Simplified regimens: Pros and...

Simplified regimens: Pros and Cons

Pedro Cahn

Rio de Janeiro, 2018

Treatment Strategies: A long way……

MonotherapyDual therapy

Triple therapy

Mega HAART

STIs

Simplification

Long Acting/Extended Release Regimens

Non daily regimens

PLHIV are aware their treatments have long-term effects

AE, adverse event; PLHIV, people living with HIV.1. Marcotullio S, et al. EACS 2017, poster PE25/9.

Man by Bluetip Design, clock by Three Six Five, dizzy by Gan Khoon Lay, fewer pills by Alex Arseneau, chemical reaction by Maxim Basinski, pills by Daniel DeLorenzo, food by Gregor Cresnar, capsule by Chameleon Design; all from the Noun Project.

0 50 100 150 200 250 300

Reduces long-term effects of HIV medicine on my body

Longer lasting so I can take treatment less often (e.g. monthly injection administered by a doctor/nurse)

Fewer side effects

Can take less HIV medicine and get the same effect

Does not cause a problem with medication I currently take for other illnesses

Fewer pills each day

No food restrictions or requirements

Smaller pill sizes

Weight, %

25.0

21.4

19.3

13.8

9.6

4.7

4.5

1.5

100

• 73% of participants (n = 1,111) sometimes worried about the long-term effects of their HIV medication1

• Reduction of long-term AEs and longer treatment intervals were viewed as more important potential medication improvements than reduction of side effects and pill burden1

Score (100 = average importance)

PLHIV are interested in new antiretroviral approaches, including longer-acting formulations

141

154

6638

514 3

3858

2

13

5

18

0

20

40

60

80

100

120

140

Not at allinterested

Somewhatinterested

Very interested

Res

po

nd

ents

(%

)

How interested would you be in switching to a new treatment that involves…

Two small plastic implants in forearm every 6 months

Two shots in clinic EOM

Single pill QW

EOM, every other month; PLHIV, people living with HIV; QW, every week.Osterman J, et al. CROI 2018, poster 503.

Survey n = 263

HAART: Is it about number of drugs or aboutpotency and safety?

✓ To reduce ARV exposure making treatment safer without sacrificing virologic control

✓ To reduce pill burden/improved patient adherence and quality of life

✓ To reduce drug-drug interactions

✓To reduce cost

✓Potential for longer-term success

✓Downstream options with “spared” class in case of first-regimen failure

Reducing drug burden in HAART: Why would you do that?

✓ Reduced potency?

✓ Less forgivness for missing doses?

✓Reduced penetration in sanctuaries?

✓ More frequent viral load monitoring?

✓Less durability?

✓ Loss of TDF lipid-lowering effect

✓ Contraindicated in HBV coinfection (3TC-based DT)

Reducing drug burden in HAART: Potential disavantages

Dual Therapy: not always good

• LPV/r - EFV• ATV/r - EFV• LPV/r - NVP

Good virological response, but increased rateof side effects

• ATV 300 mg BID + RAL (SPARTAN)• MVC QD + DRV/RTV (MODERN)• DRV/r + RAL (ACTG 5262)• DRV/r + RAL (NEAT 001)*• ATV/r + RAL (HARNESS – switch)• MARAVIROC+ bPI (MARCH -Switch)

* Strata high pVL and/or low CD4

Dual Therapy: Potential Boosted PI Regimens for Initial/Maintenance Therapy

Study Treatment Setting N Regimen Results

NEAT001 Initial 805 DRV/RTV + RALSimilar efficacy as DRV/RTV + FTC/TDF; poor efficacy in pts with high HIV-1 RNA, low CD4+ cell counts

GARDEL Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs

MODERN Initial 813 DRV/RTV + MVC Inferior efficacy vs DRV/RTV + FTC/TDF

SPARTAN Initial 94 ATV + RALSimilar virologic suppression, higher VF and hyperbilirubinemia rates vs ATV/RTV + FTC/TDF

OLE Switch 250 LPV/RTV + 3TC Similar efficacy as continued standard ART

KITE Switch 60 LPV/RTV + RAL Small study; encouraging efficacy

SALT Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs

ATLAS-M Switch 266 ATV/RTV + 3TC Improved efficacy vs ATV/RTV + 2 NRTIs

DUAL-GESIDA Switch 257 DRV/RTV + 3TC Similar efficacy as DRV/RTV + 2 NRTIs

Slide credit: clinicaloptions.comModified from Eron J and Sax P

http://www.clinicaloptions.com/hiv

7 randomised trials of PI/r + RAL versus PI/r + 2NRTIsHIV RNA <50 copies/mL (switch = failure endpoint)

Overall, in 7 randomised trials of 1266 patients, PI/r + raltegravir showed HIV RNA suppressionrates 10% lower than PI/r + 2NRTIs (p=0.008).

