Taiwan's Experiences with Integrase...
Transcript of Taiwan's Experiences with Integrase...
Taiwan's Experiences with Integrase Inhibitors
Chien-Ching Hung, MD, PhDDepartment of Internal Medicine
National Taiwan University Hospital, Taipei
Disclosures
• I have received honoraria for speaking at educational events or consulting from:
– AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, and ViiV
• I have received research funding from
– Bristol-Myers Squibb, Janssen, Merck, Gilead Sciences, and ViiV
Outline
• Current status of HIV infection in Taiwan
• Taiwan HIV Treatment Guidelines
• Single-tablet regimens as recommended first-line treatment
• Stable switch
– Dolutegravir (DTG) plus rilpivirine (RPV) (SWORD trials)
– Truvada (coformulated TDF/FTC) plus DTG
HIV epidemiology and care in Taiwan
• HIV epidemiology (as of 2017/12/31) [est. pop., 24 million]– Total number, 35,935 with a M:F ratio of 16.9 (33,926/2,009), 1984-
2017
– Risk groups: male-to-male sex, 62.5%; heterosexual, 16.5%; injection drug use, 19.4%
• HIV care– >70 designated hospitals and clinics
– Health care workers: infectious specialists and case managers (registered nurses)
– Totally reimbursed by the National Health Insurance and special budget
• Antiretroviral therapy
• CD4 and plasma HIV RNA load monitoring
• Treatment regulations by Taiwan CDC and Taiwan AIDS Society
Trends of late presentation for HIV care in Taiwan
Lin KY, et al. PLoS One 2017
PVL >100,000 copies/ml, 36.6%PVL >500,000 copies/ml, 8.7%
Current status of achieving WHO “90-90-90” goal in Taiwan
6
Taiwan2016
79%84%
88%
1st 90
2nd 903rd 90
Global2016
70% 77% 82%
HIV infection detected
Linkage to care and ART started
Virally suppressed
73%
58%
Home-based HIV testingVCT at NGO, hospitals Case management
Rapid initiation of cART Treat-all; Rapid cART initiation;InSTI-based regimens
Recommended initial treatment for ARV-naïve HIV-positive patients in Taiwan, 2018
Class Recommended regimens
NNRTI EFV/TDF/FTC (Atripla)
RPV/TDF/FTC (Complera)
*PVL <100,000 copies/ml and CD4 >200 cells/mm3
InSTI DTG/ABC/3TC (Triumeq) [since 2016]
EVG/cob/TAF/FTC (Genvoya) [since 2017]
*Protease inhibitors available: Atazanavir (boosted or unboosted); boosted lopinavir(Kaletra); boosted darunavir (600-mg; 400-mg)**Antiretroviral therapy has been recommended to be initiated for any HIV-positive patients, regardless of CD4 counts since 2015
Prevalence of transmitted drug resistance in Taiwan, 2012-2017
Chang SY, et al. (unpublished data)
Chang SY, et al. Sci Rep 2016
0
2
4
6
8
10
12
14
16
18
20
2012 2013 2014 2015 2016 2017
PI
NRTI
nNRTI
INSTI
MDR
Any
Prevalence of transmitted drug resistance to nNRTIsin Taiwan, 2012-2017
0
2
4
6
8
10
12
14
2012 2013 2014 2015 2016 2017
nNRTI
NVP
EFV
RPV
ETR
Chang SY, et al. (unpublished data)
Chang SY, et al. Sci Rep 2016
On-treatment virologic failure to nNRTI-containing regimens in northern Taiwan, 2012-2016
Cheng CY, et al. Infect Drug Resist 2018
Current status of achieving the goal of rapid cART initiation
HIV-1 decay dynamics in blood plasma (BP) and seminal plasma (SP) with DTG-based ART
Imaz A, et al. J Infect Dis 2016;214:1512-9.
