Integrating Recent Data When Selecting First-line Antiretroviral Therapy.2015 [DHHS recommendations for first-line antiretroviral therapy ]

Integrating Recent Data When Selecting First-line Antiretroviral Therapy

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Faculty

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

W. David Hardy, MDClinical Professor of MedicineDavid Geffen School of Medicine at UCLALos Angeles, California

Paul E. Sax, MDClinical DirectorHIV Program and Division of Infectious DiseasesBrigham and Women’s HospitalProfessor of MedicineHarvard Medical SchoolBoston, Massachusetts


DisclosuresJoseph J. Eron, Jr., MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Merck, Tibotec/Janssen, and Tobira; has served on data and safety monitoring boards for Vertex; and has received funds for research support from AbbVie and GlaxoSmithKline/ViiV.

W. David Hardy, MD, has disclosed that he has received consulting fees from Gilead Sciences, GlaxoSmithKline/ViiV, and Janssen; has received funds for research support from Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Vertex; and has ownership interest (stocks, stock options or other ownership interest) in Merck.

Paul E. Sax, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, Janssen, and Merck and funds for research support (paid to Brigham and Women’s Hospital) from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline/ViiV, and Merck.

Overview of First-line Antiretroviral Therapy


DHHS and IAS-USA Guidelines: 2014 Recommended Regimens for First-line ART

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

Class

DHHS[1]

IAS-USA[2]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

EFV/TDF/FTC or EFV + ABC/3TC*‡ or RPV/TDF/FTC‡

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

ATV/RTV + ABC/3TC* ATV/RTV + TDF/FTC or ATV/RTV + ABC/3TC*‡

DRV/RTV + TDF/FTC

INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC║

DTG + ABC/3TC*§

DTG + TDF/FTC

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.‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.║Only for pts with pre-ART CrCl > 70 mL/min.§Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen.


DHHS Guidelines: 2015 Recommended Regimens for First-line ART

DHHS Guidelines. April 2015.

Class DHHS Recommended TherapyRegardless of BL VL or CD4+ Count Alternative Regimens

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

DTG + TDF/FTC

Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC*†

DRV/COBI + TDF/FTC*

NNRTI EFV/TDF/FTC RPV/TDF/FTC‡

*Only for pts with pre-ART CrCl ≥ 70 mL/min.†Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm 3.

Selecting Initial Antiretroviral Therapy


Selected Drug–Drug Interactions of INSTIs

Agent Potential Drug–Drug InteractionsRaltegravir[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].


DHHS Guidelines, April 2015: What to Start

An alternative regimen may be the preferred regimen for some pts

Alternative Regimens

NNRTI based

EFV/TDF/FTC RPV/TDF/FTC*

PI based ATV/COBI + TDF/FTC†

ATV/r + TDF/FTC DRV/COBI + ABC/3TC‡

DRV/r + ABC/3TC‡

DRV/COBI + TDF/FTC† *Only for pts with pre-ART HIV RNA < 100,000 copies/mL and CD4 > 200 cells mm3.†Only for pts with pre-ART CrCl ≥ 70 mL/min.‡Only for pts who are HLA-B*5701 negative.



The International Antiviral Society–USA Recommended Treatment Regimens

Currently preferred WHO regimens: EFV/TDF/FTC or EFV/TDF/3TC due to efficacy and cost of treatment[2]

1. Günthard HF, et al. JAMA. 2014;312:410-425. 2. WHO. The strategic use of antiretrovirals to help end the HIV epidemic. 2012.

Class IAS-USA[1]

NNRTI EFV/TDF/FTC or EFV + ABC/3TC*† RPV/TDF/FTC†

Boosted PI ATV/RTV + TDF/FTC or ATV/RTV + ABC/3TC*†

DRV/RTV + TDF/FTC

INSTI RAL + TDF/FTC EVG/COBI/TDF/FTC‡

DTG + ABC/3TC*§

DTG + TDF/FTC

*Only for pts who are HLA-B*5701 negative. Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.‡Only for pts with pre-ART CrCl ≥ 70 mL/min.§Publication of these guidelines preceded the availability of DTG/ABC/3TC as a single-tablet regimen.

Comparing Integrase Inhibitor Regimens


FLAMINGO: Wk 96 Subgroup Efficacy Analysis

Molina JM, et al. Glasgow HIV 2014. Abstract O153.

HIV

-1 R

NA

< 5

0 c/

mL

(%)

DTG + NRTIs (n = 242) DRV/RTV + NRTIs (n = 242)

8275 79

6452

8273

8068

80

100

80

60

40

20

0TDF/FTC(n = 325)

ABC/3TC(n = 159)

> 100,000(n = 122)

≤ 100,000(n = 362)

Overall

BL HIV-1 RNA (c/mL) Background NRTI


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

Favors RAL

Favors RAL

Favors DRV/RTV

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

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

Cum

ulat

ive

Inci

denc

e

0

Wks Since Study Entry

24 48 64 80 96 112 128 144

ATV/RTV + TDF/FTCRAL + TDF/FTCDRV/RTV + TDF/FTC


STARTMRK: Drug-Related Adverse Events

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

5-Yr Drug-Related AEs in ≥ 5% of Pts, % RAL + TDF/FTC (n = 281) EFV + TDF/FTC (n = 282)Gastrointestinal 21.7 29.4

