Transcript Harvard School of Public Health PEPFAR

ART drug resistance
mutations
Implications for TDF use
Phyllis Kanki and Beth Chaplin
Harvard PEPFAR
Harvard School of Public Health
• Drug resistance to current d4t or ZDV
based regimens?
– Implications for TDF in alternative or second
line regimens
• What do we know about drug resistance to
TDF as first line regimens?
– HIV subtype issues
• Preliminary data on TDF resistance (K65R)
transmission potential
• Baseline and toxicity issues with TDF
K65R
Mutation of Lysine to Arginine in Codon 65 of the
reverse transcriptase.
It was first identified in response to TDF; only drug
resistance mutation for TDF
It confers resistance to TDF and also causes cross
resistance to other NRTIs (ABC, ddI, FTC, 3TC)
except zidovudine.
In subtype B virus it is uncommon in patients who
are not on a regimen containing TDF
Drug resistance in d4t or AZT based
first line regimens
“Options for 2nd line ART regimens whose initial
regimen of d4T+3TC+NVP fails”
• 92-95% of mulit-drug resistance to NRTIs and
NNRTIs (89% M184V)
• TAMs (37%), K65R (6%), Q151M (8%)
(Sungkanuparph et al, CID 2007:44-447)
Preliminary data on drug resistance
mutations in Nigerian patients on
non-TDF regimens
• 194 Nigerian patients on a regimen of d4T-3TCNVP/EFV in virologic failure
• Virologic failure defined as VL >2000 copies/ml
with history of 6 month regular drug pickup.
•
10/194 (5.2%) had the K65R mutation
Possible Implications:
•Drug resistance to TDF (K65R) observed in nonTDF based regimens was not predicted.
• Coupled with M184V will effectively limit options
for alternative or second line regimens.
What do we know about drug
resistance to TDF as first line
regimens?
<9 month VL
10 to 15 months VL
Viral Load at 4.5 to 9 months
Viral Load at 10 to 15 months
Regimen
total from Pharmacy withPatients
Number with VL
Mean
Viral
Median Viral
with
Mean Viral Median
Median Viral
Median
VLNumber
Patients
VL
DispenseNo = 1, and from
during this time
Load
Load
VL during this
Load
Load
are naïve
period
TDF+3TC/ZDV+NVPpatients
or that
EFV
620
<400 time period
439
<400
TDF-FTC-NVP/EFV
n = 1092
n = 610
21,811
200
n = 439
11,556
200
TDF/FTC+NVP
or EFV
(or Truvada-NVP/EFV)
Regimen
d4T-3TC-NVP/EFV
n = 1076
n = 682
8,256
AZT-3TC-NVP/EFV
n = 2242
d4T+3TC+NVP
or EFV
n = 1500
682
13,516
ZDV+3TC+ NVP or EFV
1500
200
n = 810
200
<400
n = 1147
<400
9,090
200
81015,258
200
1147
<400
<400
No significant difference in efficacy measured by viral
suppression
What do we know about drug
resistance to TDF as first line
regimens?
• Preliminary data from Nigeria:
-Evaluated drug resistance in patients initiating
TDF first line regimens in virologic failure
-4 of 10 TDF virologic failures had K65R
-K65R was accompanied by multi-drug resistance
mutations including M184V and TAMS
What do we know about drug
resistance to TDF as first line
regimens?
1
2
3
4
5
6
Duration
of ART
14.8
5.6
5.5
5.5
2.5
11.8
7
22.3
8
31.1
9
42.9
10
47.1
Subtype
Drug Resistance Mutations
CRF 02 K065R, T069N, K103N, Y181C, M184I,M230L
CRF 02 K065R, Y181C, M184I, M184V, M230L
G
K065R, K101E, M184V, G190A
G
K065R, K101E, M184V, G190A
CRF 02
CRF 02 M184V, Y188L
D067N, K070R, A098G, K103N, M184V,K219Q,
CRF 02 K219E
A062V, T069N, T069D, T069A, A098G,
CRF 02 K103N,Q151M, Y181C, M184V, T215Y
M041L, D067N, T069D, K070R, V075M,
K101E,V118I, Y181C, M184V, G190A, L210W,
CRF 06 T215F, K219Q
G
K103N, Y181C, M184V, T215F
5
4
NNRTIs:
NVP
EFV
3
2
1
Patients with only one mutation
Y181C
V179E
G190A
A98G
V90I
V106I
M184V
Y181C
0
K103N
# of patients with this mutation
Which mutations are the
first to appear?
