clinicaloptions.com/hiv What’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/hiv What’s New in Coformulated Antiretroviral Regimens Currently Available Coformulated Antiretroviral Agents and Regimens AgentTypeYear of FDA Approval ZDV/3TCDual NRTI1997 ZDV/3TC/ABCTriple NRTI2000 LPV/RTVBoosted PI2000 ABC/3TCDual NRTI2004 TDF/FTCDual NRTI2004 TDF/FTC/EFVNNRTI + dual NRTI2006 TDF/FTC/RPVNNRTI + dual NRTI2011 TDF/FTC/EVG/COBIDual NRTI + INSTI + booster2012

clinicaloptions.com/hiv What’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/hiv What’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: DHHS Guidelines February TDF/FTC/EVG/COBI [package insert]. 4. RPV [package insert]. 5. DTG [package insert].

clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens Renal Monitoring With Cobicistat 9. TDF/FTC/EVG/COBI [package insert]. 10. DHHS Guidelines February Wk 4—new baseline against which further changes should be measured Change From BL in Serum Cr (mg/dL; IQR) Wks BL *Serum phosphorus should be measured in patients at risk for renal impairment At BL,*  Estimated CrCl  Urine glucose  Urine protein

clinicaloptions.com/hiv What’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 Serum Cr* UA Change From BL in Serum Cr (mg/dL; IQR) At BL,*  Estimated CrCl  Urine glucose  Urine protein Wk 4—new baseline against which further changes should be measured Wks BL *Serum phosphorus should be measured in patients at risk for renal impairment

clinicaloptions.com/hiv What’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/hiv What’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/hiv What’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 Sax P, et al. Lancet. 2012;379: DeJesus E, et al. Lancet. 2012;379: 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 [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/hiv What’s New in Coformulated Antiretroviral Regimens EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through Wk Sax PE, et al. Lancet. 2012;379: Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63: Wohl D, et al. ICAAC Abstract H-672a. Wk 48 Wk 144 EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) Subjects (%) Wk Wk 48 Wk 144 Wk 96 Wk 48 Wk 144 Wk 96 Virologic Success*Virologic FailureD/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/hiv What’s New in Coformulated Antiretroviral Regimens EVG/COBI/TDF/FTC Noninferior to ATV/RTV + TDF/FTC Through Wk De Jesus E, et al. Lancet. 2012;379: Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62: Clumeck N, et al. EACS Abstract LBPS7/2. ATV/RTV + TDF/FTC (n = 355) Wk 48 Wk Wk 96 Wk 48 Wk 144 Wk 96 Wk 48 Wk 144 Wk 96 Virologic Success*Virologic Failure % 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) Subjects (%)

clinicaloptions.com/hiv What’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 PE7/ ClinicalTrials.gov. NCT ClinicalTrials.gov. NCT

clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens DHHS Guidelines Update: October DHHS Guidelines. February DHHS Recommendation on INSTIs. October Preferred RegimensAlternative 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/hiv What’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 pts VL ≥ 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 pts VL ≥ 1000 c/mL HLA-B*5701 neg CrCl > 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 pts VL ≥ 1000 c/mL (N = 484) FLAMINGO [32] (open label) 30. Raffi F, et al. Lancet. 2013;381: Walmsley S, et al. N Engl J Med. 2013;369: Feinberg J, et al. ICAAC Abstract H1464a VL < 50 at Wk 48 VL < 50: DTG/ABC/3TC

clinicaloptions.com/hiv What’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 ClinicalTrials.gov. NCT

clinicaloptions.com/hiv What’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 Gallant JE, et al. J Infect Dis. 2013;208: ATV/COBI ATV/RTV Δ-2.2% 95% CI: -7.4 to 3.0) Virologic Success* Virologic Nonresponse Patients, % 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 48 Wk

clinicaloptions.com/hiv What’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 Abstract O_ Kakuda TN, et al. IAS Abstract MOPE Hrs Plasma Concentration of DRV (ng/mL) (Mean ± SD) Hrs DRV/RTV 800/100 mg QD as single agents (n = 32) 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)

clinicaloptions.com/hiv What’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 48 Wk ClinicalTrials.gov. NCT

clinicaloptions.com/hiv What’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 Abstract 99LB. 39. Sax P, et al. ICAAC Abstract H-1464d. HIV-infected, ART-naive patients, with CD4+ cell count > 50 cells/mm 3 and eGFR ≥ 70 mL/min (N = 170) TAF/FTC/EVG/ COBI (n = 112) TDF/FTC/EVG/ COBI (n = 58) Wk 48 Wk 24 Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF TFV TFV-MP TFV-DP Cathepsin A

clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens TAF/FTC/EVG/COBI Noninferior to TDF/FTC/EVG/COBI Through Wk 48 Patients (%) Δ 1.0% (95% CI: to +10.0; P =.84) TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI Virologic Success* Virologic Nonresponse No Data 40. Sax P, et al. ICAAC 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) Wks Median (Q1, Q0) Change in BMD Wks Median (Q1, Q3) Change in BMD Spine Hip P <.001

clinicaloptions.com/hiv What’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 ClinicalTrials.gov. NCT ART-naive patients, HIV-1 RNA ≥ 5000 c/mL; CD4+ cell count > 50 cells/mm 3 ; eGFR ≥ 70 mL/min (N = 150) TAF/FTC/DRV/COBI (n = 100) TDF/FTC + DRV/COBI (n = 50) Wk 48 Wk 24

clinicaloptions.com/hiv What’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