what’s new in coformulated antiretroviral regimens.2014

Andrew R. Zolopa, MDProfessor of Medicine Director, Stanford Positive Care ProgramPrincipal Investigator, Stanford AIDS Clinical Trials UnitStanford University School of MedicineStanford, California

What’s New in Coformulated Antiretroviral Regimens

This program is supported by an educational grant from

clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens

Faculty

Andrew R. Zolopa, MDProfessor of Medicine Director, Stanford Positive Care ProgramPrincipal Investigator, Stanford AIDS Clinical Trials UnitStanford University School of MedicineStanford, California

Andrew R. Zolopa, MD, has disclosed that he has received consulting fees from Gilead Sciences and funds for research support from Gilead Sciences, Janssen, Pfizer, and VirXSys.

Please review the slide notes for a discussion by

Andrew R. Zolopa, MD


Advantages and Disadvantages of Coformulated Agents and Regimens

Inability to adjust dosages of components

Simplicity

Convenience

Fewer copays

Reduces selective nonadherence to components of regimen

Unclear what impact the release of generic drugs will have on the ability of physicians to continue prescribing coformulated drugs and regimens


Currently Available Coformulated Antiretroviral Agents and RegimensAgent Type Year of FDA Approval

ZDV/3TC Dual NRTI 1997

ZDV/3TC/ABC Triple NRTI 2000

LPV/RTV Boosted PI 2000

ABC/3TC Dual NRTI 2004

TDF/FTC Dual NRTI 2004

TDF/FTC/EFV NNRTI + dual NRTI 2006

TDF/FTC/RPV NNRTI + dual NRTI 2011

TDF/FTC/EVG/COBI Dual NRTI + INSTI + booster 2012


What’s New in Coformulated Agents and Regimens Coformulated regimens including approved agents

– EVG/COBI/TDF/FTC

– DTG/ABC/3TC

PIs coformulated with cobicistat as the pharmacologic booster

– ATV/COBI

– DRV/COBI

Coformulated regimens using investigational agents

– EVG/COBI/TAF/FTC

– DRV/COBI/TAF/FTC


Cobicistat: A New Boosting Agent

Small molecule with no HIV activity

– No concern of drug resistance in pts with suboptimal virologic response

Similar from BL in fasting TC and TGs compared with RTV when boosting same agent[1]

Inhibitor of CYP3A4; many drug–drug interactions[2,3]

Modest, rapid increase in serum Cr due to inhibition of tubular secretion[3]

– Not associated with any change in actual GFR

– Other drugs (including ARVs) have similar effect[4,5]

Availability of cobicistat has allowed for development of new coformulated agents and regimens

1. Gallant JE, et al. J Infect Dis. 2013;208:32-39. 2. DHHS Guidelines February 2013. 3. TDF/FTC/EVG/COBI [package insert]. 4. RPV [package insert]. 5. DTG [package insert].


Renal Monitoring With Cobicistat

7. TDF/FTC/EVG/COBI [package insert]. 8. DHHS Guidelines February 2013.

Ch

ang

e F

rom

BL

in

S

eru

m C

r(m

g/d

L;

IQR

)

0-0.05

-0.10

0.150.10

0.05

0.20

*Serum phosphorus should be measured in patients at risk for renal impairment

2 4 8 12 16 24 32 40 48Wks

BL

At BL,*Estimated CrClUrine glucose Urine protein




Wk 4—new baseline against which further changes should be measured

Ch

ang

e F

rom

BL

in

S

eru

m C

r(m

g/d

L;

IQR

)

0-0.05

-0.10

0.150.10

0.05

0.20

2 4 8 12 16 24 32 40 48Wks

BL





Coformulated drugs containing COBI should not be initiated in pts with estimated CrCl < 70 mL/min – Studies ongoing in pts with CrCl < 70

Interpretation of changes in renal function may be problematic when using coformulations of COBI and TDF

TDF/FTC/EVG/COBI should not be used with other nephrotoxic drugs


Serum Cr* Serum Cr*Serum Cr* Serum Cr*

UA UA

Ch

ang

e F

rom

BL

in

S

eru

m C

r(m

g/d

L;

IQR

)

0-0.05

-0.10

0.150.10

0.05

0.20


Wk 4—new baseline against which further changes should be measured

2 4 8 12 16 24 32 40 48Wks

BL



Key Drug–Drug Interactions With COBI

Antacids

Benzodiazepines

Beta-blockers

Calcium channel blockers

Erectile dysfunction drugs

Inhaled/injectable corticosteroids

MVC

OCPs (norgestimate)

Rifampin

Statins

14. DHHS Adult Guidelines. February 2013

There is no interaction between COBI and methadone


Cobicistat—Status in EU and US

In July 2013, EMEA approved cobicistat as a PK enhancer of atazanavir 300 mg once daily or darunavir 800 mg once daily as part of a complete ART regimen in adults

In US, currently approved only as part of coformulated single-tablet regimen TDF/FTC/EVG/COBI

– Approval as single agent pending

15. EMA.europa.eu. Assessment report on cobicistat. 16. FDA.gov. Approval of TDF/FTC/EVG/COBI.


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

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

17. Sax P, et al. Lancet. 2012;379:2439-2448. 18. DeJesus E, et al. Lancet. 2012;379:2429-2438.

Treatment naive HIV-1 RNA ≥ 5000 copies/mL

Any CD4+ cell countSusceptible to TDF, FTC, and EFV, or ATV

eGFR ≥ 70 mL/min

Study 102[17]

(N = 700)

Study 103[18]

(N = 708)

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

EFV/FTC/TDF QD(n = 352)

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

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


EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through Wk 144

19. Sax PE, et al. Lancet. 2012;379:2439-2448. 20. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 21. Wohl D, et al. ICAAC 2013. Abstract H-672a.

