should integrase inhibitors be your first choice when starting hiv therapy- expert faculty debate...

Joseph J. Eron, Jr., MDUniversity of North CarolinaChapel Hill, North Carolina

Daniel R. Kuritzkes, MDBrigham and Women’s HospitalHarvard Medical SchoolBoston, Massachusetts

Should Integrase Inhibitors Be Your First Choice When Starting HIV Therapy? Expert Faculty Debate the Evidence

This activity is supported by an educational grant from ViiV

clinicaloptions.com/hivShould Integrase Inhibitors Be Your First Choice When Starting HIV Therapy?

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Program Director

Joseph J. Eron, Jr., MD Professor of Medicine and EpidemiologyUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

Faculty

Daniel R. Kuritzkes, MDChief, Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts


Additional Faculty Contributing to Content

Eric S. Daar, MDChief, Division of HIV MedicineHarbor-UCLA Medical CenterProfessor of MedicineDavid Geffen School of Medicine at UCLALos Angeles, California

Sally Hodder, MDDirector, Clinical Translation Science InstituteProfessor of MedicineWest Virginia UniversityMorgantown, West Virginia

Kathleen E. Squires, MDW. Paul and Ida H. Havens Professor of Infectious DiseasesDirector, Division of Infectious DiseasesSidney Kimmel Medical College of Thomas Jefferson UniversityPhiladelphia, Pennsylvania

Introduction to the Use of Integrase Inhibitor–Based

Regimens in First-line Therapy


The Current Landscape: DHHS 2014 Recommended First-line ART Regimens

IAS-USA guidelines panel recommend similar approach

Guidelines published before approval of DTG/ABC/3TC single-tablet regimen

DHHS Guidelines. May 2014. Günthard HF, et al. JAMA. 2014;312:410-425.

ClassAll Pts, Regardless of BL VL or CD4+ Count

Pts With Pre-ART VL < 100,000 c/mL

NNRTI EFV/TDF/FTC EFV + ABC/3TC*

RPV/TDF/FTC

Boosted PI ATV/RTV + TDF/FTC DRV/RTV + TDF/FTC

ATV/RTV + ABC/3TC*

INSTI

RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC

*Only for pts who are HLA-B*5701 negative. Only for those with CD4+ cell counts > 200 cells/mm3.

Daniel R. Kuritzkes, MDChief, Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts

Current Evidence on Integrase Inhibitors in First-line Therapy

Raltegravir


STARTMRK: Final 5-Yr Data

Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;63:77-85.

281282

100

80

60

40

20

0 HIV

-1 R

NA

< 5

0 c

/mL

(%

)

0 48 72 96 120 144

Wks

RALEFV

Pts at Risk, n281282

278282

280281

281282

277281

280281

86

82

81

79

75

69

281282

192

76

67

24012 216

71

61

277282

279279

24

279282

168

281282

RAL + TDF/FTC

EFV/TDF/FTC

250243

400

300

200

100

500 C

ha

ng

e F

rom

Ba

se

lin

e

CD

4+

Ce

ll C

ou

nt

(ce

lls

/mm

3)

0 48 72 96 120 144

Wks

RALEFV

Pts at Risk, n281281

272268

258251

255252

240234

235228

189

163

240

225

331

295

235220

192

361

301

24012 216

374

312

227218

222212

24

266266

168

231224

RAL + TDF/FTC

EFV/TDF/FTC

350

250

150


ACTG 5257: ATV/RTV vs RAL vs DRV/RTV in Treatment-Naive Pts Randomized, open-label phase III trial

Primary endpoints

– VF: confirmed HIV-1 RNA > 1000 c/mL (at or after Wk 16 and before Wk 24) or > 200 c/mL (at or after Wk 24)

– TF: time to discontinuation of randomized component for toxicity

Secondary composite endpoint: the earlier occurrence of either VF or TF

Lennox JL, et al. Ann Intern Med. 2014;161:461-471.

ART-naive pts with HIV-1 RNA

≥ 1000 c/mL (N = 1809)

ATV/RTV 300/100 mg QD + TDF/FTC(n = 605)

RAL 400 mg BID + TDF/FTC(n = 603)

Stratified by HIV-1 RNA < or ≥ 100,000 c/mL, participation in

metabolic substudy, CV risk

DRV/RTV 800/100 mg QD + TDF/FTC(n = 601)

Wk 96 after last pt enrolled

Regimen switch allowed for tolerability.


