New ARVs, new strategies

Pablo Tebas, MD

Outline

• New ARVs• TAF/FTC/Bictegravir Bictarvy (February 2018)• TAF/FTC/c/DRV Symtuza (July 2018)• Doravirine/3TC/TDF Delstrigo (August 2018)

• New strategies• Dual therapy DTG/3TC. Dovato (April 2019)

• Initial• Maintenance

• Drugs for MDR patients• Ibalizumab Trogarzo (March 2018)• Fostemsavir

• Future drugs*• Cabotegravir/Rilpivirine IM• PRO 140• Islapravir

New ARVs

▪ Design

▪ Objective– Non inferiority of BIC/F/TAF at W48: % HIV RNA < 50 c/mL by intention to treat,

snapshot analysis (lower margin of the 2-sided 95.002% CI for the

difference= -12%, 95% power)

BIC/F/TAF QD

DTG/ABC/3TC placebo QD

DTG/ABC/3TC QD

BIC/F/TAF placebo QD

Randomisation*1 : 1

Double-blind

> 18 years, ARV-naïve HIV RNA > 500 c/mLAny CD4 cell count

HLA B*5701 negativeeGFR ≥ 50 mL/min

HBs Ag negativeNo resistance to

FTC/3TC, TDF or ABC

Study GS-US-380-1489: BIC/F/TAF QD vs DTG/ABC/3TC QD

N = 315

N = 314

W48 W144

* Randomisation was stratified by HIV RNA (< 100 000 c/mL, 100 000-4000 000 c/mL or > 100 000 c/mL),

CD4 (< 50/mm3, 50-199/mm3 or ≥ 200/mm3) at screening and geographic region (USA vs non-USA)

BIC/F/TAF: 50/200/25 mg, as STR

Gallant J. Lancet. 2017 Nov 4;390(10107):2063-2072 ; Wohl DA Lancet HIV 2019 ; 6:e355-63

BICTARVY

Virologic outcome at week 48

DTG/ABC/3TC BIC/F/TAF

0 ‒ 12% + 12%

3.6- 4.8

- 0.6

Difference (95 % CI)BIC/F/TAFDTG/ABC/3TC

92.4

1.06.7

93.0

2.5 4.4

0

20

40

60

80

100

HIV RNA

< 50 c/mL

HIV RNA

≥ 50 c/mLNo data

%

▪ Met criteria for resistance testing (HIV RNA ≥ 200 c/mL)– BIC/F/TAF: 1 vs DTG/ABC/3TC: 4

– No resistance emergence

▪ Mean CD4 increase at W48– BIC/F/TAF: + 233/mm3

– DTG/ABC/3TC: + 229/mm3

▪ HIV RNA < 50 c/mL (per-protocol)‒ BIC/F/TAF: 99.3%

‒ DTG/ABC/3TC: 98.6%

Study GS-US-380-1489: BIC/F/TAF QD vs DTG/ABC/3TC QD

Gallant J. Lancet. 2017 Nov 4;390(10107):2063-2072

▪ Design

▪ Objective– Non inferiority of E/C/F/TAF at W48: % HIV RNA < 50 c/mL by intention to

treat, snapshot analysis (lower margin of the 95% CI for the difference = -10%)

D/C/F/TAF QD

D/C + F/TDF placebo

D/C + F/TDF QD

D/C/F/TAF placebo

Randomisation*1:1

Double-blind

HIV+ AdultsARV-naïve

HIV RNA > 1 000 c/mLCD4 cell count > 50/mm3

eGFR > 50 mL/min

* Randomisation was stratified by HIV RNA (< or ≥ 100 000 c/mL) and CD4 cell count (< or ≥ 200/mm3)

** Patients were switched to open-label D/C/F/TAF after unblinding that occurred at various time after W4

AMBER Study: D/C/F/TAF QD vs D/C + F/TDF QD

N = 363

N = 362

W96W48

Eron J. AIDS 2018 ;32:1431-42

D/C/F/TAF QD

D/C/F/TAF QD **

Median duration of exposure (weeks) : D/C/F/TAF = 96.1 ; D/C + F/TDF = 73.1 ; D/C/F/TAF deferred switch = 22.3