Diarrhea 5.3 9.9

Flatulence 3.6 5.0

Nausea 8.9 11.0

General disorders 10.0 16.7

Fatigue 4.3 8.9

Nervous system disorders 18.5 49.6

Dizziness 7.8 35.1

Headache 9.3 14.2

Somnolence 1.1 7.4

Psychiatric disorders 18.5 30.9

Abnormal dreams 6.8 13.1

Insomnia 7.5 8.2

Nightmares 2.8 5.3

Skin and subcutaneous tissue disorders 6.0 22.3

Rash 1.1 8.2


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)84 82

Wk 96

Δ: 2.7% (-2.9 to 8.3)

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

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

Δ: 2.7% (-2.1 to 7.5) 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)

83 82

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 104 and 111: HIV-1 RNA < 50 c/mL at Wk 48 (Primary Endpoint)

CD4+ significantly higher for TAF than TDF (P = .024)

D/C for adverse events: TAF 0.9%, TDF 1.5%

Resistance with failure: TAF 7/866 (0.8%), TDF 5/867 (0.6%)

Favors E/C/F/TAF

0

4.7%‒0.7%2.0%

HIV

-1 R

NA

<50

c/m

L (%

)

Treatment Difference (95% CI) Virologic Outcome

‒12% +12%

Favors E/C/F/TDF

Wohl D, et al. CROI 2015. Abstract 113LB.

100

80

60

40

20

0Success Failure No Data

92 90

4 4 4 6

E/C/F/TAF (n = 866)E/C/F/TDF (n = 867)


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 YesElvitegravir Once daily Yes Yes Yes YesDolutegravir Once daily Yes No None so far Partial


DHHS Guidelines: 2015 Recommended and Alternative Regimens for First-line ART





DTG + TDF/FTC

Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC†

DRV/COBI + TDF/FTC*




SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in Tx-Naive Pts To Wk 144 Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV)

Virologic Success*

Virologic Nonresponse

No Virologic Data

Pts

(%)

FavorsEFV/TDF/FTC

95% CI for Difference

0

Wk 48

Wk 96

Wk 144

7.4%

8.0%

8.3%

2.5%

2.3%

2.0% 14.6%

13.8%

12.3%

FavorsDTG + ABC/3TC

15%

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

8881 80

72 7163

5 6 7 8 10 7 713 12

20

30

18

100

80

60

40

20

0

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

Wk 48 96 144 Wk 48 96 144 Wk 48 96 144

*HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.-10% noninferiority margin.Pts with HBV infection were excluded from this study.

15%


Molina JM, et al. Glasgow HIV 2014. Abstract O153.

FLAMINGO: DTG + 2 NRTIs Superior to DRV/RTV + 2 NRTIs in Tx-Naive Pts at Wk 96

DTG + 2 NRTIs (n = 242)DRV/RTV + 2 NRTIs (n = 242)

Wk 96

*HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm.

Adjusted difference at Wk 96:12.4% (95% CI: 4.7-20.2; P = .002)

Randomized, open-label phase III study of DTG + 2 NRTIs vs DRV/RTV + 2 NRTIs

Protocol defined VF: <1% (2/242) with DTG vs 2% (4/242) with DRV/RTV

– No treatment-emergent resistance in either arm Virologic

Success*Virologic

NonresponseNonresponse Due to Other

Reasons

Pts

(%)

100

80

60

40

20

0

8068

8 12 1221


Studies Addressing Abacavir and MIStudy Association DescriptionD:A:D[1] Cohort collaboration (prospective)

Danish HIV Cohort[2] Cohort (linked with registries)

Montreal study[3] Nested case-control study

SMART[4] Post hoc subgroup analysis of RCT (use of ABC not randomized)

STEAL[5] Preplanned secondary analysis of RCT (use of ABC randomized)

Swiss HIV Cohort[6] Cohort (retrospective)

FHDH ANRS CO4[7] ? Nested case-control study

NA-ACCORD[8] ? Cohort (retrospective)

VA Clinical Case Registry[9] X Cohort (retrospective)

Brothers et al. analysis[10] X Post hoc meta-analysis of RCTs

ACTG A5001/ALLRT[11] X Post hoc meta-analysis of RCTs

FDA meta-analysis[12] X Post hoc meta-analysis of RCTs

1. Friis-Møller N, et al. N Engl J Med. 2003;349:1993-2003. 2. Obel N, et al. HIV Med. 2010;11:130-136. 3. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 4. Phillips AN, et al. Antiviral Ther. 2008;13:177-187. 5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Young J, et al. J Acquir Immune Defic Syndr. 2015. [Epub ahead of print] 7. Lang S, et al. AIDS. 2010;24:1228-1230. 8. Palella F, et al. CROI 2015. Abstract 749LB. 9. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 10. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28. 11. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 12. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447.