However there was evidence for heterogeneity between the trials (p=0.03).

Favours 3-drug

treatment

Favours 2-drug

treatment

Courtesy Andrew Hill

Lamivudine

• Once daily NRTI

• Very well tolerated– Almost no side effects reported

• No drug-drug interactions

• Generic, low cost

• Low genetic barrier, selects M184V or I

• Residual antiviral activity even after selecting the mutation

• Enhances antiviral activity of TDF and ZDV

88.3% 90.3%

83.7%84.4%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BSL W4 W8 W12 W24 W36 W48 W96DT TT

GARDEL: Viral load <50 copies/mL at weeks 48 and 96 (ITTe)

Week 48(p= 0.171, difference +4.6%

[CI95%: -2.2% to +11.8%])

Week 96(p= 0.165, difference % [CI95%: -2.3%; to 14.1 %])

Pat

ien

ts w

ith

HIV

-1 R

NA

<5

0 c

op

ies/

mL

(%)[1

]

GARDEL: Viral load <50 copies/mL at weeks 48 and 96 (ITTe), baseline VL

> 100,000 copies/mL

87.2%90.7%

77.9%80.7%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

BSL W4 W8 W12 W24 W36 W48 W96

DT TT

Pat

ien

ts W

ith

HIV

-1 R

NA

<

50

co

pie

s/m

L(%

)[1]

W48(p=0.145, difference +9.3% [CI95%: -2.8% to +21.5%])

W96(p=0.163, difference % [CI95%: -3.8% ; 23.7 %])

OLE: Main endpoints

Difference (95% CI)0.05% (-5.3% to + 5.1%)

Difference (95% CI)0.3% (- 8.5 to + 8.3%)

Difference (95% CI)-0.25% (- 8.2 to + 7.6%)

Protocol defined VF: 2 consecutive VL>= 50 copies/ml; VF or any blip: any detectable VL >= 50 copies/ml

97.3% 97.3%

87.3% 87.6%89.8% 90.1%

Protocol defined VF Any blip Protocol defined VF or any blip

Atlas-M: ATV/r + 3TC non-inferior to

ATV/r + 2 N(t)RTI-s

DUAL-GESIDA Switch study: DRV/RTV + 3TC Dual ART Noninferior to Triple ART at Wk 48

• No resistance detected for 2 pts with resistance data in dual arm

• AE rates similar between arms

• D/c for AEs: 0.8% dual vs 1.6% triple ART (P = .55)

Pulido F, et al. HIV Glasgow 2016. Abstract O331.

Pts With 1,

2, or 3

Blips,* %

Dual

ART

Triple

ART

P

Value

1 8.9 13.2 .31

2 4.5 2.6 .46

3 0.9 0 .31

*Defined as transitory HIV-1 RNA ≥ 50

copies/mL in pts with HIV-RNA < 50

copies/mL at Wk 48.

Pts

(%

)

Wk 48 difference: -3.8%

(95% CI: -11.0% to 3.4%)

Dual ART

Triple ART

Virologic

Success

Virologic

Nonresponse

No Virologic

Data at Wk 48

100

80

60

40

20

0

8993

3 28 6

• Stable regimen: DRV/r + TDF/FTC or ABC/3TC ≥ 2 months

• VL < 50 c/mL > 6 months• HBs Ag (-)

ANDES: FDC of DRV/RTV+3TC was non-inferior to SOC DRV/RTV+TDF/3TC at 48 weeks

0

20

40

60

80

100

ITT snapshot(n=145)

ITT snapshot,baseline VL

>100,000copies/mL (n=35)

Observed cases(n=140)

Total 3DR 2DR

∆-1.5%

(95% CI, -0.9; 3.9%)∆-1.4%

(95% CI, -17.2; 14.4)

∆-1.0%

(95% CI, -7.5; 5.6)

Proportion of patients with

plasma HIV-1 RNA < 50 copies/mL

Primary outcome: VL<50

copies/mL at Week 48

n=

136

n=

66

n=

70

n=

32

n=

12

n=

20n=

136

n=

66

n=

70

Pati

ents

, %

Figueroa M, et al. 25th CROI; Boston, MA; March 4-7, 2018. Abst. 489.