Undetectable=Untransmittable
The earlier, the better
HIV 4th generation assay (+) or western-blot (+)at NTUH during 2014/03/01 - 2018/4/20
n=762
Repeat 4th generation assay (-), n=36
Diagnosed in other hospital, n=41
Never returned for confirm testing, n=19
Newly diagnosed HIV infection, n=666
Aged <18 years, n=9
Enrolled in clinical trial, n=48
All subjects with cART initiation, n=609
Rapid cART study Flow
Luo YZ, et al. APACC 2018Huang YC, et al. IAS 2018
*HIV diagnosis made by positive for WB or HIV viremia
All subjects with cART initiation, n=609
Rapid ART initiation(≤7 days)
n=308
Standard of Caren=301
Initiation cARTn=258
Deferral of cARTn=43
Follow-up lab tests*1 m, 4 m, 6-7 m, 11-13 m
after ART initiation
Follow-up lab tests*every 3 m to 6 m
*HIV viral load, CD4, CD8, RPR
Current status of rapid cART initiation
0
50
100
150
200
250
2014/4-2015/3 2015/4-2016/3 2016/4-2017/3 2017/4-2018/4
HIV-positive patients initiating cART at NTUH, 2014-2018
Number
Baseline Characteristics
All subjects (n=609)
Male, n (%) 600 (98.5)
Age, mean (SD), years 32.9 (9.6)
Acute HIV infection, n (%) 72 (11.8)
Anti-HCV positivity, n (%) 27 (4.6)
HBsAg positivity, n (%) 51 (8.8)
Plasma HIV RNA load at baseline, median (IQR), log10 copies/ml
4.99 (4.5-5.5)
CD4 percentage at baseline, median (IQR), % 15 (10-22)
CD4 counts at baseline, median (IQR), cells/μl293.8 (129.7-
441.5)
CD4/CD8 ratio at baseline, median (IQR) 0.28 (0.15-0.44)
Characteristics of patients initiating cART
2014 (n=201) 2015 (190) 2016 (117) 2017 (101)
Male, n (%) 197 (98.0) 188 (98.9) 116 (99.1) 99 (98.0)
Age, mean (SD), years 32.4 (9.9) 33.5 (9.7) 31.6 (9.4) 34.2 (8.8)
Baseline plasma HIV RNA
load, median (IQR), log10
copies/ml
5.0 (4.5-5.5) 5.0 (4.5-5.4) 5.2 (4.6-5.8) 4.8 (4.5-5.5)
PVL ≥105 copies/ml, n (%) 100 (49.7) 91 (47.9) 72 (61.5) 40 (39.6)
Baseline CD4 count ,
median (IQR), cells/µl 323 (133-483) 286 (135-452) 225 (79-362) 321 (148-439)
CD4 <200 cells/µl, n (%) 56 (27.9) 67 (35.3) 48 (41.0) 34 (33.7)
Anti-HCV positivity, n (%) 7 (8.7) 7 (8.5) 8 (5.2) 5 (4.6)
HBsAg positivity, n (%) 14 (16.3) 19 (16.1) 10 (10.0) 8 (8.7)
Syphilis, n (%) 46 (22.9) 47 (24.7) 28 (23.9) 34 (33.7)
Trends of rapid cART initiation at NTUH, 2014-2018
33,8
53,2 53,8
64,4
0
10
20
30
40
50
60
70
80
90
100
2014/4-2015/3(n=201)
2015/4-2016/3(190)
2016/4-2017/3(111)
2017/4-2018/4(107)
cART initiated Rapid initiation
Time from diagnosis to cART initiation
2 NRTIs plus 3rd agent, 2014-2018
0
10
20
30
40
50
60
70
80
90
100
2014/4-2015/3(201)
2015/4-2016/3(190)
2016/4-2017/3(111)
2017/4-2018/4(107)
nNRTI PI InSTI%
Time from diagnosis to HIV RNA load <200 copies/ml
Short-term clinical experience with DTG-based single-tablet regimens (STRs)
E/C/F/TAF (Genvoya) was not available until 27 March, 2018
Clinical characteristics of patients initiating STRs at NTUH, Sep 2016 - Oct 2017
