1. 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

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) NNRTINRTI 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 Recently infected populations

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

5. Number of people receiving ART in low and middle income countries Source: WHO, 2010 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

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! 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 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 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 critical to the success of global ART scale-up and the minimization of HIVDR 1. Patient factors 2. Antiretroviral drug/regimen factors 3. ART programmatic factors 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

11. Four-Step Approach Step 1: Assess HIVDR 1.Assess transmitted and acquired HIVDR using standardized methods 2.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. 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 Four-Step Approach

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

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

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) Indicator % clinics meeting target Target Lost to follow-up (LTFU) at 12 months69%≤20% Retention on appropriate 1 st line ART at 12 months 67%≥ 70% On time pill pick-up17%≥90% On time appointment keeping58%≥ 80% Drug stock out at the level of ART clinic65%0%

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 Weigel R, et al BMC Infectious Diseases 2011 60% untraceable (no phone or address) 40% possible to trace 41% died 59% alive 50% on ART at clinic 40% on ART in other clinics 10% stopped ART

17. LTFU Study (Malawi, Lilongwe) Step 2 OPERATIONAL RESEARCH Step 3 INTERVENTION Step 4 IMPACT ASSESSMENT Having a phone number recorded doubled odds of successful tracing (aOR 2.07, p<0.001) Regular collection of contact information introduced Clinic is now able to successfully trace 85% (instead of 40%) of LTFU 50% of LTFU were alive and still on ART at the clinic: "2 wks after last missed visit is too early to trigger active tracing" Time before active tracing altered from 2 to 3 weeks after last missed visit Not assessed 40% of LTFU were silent transfer out Improved information transfer between facilities prevent costly tracing (Not implemented) Not assessed

19. 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

20. 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

21. 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 Kelley K et al. (submitted to CID) Additional assessments will be required to evaluate the barriers to using Global Fund grants to support HIVDR Surveillance

22. 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

23. 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 …..