NRTIs:
3TC
d4T
ZDV
“Early” and “Late” NNRTI Mutations
early
mutation
mutations that seem to appear
later in the course of resistance
40%
35%
30%
25%
20%
15%
10%
5%
1 NNRTI Mutation
2 NNRTI Mutations
3 NNRTI Mutations
V106I
V179E
V090I
V108I
K101E
G190A
A098G
K103N
Y181C
0%
Implications:
• Use of TDF in first line may lead to high rates of
resistance (K65R)
• TDF resistance mutations would occur late
• Therefore, AZT could still be employed in
alternative and second line regimens
What do we know about drug resistance to
TDF as first line regimens?
HIV subtype issues
• Botswana : Increased In vitro resistance to TDF in
subtype C virus (Wainburg et al)
• Nigeria: Genotype data
-Subtype CRF 02 increased development of
resistance to TDF
- Subtype 06 decreased development of
resistance to TDF
Emergence of Resistance to Tenofovir (TDF) in Subtype C
Compared to Other Subtypes in Vitro
Subtype
7
12
C (BG-05) wt K65R
C (Mole 18) wt K65R
12-23
Weeks of selection
20–25
35–40
K65R
K65R
K65R
K65R
C (BG-15)
C (4742)
B (n=4)
wt K65R, A62V K65R, A62V K65R, A62V
wt K65R
K65R, M41L K65R, M41L
wt wt
wt
wt
AE (n=2)
A (n=2)
G (n=1)
HIV-2
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
wt
AIDS 20:F9-F13,2006
JUTH
UMTH
UCH
Plateau State
N = 123
Borno State
N = 31
Oyo State
N = 39
CRF11 A
CRF06
REC
F2
CRF13
REC
REC D
A
CRF02
A
CRF06
CRF02
CRF02
CRF06
G
G
G
LUTH
NIMR
68Military
Lagos State
N = 47
Lagos State
N = 58
Lagos State
N = 43
REC
F2 REC
CRF06
CRF06
A
REC
CRF06
CRF02
G
G
CRF02
CRF02
G
K65R by subtype
Subtype
K65R
%
Subtype G
3/87
3.4%
CRF_02 A/G
7/76
9.2%
CRF_06
0/9
0%
Frequency of Mutations Associated with NRTI Resistance
Grouped by Subtype
Subtype:
G
CRF02
CRF06
Multi-nRTI
Resistance
Zidovudine
Stavudine
M41L
14/87
6/76
4/9
E44D
3/87
1/76
0/9
K65R
3/87
7/76
0/9
D67N
18/87
10/76
5/9
K70R
25/87
11/76
4/9
L74V
2/87
0/76
0/9
Y115F
2/87
2/76
0/9
V118I
6/87
2/76
1/9
M184V M184I L210W T215Y T215F K219Q K219E
72/87 2/87
4/87 13/87 11/87 12/87 6/87
65/76 3/76
3/76 14/76 13/76 6/76 4/76
7/9
1/9
0/9
3/9
3/9
0/9
1 /9
M41L E44D
D67N
K70R
V118I
L210W
T215YF
K219QE
M41L E44D
D67N
K70R
V118I
L210W
T215YF
K219QE
D67N
K70R
V118I
L210W
T215YF
K219QE
M41L E44D
K65R
Didanosine
K65R
L74V
Abacavir
K65R
L74V
Lamivudine
K65R
M184VI
Emtricitabine
K65R
M184VI
Tenofovir
K65R
Subtype:
G
CRF02
CRF06
Multi-NRTI
Resistance
Ins. Complex
Multi-NRTI
Resistance
151 Complex
A62V
2/87
5/76
0/9
M41L
A62V
A62V
Y115F
V75I F77L
9/87 3/87
5/76 5/76
0/9
0/9
69ins
M184V
F116Y
2/87
3/76
0/9
Q151M
3/87
5/76
0/9
K70R
L210W
V75I F77L
F116Y
Q151M
T215YF
K219QE
Implications:
HIV subtype may influence (increase)
development of K65R
•
• More studies need to evaluate potential impact of
geographic (subtype) implications for TDF use
• However, even with K65R subtype differences AZT could still be employed in alternative and
second line regimens
Preliminary data on TDF resistance (K65R)
transmission potential
• Preliminary data from Nigeria:
- Clustering of TDF resistance (K65R)
-3 possible cases of TDF resistance(K65R) - where
resistance seen prior to ART
Responsive to a regimen of Kaletra (LPV/r), AZT and TDF
G
K65R
T69del
V75I
F77L
Q151M
K219R
-NNRTIs
d4T-3TC-NVP
K65R
T69del
V75I
F77L
Q151M
K219R
-NNRTIs
AZT-TDF-LPV/r
This patient may represent a case of transmitted resistance.