NA-ACCORD: Recent Abacavir Use and Risk of MI Retrospective analysis of pts in 7

clinical cohorts with recent ABC use from 1/1/1995 to 12/31/2010

“Recent” ABC initiation: prescribed within previous 6 mos

ABC initiators (n = 1948) vs non-ABC initiators (n = 14,785):

– “Full” study population: all ART users excluding persons on ABC at study entry

– “Restricted” population: ART-naive persons who initiated ART in the cohort

Endpoint of incident MIs: presence of clinical diagnosis or elevation of cardiac enzymes

– All MIs independently adjudicated

Palella F, et al. CROI 2015. Abstract 749LB.

0 2.001.00 4.003.00

Full Study

Restricted Study

D:A:DReplication

1.95

1.33

Recent ABC use significant in restricted population and D:A:D replication

Association diminished after adjusting for additional CVD risk factors in multivariate analysis

Significant factors– Both: age 60+ yrs, HTN, eGFR < 30, AIDS

– Full: smoking, DM

Adjusted HRs for MI in Those With Recent ABC Use


DHHS Guidelines: 2015 Recommended and Other Regimens for First-line ART


Class DHHS Recommended TherapyRegardless of BL VL or CD4+ Count Other Regimens


DTG + TDF/FTC

RAL + ABC/3TC†

Boosted PI DRV/RTV + TDF/FTC ATV/RTV or COBI + ABC/3TC†‡

LPR/RTV + ABC/3TC†

LPR/RTV + TDF/FTC

NNRTI EFV + ABC/3TC†‡

When TDF or ABC cannot be used DRV/RTV + RAL§

LPV/RTV + 3TC*Only for pts with pre-ART CrCl ≥ 70 mL/min.†Only for pts who are HLA-B*5701 negative. ‡Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL.§Not recommended in pts with baseline HIV-1 RNA > 100,000 copies/mL and CD4+ cell counts < 200 cells/mm 3.


DHHS Guidelines: 2015 Recommended and Alternative Regimens for First-line ART





DTG + TDF/FTC

Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC†

DRV/COBI + TDF/FTC*



Evolving Options for First-line Antiretroviral Therapy


Favors E/C/F/TAF

0

4.7%‒0.7%2.0%

HIV

-1 R

NA

<50

c/m

L (%

)

Treatment Difference (95% CI) Virologic Outcome

‒12% +12%

Favors E/C/F/TDF100

80

60

40

20

0Success Failure No Data

92 90

4 4 4 6

E/C/F/TAF (n = 866)E/C/F/TDF (n = 867)

Studies 104 and 111: HIV-1 RNA < 50 c/mL at Wk 48 (Primary Endpoint)

CD4 significantly higher for TAF than TDF (P = .024)

D/C for adverse events: TAF 0.9%, TDF 1.5%

Resistance with failure: TAF 7/866 (0.8%), TDF 5/867 (0.6%)Wohl D, et al. CROI 2015. Abstract 113LB.


TAF vs TDF: Renal Outcomes TAF vs TDF

– Significantly smaller decreases in eGFR (P < .001)

– Significantly less proteinuria, albuminuria, and tubular proteinuria (P < .001)

No cases of tubulopathy/Fanconi syndrome in either arm

Discontinuations due to renal adverse events

– E/C/F/TAF: 0 (0%)

– E/C/F/TDF: 4 (0.5%)

Mean Change in eGFR

Mea

n C

hang

e (m

L/m

in)

-11.2

E/C/F/TAF (n = 866)E/C/F/TDF (n = 867)

-6.6

0 12 24 36 48

P < .001

Treatment Wk

Sax PE, et al. CROI 2015. Abstract 143LB.

10

5

0

-5

-10

-15

-20


TAF vs TDF: Changes in Spine and Hip BMD

E/C/F/TAF, n 845E/C/F/TDF, n 850

797816

784773

836848

789815

780767

‒0.66

P < .001

‒2.95

‒1.30

P < .001

‒2.86

HipSpine

Mea

n (S

D) %

Cha

nge

From

Bas

elin

e

24 48

Wk0 24 48

Wk0

Sax PE, et al. CROI 2015. Abstract 143LB.

2

0

-2

-4

-6

2

0

-2

-4

-6


TAF-Based Therapies in Development Studies all under way or completed

– EVG/COBI/FTC/TAF

– TAF/FTC

– RPV/TAF/FTC

– Darunavir/COBI/FTC/TAF

– TAF for HBV

TAF/FTC for PrEP: studies planned


DHHS Guidelines: 2015 Recommended Regimens for First-line ART




DTG + TDF/FTC

Boosted PI DRV/RTV + TDF/FTC ATV/RTV + TDF/FTC ATV/COBI + TDF/FTC* DRV/RTV + ABC/3TC† DRV/COBI + ABC/3TC*†

DRV/COBI + TDF/FTC*




Initial Factors that Influence Selection of Firstline ART Pt preference

– Single vs multi-pill regimens

– Tolerability issues

Drug–drug interactions

Comorbidities

Potential adherence issues

– Adherence to regimen

– Adherence to follow-up care

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Integrating Recent Data When Selecting First-line Antiretroviral Therapy.2015 [DHHS recommendations for first-line antiretroviral therapy ]