switching therapy to integrase inhibitors in patients with...

Switching Therapy to Integrase Inhibitors in Patients with Virologic Suppression

Ian Frank, MD

Professor of Medicine

Perelman School of Medicine

University of Pennsylvania

Reasons for Switching Therapy

• Convenience – switch to single tablet regimen

• Improved tolerability

• Comorbidities• Increased risk for cardiovascular disease (avoid abacavir, lopinavir/r, darunavir)

• Hyperlipidemia (avoid boosted PIs, efavirenz)

• Low bone density (avoid tenofovir DF)

• Renal dysfunction (avoid atazanvir, tenofovir DF, lopinavir/r)

• Hepatitis B (use tenofovir)

• Hepatitis C (use tenofovir AF and integrase inhibitors; avoid boosters)

• Drug-drug interactions – there are many

• Proton pump inhibitors (avoid rilpivirine, atazanavir)

• Rifampin (use dolutegravir, efavirenz)

• Pregnancy• Avoid elvitegravir/cobi, dolutegravir (at the moment), bictegravir; use raltegravir

Comorbidities of Newly Diagnosed HIV Patients in the US: A Longitudinal Analysis of Prevalent HIV Patients

0

10

20

30

40

50

60

70

Pre

va

len

ce

(%

)

CV Events

3%

7%

Gallant J, et al. J Infect Dis. 2017;216:1525-1533.

≥1 outpatient claim, >6 months of continuous care, and contributed data for 2003-2013 (continuous enrollment during the entire year).Baseline Commercial/Medicaid/Medicare: mean age 42/41/71 years; male: 78%/51%/64%.

RenalImpairment

Fracture/Osteoporosis

Hypertension Diabetes Obesity Hyperlipidemia

5% 6%3%

6%

25%

48%

9%

19%

5%

14%

22%

27%

2013 Databases

Commercial (n=14,638)

Medicaid (n=4869)

Medicare (n=848)

16%

20%

65%

31%

6%

48%

11%

EuroSIDA: Age and Chronic Kidney Disease Among Persons With HIV on ART (2014)

• Cross-sectional analysis of a prospective cohort (2014; n=12,882)

• Chronic kidney disease (ie, eGFR <60 mL/min 2 measurements >3 months apart): 7%

• Other comorbidities: dyslipidemia (69%), hypertension (60%), diabetes (6%), CVD (5%)

• Prevalence of chronic kidney disease increased by age group

• ≥60 versus ≤60 years: 16% versus 1% to 7%

• D:A:D 5-year risk for chronic kidney disease increased with increasing age

Pelchen-Matthews A, et al. AIDS. 2018;32:2405-2416.

D:A:D 5-Year Risk Score

0

20

40

60

80

100

Pa

rtic

ipa

nts

(%

)

<30(n=491)

Age (years)

30-39(n=2534)

40-49(n=4123)

50-59(n=3797)

≥60(n=1837)

Risk: Low (<0) Moderate (1-4) High (≥5)

A case

• You are caring for a 52 yo woman with HIV infection who has been on suppressive therapy with TDF/3TC/EFV for the past 8 years. She has no history of virologic failure. She has hypertension.

• She is undergoing menopause

• Recent VL = <20 copies/mL, CD4+ count = 890 cells/mm3,

• Creatinine = 1.2 mg/dL (CrCl = 54 mL/min)

Question

• Do you recommend your patient switch her antiretroviral therapy?

A. Yes

B. No

Possible Reasons to Switch Your Patient’s Regimen off TDF/3TC/EFV

• Need to take medication on an empty stomach at bed time

• Her creatinine clearance is 54 mL/min, and she has hypertension

• She’s at increased risk for worsening renal function

• If her CrCl falls to <50 mL/min she will need to have TDF dose reduced

• She’s a woman >age 50, therefore at increased risk for osteopenia

• EFV increases cholesterol levels by approximately 20%

Efavirenz and Risk of Suicidality

• Association reported in analysis of ACTG A5095, A5142, A5175, A5202

• Efavirenz (n=3241) versus no efavirenz (n=2091)

• Suicidality was uncommon (8.08 per 1000 person-years)

• 2-fold increase in risk of suicidality with efavirenzamong patients beginning ART

• Hazard ratio: 2.28 (95% CI 1.27 to 4.10, P=0.006)

• Factors associated with higher risk of suicidality

• Efavirenz treatment, younger age, IDU history, and psychiatric history

• No association found in other analyses

• D:A:D cohort

• FDA Adverse Event Reporting System database

Mollan KR, et al. Ann Intern Med. 2Smith C, et al. J Int AIDS Soc. 2014;17(suppl 3):19512. Abstract O315.Napoli AA, et al. J Int AIDS Soc. 2014;17:19214.