Dual Therapy: Potential InSTI-Based Regimens for Initial/Maintenance Therapy

Regimen Treatment Setting Studies

DTG + 3TCInitial

▪ PADDLE (open-label phase IV)▪ ACTG A5353 (phase II)▪ GEMINI 1/2 (randomized phase III)

Maintenance ▪ ASPIRE (randomized phase III)

DTG + RPV Maintenance ▪ SWORD 1/2* (randomized phase III)

DTG + DRV/RTV Maintenance ▪ DUALIS (randomized phase III)

DTG + ATV/RTV Maintenance ▪ DOLATAV (phase II)

DTG + MVC Maintenance ▪ HP-00056162 (single-arm phase III)

RAL + ETR Maintenance ▪ ETRARAL

#W96 SCR BSL DAY 4 DAY 7 W.2 W.3 W.4 W.6 W.8 W.12 W.24 W.36 W.48 W 96

1 5.584 10.909 383 101 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

2 8.887 10.233 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

3 67.335151.56

9 1.565 1.178 97 53 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

4 99.291148.37

0 3.303 432 178 55 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

5 34.362 20.544 1.292 570 107 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

6 16.024 14.499 1.634 162 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

7 37.604 18.597 819 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

8 25.071 24.368 1.377Not

done 105 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

9 14.707 10.832 516 202 < 50 < 50 < 50 < 50 < 50 < 50 < 50 SAE

10 10.679 7.978 318 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 <50

11 50.089273.67

6 68.129 3.880 784 290 288 147 < 50 < 50 < 50 < 50 < 5070/<50

*

12 13.508 64.103 3.296 135 351 84 67 < 50 < 50 < 50 < 50 < 50 < 50 < 50

13 28.093 33.829 26.343 539 61 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 5014 15.348 15.151 791 198 < 50 61 64 < 50 < 50 < 50 < 50 < 50 < 50 < 50

15 23.185 23.500 4.217 192 < 50 < 50 < 50Not

done < 50 < 50 < 50 < 50 < 50 < 50

16 11.377 3.910 97 143 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

17 39.100 25.828 1.970 460 52 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

18 60.771 73.069 2.174 692 156 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50

19 82.803106.32

0 2.902 897 168 76 < 50 < 50 < 50 < 50 < 50 PDVF

20 5.190 7.368 147 56 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 < 50 <50

Virologic Outcome at Wk 24, n (%)

[Primary endpoint]

Baseline HIV-1 RNA, copies/mL

Total(N = 120)> 100,000

(n = 37)≤ 100,000

(n = 83)

Success (pVL<50

copies/mL)33 (89) 75 (90) 108 (90)

Nonsuccess 3 (8) 2 (2) 5 (4)

No data 1 (3) 6 (7) 7 (6)

Taiwo: CID 2018,

n = 3 with PDVF; n = 1 with emergent M184V and R263RK

ITT-e: 90% < 50 copies/mL at W 48 & 96 Observed data: 95% <50 copies/mLn=1 with PDVF; No mutations detected

Cahn: JIAS 2017

ITT-e: 90% < 50 copies/mL at W 24

a−10% noninferiority margin for individual studies.

GEMINI-1 and -2 Phase III Study Design

Cahn et al. AIDS 2018; Amsterdam, the Netherlands. Slides TUAB0106LB.