SYMTUZA

▪ Resistance analysis– Virologic failures with paired genotypes (baseline and failure with HIV

RNA ≥ 400 c/mL), N = 9 [7 D/C/F/TAF + 2 D/C + F + TDF]:

1 patient with emergence of M184I/V (D/C/F/TAF)

Virologic outcome at W48 (ITT, snapshot)

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

2.7

7.1 - 1.6

Adjusted difference, % (95% CI)

Favours

D/C/F/TAF

Favours

D/C + F/TDF

66

D/C/F/TAF (N = 362)D/C + F/TDF (N = 363)

91.4

4.4 4.1

88.4

3.38.3

0

20

40

60

80

100

HIV RNA

< 50 c/mL

HIV RNA

≥ 50 c/mLNo data

%

AMBER Study: D/C/F/TAF QD vs D/C + F/TDF QD

Eron J. AIDS 2018 ;32:1431-42

▪ Design

▪ Objectives– Non inferiority of DOR at W48: % HIV RNA < 50 c/mL by intention to treat,

snapshot analysis (lower margin of the 95% CI for the difference = - 10%,

90% power)

– Superiority of DOR for neuropsychiatric adverse events by W48

DOR 100 mg/3TC/TDF QD + placebo

EFV/FTC/TDF + placebo

Randomisation*1 : 1

Double-blind

* Randomisation was stratified by HIV RNA (< or > 100 000 c/mL) at screening and chronic hepatitis B or C

N = 364

N = 364

W48 W96

DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF

> 18 yearsARV-naïve

HIV RNA > 1 000 c/mLAny CD4 cell count

eGFR (CG) ≥ 50 mL/minNo primary resistance

to DOR, EFV, NRTI

DOR/3TC/TDF : 1 tablet QD as STR

Orkin C. Clin Infect Dis. 2019 ;68:535-44

DELSTRIGO

EFV DOR

0 ‒ 10% + 10%

9.0-2.0

3.5

Difference (95 % CI)EFV/FTC/TDF (N = 364)

84

115

81

10 9

0

20

40

60

80

100

Virologic

response

Virologic

non-responseNo data

DOR/3TC/TDF (N = 364)%

58

Primary endpoint: HIV RNA < 50 c/mL at W48 (ITT, snapshot)

▪ CD4 increase at W48 (ITT, NC = F)– DOR: + 198/mm3

– EFV: + 188/mm3

▪ HIV RNA < 50 c/mL at W48 (observed failure approach)‒ Baseline HIV RNA ≤ 100 000 c/mL: DOR: 90.6% vs EFV: 91.1 %

‒ Baseline HIV RNA > 100 000 c/mL: DOR: 81.2 % vs EFV: 80.8 %

DRIVE-AHEAD Study: DOR/3TC/TDF vs EFV/FTC/TDF

Orkin C. Clin Infect Dis 2019; 68: 535-44

DHHS[1] IAS-USA[2] EACS[3] WHO[4]

▪ BIC/FTC/TAF▪ DTG/3TC/ABC▪ DTG + FTC/(TAF or TDF)▪ RAL + FTC/(TAF or TDF)

▪ BIC/FTC/TAF▪ DTG/3TC/ABC▪ DTG + FTC/TAF

▪ BIC/FTC/TAF▪ DTG/3TC/ABC▪ DTG + FTC/(TAF or TDF)▪ RAL + FTC/(TAF or TDF) ▪ RPV/FTC/(TAF or TDF)▪ DRV(COBI or RTV) +

FTC/(TAF or TDF)

▪ DTG + (3TC or FTC)/TDF

How these new drugs fit in the current guidelines?How should they be used?

