St State of of th the Art t on on ART Two new medications here - - PDF document

12/8/18

St State of

• f th

the Art t on

• n ART

Medical Management of AIDS, CME course December 6, 2018

Monica Gandhi MD, MPH Medical director, Ward 86 HIV Clinic =Division of HIV, Infectious Diseases, and Global Medicine

Outline of talk

• Review new antiretroviral medications

recently approved, including single pill combinations

• Two new medications here or close for

very experienced patients

• Review new paradigms in HIV medicine
• Two drug therapy
• Switches
• Barriers to resistance
• Predictors of doing well on 2-drug therapy
• (Injectables)
• (No financial disclosures)

Case #1

• 52 yo man diagnosed with HIV 30 years ago
• AZT/3TC then AZT/3TC/nevirapine then TDF/FTC + efavirenz in

2002 (and single pill combination in 2007)

• Had off-and-on problems with adherence and viral load

detectability over time with emergence of M184V, K103N, Y181C, D67N and switched to RAL/ETR/TDF/FTC in 2008 (declined PI)

• Pt liked regimen and initially did well but then low-grade viremia

recently, admits to missed doses – usually low-grade but when >500 copies/mL, able to genotype and shows K103N, M184V, D67N in the RT gene; N155H in the integrase gene

• Pt finally agrees to regimen change but ideally wants once daily

AR ARS: S: What t is th the regimen you

• u wou
• uld ch

choos

• ose

fo for this patient?

• 1. BIC/TAF/FTC
• 2. DRV/cobi/TAF/FTC
• 3. DRV/cobi/TAF/FTC + doravirine
• 4. DTG/RPV + DTG extra dose
• 5. DRV/cobi/TAF/FTC + DTG BID
• 6. DRV/cobi/TAF/FTC + DTG daily

Genotype shows Y181C, K103N, M184V, D67N in the RT gene; N155H in the integrase gene

12/8/18

AR ARS: S: What t are th the 4 4 mos

• st

t rece centl tly-ap approved HI HIV V me meds ds (all in n 2018)?

• 1. Bictegravir/TAF/FTC, fostemsavir, dolutegravir/TAF/FTC, ibalizumab
• 2. Fostemsavir, ibalizumab, bictegravir/TAF/FTC, doravirine (±TDF/3TC)
• 3. Doravirine (±TDF/3TC), DRV/cobi/TAF/FTC, bictegravir/TAF/FTC,

ibalizumab

• 4. DRV/cobi/TAF/FTC, cabotegravir, doravirine (±TDF/3TC),

bictegravir/TAF/FTC

• 5. Fostemsavir, ibalizumab, doravirine, bictegravir

Bictegravir/TAF/FTC approved February 8, 2018

• INSTI-based
• Well tolerated to date
• Single pill
• Small pill
• TAF/FTC as backbone

so no pre-testing (e.g. no HLA-B5701)

PROS

• Data only in naives

and switch mandated no historical genotype with resistance

• Do not yet know

signature mutations

• Can’t use bictegravir

nor TAF with rifampin

• Limited real-world

data

CONS

Gallant J. Lancet HIV 2017; Sax P. Lancet HIV 2017; Molina J. CROI 2018; Daar E. Lancet HIV 2018; Andreatta K CROI 2018

B/F/TAF Phase 3 Efficacy through Weeks 48 to 96

7

Study Population Comparator Efficacy Resistance 1489 Naïve DTG/ABC/3TC (96 weeks data ID week 2018) Non-inferior 1490 Naïve DTG+FTC/TAF (96 week data HIV Drug Therapy, Glasgow 2018) Non-inferior 1844 Suppressed DTG/ABC/3TC Non-inferior 1878 Suppressed Boosted PI + 2 NRTIs Non-inferior 0 to INSTI but 1 L74V in PI arm 1961 (women) Suppressed E/C/F/(TAF or TDF) ATV+RTV + FTC/TDF Non-inferior 0 to INSTI but 1 M184V in ELV/cobi arm

Gallant J. Lancet HIV 2017; Sax P. Lancet HIV 2017; Molina J. CROI 2018; Daar E. Lancet HIV 2018; Kotyo CROI 2018; Wohl D; ID week 2018 LB4; Andreatta K CROI 2018; Andreatta. Glasgow 2018