CRF02
K65R
Q151M
-NNRTIs
K65R
V75I
F77L
F116Y
Q151M
-NNRTIs
K65R
V75I
F77L
Y115F
F116Y
Q151M
-NNRTIs
d4T-3TC-NVP AZT-TDF-LPV/r
Another case of transmitted resistance?
K65R
F116Y
Q151M
M184V
-NNRTIs
CRF02
K65R
T69I
F77L
F116Y
Q151M
M184V
-NNRTIs
AZT-3TC- AZT-3TCNVP
TDF-LPV/r
Surveying for possible cases of transmitted resistance...
Implications:
• Surveillance is needed to evaluate possibility of
transmission of drug resistant viruses
• TDF-first line regimens might have reduced
efficacy in the face of transmitted resistant virus
(K65R) but we need much more data
• In our small numbers patients still responded to
TDF-second line even with the drugs resistance
mutations (K65R)
Baseline and toxicity issues with TDF
• Reports of renal dysfunction in TDF-treated
patients raise concerns about the potential for
nephrotoxicity despite its excellent safety profile in
clinical trials; particularly in patients with other risk
factors for renal dysfunction, or deranged baseline
renal function.
Baseline and toxicity issues with TDF
Preliminary data from Nigeria:
• Baseline chemistries suggest that abnormal renal
function will be low -- TDF could be used in the
majority of patients.
• Serum CR and creatinine clearance compromised
in patients on TDF- regimens
Laboratory values at baseline (n= 25,747)
TEMPORAL CHANGES IN RENAL FUNCTION ASSOCIATED WITH THE
USE OF TENOFOVIR DISOPROXIL FUMARATE (TDF) IN HIVINFECTED NIGERIAN ADULTS
Agbaji O1, Agaba P1, Sule H1, Ojoh R1, Audu E1, Sani M1, Akintunde L1, Taiwo B2, Idoko J1, Murphy R²
Kanki P3
1AIDS
Prevention Initiative in Nigeria Plus, Jos University Teaching Hospital, Jos, Nigeria; 2Division of
Infectious Diseases, Northwestern School of Medicine, Chicago, IL, USA;
3Harvard School of Public Health Boston, MA, USA.
•Clinical/laboratory data for 84 on TDF-regimen and
102 on other NRTI regimens evaluated at 12 months
•Creatinine clearance (CLcr) estimated using the
Cockcroft-Gault equation.
•Changes in serum creatinine and CLcr from
baseline for each patient were compared between the
TDF-treated patients and those in the non-TDF NRTI
group.
•Multivariate analysis to control for other factors.
Results
• Serum creatinine increased by 23% (97.8 ±
25.9) and 3% (89.0 ± 26.2) in the TDF and nonTDF NRTI arms, at 48 weeks (p=0.02).
• Greater mean decrease in CLcr reduction
from baseline in TDF (14.7 ± 44.4 ml/L) versus
the non-TDF NRTI (10.4 ± 37.7 ml/L) arm at 48
weeks (p=0.001).
•In multivariate analyses, variables predictive
of reduced CLcr were TDF use (p=0.005), age
(p=0.002) and male gender (p=0.004).
Implications:
• TDF-regimens associated with a small, but
statistically significant renal compromise compared
with non-TDF- regimens.
• CLcr however remained within normal range.
• Assessment of renal function prior to initiation of
tenofovir therapy is recommended for all patients.
• Therefore, frequent monitoring of renal function
may not be necessary in patients with baseline
normal renal function.
Future Directions
•Are second line therapies containing tenofovir effective
over the long-term for resistant (K65R) patients?
- How do failure rates compare to patients with other
mutation patterns?
-
Does TDF in a 2nd line regimen impact efficacy?
• Testing partners where available and examining cases of
transmitted resistance.
Harvard PEPFAR
P. Kanki
B. Chaplin
R. Murphy
J-L Sankalé
S. Meloni
A-Dieng Sarr
S. Calves
J. Hosseini
W. Odutolu
P. Okonkwo
E. Ekong
T. Jolayemi
J. Samuels
S. Ochigbo
P. Akande
B. Aluko
B. Taiwo
K. Scarsi
K. Hurt
J. Idoko
O. Idigbe
I. Adewole
D. OIaleye
C. Okany
S. Akanmu
S. Ogunsola
W. Gashau
M. Garbati
R. Nkado
D. Owujekwe
H. Muktar
S. Garko
J. Abah
R. Marlink
T. Gaolathe
J. Mukhema
N. Ndwapi
P.J. Burns
P. Mwala
K. Mukendi
J. Puvimanasinghe
M. Mine
C. Bussmann
M. Essex
V. Novitsky
M. Wainburg