ANTIRETROVIRAL THERAPY

The New Patient With What & When?

17TH EUROPEAN MEETING ON HIV & HEPATITIS

22-24 MAY 2019, ROME, ITALY

PETER REISS, MD, PhDDirector HIV Monitoring foundation

Professor of MedicineAmsterdam UMC, University of Amsterdam

iStock.com/royalty-free image

Disclosures

• Grants support to my institution from EU FP7, ZonMW, AIDSfonds, Gilead Sciences, ViiVHealthcare, Janssen, and Merck

• Consultancy fees to my institution from GileadSciences, ViiV Healthcare, Janssen, Merck, andTeva pharmaceuticals

Outline

• What To Start?:

• Guidelines & Practice

• 2 Drugs for Initial Treatment

• Weight Gain on INSTI-based ART

• Long-acting ART: some perspectives

• When To Start?:

• What Happens in Daily Practice

• Same Day ART

WITH WHAT?

ANTIRETROVIRAL DRUG APPROVAL IN EUROPE1987-2019

Rosan van Zoest, Academic thesis, University of Amsterdam 2019 ( with permission)

Recommended, preferred regimens + Alternative/recommended incertain clin.situations

GUIDELINES

EACS (2018)1

DHHS (2018)2

IAS USA

(2018)3

BHIVA (2016)4

WHO (2018)5

TAF/FTC

TDF/FTC

ABC/3TC*

TAF/FTC

TDF/FTC

ABC/3TC*

TAF/FTC

ABC/3TC*

TAF/FTC

TDF/FTC

TDF/XTC

NRTI BACKBONE NNRTI INSTI PI

RPV*

−

−

RPV*

EFV

BIC

DTG

RAL

BIC

DTG

RAL

BIC

DTG

DTG

RAL

EVG/c

DTG

RAL (neonates)

DRV/c

or /r

−

−

DRV/r

ATV/r

−

NRTI-

REDUCING

DRV/c or /r + RAL

DTG + 3TC

DRV/c or /r + RAL

DTG + 3TC

DRV/c or /r + 3TC

DRV/c or /r + RAL

DTG + 3TC

DRV/c or /r + 3TC

DRV/c or /r + RAL

−

−

−

TDF/XTC

ABC/3TC*

AZT/XTC

EFV

DOR

EFV

RPV*

DOR

EFV

RPV

EFV

EFV 400

NVP

EVG/c

EVG/c

RAL

EVG/c

−

RAL(infants&

children if

DTG not

available)

ATV/c

or /r

DRV/c

or /r

ATV/c

or /r

DRV /c

or /r

−

−

First-line ART

*Use recommended only if baseline viral load <100,000 copies/mL.

3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; BIC, bictegravir; BHIVA, British HIV Association; c, cobicistat; DHHS, Department of Health and Human Services; DOR, doravirine; DRV, darunavir; DTG, dolutegravir;

EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS USA, International Antiviral Society–USA; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor;

NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate;

WHO, World Health Organization; XTC, FTC or 3TC.

1. EACS Guidelines Version 9.1. Available from: http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html. Accessed January 2019;

2. DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0. Accessed January 2019;

3. Saag MS, et al. JAMA 2018;320:379–396;

4. BHIVA Guidelines. Available from: http://www.bhiva.org/documents/Guidelines/Treatment/2016/treatment-guidelines-2016-interim-update.pdf. Accessed January 2019;

5. WHO. December 2018 Supplement to the 2016 Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Available from: https://apps.who.int/iris/bitstream/handle/10665/277395/WHO-CDS-HIV-18.51-eng.pdf?ua=1 Accessed

January 2019.

Slide courtesy of Prof. Chloe Orkin (updated)

Shifts in Use of Initial cART regimens in the Netherlands (2013-2017)

2013 2014

2015 2016 2017

TAF/FTC/EVGc

ABC/3TC/DTG

TDF/FTC/DTG

TDF/FTC/EVGc

TAF/FTC/DTG

TDF/FTC/EFV

TDF/FTC/EFV

SYMTUZA Darunavir / COBI /

TAF / FTC

BIKTARVYBictegravir/TAF/FTC

DELSTRIGODoravirine + tenofovir DF +

lamivudine

https://www.hiv-monitoring.nl/en/resources/monitoring-report-2018

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

Snapshot Outcomes at Week 48 for GEMINI-1 and -2

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) and CD4+ cell count (≤200 cells/mm3 vs >200 cells/mm3).