ACTG 5257: Cumulative Incidence of Virologic Failure at Wk 96


Difference in 96-Wk Cumulative Incidence (97.5% CI)

-20 0-10 10 20

ATV/RTV vs RAL3.4% (-0.7% to 7.4%)

DRV/RTV vs RAL5.6% (1.3% to 9.9%)

ATV/RTV vs DRV/RTV-2.2% (-6.7% to 2.3%)

1.00

0.75

0.50

0.25

0

Cu

mu

lati

ve I

nci

den

ce

0

Wks Since Study Entry

24 48 64 80 96 112 128 144

ATV/RTVRALDRV/RTV


Favors RAL

Favors DRV/RTV


ACTG 5257: Cumulative Incidence of Tolerability Failure at Wk 96


-20 0-10 10 20

ATV/RTV vs RAL12.7% (9.4% to 16.1%)

DRV/RTV vs RAL3.6% (1.4% to 5.8%)

ATV/RTV vs DRV/RTV9.2% (5.5% to 12.9%)

1.00

0.75

0.50

0.25

0

Cu

mu

lati

ve I

nci

den

ce

0


24 48 64 80 96 112 128 144

ATV/RTVRALDRV/RTV



Favors RAL

Favors RAL

Favors DRV/RTV


ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure at Wk 96

-20 0-10 10 20

ATV/RTV vs RAL15% (10.2% to 19.6%)

DRV/RTV vs RAL7.5% (3.2% to 11.8%)

ATV/RTV vs DRV/RTV7.5% (2.3% to 12.7%)

1.00

0.75

0.50

0.25

0

Cu

mu

lati

ve I

nci

den

ce

0


24 48 64 80 96 112 128 144

ATV/RTVRALDRV/RTV


ACTG 5257: Tolerability Failure at Wk 96


Toxicity-Associated d/c of Randomized ART*

ATV/RTV(n = 605)

RAL(n = 603)

DRV/RTV(n = 601)

Any, n (%) 95 (15.7) 8 (1.3) 32 (5.3)

Gastrointestinal, n 25 2 14

Hyperbilirubinemia, n 47 0 0

Other hepatic, n 4 1 5

Skin, n 7 2 5

Metabolic, n 6 0 2

Renal, n 4 0 0

Abnormal chemistry/hematology findings (excluding LFTs), n

0 0 2

Other, n 2 3 4

*Participants allowed to switch therapy for intolerable toxicity.

Elvitegravir


Elvitegravir/Cobicistat vs EFV or ATV/RTV + TDF/FTC in Treatment-Naive Pts Randomized, double-blind, active-controlled phase III studies

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

1. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. 2. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.

Treatment naive;HIV-1 RNA ≥ 5000 copies/mL;

any CD4+ cell count;susceptible to TDF, FTC, and EFV, or

ATV;eGFR ≥ 70 mL/min

Study 102[1]

(N = 700)

Study 103[2]

(N = 708)

EVG/COBI/TDF/FTC QD(n = 348)

EFV/TDF/FTC QD(n = 352)

EVG/COBI/TDF/FTC QD(n = 353)

ATV/RTV + TDF/FTC QD(n = 355)


EVG/COBI Noninferior to EFV and to ATV/RTV, With TDF/FTC, Through Wk 144

Wk 48 Wk 144

EVG/COBI/TDF/FTC (n = 348)

EFV/TDF/FTC (n = 352)

8075

0

20

40

60

80

10088 84

Δ: 3.6% (-1.6 to 8.8)

Δ: 4.9% (-1.3 to 11.1)

8482

Wk 96

Δ: 2.7% (-2.9 to 8.3)

EVG/COBI/TDF/FTC (n = 353)

ATV/RTV + TDF/FTC (n = 355)

Δ: 3.0% (-1.9 to 7.8) Δ: 1.1%

(-4.5 to 6.7)

Wk 48 Wk 144

78 75

0

20

40

60

80

10090 87

Δ: 3.1% (-3.2 to 9.4)

8382

Wk 96

Study 102[1] Study 103[2]

1. Wohl DA, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. 2. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124.