Wk 48

Wk 144

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

EFV/TDF/FTC (n = 352)

8075

0

20

40

60

80

10088

84 8482

Wk 96

7 7 68 7 10

4 5 57 6 7

Wk 48

Wk 144

Wk 96

Wk 48

Wk 144

Wk 96

Virologic Success* Virologic Failure D/c due to AEs

95% CI for Difference

Wk 48[1]

Wk 96[2]

Wk 144[3]

-12% 12%0

Favors EFV

Favors EVG/COBI

-1.3% 11.1%

4.9%

3.6%

8.8%

2.7%

-1.6%

-2.9%

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


EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 144

22. De Jesus E, et al. Lancet. 2012;379:2429-2438. 23. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 24. Clumeck N, et al. EACS 2013. Abstract LBPS7/2.

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

78 75

90 87

Wk 48

Wk 144

0

20

40

60

80

100

Wk 96

Wk 48

Wk 144

Wk 96

Wk 48

Wk 144

Wk 96

Virologic Success* Virologic Failure

83 82

5 5 47 7 78 5 4 6 6 8

-12% 12%0

Favors ATV/RTV

Favors EVG/COBI

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

-3.2% 9.4%

3.1%

2.7%

7.5%1.1%

6.7%

-2.1%

-4.5%

Wk 48[22]

Wk 96[23]

Wk 144[24]

D/c due to AEs

95% CI for Difference

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


Examples of Ongoing Switch Studies in Suppressed Patients EVG/COBI/TDF/FTC (primarily switches for simplicity)

– RAL + TDF/FTC → EVG/COBI/TDF/FTC[25]

– Open-label, pilot phase IIIb study

– At 48 wks, all patients (n + 48) remained virologically suppressed with no relevant changes in serum creatinine or serum lipids

– NNRTI + TDF/FTC → EVG/COBI/TDF/FTC[26]

– Open-label phase IIIb study

– Boosted PI + TDF/FTC → EVG/COBI/TDF/FTC[27]

– Open-label phase IIIb study

25. Mills A, et al. EACS 2013. PE7/5. 26. ClinicalTrials.gov. NCT01495702. 27. ClinicalTrials.gov. NCT01475838.


DHHS Guidelines Update: October 2013

28. DHHS Guidelines. February 2013. 29. DHHS Recommendation on INSTIs. October 2013.

Preferred Regimens Alternative Regimens

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

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

ATV/RTV + ABC/3TC DRV/RTV + ABC/3TC FPV/RTV + (TDF/FTC or ABC/3TC) LPV/RTV + (TDF/FTC or ABC/3TC)

INSTI

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

RAL + ABC/3TC


Dolutegravir Phase III Trials in Treatment-Naive Patients Randomized, noninferiority phase III studies Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48

ART-naive ptsVL ≥ 1000 c/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.

ART-naive ptsVL ≥ 1000 c/mLHLA-B*5701 negCrCl > 50 mL/min

(N = 833)

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

EFV/TDF/FTC QD (n = 419)

SPRING-2[30]

(active controlled, double blind)

SINGLE[31]

(active controlled, double blind)

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

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

ART-naive ptsVL ≥ 1000 c/mL

(N = 484)

FLAMINGO[32]

(open label)

30. Raffi F, et al. Lancet. 2013;381:735-743. 31. Walmsley S, et al. N Engl J Med. 2013;369:1807-1818.32. Feinberg J, et al. ICAAC 2013. Abstract H1464a. .

88 86

85

88 88

81

90 90

83

VL

< 5

0 at

Wk

48

VL

< 5

0:

DT

G/A

BC

/3T

C


Fixed-Dose Dolutegravir/ABC/3TC vs ATV/RTV + TDF/FTC in ART-Naive Women Ongoing, randomized, open-label phase IIIB study

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

ART-naive women, HIV-1 RNA ≥ 500 c/mL; HLA-B*5701

negative(N = 474)

DTG/ABC/3TC(n = 237)

ATV/RTV + TDF/FTC(n = 237)

Wk 48Wk 24

33. ClinicalTrials.gov. NCT01910402.


ATV/COBI + TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 48 Randomized, double-blind, phase III trial in ART-naive patients


34. Gallant JE, et al. J Infect Dis. 2013;208:32-39.

ATV/COBIATV/RTV

Δ-2.2% 95% CI: -7.4 to 3.0)