Virologic outcome Adjusted treatment difference (95% CI)a

Percentage-point difference

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

DTG + TDF/FTC

-6.7 1.5

-4.3 2.9

GEMINI-1

GEMINI-2 -0.7

-2.6

DTG + TDF/FTC DTG + 3TC

90

4 6

93

26

93

25

94

2 4

0

20

40

60

80

100

Virologicsuccess

Virologicnonresponse

No virologicdata

HIV

-1 R

NA

<50

c/m

L, %

GEMINI-1 DTG + 3TC (N=356) DTG + TDF/FTC (N=358)

GEMINI-2 DTG + 3TC (N=360) DTG + TDF/FTC (N=359)

Cahn. Lancet. 2019;393:P143.

Two Drug Regimens for Initial Treatment

DHHS, IAS-USA, EACS Guidelines: Recommendations on 2DR for First-line ART

▪ Caveats to first-line DTG + 3TC use: HBV coinfection, GEMINI-1/2 excluded patients with HIV-1 RNA > 500,000 copies/mL, tuberculosis, pregnancy/woman with childbearing potential

▪ Data that could potentially support DTG + 3TC as a recommended initial regimen in DHHS guidelines: durability (96-wk GEMINI data), longer-term resistance data

DHHS*[1] IAS-USA†[2]

Consider when ABC, TAF, or TDF cannot be used or are not optimal:▪ DTG + 3TC▪ DRV/RTV + RAL BID, if HIV RNA < 100,000

copies/mL and CD4+ cell count > 200 cells/mm3

▪ DRV/RTV QD + 3TC

Initial 2DR only recommended when patient cannot take ABC, TAF, or TDF:▪ DTG + 3TC ( short term data may provide support)▪ DRV/RTV + RAL, if HIV RNA < 100,000 copies/mL

and CD4+ cell count > 200 cells/mm3

▪ DRV/RTV + 3TC

Modified from: clinicaloptions.com

EACS#[3]

Consider when none of the preferred regimens are feasible or available, whatever the reason :▪ DTG + 3TC▪ DRV/RTV or COBI QD + RAL BID, if HIV RNA <

100,000 copies/mL and CD4+ cell count > 200 cells/mm3

1.*DHHS Guidelines. October 2018. 2.† Saag. JAMA. July 24, 2018. 3.# EACS Guidelines vs 9.1, October 2018

Take-home message on DTG + 3TC: It is a new initial ART option for some patients

An Emerging Concern with IntegraseInhibitor-based Regimens:

More Weight Gain?

iStock.com/royalty-free image

NA-ACCORD: Weight Gain Among 24,001

ART-Naive Patients Initiating Treatment

▪ Multivariate analysis of weight gain following ART initiation (January 2007 - December 2016)

‒ INSTI-based regimens: n = 4740

‒ EVG: n = 2124; RAL: n = 1681; DTG: n = 935

‒ PI-based regimens: n = 7436

‒ NNRTI-based regimens: n = 11,825

▪ Higher weight gain with INSTI-based vs NNRTI-based regimens, with DTG or RAL vs EVG

‒ Weight gain with INSTIs did not vary by sex or race

Slide credit: clinicaloptions.comBourgi. CROI 2019. Abstr 670.

NA-ACCORD: Weight Gain by Class or Specific

INSTI

Slide credit: clinicaloptions.com

Pre

dic

ted

We

igh

t (k

g)

Yrs Since ART Initiation

86

84

82

80

0 1 2 3 4 5

Yr 2

Yr 5

INSTI

PI

NNRTI

+4.9

+4.4

+3.3

+6.0

+5.1

+4.3

Pre

dic

ted

We

igh

t (k

g)

86

84

82

80

Yrs Since ART Initiation0 0.5 1.0 1.5 2.0

Yr 2

DTG

RAL

EVG

+6.0

+4.9

+3.8

PI

NNRTI

Bourgi. CROI 2019. Abstr 670.

Weight Gain After Switch to INSTI-Based ART

▪ Prospective, observational cohort study of weight gain after switch to INSTI-based ART in patients enrolled on ACTG A5001, A5322 from 2007-2017 (N = 691)

‒ HIV-1 RNA < 200 copies/mL at time of switch required for inclusion

▪ Annual weight gain increased following switch to INSTI, with greater increases among women, blacks, and individuals 60 yrs of age or older

Slide credit: clinicaloptions.comLake. CROI 2019. Abstr 669.