Studies 102 and 103: Common Adverse Events Study 102[1]

– More CNS effects, rash observed with EFV vs EVG/COBI

– More nausea with EVG/COBI vs EFV

Study 103[2]

– More ocular icterus observed with ATV/RTV vs EVG/COBI

– Common adverse events of EVG/COBI included nausea and diarrhea; frequency similar to that observed with ATV/RTV

1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.


Studies 102 and 103: Change in Serum Creatinine Through Wk 48

1. Sax P, et al. Lancet. 2012;379:2439-2448. 2. DeJesus E, et al. Lancet. 2012;379:2429-2438.

Study 102[1] Study 103[2]

Ch

ang

e F

rom

Bas

elin

e in

S

eru

m C

reat

inin

e (µ

mo

l/L

)

20

15

10

5

0

-5

-100 2 4 8 12 16 24 32 40 48

EVG/COBI/TDF/FTCEFV/TDF/FTC

Ser

um

Cre

atin

ine

Co

nce

ntr

ati

on

Ch

an

ge

(µm

ol/

L) 20

15

10

5

0

-5

-100 2 4 8 12 16 24 32 40 48

EVG/COBI/TDF/FTCATV/RTV + TDF/FTC

Wks Wks

Dolutegravir


SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Treatment-Naive Pts Randomized, double-blind, noninferiority phase III study

Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

ART-naive pts,HIV-1 RNA

≥ 1000 copies/mL,HLA-B*5701 negative,

CrCl > 50 mL/min(N = 833)

DTG 50 mg QD + ABC/3TC QD(n = 414)

EFV/TDF/FTC QD (n = 419)

Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.


Wk

71%

63%

80%

72%81%

88%

TreatmentCD4 Wk 144 ∆ From BL

Adjusted Mean SEDifference in Response

(95% CI)

DTG + ABC/3TC (n = 414) 378.5 11.0 46.9 (15.6-78.1)P = .003EFV/TDF/FTC (n = 419) 331.6 11.6

BL 4 8 1216 24 32 40 14448 60 72 84 96 108 120 132

Adjusted treatment difference between groups at Wk 144: 8.3% (95% CI: 2.0-14.6; P = .01)

CD4 ∆ CD4 ∆ From BLFrom BL

Pappa K, et al. ICAAC 2014. Abstract H-647a.

SINGLE: DTG + ABC/3TC vs EFV/TDF/FTC in Treatment-Naive Pts at Wk 144

Pat

ients

With H

IV-1

RN

A <

50 c

/mL,

% DTG + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419)

100

90

80

70

60

50

40

30

20

10

0


AE in > 5% of Pts in Either Arm, %

DTG + ABC/3TC QD(n = 414)

Wk 96 Wk 144

EFV/TDF/FTC QD(n = 419)

Wk 96 Wk144

Any 44 +1 67 +1.2

Dizziness 7 +0 33 +0.2

Abnormal dreams 7 +0 16 +0.2

Nausea 11 +0.2 12 +0

Insomnia 10 +0 6 +0.7

Diarrhea 6 +0 8 +0

Fatigue 7 +0 7 +0

Headache 6 +0 7 +0

Rash < 1 +0 8 +0

Pappa K, et al. ICAAC 2014. Abstract H-647a.

SINGLE: Common Adverse Events at Wk 144

Overall low rate of elevated liver chemistries in both treatment groups AEs leading to d/c occurred in 4% (DTG) vs 14% (EFV)


SPRING-2: DTG + NRTIs vs RAL + NRTIs in Treatment-Naive Pts Randomized, double-blind, noninferiority phase III study Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48


≥ 1000 copies/mL(N = 822)

DTG 50 mg QD + 2 NRTIs*(n = 411)

RAL 400 mg BID + 2 NRTIs*(n = 411)

*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.

Raffi F, et al. Lancet. 2013;381:735-743.


SPRING-2: DTG vs RAL + 2 NRTIs in Treatment-Naive Pts at Wk 96

Raffi F, et al. Lancet Infect Dis. 2013;13:927-935.

DTG + 2 NRTIs (n = 411)

RAL + 2 NRTIs (n = 411)

81%

76%

100

80

60

40

20

0

Baseline Wk

4 8 16 24 32 48 60 72 968440120

88%

85%


SPRING-2: Change in Creatinine

Raffi F, et al. Lancet Infect Dis. 2013;13:927-935.