Suicidal Ideation orAttempted or Completed Suicide

Cu

mu

lati

ve

In

cid

en

ce

Weeks to Suicidality0 48 96 144 192

EfavirenzEfavirenz free

ITT DSMBGray P=0.005

Switching from Efavirenz to RilpivirineImproves Symptoms, Even if “Asymptomatic”

• Improvements in QoL, sleep, anxiety score, composite CNS score and lipids observed

Vera. IAS 2017. Abstr WEPEB0536.

Point estimates are median change. Error bars are interquartile range.

P = .008

P = .004P = .009

Change in Total Sleep Score from Switch to RPV

Improvement

Deterioration

Study Visit Time Points

Wk 4 Wk 12 Wk 3612

10

8

6

4

2

0

-2

-4

Perc

ent

Ch

ange

in T

ota

l Sl

eep

Sco

re F

rom

Bas

elin

e

Change in Anxiety Score from Switch to RPV

Improvement

Deterioration

Study Visit Time Points

Wk 4 Wk 12 Wk 3640

35

30

25

20

15

10

5

0Perc

ent

Ch

ange

in

An

xiet

y Sc

ore

Fro

m B

asel

ine

-5

-10

P < .001P = .029

P = .053

Changes in Spine and Hip BMD Following Switch to F/TAF in Virologically Suppressed Patients

Hip BMD

Me

an

Ch

an

ge (

%)

Spine BMD

Me

an

Ch

an

ge

(%

)

Treatment Week

-3

-2

-1

0

1

2

3

0 48 96

-0.2

F/TAF (n=321)

F/TDF (n=320)

1.5

P<0.001

-0.2

2.2

P<0.001

-3

-2

-1

0

1

2

3

-0.2

F/TAF (n=321)

F/TDF (n=317)

1.1

0 48 96

P<0.001

Treatment Week

-0.3

1.9

P<0.001

Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.Raffi F, et al. JAIDS. 2017;75:226-231.

Next question

• You recommend to your patient that she switches her antiretroviral because her risk for renal insufficiency, loss of bone density, and to increase the flexibility of her medication schedule

• She tells you she doesn’t want to switch because: 1) TDF/3TC/EFV saved her life, and 2) “Se não estiver quebrado, não conserte.”

• You say:

A. No problem. Forget about it.

B. I will put you on something that will be just as effective, easier to take and safer

How I Talk to My Patients About Switching Therapy

Ian’s car: 2004 Volvo S60Phyllis’ new car (maybe): 2019 Mercedes GLC

• Whose car do you want to drive?

A. Ian’s car

B. Phyllis’ car

Considerations When Switching Regimens in Virologically Suppressed Patients

Comorbidity:▪ HBV coinfection

▪ Cardiovascular disease or risk

▪ Renal function

▪ Bone mineral density

▪ Pregnancy

▪ Other coinfections

Safety:

▪ Review ART history for intolerance

▪ Must be HLA-B*5701 negative if considering ABC

▪ Consider drug–drug interactions with comedications

Drug Resistance:

▪ Review ART history for possible VF

▪ Review all available resistance test results

▪ If earlier resistance uncertain, only consider switch if new regimen likely to maintain suppression of resistant virus

▪ Caution when switching from boosted PI to another class if full treatment/resistance history not known

▪ Consult an expert when switching if resistance to ≥ 1 class

▪ Within-class switches usually maintain virologic suppression if no resistance to drugs in that class are present

Switching From Suppressive ART to an STR: Key Studies With Contemporary Regimens

• Noninferior efficacy for all switch regimens vs baseline regimen; all FDA approved to treat virologically suppressed patients

Key Studies Switch From Switch to

380-1878[1]

380-1844[2]

Boosted PI + 2 NRTIs DTG/ABC/3TC

BIC/FTC/TAF

SWORD 1 & 2[3] Third agent + 2 NRTIs DTG/RPV

STRIIVING[4] Third agent + 2 NRTIs DTG/ABC/3TC

EMERALD[5] Boosted PI + FTC/TDF DRV/COBI/FTC/TAF

GS-109[6] TDF-based regimen EVG/COBI/FTC/TAF

GS-1216[7]

GS-1160[8]RPV/FTC/TDFEFV/FTC/TDF

RPV/FTC/TAF

▪ Most recent FDA approvals: for BIC/FTC/TAF and DTG/RPV, must have no history of treatment failure and no resistance to regimen components; for DRV/COBI/FTC/TAF, must have no resistance to DRV, TFV

1. Daar. Lancet HIV. 2018;5:e347. 2. Molina. Lancet HIV. 2018;5:e357. 3. Llibre. Lancet. 2018;391:839. 4. Trottier. Antivir Ther. 2017;22:295.

