Global HIV Resistance: The Implications of Transmission Deenan Pillay, MD, PhD Professor of Virology Royal Free & University College Medical School University College London London, UK

Disclosures

Structure of Talk Basis of resistance Resistance in treated: prevalence and predictors Resistance in untreated: prevalence, risk groups, persistence, minority populations and consequences Potential for resistance in developing world

Replication Cycle of HIV maturation inhibitor reverse transcriptase inhibitors integrase inhibitors DS dna COMPLEX protease inhibitors CD4 attachment inhibitors fusion inhibitor chemokine receptor inhibitors HIV entry inhibitors

The Biological Basis of HIV Drug Resistance

Question: Drug resistance emerges during antiretroviral therapy Because the drug interacts with the virus to cause resistance mutations Because pre-existing variants of virus preferentially replicate in the presence of drug Regardless of the level of viral suppression achieved

Virological Response to Antiretroviral Therapy rebound 105 104 103 102 101 100 10-1 10-2 10-3 assay limit of detection Copies/mL Suppression

Selective Pressure of Therapy Drug-susceptible quasispecies Drug-resistant quasispecies Viral load Time

Selective Pressure of Therapy Treatment begins Drug-susceptible quasispecies Drug-resistant quasispecies Viral load Time

Selective Pressure of Therapy Treatment begins Drug-susceptible quasispecies Drug-resistant quasispecies Selection of resistant quasispecies Viral load Incomplete suppression Inadequate potency Inadequate drug levels Inadequate adherence Pre-existing resistance Time

Resistance Accumulates Mutations Fold Change Susceptible Resistant Determine clinical relevance for each drug

How Much Resistance in ARV Treated Individuals?

Prevalence of Resistance as a Proportion of Treated Patients important to place resistance in context of all TREATED patients Pillay et al. JID 2005;192:967-73.

Predictors of Resistance in ARV-treated Patients

Prevalence of Triple-class Drug Failure Over Calendar Time Treatment experienced at start of HAART Treatment naïve at start of HAART 1/97 1/98 1/99 1/00 1/01 1/02 1/03 1/97 1/98 1/99 1/00 1/01 1/02 1/03 Follow-up (n) 554 1482 1814 1944 1988 2029 2028 140 514 716 860 958 1174 1212 0 10 68 163 241 282 3 15 0 0 10 21 33 3 8 58 Triple-class treatment failure (n) Mocroft et al. JID 2004;190:1947–56.

Years from start of ART (≥3 drugs) Cumulative Risk of Triple-class Virologic Failure (incl boosted PIs) in 10,603 Patients Years from start of ART (≥3 drugs) 2 4 6 8 10 Extensive failure of: Nucleosides 4% 9% 15% 21% 28% PIs 2% 8% 11% 16% NNRTI 13% 20% 26% 31% 35% TCF 5% Extensive TCF 0% 1% 3% PI failure = boosted PIs; TCF = triple class failure Phillips et al. CROI 2007. Abst 532.

Resistance in Treated Individuals is… Decreasing since initiation of triple therapy Low in those using RTV boosted PIs Managed by new drugs within existing classes and new classes

Transmission of Resistance ARV treated individuals living longer Incident infections continue to increase worldwide Transmitted resistance well recognised in countries with wide ARV coverage

Transmission of Resistance in Europe (17 countries) SPREAD Route of Infection p-value OR CI IDU 6.8% 6/88 0.35 0.65 0.27 1.58 Origin / infect. in HPC 5.2% 10/193 0.046 0.49 0.24 0.99 Heterosexual 12.0% 30/246 0.38 1.24 0.76 2.02 MSM (reference) 10.0% 47/467 1.00 Origin / infect. in HPC* 5.2% 10/193 0.046 0.49 0.24 0.99 *HPC = high prevalence countries n=989; 22% recent infections Wensing et al. JID 2005;192:958-66.

Samples with IAS mutation(s) (%) In resource rich world, transmitted resistance appears to be stabilising or even reducing 14 Chronic infection 12 10 8 Samples with IAS mutation(s) (%) 6 4 Acute infection 2 1997 1998 1999 2000 2001 2002 2003 2004 2005 Year of sample UK Collaborative Group on HIV Drug Resistance. AIDS 2007;21:1035-9.

Persistence of Transmitted Resistance in Primary HIV Infection Persistent resistance n=11 Primary resistance n=2 Reversion to wild type US; F/U median 9 months n=14 Persistent resistance n=16 Primary resistance n=2 Reversion to wild type UK; F/U up to 3 years Variable persistence according to mutations: TAMs persist, K103N persists, PI persist, MDR persist Little et al. 11th CROI 2004, San Francisco, CA. Abs 36LB. Pao et al. JAIDS 2004;37:1570-3.

In resource rich world... Rates of transmitted resistance stabilising or reducing Transmitted resistant species persist prior to initiating treatment, and represents a risk for onward transmission

Implications of ARV Rollout in Resource Poor World for Resistance

Implications of HAART Without Virological Monitoring: Therapy Failure? Increasing Resistance Implications of HAART Without Virological Monitoring: Therapy Failure? Treatment onset Virological failure (>1000c/mL) Clinical failure (AIDS events) VL 1000 Months Years CD4 count VL

Resistance Following First-line ART Country Most common ART regimen Other drugs % failure resistance Most common mutation Others mutations Abstract number South Africa d4T + 3TC + NNRTI LPV/r AZT ddI 2% 68% M184V 43% NRTI (TAMs); NNRTI PI (M46I, G48V, I54V, V82A, L90M) 661 Mali d4T + 3TC + NVP None 23% 50% 100% 662 Botswana AZT + ddI + d4T 3TC NA 78% 74% NRTI (TAMs) 52% 664 CROI 2007

DART TRIAL ZDV/3TC/TDF (n=300) Prevalence of mutations at 24 and 48 weeks in absence of virological monitoring Mutation Week 24 (n=24) Week 48 (n=41*) M184V 15 (62%) 32 (78%) K65R 3 (12%) 6 (15%) M41L 7 (29%) 17 41%) D67NG 9 (38%) 23 (56%) K70R 8 (33%) L210W 0 (0%) 3 (7%) T215FY 17 (41%) K219QEN 1 (4%) 9 (22%) Total TAMs: 0 1–3 4–6 10 (42%) 13 (54%) 11 (27%) 18 (44%) 12 (39%) TAM Group** I II I and II 5 (36%) 4 (11%) 2 (7%) 11 (37%) 17 (57%) Pillay et al. CROI 2007. Abstr. 642.

Summary Resistance develops following failure of therapy Resistance can be transmitted Improvements in ARV use reduces emergence and transmission of resistance Extensive resistance may develop in absence of monitoring of ARV use

Question: Risk of resistance is increased by: Mono and/or dual therapy prior to HAART Use of ritonavir boosted PIs Initiation of HAART at CD4 counts >200/L