1. HIV Drug Resistance in Well-Resourced Settings Vincent Marconi, MD

2. Transmitted Drug Resistance Acquired Drug Resistance

3. Europe North America Japan Australia

4. 23K pts from 75 studies in 20 countries Frentz 2012

5. Wittkop 2011 25 cohorts with >10K pts (after 1998) 9.5% TDR *Trend for more NNRTI VF if TDR even when fully-active Minority Resistance PI durability More NRTI mutations

6. StudyLocationPatientsPeriodOverallNRTINNRTIPI Jain (Options) 2010 CA372 acute/early 02-09161184-6 Wheeler 201010 states2K newly diagnosed 200614.65.67.84.5 Poon (CFAR) 2011 WA, MA, CA 14K mostly chronic 03-0814.2%8.2%8.3%4.2% Markovitz (CDC) 2011 WA, CO506 recent/chronic 03-07171163 Frentz 2012*US + CAN8K93-0812.97.45.73.2 *In contrast to Europe, TDR may have increased in North America from 11.6% in the early era to 14.3% in the late era, due to an increase in NNRTI TDR (4.1- 8.3%), while NRTI TDR decreased (8.0-6.4%)

7. Jain 2010Poon 2011 Essentially unchanged despite improved ART Transmission early in infection TDR led to low CD4 and opposing effects to pVL Specific mutations (67, 184) impacted VL & CD4

8. New HIV pts TDR doubled 5.9% to 11.9% (2003-2010) NRTI TDR most prevalent early (4% in 2003) PI TDR most prevalent late (4.9% in 2010) Less NNRTI resistance than Europe/NA (0.8%) Hattori 2010, 2012 (CROI)

9. Sydney (1992-2001) 185 recent pts N/NRTI TDR peaked in 1990s and plateau of 10–15% 1999–2001 Victoria (1996-2007) 466 recent pts TDR 16%, predominantly associated with NRTI and NNRTI; PI uncommon Ammaranond 2003 Russell 2009 RT PR 1⁰ 2⁰

10. Factors contributing to trends are complex Specific changes over the past 20 years More tolerable & simpler first-line cART (FDC/STR) Improved strategies for adherence Better use of VL monitoring and resistance testing More effective second-line and salvage agents (fewer single ARV additions, better ART mgt) Suboptimal ART (mono-/dual-Tx)  cART, PI/r, TDF Maybe less transmitted drug resistance? Less Virologic Failure and Drug Resistance

11. StudyLocationPatientsPeriodFindings van de Vijver 2010 15 Euro sites 2K VF00-0480.7% > 1 DRM (NRTI 75.5%, NNRTI 48.5%, PI 35.8); predicted resistance to most PI/r was 25% Prosperi (SEHERE) 2011 7 Euro sites 12K VF + 3K naïve controls 99-0880.1% > 1 DRM (NRTI 67.2%, NNRTI 53.7%, PI 32.4%); with 17.2% triple- class; decline in overall resistance to NRTI and PI but not to NNRTI Gill 2010BC5K VF96-08DRM 12-fold decrease from 1996 to 2008 (1.73 to 0.13 cases/pt mos tx); VS increased from 64.7% (2000) to 87.7% (2008) Buchacz 2012 US – HOPS 906 > 4 mos ART VL >1000 99-08DRM from 88% to 79% (esp PI/r), decrease in viremic pts

12. Prosperi 2011

13. Buchasz 2011

14. Lima 2008 Hull 2009 Lima 2010

15. Gupta 2008 ITT Genotypes

16. Hogg 2006 Cozzi-Lepri EUROSIDA 2008 Deeks 2010

17. Transmitted Drug Resistance 10-17% ARV-naïve patients in Europe, North America, Japan and Australia have DR > ARV NNRTI stable or increased over time Acquired Drug Resistance VS has increased over time, thus minimizing the emergence of acquired DR and its subsequent transmission DR frequency following VF: NRTI > NNRTI > PI Mortality association