5/25/17 HIV Clinical Update: Treatment in 2017 and Beyond

72017 HIV Clinical Update

5/25/17

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HIVClinicalUpdate:Treatmentin2017andBeyond

ShobhaSwaminathan,MDAssociateProfessorofMedicine

RutgersNewJerseyMedicalSchool

Overview

• Whats newintheguidelines• Startingantiretroviraltherapy• Switchingantiretroviraltherapy• Newmedications• Hopeforthefuture

CasePresentation-1

• A23yearoldmalecomestoyourclinicaftergoingtotheERforaurethraldischargeandwasdiagnosedwithgonorrheaandatthesametimehadanHIVtestthatwasreactive.Hewasthenreferredtoyou.• Statesthathefeelsfineanddoesheneedmeds• Ifheneedsmedsthenhewantsasfewpillsaspossible• CD4-467,HIVVL- 27,000copies/ml• RPR- negative,HCVneg

8 2017 HIV Clinical Update

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DHHSGuidelinesforInitialHIVTreatment(Preferred)

• IntegraseStrandTransferInhibitor-Based(INSTI)Regimens:• Dolutegravir (DTG)/abacavir (ABC)/lamivudine(3TC)—only forpatientswhoareHLA-B*5701negative

• DTGpluseithertenofovirdisoproxil fumarate (TDF)/emtricitabine(FTC) ortenofoviralafenamide (TAF)/FTC

• Elvitegravir (EVG)/cobicistat (c)/TAF/FTC• EVG/c/TDF/FTC• Raltegravir (RAL)pluseitherTDF/FTC orTAF/FTC

• ProteaseInhibitor-BasedRegimens:• Darunavir(DRV)/ritonavir(r)pluseitherTDF/FTC orTAF/FTC

DHHSGuidelines,updatedJuly2016

DHHSGuidelinesforInitialHIVTreatment(Alternate)• NNRTIplus2NRTIs:

• EFV/TDF/FTC• EFVplusTAF/FTC• RPV/TDF/FTCorRPV/TAF/FTC—ifHIVRNA<100,000copies/mLandCD4>200cells/mm3

• BoostedPIplus2NRTIs:• ATV/corATV/rpluseitherTDF/FTCorTAF/FTC• DRV/c orDRV/r plusABC/3TC—ifHLA-B*5701negative• DRV/cpluseitherTDF/FTCorTAF/FTC


CasePresentation-1

• A23yearoldmalecomestoyourclinicaftergoingtotheERforaurethraldischargeandwasdiagnosedwithgonorrheaandatthesametimehadanHIVtestthatwasreactive.Hewasthenreferredtoyou.• Statesthathefeelsfineanddoesheneedmeds• Ifheneedsmedsthenhewantsasfewpillsaspossible• CD4-467,HIVVL- 27,000copies/ml• RPR- negative,HCVneg


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Whatwouldyourecommendforhim

1. EFV/TDF/FTC2. RPV/TDF/FTC3. TDF/FTC/RAL4. TDF/FTC/DRV/r5. EVG/c/TDF/FTC

CasePresentation-2

• A32yearoldwomandiagnosedwithHIVin2011• BaselineCD4- 145cells/cumm,HIVVL250,000copies/ml• HIVgenotype- wildtype• HLAB5701negative• HasbeenonEFV/TDF/FTC

• Usuallywellcontrolled,hasrareblips• CurrentCD4- 564cells/cumm,HIVVL<50copies/ml

• Feelsgratefultohercurrentregimenforsavingherlife

Wouldyouadvisehertochangeherregimen

• Yes• No


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Whatwouldyouswitchto

1. EFV/TDF/FTC2. RPV/TDF/FTC3. TDF/FTC/RAL4. TDF/FTC/DRV/r5. EVG/c/TDF/FTC

SwitchingFromSuppressiveART:StudyResults

1. Nelson M, et al. ICAAC 2013. Abstract H-672b. 2. Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599. Slide credit: clinicaloptions.com

Trial Switch From Switch To Findings

UK Multicenter Study[1]

