What’s New in Coformulated Antiretroviral Regimens.2014
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Andrew R. Zolopa, MD, discusses how new agents are contributing to the development of novel coformulated antiretroviral agents and regimens. Format: Microsoft PowerPoint (.ppt) File size: 1.33 MB
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What’s New in Coformulated Antiretroviral Regimens.2014
- 1. Andrew R. Zolopa, MD Professor of Medicine Director, Stanford Positive Care Program Principal Investigator, Stanford AIDS Clinical Trials Unit Stanford University School of Medicine Stanford, California What’s New in Coformulated Antiretroviral Regimens This program is supported by an educational grant from
- 2. clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens Faculty Andrew R. Zolopa, MD Professor of Medicine Director, Stanford Positive Care Program Principal Investigator, Stanford AIDS Clinical Trials Unit Stanford University School of Medicine Stanford, 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.
- 3. Please review the slide notes for a discussion by Andrew R. Zolopa, MD
- 4. 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
- 5. clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens Currently Available Coformulated Antiretroviral Agents and Regimens Agent 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/COB I Dual NRTI + INSTI + booster 2012
- 6. 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
- 7. 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;208:32-39. 2. DHHS Guidelines February 2013. 3. TDF/FTC/EVG/COBI [package insert]. 4. RPV [package insert]. 5. DTG [package insert].
- 8. clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens Renal Monitoring With Cobicistat 7. TDF/FTC/EVG/COBI [package insert]. 8. DHHS Guidelines February 2013. ChangeFromBLin SerumCr (mg/dL;IQR) 0 -0.05 -0.10 0.15 0.10 0.05 0.20 *Serum phosphorus should be measured in patients at risk for renal impairment 2 4 8 12 16 24 32 40 48 Wks BL At BL,* Estimated CrCl Urine glucose Urine protein
- 9. 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 2013. Wk 4—new baseline against which further changes should be measured ChangeFromBLin SerumCr (mg/dL;IQR) 0 -0.05 -0.10 0.15 0.10 0.05 0.20 2 4 8 12 16 24 32 40 48 Wks BL *Serum phosphorus should be measured in patients at risk for renal impairment At BL,* Estimated CrCl Urine glucose Urine protein
- 10. 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 2013. Serum Cr* Serum Cr*Serum Cr* Serum Cr* UA UA ChangeFromBLin SerumCr (mg/dL;IQR) 0 -0.05 -0.10 0.15 0.10 0.05 0.20 At BL,* Estimated CrCl Urine glucose Urine protein Wk 4—new baseline against which further changes should be measured 2 4 8 12 16 24 32 40 48 Wks BL *Serum phosphorus should be measured in patients at risk for renal impairment
- 11. 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
- 12. 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.
- 13. 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 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 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)
- 14. clinicaloptions.com/hiv What’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) 80 75 0 20 40 60 80 100 88 84 8482 Wk 96 7 7 6 8 7 10 4 5 5 7 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.
- 15. clinicaloptions.com/hiv What’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)
- 16. 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 2013. PE7/5. 26. ClinicalTrials.gov. NCT01495702. 27. ClinicalTrials.gov. NCT01475838.
- 17. clinicaloptions.com/hiv What’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
- 18. 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;381:735-743. 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<50 atWk48 VL<50: DTG/ABC/3TC
- 19. 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 24 33. ClinicalTrials.gov. NCT01910402.
- 20. 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 48 34. Gallant JE, et al. J Infect Dis. 2013;208:32-39. ATV/COBI ATV/RTV Δ-2.2% 95% CI: -7.4 to 3.0) Virologic Success* Virologic Nonresponse Patients,% 85 87 293 304 0 20 40 60 80 100 5.8 4.0 9.0 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
- 21. 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. 2012. Abstract O_20. 36. Kakuda TN, et al. IAS 2013. Abstract MOPE029. 8000 6000 4000 2000 0 0 6 12 18 24 Hrs PlasmaConcentrationofDRV (ng/mL)(Mean±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
- 22. 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 48Wk 24 37. ClinicalTrials.gov. NCT01440569.
