Treatment regimens for the public health approach: do we need to change?

Nicholas Paton MD FRCP

Professor of Medicine

National University of Singapore

2

Disclosures (1)

Dr Paton has received research grants awarded

to his institution from Janssen, GSK, and Merck;

has received speakers fees from AbbVie, Janssen,

and Merck; and serves as a member of data-

monitoring committees for Roche-sponsored

clinical trials.

3

Estimated numbers on ART P

eo

ple

re

ceiv

ing

AR

T (m

illio

ns)

Global AIDS Response Progress Reporting (UNAIDS/UNICEF/WHO). Available at: http://www.who.int/hiv/data/art_2003_2015.png?ua=1

3Global AIDS Response Progress Reporting (UNAIDS/UNICEF/WHO). Available at: http://www.who.int/hiv/data/art_2003_2015.png?ua=1

0,0

2,0

4,0

6,0

8,0

10,0

12,0

14,0

16,0

18,0

20,0

非洲地区

美洲地区

地中海东部地区

欧洲地区

东南亚地区

西太平洋地区

>20m in 2017

2000 2010 2016 year

<1m

7.5m

Source: UNAIDS/WHO estimates.

African region

Region of the Americas

Eastern Mediterranean region

European region

South-East Asia region

Western Pacific region

4

Standardised ART sequence in WHO public health approach

Standardised first line Standardised second line~3% fail/year Standardised third line

ART, antiretroviral therapy; NRTI, nucleoside reverse-transcriptase inhibitors;NNRTI, non-NRTI; PI, protease inhibitor; RAL, raltegravir; WHO, World Health Organization.

PINRTIPINNRTI

NRTI

NRTI

NRTI

5

WHO ART Guidelines 2003

WHO ART guidelines 2003

6

First-line therapy (2016 guidelines)

WHO guidelines, 2016. Available at: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. Accessed May 2017.

3TC, lamivudine; ABC, abacavir; AZT, zidovudine; DTG, dolutegravir; EFV, efavirenz; HIV, human immunodeficiency virus; FTC, emtricitabine;

LPV/r, lopinavir/ritonavir; TB, tuberculosis; TDF, tenofovir disoproxil fumarate; NVP; nevirapine.

First-line ART Preferred first-line regimens Alternative first-line regimens

Adults TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP) TDF + 3TC (or FTC) + DTG*

TDF + 3TC (or FTC) + EFV400*

TDF + 3TC (or FTC) + NVP

Pregnant or breastfeeding women

TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP) TDF + 3TC (or FTC) + NVP

Adolescents TDF + 3TC (or FTC) + EFV AZT + 3TC + EFV (or NVP) TDF (or ABC) + 3TC (or FTC) + DTG*

TDF (or ABC) + 3TC (or FTC) + EFV400*

TDF (or ABC) + 3TC (or FTC) + NVP

Children 3 years to less than10 years

ABC + 3TC + EFV ABC + 3TC + NVP AZT + 3TC + EFV (or NVP) TDF + 3TC (or FTC) + EFV (or NVP)

Children less then 3 years ABC (or AZT) + 3TC + LPV/r ABC (or AZT) + 3TC + NVP

*Safety and efficacy data on the use of DTG and EFV400 in pregnant women, people with HIV/TB coinfection and adolescents younger than 12 years of age are not yet available

DTG + 2NRTIs

8

SINGLE

100

90

80

70

60

50

40

30

20

10

0

BL 4 8 12 16 24 32 40 48 60 72 84 96 108 120 132 144

Pat

ien

ts (

%)

Week

TreatmentCD4 Week 144 ∆ from

BL adjusted mean SE

Difference in response(95% CI)

CD4 ∆ DTG + ABC/3TC QD (n=414) 378.5 11.0 46.9 (15.6 to 78.1);P=0.003From BL EFV/TDF/FTC QD (n=419) 331.6 11.6

Difference in responseWeek 96, 8.0% (95% CI, 2.3% to 13.8%); P=0.006

Week 144, 8.3% (95% CI, 2.0% to 14.6%); P=0.010

88%

81%

80%

72%

71%

63%

BL, baseline; CI, confidence interval; QD, daily; SE, standard error.