EFV/TDF/FTC

RPV/TDF/FTC

• Pts switched due to CNS toxicity (N = 40)• 100% maintained virologic suppression following switch• Grade 2-4 CNS AEs significantly decreased at Wks 4, 12, including

dizziness, depression, insomnia, aggressive mood, abnormal dreams

STRATEGY-NNRTI[2]

NNRTI + TDF/FTC

EVG/COBI/TDF/FTC

• Phase IIIb randomized study; pts switched (n = 291) or remained on original regimen (n = 143)

• Switch to EVG/COBI/TDF/FTC noninferior to remaining on stable NNRTIs at Wk 48 (93% vs 88% HIV-1 RNA < 50 c/mL)

• Dizziness, insomnia, anxiety, vivid dreams significantly decreased from BL at Wk 48 in switch group; no changes noted for pts who remained on EFV + TDF/FTC

•

SwitchingFromSuppressiveART:StudyResults

1. Lake JE, et al. IAC 2016. Abstract THAB0203. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. Slide credit: clinicaloptions.com

Trial Switch From Switch To Findings

STRIIVING[1

]

2 NRTIs + NNRTI, PI, or

INSTI

DTG/ABC/3TC

• Phase IIIb randomized study; pts switched (n = 275) or remained on original regimen (n = 278)

• Switch to DTG/ABC/3TC noninferior to maintaining baseline ART (Wk 24 HIV-1 RNA < 50 c/mL 85% vs 88%, respectively)

• For pts initially switched to DTG/ABC/3TC, 83% maintained suppression through Wk 48

GS-109[2] TDF-based regimen

EVG/COBI/TAF/FTC

• Pts randomized to switch regimen (n = 959) or remaining on previous regimen (n = 477)

• Switch to TAF regimen noninferior to maintaining TDF-based ART (97% vs 93% HIV-1 RNA < 50 c/mL; P = .0002)

• Prior EFV/TDF/FTC, HIV-1 RNA < 50 c/mL 96% with switch vs 90% with remaining on EFV/TDF/FTC

•


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DrugsThatShouldNotBeUsedWithAntiretroviralAgents

ARV Drugs That Should Not Be Used Concomitantly

DTG[1] Dofetilide, rifapentine, St John’s wort

EFV[1] St John’s wort, dasabuvir, ombitasvir, paritaprevir, simeprevir, elbasvir/grazoprevir

EVG/COBI[1] Ranolazine, eplerenone, ivabradine, lovastatin, simvastatin, rifampin, rifapentine, carbamazepine, phenobarbital, phenytoin, lurasidone, pimozide, midazolam, triazolam, St John’s wort, dasabuvir, elbasvir/grazoprevir,ledipasvir, ombitasvir, paritaprevir, simeprevir, alfuzosin, cisapride, ergot derivatives, flibanserin, salmeterol, sildenafil for PAH

RPV[1] Rifampin, rifapentine, carbamazepine, oxcarbazepine, phenobarbital, phenytoin, St John’s wort, dasabuvir, ombitasvir, paritaprevir, PPIs (eg, omeprazole)

TDF/FTC[2] Nephrotoxic drugs

1. DHHS guidelines. July 2016. 2. TAF/FTC [package insert]. 2016. 3. TDF/FTC [package insert]. 2016. Slide credit: clinicaloptions.com

•

Ifthept wishedtobecomepregnantviaspermdonation,whatregimenwouldyourecommend?

A. RAL+TAF/FTCB. EVG/COBI/TDF/FTCC. EVG/COBI/TAF/FTCD. RPV/TDF/FTCorRPV/TAF/FTCE. DRV+RTV+TDF/FTCF. Maintaincurrentregimen

DHHSRecommendations:ARTinPregnantWomenDHHS Guidelines[1] PIs NNRTIs NRTIs Entry Inhibitors Integrase Inhibitors

Recommended Atazanavir/RTV*Darunavir/RTV* Efavirenz*†

ABC/3TCTDF/FTC

TDF + 3TCZDV/3TC

Raltegravir*

Alternative Lopinavir/RTV* Rilpivirine*

Insufficient data to recommend Fosamprenavir RPV/TAF/

FTC[2]TAF/FTC[3]

MaravirocDolutegravir

EVG/COBI/TDF/ FTCEVG/COBI/TAF/FTC[2]

Not recommended

Indinavir/RTVNelfinavirRitonavir

Saquinavir/RTVTipranavir/RTV

EtravirineNevirapine

ABC/3TC/ZDVd4TddI

Enfuvirtide

1. DHHS Perinatal Guidelines. August 2015. 2. EVG/COBI/TAF/FTC [package insert]. 2015. 3. RPV/TAF/FTC [package insert]. 2016. 4. TAF/FTC [package insert]. 2016.