Variable AllTriumeq®
(DTG/ABC/3TC)
Atripla®
(EFV/TDF/FTC)
Complera®
(RPV/TDF/FTC)
Male 161(97.5) 88(97.8) 43(97.7) 30(96.8)
Age, years 31.8 ± 8.1 31.5±7.9 33.2±8.9 30.9±7.7
MSM 158(95.8) 86(95.6) 43(97.7) 29(93.6)
CD4, cells/mm3 316(158-476) 316(161-495) 210(76-415) 413(287-550)
CD4<200* 51(30.9) 25(27.8) 19(43.2) 5(16.1)
HIV RNA viral
load, log10
copies/mL
4.8(4.3-5.8) 4.8(4.4-5.4) 5.2(4.7-5.6) 4.4(4.2-4.6)
HBsAg-positive* 11(6.8) 2(2.3) 5(11.6) 4(12.9)
Anti-HCV-positive 9(5.6) 6(6.9) 2(4.6) 1(3.2)
AIDS 54(32.7) 28(31.1) 20(45.5) 6(19.4)
Smoking 51(32.3) 26(30.6) 18(40.9) 7(24.1)
Substance abuse 4(3.6) 2(3.4) 1(3.0) 1(5.0)
Treatment response to DTG/ABC/3TC (Triumeq)
0
10
20
30
40
50
60
70
Virologic success Virologic non-response
No data
Virologic outcome at 24-28 weeks of cART
Virologic success
Virologic non-response
No data
Huang WC, et al. (unpublished data)
含 含 含 含 含 含 含 含 含
Product-LimitSurvival Estimates
44 34 29 21 0
31 26 24 19 0
90 86 79 55 0
1
2
3
0 100 200 300
Censor12
0.0
0.2
0.4
0.6
0.8
1.0
含含
含含
3: Triumeq / tab2: Complera / tab1: Atripla / tabDrug
0 100 200 300
Censor12
0.0
0.2
0.4
0.6
0.8
1.0
含含
含含
3: Triumeq / tab2: Complera / tab1: Atripla / tabDrug
Logrank p=0.0016
+ 含 含
Discontinuations due to any reasons
含 含 含 含 含 含 含 含 含
Product-LimitSurvival Estimates
44 34 29 21 0
31 26 24 19 0
90 86 79 55 0
1
2
3
0 100 200 300
Censor12
0.0
0.2
0.4
0.6
0.8
1.0
含含
含含
3: Triumeq / tab2: Complera / tab1: Atripla / tabDrug
0 100 200 300
Censor12
0.0
0.2
0.4
0.6
0.8
1.0
含含
含含
3: Triumeq / tab2: Complera / tab1: Atripla / tabDrug
Logrank p=0.0014
+ 含 含
Discontinuations due to adverse effects
Discontinuations due to emergent adverse effects
Adverse event, n
(%)
All Triumeq Atripla Complera P-value
Hypersensitivity 9(5.5) 2(2.2) 6(13.6) 1(3.2) 0.0276
Neuropsychiatric
disorders8(4.8) 3(3.3) 5(11.4) 0(0)
0.0594
Nervous system
disorders4(2.4) 1(1.1) 3(6.8) 0(0)
0.0944
Psychiatric
disorders6(3.6) 4(4.4) 2(2.2) 0(0)
0.0938
Gastrointestinal
disorders2(1.2) 2(2.2) 0(0) 0(0)
1.0000
Other 5(3) 4(4.4) 0(0) 1(3.2) 0.3917
Total 1(0.6) 5(5.5) 10(22.7) 1(3.2) 0.0054
Clinical experience with switch from nNRTI-or protease inhibitor (PI)-based regimens to
DTG-based regimens among virally-suppressed patients
VH CONFIDENTIAL INFORMATION
SWORD-1 and SWORD-2: Phase III study design
Identically designed, randomised, multicentre, open-label, parallel-group, non-inferiority studies
Inclusion criteria
● On stable CAR ≥6 months before
screening
● First or second ART with no change in
prior regimen due to virological failure
● Confirmed HIV-1 RNA <50 copies/mL
during the 12 months before
screening
● HBV negative
DTG + RPV (N=513)
Day 1
Screening
Week 148
CAR (N=511)
DTG + RPVVL <50 copies/mL
on INI, NNRTI,
or PI + 2 NRTIs
1:1
DTG + RPV
Week 52
Primary endpoint
at 48 weeks:
Subjects with
VL <50 copies/mL
