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

Transmitted Drug Resistance Acquired Drug Resistance

Europe North America Japan Australia

23K pts from 75 studies in 20 countries Frentz 2012

Wittkop 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

StudyLocationPatientsPeriodOverallNRTINNRTIPI Jain (Options) 2010 CA372 acute/early Wheeler states2K newly diagnosed Poon (CFAR) 2011 WA, MA, CA 14K mostly chronic %8.2%8.3%4.2% Markovitz (CDC) 2011 WA, CO506 recent/chronic Frentz 2012*US + CAN8K *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 ( %), while NRTI TDR decreased ( %)

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

New HIV pts TDR doubled 5.9% to 11.9% ( ) 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)

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

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

StudyLocationPatientsPeriodFindings van de Vijver Euro sites 2K VF % > 1 DRM (NRTI 75.5%, NNRTI 48.5%, PI 35.8); predicted resistance to most PI/r was 25% Prosperi (SEHERE) Euro sites 12K VF + 3K naïve controls % > 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 > DRM from 88% to 79% (esp PI/r), decrease in viremic pts

Prosperi 2011

Buchasz 2011

Lima 2008 Hull 2009 Lima 2010

Gupta 2008 ITT Genotypes

Hogg 2006 Cozzi-Lepri EUROSIDA 2008 Deeks 2010

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