HIV Drug Resistance in Well-Resourced Settings

Vincent Marconi, MD

Outline

Transmitted Drug ResistanceAcquired Drug Resistance

Transmitted Drug Resistance

EuropeNorth AmericaJapanAustralia

Europe

23K pts from 75 studies in 20 countries

1985-2003 2004-20090tan28a566028

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OverallNRTINNRTIPIPe

rcen

tage

Frentz 2012

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

North America

Study Location Patients Period Overall NRTI NNRTI PI

Jain (Options) 2010

CA 372 acute/early

02-09 16 11 8 4-6

Wheeler 2010 10 states 2K newly diagnosed

2006 14.6 5.6 7.8 4.5

Poon (CFAR) 2011

WA, MA, CA

14K mostly chronic

03-08 14.2% 8.2% 8.3% 4.2%

Markovitz (CDC) 2011

WA, CO 506 recent/chronic

03-07 17 11 6 3

Frentz 2012* US + CAN 8K 93-08 12.9 7.4 5.7 3.2

*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%)

Jain 2010 Poon 2011

Essentially unchanged despite improved ARTTransmission early in infection

TDR led to low CD4 and opposing effects to pVLSpecific mutations (67, 184) impacted VL & CD4

Japan

• 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)

Australia

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

Ammaranond 2003Russell 2009

RT

PR

1⁰2⁰

Acquired Drug Resistance

Factors contributing to trends are complexSpecific changes over the past 20 years

More tolerable & simpler first-line cART (FDC/STR)Improved strategies for adherenceBetter use of VL monitoring and resistance testingMore effective second-line and salvage agents (fewer single ARV additions, better ART mgt)Suboptimal ART (mono-/dual-Tx) cART, PI/r, TDFMaybe less transmitted drug resistance?

Less Virologic Failure and Drug Resistance

Cohort StudiesStudy Location Patients Period Findings

van de Vijver 2010

15 Euro sites

2K VF 00-04 80.7% > 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

99-08 80.1% > 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 2010 BC 5K VF 96-08 DRM 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

99-08 DRM from 88% to 79% (esp PI/r), decrease in viremic pts

Europe

Prosperi 2011

United States

Buchasz 2011

Canada

Lima 2008Hull 2009Lima 2010

Clinical Trial Resistance 96 wks

Gupta 2008

ITT

Genotypes

Mortality

Hogg 2006Cozzi-LepriEUROSIDA 2008Deeks 2010

Summary

Transmitted Drug Resistance10-17% ARV-naïve patients in Europe, North America, Japan and Australia have DR > ARVNNRTI stable or increased over time

Acquired Drug ResistanceVS has increased over time, thus minimizing the emergence of acquired DR and its subsequent transmissionDR frequency following VF: NRTI > NNRTI > PIMortality association