*In addition to 2-NRTI backbone. †May be initiated after first 8 wks of pregnancy.

Slide credit: clinicaloptions.com


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HIVCoinfection

• TAF/FTCORTDF/FTCrecommendedforpatientswithHIV/HBV• HCVinfection

• Allpatientsshouldbetreated• UseDirectactingagents• MonitorforDDI

AASLDGuidanceonHCV/HIVDDIsSMV SOF LDV VEL DCV PrOD Grazo/ElbXa

sAtazanavir/r C Ö » » » Ö XDarunavir/r C Ö » » Ö » XLopinavir/r C Ö » » Ö C XTipranavir/r C C C Nodata C C NodataEfavirenz C Ö Ö X » C XRilpivirine Ö Ö Ö Ö Ö C ÖEtravirine » Ö Nodata Nodata » Nodata NodataRaltegravir Ö Ö Ö Ö Ö Ö ÖElvitegravir/c C » » » » Nodata XDolutegravir Ö Ö Ö Ö Ö Ö ÖMaraviroc Ö Ö Ö Ö Ö » NodataTDF Ö Ö » » Ö Ö Ö

TAF Ö Ö Ö Ö Ö Ö Ö

AASLD/IDSA. HCV guidelines. July 2016.

Noclinicallysignificantinteractionexpected Potentialinteractionmayrequiredoseadjustment,timing,ormonitoring Donotcoadminister


WhyDoWeNeedNewOptionsforPts WithHIV• Short-termandlong-termsafety• Tolerability• Convenience• Cost• Activityagainstpanresistant virus• Stillnoavailablecure


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LongActingART

• CanwemoveawayfromdailyoraltherapyforHIV?• Areemerginglong-actingtherapiesaseffectiveasoraltherapies?• Whatabouttoxicity?• Isself-administrationfeasible?Isitdesirable?• Whatpts mightbeidealcandidatesforlong-actingtherapy?• Howcanresistancebepreventedifpts missdoses?• CantheseagentsbeusedasPrEP?

LATTE-2:CabotegravirIM+RilpivirineIMforLong-ActingMaintenanceART

• Multicenter,open-label,randomizedphaseIIbstudy• Cabotegravir:INSTIformulatedasoraltabletandforlong-actingIMinjection

Margolis DA, et al. IAC 2016. Abstract THAB0206LB. ClinicalTrials.gov. NCT02120352.

CAB 400 mg + RPV 600 mg IM Q4W†

(n = 115)

CAB 600 mg + RPV 900 mg IM Q8W‡

(n = 115)

*Pts with HIV-1 RNA < 50 copies/mL from Wks 16-20 continued to maintenance phase. †CAB loading dose at Day 1. ‡CAB loading doses at Day 1 and Wk 4.

ART-naive HIV-infected pts

> 18 yrs of age with CD4+ cell count > 200 cells/mm3

(N = 309) CAB 30 mg + ABC/3TC 600/300 mg PO QD(n = 56)

CAB 30 mg + ABC/3TC 600/300 mg PO QD

Wk 32

Wk 20

Induction Phase* Maintenance Phase

Day 1 Wk 96Wk 16: RPV 25 mg PO QD added

Wk 48


§ Injectionswere2-3mL,IM(glutealregion),provideradministered

•

VirologicSuccess*

LATTE-2: Efficacy and Safety Through Maintenance Wk 48§ Virologic efficacy of Q4W/Q8W IM

therapy similar to PO therapy[1]

– Phase III maintenance trials (ATLAS and FLAIR) moving forward with Q4W dose[2,3]

§ 99% of ISRs for pts receiving injectable therapy grade 1 (82%) or 2 (17%); none grade 4– Most frequent ISRs: pain (67%), nodules

(7%), swelling (6%)– 2/230 pts (< 1%) withdrew for ISRs

(both in Q8W arm)§ AEs leading to withdrawal

– Pooled Q4W/Q8W IM arms, 4%– PO arm, 2%

References in slidenotes.

