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Silvia Bertagnolio, MD World Health Organization Geneva, Switzerland

Assessment Strategies and Interventions to Minimize the Selection and Transmission of Drug Resistant HIV in Resource Limited Settings. Silvia Bertagnolio, MD World Health Organization Geneva, Switzerland. ART in Resource-Limited Settings.

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Silvia Bertagnolio, MD World Health Organization Geneva, Switzerland

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  1. Assessment Strategies and Interventions to Minimize the Selection and Transmission of Drug Resistant HIV in Resource Limited Settings Silvia Bertagnolio, MD World Health Organization Geneva, Switzerland

  2. ART in Resource-Limited Settings 6.6 million on ART in low- and middle-income countries at the end of 2010 • - 22-fold increase since 2001 • - 1.4 million people started ART in 2010

  3. WHO surveys of Transmitted Drug Resistance (n=2788) Recently infected populations NNRTI NRTI PI Overall prevalence of any DRM: 3.7% (95% CI 3%-4.4%) Gupta et al., Antivir Ther, 2011: Overall Transmitted HIVDR: 2.5% - 4 % Bertagnolio S et al., CROI 2011; Jordan M et al, Antiviral Therapy, 2011

  4. WHO surveys: HIVDR (n=1503) 5.7% (95% CI 4.8-6.7) 2.2% 1.4% 3.4% 1.3% 1.1% Hamers R et al., CROI 2011 # 622 Chronically Infected, ARVs-naive populations NNRTI NRTI PI ≥1 TAMs: 1.3% (N = 19; 13 pathway 2) ≥3 TAMS: 0.3% (N = 4) Bertagnolio S, CROI 2011 Jordan M, Antiviral Therapy, 2011

  5. Number of people receiving ART in low and middle income countries Emergence of HIVDR is inevitable • Time since start of ART scale-up a risk factor for TDR (OR 1.38 per year, p<0.001) Hammers R et al, CROI, 2011 Source: WHO, 2010

  6. HIVDR testing realities: RLS • TDR is associated with poor virological outcome Wittkop, Lanc Infect Dis, 2011 • Individualized approach for HIVDR testing currently not routinely available nor recommended • Expensive: would take away resources from other important priorities • Complex: limited capacity and infrastructure • Limited treatment options leave little room for regimen change based on genotyping results • Lack of accessible individual HIVDR testing should not be an excuse to limit optimization of patient care and global efforts to minimize HIVDR Jordan M, CID, 2011

  7. Earlier treatment initiation of ART (CD4 <350): estimated 50% increase in the number of people eligible for ART (UNAIDS, 2010) Median time from seroconversion to CD4 <200 and <350 cell/mm3: 4.19 and 7.93 years, respectively Additional 3.7 years of exposure to ART (S.Lodi, CID, in press) The longer the exposure to ARVs, the greater the risk of developing HIVDR What is the public health impact of expanded ART access on HIVDR? • Will HIVDR increase to alarming levels? • Yes • No • Maybe

  8. YES! NO! "Expanded coverage can reduce HIV incidence in populations, and therefore the actual number of new resistant infections" Gill VS et al. Clin Infect Dis. 2010 HIVDR in an inevitable consequence of expanded ART coverage and prevention interventions using ARVs • More people on ART=more people failing ART • More people failing ART=more people with HIVDR virus • Therefore, the relative contribution to new infections from people that are failing ART with HIVDR will increase Increased proportion of new infections that are resistant among those which are not averted R.F.Baggaley et al. Curr Opin HIV and AIDS, 2011 • MAYBE…. • 1. Fear of resistance should not be an argument against expansion of ART coverage • 2. Routine, standardized, population-based surveillance of HIVDR is imperative • 3. Robust programmatic evaluation of factors associated with HIVDR is a critical component of successful ART scale-up • 4. Operational research to identify best practices is essential

