State of the art of ART Medical Management of AIDS December 7, 2017 - - PDF document

1

“State of the art” of ART

Medical Management of AIDS December 7, 2017

Monica Gandhi MD, MPH Professor of Medicine, Division of HIV, Infectious Diseases and Global Medicine, UCSF Medical Director, “Ward 86”, San Francisco General Hospital

No disclosures

Outline

Ascent of the integrase inhibitor

• Raltegravir once daily
• Dolutegravir’s limitations
• Darunavir/ritonavir- DHHS demotion deserved?
• Bictegravir coming
• Drug drug interactions

2-drug starts or simplifications New single pill combinations In all of the rush, remember cobicistat ≠ ritonavir New: Doravirine, monoclonal Abs

Ascent of the integrase inhibitors

2

ONCEMRK: Raltegravir 1200mg daily ~ 400mg BID in naives

Cahn P. Lancet HIV 2017; Di Perri G, . EACS 2017. Abstract BPD1/3 (96 week data) Raltegravir HD (600mg) approved 5/17

Dolutegravir: Good drug but difficult year ARS: How does DTG compare to PIs as monotherapy after suppression?

• 1. Both show acceptable rates of maintaining

virologic suppression after switching to monotherapy

• 2. DTG better at maintaining suppression than

boosted PIs

• 3. Boosted PIs better at maintaining suppression

than DTG

• 4. Rates of virologic suppression after switch to

either monotherapy strategy unacceptably high (but more resistance likely with DTG)

DOMONO: Switch to DTG monotherapy

Single center Netherlands- RCT of taking patients with virologic suppression (<50, never CD4 <200 or viral load >100K) and switching to DTG monotherapy versus continuing ART 24 weeks- VF ~same, study continues 48 weeks: Of 77 patients on DTG monotherapy, 8 with VF (92% vs 98%, p 0.03)

#451LB

3

Of 8 patients, 6 could get integrase inhibitor genotyping – 3 had new INSTI resistance (50%)

DOMONO: Switch to DTG monotherapy

“Pathways of Resistance in Subjects Failing Dolutegravir” (Redomo study, abstract 42)

OR VF mono 1.58 (0.73-3.13) Clinic settings in Barcelona, Munich, Montreal –simplifying to monotherapy without evidence (10440 pts)

DTG bi or tri therapy (1082) 10% DTG monotherapy (122) 1.17%

VF 64 (6%; 95% CI 5-7%) VF 11 (9%, 95% CI 6-18%) 9/11 with INSTI resistance (multiple pathways, 155, 18, 92, 148) No INSTI resistance

• 5/11, DTG was first INSTI
• 8/11 had been suppressed

for >3 years

• Adherence <95% in 4/11
• Weeks (median, IQR) from VF

until genotype 5 (3-14)

MOBIDIP: Monotherapy switch to boosted PI

Pts with virologic suppression randomized to monotherapy (133)

• r boosted PIs (LPV or DRV)+3TC (132) – study d/c’d 48 wks.

VF in 3% of boosted PI/3TC and 24% with monotherapy – no resistance testing performed Meta-analysis of 13 studies shows 8% more VF with boosted PI monotherapy vs triple but very little resistance (Arribas HIV Med 2015)

Ciaffi et al. 9/2017

24.8% 3%

Adverse effects with DTG in real- world cohorts and switch studies

Increased number of neuropsychiatric, CNS, GI side effects in women and older individuals in real-world cohorts Some switch trials show surprisingly high rates of AEs with DTG switch (13% more in STRIIVING and SWORD) Associated with PK levels of DTG like with EFV

de Boer M. AIDS. 2016; Hoffmann C. HIV Med. 2017; Solasi C. 18th Clinical Pharm HIV Workshop 2017; Kheloufi AIDS 2017; Menard AIDS 2017; Peñafiel JAC 2017; Yagura BMC ID 2017 (Figure from CROI 2017#426); Trottier Antiviral Therapy 2017; Llibre JM et al. CROI 2017; Abstract 44LB.; Walmsley S et al, IDWeek 2017, Abstract 1382.