DTG + 3TC (N=716)

Day

1

Screening

(28 d)

Identically designed, randomized, double-blind, parallel-group,

multicenter, noninferiority studies

DTG + TDF/FTC (N=717)

DTG + 3TC

Week

48

Primary endpoint

at Week 48:

participants with

HIV-1 RNA <50 c/mL

(ITT-E snapshot)a

Double-blind

phase

Open-label

phase

Continuation

phase

CountriesArgentina Australia Belgium

Canada France Germany

Italy Republic of Korea Mexico

Netherlands Peru Poland

Portugal Romania Russian Federation

South Africa Spain Switzerland

Taiwan United Kingdom United States

Week

144

Week

24

Week

96

• ART-naive adults

• VL 1000-500,000 c/mL

1:1

Eligibility criteria• ≤10 days of prior ART

• No evidence of pre-existing viral resistance

based on presence of any major resistance-

associated mutation

• No HBV infection or need for HCV therapy

Baseline stratification factors: plasma HIV-1 RNA (≤100,000 c/mL vs >100,000 c/mL) CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).

GEMINI 1 & 2: Snapshot Analysis by Visit (Pooled)

Cahn et al. AIDS 2018; Amsterdam, the Netherlands.-Abstr TUAB0106LB.

<1

72

87 89

88

93

90 91

0

7085 89

9093

91 93

-20

0

20

40

60

80

100

-4 0 4 8 12 16 20 24 28 32 36 40 44 48

HIV

-1 R

NA

<5

0 c

/mL

%

Study visit

DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

DTG + TDF/FTC DTG + 3TC

-10 -8 -6 -4 -2 0 2 4 6 8 10

-4.4 1.1

-1.7

Adjusted treatment difference (95% CI)a

Percentage-point difference

Pooled analyses supports noninferiority

of DTG + 3TC versus DTG + TDF/FTC

with respect to snapshot in the ITT-E

population (<50 c/mL) at Week 48

-3.9

-1.3

-1.2

DTG + 3TC non-inferior to DTG + TDF/FTC at 48 weeks

Pooled Snapshot Outcomes at Week 48: ITT-E and Per Protocol Populations


aBased on Cochran-Mantel-Haenszel stratified analysis adjusting for the following baseline stratification factors: plasma HIV-1

RNA (≤100,000 c/mL vs >100,000 c/mL), CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3), and study (GEMINI-1 vs GEMINI-2). bPP, per protocol: population consisted of participants in the ITT-E population except for significant protocol violators, which could

potentially affect efficacy outcomes as determined by the medical monitor prior to database lock.

Virologic outcome Adjusted treatment difference (95% CI)a

DTG + TDF/FTC DTG + 3TC

-10 -8 -6 -4 -2 0 2 4 6 8 10

-4.4 1.1

-1.7


DTG + 3TC is non-inferior to DTG +

TDF/FTC with respect to proportion

<50 c/mL at Week 48 (snapshot, ITT-E

population) in both studies

-1.3

-3.9 1.2

ITT-E

PP

91

36

93

25

93

25

94

14

0

20

40

60

80

100

Virologicsuccess

Virologicnonresponse

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

ITT-E DTG + 3TC (N=716) DTG + TDF/FTC (N=717)

PPb DTG + 3TC (N=694) DTG + TDF/FTC (N=693)

Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA: Snapshot Analysis


91 9394 9392

79

9093

0

20

40

60

80

100

HIV

-1 R

NA

<5

0 c

/mL

, %

Snapshot Analysis

• 2% of participants in each arm had baseline HIV-1 RNA >500,000 c/mL

DTG + 3TC DTG + TDF/FTC

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

526

576

531

564

129

140

138

153

605

653

618

662

50

67

51

55

Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+ Cell Count: Snapshot Analysis


91 9394 9392

79

9093

0

20

40

60

80

100

HIV

-1 R

NA

<5

0 c

/mL

, %

Snapshot Analysis



>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+


526

576

531

564

129

140

138

153

605

653

618

662

50

63

51

55

98 9898 9899 9897 100

0

20

40

60

80

100

Wit

ho

ut

TR

DF,

%

TRDF Analysis

566

576

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+


Pooled Outcomes at Week 48 Stratified by Baseline HIV-1 RNA and CD4+

Cell Count: Snapshot and TRDF Analysis


91 9394 9392

79

9093

0

20

40

60

80

100

HIV

-1 R

NA

<5

0 c

/mL

, %

Snapshot Analysis


• Treatment related discontinuation = failure (TRDF) population accounts for confirmed virologic withdrawal (CVW), withdrawal

due to lack of efficacy, withdrawal due to treatment-related AE, and participants who met protocol-defined stopping criteria