DTG + ABC/3TC QD (n=414)EFV/TDF/FTC QD (n=419)

Walmsley S, et al. J Acquir Immune Defic Syndr 2015;70:515–9.

9

SINGLE (2)

c/mL=copies/mL; VL, viral load.

VL failure (2 VL > XX c/mL after Week 24):

DTG EFV

≥50 c/mL: 39/414 (9%) 33/419 (8%)

>200 c/mL: 29 (7%) 23 (5%)

>1000 c/mL: 5 (1%) 2 (<1%)

10

SINGLE (3): AEs leading to discontinuation

Walmsley S, et al. N Engl J Med 2013;369:1807–18. AE, adverse event.

AEsDTG + ABC/3TC

(n=414)

EFV/TDF/FTC

(n=419)

Number of participants (%)

AE leading to discontinuation ofstudy drug (by Week 48)

10 (2%) 42 (10%)

Psychiatric disorder 2 (<1%) 15 (4%)

Nervous system disorder 0 (0%) 13 (3%)

Skin and subcutaneous-tissue disorder 2 (<1%) 8 (2%)

Gastrointestinal disorder 0 (0%) 8 (2%)

General disorder or administration-site condition 0 (0%) 7 (2%)

11

SINGLE

100

90

80

70

60

50

40

30

20

10

0

BL 4 8 12 16 24 32 40 48 60 72 84 96 108 120 132 144

Pat

ien

ts (

%)

Week

TreatmentCD4 Week 144 ∆ from

BL adjusted mean SE

Difference in response(95% CI)

CD4 ∆ DTG + ABC/3TC QD (n=414) 378.5 11.0 46.9 (15.6 to 78.1);P=0.003From BL EFV/TDF/FTC QD (n=419) 331.6 11.6

Difference in responseWeek 96, 8.0% (95% CI, 2.3% to 13.8%); P=0.006

Week 144, 8.3% (95% CI, 2.0% to 14.6%); P=0.010

88%

81%

80%

72%

71%

63%

BL, baseline; CI, confidence interval; QD, daily; SE, standard error.

DTG + ABC/3TC QD (n=414)EFV/TDF/FTC QD (n=419)

Walmsley S, et al. J Acquir Immune Defic Syndr 2015;70:515–9.

12

Resistance in SINGLE

Tested for resistance in all with VL >50 copies/mL

At week 144:

• DTG: 0/414 (0%) EFV: 7/419 (1.7%; 6 NNRTI, 1 K65R)

• DTG has a high barrier to resistance

• Like PI, but also protects the NRTIs

Walmsley S, et al. JAIDS 2015;70:515–9.

13

Key populations: DTG

Patients with TB Pregnant women

PK and efficacy PK and efficacy (rifampicin, UGT1A1) Safety

14

Effect of RIF on DTG

7.00

6.00

5.00

4.00

1.00

0.000 4 8 12 16 20 24

DTG

co

nce

ntr

atio

n (

µg

/mL)

Time after dose (h)

3.00

2.00

DTG 50 mg QDDTG 50 mg BID

BID, twice daily; h, hour; RIF, rifampin.Dooley KE, et al. J Acquir Immune Defic Syndr 2013;62:21–7.

15

Effect of RIF on DTG

7.00

6.00

5.00

4.00

1.00

0.000 4 8 12 16 20 24

DTG

co

nce

ntr

atio

n (

µg

/mL)

Time after dose (h)

3.00

2.00

DTG 50 mg QDDTG 50 mg BIDDTG 50 mg BID + RIF 600 mg QD

BID, twice daily; h, hour; RIF, rifampin.Dooley KE, et al. J Acquir Immune Defic Syndr 2013;62:21–7.