9291 89

7< 1 2 < 18 9

VirologicNon-

response

No Virologic

Data

Pts

(%)

100

80

60

40

20

0

IM CAB + RPV Q4W (n = 115)IM CAB + RPV Q8W (n = 115)PO CAB + ABC/3TC (n = 56)

n/N =105/115

106/115

50/56

*HIV-1 RNA < 50 copies/mL. Slide credit: clinicaloptions.com

•


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LATTE-2: Wk 48 Pt Satisfaction With IM and PO Regimens§ Pt satisfaction assessed using 0-6 scoring (0 = very dissatisfied,

6 = very satisfied)

Margolis DA, et al. IAC 2016. Abstract THAB0206LB.

Wk 48 Pt-Reported Outcomes, % IM CAB + RPV Q4W (n = 103)

IM CAB + RPV Q8W (n = 109)

PO CAB + ABC/3TC (n = 49)

How satisfied are you with your current treatment?§ 6 (very satisfied) 79 83 67§ 5 20 14 29§ < 5 1 3 4

How satisfied would you be to continue with your present form of treatment?§ 6 (very satisfied) 85 88 55§ 5 13 11 33§ < 5 2 1 12


•

Additional Longer-Acting Investigational Agents (Phase II/III)Agent MoA Phase Implications

3BNC117[1,2] Anti-CD4 receptor mAb II § Studies ongoing in treatment-

experienced and naive pts

TMC278 LA[3] LA injectable RPV (IM) II § Potential as long-acting injectable

(Q8W)

UB-421[4] Anti-CD4 receptor mAb II § Studied as possible ART alternative for

maintenance therapy in suppressed pts

VRC01[5,6] Anti-CD4 receptor mAb II § Phase II PrEP and treatment trials

ongoing

1. Caskey M, et al. Nature. 2015;522:487-491. 2. ClinicalTrials.gov. NCT03041012. 3. Bekker L-G, et al. CROI 2017. Abstract 421LB. 4. Wang C-Y, et al. CROI 2017. Abstract 450LB. 5. ClinicalTrials.gov. NCT02716675. 6. ClinicalTrials.gov. NCT02568215. Slide credit: clinicaloptions.com

Role of Long Acting Agents

§ Maintenance therapy§ First line therapy for patients with adherence issues

§ Prevention§ Something else


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EmergingInvestigationalAgents

Bictegravir + FTC/TAF vs DTG + FTC/TAF for Treatment-Naive Pts§ Randomized, double-blind, active-controlled phase II trial

– Bictegravir: novel QD unboosted INSTI, active against most INSTI RAVs, low DDI potential

§ At baseline, 15% to 21% HIV-1 RNA > 100,000 copies/mL, 5% to 9% CD4+ cell count ≤ 200 cells/mm3

Sax PE, et al. CROI 2017. Abstract 41. Sax PE, et al. Lancet HIV. 2017;[Epub ahead of print].

Open-label extension

Wk 48

BIC + FTC/TAF QD +Placebo for DTG QD

(n = 65)

DTG + FTC/TAF QD +Placebo for BIC QD

(n = 33)

Wk 24Primary Endpoint

ART-naive pts with HIV-1 RNA

≥ 1000 copies/mL; CD4+ ≥ 200 cells/mm3;HBV and HCV negative

(N = 98)


•

Bictegravir + FTC/TAF vs DTG + FTC/TAF: Key Results

§ No drug resistance among pts with virologic failure in either arm through Wk 48

Sax PE, et al. CROI 2017. Abstract 41. Sax PE, et al. Lancet HIV. 2017;[Epub ahead of print].