40

30

20

10

0

-20

-10

Wk

4 8 16 24 32 48 60 72 968440120

DTG + 2 NRTIs (n = 411)

RAL + 2 NRTIs (n = 411)

Dolutegravir n = Raltegravir n =

401403

397400

393391

389388

390387

384375

371354

374354

364355

358348

351338

342327


FLAMINGO: DTG + NRTIs vs DRV/RTV+ NRTIs in Treatment-Naive Pts Randomized, open-label, noninferiority phase III study Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

*Investigator-selected NRTI backbone: either TDF/FTC or ABC/3TC.

DTG 50 mg QD + 2 NRTIs*(n = 242)

DRV/RTV 800/100 mg QD + 2 NRTIs*(n = 242)


≥ 1000 c/mL,no PI or NRTI

resistance(N = 484)

Clotet B, et al. Lancet. 2014;383:2222-2231.


FLAMINGO: DTG vs DRV/RTV + 2 NRTIs in Treatment-Naive Pts at Wk 48


DTG + 2 NRTIs (n = 242)

DRV/RTV + 2 NRTIs

(n = 242)90%

83%

100

80

60

40

20

0

Baseline Wk

Adjusted difference at Wk 48:7.1% (95% CI: 0.9-13.2; P = .025)

4 8 12 16 24 36 480


FLAMINGO: Common Adverse EventsAE, % DTG + 2 NRTIs

(n = 242)DRV/RTV + 2 NRTIs

(n = 242)

D/c due to AE or death 1 4

Any event, ≥ 5% in either arm 85 85

Diarrhea 17 29

Nausea 16 18

Headache 15 10

Nasopharyngitis 9 8

Upper respiratory tract infection 5 10

Insomnia 7 6

Cough 5 7

Vomiting 6 6

Fatigue 6 5

Pyrexia 5 6

Dizziness 6 5

Rash 4 6

Back pain/arthralgia 4/2 5/5

Pharyngitis/bronchitis/sinusitis 3/2/2 5/5/5

Depression 5 2


Use in Clinical Practice


Integrase Inhibitor Options for First-line Antiretroviral TherapyDrug Dosing STR Boosting

RequiredAny Resistance

in Pts With Failure

Cross- Resistance

Raltegravir Twice daily No No Yes Yes

Elvitegravir Once daily Yes Yes Yes Yes

Dolutegravir Once daily Yes No None so far Partial


Major Primary INSTI Resistance Mutations

HSA

G

HRK

NQ

G

S

Q

E

IAK

T

Adapted from the Stanford HIV Drug Resistance Database.

H

N

RCH

Y

KA

E

HRK

Q

Q

E

SA

HRK

Q

Q

E

G

E

KA

T

A

E

KA

G

SA

R

K

Mutations in ORANGE associated with highest levels of reduced susceptibility or response.

Mutations in YELLOW reduce INSTI susceptibility or response.

15597 14814792 155140 1481479266 138Elvitegravir

155143140 14892 13866 Raltegravir

263140 14813892 Dolutegravir


Selected Drug–Drug Interactions of INSTIs

Agent Potential Drug-Drug Interactions

Raltegravir[1] Metabolized by UGT1A ATV increases RAL concentrations; dose adjustment not recommended Avoid aluminum- and/or magnesium-containing antacids Rifampin decreases RAL levels; double RAL dose if coadministered with

rifampin

Elvitegravir/cobicistat[2]

Metabolized by CYP3A, CYP2D6 COBI increases levels of drugs metabolized by CYP3A Separate dosing with aluminum- and/or magnesium-containing antacids Not recommended for use with rifamycins

Dolutegravir[3] Metabolized by UGT1A, with contribution from CYP3A Avoid use with ETR unless coadministered with boosted PI; avoid dosing

with NVP Separate dosing with aluminum- and/or magnesium-containing antacids DTG may increase metformin concentrations; metformin dose adjustment

may be needed; monitor clinically when starting or stopping DTG

1. Raltegravir [package insert]. 2. EVG/COBI/TDF/FTC [package insert]. 3. Dolutegravir [package insert].


Current DHHS and IAS-USA Guidelines: Recommended INSTIs for First-line ART RAL + TDF/FTC

EVG/COBI/TDF/FTC

– Only for pts with pretreatment CrCl ≥ 70 mL/min[1,2]

DTG + TDF/FTC

DTG + ABC/3TC*

– Only for pts who are HLA-B*5701 negative[1,2]

1. DHHS Guidelines. May 2014. 2. Günthard H, et al. JAMA. 2014;312:410-425.

*Guidelines predate availability of single-tablet regimen.

