Download minority variants (MVs)

Prevalence and clinical implications of NRTIand NNRTI-associated minority variant drugresistance mutations in ARV-naïve patients with
and without transmitted drug resistance
IDWeek
October 29th, 2016
Dana Clutter
Stanford University School of Medicine
Division of Infectious Diseases and Geographic Medicine
Financial disclosures

D Clutter: Bristol-Myers Squibb Virology
Fellows Research Program

Co-investigators:


R Swanstrom: Co-inventor of Primer ID
R Shafer: Research funding from Gilead Sciences, BristolMyers Squibb, Merck, and Vela Diagnostics
Background
Minority variants

Limit of detection for drug resistance mutations
(DRMs) by Sanger sequencing is 15-20%

Additional low-abundance HIV-1 variants below
Sanger threshold are “minority variants (MVs)”

MVs require ultrasensitive methods for detection
(allele-specific PCR, NGS)
Clinical implications of
pre-therapy MVs

Prevalence of transmitted drug resistance (TDR) is
~10-20%

An additional 10-20% of ART-naïve individuals
harbor MVs bearing DRMs (MV-DRMs)

MV-DRMs associated with increased virological
failure (VF)
Li et al. JAMA 2011; Panichsillapakit et al. JAIDS 2016; Rhee et al. PLOS Med
Are patients with isolated NNRTI TDR
at high risk of having MV-DRMs?

NRTI DRMs occur commonly in combination with
NNRTI DRMs during VF

Following transmission of multiple DRMs, low-fitness
DRMs decay


M184V >> NNRTI DRMs > 215 revertants
Several small uncontrolled studies have shown that
patients with TDR frequently have MV-DRMs
Jain et al. JID 2011; Castro et al. JID 2013; Toni et al. AAC 2009; Varghese et al. JAIDS 2009
Aim

Determine if NRTI and NNRTI MVDRMs occur more commonly in
individuals with isolated NNRTI TDR
compared to those without
Methods
Study population

ART-naïve
Kaiser Permanente Northern California
Baseline genotype (Sanger): 2004 – 2012
Cryopreserved plasma sample available
HIV RNA >10,000 copies/mL

Groups:






TDR: consecutively sampled, isolated NNRTI DRM(s)
Wild type (WT): matched by HIV RNA level, CD4 count,
sampling year, and ART regimen where possible
Primer ID-Illumina MiSeq
sequencing

Accurate quantification of
MV-DRMs

Distinguish MV-DRMs from
technical artifact
Zhou et al. J Virol 2015; Jabara et al. PNAS 2011; Keys et al. AIDS Res Hum Retrovirus 2015
Statistical analysis

Definitions:



MV-DRM: NNRTI or NRTI surveillance DRM detected only
by Primer ID Illumina sequencing
VF: HIV RNA > 50 copies/mL at week 48
Analysis:



Compare proportions with MV-DRMs between groups
Compare outcomes (VF, regimen change) between
groups
Describe outcomes when MV-DRMs conferred resistance
to ART regimen (HIVDB v 7.0)
Bennett et al. PLOS ONE 2009; HIVDB
Results
Baseline characteristics
Characteristic
WT n = 49
TDR n = 33
Age, median (IQR)
Male, n (%)
Race/ethnicity, n (%)
White
Black
Hispanic
Other
Baseline log viral load, median (IQR)
Baseline CD4 count, median (IQR)
Initial anchor drug, n (%)
RAL
ATVr
Other
Initial NRTIs, n (%)
FTC/TDF
3TC/ABC
Other
Sample year, median (IQR)
42 (35-49)
46 (94)
42 (34-46)
28 (85)
25 (51)
10 (20)
8 (16)
6 (12)
4.8 (4.3-5.2)
339 (128-403)
20 (61)
5 (15)
6 (18)
2 (6)
4.7 (4.5-5.1)
339 (218-466)
21 (43)
16 (33)
12 (24)
20 (61)
13 (39)
0
41 (84)
4 (8)
4 (8)
2010 (2006-2010)
31 (94)
1 (3)
1 (3)
2009 (2007-2011)
MV-DRM prevalence and
between-group comparisons
P = 0.82



Overall 60% had MV-DRMs
Abundance: 0.2 (0.1-0.6)%
No between-group differences
MV-DRMs conferred resistance
to ART regimen in 10 individuals:



P = 0.25
P = 0.65
Proportion

P = 0.06
M184V/I: 7
G190E: 2
K65R: 1
Any
NNRTI
NRTI
MV-DRM Pattern
Both
Group
WT
TDR
Clinical outcomes
Outcome
Regimen change
VF
VF with emergent resistance

WT n = 49
n (%)
13 (27)
5 (10)
1 (2)
TDR n = 33
n(%)
3 (9)
3 (9)
0
P
0.09
1.00
1.00
1 of 10 with MV-DRMs conferring resistance to ART
regimen developed VF:



MV-DRM: M184V
Regimen contained 3TC and ABC
No repeat genotype available at VF
Conclusions

MV-DRMs common in this Northern
California cohort

MV-DRMs were not associated with isolated
NNRTI TDR

Despite high prevalence of MV-DRMs,
responses to ART were favorable
Acknowledgments

Participants

UNC



Kaiser Permanente Northern California





Shuntai Zhou
Ronald Swanstrom
Daniel Klein
Jeffrey Fessel
Leo Hurley
Michael Silverberg
Stanford




Vici Vargese
Soo-yon Rhee
Robert Shafer
Benjamin Pinsky
This work was conducted with support from a KL2
Mentored Career Development Award of the Stanford
Clinical and Translational Science Award to Spectrum
(NIH KL2 TR 001083) and (UL1 TR 001085)
Questions?
Thank you!