Have data from 2 naïve studies and switch studies in suppressed patients but no data among patients with baseline resistance yet (have some data with archive Genosure sequencing, but not used in clinical practice like historical genotype data). Real-world practice will help define this, as will trials in patients with resistance like SAILING, VIKING with DTG)

Archived genotype resistance and bictegravir switch

• We do not know signature mutations of BIC (In vitro data for DTG suggested

R263K/G188R were major mutations, clinical data from VIKING identified Q1481)

• Switch studies (1844, 1878) – excluded patients with h/o historical resistance to

TDF/(3)FTC/ABC/DTG (71% had historical genotypes)

• Retrospectively performed Archive genotypes on some patients in the 1844, 1898

switch studies (collected whole blood at baseline visit)2,3

• We don’t archive in clinical care

1Castagna JID 2014; 2Andreatta K CROI 2018; 3Andreatta K

Glasgow 2018 Glasgow analysis similar but looked at M184V only (15% in archived genotypes)

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Bottom line on BIC/TAF/FTC

§ Potent INSTI-based single pill combination (potent, well-tolerated) with TAF/FTC backbone § Patients without resistance: Naïve studies and switch studies indicate non-inferior to DTG or PI-based regimens without h/o resistance or virologic failure § Patients with resistance: Will need post-marketing surveillance data to understand potency in face of underlying NRTI resistance or prior INSTI mutations (had SAILING1 and VIKING2 studies, respectively, for dolutegravir prior to approval for these indications)

1Cahn P. Lancet 2013; 2Castagna A. JID 2014

Case #1 (continued)

§ You think about DRV/cobi/TAF/FTC + DTG BID but the patient REALLY does not want BID § Also, he tells you firmly that he is “addicted to Maalox” and will never change that

AR ARS: S: Is it t ok

• kay to
• co-ad

administer al aluminum an and DT DTG?

• 1. No, never
• 2. Yes, but you must space them out
• 3. Yes, if you take with food
• 4. Oh no- cations and INSTIs! What is it again?

Cations and INSTIs

RAL à 400mg and 600mg HD formulation – Space out from Ca/Fe supplements (RAL first); don’t give with antacids– WAIT for CATS (no acid) ELV–> Space out from all x 2 hours (ELV first) – WAIT for CATS DTG and BICà Can take with Ca

• r Fe supplement with meal;

space out from antacids– FEED YOUR CATS (wait for acid)

• Mathias. Glasgow 2018. Abstr P260; Song J. Clinical Pharm. 2015

12/8/18

DRV/cobi/TAF/FTC approved July 12, 2018

• DRV has the highest

genetic barrier to resistance of ARVs

• First PI single pill
• 10mg of TAF so no

more 25mg TAF with DRV/cobi

• Works against NRTI-

resistant virus (EMERALD)

PROS

• PI-based and has cobi

booster

• DRV trough with

DRV/cobi lower than with DRV/RTV

• Use a PI when you

need a PI only, not 1st-line

CONS

Orkin et al, Lancet HIV, 2018 and package insert; Eron et al. CROI 2018 abs 502; Kakuda T et al. JAC 2014; Orkin C. Glasgow 2018

• Objective: Assess efficacy (non-inferiority) and safety of switching to

D/C/F/TAF vs. continuing boosted-PI + F/TDF regimens in suppressed pts

• Key inclusion criteria:

– On stable bPI + F/TDF regimen for at least 6 months – Viral load (VL) <50 for ≥2 months before screening – Previous ART virologic failure (VF) allowed – Absence of history of VF on DRV, and if historical genotype available, absence of DRV RAMs

Single pill PI-based Combination (Symtuza™) EMERALD: Switch to DRV/Cobi/FTC/TAF

763 378 Orkin et al, Lancet HIV, 2018; Eron J. ID Week 2018

• Switch was non-inferior
• Not strict criteria for switch study

– 58% had ≥5 prior ARV regimens – 15% had prior VF – No DAMs but could have resistance to TDF or 3TC – (Bictegravir switches – genotypic resistance to TDF/TAF/3TC/ABC excluded; SWORD or STRIIVING DTG switch -resistance to any class excluded) – In few failures, NO resistance to any study drugs emerged

