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 (unpublished data)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


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


0 100 200 300

Censor12

0.0

0.2

0.4

0.6

0.8

1.0

含含

含含


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


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


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


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


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


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


DAWNING trial: Study Disposition

11% of subjects withdrawn

(n=34)


Lack of efficacy 8 (3%)


Lost to follow-up 6 (2%)

Protocol-defined

stopping criteria0

Withdrew consent 5 (2%)

17% of subjects withdrawn

(n=52)


Lack of efficacy 19 (6%)


Lost to follow-up 3 (<1%)

Protocol-defined

stopping criteria1 (<1%)

Withdrew consent 4 (1%)


DTG + 2 NRTIs

(n=312)


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


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

Taiwan's Experiences with Integrase...

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