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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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral 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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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].
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
Renal Monitoring With Cobicistat
9. TDF/FTC/EVG/COBI [package insert]. 10. DHHS Guidelines February 2013.
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
*Serum phosphorus should be measured in patients at risk for renal impairment
At BL,*Estimated CrClUrine glucose Urine protein
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
Renal Monitoring With Cobicistat
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
12. TDF/FTC/EVG/COBI [package insert]. 13. DHHS Guidelines February 2013.
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
At BL,*Estimated CrClUrine glucose Urine protein
Wk 4—new baseline against which further changes should be measured
2 4 8 12 16 24 32 40 48Wks
BL
*Serum phosphorus should be measured in patients at risk for renal impairment
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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.
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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)
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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.
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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)
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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.
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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.
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
ATV/COBI + TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk 48 Randomized, double-blind, phase III trial in ART-naive patients
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 48
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
37. ClinicalTrials.gov. NCT01440569.
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
Ongoing: TAF/FTC/DRV/COBI vs TDF/FTC + DRV/COBI in ART-Naive Patients Ongoing, randomized, placebo-controlled phase II trial
– Primary endpoint: HIV-1 RNA < 50 copies/mL at Wk 24
41. ClinicalTrials.gov. NCT01565850.
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
clinicaloptions.com/hivWhat’s New in Coformulated Antiretroviral Regimens
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