• D/C/F/TAF safe- no benefit in renal

biomarkers, but was benefit in bone biomarkers

EMERALD: D/C/F/TAF Switch (Week 48 & 96)

Most rebounders (12/19 week 48 and 14/24 week 96) resuppressed (<50) Orkin et al, Lancet HIV, 2018; Eron J CROI 2018; Eron J ID week 2018

Per package insert: 7 subjects had h/o TDF- associated resistance mutations; 53 had h/o 3TC (mainly M184). All suppressed

Bottom line on DRV/cobi/TAF/FTC

§ DRV-based regimens are listed as alternative on DHHS and IAS-USA guidelines but indicated when non-adherence suspected § Patients without resistance: Used when non- adherence or variable adherence is of concern given high genetic barrier to resistance. Of note, DRV trough with DRV/cobi lower than with DRV/RTV1 § Patients with resistance: Good data from EMERALD study2 on efficacy of DRV/cobi/TAF/FTC even in setting of lots of prior experience (only excluded DAMS; allowed TDF, 3TC resistance)

1Kakuda T. JAC 2014; 2Orkin Lancet HIV 2018 (darunavir package insert)

12/8/18

Doravirine (+/-TDF/3TC) approved August 30, 2018

• Well tolerated
• OK in hepatic and

renal failure

• No food requirements
• Works against Y181C

AND K103N (and G190A) containing viruses

PROS

• Lowish genetic barrier

to resistance like all NNRTIs (emerging resistant mutation V106)

• Single pill combination

is with TDF/3TC

• Can’t use with

rifampin (can double dose with rifabutin)

CONS

Molina JM, et al. AIDS 2018. Abstract LBPEB017; Lai M-T, et al. AIDS 2018. Abstract THPDB101; Molina JM, Lancet HIV 2018; 2. Squires KE, et al. IAS 2017. Abstract TUAB0104LB; Squires K ID week 2018 LB 1; Kumar P ID week 2018 LB2

DRIVE AHEAD – think “head-to-head” with another NNRTI

• 1. Molina JM, Lancet HIV 2018; 2. Orkin C. CID 2018. 3. Squires K, ID week 2018

§ Multicenter, randomized, double-blind phase III noninferiority trial[1] § Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48 (noninferiority margin: -10%)[2]

Treatment-naive adults with HIV-1 RNA ≥ 1000 copies/mL and no resistance to study drugs (N = 728) ID week Analysis Wk 96 Primary Analysis Wk 48 Stratified by HIV-1 RNA (> vs ≤ 100,000 copies/mL), chronic HBV or HCV coinfection status DOR/3TC/TDF 100/300/300 mg QD + EFV/FTC/TDF Placebo (n = 364) EFV/FTC/TDF 600/200/300 mg QD + DOR/3TC/TDF Placebo (n = 364) Open-label extension for 96 wks

DRIVE-AHEAD: Key Efficacy Findings

*Primary NNRTI resistance mutations

DOR/3TC/TDF: Y188L, V106I, F227C, H221H/Y, P225H, Y318Y/F; EFV/FTC/TDF: K103N, E138E/G, G190E, M230L, G190E, K101K/N, P225P/H *Primary NRTI resistance mutations, DOR/3TC/TDF: M41L, M184V, K65R; EFV/FTC/TDF: V118I, M184V, K219K/E, K65K/R

Squires KE, ID Week 2018 and Orkin C. CID 2018.

Outcome at Wk 48, n (%) DOR/3TC/TD F (n = 364) EFV/FTC/TDF (n = 364) PDVF 22 (6.0) 14 (3.8) Genotyped 23 24 Primary NNRTI* resistance 6 (1.6) 12 (3.3) Primary NRTI* resistance 5 (1.4) 5 (1.4)

Bottom line: No difference in efficacy

FDA Snapshot Analysis

Treatment difference: 3.8% (95% CI: -2.4% to 10.0%) 100 80 60 40 20 77.5 73.6 HIV-1 RNA < 50 copies/mL (%) DOR/3TC/TDF EFV/FTC/TDF

DRIVE-FORWARD: NRTIs + Either Doravirine or DRV/RTV in Treatment-Naive Adults (PI = FORWARD)

§ Multicenter, randomized, double-blind phase III study[1] § Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48[2]

Stratified by HIV-1 RNA (> vs ≤ 100,000 copies/mL) and NRTI selection (TDF/FTC or ABC/3TC) Current Analysis Wk 96 *Investigator choice prior to randomization of open-label TDF/FTC or ABC/3TC.