16

DTG and TB Treatment: INSPIRING Trial

PatientsHIV (ART naïve, starting ART) + DS-TB (on RIF-based TB Rx for ≤ 8 weeks)

Randomisation: 2NRTIs + DTG vs 2NRTIs + EFV NRTIs investigator-selected; DTG 50mg bd during TB Rx +2wks, then 50mg daily; EFV: 600mg once daily throughout

Primary outcome: HIV RNA < 50 copies/ml at week 48

Week 24 (interim) analysis: DTG: 56/69 (81%) (95% CI: 72%, 90%) EFV: 39/44 (89%) (95% CI: 79%, 98%) [Difference due to 7% discontinuations in DTG arm vs 0% in EFV arm]

Conclusions (to date):DTG effective in suppressing VL with RIF-containing TB Rx[NB: no information about TB outcomes]

Dooley et al, CROI 2018, Abstract O-03

17

DTG PK in pregnancy

DTG AUC and trough lower in pregnancy (compared with post-partum)

Levels similar to those in non-pregnant adults

Mulligan, CROI 2016

DTG efficacy in pregnancy: DOLPHIN and VESTED trials

18

DTG efficacy in pregnancy

Hill J Vir Erad 2018

19

DTG Safety in Pregnancy

18 May 2018, WHO statement:

Update from Botswana study

0.9% of babies (4 of 426) whose mothers became pregnant while taking DTG had a neural tube defect

0.1% of babies (14 of 11,173) whose mothers took other HIV meds had neural tube defect

EMA guidance:

20

Relevance of DTG + 2NRTI as first-line regimen (from perspective of public health approach)

• Advantages

– Reduced toxicity c/w EFV (but other strategies for that)

– Potential resistance prevention (impact on outcomes not known)

– Reduced cost (eventually)

• Neutral

– Not virologically superior to EFV

– Efficacy during TB treatment demonstrated (need complete data)

• Disadvantages

– Efficacy in pregnancy (not known)

– Safety in pregnancy (potential risk)

– Dose modification for TB (almost certainly needed)

– First-line DTG would mean retrench EFV from prescription armamentarium

– Logistics of change

– Generally limited comparative data in resource limited settings / strategic thinking

• Conclusion: Relevant, but considerations are complex

EFV (lower dose) + 2NRTIs

22

Lower-dose EFV (400 mg)Mean change in HIV RNA viral load from BL to Week 96 for the

modified ITT population

EFV 400 mgEFV 600 mg

0

–0.5

–1.0

–1.5

–3.5

–4.00 12 24 36 48 72 96

Ch

ange

fro

m B

L H

IV R

NA

Log 1

0 c

op

ies

pe

r m

L

Week

–2.0

–3.0

60 84

–2.5

Mean difference –0.02 Log30 copies/mL(95% CI, –0.14 to 0.10); P=0.74

321309

316302

312301

310299

312295

307291

304290

300289

299286

Number at riskEFV 400 mgEFV 600 mg

ITT, intention-to-treat.ENCORE 1 Study Group. Lancet Infect Dis 2015;15:793–802.

23

EFV 400-mggroup (n=321)

EFV 600-mg group (n=309)

Difference(95% CI)

Pvalue

AEs (total=3337)

Total number of AEs 1653 (49.5) 1684 (50.5) – 0.42

Grade 1 1202 (73) 1236 (73) – –

Grade 2 381 (23) 363 (22) – –

Grade 3 62 (4) 77 (5) – –

Grade 4 8 (1) 8 (1) – –

Patients reporting AEs 291 (91) 285 (92) –1.6 (–2.8 to 5.9) 0.48

Patients with AE related to EFV* 126 (39) 148 (48) –8.6 (–16.4 to –0.9) 0.03

Patients stopping EFV because of treatment-related AE*†

16 (13) 32 (23) –10.3 (–19.2 to –1.4) 0.03

Serious AEs

Total number of serious AEs 32 (40) 48 (60) - -

Patients reporting serious AEs 24 (8) 32 (10) –2.9 (–7.3 to 1.5) 0.20

Patients reporting serious AEs related to EFV*‡ 2 (1) 4 (1) –0.7 (–2.4 to 1.1) 0.44

Lower-dose EFV (400 mg)

AEs and serious AEs

Data are n (%) unless otherwise indicated.*Definitely or probably related to EFV.

†Relationship interaction P=0.046.‡Events included Grade 3 dizziness and possible Stevens-Johnson syndrome

with the 400-mg dose and rash with fever, septic shock possibly due to an adverse reaction, rash with labial oedema, suicide and attempted suicide

with the 600-mg dose (1 event each in 3 patients, except for rash with fever and septic shock, which occurred in the same patient).