▪ Recommendations may differ based on baseline HIV-1 RNA, CD4+ cell count, CrCl, eGFR, HLA-B*5701 status, HBsAg status, bone mineral density, and pregnancy status or intent

1. DHHS ART. Guidelines. October 2018. 2. Saag. JAMA. 2018;320:379. 3. EACS. 2019. 4. WHO ART. December 2018.

• One of the

options for

“most” patients

starting ART

• Is an option for patients

with comorbidities

• May become popular if

the weight signal is

better than INSTIs/TAF

• Rapid initiation in

people with

adherence concerns

BICTARVYSYMTUZADELSTRIGO

New strategiesCan you induce and maintain

suppression with 2 drugs?

▪ Design

▪ Primary endpoint– 2 parallel studies (GEMINI-1 and GEMINI-2), each with a combined

number of 710-720 patients and similar endpoint

– Proportion of patients with HIV RNA < 50 c/mL at W48, ITT-E analysis,

snapshot algorithm ; non-inferiority if lower margin of a one-sided 97.5% CI

for the difference = - 10%, 90% power

DTG + 3TC

DTG + TDF/FTC

Randomisation *1 : 1

Double-blind

HIV+ ≥ 18 yearsARV-naïve

HIV RNA 1 000-500 000 c/mLNo HBV co-infection

No major HIV resistance mutationsN = 717

N = 716

W96

GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line

* Randomisation stratified by HIV RNA (≤ or > 100 000 c/mL) and CD4 (≤ or > 200/mm3)

Cahn P. Lancet. 2019; 393(10167):143-155

DOVATO

GEMINI-1 and -2 Studies:Virologic Outcomes at Week 96

Cahn P, et al. J Int AIDS Soc. 2019;22(suppl 5):103. Abstract WEAB0404LB.

Pati

en

ts (

%)

HIV RNA <50 Copies/mL at Week 96 (ITT)

0

20

40

60

80

100

Overall (ITT)(n=716/717)

86%90%

≤100K(n=576/564)

Non-InferiorityMaintained

Difference (%):-3.4 (-6.7, 0.0)

>100K(n=140/153)

Baseline HIV RNA (copies/mL)

>200(n=653/662)

≤200(n=63/55)

Baseline CD4 Count (cells/mm3)

87%90%

84% 86%

68%

90%88% 87%

Dolutegravir + 3TC Dolutegravir + F/TDF

GEMINI-1 and -2 Studies:Pooled Resistance and Safety Outcomes at Week 96

• No treatment-emergent INSTI or NRTI mutations in

either arm

• Safety and tolerability profile was similar between

both arms

• Dolutegravir + 3TC versus dolutegravir + F/TDF

– Confirmed virologic withdrawals: <1% in both arms

– Significantly smaller changes in renal markers

– Significantly less severe change in bone markers (serum

bone-specific phosphatase, serum osteocalcin, serum

procollagen-1 N-terminal propeptide, serum type 1

collagen C-telopeptide)

• 96-week data support the use of dolutegravir + 3TC

as a potential option for initial treatment in select

patients

Cahn P, et al. J Int AIDS Soc. 2019;22(suppl 5):103. Abstract WEAB0404LB.

Safety Outcomes at Week 96

Dolutegravir

+ 3TC

(n=716)

Dolutegravir

+ F/TDF

(n=717)

Discontinuations due to

adverse events (%)

3 3

Adverse events (%)

Serious

Drug-related

Most common

Diarrhea

Headache

Nasopharyngitis

9

20

12

11

10

9

25

13

12

16

Change in renal markers

GFR-cystatin C (mL/min)

Creatinine (µmol/L)

GFR-creatinine (mL/min)

11*

12†

-15*

9

15

-18

*P<0.001 and †P<0.005 versus dolutegravir + F/TDF.

Underwood M, CROI 2019, Abs. 490

Time to HIV RNA < 40 c/mL with target not detected (Kaplan-Meier )

All participants

DTG + 3TC (N = 716)

DTG + TDF/FTC (N = 717)

0 4 8 1216 24 36 48 60 72

0

0.2

0.4

0.6

0.8

1.0 77 %

73 %

Weeks

Baseline HIV RNA < 100 000 c/mL

0 4 8 1216 24 36 48 60 72

0

0.2

0.4

0.6

0.8

1.080 %

79 %

Weeks

(N = 576)

(N = 564)

Baseline HIV RNA > 100 000 c/mL

0 4 8 1216 24 36 48 60 72

0

0.2

0.4

0.6

0.8

1.0

64 %

52 %

Weeks

(N = 140)

(N = 153)

GEMINI 1 & 2 Studies: DTG + 3TC vs DTG + TDF/FTC in first-line

TANGO Study: Dolutegravir/3TC inTreatment-Experienced Patients on Stable TAF-Based ART

van Wyk J, et al. J Int AIDS Soc. 2019;22(suppl 5):102-103. Abstract WEAB0403LB.