Ongoing Development


Recent and Anticipated Developments in the INSTI Field DTG/ABC/3TC single-tablet regimen

EVG/COBI/TAF/FTC single-tablet regimen

DTG/RPV single-tablet regimen

RAL/3TC once-daily coformulation

Cabotegravir (S/GSK1265744)


Summary

INSTI-based regimens have demonstrated at least noninferior efficacy vs regimens containing boosted PIs or NNRTIs in treatment-naive pts

– INSTIs generally well tolerated

– Some INSTIs have low resistance barrier (RAL, EVG)

– No emergent resistance to date with first-line DTG failure

INSTI-based regimens are among preferred options for first-line ART

Once-daily INSTI-based STRs are available (EVG, DTG)

– More anticipated in future

Joseph J. Eron, Jr., MD Professor of Medicine and EpidemiologyUniversity of North Carolina School of MedicineDirector, AIDS Clinical Trials UnitUniversity of North CarolinaChapel Hill, North Carolina

Panel Discussion: Are Integrase Inhibitors the New Gold Standard for First-line Antiretroviral Therapy?

Panel Discussion


Key Questions for Debate

When selecting a first-line regimen, should INSTI-based options be the “default” choice?

For which pts, if any, might there not be an appropriate first-line INSTI-based regimen?

In the absence of head-to-head first-line trials, what considerations related to efficacy and safety should influence the choice between available INSTI-based regimens?

How do considerations such as availability of coformulations, dosing frequency, drug–drug interactions, and so on, affect the decision-making process for individual pts?

Case 1: A 24-Yr-Old Male Recently Diagnosed HIV Positive


Case 1: 24-Yr-Old Male Recently Diagnosed HIV Positive 24-yr-old black MSM recently diagnosed HIV positive

HIV-1 RNA: 187,000 c/mL; CD4+ count: 448 cells/mm3

HIV genotype: WT, HBV immune, HCV Ab negative; CrCl: 120 mL/min; AST/ALT normal; HLA-B*5701 negative

No significant past medical history, no medications, occasional alcohol and marijuana use, sexually active with 1 steady HIV-negative partner

Has attended several clinic visits and is interested in starting HIV therapy; prefers to take as few pills as possible but wants what you think is best


Summary of Panel Discussion

Many options are available for initial therapy

Most pts opt for a single-tablet regimen over a multitablet regimen, given the choice

– Simpler dosing, fewer copays

A variety of single-tablet regimens would be appropriate choices for the case pt

– He is young and healthy and has no comedications or comorbidities



Efavirenz/TDF/FTC: extensive clinical experience with this agent, but CNS adverse events may persist

Rilpivirine/TDF/FTC: not recommended for this pt due to HIV-1 RNA > 100,000 copies/mL

Dolutegravir/ABC/3TC: data are supportive of this option, including in pts with high HIV-1 RNA

Elvitegravir/COBI/TDF/FTC: also a popular choice as it is well tolerated and trials have demonstrated noninferior efficacy vs PI-based or NNRTI-based therapy


Panel Discussion

What if the pt were a woman with HIV-1 RNA 87,000 c/mL who is considering pregnancy in the near future

– Would this change your approach?

24-yr-old black woman recently diagnosed HIV positive HIV-1 RNA: 87,000 c/mL; CD4+ count: 448 cells/mm3

HIV GT: WT, HBV immune, HCV Ab-; CrCl: 120 mL/min; AST/ALT normal; HLA-B*5701- No comedications, occasional alcohol/marijuana use, steady HIV-negative partner Starting HIV therapy, prefers few pills as possible



Important to discuss risk and assess the pt’s knowledge and plans

Most data on ART in pregnancy concerns boosted PIs, particularly ATV/RTV, LPV/RTV

– Most NRTI data with ZDV/3TC, increasingly with TDF/FTC

Panel believed most women choose not to take an STR when presented with these data

Panel would not choose an EFV-based regimen for a woman planning pregnancy; however, therapy should not be switched if a woman receiving EFV-based therapy becomes pregnant

Other STRs could be considered for this pt, although data on their use in pregnancy are lacking

Data from women receiving ART in pregnancy should be added to the Antiretroviral Pregnancy Registry (www.apregistry.com)

