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

DS dna COMPLEX

reversetranscriptase

inhibitors

proteaseinhibitors

integrase inhibitors

HIV entry inhibitors

maturation inhibitor

fusion inhibitor

chemokine receptor

inhibitors

CD4 attachment 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

105

104

103

102

101

100

10-1

10-2

10-3

Cop

ies/

mL

Therapy

Suppression

Virological rebound

assay limit of detection

Selective Pressure of Therapy V

iral l

oad

Time

Drug-susceptible quasispecies

Drug-resistant quasispecies

Selective Pressure of Therapy

Treatment begins

Vira

l loa

d

Time

Drug-susceptible quasispecies

Drug-resistant quasispecies

Selection of resistant quasispecies

Selective Pressure of Therapy

Incomplete suppression• Inadequate potency• Inadequate drug levels• Inadequate adherence• Pre-existing resistance

Vira

l loa

d

Time

Treatment begins Drug-susceptible quasispecies

Drug-resistant quasispecies

Resistance Accumulates

Susceptible Resistant

Mutations

Fold Change

Determine clinical relevance for each drug

How Much Resistance in ARV Treated Individuals?

Pillay et al. JID 2005;192:967-73.

Prevalence of Resistance as a Proportion of Treated Patients

0

5

10

15

20

1998 1999 2000 2001 2002 2003 2004 2005

Prevalence of Resistance

>/=1 classes >/=2 classes 3 classes

Predictors of Resistance in ARV-treated Patients

Prevalence of Triple-class Drug Failure Over Calendar Time

0

5

10

15

20

Calendar year

Mocroft et al. JID 2004;190:1947–56.

Follow-up (n)554 1482 1814 1944 1988 2029 2028 140 514 716 860 958 1174 12120 10 68 163 241 282 315 0 0 10 21 33 38 58

Triple-class treatment failure (n)

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

Prevalence (%)

Cumulative Risk of Triple-class Virologic Failure (incl boosted PIs) in 10,603 Patients

PI failure = boosted PIs; TCF = triple class failure

Phillips et al. CROI 2007. Abst 532.

2 4 6 8 10

Extensive failure of:

Nucleosides 4% 9% 15% 21% 28%

PIs 2% 4% 8% 11% 16%

NNRTI 13% 20% 26% 31% 35%

TCF 2% 5% 9% 13% 20%

Extensive TCF 0% 1% 3% 5% 8%

Years from start of ART (≥3 drugs)

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)

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

Wensing et al. JID 2005;192:958-66.

n=989; 22% recent infections*HPC = high prevalence countries

In resource rich world, transmitted resistance appears to be stabilising or even reducing

UK Collaborative Group on HIV Drug Resistance.AIDS 2007;21:1035-9.

Chronic infection

Acute infection

14

12

10

8

6

4

2

0

1997 1998 1999 2000 2001 2002 2003 2004 2005

Year of sample

Sam

ples

with

IA

S m

utat

ion(

s) (

%)

Persistence of Transmitted Resistance in Primary HIV Infection

n=9Persistent resistance

n=2Reversion to wild type

n=14Persistent resistance

n=2Reversion to wild type

Variable persistence according to mutations: TAMs persist, K103N persists, PI persist, MDR persist

n=11Primary resistance

US; F/U median 9 months

n=16Primary resistance

UK; F/U up to 3 years

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

Treatment onset Virological failure (>1000c/mL)

Clinical failure (AIDS events)

VL 1000

Months Years

CD4 count

VL

Resistance Following First-line ART

Country

Mostcommon

ARTregimen

Otherdrugs

%failure

%resistance

Mostcommonmutation

Othersmutations

Abstract number

South Africad4T + 3TC+ NNRTI

LPV/r AZTddI

2% 68%M184V

43%

NRTI (TAMs);NNRTI

PI (M46I, G48V,

I54V, V82A, L90M)

661

Malid4T + 3TC

+ NVPNone 23% 50%

M184V100%

NNRTI 662

BotswanaAZT + ddI +

NNRTId4T 3TC

NA 78%NNRTI 74%

NRTI (TAMs)52%

664

CROI 2007

DART TRIAL ZDV/3TC/TDF (n=300)

MutationWeek 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%) 23 (56%)L210W 0 (0%) 3 (7%)T215FY 7 (29%) 17 (41%)K219QEN 1 (4%) 9 (22%)Total TAMs: 0

1–34–6

10 (42%)13 (54%)

1 (4%)

11 (27%)18 (44%)12 (39%)

TAM Group** I II

I and II

5 (36%)4 (11%)5 (36%)

2 (7%)11 (37%)17 (57%)

Pillay et al. CROI 2007. Abstr. 642.

Prevalence of mutations at 24 and 48 weeks in absence of virological monitoring

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