†Option for eligible participants to receive doravirine + 2 NRTIs in extension phase.

• 1. Molina JM, et al. AIDS 2018. Abstract LBPEB017. 2. Molina JM, et al. CROI 2017. Abstract 45LB

ART-naive adults with HIV-1 RNA ≥ 1000 copies/mL within 45 days; no resistance to study drugs by genotype test (N = 766) Open-label extension for 96 wks† Doravirine 100 mg QD + 2 NRTIs* + DRV/RTV Placebo (n = 383) DRV/RTV 800/100 mg QD + 2 NRTIs* + Doravirine Placebo (n = 383) Primary Analysis Wk 48

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DRIVE-FORWARD: Virologic Outcomes at Wk 96

Molina JM, et al. AIDS 2018. Abstract LBPEB017. HIV-1 RNA < 50 copies/mL by Observed Failure Analysis, % (n)* DOR DRV/RTV All participants 81.0 (342) 76.8 (323) BL HIV-1 RNA, copies/mL § ≤ 100,000 § > 100,000 § ≤ 500,000 § > 500,000 85.6 (264) 65.4 (78) 81.8 (325) 64.7 (17) 79.7 (282) 65.2 (72) 78.1 (311) 36.4 (11) BL CD4+ cell count, cells/mm3 § ≤ 50 § 51-200 § > 200 80.0 (5) 71.0 (31) 82.0 (306) 52.9 (17) 65.8 (38) 79.9 (268) NRTI § TDF/FTC § ABC/3TC 80.3 (295) 85.1 (47) 76.3 (283) 80.0 (40)

FDA Snapshot Analysis

Treatment Difference: 7.1% (95% CI: 0.5% to 13.7%)

*Discontinuation for lack of efficacy considered failure, other missing data excluded; n refers to total number of participants per subgroup.

100 80 60 40 20 73.1 66.0 HIV-1 RNA < 50 copies/mL (%) DOR + 2 NRTIs DRV/RTV + 2 NRTIs 280/ 383 252/ 383 n/N = Fold Change by Virus NRTI NNRTI ZDV d4T ddI ABC FTC 3TC TFV DOR EFV ETR RPV WT 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 1.0 A98G/F227C/M184V 0.1 0.7 1.2 2.7 > 100 > 100 0.5 > 93 9.0 2.8 3.8 A98G/V106I/H221Y/F227C/ M184V 0.1 0.6 1.2 3.2 > 100 > 100 0.6 > 110 19 7.9 10 V106A/P225H/Y318F/K65R 1.0 1.4 1.8 2.4 7.7 12 1.6 > 210 4.8 0.7 1.0 V106I/F227C 0.2 0.7 1.0 0.7 2.8 3.1 0.3 > 105 2.5 4.0 3.4 V106I/H221Y/F227C/M184V 0.2 0.8 1.1 3.9 > 100 > 100 0.4 > 96 1.7 1.5 1.2 V106M/F227C/K65R/M184V 0.1 0.5 1.5 2.8 > 100 > 100 0.4 > 98 11.0 0.6 0.4 Y188L/M184V 0.5 0.8 1.6 2.9 > 100 > 100 0.8 > 181 > 120 3.4 11

DRIVE-FORWARD and DRIVE-AHEAD: 7 failed with resistance

§ Susceptibility analysis of the 7 doravirine-resistant mutants from DRIVE- FORWARD (2) and DRIVE-AHEAD (5) phase 3 studies (V106, H221, F227C)

Lai M-T, et al. AIDS 2018. Abstract THPDB101.

Orange shading denotes resistance. Green shading denotes susceptibility. Bolded italics indicate partial sensitivity.

