The Future of HIV Resistance

Richard Harrigan

Division of AIDS, University of BC

Vancouver, Canada

“The future is the hardest thing to predict”

- Y. Berra

New

Canada

If present trends continue…

Elvis Presley Imitator:The Fastest Growing Profession (1975-95)

Employment

1

10

100

1000

10000

100000

1000000

10000000

100000000

1000000000

10000000000

1975 1985 1995 2005 2015

Year

Nu

mb

er

of

Elv

is Im

ita

tors

Died,

Aug 16, 1977

Resistance acquired after therapy has declined drastically over time in BC, Canada

Perc

en

tag

e a

cq

uir

ing

resis

tan

ce

Rocheleau et al., Clin Microbiol Infect. Feb 2018

Rocheleau et al., Clin Microbiol Infect. Feb 2018

Is PrEP all we need ?

What type of patient is getting resistance ?

0

0.5

1

1.5

2

2.5

<40 40-60 60-80 80-90 90-95 >95

0

2

4

6

8

<40 40-60 60-80 80-90 90-95 >95

Multi-variable

odds ratio

Adherence Category (% refilled)

2001-05

2011-14

Adapted from Rocheleau et al.,

Clin Microbiol Infect.2018

Implications

•Low overall risk and the patients with resistance issues are least likely to return

•Physicians (funders, pharma) won’t consider resistance a priority medical care issue

•Harder to get samples and data to demonstrate what resistance actually IS

Since 2009, Transmitted Drug Resistance has Exceeded Acquired Drug Resistance in BC

0

10

20

30

40

1996 2002 2008 2014

Acquired Drug

Resistance Transmitted Drug

Resistance

Participants

starting

HAART in a

given year

(%)

N=6543YearAdapted from Rocheleau et al., Clin Microbiol Infect.2018

Rates of

Transmitted

HIV Drug

Resistance

Increasing in

much of the

world

13

Large NNRTI-resistant transmission clusterin injection drug users from Regina, Saskatchewan

Red dots represents individuals with G190A mutation

• Of 255 individuals with a first-recorded genotype, 82 had a G190A mutation present (32%)

Wong et al CROI 2015

Something to worry about…

15

Transmission and clustering of HIV Protease resistance in Ontario, Canada

Harrigan et al. CROI 2016

49 treatment-naïve patients with PI resistance were identified in a single large cluster (young MSM)

Virus contains >6 PI mutations (+ M41L T215L or S)

10I, 33F, 48V, 54T, 71V, 74S and 82A

>40-fold shifts in IC50 to most PIs !!

NNRTIs are dead (for 2039) or wounded

(for PreP)

Transmission clusters can be identified by

sequence

We may eventually more drug classes in

localized “bursts”

Implications of transmitted resistance

Sequencing for resistance will become easier

Phenotyping will remain hard (but essential)

Testing for Resistance

Nanopore DNA Sequencing

Membrane

Transmembrane

Pore

$5000

portable

DNA

sequencer

AND

computer

that fits in

your hand

What about integrase inhibitors?

A Systematic Public Integrase Geno-Pheno databaseNumber H51 T66 L68 L74 V79 E92 Q95 T97 H114 G118 F121 A128 E138 G140 Y143 P145 Q146 S147 Q148 V151 S153 N155 E157 G163 S230 D232 R263

8514

768 N

429 E

332 I

321 I

275 E

119 Q

91 A

63 N E

52 E N

47 I E

40 A

38 T

34 H

30 Q

29 D

29 M

28 Q

25 H

25 S H

23 Q

22 I H N

22 V

19 I A

Some patients already have VERY high level resistance to all the integrase inhibitors

Mutations G140S + Q148H G140S + Q148H

+ T97A

G140S + Q148H

+ T97A + L74M

N (patients) 6 2 3

RAL >100 >50 >50

EVG >100 >100 >100

DTG 3.3 25 344

BIC 2.7 6.6 67

CAB 3.7 54 448

*fold-shift in IC50 W Zhang et al, (submitted)

Extensive Phenotypic Cross-Resistance between

the newest Integrase Inhibitors

*fold-shift in IC50 W Zhang et al, (submitted)

Dolutegravir - 6 Carbon

ring

Cabotegravir - 5 Carbon

ring

Bictegravir - 7 Carbon

ring

Implication:

for

resistance,

the new

drugs are

same drug

wearing

different hats

DTG

CBT

BIC

What will happen with global dolutegravir use without monitoring?

Summary

• Developing resistance on therapy is now rare and associated with LOWEST adherence

• Currently not much of a risk for PrEP, but possible

• BUT our drugs classes in danger of being compromised by transmitted resistance

• Shift from medical care -> Public Health issue

• We all need to work together now