment (Pepper,PLoS One 2009) • Kaposi’s sarcoma • 35% mortality and 25% loss to follow-up in a cohort of patients with KS starting ART (Chu, CROI 2009, R-138) • Cryptococcal meningitis • Cryptococcal antigen screening pre-ART in patients with low CD4 counts identifies those at risk for incident disease on ART (Jarvis CID 2009) • See editorial review (Lawn, Harries et al, AIDS 2008) 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  14. Introduction Improving survival Improving adherence Summary Excellent outcomes require a targeted approach Who to target / what to measure Pragmatism Programme outcomes where routine viral load is available Boulle, B-WHO, 2008 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  15. Introduction Improving survival Improving adherence Summary Excellent outcomes require a targeted approach Who to target / what to measure Pragmatism Meta-analysis of DOT as an adherence intervention Ford et al., 2009review of studies until April 2009 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  16. Introduction Improving survival Improving adherence Summary Excellent outcomes require a targeted approach Who to target / what to measure Pragmatism How do we identify who needs an intervention above In care Appointments on time Pharmacy recall (Bisson PLoS Med 2009,Nachega Ann Intern Med 2007) Self-report Pill counts Electronic medication monitoring All doses and doses on time Viral load suppressed Viral load 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  17. Introduction Improving survival Improving adherence Summary Excellent outcomes require a targeted approach Who to target / what to measure Pragmatism Conserving first line therapy Orrell, Antivir Ther, 2007 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  18. Introduction Improving survival Improving adherence Summary Excellent outcomes require a targeted approach Who to target / what to measure Pragmatism Missed opportunities to do the sensible things Policy • Clinical guidelines and regimen choice • Adequate data on pill burden and toxicity therefore we need new regimens • Drug procurement and distribution • Unprecedented leverage due to volume • Incomprehensible that we do not have 28 day packs, blistered to obviate the need for pillboxes • Distribution chain already assured, why not use for adherence promotion material • Health systems • Primary care location of treatment (Bedelu JAIDS 2007) Target interventions • Seek to identify patients with early viraemia • At-risk populations • Pregnant women (Kaplan, AIDS 2008) • Young adults and adolescents • Substance abuse / depression / marginalised groups • Men? 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  19. Introduction Improving survival Improving adherence Summary Summary • Expanded access to ART the single most important factor in reducing ART programme mortality • Targeting both clinical and adherence interventions is required given the scale of the service, and the excellent clinical and adherence outcomes in the majority of patients. • Adequate technologies are required such as expanded access to viral load measures and improved tuberculosis diagnostics • There are aspects to ART delivery which are likely to promote adherence and retention in care and which do not further burden the health services 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  20. Acknowledgements Gary Maartens Matthias Egger Nathan Ford Eric Goemaere Graeme Meintjes Gilles Van Cutsem David Coetzee Katherine Hilderbrand Meg Osler Louise Knight Kathryn Stinson Chris Kenyon Robert Wilkinson Molebogeng Rangaka 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009

  21. Questions? 5th IAS Conference on HIV Pathogenesis, Treatment and Prevention. Cape Town, South Africa, July 2009