(ITT-E snapshot)*
Early-switch phase Late-switch phase Continuation phase
Study sites
Argentina Australia Belgium Canada
France Germany Italy Netherlands
Russia Spain Taiwan UK
USA
*8% non-inferiority margin for pooled data, 10% non-inferiority margin for individual studies Llibre JM et al. Lancet 2018
VH CONFIDENTIAL INFORMATION
Subject disposition: Early-switch phase (through week 52)
Withdrawals through week 52
n=29 (6%)
Adverse event 17 (3%)
Investigator discretion 0
Lack of efficacy 3 (<1%)
Loss to follow-up 2 (<1%)
Protocol deviation 1 (<1%)
Protocol-defined stopping criteria 1 (<1%)
Withdrawn consent 5 (<1%)
Randomised and treated
DTG + RPV
n=513
Randomised and treated
CAR
n=511
Contributed VL
to week 48
n=486 (95%)
Contributed VL
to week 48
n=487 (95%)
Screened*
N=1339
Withdrawals through week 52
n=34 (7%)
Adverse event 3 (<1%)
Investigator discretion 3 (<1%)
Lack of efficacy 3 (<1%)
Loss to follow-up 3 (<1%)
Protocol deviation 7 (1%)
Protocol-defined stopping criteria 1 (<1%)
Withdrawn consent 14 (3%)
Completed early-
switch phase†
n=484 (94%)
Completed early-
switch phase†
n=477 (93%)
*Data pooled across SWORD-1 and SWORD-2; †Early-switch phase ends at week 52 Llibre JM et al. Lancet 2018
VH CONFIDENTIAL INFORMATION
Demographics and baseline characteristics*
DTG + RPV(n=513)
n (%)
CAR(n=511)
n (%)
Mean age, years (SD)≥50 years
43 (11.1)147 (29)
43 (10.2)142 (28)
Female 120 (23) 108 (21)
Race, non-white 92 (18) 111 (22)
Median CD4+ cell count, cells/mm3
≤500 cells/mm3
>500 cells/mm3
611165 (32)348 (68)
638149 (29)362 (71)
Baseline third-agent classPINNRTIINI
133 (26)275 (54)105 (20)
136 (27)278 (54)97 (19)
Baseline TDF use 374 (73) 359 (70)
Median duration of ART prior to day 1, months 51 53
*Data pooled across SWORD-1 and SWORD-2 Llibre JM et al. Lancet 2018
VH CONFIDENTIAL INFORMATION
Snapshot outcomes at week 48 (pooled)
Virological outcomes Adjusted treatment difference (95% CI)*
Percentage-point difference
DTG + RPV is non-inferior to CAR
with respect to snapshot in the ITT-E
population (<50 copies/mL) at week 48
95
<15
95
1 40
20
40
60
80
100
Virological
success
Virological
non-response
No virological
data
HIV
-1 R
NA
<50 c
op
ies/
mL
(%) DTG + RPV (n=513)
CAR (n=511)
CAR DTG + RPV
-8 -6 -4 -2 0 2 4 6 8
–3.0 2.5
–0.2
*Adjusted for age and baseline third agent Llibre JM et al. CROI 2017. Lancet 2018
VH CONFIDENTIAL INFORMATION
Snapshot outcomes at week 48 (SWORD-1 and -2)
95
<1 4
96
<1 4
94
<15
94
2 4
0
20
40
60
80
100
Virological
success
Virological
non-response
No virological
data
HIV
-1 R
NA
<50 c
op
ies/
mL
(%) DTG + RPV (n=252)
CAR (n=256)
DTG + RPV (n=261)
CAR (n=255)
CAR DTG + RPV
-10 -8 -6 -4 -2 0 2 4 6 8 10
–4.3 3.0
–3.9 4.2
SWORD-1
SWORD-20.2
–0.6
Virological outcomes Adjusted treatment differences (95% CI)*
*Adjusted for age and baseline third agent Llibre et al. Lancet 2018.