5. Orkin. Lancet HIV. 2018;5:e23. 6. Mills. Lancet Infect Dis. 2016;16:43. 7. Orkin. Lancet HIV. 2017;4:e195. 8. DeJesus. Lancet HIV. 2017;4:e205.

SWORD-1 and -2: Switch to Dolutegravir + Rilpivirinevs Continue Therapy in Patients on Stable ART

Aboud M, et al. J Int AIDS Soc. 2018;21(suppl 6). Abstract THPEB047.

Dolutegravir + Rilpivirine

(n=513)

Stable ART

(n=511)

Week 0 52 100 148

Randomization1:1

48


Late-SwitchPhase

Early-SwitchPhase

ContinuationPhase


PrimaryEndpoint

HIV RNA <50 copies/mL(ITT-E snapshot)

2 IdenticalPhase 3 StudiesOpen-labelOn stable ART ≥6 months

(INSTI, NNRTI, or PI + 2 NRTIs)

HIV RNA <50 copies/mLfor 12 months

HBV negative

CurrentAnalysis

SWORD-1 and -2: Pooled Outcomes After Switch to Dolutegravir + Rilpivirine in Patients on Stable ART

• Dolutegravir + rilpivirine

• Non-inferior to stable ART at week 48

• Durable efficacy maintained through 100 weeks

• Stable ART late switch to dolutegravir + rilpivirine

• Consistent outcomes with week-48 results

• Virologic failures in both arms (n=10)

• None with emergent INSTI mutations

• Emergent NNRTI mutations with dolutegravir + rilpivirine (0.3%)

• Minimal impact on future ART options

• Safety of dolutegravir + rilpivirine was consistent with full prescribing information of each drug

Aboud M, et al. J Int AIDS Soc. 2018;21(suppl 6). Abstract THPEB047.

HIV RNA <50 Copies/mL

0

20

40

60

80

100

Week 48(Primary Outcome)

(n=513/511)

Day 1 to Week 100

(n=512)

Pa

tie

nts

(%

)

Week 52 to 100(Late Switch From

Stable ART)(n=477)

95% 95% 93%89%

Dolutegravir + rilpivirine Stable ARTTreatment Difference-0.2 (-3.0, 2.58)

TANGO Phase III Study Design

van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB. 18

Randomized, open-label, multicenter, parallel-group, non-inferiority study

DTG/3TC (N=369)b

Day

1

Screening

TAF-based regimen (N=372)

DTG/3TC

Week

48

Early-switch phase Late-switch

phase

Continuation

phase

Week

144

Week

24

Week

96

•Adults, virologically

suppressed (HIV-1 RNA

<50 c/mL) for >6 months

•Stable TAF-based regimen

Randomizationa

1:1

Week

148

Week

196

DTG/3TC DTG/3TC

Primary endpointc:

participants with

virologic failure per

FDA Snapshot (ITT-E)d

Eligibility criteria• ≥2 documented HIV-1 RNA

measurements <50 c/mL

• No HBV infection or need for

HCV therapy

• No prior VF and no documented

NRTI or INSTI resistance

• TAF/FTC + PI or INI or NNRTI as

initial regimenc

Australia

Belgium

Canada

France

Germany

Japan

Netherlands

Spain

United

Kingdom

United States

Countries

• In the per-protocol population, 0/352 participants in the DTG/3TC group and 2/358

participants in the TAF-based regimen group had HIV-1 RNA ≥50 c/mL at Week 48

(adjusted difference, −0.6; 95% CI, −1.3 to 0.2)

DTG/3TC Is Non-inferior to TAF-Based 3-Drug Regimen at Week 48


0

93.2

6.50.6

93.0

6.5

0

20

40

60

80

100

HIV-1 RNA ≥50 c/mL

HIV-1 RNA<50 c/mL

No virologicdata

Pro

po

rtio

n o

f p

art

icip

an

ts,

%

DTG/3TC(N=369)

TAF-basedregimen (N=372)

Virologic outcomes Adjusted treatment difference (95% CI)

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

-3.4 3.9

Difference, %

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

-1.2 0.7

TAF-based regimen Primary endpoint:

DTG/3TC non-inferior to

TAF-based regimen

(≥50 c/mL) at Week 48

Key secondary endpoint:

DTG/3TC non-inferior to

TAF-based regimen

(<50 c/mL) at Week 48

DTG/3TC

TAF-based regimen DTG/3TC

-8% non-inferiority margin

Change in Serum Lipids From Baseline at Week 48: Safety Population

van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.