Adjusted Annual Weight Change,* kg/yr (P Value)

Women Men Women Men Women ≥ 30 kg/m2

at SwitchBlack White Black White40 Yrs or Younger

60 Yrs or Older

40 Yrs or Younger

60 Yrs or Older

2 yrs pre-INSTI0.4

(.08)0.6

(.03)0.4

(.02)0.4

(< .0001)1.5

(.01)-0.2(.61)

0.8(.009)

0.1(.46)

0.2(.54)

2 yrs post-INSTI1.3

(< .0001)2.0

(< .0001)1.0

(.002)0.2

(.09)-1.0(.17)

1.8(.0005)

-0.1(.88)

0.9(.0008)

1.9(< .0001)

Post–pre difference

0.9(.04)

1.4(.02)

0.6(.11)

-0.2(.38)

-2.5(.02)

2.0(.008)

-0.9(.20)

0.8(.04)

1.7(.002)

*Adjusted for age at switch, sex, race/ethnicity, BL BMI and their interactions, nadir CD4+ cell count, smoking history, diabetes, and % time with HIV-1 RNA < 200 c/mL.

Weight Gain After Switch to INSTI-Based ART by

Agent, Pre-Switch ART Class, and NRTI Backbone

at Switch

▪ Change in weight gain rate greater with DTG vs EVG or RAL

▪ Increases in weight change per yr from pre- to post-INSTI periods statistically significant (P < .05) with:

‒ Switch to DTG from PI or NNRTI

‒ Switch to EVG from NNRTI

‒ Switch to any INSTI + ABC

‒ Switch to EVG + TAF

▪ However, analysis limited by small sample sizes in subsets

Slide credit: clinicaloptions.comLake. CROI 2019. Abstr 669.

Adjusted Annual Weight Change, kg/yr (P Value)

DTG (n = 198)

EVG(n = 204)

RAL(n = 289)

2 yrs pre-INSTI0.2

(.11)0.5

(.008)0.5

(< .0001)

2 yrs post-INSTI1.3

(< .0001)0.9

(< .0001)0.3

(.045)

Post–pre difference

1.0(.0009)

0.5(.11)

-0.2(.37)

Changes in Weight Through Wk 41 (Primary Endpoint)

▪ No significant weight gain with LA CAB vs PBO in HIV-uninfected individuals through Wk 41

‒ ≥ 5% weight gain: 22% with LA CAB vs 18% with PBO (P = .62)

‒ No differential effects by BMI category, sex at birth, race/ethnicity, dosing cohort, or smoking status

▪ No statistically significant differences in fasting glucose or lipid changes through Wk 41 with LA CAB vs PBO

Landovitz. CROI 2019. Abstr 34LB. Slide credit: clinicaloptions.com

LA CAB (n = 108) PBO (n = 38)

+0.9 (-1.2, 2.8)

+0.7 (-1.5, 2)

P = .65+1.1 (-0.9, 3)

+1.0 (-1.2, 3.2)

P = .66

+0.4 (-0.4, 1)

+0.1 (-0.6, 1)

P = .60

Overall Wks 0-41

Oral Phase Wks 0-4

Injection Phase Wks 5-41

Med

ian

Ch

ange

in W

eigh

t, k

g (I

QR

)

1.00

0.25

0.75

0.50

0

HPTN 077: Body Weight Change in Patients

Without HIV Enrolled in Long-Acting Cabotegravir

Safety Trial

What’s coming?

Longer acting approaches to HIV Treatment

• Oral: MK-8591 (NRTTI)

• Injectable• Subcutaneous: PRO140 (humanized IgG4 MoAb against

CCR5)

• Intramuscular: cabotegravir; rilpivirine

• Infusion: bNAb’s

• Implantable: MK-8591 (NRTTI)

Do we need LA-ARVs for treatment and why?

Many patients perfectly happy with daily STR

Some might prefer less frequently dosed ART

– Greater convenience

– Less stigma

LA-ART could enhance treatment of patients with

adherence challenges

– Adolescents

– Patients with substance use disorder, psychiatric

disease, chaotic lives

Long-acting cabotegravir plus rilpivirineFLAIR: Study Design

▪ Multicenter, randomized, open-label phase III noninferiority trial

Orkin. CROI 2019. Abstr 140LB. NCT02938520. Slide credit: clinicaloptions.com

LA CAB 400 mg IM +LA RPV 600 mg IM Q4W

(n = 278)

Continue DTG/ABC/3TC PO QD‡

(n = 283)

ART-naive patients withHIV-1 RNA ≥ 1000

copies/mL,HBsAg negative,no NNRTI RAMs*

(N = 629)

*K103N permitted. †Patients with HIV-1 RNA < 50 copies/mL from Wk 16 to Wk 20 continued to maintenance phase. ‡Alternative, non-ABC NRTIs permitted for intolerance or HLA-B*5701 positivity. §Loading dose: LA CAB 600 mg IM + LA RPV 900 mg IM; regular dosing begun at Wk 8.

