Reduced drug regimens: Pros and Cons

Pedro Cahn

Hong Kong , 2019

Disclosures

• Advisory boards: Merck – ViiV

• Research funds: Abbvie – Merck – Richmond –ViiV

• Speaker at educational activities: Abbvie –Gilead – Merck - ViiV

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

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

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

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

GARDEL: Viral load 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

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

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 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.

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

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

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

Percentage-point difference

DTG + 3TC is non-inferior to DTG +

TDF/FTC with respect to proportion

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

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

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

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+

cell count, cell/mm3

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

Cell Count: Snapshot and TRDF Analysis

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

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• 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 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)

DTG + 3TC DTG + TDF/FTC

>100,000≤100,000 >200 ≤200

Baseline HIV-1

RNA, c/mL

Baseline CD4+

cell count, cell/mm3

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 (

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.

Phase III, randomised, open-label, multicentre, parallel-group, non-inferiority, 200-week study

• Objective: to demonstrate non-inferior antiviral activity of switching to DTG/3TC QD compared with continuation of current TAF-based regimen over 48 weeks in HIV-1-infected, ART-experienced, virologicallysuppressed subjects, and to characterise long-term efficacy and safety/tolerability

• Primary endpoint: Proportion of Subjects with HIV-1 RNA plasma ≥50 c/mL at Week 48 - Snapshot Algorithm

TANGO: Switch Study Design

TAF, tenofovir alafenamideTANGO. Available from: https://clinicaltrials.gov/ct2/show/NCT03446573. Accessed November 2018

DTG + 3TC (n≈375)

Day 1

Screening

CAR (n≈375)

Week 148

switch

VL

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

Percentage-point difference

DTG + RPV is non-inferior to CAR with

respect to snapshot in the ITT-E population

(

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

Conference on Retroviruses and Opportunistic Infections; March 4–7, 2019; Seattle, WA

FLAIR Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in ART-Naïve Adults (Ongoing)

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; CAB, cabotegravir; DTG, dolutegravir; IM, intramuscular; HBsAg, hepatitis B surface antigen; LA, long-acting;

NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; RAM, resistance-associated mutation; RPV, rilpivirine.

*NNRTI RAMS but not K103N were exclusionary; †DTG plus 2 alternative non-ABC NRTIs was permitted if participant was intolerant or HLA-B*5701-positive (n=30 as last regimen during

induction: n=2 discontinued during induction, n=14 randomized to CAB LA + RPV LA, n=14 randomized to DTG/ABC/3TC arm and continued on DTG plus 2 alternative non-ABC NRTIs

in Maintenance Phase); ‡Participants who withdraw/complete CAB LA + RPV LA enter 52-week long-term follow-up; §Participants received initial loading doses of CAB LA 600 mg and

RPV LA 900 mg at Week 4. Beginning Week 8, participants received CAB LA 400 mg + RPV LA 600 mg injections every 4 weeks.

Day 1 100484§ 96

Induction

Phase Maintenance Phase Extension Phase

Extension

DTG/ABC/3TC

Oral daily n=283

N=629

DTG/ABC/3TC

single-tablet

regimen for

20 weeks†

Randomization (1:1)

Oral CAB+ RPV n=283

Primary Endpoint

Screening

Phase

N=809

ART-naïve

HIV-1 RNA ≥1000

Any CD4 count

HBsAg-negativeNNRTI RAMs excluded*

−4

Confirm HIV-1 RNA

FLAIR Virologic Snapshot Outcomes at Week 48 for ITT-E:Noninferiority Achieved for Primary and Secondary Endpoints

Orkin C, et al. CROI 2019; Seattle, WA. Abstract 3947.

3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; CI, confidence interval; DTG, dolutegravir; ITT-E, intention-to-treat exposed; LA, long-acting; NI, noninferiority; RPV, rilpivirine.

*Adjusted for sex and baseline HIV-1 RNA (< vs ≥100,000 c/mL).

Virologic Outcomes

2.1

93.6

4.22.5

93.3

4.2

0

20

40

60

80

100

Pro

po

rtio

n o

f P

art

icip

an

ts (

%)

CAB LA + RPV LA(n=283)

DTG/ABC/3TC(n=283)

Primary endpoint:

LA noninferior to

DTG/ABC/3TC

(≥50 c/mL) at

Week 48

Adjusted Treatment Difference (95% CI)*

6% NI

margin

Key secondary

endpoint:

LA noninferior to

DTG/ABC/3TC

(

ATLAS Study Design: Randomized, Multicenter, International, Open-Label, Noninferiority Study in Adults with Virologic Suppression (Ongoing)

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

ART, antiretroviral therapy; CAB, cabotegravir; CAR, current antiretroviral; IM, intramuscular; INSTI, integrase strand transfer inhibitor;

LA, long-acting; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside RTI; PI, protease inhibitor; RPV, rilpivirine; VL, viral load.

*Uninterrupted ART 6 months and VL

ATLAS Virologic Snapshot Outcomes at Week 48 for ITT-E: Noninferiority Achieved for Primary and Secondary Endpoints

Swindells S, et al. CROI 2019; Seattle, WA. Abstract 1475.

Virologic Outcomes Adjusted Treatment Difference (95% CI)*

1.6

92.5

5.81.0

95.5

3.6

0

20

40

60

80

100

Pro

po

rtio

n o

f P

art

icip

an

ts (

%) CAB LA + RPV LA

(n=308)

CAR(n=308)

Virologic

nonresponse

(≥50 c/mL)

Virologic

success

(

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

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, 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 the programmatic challenges 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 and an option as switch therapy

• 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