ENCORE 1 Study Group. Lancet Infect Dis 2015;15:793–802.

24

Key populations: EFV400

Patients with TB Pregnant women

PK and efficacy PK and efficacy (rifampicin, CYP3A4) Safety

25

EFV400 with TB treatment

Cerrone et al, CROI 2018, Abstract 1824

Limited changes in EFV400 exposure (<25%)Plasma levels > 1000 ng/ml (MEC from ENCORE-1) irrespective of CYP2B6 genotype EFV400 maintained undetectable VL in allEFV400 can be administered with TB treatment

Open label PK study; HIV+ (not active TB) 26 enrolled, 22 completed PK2 (42d on RIF/INH), 18 completed PK3 (92d on RIF/INH) 4 withdrawals due to EFV levels < 800ng/ml

26

EFV 400 in pregnancy

22 pregnant HIV+ women (African origin) on TDF/FTC/EFV600 with VL<50 copies/ml switched to TDF/FTC/EFV400

All women maintained VL< 50

Conclusion: EFV400 can be used in pregnancy

Lamorde et al., IAS 2017

In 3rd trimester, Cmax, AUC, and C24h were 14%, 26% and 38% lower compared to post-partum (both on EFV400)

Levels within ranges for EFV600 during 3rd trimester in previous studies (Schalkwijk et al. 2016)

and in ARV-naïve patients on EFV400 (Dickinson et al. 2015).

27

Relevance of EFV400 +2NRTI first-line regimen (for public health approach)

• Advantages – Reduced toxicity c/w standard EFV dose– Reduced cost

• Neutral– Equal VL efficacy c/w standard EFV dose – Equal efficacy in pregnancy (limited data) – Equal efficacy with TB treatment (limited data)

• Disadvantages -

• Conclusion: Highly relevant

28

DTG vs EFV400

29

NAMSAL trial

• Phase III, randomized, open-label trial

• N=606; Cameroon

• Randomised to

– DTG + TDF/XTC

– EFV 400 + TDF/XTC

•Primary outcome: VL < 50 c/ml at 48 weeks

• Estimated completion: September 2018

30

Impact of pre-treatment drug resistance on treatment outcomes

Philipps Lancet HIV 2017

OPTION 1: Start EFV in all (current policy, no change)

OPTION 2: Resistance tests for ART initiators with previous ART exposureStart DTG if NNRTI resistance

OPTION 3: Resistance tests for all ART initiators. Start DTG if NNRTI resistance

OPTION 4: Start DTG for ART initiators with previous ART exposure

OPTION 5: Start DTG in all

31

The Lancet HIV 2018 5, e146-e154DOI: (10.1016/S2352-3018(17)30190-X)

Mean annual cost (2018-38) according to policy option where > 10% initiators have NNRTI resistance

Impact of pre-treatment drug resistance on costs

Philipps Lancet HIV 2017

32

Impact of pre-treatment NNRTI resistance

Gupta et al, Lancet Infectious Diseases, 2017

33

Second-line ART: WHO 2016 guidelines

PI/r + INSTI in second-line therapy

35

PI/r + INSTI as second-line therapy

• LPV/r + RAL

-EARNEST: LPV/r+2NRTIs（N=426）LPV/r+RAL（N=433）LPV/r（N=418）

-SECOND-LINE: LPV/r+2NRTIs（N=271）LPV/r+RAL（N=270）

- ACTG 5273: LPV/r+NRTIs（N=255） LPV/r+RAL（N=260）

• DRV/r + RAL

– Nil

• ATV/r + RAL

– Nil

• XXV/r + DTG

– Nil

ACTG, AIDS Clinical Trials Group.

36

VL suppression

86%

76%

90%

81% 80%

92%

0%

20%

40%

60%

80%

100%

EARNESTWeek 144<400 c/mL

SECOND-LINEWeek 96

<200 c/mL

ACTG 5273Week 48

<400 c/mL

Pe

rce

nta

ge s

up

pre

sse

d

PI/NRTI PI/RAL

~ ~

EARNEST: Hakim J, et al. CROI 2015. Seattle, WA. Poster 552; SECOND-LINE: Amin J, et al. PLoS ONE 10:e0118228;ACTG 5273: La Rosa AM, et al. CROI 2016. Boston, MA. Abstract 30.