Case 2: A 28-Yr-Old Male With Advanced HIV Infection


Case 2: 28-Yr-Old Male With Advanced HIV Infection 28-yr-old HIV-infected MSM, previously refused ART, now

referred to you for specialist care


HIV GT: WT RT/pro; HBV Ag+; HBV DNA: 34 million IU/mL, HCV neg; ALT: 78 IU/L; Cr: 0.8 mg/dL (70.7 µmol/L); CBC: normal

Physical exam reveals woody edema of right leg with some discoloration at the ankle, no palpable adenopathy; subsequent biopsy shows KS

Binges on alcohol; denies other drug use or sexual activity

He will try ART if you recommend it



Nonadherence is a concern in this pt

Some panelists would choose a boosted PI due to low risk of resistance at failure

DTG + TDF/FTC may be another option, as it is well tolerated and convenient, and available data suggest risk of resistance at failure is also very low

RAL-based therapy may be a good choice for coadministration with chemotherapy due to lack of drug–drug interactions

RPV-based therapy is not recommended for this pt due to CD4+ cell count < 200 cells/mm3

Use of Integrase Inhibitorsin Primary NNRTI Resistance


Case 3: 68-Yr-Old Female With Primary NNRTI Resistance 68-yr-old black woman recently diagnosed HIV positive

Ready to begin ART following several clinic visits


Believes she acquired HIV from her husband who died 8 or 9 yrs ago

HTN well controlled on diuretic; UA: 1+ protein; CrCl: 50 mL/min; US shows slightly enlarged kidneys with no obstruction; nonsmoker, no alcohol use

Anti-HBs positive; HCV Ab negative; ALT: 37 IU/L, HLA-B*5701 negative

HIV RT/pro genotype detects K103N, no other mutations



The pt likely acquired HIV from her husband at least 8 or 9 yrs ago; therefore, integrase resistance is unlikely

Most panelists do not routinely order integrase genotypes

– May be more likely to do so in recently infected pts, particularly those with transmitted resistance

A combined genotype test is available that assesses RT, protease, and integrase genes



Renal biopsy may be considered to assess whether the pt’s renal dysfunction is related to HIV infection

ABC/3TC or daily TDF/FTC may be reasonable options with careful monitoring

– ABC/3TC may be less active if M184V is present as a minority species that was not detected on genotyping

Panelists would not choose ZDV/3TC or a regimen that did not include 2 NRTIs



Rilpivirine is not recommended due to HIV-1 RNA > 100,000 copies/mL

Atazanavir/ritonavir is associated with renal dysfunction and may not be the best choice for this pt

Darunavir/ritonavir could be used, but simpler regimens are available

Elvitegravir/cobicistat is not recommended for pts with creatinine clearance < 70 mL/min

Dolutegravir or raltegravir are both options for this pt


Efficacy of EVG/COBI/TDF/FTC in Pts With Primary NNRTI Resistance

White KL, et al. Resistance Workshop 2012. Abstract 4.

Baseline Primary NNRTI Mutation

Pts, n (%) Pts With HIV-1 RNA < 50 c/mL at Wk 48

Resistance Analysis

Any primary NNRTI mutation

96 (13.7) 83 (86.5) 5 analyzed; no resistance

K103N 27 (3.7) 24 (89) 2 analyzed; no resistance

V90I 14 (2.0) 11 (79) None analyzed

A98G 3 (0.6) 3 (100) NR

V106A/I/M 17 (2.4) 17 (100) NR

V108I 3 (0.4) 2 (67) 1 analyzed; no resistance

E138A 12 (1.7) 11 (92) None analyzed

V179D/F/T 19 (2.7) 15 (79) 1 analyzed; no resistance

Y181C/I/V 4 (0.6) 3 (75) None analyzed

Y188C/H/L 2 (0.3) 2 (100) NR

G190A/S 2 (0.3) 1 (50) 1 analyzed; no resistance

P225H 2 (0.3) 2 (100) NR



Dolutegravir/ABC/3TC is available as a fixed-dose combination and was a popular choice for this pt

– However, data on the activity of dolutegravir-based therapy in pts with primary NNRTI resistance are lacking

Data on the use of darunavir/ritonavir with ABC/3TC are limited

Rilpivirine and atazanavir/ritonavir remain unsuitable

Raltegravir has been studied with ABC/3TC and may be considered in this pt


Similar Efficacy of INSTIs (RAL or DTG) + ABC/3TC or TDF/FTC, Even for High BL VL In SPRING-2, similar efficacy with ABC/3TC or TDF/FTC + RAL or

DTG, including with high BL HIV-1 RNA*

Eron J, et al. Glasgow 2012. Abstract P204.