4

DHHS Guidelines for the Use of Antiretroviral Agents in Adults and Adolescents Living with HIV October 17, 2017

ARS: Was change in DHHS guidelines re: darunavir based on new clinical evidence?

• 1. Yes, darunavir is inferior

to INSTIs, shouldn’t be in “drugs for everybody” Table

• 2. No, don’t think this

change was indicated, DRV/r is complicated but so is DTG, EVG/cobi and RAL

Darunavir/r DHHS demotion deserved?

Agree with ATV/r demotion

• WAVES trial (ELV/cobi > ATV in women, mainly tolerability,

failures with PI resistance); A5257 trial (RAL>ATV/, mainly tolerability); ARIA trial (DTG >ATV in women, potency)

DRV/r complicated

• FLAMINGO (DTG>DRV/r) and A5257 (RAL>DRV/r) mainly driven

by tolerability but RAL failures in A5257 with INSTI resistance and DRV/r doesn’t fail with resistance

My bottom line (opinion):

• DTG and DRV/r both have AEs, low resistance when supported,

DTG more resistance when alone; RAL well-tolerated but more resistance; EVG/cobi fails with resistance and cobi affects tolerability - I would have kept DRV/r up in table with INSTIs

(opinion)

Bictegravir

New INSTI to be combined with TAF/FTC Two naïve trials and one switch trial

Bictegravir/FTC/TAF* (n = 314) Dolutegravir/ABC/3TC† (n = 315) ART-naive, HLA-B*5701–negative pts with eGFRCG ≥ 50 mL/min (N = 629)

Wk 48

§ GS-1490: randomized, double-blind, active-controlled phase III trial[2] Bictegravir/FTC/TAF* (n = 320) Dolutegravir + FTC/TAF‡ (n = 325) ART-naive pts with eGFRCG ≥ 30 mL/min (N = 645)

Wk 48

GS1489 GS1490

Gallant J. Lancet HIV 2017; Sax P Lancet HIV 2017

5

Two Bictegravir naïve trials

Baseline Characteristic

GS-14891 GS-14902

BIC/FTC/TAF (n = 314) DTG/ABC/3TC (n = 315) BIC/FTC/TAF (n = 320) DTG + FTC/TAF (n = 325)

Median age, yrs (range)

31 (18-71) 32 (18-68) 33 (18-71) 34 (18-77)

Male, %

91 90 88 89

Median HIV-1 RNA, log10 copies/mL (IQR)

4.42 (4.03- 4.87) 4.51 (4.04-4.87) 4.43 (3.95- 4.90) 4.45 (4.03-4.84)

§ HIV-1 RNA > 100,000 copies/mL, %

17 16 21 17

Median CD4+ cell count, cells/mm3 (IQR)

443 (299- 590) 450 (324-608) 440 (289- 591) 441 (297-597)

§ CD4+ cell count < 200 cells/mm3, %

11 10 14 10

1Gallant J. Lancet HIV 2017; 2Sax P Lancet HIV 2017

Bictegravir naïve studies

Bictegravir noninferior to dolutegravir More nausea with DTG in naïve trials Otherwise, same side effects, no changes in lipids, no resistance with either in failures

Gallant J. Lancet HIV 2017; Sax P Lancet HIV 2017

B/F/TAF switch study

• Phase 3 Randomized, Controlled Trial of Switching to Fixed-Dose

Bictegravir/Emtricitabine/Tenofovir Alafenamide (B/F/TAF) from Boosted Protease Inhibitor-Based Regimens in Virologically Suppressed Adults: Week 48 Results

Abstract 67504

B/F/TAF switch study

Abstract 67504

• Bictegravir noninferior to SBR (92.1% vs 88.9% VS)- excluded those

with ABC/3TC/TAF/TDF resistance in past

• Better lipids with bictegravir; no changes in other AEs except more

HA with bic; more bili with ATV; 1 case of ABC-resistance on DRV/r/ABC/3TC

Jurgen K. ID Week San Diego 2017

6

ARS: Besides the efficacy, what do we know about bictegravir at this point given its imminent release?