TC, total cholesterol; TGL, triglycerides.an = number of participants with non-missing fasting lipid data at Week 48, removing participants with lipid-modifying agent administered at baseline (lipid data collected after a lipid-modifying agent are censored and uses last on-treatment pre-modifying agent LOCF method). bNCEP categories at Week 48 vs baseline. cPurple shading indicates High for LDL.

20

NA, NA, Borderline high, High, 4.4 to <5

High, Low, Very high, Very high, ≥5

Missing

Desirable, High, Optimal, Normal, <3.5

Borderline high, Normal, Near/Above optimal, Borderline high, 3.5 to <4.4

0

25

50

75

100

TCb

BL W48

Pa

rtic

ipa

nts

, %

TAF-based regimen (n=277)a

HDLb LDLb,c TGLb TC/HDL TCb HDLb LDLb,c TGLb TC/HDL

BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48 BL W48

DTG/3TC (n=291)a

Change in Renal Biomarkers at Week 48


-2.9

6.3

-2.7

1.6

6.7

-7.8

-20-15-10-505

101520

Ch

an

ge

fro

m b

ase

line

, %

b6.67

-7.8

0.12.19

-3.0-1.6

-10

-5

0

5

10

Ad

juste

d m

ea

n c

ha

ng

e

fro

m b

ase

line

a

eGFR from

creatinine,

CKD-EPI

(mL/min/1.73 m2)

Creatinine

(µmol/L)

Protein/

Creatinine

(g/mol)

Retinol-binding

protein/

Creatinine

(µg/mmol)

Beta-2

microglobulin/

Creatinine

(mg/mmol)

DTG/3TC (N=369) TAF-based regimen (N=371)

*P<0.001

*

*

Plasma/Serum markers Urine markers

eGFR from

cystatin C,

CKD-EPI

(mL/min/1.73 m2)

• All participants in the DTG/3TC group with pro-viral M184V/I at baseline maintained HIV-1 RNA <50 c/mL at Week 48

Virologic Response by Pro-Viral M184V/I Status:Post Hoc Analysis of Stored Baseline Samples

van Wyk et al. IAS 2019; Mexico City, Mexico. Slides WEAB0403LB.22

Participants, n (%)DTG/3TC (N=318)a

TAF-based regimen(N=308)

Pro-viral M184V/I at baselineb 4 (1) 3 (1)

HIV-1 RNA <50 c/mL at Week 48 4 (100) 3 (100)

HIV-1 RNA ≥50 c/mL at Week 48 0 0

No pro-viral M184V/I at baseline 314 (99) 305 (99)

HIV-1 RNA <50 c/mL at Week 48 314 (100) 303 (99)

HIV-1 RNA ≥50 c/mL at Week 48 0 2 (1)

GS-4030: Switching to TAF/FTC/BIC from DTG Plus FTC/TAF or FTC/TDF

• Phase 3, randomized, double-blind, active-controlled study

• Documented or suspected NRTI, NNRTI and PI resistance permitted

• Randomization stratified by known or suspected NRTI resistance category at baseline

• 1) K65R or ≥3 TAMS; 2) other NRTI mutations; 3) no known NRTI resistance

• Primary endpoint: proportion with HIV-1 RNA ≥50 c/mL at Week 48

• Noninferiority margin of 4% based on FDA snapshot algorithm

Week 0 48

Adults with HIV on DTG + F/TAFor DTG + F/TDF

▪ HIV-1 RNA <50 c/mL for ≥3 or 6 mo

▪ eGFRCG ≥30 mL/min

▪ No known INSTI resistance

▪ No prior virologic failure on INSTI

DTG + F/TAF placebo qd

B/F/TAF qd

B/F/TAF Placebo qd

DTG + F/TAF qd

n=284

n=281

Primary Endpoint

1:1

N=565

Sax PE et al. IAS 2019; Mexico City, Mexico. Abs MOAB0105.