SWORD-1
SWORD-2
Percentage-point difference
DTG + RPV is non-inferior to CAR with
respect to snapshot in the ITT-E population
(<50 copies/mL) at week 48 in both studies
Screening
PI/2NRTIs switch to DTG/TDF/FTC: Study design
¶Inclusion criteria• HIV-1 infected individuals, aged ≥20 years, PVL <200 copies/ml at screening• Had a history of failing first-line nNRTI-based antiretroviral therapy due to virological failure or
intolerance• Taking PI-based ARVs (boosted darunavir, boosted or unboosted atazanavir, or boosted
lopinavir), in combination with NRTIs and/or InSTIs for more than 3 months.
Open-label, prospective observational cohort study
Protease inhibitorsplus2 NRTIs or InSTI¶
Baseline Primary endpointPlasma HIV RNA <50 copies/mL at week 48
Week 24
Dolutegravir (50 mg once daily)Plus2 NRTIs (at the discretion of attending doctor) [mainly TDF/FTC]
ContinueDTG-based therapy
Patient characteristics
All, n=189
Age, median (IQR), years 39 (32.9-46.2)
Male sex, n (%) 185 (97.9)
HBsAg-positive at baseline, n (%) 24/137 (17.5)
Anti-HCV-positive, n (%) 32/175 (18.3)
Previous history of virological failure, n (%) 81 (42.9)
Genotypic resistance testing available, n (%) 81 (42.9)
HIV-1 habouring M184I/V mutation, n (%) 34/81 (42.0)
Plasma HIV RNA load at baseline, median (IQR), log10 1.3 (1.3-1.3)
CD4 T-lymphocyte at baseline, median (IQR), cells/µL 608 (418-768)
ARV regimens before switch
N=189
Protease inhibitors, n (%) 189 (100)
boosted darunavir, n (%) 49 (25.9)
boosted or unboosted atazanavir, n (%)
57 (30.2)
boosted lopinavir, n (%) 83 (43.9)
N=189
NRTIs, n (%) 182 (96.3)
3TC or FTC 182 (96.3)
tenofovir DF 119 (65.4)
abacavir 43 (22.8)
zidovudine 23 (12.2)
InSTI, n (%) 8 (4.2)
raltegravir 7 (3.7)
dolutegravir 1 (0.5)
Etravirine 1 (0.5)
Those who had no virological data…
N=24
Did not return for follow-up and refill 4
Did not perform blood testing, but remained stable on DTG
11
Switch to other medication due to adverse effect 7
GI upset 2
Skin rash 1
Dizziness 2
Insomnia 1
Joint pain 1
Death (lung adenocarcinoma) 1
Incarcerated 1
24 of 189 patients (12.7%) had no virological data at week 48.
Changes of lipid profiles after switch
168,8 171,5
100,0
127,0
163,1
96,9
128,6
166,4
99,9
0
40
80
120
160
200
Baseline Week 24
Triglycerides LDL-cholesterolT-cholesterol
Baseline Week 24 Week 48
Triglyceride, mean (SD), mg/dL 168.8 (85.2) 127.0 (97.1) 128.6 (99.0)
Total cholesterol, mean (SD), mg/dL 171.5 (45.2) 163.1 (37.4) 166.4 (34.2)
LDL, mean (SD), mg/dL 100.0 (35.6) 96.9 (29.3) 99.9 (25.3)
Cholesterol to HDL ratio, median (IQR) 4.0 (3.3-4.7) 3.7 (3.3-4.5) 3.7 (3.2-4.4)
Week 48
4,03,7 3,7
T-CHO:HDL-C ratio
P <0.05P<0.05
P >0.05
P >0.05
Change of eGFR after switch to DTG-based regimens
Baseline Week 24 Week 48
Estimated GFR, median (IQR)
100.8 (88.9-119.1) 84.3 (74.6-94.2) 83.4 (73.9-93.3)
Baseline vs. week 24: p<0.001Baseline vs. week 48: p<0.001Week 24 vs. week 48: p<0.001
Virological response at week 48
85,7
1,6
12,7
81,5
5,8 12,7
0
20
40
60
80
100FDA snapshot analysis; viral suppression defined as PVL <50 copies/mL
FDA snapshot analysis; viral suppression defined as PVL <20 copies/mL
Virologic suppression Virologic non-response No virological data
After excluding HIV-positive patients who did not complete 48-week of DTG therapy, the virological efficacy was 98.2% (95% CI, 94.8-99.6%)
Does the presence of M184I/V mutation impact the effectiveness of DTG-based therapy?