Virologic Success*

Virologic Nonresponse

Pat

ien

ts,

%

85 87

293 3040

20

40

60

80

100

5.8 4.09.0 8.6

6

20 14

No Data

n =

HIV-infected, ART-naive

patients, with HIV-1 RNA

≥ 5000 c/mL and eGFR ≥ 70

mL/min(N = 692)

TDF/FTC + ATV/COBI(n = 344)

TDF/FTC + ATV/RTV(n = 348)

Wk 48Wk 24

31 30


DRV/COBI FDC Bioequivalent to DRV + RTV and to DRV + COBI PK analyses in healthy subjects

DRV Concentration When DRV and COBI Administered as Single Agent or in

Coformulation[36]

DRV Concentration When Administered as DRV + RTV or as DRV/COBI Coformulation[35]

35. Kakuda TN, et al. Clin Pharmacol. 2012. Abstract O_20. 36. Kakuda TN, et al. IAS 2013. Abstract MOPE029.

8000

6000

4000

2000

00 6 12 18 24

HrsPla

sma

Co

nce

ntr

atio

n o

f D

RV

(n

g/m

L)

(Mea

n ±

SD

) 8000

6000

4000

2000

0

Hrs

DRV/RTV 800/100 mg QD as single agents (n = 32)DRV/COBI 800/150 mg QD as FDC (n = 33)DRV/COBI 800/150 mg QD as FDC (n = 33)

Single agents; fed (n = 38)FDC; fed (n = 40)Single agents; fasted (n = 72)FDC; fasted (n = 74)

0 4 8 12 16 20 24


Ongoing: Single-Arm Study of DRV QD + COBI + 2 NRTIs Phase IIIb study in treatment-naive and treatment-experienced

pts with no DRV RAMs

– Primary endpiont: Onset of any treatment emergent Grade 3 or Grade 4 adverse events by Wk 24

– Secondary endpoints: HIV-1 RNA at Wk 24 and Wk 48

HIV+ patients, HIV-1 RNA

≥ 500 c/mL; naive or on stable ART for 12 wks

and sensitive to 2 NRTIs + no DRV RAMS

(N = 300)

DRV + COBI + 2 NRTIs

Wk 48Wk 24



Tenofovir Alafenamide vs Tenofovir DF in ART-Naive Patients TAF (GS-7340), investigational

prodrug of tenofovir with lower plasma concentrations, increased delivery to hepatocytes, lymphoid cells

Randomized, placebo-controlled phase II trial in ART-naive patients

38. Zolopa A, et al. CROI 2013. Abstract 99LB. 39. Sax P, et al. ICAAC 2013. Abstract H-1464d.

HIV-infected, ART-naive

patients, with CD4+ cell count > 50 cells/mm3

and eGFR ≥ 70 mL/min

(N = 170)

TAF/FTC/EVG/COBI

(n = 112)

TDF/FTC/EVG/COBI

(n = 58)

Wk 48Wk 24GutTFVTDFTAF

Plasma

TDF/TFV TAF

Lymphoid Cells

TAF TFV

TFV-MP

TFV-DP

Cathepsin A


TAF/FTC/EVG/COBI Noninferior to TDF/FTC/EVG/COBI Through Wk 48

Pat

ien

ts (

%)

88.4 87.9

Δ 1.0% (95% CI: -12.1 to +10.0;

P = .84)

TAF/FTC/EVG/COBITDF/FTC/EVG/COBI

99 510

20

40

60

80

100

6.3 10.35.4 1.7 6 1 7 6

Virologic Success*

Virologic Nonresponse

No Data

40. Sax P, et al. ICAAC 2013. Abstract H-1464d.

n =

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

TAF/FTC/EVG/COBI (n = 112)TDF/FTC/EVG/COBI (n = 58)

12 24 36 48

2

Wks

-2

-4

0-6

Med

ian

(Q

1, Q

0)

Ch

ang

e i

n B

MD

12 24 36 48

2

Wks

-2

-4

0-6

Med

ian

(Q

1, Q

3)

Ch

ang

e i

n B

MD

Spine

Hip

P < .001

P < .001


Ongoing: TAF/FTC/DRV/COBI vs TDF/FTC + DRV/COBI in ART-Naive Patients Ongoing, randomized, placebo-controlled phase II trial



ART-naive patients, HIV-1 RNA

≥ 5000 c/mL; CD4+ cell count > 50 cells/mm3;

eGFR ≥ 70 mL/min(N = 150)

TAF/FTC/DRV/COBI(n = 100)

TDF/FTC + DRV/COBI(n = 50)

Wk 48Wk 24


Conclusions

Coformulated drugs and regimens offer opportunities for simpler dosing for ART

May have benefits for adherence, patient copays

Cobicistat new pharmacologic booster investigated with elvitegravir, PIs

– Effective in increasing exposure of these drugs with no HIV activity

– However, effects on serum creatinine and need for renal monitoring important for use with this drug

Other coformulated regimens which do not require pharmacologic boosting also being developed which may be favorable for patients

what’s new in coformulated antiretroviral regimens.2014

Health & Medicine