§ Multicenter, randomized, open-label phase III noninferiority trial § Primary endpoint: HIV-1 RNA < 50 copies/mL (FDA Snapshot)

DRIVE-SHIFT: Switch to DOR/3TC/TDF vs Continuation

• f Baseline ART in Virologically Suppressed Adults

DOR/3TC/TDF* (n = 447) Baseline ART† (n = 223) DOR/3TC/TDF* (n = 209) DOR/3TC/TDF* (n = 427) Adults with HIV-1 RNA < 40 copies/mL, stable ART for ≥ 6 mos with no prior virologic failure or resistance to study drugs, and eGFR ≥ 50 mL/min (N = 670) Wk 48 *DOR/3TC/TDF dosing: 100/300/300 mg QD.

†2 NRTIs + RTV- or COBI-boosted PI (ATV, DRV, LPV), EVG/COBI, or NNRTI (EFV, NVP, RPV).

Wk 24

• Kumar. IDWeek 2018. Abstr LB2.

DRIVE-SHIFT: Efficacy of Switch to DOR/3TC/TDF (48 wks)

• Kumar. IDWeek 2018. Abstr LB2.

§ No evidence of treatment-emergent resistance in patients receiving DOR/3TC/TDF

12/8/18

Bottom line on doravirine

§ None of the NNRTIs are first-line in the U.S. Replacement of EFV/TDF/3TC with DOR/TDF/3TC internationally depends on cost (TDF/3TC generic available this year, Temixys out 11/28/18) § In our setting ‒ Patients without resistance: RPV/TAF/FTC used as alternative; DOR/TDF/3TC has TDF and not TAF; DOR/TAF/FTC could eliminate food concerns but not single pill ‒ Patients with resistance: Etravirine or rilpivirine used in a TRIO like regimen (ANRS 139)2 which was ETR/DRV/r/RAL BID, modified is DTG/RPV/DRV/r and could use DTG/DOR/DRV/r if concerned about food or Y181C. Of note, ritonavir will increase doravirine exposure.2 Data indicates ability to give doravirine and dolutegravir together3

1Yazdanpanah Y. CID 2009; 2Khalilieh S et al. CROI 2017; 3Anderson MS et al. Clin Pharmacokinetics 2017

‒ 52 yo man diagnosed with HIV 30 years ago

• AZT/3TC then AZT/3TC/nevirapine then TDF/FTC + Efavirenz in 2002 (and

single pill combination in 2007)

• Had off-and-on problems with adherence and viral load detectability over

time with emergence of M184V, K103N, Y181C, D67N and switched to RAL/ETR/TDF/FTC in 2008 (declined PI)

• In 2010, with multiple failures, switched to DRV/r/TDF/FTC, then

rilpivirine added in 2013 as ongoing viremia, then DTG BID added in 2015. Pt never really suppressed and now genotype shows multiple NRTI mutations (4 TAMS, M184V, K65R), multiple NNRTI mutations (K103N, E138K, Y181C), multiple INSTI mutations (N155H, E92Q, Q148H), multiple darunavir-associated mutations (I50V, I54M, T74P, L76V, I84V, L89V)

• Phenotype test doesn’t look much better – no suppressive regimen with

INSTIs, PIs, NNRTIs, NRTIs

Case #1 - modified AR ARS: S: What t is th the regimen you

• u wou
• uld ch

choos

• ose

fo for this patient?

• 1. DRV/cobi/TAF/FTC + DTG BID
• 2. DRV/cobi/TAF/FTC + DTG BID + Enfuvirtide
• 3. DRV 600mg po BID; RTV 100mg po BID; BIC/TAF/FTC; Doravirine

100mg po daily

• 4. DRV 600mg po BID; RTV 100mg po BID; BIC/TAF/FTC; Doravirine

100mg po daily + Enfuvirtide

• 5. Fostemsavir (compassionate use) + Ibalizumab

Ibalizumab monoclonal Ab approved March 6, 2018

Emu B. NEJM Aug 2018; Dejesus E. Glasgow 2018

§ Monoclonal Ab- Binds CD4 receptor on T-cell, preventing attachment of gp120 § Phase 3 open-label single group study of 40 patients with MDR HIV, OBR § At week 25, ibalizumab + OBR had mean decrease in VL 1.6 log10 copies/ml from baseline (43% <50; 50% <200) § 17 (43%) had co-administration investigational attachment inhibitor fostemsavir § Diminished ibalizumab susceptibility in vitro in pts with VF

12/8/18

BRIGHTE: Fostemsavir in Heavily Treatment– Experienced Adults at Wk 48

• Aberg. Glasgow 2018. Abstr O344A.