CAB 30 mg +RPV 25 mg PO QD

(n = 283)

Current AnalysisWk 48 Wk 4§

DTG/ABC/3TC PO QD‡

Induction Phase†

Maintenance Phase

Wk 96Day 0

Wk 20

▪ Primary endpoint: HIV-1 RNA ≥ 50 copies/mL at Wk 48 by FDA Snapshot (6% noninferiority margin)

▪ Secondary endpoints: HIV-1 RNA < 50 copies/mL at Wk 48 by FDA Snapshot, resistance at confirmed virologic failure, safety and tolerability, patient-reported outcomes

Difference (%)

Difference (%)

FLAIR: Efficacy at Wk 48 in ITT-E Population

▪ Confirmed VF: n = 3 per arm; emergent NNRTI + INSTI resistance in all CAB + RPV failures (all HIV-1 subtype A1), no resistance in DTG/ABC/3TC failures

Orkin. CROI 2019. Abstr 140LB. Reproduced with permission. Slide credit: clinicaloptions.com

Pat

ien

ts (

%)

100

80

40

60

20

0Virologic

Nonresponse (≥ 50 c/mL)

Virologic Success

(< 50 c/mL)

No Virologic

Data

2.1 2.5

93.6 93.3

4.2 4.2

LA CAB + LA RPV(n = 283)

DTG/ABC/3TC(n = 283)

-10% NImargin

Difference (%)

-3.7

0.4

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

4.5

-2.8 2.1

-0.4

6% NImargin

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

Virologic Outcomes (FDA Snapshot) Adjusted Treatment Difference (95% CI)*

DTG/ABC/3TCLA CAB + LA RPV

DTG/ABC/3TC LA CAB + LA RPV

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

to DTG/ABC/3TC

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

to DTG/ABC/3TC

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

FLAIR: Injection-Site Reactions

▪ 99% of ISRs were grade 1/2, 88% resolved within 7 days

Orkin. CROI 2019. Abstr 140LB. Reproduced with permission. Slide credit: clinicaloptions.com

*No grade > 3 events reported. †2 additional patients d/c for injection intolerability.

ISR Incidence Over TimeCharacteristic to Wk 72

LA CAB + LA RPV (n = 283)

Patients receiving injections, n

278

Injections given, n 7704

ISR events, n (%)▪ Pain▪ Nodule▪ Induration▪ Swelling▪ Warmth▪ Grade 3 ISR pain*

2203 (28.6)1879 (85.3)

86 (3.9)82 (3.7)38 (1.7)38 (1.7)

12 (< 1.0)

Median duration of ISRs, days 3

ISR pain leading to d/c,† n (%) 2 (< 1.0)

Pa

rtic

ipa

nts

Wit

h IS

Rs

(%

)

Study Wk

100

80

60

40

20

04 8 12 16 20 24 28 32 36 40 44 48

71

43 3832 31 33 29 27 27

3424 20

FLAIR: Patient-Reported Outcomes

Orkin. CROI 2019. Abstr 140LB. Slide credit: clinicaloptions.com

‡Per single question in Wk 48 participant survey.

Drug Delivery Preference

of Patients in CAB + RPV Arm

Patient Satisfaction With

Regimen at Wk 48 vs Oral

Induction

HIVTSQc Mean Total Score*

Switch to LA CAB + LA RPV

(n = 263)

Continue DTG/ABC/3TC

(n = 266)

Wk 48† 29.6 25.5

PopulationPreferred Regimen,‡ % (n/N)

Long-Acting IM Daily PO

ITT-E 91 (257/283) 1 (2/283)

Responding participants

99 (257/259) NA*Scores can range from -33 to +33.†Difference: 4.1 (95% CI: 2.8-5.5; P < .001).