Phase 3

Open-labelTreatment-experiencedStable TAF-based ART

(HIV RNA <50 copies/mL)No HBVNo prior virologic failure or

NRTI or INSTI resistance

Randomization1:1

Continue TAF-Based ART(n=372)

Switch to Dolutegravir/3TC(n=369)

Week 0 48 96 144

Primary EndpointVirologic Failure (ITT)

(4% non-inferiority margin)Virologic failure: includes changing background therapy component,

discontinued due to lack of efficacy, or HIV RNA ≥50 copies/mL by week 48.Baseline demographics:

Male: 92%.Age: 39-40 years.Black: 15%.CD4 count:

Mean: 682-720 cells/µL.<350 cells/µL: 9%.

Duration of ART: 34 months.3rd ART class:

INSTI (79%), NNRTI (13%), boosted PI (8%).

TANGO Study:Treatment Outcomes With Dolutegravir/3TC at Week 48

• Switching to dolutegravir/3TC was non-inferior to

continuing TAF-based regimen

– Virologic failure

– HIV RNA <50 copies/mL

• No emergent resistance after switching to

dolutegravir/3TC

• Both treatment arms were well tolerated (switching

to dolutegravir/3TC versus continuing TAF-based

regimen)

– Discontinuations due to drug-related adverse events:

2% versus <1%

– Any serious adverse events: 6% versus 4%

(none were treatment related)

– Weight increase: 0.8 kg in both arms

van Wyk J, et al. J Int AIDS Soc. 2019;22(suppl 5):102-103. Abstract WEAB0403LB.

Pati

en

ts (

%)

Virologic Outcomes at Week 48

0

20

40

60

80

100

HIV RNA≥50 Copies/mL

<1% <1%

7%

93% 93%

7%

HIV RNA<50 Copies/mL

No VirologicData

Switch to DTG/3TC (n=369) Continue TAF-based regimen (n=372)

Difference (%):-0.3 (-1.2, 0.7)

Can we use dual therapy in all naive?Some questions remain

• Rapid start?

• Transmitted M184V?

• Women with childbearing potential?

• Opportunistic infection/TB?

• HIV-1 RNA level and CD4+ cell count?

• HIV-1 RNA > 500,000 copies/mL?

• CD4+ cell count < 200 cells/mm3?

• Hepatitis B coinfection?

• 3TC as sole agent with anti-HBV activity associated with considerable risk of HBV antiviral resistance

DHHS ART. October 2018.

New drugs for the patient with few optionsLight at the end of the tunnel

N Engl J Med 2018; 379:645-654

Trial Design, Enrollment, and Outcomes.

Emu B et al. N Engl J Med 2018;379:645-654

N Engl J Med 2018; 379:645-654

BRIGHTE: Fostemsavir in Heavily Treatment–Experienced Adults With Multidrug Resistant HIV▪ Wk 96 analysis of randomized, double-blind phase III trial in heavily treatment–experienced adults

experiencing failure of current ART with confirmed HIV-1 RNA ≥ 400 c/mL

‒ At BL: median HIV-1 RNA, 4.6 log10 c/mL; median CD4+ cell count, 80 cells/mm3; AIDS history, 86%

Slide credit: clinicaloptions.com

Randomized Cohort1-2 remaining ARV classes

(≥ 1 fully active§approved agent/class), cannot construct viable regimen with

remaining agents(n = 272)

*Blinded. †Day 8 adjusted by Day 1. ‡Open-label. §No evidence of resistance; patient eligible for, tolerant of, willing to receive the ARV. ║Measured from start of open-label tx. Study conducted until another option, rollover study, or approved ARV available.