Randomized Cohort

HTE adults failing current; have 1-2 remaining ARV classes (≥ 1 fully active available agent/ class), unable to construct viable regimen with remaining agents (n = 272)

1 Analysis Day 8

Blinded Phase

Adjusted* Mean Δ in HIV-1 RNA at Day 8 vs Day 1, log10 c/mL (95% CI)

• 0.79

(-0.88 to -0.70)†

• 0.17

(-0.33 to -0.01) Day 9 Wk 24

Open-Label Extension FTR 600 mg BID + Failing Regimen (n = 203) Placebo BID + Failing Regimen (n = 69) FTR 600 mg BID + OBT‡ FTR 600 mg BID + OBT‡

Treatment ∆, % (95% CI)

• 0.63 (-0.81 to -0.44)

Primary Endpoint

Current Analysis Wk 48

Nonrandomized Cohort

HTE adults failing current ART with 0 remaining ARV classes and no fully active agents (n = 99) FTR 600 mg BID + OBT‡

Day 0

Metabolized into temsavir which binds to viral glycoprotein 120, preventing binding to CD4

Results of BRIGHTE

§ Randomized cohort: -0.79 log HIV RNA reduction in fostemsavir arm versus -0.17 log reduction in OBT arm (p <0.0001); 54% virologic suppression (146/272) in those

• n fostemsavir

§ Non-randomized cohort (like

• ur patient!- 81% had ONLY

fostemsavir as an active agent): 38% virologic suppression rate (38/99) – 15 of those 99 were

• n ibalizumab
• Aberg. Glasgow 2018. Abstr O344A.

Case #2

• 32 yo man diagnosed with HIV 3 months

ago

• Started on DTG/TAF/FTC as part of RAPID

protocol in our clinic, baseline genotype W.T., did extremely well, viral load down from 132,000 copies/ml to undetectable within 4 weeks

• Wonders now – I am only 32 years old- can I

be on as few drugs as possible?

AR ARS: S: Is it t ok

• kay to
• ch

change him to

• a 2-dr

drug ug re regimen?

• 1. Yes, let’s do DTG/3TC
• 2. Yes, let’s do DRV/r + 3TC
• 3. Yes, let’s do DTG/RPV
• 4. I am not quite ready for two drug regimens yet

12/8/18

Case #2- modified

• 32 yo man diagnosed with HIV 3 years ago
• Was started on DTG + TAF/3TC as part of RAPID protocol in our

clinic 3 years ago, baseline genotype W.T., then on DTG/ABC/3TC

• Took meds somewhat irregularly and frequent blips, remains W.T.
• n two occasions when could genotype
• Switched back to DTG + TAF/FTC a year ago and generally did well

but last VL 700 copies/mL, wild-type virus

• Wonders now – I am only 32 years old- can I be on as few drugs as

possible?

AR ARS: S: Is it t ok

• kay to
• ch

change him to

• a 2-dr

drug ug re regimen?

• 1. Yes, let’s do DTG/3TC
• 2. Yes, let’s do DRV/r + 3TC
• 3. Yes, let’s do DTG/RPV
• 4. I don’t think he is a good candidate
• 5. I am not quite ready for two drug regimens yet

Comment on Ward 86 RAPID outcomes

§ Of 225 patients referred to RAPID-ART from 2013-17

‒ 216 (96%) were started on immediate ART (4 declined; 3 not started by clinician) ‒ Median age: 30; 7.9% women; 11.6% African-American, 26.9% Hispanic, 36.6% white ‒ 51.4% with substance use; 48.1% with mental health diagnosis; 30.6% unstably housed ‒ Median CD4 441; median VL 37,011 copies/mL ‒ Median # VLs 4 (1-22) over median 1.09 years (0-3.92) years of f/u

Coffey S. CROI 2019

12/8/18

Is Dual ART the Future?