<1

93

61

91

8

0

20

40

60

80

100

HIV-1 RNA

<50 c/mL

HIV-1 RNA

≥50 c/mL

No Virologic

Data

1

284

3

281

265

284

256

281

22

281

18

284

GS-4030: Virologic Outcome at Week 48

• Switching to B/F/TAF was noninferior to remaining on DTG + F/TAF

• No participant with pre-existing NRTI resistance had HIV-1 RNA ≥50 c/mL in either group

Treatment Difference in % Participants With HIV-1 RNA ≥50 c/mL (95.001% CI)

-… 1.0

-0.7

-4 -2 0 2 4

FavorsB/F/TAF

Favors DTG + F/TAFDTG+ F/TAF (n=281)

B/F/TAF (n=284)

Virologic Outcome by FDA

Snapshot

Pa

rtic

ipan

ts, %

Sax PE et al. IAS 2019; Mexico City, Mexico. Slides MOAB0105.

GS-4030: Pre-existing NRTI Resistance

*20 participants stratified to categories 1 or 2 based on investigator-suspected NRTI resistance (19 participants category 2, and 1 participant category 1); †Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions; ‡Includes only M184V/I mutations confirmed by genotype.

Category NRTI Mutation, n (%)

Stratification at randomization*

n=565Final analysis

n=565B/F/TAFn=284

DTG + F/TAFn=281

1K65R/E/N or ≥3 TAMs† 15 (3) 30 (5) 16 (6) 14 (5)

2 Any other pattern 63 (11) 108 (19) 55 (19) 53 (19)

3 No NRTI mutation 487 (86) 427 (76) 213 (75) 214 (76)

M184V/I‡ ± other mutations (from category 1 or 2)

29 (5) 81 (14) 47 (17) 34 (12)

M184V/I‡ only 12 (2) 21 (4) 15 (5) 6 (2)

Sax PE et al. IAS 2019; Mexico City, Mexico. Abs MOAB0105.

91 9487 91 91 8786

9387 85 86 85

0

20

40

60

80

100

Overall

GS-4030: Sensitivity Analysis for Low-level Viremiaby Resistance Mutations

♦ Undetectable HIV-1 RNA (target not detected) by overall B/F/TAF 64.1% vs DTG +F/TAF 60.5%

*Includes K65R/E/N, or ≥3 TAMs that include M41L or L210W, or T69 insertions.

26

Virologic Outcome HIV-1 RNA <20 c/mL by FDA Snapshot

Pa

rtic

ipan

ts, %

DTG+ F/TAF (n=281)

B/F/TAF (n=284)

K65R or

≥3 TAMs*

Other NRTI

resistance

No NRTI

resistance

15

16

13

14

194

213

182

214

48

55

46

53

M184V/I ±

other resistance

No M184V/I

216

237

212

247

41

47

29

34

257

284

241

281

Sax PE et al. IAS 2019; Mexico City, Mexico. Slides MOAB0105.

ATLAS: Phase 3 Trial, IM Cabotegravir + Rilpivirine vsOral Therapy in Patients with Virologic Suppression

Swindells S, et al. CROI 2019. Abs. 139.

CAB LA (400 mg) + RPV LA (600 mg)§

IM monthly n=303

Screening Phase Maintenance Phase Extension Phase

PI, NNRTI or INSTI†

Current daily oral ART n=308N=705PI-, NNRTI-, or INSTI-based regimen with 2 NRTI backbone* R

and

om

izat

ion

1:1

Extension Phase or transition to the ATLAS-2M study

Oral CAB + RPV n=308

Primary Endpoint

Day 1Baseline

Week 96

Week 48

Week 4‖

Week 52

ATLAS

Rate of Virologic Success

Swindells S, et al. CROI 2019. Abs. 139.

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)

Virologic nonresponse (≥50 c/mL)

Virologic success

(<50 c/mL)

No virologic data

-1.2 2.5

0.6

-10 -8 -6 -4 -2 0 2 4 6 8 10Difference (%)

-6.7

-3.0

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

0.7

Key Secondary Endpoint(HIV-1 RNA < 50 copies/mL)LA CAB + LA RPV noninferior

to continued BL ART

Primary Endpoint(HIV-1 RNA ≥ 50 copies/mL)LA CAB + LA RPV noninferior

to continued BL ART

6% NImargin

*Adjusted for sex and BL third agent class.

Continued ARTLA CAB + LA RPV

Continued ART LA CAB + LA RPV

Take Home Messages

• Switching therapy in patients with virologic suppression to better tolerated drugs with less potential for toxicity is an essential ARV strategy

• We should be switching regimens when there is an opportunity

• Combinations with next generation integrase inhibitors offer the opportunity to use well tolerated 3-drug and 2-drug combinations as maintenance therapy

switching therapy to integrase inhibitors in patients with...

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