Primary EndpointMean Δ in HIV-1 RNA,†

log10 c/mL (95% CI)

-0.79 (-0.88 to -0.70)

-0.17 (-0.33 to -0.01)

Day 9

FTR 600 mg BID + Failing Regimen*

(n = 203)

Placebo + Failing Regimen*

(n = 69)

FTR 600 mg BID + OBT‡

FTR 600 mg BID + OBT‡

Treatment ∆: -0.63

Nonrandomized CohortNo remaining ARV classes and no

fully active§ approved agents(n = 99)

FTR 600 mg BID + OBT‡ (investigational agents allowed)

Day 1

Lataillade. IAS 2019. Abstr MOAB0102. Pialoux. IAS 2018. Abstr THPEB045.

Day 8 Wk 96‖

BRIGHTE: ITT-E Virologic Response Through Wk 96

Lataillade. IAS 2019. Abstr MOAB0102. Reproduced with permission.

Randomized Cohort (n = 272)

Nonrandomized Cohort (n = 99)

HIV

-1 R

NA

< 4

0 c

op

ies/

mL

(%)

*Snapshot analysis excluded baseline data. 1 patient had BL HIV-1 RNA < 40 copies/mL.

100

80

60

40

20

0

Baseline* Wk 24 Wk 48 Wk 72 Wk 96

53 54 5360

37 38 35 37

Outcome at Wk 96, n (%)Randomized

Cohort(n = 272)

Nonrandomized Cohort(n = 99)

HIV-1 RNA < 40 copies/mL 163 (60) 37 (37)

HIV-1 RNA ≥ 40 copies/mL▪ Data in window not below

threshold▪ D/c for lack of efficacy▪ D/c for other reason while

not below threshold▪ Change in ART*

81 (30)33 (12)10 (4)17 (6)21 (8)

43 (43)15 (15)

3 (3)6 (6)

19 (19)

No virologic data▪ D/c due to AE or death▪ D/c for other reasons▪ Missing data during

window

28 (10)15 (6)8 (3)5 (2)

19 (19)14 (14)

4 (4)1 (1)

▪ Mean change from BL to Wk 96 in CD4+ count, cells/mm3: randomized cohort, 205; nonrandomized cohort, 119

▪ In the randomized cohort, mean CD4+/CD8+ cell ratio increased from BL (0.2) to Wk 96 (0.443)Slide credit: clinicaloptions.com

BRIGHTE: Safety Through Wk 96

Slide credit: clinicaloptions.comLataillade. IAS 2019. Abstr MOAB0102.

Cumulative Safety Outcomes Through Wk 96, n (%)

Randomized Cohort(n = 272)*

Nonrandomized Cohort(n = 99)

All Treated Patients(N = 371)

Any event 249 (92) 98 (99) 347 (94)

▪ Any grade 2-4 AE 216 (79) 87 (88) 303 (82)

▪ Drug-related grade 2-4 AEs 57 (21) 22 (22) 79 (21)

▪ Any grade 3/4 AE 78 (29) 49 (49) 127 (34)

▪ Any serious AE 92 (34) 48 (48) 140 (38)

▪ Drug-related serious AE 9 (3) 3 (3) 12 (3)

▪ Any AE leading to d/c 14 (5) 12 (12) 26 (7)

▪ Any CDC class C event 23 (8) 15 (15) 38 (10)

▪ Death 12 (4) 17 (17) 29 (8)†

*Includes patients initially randomized to placebo. Data are from initiation of open-label fostemsavir.†AIDS-related events or acute infections, n = 18 (1 case of IRIS considered treatment-related); occurring after study d/c, n = 5.

In summary

▪ It has been a busy year of new drug approvals

▪ First line therapy “for most patients with HIV” is clear (caveats: women of childbearing potential, weight gain issues). Are two drugs an option?

▪ New drugs and new formulations continue to be developed

▪ We will have better options in the future for the MDR patient

▪ The future is intermittent therapy (cabotegravir, ED, bNAbs, Capsid antagonists…)