Clinical Trials (of 2 drugs)

„ Initial ART

„ DTG + 3TC (ACTG 5353,* GEMINI*) „ DRV/RTV + 3TC (ANDES^) „ DRV/cobi+ RPV (PREZENT^)

„ Maintenance ART

„ DTG/RPV (SWORD1&2*) „ DRV/RTV + DTG (DUALIS) „ DTG + 3TC (LAMIDOL*, ASPIRE*) „ DRV/RTV + 3TC (DUAL GESIDA*) „ CAB IM + RPV-LA IM (LATTE-2,* ATLAS, FLAIR)

*Published; ^Presented

SWORD-1 and -2: Switch to DTG + RPV vs Continuation of Baseline ART in Virologically Suppressed Adults (100 wks)

§ Parallel, randomized, open-label, multicenter phase III noninferiority studies[1,2] § Primary endpoint: HIV-1 RNA < 50 copies/mL maintained in 95% of patients in each arm at Wk 48; adjusted treatment difference: -0.2% (95% CI: -3.0 to 2.5)[2]

Switch to DTG + RPV (n = 513) Continue Baseline ART (n = 511) Switch to DTG + RPV Continue DTG + RPV Early Switch Phase

• 1. Llibre JM, et al. Lancet. 2018;391:839-849 (48 weeks); 2. Aboud M, et al. AIDS 2018. Abstract THPEB047 (100 weeks)

Adults on stable ART (INSTI, NNRTI, or PI + 2 NRTIs) with HIV-1 RNA < 50 copies/mL for ≥ 6 mos at screening; no previous VF or current HBV infection (N = 1024) Late Switch Phase Wk 148 Wk 52 Current Analysis Wk 100 DTG dosed 50 mg PO QD; RPV dosed 25 mg PO QD. Primary Endpoint Wk 48 *70% to 73% of patients receiving TDF at baseline. Virologic Response With DTG + RPV by FDA Snapshot

89% 93%

(HIV-1 RNA < 50, Wk 100)

SWORD-1 and -2: Resistance

§ 10/990 (1%) confirmed virologic withdrawals through Wk 100

‒ Treatment-emergent NNRTI resistance mutations documented in 3/10*; G193E is polymorphism selected by DTG doesn’t confer resistance

Time of Failure Previous Regimen Mutations at Baseline Mutations at Confirmed Virologic Withdrawal NNRTI INSTI NNRTI INSTI Wk 36 EFV/TDF/FTC None None K101K/E None Wk 88 DTG/ABC/3TC None None E138E/A None Wk 100 EFV/TDF/FTC K101E, E138A G193E K101E, E138A, M230M/L Assay failure

Aboud M, et al. AIDS 2018. Abstract THPEB047. *For these 3 patients, HIV-1 RNA at last measurement: < 50 copies/mL, 55 copies/mL, 300 copies/mL, respectively.

GEMINI-1 and -2: DTG + 3TC vs DTG + TDF/FTC in Treatment-Naive Patients (Phase 3)

§ Parallel, international, randomized, double-blind phase III noninferiority studies § Primary endpoint: HIV-1 RNA < 50 copies/mL at Week 48 by FDA Snapshot analysis

ART-naive adults with HIV-1 RNA 1000-500,000 copies/mL, ≤ 10 days on previous ART, no major resistance associated mutation, no HBV infection

• r HCV requiring therapy

(N = 1433) DTG + 3TC PO QD (n = 716) DTG + TDF/FTC PO QD (n = 717) Wk 144 Primary Analysis Wk 48 Stratified by HIV-1 RNA (≤ vs > 100,000 copies/mL), CD4+ cell count (≤ vs > 200 cells/mm³) Cahn P, et al. The Lancet. November 2018 Screening within 28 days of study start; studies double-blinded until Wk 96, open-label until Wk 144. Continuation of DTG + 3TC permitted

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GEMINI-1 and -2: Virologic Response at Wk 48 (also stratified by CD4/viral load)

DTG + 3TC DTG + TDF/FTC Virologic Outcomes by FDA Snapshot Analysis

Baseline CD4+ Cell Count, cells/mm 3

100 80 60 40 20

91 94 92 90 93 93 79 93 ≤ 100,000 > 100,000 Baseline HIV-1 RNA, c/mL > 200 ≤ 200 526/ 576 531/ 564 129/ 140 138/ 153 605/ 653 618/ 662 50/ 63 51/ 55