• 1. Should have fewer side effects than dolutegravir
• 2. Can use with TB therapy
• 3. Higher barrier to resistance than dolutegravir
• 4. We know its resistance pathways
• 5. Smaller pill than DTG/ABC/3TC

Drug-drug interactions with bictegravir

Atazanavir Rifampin

• Both DTG and BIC

metabolized by UGT1A1 and CYP3A4- BIC ½ by each, but DTG more by UGT1A1 and 3rd pathway also involved

• BIC increases metformin

(like DTG) but less (39 vs 79% AUC)

• 75% reduction in BIC

with rifampin (must BID DTG with rifampin)

• No dose adjustment

required in moderate liver or renal insufficiency

Voriconazole Atazanavir Rifabutin Rifampin

HIV Pharmacology June 2017; CROI 2017; ID week 2017

Bictegravir

• Noninferior to DTG
• Will be available in single pill

combination with TAF/FTC

• Smaller pill than

DTG/ABC/3TC

• No food requirements
• Need to space out from

cations

• Can’t co-administer with

rifampin

• Increases tubular secretion of

creatinine like DTG

WHAT WE KNOW

• Do not know extent of drug-

drug interactions – may be more or less than with DTG

• Do not know side effects in

real-world populations

• Do not know its major

resistance pathways or which mutations matter

• Do not know genetic barrier

to resistance yet (in vitro is not in vivo)

• Do not know how food will

affect (meals increase DTG)

• Don’t know pregnancy safety
• Don’t know if can co-

administer with Ca, Fe with meals like with DTG

WHAT WE DON’T KNOW

ARS: What do we know about cations and integrase inhibitors?

• 1. Raltegravir 400mg okay to co-administer with

calcium

• 2. Dolutegravir okay to co-administer with

calcium with meal

• 3. Elvitegravir not okay to co-administer with

calcium

• 4. A, B and C
• 5. Simple algorithm eludes me so I avoid all

integrase inhibitors with all cations

7

Making it simple: Cations and INSTIs

RAL à 400mg ok with Ca but not 600mg; no with Mg, Alà ”NO CATS” ELV and BIC –> Space out from all x 2 hours (with food) – “WAIT FOR CATS” DTG à Can take with Ca or Fe with meal; space out from Al, Mg à “KFC BUT WAIT for MA”

TWO DRUG STARTS

• Dr. Havlir discussed

Switches of SWORD (RPV/DTG), LATTE-2 (Cabotegravir/RPV), LAMIDOL (DTG/3TC), EMERALD (DRV/cobi/FTC/TAF)

ARS: What are the two drug combinations you would consider starting in naïve patients?

• 1. DRV/ritonavir (cobi) + DTG
• 2. DRV/ritonavir (cobi) + 3TC
• 3. DTG + 3TC
• 4. DRV/ritonavir (cobi) + RAL
• 5. DRV/ritonavir (cobi) + TAF (or TDF)
• 6. Data not yet convincing for any of these to

me

ARS: What are the two drug combinations you would consider starting in naïve patients?

• 1. DRV/ritonavir (cobi) + DTG: phase 3 – DUALIS- in

progress)

• 2. DRV/ritonavir (cobi) + 3TC: will discuss
• 3. DTG + 3TC: will discuss
• 4. DRV/ritonavir (cobi) + RAL: phase 3 (NEAT study.