< 100k 100K - < 250K 250K - 500K > 500K0

20

40

60

80

100

HIV

-1 R

NA

< 5

0 c/

mL

at

Wk

48

by

FD

A S

nap

sho

t A

nal

ysis

(%

)

86

n/N =

88

225/257

91

306/335

36/42

82

72/88

81

13/16

76

29/38

72

13/18

64

18/28

Baseline HIV-1 RNA (c/mL)

TDF/FTCTDF/FTC

ABC/3TCABC/3TC

*Pooled data from both INSTIs.


Panel Discussion

What if the pt had CVD and renal disease?

– Modification: DM on metformin, PTCA with stent for an RCA lesion 2 yrs ago, no chest pain on β-blocker and atorvastatin, CrCl: 30 mL/min with 3+ microalbuminuria

Would you use a regimen sparing 2 NRTIs? If so, which one?

68-yr-old female recently diagnosed HIV positive HIV-1 RNA: 215,600 c/mL; CD4+ count: 350 cells/mm3

HTN controlled on therapy, DM on metformin, PTCA with stent, β-blocker and atorvastatin, CrCl: 30 mL/min

Anti-HBs+; HCV Ab-; ALT: 37 IU/L; HLA-B*5701- HIV RT/pro genotype: K103N, no integrase resistance



Some panelists would still consider a regimen containing 2 NRTIs for this pt, though perhaps utilizing tenofovir/FTC dosed every other day

NRTI-sparing or NRTI-limiting regimens could be another option


D:A:D: Current ABC Use Associated With 98% Increase in Acute MI Risk Current ABC use remained

associated with increased acute MI risk in updated post-2008 analysis

– Similar RR in post-2008 group vs pre-2008 group, despite decrease in ABC use in pts with high CVD risk

– Absolute risk in post-2008 group small: 6 cases/2000 PY vs 3 cases/ 2000 PY or absolute risk 0.15%

Overall cohort: 941 MI events during 367,599 PYs

– 0.47/100 PYs (95% CI: 0.42-0.52) with current ABC

– 0.20/100 PYs (95% CI: 0.19-0.22) with no current ABC

No Current ABC

Events/PYs 600/295,642 425/169,417 175/126,225

Rate/100 PYs0.20

(0.19-0.22)0.25

(0.23-0.28)0.14

(0.12-0.16)

Current ABC

Events/PYs 341/71917 247/40833 94/31084

Rate/100 PYs0.47

(0.42-0.52)0.61

(0.53-0.68)0.30

(0.24-0.36)Sabin C, et al. CROI 2014. Abstract 747LB. Reproduced with permission.

543

2

10.7

Overall Pre-3/08 Post-3/08

Adjusted Relative Rate of MI in Pts Currently Receiving ABC

1.98

(1.72-2.29)

1.97

(1.68-2.33)

1.97

(1.43-2.72)


FDA Meta-analysis of Risk of Myocardial Infarction in ABC Trials FDA trial-level meta-analysis of 26 completed RCTs of

ABC in adults, with N > 50 subjects

Studies

MI Events/SubjectsRisk Difference, %

(95% CI)Odds Ratio

(95% CI)ABC Non-ABC

Manufacturer trials 6/2341 9/2367 -0.11 (-0.43 to 0.21) 0.70 (0.25-2.00)

ACTG trials 12/1985 9/1610 0.03 (-0.45 to 0.51) 1.06 (0.43-2.61)

Other* 6/702 4/863 0.31 (-0.53 to 1.16) 1.60 (0.46-5.62)

Overall 24/5028 22/4840 0.008 (-0.26 to 0.27) 1.02 (0.56-1.84)

Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.

*Other non-ACTG academic sources.