Patients With HIV-1 RNA < 50 c/mL (%) n/N = Cahn P, et al. The Lancet. November 2018 Virologic Success Virologic Nonresponse No Virologic Data HIV-1 RNA < 50 copies/mL (%) ITT-E PP* 100 80 60 40 20 91 93 93 94 3 2 2 1 6 5 5 4 In participants with CD4 <200 50 (79%) of 63 on 2-drugs achieved HIV RNA <50 compared with 51 (93%) of 55 of those on 3-drugs. Most reasons cited were non-efficacy related – protocol violation, loss to follow-up, etc. (Table 4 in paper)

No treatment-emergent INSTI or NRTI mutations in patients with VF in either arm (6 failures in 2-drug; 4 in 3-drug. Are you ready at 48 weeks data?

ANRS 167 LAMIDOL: DTG/3TC switch in experienced patients (104 patients after median 4.5 years on ART; vl <50)

§ 3 patients didn’t stay <50 by wk 48: 1 lost to follow-up; 2 with virologic failure – 12 and 48 wees) § Pt who failed week 12- had been on RAL/ABC/3TC in past and switched to RAL/ETR containing regimen § Patient who failed 48 – was on TDF/FTC/EFV or RPV in past, developed L74L in LAMIDOL, switched to TDF/FTC/DTG

Joly V. J. Antimicrobial Chemotherapy. November 2018

Predictors of who “does not do well” on 2-drug therapy, Italian cohort

§ Of 2149 switchers in Italian cohort, median age 50, median CD4 577, median VL 1.57 log (<40 copies) § Lots of pre-treatment experience (99.3% had taken NRTI in past; 82.4% PI; 67.9% NNRTI; 32.2% INSTI). § ONLY PRE-treatment viral load predicted virologic failure in multivariate analysis. AND trend of having a GSS <1 (possible resistance in the pre-switch genotype) § Bottom line: If you are ready for this, only consider switching if patient 1) suppressed; 2) adherent by your experience; 3) have no history of genotypic resistance to any component of your 2-drug regimen.

• Rossetti. Glasgow HIV Therapy conference 2018. Abstract P299

TEASER FOR NEXT YEAR: Long-acting injectables, LATTE-2: Long-Acting Cabotegravir + Rilpivirine IM for Maintenance – wk 160

§ Multicenter, open-label phase IIb study[1] § Primary endpoints: HIV-1 RNA < 50 copies/mL (FDA Snapshot), PDVF, safety at maintenance Wk 32[2]

‒ 94% in Q4W arm; 95% in Q8W arm, 91% in oral treatment arm (small, bigger studies coming March 2019)

• 1. Margolis. Glasgow 2018. Abstr P118. 2. Margolis. Lancet. 2017;390:1499

CAB 400 mg IM + RPV 600 mg IM Q4W (n = 115) CAB 600 mg IM + RPV 900 mg IM Q8W (n = 115)

ART-naive HIV- infected patients with CD4+ cell count > 200 cells/mm3 (N = 309)

CAB 30 mg PO + ABC/3TC PO QD (n = 56) CAB 30 mg PO QD + ABC/3TC Wk 20 Induction Phase* Maintenance Phase Wk 1 Wk 160

*Patients with HIV-1 RNA < 50 copies/mL from Wk 16-20 continue to maintenance phase. †Patients chose Q4W or Q8W. Optimized loading dose (CAB 600 mg IM + RPV 900 mg IM) given at Wks 100 and 104.

Primary Analysis; Dose Selection Wk 32 Wk 96 Extension Phase

12/8/18

Summary

§ Between new drugs of doravirine, bictegravir, DRV/cobi/TAF/FTC with very potent former drugs, 2018 is a good year § Ibalizumab and fostemsavir reserved for very resistant patients- fewer and fewer § Two drug therapy

‒ We only have phase 3 data on DTG/RPV (switch) and DTG/3TC (naïve) ‒ Predictors of doing poorly on switch are not virologically suppressed or any resistance ‒ Are you ready?

Thank you to Drs. Diane Havlir, Annie Luetkemeyer, Meg Newman and Division of HIV, Infectious Diseases and Global Medicine