  9. What can countries do to minimize emergence and transmission of HIVDR?

  10. Factors criticalto the success of global ART scale-up and the minimization of HIVDR 1. Patient factors Stigma/discrimination 3 times more likely to be non-adherent Lance S Rintamaki, et al. AIDS Patient Care and STDs. 2006 Adherence Treatment interruption of 48 hours or more associated with virological failure and selection of drug resistant HIV Oyugi JH, et al. AIDS 2007 2. Drug/regimen factors Suboptimal regimens - Inappropriate prescribing practices - Use of non QA drugs - Sd-NVP (PMTCT) - Drug-drug interactions - Drug toxicity - High pill burden • Boulle A, JAMA 2008; Maartens G, Antivir Ther 2009; Parienti l, CID, 2009; Shah Sl, AIDS Res Hum Retr 2011; • 3. Programmatic factors • Burden on the health system: • - Increasing demand of services • - Limited human resources and infrastructure • - Fragile drug procurement and supply management systems • - Lack of routine VL monitoring • - Sustaining high quality service while decentralizing care • - Weak M&E system assessing quality of care and treatment outcomes 1. Patient factors 2. Antiretroviral drug/regimen factors 3. ART programmatic factors

  11. Four-Step Approach Step 1: Assess HIVDR • Assess transmitted and acquired HIVDR using standardized methods • Routine monitoring of patients, clinic and programmatic factors contributing to HIVDR Step 2: Operational Research • Use findings from step 1 to guide operational research • Characterize areas of programmatic weakness • Identify appropriate targeted interventions

  12. Four-Step Approach Step 3: Implement targeted intervention • Using operational research findings (step 2). Step 4: Evaluate impact of intervention • Ideally, using same methods applied in step 1

  13. Countries Implementing One or More WHO HIVDR Surveys (Feb 2011) Step 1 Laboratories accredited by WHO Laboratories undergoing assessment

  14. Transmission of DR HIV in recently infected population Emergence of HIVDR in treated patients ART site factors associated with HIVDR Emergence Surveillance Monitoring Surveys * Early Warning Indicators Non-Laboratory; Data collection only Genotyping Laboratory Genotyping, VL Laboratory TDR classified <5% 5-15% >15% HIVDR prior ART and at 12 months; VL suppression at 12 months; use results for programmatic adjustments Areas to directly target for improvement PUBLIC HEALTH ACTION Step 1 WHO HIVDR Global Assessment Strategy *Surveys to monitor HIV DR prevention and associated factors in sentinel ARV treatment sites

  15. WHO HIVDR EWI 50 countries monitored HIVDR EWI 131,686 patients initiating ART in the period 2004–09 2,107 ART clinics Bennett DE et al. (unpublished data)

  16. LTFU Study (Malawi, Lilongwe) Assessment: of 3846 ever started ART, 48% LTFU Operation research goals: Understand true outcomes of LTFU Risk factors for tracing success Findings: 1800 pts LTFU consented tracing 74% traced 60% untraceable (no phone or address) 40% possible to trace 50% on ART at clinic 40% on ART in other clinics 10% stopped ART 41% died 59% alive Weigel R, et al BMC Infectious Diseases 2011

  17. LTFU Study (Malawi, Lilongwe)

  18. Sustainability of HIV response • In 2010, international resources for HIV declined • 2011: 16 billion $ earmarked of 24 billions $ estimated to be needed • In 56 countries, international donors account for at least 70% of HIV resources

  19. HIVDR surveillance sustainability • Global Fund to fight AIDS, Tuberculosis and Malaria (GF) • largest funder of HIV programs internationally • In 2002, mechanisms to encourage countries to implement HIVDR surveillance • We reviewed documentation for funded HIV grants to assess grantee use of GF resources to support HIVDR Surveillance

  20. HIVDR surveillance sustainability • 147 HIV grants funded (2004-2008) • Only 22% (32/147) requested funding for HIVDR Surveillance • Baseline information and field experience suggest countries make limited use of GF resources to support national HIVDR surveillance activities Additional assessments will be required to evaluate the barriers to using Global Fund grants to support HIVDR Surveillance Kelley K et al. (submitted to CID)

  21. Take-Home Messages • Fear of resistance -- not an argument against expansion of ART • Robust programmatic evaluation of factors associated with HIVDR -- a critical component of successful ART scale-up • Routine, standardized, population-based surveillance of HIVDR is imperative --- must be integrated into routine M & E programmes • Operational research to identify best practices essential • Funders and national governments must step up to support and sustain population based HIVDR surveillance and efforts optimizing patient care

  22. Acknowledgments The Bill and Melinda Gates Foundation Michael R. Jordan Neil Parkin Andrew Phillips Andrea De Luca Marco Vitoria My son Alessandro….who was born 2 months ago and actively attempted to abort the preparation of this presentation …..

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