View
2
Download
0
Category
Preview:
Citation preview
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
Recommended