FLAIR: Plasma Trough Concentrations by

Visit

▪ Plasma concentrations with IM CAB and RPV similar to effective PO regimens

Orkin. CROI 2019. Abstr 140LB. Reproduced with permission. Slide credit: clinicaloptions.com

4 488 12 16 20 24 28 32 36 40 44

Visit (Wk)

0.1

1

10

Pla

sma

CA

B (

μg

/mL)

*

CAB (n = 278) PA-IC90 (0.166 µg/mL)

4 488 12 16 20 24 28 32 36 40 44

Visit (Wk)

10

100

Pla

sma

RP

V (

ng

/mL)

*

RPV (n = 278)PA-IC90 (12 ng/mL)

*Median (5th, 95th percentile) concentration–time data.

TDM-guided indidualized dosing a possibility?

Outline

• What To Start?:

• Guidelines & Practice

• 2 Drugs for Initial Treatment

• Weight Gain on INSTI-based ART

• Long-acting ART

• When To Start?:

• What Happens in Practice

• Same Day ART

Strategic Timing of AntiRetroviral Treatment(START) Study

23

Immediate ART Deferred ART

No. with Event (%) 42 (1.8%) 96 (4.1%)

Rate/100PY 0.60 1.38

HR (Imm/Def) 0.43 (95% CI: 0.30 to 0.62, p <0.001)

2.5

5.3

N Engl J Med 2015

Fred Gordin

In 2017 >85% of PWH entering care in NL started

treatment within 1 month(in 2016: 75%)

Time between entry into care and initiation of combination

antiretroviral therapy (cART) from 2007-2017

same day

within 7-13 days

within 14-20 days

within 21-31 days

within 1 week

https://www.hiv-monitoring.nl/en/resources/monitoring-report-2018

Universal rapid treatment initiation fairly

uniform across the 26 NL treatment centres

25

Proportion of patients started on cART within 6 months afterentering care, by year & treatment centre size

> 700 pts

400-700 pts < 400 pts

• In 2017, 45% overall of newly-diagnosed individuals had AIDS and/or CD4 cells <350/mm3 when entering care

At time of diagnosis far too many have likely

already been infected much longer (NL data)

% late presenters

>45 yrs <25 yrs

MSM 50% 23%

Other men 71% 48%

Women 59% 26%

63%

52%

37%

Late presentation even more common

in those over 45 at time of entry into

care (2015 or later)

Recommendations on Same-Day ART Initiation▪ DHHS guidelines, October 2018[1]:

‒ Same-day initiation of ART may be feasible and could potentially improve clinical outcomes . . . It should be emphasized, however, that ART initiation on the same day of HIV diagnosis is resource intensive . . . As these resources may not be available in all settings and the long-term clinical benefits of same-day ART initiation have yet to be proven in the United States, this approach remains investigational.

▪ IAS-USA guidelines, July 2018[2]:

‒ ART should be initiated as soon as possible after diagnosis, including immediately after diagnosis, unless patient is not ready to commit to starting therapy.

▪ EACS guidelines, October 2018 [3] :

‒ Evidence is accumulating that starting ART on the same day after establishing a diagnosis of HIV infection is feasible and acceptable to HIV-positive persons. Nevertheless, assessment of the readiness to start ART is essential to enable the HIV-positive person to express their preference and not feel pressured to start ART immediately, unless clinically indicated.

‒ Immediate (same day) start of ART should be considered, especially in thefollowing situations: In the setting of primary HIV infection, especially in case of clinical signs and symptoms of meningoencephalitis (within hours).

Slide credit: clinicaloptions.com1. DHHS Guidelines. October 2018. 2. Saag. JAMA. 2018;320:379. 3.# EACS Guidelines vs 9.1, October 2018

Phylogenetically Inferred Sources of Transmission in MSM with Recent HIV

Infection in The Netherlands

Amsterdam:

Rapid trajectory for Dx of acute/recent HIV (since 08-2015)

Dijkstra BMC Infectious Diseases 2017, Lin JAIDS 2018

Conclusions• INSTI-based therapy has become the preferred approach

• 2DR likely to become an initial option for some patients

• Issue of weight gain on INSTI-based ART is to be

resolved: watch the extremes!

• Long-acting ART:

• We’re only at the beginning with IM

cabotegravir+rilpivirine

• Use and utility in clinical practice is to be determined

• Immediate treatment increasingly being put into practice

• Early diagnosis remains the bottleneck to be resolved

• Early diagnosis of acute & recent infection + same

day ART important to contribute to epidemic control

Thank you for sharing slides:

Chloe Orkin Godelieve de Bree

Maartje DijkstraDan Kuritzkes

Christophe Fraser