• DTG + 3TC CD4 <200 Snapshot non-response (n=13): 1 CVW, 3 with VL >50 in window (2 of 3 re-suppressed), 2 discontinued due to AE (TB,

Chagas disease), 2 protocol violations, 2 lost to follow-up, 1 withdrew consent, 1 withdrew to start HCV treatment, 1 change in ART (incarcerated)

• DTG + TDF/FTC < 200 Snapshot non-response (n=4):1 investigator discretion, 1 withdrew consent, 1 lost to follow-up, 1 VL >50 (re-suppressed)


>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+


553

564

138

140

149

153

642

653

647

662

62

63

55

55

526

576

531

564

129

140

138

153

605

653

618

662

50

63

51

55

Confirmed Virologic Withdrawals Through Week 48: ITT-E Population

GEMINI 1 GEMINI 2 Pooled

Variable, n (%)

DTG + 3TC

(N=356)

DTG +

TDF/FTC

(N=358)

DTG + 3TC

(N=360)

DTG +

TDF/FTC

(N=359)

DTG + 3TC

(N=716)

DTG +

TDF/FTC

(N=717)

CVW 4 (1) 2 (<1) 2 (<1) 2 (<1) 6 (<1) 4 (<1)

Treatment-emergent

resistance

0 0 0 0 0 0

• Low rates of virologic withdrawals were observed at Week 48


• No treatment-emergent INSTI mutations or NRTI mutations were

observed among participants who met CVW (confirmed virologic

failure) criteria

Confirmed virologic withdrawal criteria is defined as a second and consecutive HIV-1 RNA value meeting virologic non-response or rebound. Virologic non-response is defined as either a decrease in

plasma HIV-1 RNA of less than 1 log10 c/mL by Week 12 with subsequent confirmation unless plasma HIV-1 RNA is <200 c/mL, or confirmed plasma HIV-1 RNA levels ≥200 c/mL on or after Week 24.

Virologic rebound is defined as confirmed rebound in plasma HIV-1 RNA levels to ≥200 c/mL after prior confirmed suppression to <200 c/mL.

.

Virologic outcomes Adjusted treatment difference (95% CI)a


DTG + RPV is non-inferior to CAR with

respect to snapshot in the ITT-E population

(<50 c/mL) at Week 48

0

20

40

60

80

100

Virologicsuccess

Virologicnon-response

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

DTG + RPV (n=513)

CAR (n=511)

95 95

<1 15 4

CAR DTG + RPV

-8 -6 -4 -2 0 2 4 6 8

-3.0 2.5

-0.2FDA label: For pts who have been virologicallysuppressed for ≥ 6 months and no history of treatment failure and no resistance to DTG or RPV

Inclusion criteria• On stable CAR >6 months before screening• 1st or 2nd ART with no change in prior regimen

due to VF• Confirmed HIV-1 RNA <50 c/mL during the 12

months before screening• HBV negative

DTG + Rilpivirine is non-inferior to continuingongoing ART in virologically suppressed

patients

• Cabotegravir: InSTIs formulated as PO tablet and for long-acting IM injection

• LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309)

Dual therapy with Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART: 96-Wk Results (LATTE-2)

Eron J, et al. IAS 2017. Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].

*HIV-1 RNA < 50 copies/mL.

Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate /

AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2%

~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB

VirologicSuccess*

9487

84

40 2 2

13 14

VirologicNon-response

No VirologicData

Pts

, Wk

96

(%

)

100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)IM CAB + RPV Q8W (n = 115)PO CAB + ABC/3TC (n = 56)

10.0%

-12 -9 -6 -3 0 3 6 9 12 15

20.5-0.6

Q8W IM

Treatment Differences (95% CI)

3.0%

-12 -9 -6 -3 0 3 6 9 12 15

14.4-8.4

Q4W IM

InjectableRilpivirinerequires

cold chain

0

25

50

75

100

DTG+3TC

% <

50

We

ek

40

• 110 Subjects

• No Hx of failure, No Hep B

• 8 week Switch to 2NRTI+DTG

• 40 Weeks FU on DTG/3TC

• 1 x VF (no resistance)

• 4 SAE• Suicidal ideation

• CK elevation post exercise

• Grade 4 Depression

• Acute Hep C

ANRS 167 LamiDol Study DTG/3TC Maintenance

Joly V, et al. 24th CROI; Seattle, WA; February 13-16, 2017. Abst. 458.

Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE)

Taiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5.

Virologic Outcomes at Week 48 (FDA Snapshot)

90,9%

2,3%6,8%

88,9%

2,2%8,9%

0,0%

10,0%

20,0%

30,0%

40,0%

50,0%

60,0%

70,0%

80,0%

90,0%

100,0%

HIV RNA <50 cpm HIV RNA >50 cpm No Virologic Data

DTG+3TC Cont ART

N 40 40 1 1 3 4

On Study 44 45 44 45 44 45

HIV-1 infected adults virologically suppressed on any 3-drug ARV regimen.

CD4 nadir > 200 cells/mm3No history

of virologic failure

Dolutegravir Plus Lamivudine for Maintenance of Suppression (ASPIRE)

No resistanceTaiwo B, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. PE8/5.

Viral Blips

Treatment Arm Week 0 Week 4 Week 12 Week 24 Week 36 Week 48

HIV RNA (cpm) DTG + 3TC <20 <20 191/<20 <20 <20 <20

AdherenceLast missed dose

(Participant Report)1-2 wks ago

HIV RNA (cpm) Cont ART <20 <20 351/<20 <20 <20 <20

Adherence Last missed dose 1-3 mo

HIV RNA (cpm) Cont ART <20 <20 <20 <20 <20 179/30

Adherence Last missed dose 1-2 wks Past week

HIV RNA (cpm) Cont ART<20

682/<20 <20 <20 <20 <20

Adherence Last missed dose >3 mo

HIV RNA (cpm) Cont ART 2268 50 31 <20 <20 <20

Adherence Last missed dose >3 mo

What’s New? DTG/RPV FDA Approved for Maintenance Therapy

▪ Once-daily single-tablet regimen of DTG and RPV

– First 2-drug STR FDA approved for use as a complete regimen in the US

Slide credit: clinicaloptions.comDTG/RPV [package insert]. November 2017.

Key US Label Information

Indication▪ For pts who have been virologically suppressed for ≥ 6 mos

▪ Pts must have no history of treatment failure and no resistance to DTG or RPV

Administration

requirements▪ Must be taken with a meal

Key DDIs

▪ Separate dose of DTG/RPV and antacid/polyvalent cation–containing

medications

▪ Avoid PPIs (eg, omeprazole, pantoprazole), dexamethasone

Dose

adjustments

▪ None required for pts with mild/moderate renal impairment; in pts with CrCl

< 30 mL/min, increase monitoring for AEs

http://www.clinicaloptions.com/oncology

SWORD Studies: Snapshot Outcomes at Week 48 (Pooled)

Virologic outcomes Adjusted treatment difference (95% CI)a


DTG + RPV is non-inferior to CAR with

respect to snapshot in the ITT-E population

(<50 c/mL) at Week 48

0

20

40

60

80

100

Virologicsuccess


No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

DTG + RPV (n=513)

CAR (n=511)

95 95

<1 15 4

CAR DTG + RPV

-8 -6 -4 -2 0 2 4 6 8

-3.0 2.5

-0.2

aAdjusted for age and baseline 3rd agent.

Switching to DTG+RPV had a neutral effect on lipids, while significantly

improving bone turnover biomarkers

Llibre et al. CROI 2017; Seattle, WA. Abstract 2421.

Inclusion criteria

• On stable CAR >6 months before

screening

• 1st or 2nd ART with no change in prior

regimen due to VF

• Confirmed HIV-1 RNA <50 c/mL during

the 12 months before screening

• HBV negative

SWORD Study: RPV/DTG: Bone markers

a. P values are from an ANCOVA model adjusting for original ART third-agent class, age, sex, body mass index category, smoking status, and baseline biomarker level.

23,8 24,0

53,0 55,3

15,9 16,219,023,1

45,6

54,7

12,917,1

0

15

30

45

60

Me

an s

eru

m

con

cen

trat

ion

, µ

g/L

Bone-specific

alkaline phosphatase

P<0.001a

Osteocalcin

P<0.001a

Procollagen 1

N-terminal propeptide

P<0.001a

Type 1 collagen

C-telopeptide

P<0.001a

0,66 0,69

0,49

0,63

0,00

0,18

0,35

0,53

0,70

0,88

Me

an s

eru

m

con

cen

trat

ion

, µ

g/L

Baseline Week 48 Baseline Week 48

CARDTG + RPV

Bone Turnover Biomarkers: Change From Baseline to Week 48

Orkin C, et al; 16th EACS, Milan, Italy, October 25-27, 2017; Abst. BPD1/5.