Raffi Lancet 2014) with more resistance in dual therapy failures

• 5. DRV/ritonavir (cobi) + TAF (or TDF): not studied
• 6. Data not yet convincing for any of these to me

8

ANDES study

• GARDEL (phase 3)1 had shown efficacy of LPV/r/3TC in naïve

pts (and Argentina has fixed dose combo of DRV/r)

1Cahn P. Lancet ID 2014; 2Cahn P. IAS 2017

Andes2

ANDES study: DRV/r + 3TC Initial Therapy

• VL <400 at wk 24: 95-97%

–Baseline VL >100K: high

response rate

• Dual therapy non-inferior

to triple therapy at wk 24

• Both arms well-tolerated
• Larger phase 4 trial

underway x 48 weeks

• No resistance testing done

Sued O, et al. J Int AIDS Soc. 2017;20(suppl 4):104. Abstract MOAB0106LB.

HIV RNA <400 Copies/mL (ITT)

Darunavir/r +: Lamivudine Lamivudine + tenofovir DF

Patients (%)

20 40 60 80 100

100% 100% 95% 97%

Overall

(n=75/70)

Baseline HIV RNA >100K Copies/mL

(n=20/15) Difference (%):

• 2.5 (-7.9, 2.9)

A5353: DTG + 3TC in naives

§PADDLE (20 pts, 48 weeks, DTG + 3TC, no failures)1 §A5353 Phase 2 single-arm, 52-week study (n=120)2

§ HIV RNA ≥1000 to <500,000 copies/mL; no resistance; no HBV

§Age (30 years), male (87%), CD4 count (350-413 cells/mm3), HIV RNA (4.2-5.2 log10 copies/mL) §Primary efficacy outcome 90% achieved HIV RNA <50 copies/mL at week 24 (FDA snapshot algorithm), regardless of baseline HIV RNA level §Virologic failure (n=3) was uncommon, associated with suboptimal adherence (did DTG plasma concentrations) BUT 1 virologic failure had emergent R263RK (DTG mutation) and M184V (3TC mutation) §Concerned about “lack of forgiveness” to adherence in real world, GEMINI phase 3 ongoing

Taiwo BO, et al. IAS 2017. Abstract MOAB0107LB; PADDLE: Cahn P. J Int AIDS Soc. 2017 May

New single pill combinations

9

ARS: What are the brand names of the two single pill combinations for treatment of HIV coming soon?

• 1. Symuca™ and Juluza ™
• 2. Symtuza™ and Juluca™
• 3. DoluRil™ and Darquad™
• 4. Symcap™ and Juluca™
• 5. Gesundheit

34

• 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

Orkin et al, Lancet HIV, 2017

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

763 378

35

• Switch was non-inferior
• Lax 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 switch - 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 detected

• D/C/F/TAF safe- no benefit in Cr

with TAF but because of cobi; better bones

EMERALD: D/C/F/TAF Switch (Wk 48)

Most rebounders (12/19 D/C/F/TAF and 4/8 control) resuppressed (<50) at Wk 48

Orkin et al, Lancet HIV, 2017

Week 48 efficacy

36

Amber study: Comparing SPC to TDF

Wk 48

DRV/COBI/FTC/TAF (n = 362) DRV/COBI + FTC/TDF (n = 363)

Treatment-naive pts with HIV-1 RNA >1000, susceptible to DRV, TDF, 3TC≥(N = 725)

Randomized, double-blind phase III trial

• High rates of virologic suppression (91.4%) - 1 treatment-emergent

resistance mutation (M184I/V) in SPC arm

• Lower rate of AE-related d/c for DRV/COBI/FTC/TAF vs DRV/COBI +

FTC/TDF (1.9% vs 4.4%)

• Hip/spine BMD changes more favorable with SPC
• Significantly higher eGFR by serum creatinine (P < .0001) and

cystatin C (P = .001) with DRV/COBI/FTC/TAF

Orkin et al. EACS. Milan, Italy Oct 2017

10

Cobicistat ≠ ritonavir…in a surreal world, apples are not apples ARS: Which of these is NOT true when comparing cobicistat to ritonavir?