37

Week-96 outcomes: Paton NI, et al. N Engl J Med 2014;371:234–47;Week-144 outcomes: Hakim J, et al. CROI 2015. Seattle, WA. Poster 552.

VL responses by randomised arm

0

20

40

60

80

100

Pat

ien

ts w

ith

VL<

40

0 c

op

ies/

mL

(%)

0 4 12 24 36 48 64 80 96 112 128 144

Time from switch to second-line (week)

PI + NRTI

PI + RAL

Global P<0.0001 PI + RAL vs. PI + NRTI global P<0.0001

38

HR (PI + RAL : PI + NRTI) = 1.08 (0.81, 1.43)

Grade 3/4 AEsP

rob

abili

ty o

f re

mai

nin

gG

rad

e 3

/4 A

E-fr

ee

0.00

0.25

0.50

0.75

1.00

0 24 48 72 96Time from randomisation (week)

PI + RAL

PI + NRTI

PI + NRTI PI + RAL PI-mono

Total participants 426 433 418

Participants with Grade 3/4 AEs, n (%) 94 (22) 100 (23) 100 (24)

HR, hazard ratio.

39

Relevance of PI + INSTI as second-line regimen (for public health approach)

• Advantages

– Theoretical advantage of non-overlapping classes with first-line (but no benefit shown)

• Neutral

– Efficacy equivalent

• Good evidence for LPV/r + RAL (3RCTs)

• Don’t know about other PI + INSTI combinations

– Toxicity equivalent

• Advantage of PI/RAL may be enhanced if AZT increasingly used in second-line in PHA

• Disadvantages

– Higher cost of INSTI (RAL) vs 2NRTI

• Conclusions

– Possibly relevant for the future, but first need to show either:

• Clear virological superiority over PI/r + 2NRTI AND/OR

• Much reduced toxicity compared to PI/r + 2NRTI AND/OR

• Cost of INSTI below 2NRTI

– Clinical trial with DRV/r + DTG (vs DRV/r + 2NRTI) … may show 1 or more of these

PHA, people living with HIV/AIDS; RCT, randomised clinical trial.

PI + NRTIs in second line therapy –contribution of NRTIs

41

PI/NRTI(0) (N>149)PI/NRTI(1) (N>86)PI/NRTI(2-3) (N>17)PI + RAL (N>280)PI Monotherapy (N>374)

Within PI+NRTIs global p=0.02

88%

77%

85%81%

61%

Perc

ent

wit

h V

L<4

00

co

pie

s/m

l

Weeks from switch to second-line

0

20

40

60

80

100

0 4 12 24 36 48 64 80 96 144128112

Global p<0.0001

NRTI() = number or active(susceptible-low resistance) NRTIs

VL response by number of active NRTIs in the regimen

42

MOBIDIP trial

ELIGIBILITY Stable PI/NRTI second-line VL ≤200 copies/mLCD4 >100Adherence >90%

OUTCOME Failure:Confirmed VL ≥500 c/mLReintroduction of NRTIsPI interruption

LPV/r +3TC

LPV/r

LPV/r +3TC

DRV/r + 3TC

DRV/r

Randomisation

96-weekfollow up

Reintroduce NRTIs (2Lady) if HIV plasma RNA >500 copies/mL

after 1 month

Arm A:FTC/TDF/LPV/r

Arm B:ABC/DDI/LPV/r

Arm C:FTC/TDF/DRV/r

48-week2Lady

Ciaffi L et al. HIV Glasgow 2016. Abstract O122; https://clinicaltrials.gov/ct2/show/NCT01905059. Accessed May 2017.

43

MOBIDIP trialResults

• 265 patients randomised (133 mono, 132 dual)

• 96% M184V mutation at first-line failure

• Week 48 VL failure:

‒ Mono 22.6% (95% CI: 15.8–30.6)

‒ Dual 3.0% (95% CI: 0.8–7.6; P<0.001)

‒ Mono discontinued by DSMB

• Week 96

Ciaffi L et al. HIV Glasgow 2016. Abstract O122.