189 patients had completed follow-up for 48 weeks
81 patients had available results ofgenotypic resistance testing
HIV with M184I/V mutation
N=34 patients
HIV without M184I/V mutation
N=47 patients
Virological responses stratified by M184I/V mutation
89,4
2,0 6,4
76,5
2,9
20,6
0
20
40
60
80
100
HIV-1 virus without M184I/V mutation
HIV-1 virus harbouring M184I/V mutation
Virologic non-response No virological dataVirologic suppression
VH CONFIDENTIAL INFORMATION
DAWNING trial: Study Disposition
11% of subjects withdrawn
(n=34)
Adverse event 7 (2%)
Lack of efficacy 8 (3%)
Protocol deviation 8 (3%)
Lost to follow-up 6 (2%)
Protocol-defined
stopping criteria0
Withdrew consent 5 (2%)
17% of subjects withdrawn
(n=52)
Adverse event 17 (5%)
Lack of efficacy 19 (6%)
Protocol deviation 8 (3%)
Lost to follow-up 3 (<1%)
Protocol-defined
stopping criteria1 (<1%)
Withdrew consent 4 (1%)
Randomised and treated
DTG + 2 NRTIs
(n=312)
Randomised and treated
LPV/RTV + 2 NRTIs
(n=312)
53% completed
Week 52
(n=165)
52% completed
Week 52
(n=161)
Screened
(N=968)
5 DTG subjects (2%) and 2 LPV/RTV subjects (<1%) became pregnant during the randomised phase and
were withdrawn from the study
Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.
Key eligibility criteria: on first-line 2 NRTIs + NNRTI regimen for ≥ 6 months, failing virologically (HIV-1 RNA ≥400 c/mL on 2 occasions); no primary viral resistance to PIs or INSTIs
VH CONFIDENTIAL INFORMATION
Snapshot Outcomes at Week 24: ITT-E and PP Populations
DTG + 2 NRTIs is superior to LPV/RTV + 2 NRTIs with respect to snapshot in the ITT-E (<50 c/mL) at Week 24, P<0.001
82
69
86
72
0
20
40
60
80
100
Virologic
success
HIV
-1 R
NA
<5
0 c
/mL,
%
DTG + 2 NRTIs (ITT-E, n=312)
LPV/RTV + 2 NRTIs (ITT-E, n=312)
DTG + 2 NRTIs (PP, n=282)
LPV/RTV + 2 NRTIs (PP, n=275)
Virologic outcomes Treatment differences (95% CI)
LPV/RTV DTG
13,8
14,5
-12 -8 -4 0 4 8 12 16 20 24
ITT-E
PP
7.3 20.3
21.08.1
Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol.
Summary
• InSTI-based single-tablet regimens are the recommended first-line treatment of HIV infection in Taiwan
• An increasing trend of rapid initiation of cARTamong HIV-positive patients in Taiwan
• DTG-based STR (Triumeq) are better tolerated than EFV/TDF/FTC (Atripla)
• DTG-based regimens are effective alternatives to PI-based regimens in stably-suppressed patients
Acknowledgements
• 台灣疾病管制署研究經費
• 張淑媛教授
• 黃怡嘉醫師、陳冠州醫師
• 羅玉珍個管師