AE at Wk 48, % (n/N) BIC + FTC/TAF

DTG + FTC/TAF

TR-SAE 0 0

Diarrhea, any grade* 12 (8/65) 12 (4/33)

Nausea, any grade* 8 (5/65) 12 (4/33)

Creatine kinase, grade 2-4* 13 (8/64) 9 (3/32)

Hyperglycemia, grade 2-4* 8 (5/64) 13 (4/32)

*HIV-1 RNA < 50 copies/mL.


Virologic Failure

Wk 48 Efficacy

Virologic Success*

No Data

100

80

60

40

20

0

9791

2 6 2 3

Treatment difference: 6.4% (95% CI: -6.0% to 18.8%)

DTG + FTC/TAF (n = 33)

Pts

(%)

BIC + FTC/TAF (n = 65)

*Showing AEs occuring in > 10% in either treatment arm.

§ 1 pt discontinued at Wk 24 in BIC arm for urticaria (past history of urticaria)

•


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Patient Isolates with INSTI Resistance Mutations: Resistance Profile of BIC and Other INSTIs

Phenotypic Analysis of Clinical Isolates

1. White K, et al., European Workshop HIV & Hep 2016. Rome, Italy. Poster O-01. 2. Tsiang M, et al., AAC 2016;60:7086-7097.

92% 89%

04%2% 4%6% 2%

0102030405060708090

100

EVG RAL

% o

f Iso

late

s by

FC

Cat

egor

ies

17%

17%

17%

49%

DTG 2%13%

15%

70%

BIC

BIC has a statistically improved resistance profile compared to RAL, EVG, and DTGMean fold changes: BIC 2.8 (ref) ; DTG 5.8, p=0.042; RAL >100, p<0.001; EVG >106, p<0.001

Each of 47 patient-derived clinical isolates (from Monogram Biosciences) had ≥ 1 primary and/or other INSTI mutations with phenotypic resistance to INSTIs and comprised all available INSTI resistant variants in the Monogram library). EC50, effective concentration of half maximal response.

24 isolates with

>2.5-fold reduced

susceptibility to DTG

Stratification of 47 HIV-1 Clinical Isolates Based on Fold Change in Resistance

< 2.5 ≥ 102.5 to < 5 5 to < 10

EC50 Fold Change (FC) vs Reference Wild Type

Bictegravir: Additional Ongoing Randomized Phase III Trials§ All assessing coformulated bictegravir/FTC/TAF

1. ClinicalTrials.gov. NCT02607956. 2. ClinicalTrials.gov. NCT02607930. 3. ClinicalTrials.gov. NCT02603120. 4. ClinicalTrials.gov. NCT02603107. 5. ClinicalTrials.gov. NCT02652624.

Treatment Setting Regimen

NaiveBictegravir/FTC/TAF vs DTG + FTC/TAF[1]

Bictegravir/FTC/TAF vs DTG/ABC/3TC[2]

Switch

Bictegravir/FTC/TAF from DTG/ABC/3TC[3]

Bictegravir/FTC/TAF from boosted ATV or DRV + FTC/TDF or ABC/3TC[4]

Bictegravir/FTC/TAF from EVG/COBI/FTC/TAF, EVG/COBI/FTC/TDF, or ATV + RTV + FTC/TDF (all women)[5]


DRIVE-FORWARD: Doravirine or DRV + RTV Plus 2 NRTIs for Treatment-Naive Pts§ Randomized, multicenter, double-blind phase III trial

– Doravirine: NNRTI with unique resistance profile, low DDI potential

Molina JM, et al. CROI 2017. Abstract 45LB.

14-day follow-up

DOR 100 mg QD + FTC/TDF or ABC/3TC QD +

Placebo for DRV + RTV(n = 385)

DRV 800 mg + RTV 100 mg QD + FTC/TDF or ABC/3TC QD +

Placebo for DOR(n = 384)

ART-naive pts with HIV-1 RNA

≥ 1000 copies/mLwithin 45 days of Day 1;

no resistance to study drugs(N = 769)

Wk 48Primary Endpoint Wk 96



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TMB-301: Key Results

§ 9 pts reported 17 serious AEs– 1 drug-related serious AE (IRIS)

resulted in discontinuation§ 8 other pts discontinued

– Death (n = 4; liver failure, Kaposi sarcoma; end-stage AIDS, lymphoma)

– Consent withdrawal (n = 3)– Lost to follow-up (n = 2)

§ Additional phase III study ongoing[3]

1. Lalezari J, et al. IDWeek 2016. Abstract LB-6. 2. Lewis S, et al. CROI 2017. Abstract 449LB.3. ClinicalTrials.gov. NCT02707861.