AtWeek96PI/r+3TCn=129

VL<50copies/ml,n(%) 102(79%)

VL<200copies/ml,n(%) 118(91%)

VL<500copies/ml,n(%) 123(95%)

VL<1000copies/ml,n(%) 125(97%)

http://programme.ias2017.org/Abstract/Abstract/915

INSTI + NRTIs in second-line therapy

9th IAS Conference on HIV Science; July 23-26 2017; Paris, France

• 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

• Stratification: by HIV-1 RNA (≤ or >100,000 copies/mL), number of fully active NRTIs in the

investigator-selected study background regimen (2 or <2)

• Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48 using the FDA snapshot

algorithm (12% noninferiority margin)

Study Design

Week 48primaryanalysis

Randomisation

FDA, US Food and Drug Administration; INSTI, integrase strand transfer inhibitor.

Open-label randomised noninferiority phase IIIb study

DTG + 2 NRTIsOpen label,

randomised

1:1LPV/RTV + 2 NRTIs

DTG + 2 NRTIs

Continuation phase

Week 24interim analysis

Week 52

Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

• 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

Snapshot Outcomes at Week 24: ITT-E and PP Populations

CI, confidence interval; ITT-E, intent-to-treat exposed; PP, per protocol.Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

82

69

86

72

0

20

40

60

80

100

Virologicsuccess

HIV

-1 R

NA

<50

c/m

L, %

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

-12-10 -8 -6 -4 -2 0 2 4 6 8 10 12 14 16 18 20 22 24

ITT-E

PP

7.3 20.3

21.08.1

Summary of Adverse Events (Randomised Phase)

Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

DTG + 2 NRTIs(n=314)a

LPV/RTV + 2 NRTIs(n=310)

Any adverse event, n (%) 204 (65) 231 (75)

Most common AEs (≥5% in either arm)

Diarrhoea 28 (9) 98 (32)

Upper respiratory tract infection 37 (12) 34 (11)

Nausea 11 (4) 28 (9)

Headache 22 (7) 16 (5)

Lower respiratory tract infection 11 (4) 14 (5)

Vomiting 5 (2) 17 (5)

Any neuropsych AE

Drug-related AE

19 (6)

47 (15)

15 (5)

113 (36)

All drug-related grade 2-4 AEs 9 (3) 40 (13)

Diarrhoea 1 (<1) 22 (7)

Serious AEs or deathb 17 (5) 18 (6)

Drug-related serious AEs 2 (<1) 2 (<1)

AEs leading to withdrawal 7 (2) 17 (5)aTwo patients received LPV/RTV instead of DTG + 2 NRTIs. bFour fatal SAEs: DTG + 2 NRTIs, n=1 (pneumonia); LPV/RTV, n=3 (pneumonia, encephalitis/IRIS, encephalitis).

RELEVANCE OF DAWNING TRIAL FOR THE PUBLIC HEALTH APPROACH?

9th IAS Conference on HIV Science; July 23-26 2017; Paris, France

• 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

• Stratification: by HIV-1 RNA (≤ or >100,000 copies/mL), number of fully active NRTIs in the

investigator-selected study background regimen (2 or <2)

• Primary endpoint: proportion with HIV-1 RNA <50 c/mL at Week 48 using the FDA snapshot

algorithm (12% noninferiority margin)

Study Design

Week 48primaryanalysis

Randomisation

FDA, US Food and Drug Administration; INSTI, integrase strand transfer inhibitor.

Open-label randomised noninferiority phase IIIb study

DTG + 2 NRTIsOpen label,

randomised

1:1LPV/RTV + 2 NRTIs

DTG + 2 NRTIs

Continuation phase

Week 24interim analysis

Week 52

Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

At least 1 fully

active NRTI based

on resistance

testing

NRTI resistance at baseline

0

20

40

60

80

100

Perc

en

tage

3TC FTC ABC TDF ZDV DDI D4T

Susceptible Potential low Low Intermediate High

Baseline sequences obtained in 92% of those randomized to PI/NRTI armFigure shows resistance data from 792 randomized patients

51

Treatment simplification in second-line: How many NRTIs needed?