IAS 2017, Abstr THPEB 542

95% pVL < 50 copies/ml(1pt with etravirine resistance

• Cabotegravir: INSTI formulated as PO tablet and for long-acting IM injection

• LATTE-2: phase IIb study in which pts randomized to CAB 400 mg + RPV 600 mg IM Q4W, CAB 600 mg + RPV 900 mg IM Q8W, or CAB 30 mg + ABC/3TC 600/300 mg PO QD after induction/virologic suppression with oral CAB + ABC/3TC (N = 309)

LATTE-2: 96-Wk Results for Cabotegravir IM + Rilpivirine IM as Long-Acting Maintenance ART

Eron J, et al. IAS 2017. Abstract MOAX0205LB. Margolis DA, et al. Lancet. 2017;[Epub ahead of print].

*HIV-1 RNA < 50 copies/mL.

Few drug-related AEs. At 96 wks, ~ 30% pts receiving IM injection experienced ISR 99% of ISRs mild/moderate /

AEs leading to withdrawal: Pooled Q4W/Q8W IM arms, 4%. PO arm, 2%

~ 88% of pts receiving IM CAB very satisfied to continue present treatment vs 43% receiving PO CAB

Virologic

Success*

9487 84

40 2 2

13 14

Virologic

Non-

response

No

Virologic

Data

Pts

, W

k 9

6 (

%)

100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)

IM CAB + RPV Q8W (n = 115)

PO CAB + ABC/3TC (n = 56)

10.0%

-12 -9 -6 -3 0 3 6 9 12 15

20.5-0.6

Q8W IM

Treatment Differences (95% CI)

3.0%

-12 -9 -6 -3 0 3 6 9 12 15

14.4-8.4

Q4W IM

SELECT (A5273): second-line LPV/r + RAL in resource-limited countries

ACTG, AIDS Clinical Trial Groups; NRTI, nucleoside reverse transcriptase inhibitor

*Three sites each in India and South Africa, two each in Malawi and Peru, and one each in Brazil, Kenya, Tanzania,

Thailand, and Zimbabwe

Adapted from La Rosa et al. Lancet HIV. 2016 June ; 3(6): e247–e258.

SELECT (A5273): Randomised, open-label, phase 3, non-inferiority study at 15 ACTG research sites in 9 resource-limited countries*

What about InSTIs monotherapy?

• Only tested with DTG

• Mixed results in regards to efficacy

• High rate of resistance selection in the integrase gene in case of VF

• Resistance mutations selected: 92Q; 97A; 118R; 140S; 148 K, R, H; 155H; 230R; 263K, among others 1,2.

• DTG monotherapy should not be used for initial therapy or as a simplification strategy

2 . Blanco Jl et al:Curr Opin Infect Dis 2018

1. Wensing A et al: Topics in Antiviral Medicine (IAS-USA), 2017

DTG Monotherapy after treatment for Primary HIV Infection

• Patients treated during primary HIV infection (within 180 days of acquiring HIV) may have lower reservoir compared to those treated with chronic infection

• Could these patients maintain suppression on DTG monotherapy?• Study design:

• Primary endpoint: Virological response, defined as proportion of patients without virological failure at week 48, or before

N=103

Braun D, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0102B3.

Continuation of cART

Randomization2:1

DTG vs cART

Week 12

Week 12

Week 24

Week 24

Week 36 Week 48

Week 48Week 36Week 2 Week 4 Week 8 Week 16 Week 20

Monotherapy Dolutegravir

DTG Monotherapy after treatment for Primary HIV Infection: Results

• Comparable slight decay of HIV-1 reservoir (cellular HIV DNA) and absence of CSF virus in both groups

• One patient with virologic failure in DTG mono arm (protocol violation - enrolled with chronic HIV and higher HIV reservoir)

• Results suggest that simplification strategies may require stratification for appropriate candidates

Braun D, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0102.