• 1. Dolutegravir levels increase when combined

with cobicistat compared to ritonavir

• 2. Darunavir/cobicistat does not seem to be as

potent as darunavir/ritonavir in a clinical cohort

• 3. Cobicistat has fewer drug-drug interactions than

ritonavir

• 4. Cobicistat combined with TDF is not as well

tolerated as well as ritonavir combined with TDF

More not less: Cobicistat has more drug-drug interactions than ritonavir

1) Switching from a RTV-boosted PI to a cobicistat- boosted PI when paired with DTG leads to 100% increased DTG trough levels 2) Cobicistat increases dabitagran levels dangerously; ritonavir okay 3) Cobicistat increases drospirenone in the Yaz contraceptive whereas ritonavir does not 4) Cobicistat with TDF leads to such high TFV levels that there were high rates of discontinuation of TDF/FTC with cobi in Italian clinic

• 1Gervasoni. JACC 2017; 2Kakadiya. AAC 2017; 2Majeed S. HIV

Pharmacology Workshop Chicago 2017; 4Cattaneo JAIDS 2017

Beware that darunavir/cobicistat may be less potent than darunavir/RTV

• Trough with DRV/cobi lower than DRV/RTV1 (DRV decreases half-life
• f cobi2) so former may be “less forgiving” than latter
• Clinical cohort3 showed 5% failure with switch to DRV/cobi – use

with food and watch carefully after switch

1Kaduda T. JAC 2014; 2Eliot JAC 2017; Nugent. 16th EAC. Milan. Oct 2017. Abstract P39

11

New anti-HIV drugs

Drug class Name of drug Comments

NNRTI Doravirine – covered this am and in panels DRIVE-FORWARD (DRV/r vs DOR looks good 48 wks); DRIVE AHEAD (DOR/TDF/FTC vs EFV/TDF/FTC, DOR better tolerated Attachment inhibitor BMS-663068 or fostemsavir Looks good in phase IIb; now in Phase III with heavily experienced pts (BRIGHTE study, EACS, 24 week good) Maturation inhibitor BMS-955176 Discontinued due to treatment emergent resistance and GI intolerability Broadly neutralizing Ab VRC01, for prevention

• r treatment

Bar et al. NEJM Nov 9, 2016 – delays viral rebound but resistance Broadly neutralizing Ab Ibalizumab, for treatment of MDR-HIV Phase III data complete in MDR-HIV and FDA review pending

Ibalizumab in Patients with Multi-Drug Resistant HIV

Emu et al, Abstract 1686, IDWeek 2017

• Monoclonal Ab: binds CD4; blocks HIV entry
• IV infusion: loading dose, then every 2 wks
• Phase 3 open label study in 40 pts on a failing

regimen with 3-class ARV resistance (highly experienced and resistant)

• Day 14: 83% had >0.5 log10 VL reduction;

60% had >1.0 log10 VL reduction

• Wk 24 results (ibalizumab + OBR):

– 43% had VL <50; 50% had VL <200 – Mean VL decrease 1.6 log10

• Expanded access: efficacy at wk 48 (n=27)

– All 15 patients with VL <50 at Wk 24 maintained viral suppression to Wk 48; another pt achieved VL <50 at wk 48

• Under FDA review (filed May 2017)

Clinical pearls from talk

Raltegravir once daily but low genetic barrier Never use dolutegravir as monotherapy, some side effects Bictegravir non-inferior to DTG but we don’t know drug-drug interactions or how will stand up with resistance in background DRV/cobi/TAF/FTC coming out, seems good even with resistance in background Still should like darunavir/ritonavir, high genetic barrier, more forgiving than darunavir/cobi for patients with adherence issues

Thank you to Drs. Diane Havlir, Meg Newman, Vivek Jain, Harry Lampiris, Annie Luetkemeyer, HIV Fellows’ Clinic, and to Jon Oskarsson, Mary Lawrence Hicks, Eva Mureithi