Paton N, et al. Lancet HIV, May 8, 2017, http://dx.doi.org/10.1016/S2352-3018(17)30065-6.

0 4 12 24 36 48 64 80 96 112 128 1440

20

40

60

80

100

VL

<40

0 c

op

ies/

mL

(%)

PI plus 0 active NRTIs (n>188)PI plus 2–3 active NRTIs (n>23)PI monotherapy (n>374)

PI plus 1 active NRTI (n>104)PI plus RAL (n>351)

9th IAS Conference on HIV Science; July 23-26 2017; Paris, France

Snapshot Outcomes by Key Baseline Subgroups at Week 24: ITT-E

8286

7074

84 83 82

6973

54 55

73

66

72

0

20

40

60

80

100

Overall ≤100,000 >100,000 2 <2 <200 ≥200

HIV

-1 R

NA

<50

c/m

L, %

DTG + 2 NRTIs

LPV/RTV + 2 NRTIs

HIV-1 RNA c/mL Fully active NRTIs

ITT-E, intent-to-treat exposed.

257/

312

215/

312

208/

242

181/

249

49/

70

34/

63

138/

166

100/

151

119/

146

Aboud et al. IAS 2017; Paris, France. Slides TUAB0105LB.

CD4+ count cells/mm3

45/

61

35/

64

212/

251

180/

248

115/

160

53

Week-96 outcomes: Paton NI, et al. N Engl J Med 2014;371:234–47;Week-144 outcomes: Hakim J, et al. CROI 2015. Seattle, WA. Poster 552.

EARNEST VL responses by randomised arm

0

20

40

60

80

100

Pat

ien

ts w

ith

VL<

40

0 c

op

ies/

mL

(%)

0 4 12 24 36 48 64 80 96 112 128 144

Time from switch to second-line (week)

PI + NRTI

PI + RAL

Global P<0.0001 PI + RAL vs. PI + NRTI global P<0.0001

Dawning outcome (24 weeks)

Compared with treatment for a lifetime…..

55

LIMITATIONS OF DAWNING TRIAL (for the public health approach)

1. Excluded people with no “fully active” NRTIs – trial population not generalizable to the public health approach

2. Excluded people with active CDC stage C conditions – trial population not generalizable to the public health approach

3. Strategy of resistance testing, regular VL monitoring (3 monthly?) not testing effects of prolonged failure –laboratory monitoring strategy of limited relevance to the public health approach

4. Duration of randomized follow-up 24 weeks (overall ≈ 36 weeks) – questionable relevance to the public health approach (or any approach to lifelong therapy)

56

Relevance of INSTI + 2NRTI as second-line regimen (for public health approach)

• Advantages

– Apparent virological advantage in short-term follow-up with DTG (vs PI + 2NRTIs)

– Apparent toxicity advantage with DTG (vs PI + 2NRTIs)

• Disadvantages

– Data are inadequate for typical populations in public health approach

– If DTG becomes first line, have no data on second line after DTG failure

– (Would not dare do this with RAL or other INSTIs)

– Have woefully inadequate long term data

• Conclusions

– Possibly relevant for the future, but need a trial relevant to the public health approach!

.

57

Potential revised ART sequence in WHO public health approach

PINRTI

PI

Standardised 1st line Standardised 2nd line≈ 3% fail/y Standardised 3rd line

NNRTI

NNRTI

DTG

58

Overall conclusions

• First-line– Lower dose EFV may become preferred regimen – DTG may be suitable for large-scale programme use (but concerns about

safety data in pregnancy)

• Second-line – PI + 2NRTI still preferred – May not need much NRTI activity: PI + 3TC may be OK (at least as switch) – PI + INSTI: no compelling case currently – INSTI + 2NRTI: early data with DTG look appealing (but study deceptive)

• Should be a high barrier for change in public health approach for RLS• Should require compelling RCT data to support change• Need to consider pragmatic issues, including monitoring support

RLS, resource-limited setting.