Virologic Outcome Ibalizumab(N = 40)

Day 14[1]

§ ≥ 0.5 log10 HIV-1 RNA decrease, % 83*§ ≥ 1.0 log10 HIV-1 RNA decrease, % 60§ Mean log10 HIV-1 RNA decrease 1.1

Wk 24[2]

§ ≥ 1.0 log10 HIV-1 RNA decrease, % 55§ ≥ 2.0 log10 HIV-1 RNA decrease, % 48§ HIV-1 RNA < 50 copies/mL, % 43§ HIV-1 RNA < 200 copies/mL, % 50§ Mean HIV-1 RNA decrease from

baseline, log10

1.6

*P < .0001 vs 3% at end of control period.


Fostemsavir vs ATV/RTV Both With RAL + TDF for Treatment-Experienced Pts§ Fostemsavir: attachment inhibitor; binds to HIV-1 gp120

§ AI438-011: randomized, active-controlled, partially blinded, dose-ranging phase IIb study of fostemsavir vs ATV/RTV, each with RAL + TDF, for treatment-experienced pts with HIV-1 RNA ≥ 1000 copies/mL and susceptibility to study agents (N = 254)[1,2]

§ Key results:

– 90% of pts had HIV-1 RNA < 50 copies/mL at Wk 96 in fostemsavir and ATV/RTV arms in observed analysis

– Compared with pts in fostemsavir arm, pts in ATV/RTV arm had higher rates of treatment-related grade 2-4 AEs (37% vs 9%) and d/c for AEs (10% vs 3%) at Wk 96

§ Phase III trial in heavily treatment–experienced pts ongoing[3]

1. Granados-Reyes ER, et al. HIV Glasgow 2016. Abstract O335A.2. Llamoso C, et al. HIV Glasgow 2016. Abstract O335B.3. ClinicalTrials.gov. NCT02362503.


Wk 49

Placebo

Pts with HIV-1 RNA ≥ 400 copies/mL on current regimen; ≤ 2 classes of active

approved ARVs left to compose OBR due to resistance, intolerance, or contraindications Fostemsavir + OBR

Day 8*

Fostemsavir Fostemsavir + OBR

FostemsavirAs above but with no active approved ARV options remaining

Additional Emerging Investigational Agents and Formulations (Phase II/III)Agent MoA Phase Implications

RAL QD[1] INSTI III § Potential for RAL QD dosing (2 600-mg tablets)

PRO140[2-4] Humanized IgG4 CCR5 mAb IIb/III § Possible switch/failure strategy for pts with

R5-tropic HIV

Cenicriviroc[5] CCR2/5 antagonist IIb § Assessed in treatment-naive pts with R5-tropic HIV

Elsulfavirine[6] Prodrug of new NNRTI VM1500A IIb § Potentially less toxic alternative to EFV for

initial ARTVaccines II/III § Numerous strategies in clinical development

1. Cahn P, et al. IAC 2016. Abstract FRAB0103LB.2. Lalezari J, et al. CROI 2017. Abstract 437. 3. ClinicalTrials.gov. NCT02859961. 4. ClinicalTrials.gov. NCT02483078. 5. Thompson M, et al. AIDS. 2016;30:869-878. 6. Murphy R, et al. CROI 2017. Abstract 452LB. Slide credit: clinicaloptions.com


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Summary

§ Newer regimens– STR

– Safety and tolerability

– DDI

§ Injectable agents will be here soon§ New ARV will be available for MDR virus


Notes


Notes

Documents

5/25/17 HIV Clinical Update: Treatment in 2017 and Beyond