1. 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

2. Disclosures

3. 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

4. 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

5. The Biological Basis of HIV Drug Resistance

6. 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

7. 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

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

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

10. 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

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

12. How Much Resistance in ARV Treated Individuals?

13. 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:

14. Predictors of Resistance in ARV-treated Patients

15. 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)
Triple-class treatment failure (n)
Mocroft et al. JID 2004;190:1947–56.

16. 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 Abst 532.

17. 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

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

19. Transmission of Resistance in Europe (17 countries)
SPREAD
Route of Infection p-value OR CI
IDU 6.8% /
Origin / infect. in HPC 5.2% 10/
Heterosexual 12.0% 30/
MSM (reference) 10.0% 47/
Origin / infect. in HPC* 5.2% 10/
*HPC = high prevalence countries
n=989; 22% recent infections
Wensing et al. JID 2005;192:

20. 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:

21. 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:

22. 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

23. Implications of ARV Rollout in Resource Poor World for Resistance

24. 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

25. 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

26. 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 Abstr. 642.

27. 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

28. 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