100% 98,50%100% 100%

0%

20%

40%

60%

80%

100%

Pre-protocol Intention-to-treat

Pro

po

rtio

n o

f p

atie

nts

w

ith

vir

olo

gica

lre

spo

nse

[%

]

DTG monotherapyStandard of care therapy (cART)

67/67 32/32 67/68 33/33

Moncay study: switch to DTG monotherapy vs remain on ABC/3TC/DTG

Stable, efficient and well-tolerated DTG/ABC/3TC regimen*

Randomization 1:1(n=158)

DTG 50 mg QD (n=78)

Baseline Week 24 Week 48

DTG/ABC/3TC single tablet QD (n=80)

Screening**

Non-inferiority margin: 12%

* HIV-RNA (pVL) <50 c/mL for >12 months, no AIDS event (except past tuberculosis), nadir CD4 >100/mm3, no mutation to or failure on any INSTI-based regimen** pVL < local threshold (20 to 40 c/mL)

Hocqueloux L, et al. AIDS 2018; Amsterdam, the Netherlands; July 23-27, 2018; Abst. TUAB0103.

Open-label, randomized, controlled trial in 9 reference centers in France

Primary endpoint: proportion with pVL <50 c/mL in ITT, mITT and PP analyses (with a pre-planned non-inferiority margin of 12%);virologic failure (VF) = 2 consecutive pVL >50 c/mL; ITT, missing or switch = failure (M=F)

Secondary endpoints: changes in CD4 count, CD4:CD8 ratio, eGFR, lipids; HIV-DNA and genital sub-studies

96

1 3

94

3 4

0

20

40

60

80

100

Virologicsuccess


No virologicdata

HIV

-1 R

NA

<5

0 c

/mL,

% DTG/ABC/3TC (n=80)

DTG (n=78)

Moncay study: 24 week results

Virologic outcomes (ITT) W24 treatment difference

Virologic success (%) difference

DTG was non-inferior to DTG/ABC/3TC at Week 24 with respect to snapshot in the ITT, mITT and PP population


-15 -10 -5 0 5 10 15

TC/DTG arm Risk difference (95% CI)95%

ConfidenceInterval

7/80 (96.3%) [-5 to 10.8]

7/78 (98.7%) [-4.5 to 8.1]

6/77 (98.7%) [-4.5 to 8.8]

DTG better DTG/ABC/3TC better

0

25

50

75

100

0 12 24 36 48

VF-

Fre

e S

urv

ival

(%

)

Time in Weeks

DTG/ABG/3TC arm

DTG armP=0.005 (Log-Rank Test)

Moncay study : extended follow up

• Excess virologic failures in DTG monotherapy arm led to DSMBrecommendation to stop the study

• 2/7 study subjects with virologic failure developed resistance to DTG (1 pt with S147G, N155H, another with R263K)


Similar results in DOMONO trial of DTG maintenance monotherapy:

Noninferior virologic suppression atWk 24, unacceptable VF afterward[3

What Data Are Needed to Change the Treatment Paradigm of HIV Therapy?

• Well-designed noninferiority trials vs triple-combination therapy– With a clear definition of treatment success and

failure

• Sufficient number of patients in new strategies• Robust risk assessment (for both the individual

patient and for public health concerns) • Criteria for identification of patients who are

likely to succeed/benefit from new strategies• Assessment of response durability on

experimental arm

Dual therapy: Remaining questions

• How would dual therapy perform in the context of PW, TB co-treatment, Hepatitis B, adolescents, and children?

• What are the pragmatic issues related to having patients on both three-drug and two-drug regimens?

• - How do we balance the financial impact of dual therapy with treatment durability in low-resource settings?

The future of dual therapy

• Reverse –transcriptase inhibition seems to be crucial for DT

• The anchor drug must have high genetic barrier

• DT can be safely prescribed in virologically suppressed patients, with no previous failure

• So far, DT is only considered as alternative option in naive pts

• If the results of ongoing trials are sustainable, a new paradigm for first line treatment and early switch might be generated.

• In the era of Test & Treat, DT could be a first line preferred strategy, with minimal monitoring requirements, leaving future treatment options in case of failure, as only M184V (or NNRTI) mutations would be expected to emerge.

• This could be an important contribution to the 90/90/90 targets.

Thank you for your attention

Simplified regimens: Pros and...

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