Darunavir/RTV plus raltegravir was noninferior to darunavir/RTV plus TDF/FTC in NEAT

– NRTI-sparing regimen appeared less efficacious at high HIV-1 RNA, although the difference between regimens was not statistically significant

Darunavir/RTV plus maraviroc was inferior to darunavir/RTV plus TDF/FTC in MODERN

Lopinavir/RTV plus raltegravir was comparable to lopinavir/RTV plus TDF/FTC in PROGRESS; although this was a small study

Lopinavir/RTV plus 3TC was comparable to lopinavir/RTV plus 2 NRTIs in GARDEL, including in pts with high HIV-1 RNA

Most panelists opted for darunavir/RTV plus dolutegravir plus 3TC; although this is an untested regimen


NEAT: RAL + DRV/RTV Noninferior to TDF/FTC + DRV/RTV in Naive Pts at 96 Wks Randomized, open-label phase III study of DRV/RTV + RAL vs

DRV/RTV + TDF/FTC in ART-naive pts

Raffi F, et al. Lancet. 2014;[Epub ahead of print].

Overall N = 805

BL HIV-1 RNA

< 100,000 c/mL

≥ 100,000 c/mL

n = 530

n = 275

BL CD4+ cell count

< 200/mm3

≥ 200/mm3

n = 123

n = 682

Primary Endpoint at Wk 96: Adjusted Difference Estimate (95% CI) RAL - TDF/FTC

RAL TDF/FTC Adjusted Diff. (95% CI)

17.8 13.8 4.0 (-0.8 to 8.8)

7.4

36.8

7.3

27.3

0.1 (-3.8 to 4.0)

9.6 (-0.1 to 20.1)

43.2

13.7

20.9

12.3

22.3 (7.4 to 37.1)

1.4 (-3.5 to 6.3)

-10 0 10 20 4030

Use of Integrase Inhibitorsin HIV/HCV Coinfection


Case 4: 45-Yr-Old Male With HIV/HCV Coinfection 45-yr-old white man referred to hepatology for low platelet

count (74,000/mL); ALT: 45 IU/L; AST: 101 IU/L; and a brief episode of hematemesis

HCV GT1a; HCV RNA: 1.2 million IU/mL

HIV-1 RNA: 13,000 c/mL; CD4+ count: 450 cells/mm3; HIV genotype WT; Cr: 2.5 mg/dL (221 µmol/L); HLA-B*5701 negative

EGD: small nonbleeding varices; TE: 17 kPa, no liver biopsy; US: likely cirrhosis, no masses; AFP: 5.6 μg/L

He is referred to you for ART consultation before beginning HCV therapy with sofosbuvir + simeprevir



There was no consensus among panelists about the best approach for this pt

– HIV therapy could be deferred until HCV therapy is completed, given the relatively short duration of the latter

– HCV therapy could be initiated soon after initiation of HIV therapy, once the pt is tolerating ART

Panelists would not defer HIV therapy in pts with low CD4+ cell counts



Efavirenz, atazanavir/ritonavir, and darunavir/ritonavir should not be coadministered with simeprevir

Rilpivirine is an option for this pt, although this agent is more commonly used with TDF/FTC than with ABC/3TC

Most panelists opted for dolutegravir or raltegravir

– Raltegravir can be administered with simeprevir; requires twice-daily dosing but switch to simpler HIV therapy may be possible following completion of HCV therapy

– Dolutegravir can be administered with ABC/3TC as a fixed-dose combination, although estimated CrCl would require close monitoring in this pt to assess 3TC dosing


Drug–Drug Interactions With ARVs

ARV Simeprevir Sofosbuvir

EFV Do not coadminister Use standard doses

DRV/RTV Do not coadminister Use standard doses

COBI Do not coadminister Use standard doses

DLV, ETR, NVP Do not coadminister Use standard doses

RTV Do not coadminister Use standard doses

Any PI Do not coadminister --

RAL Use standard doses Use standard doses

RPV Use standard doses Use standard doses

TDF, FTC, ABC, 3TC Use standard doses Use standard doses

TPV/RTV Do not coadminister Do not coadminister

DTG No data; interactions unlikely No data; interactions unlikely

Sofosbuvir [package insert]. Simeprevir [package insert]. Kirby B, et al. AASLD 2012. Abstract 1877. Ouwerkerk-Mahadevan S, et al. IDSA 2012. Abstract 49. http://www.hep-druginteractions.org/


Summary

When selecting a first-line regimen, each of the INSTI-based options can be considered

For most pts, at least 1 INSTI-based regimen is likely to be an option

Issues such as single-tablet options, choice of NRTI backbone, drug–drug interactions, tolerability, and once- vs twice-daily dosing should influence choice between available INSTI-based regimens

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