- 23. 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 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 24 Gut TFV TDF TAF Plasma TDF/TFV TAF Lymphoid Cells TAF TFV TFV-MP TFV-DP Cathepsin A
- 24. clinicaloptions.com/hiv What’s New in Coformulated Antiretroviral Regimens TAF/FTC/EVG/COBI Noninferior to TDF/FTC/EVG/COBI Through Wk 48 Patients(%) 88.4 87.9 Δ 1.0% (95% CI: -12.1 to +10.0; P = .84) TAF/FTC/EVG/COBI TDF/FTC/EVG/COBI 99 51 0 20 40 60 80 100 6.3 10.3 5.4 1.7 6 17 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 Median(Q1,Q0) ChangeinBMD 12 24 36 48 2 Wks -2 -4 0 -6 Median(Q1,Q3) ChangeinBMD Spine Hip P < .001 P < .001
- 25. 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 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
- 26. 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
Editor's Notes
- There are numerous advantages and disadvantages related to the use of coformulated agents and antiretroviral regimens; many are listed on this slide. Coformulations provide patients with increased simplicity and convenience related to their regimen: Many of the coformulated agents are dosed once daily, and the coformulated regimens are all 1 pill once daily. For patients who have private insurance, coformulations offer the opportunity for fewer copays. Related to efficacy, coformulation reduces selective nonadherence to the components of their regimens. We know it is important that we use multiple medications in controlling HIV infection; if any one part of that combination is left out, then the patient is at risk for virologic failure and resistance. By combining all of the medications into a single tablet, or fewer fixed-dose tablets, we reduce that risk of selective nonadherence and the possibility of resulting resistance to a suboptimal nonsuppressive regimen. An important disadvantage to using a fixed-dose combination is that one cannot adjust the dosage of the various components in that pill. For instance, a patient with moderate renal dysfunction may not be able to use any of the fixed-dose regimens if their renal function is in the range where the tenofovir disoproxil fumarate (TDF) (or lamivudine or emtricitabine) dose should be decreased. As more generic drugs become available for the treatment of HIV, it is not clear whether there will be additional restrictions placed on physicians in prescribing these newer coformulated drugs and regimens.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; LPV, lopinavir; RPV, rilpivirine; TDF, tenofovir; ZDV, zidovudine. There are currently numerous coformulated antiretroviral agents and regimens available. Some of the earliest coformulations included the dual-NRTI combination of zidovudine/lamivudine and the triple NRTI combination zidovudine/lamivudine/abacavir, both of which have been available for more than a decade. The first (and currently only) fixed-dose combination boosted PI, lopinavir/ritonavir, also has been available for almost a decade. In 2007, the first single‑tablet preferred regimen—TDF/emtricitabine/efavirenz—was introduced. That was followed recently by 2 other complete regimens, TDF/emtricitabine/rilpivirine and TDF/emtricitabine/elvitegravir/cobicistat. As discussed later in this program, additional complete regimens and other coformulated agents are in development.
- This program focuses on what is new in coformulated antiretroviral regimens and agents. I will first discuss the newer coformulated regimens that include approved agents. This category includes the currently approved regimen elvitegravir/cobicistat/TDF/emtricitabine and one in development, dolutegravir/abacavir/lamivudine. Interestingly, both of these combinations are already preferred regimens for first-line ART in the US Department of Health and Human Services (DHHS) guidelines. The next section of the program will address boosted PI options in development in which cobicistat replaces low-dose ritonavir as the boosting agent. These include the combination of atazanavir with cobicistat and the combination of darunavir with cobicistat. We will then look a little further into the future, to coformulated regimens that include the new tenofovir prodrug, tenofovir alafenamide fumarate (TAF). TAF is being studied in an INSTI-based regimen, combined with emtricitabine and elvitegravir/cobicistat, and a PI-based regimen, combined with emtricitabine and darunavir/cobicistat.
- ARV, antiretroviral; BL, baseline; Cr, creatinine; GFR, glomerular filtration rate; RTV, ritonavir; TC, total cholesterol; TG, triglycerides. A key component of many of the new coformulations is cobicistat, the new pharmacologic boosting agent. It is a small molecule and, importantly, has no HIV activity. As such, concerns about drug resistance related to cobicistat in patients who might have suboptimal virologic responses with this agent are lessened. Cobicistat has similar effects on metabolic parameters as ritonavir, that is, when compared with ritonavir used to boost the same agent. For example, in the study comparing ritonavir and cobicistat as boosting agents for atazanavir, the resulting changes in lipids were quite similar between the 2 arms of the study.[1] The mode of action of cobicistat is similar to that of ritonavir: both are inhibitors of the cytochrome isoenzyme CYP3A4. Therefore, the drug–drug interactions seen with cobicistat are similar to those seen with ritonavir.[2,3] It is important that physicians who prescribe the fixed-dose combinations that include this pharmacokinetic enhancer are aware of these drug–drug interactions. Some of these can lead to serious problems if physicians are not aware of them. Cobicistat also causes a modest and rapid increase in serum creatinine that is caused by the inhibition of tubular secretion of creatinine. This is not related to any change in the actual glomerular function. Other drugs, including several antiretrovirals in use for HIV treatment, have similar effects on the tubular handling of creatinine.[4,5] These include ritonavir, the NNRTI rilpivirine, and the new INSTI dolutegravir. The availability of cobicistat has allowed the development of new coformulated agents and regimens that are quite promising in the care of HIV infected patients.
- BL, baseline; CrCl, creatinine clearance; Cr, creatinine; IQR, interquartile range. The accompanying slides illustrate the modest increase seen in patients’ serum creatinine once they receive cobicistat and renal monitoring that is recommended when cobicistat is used. This curve is from the results of Study 102, in which elvitegravir/cobicistat/TDF/emtricitabine was compared with efavirenz/TDF/emtricitabine.[6] At baseline, one should measure estimated glomerular filtration rate, urine glucose, and urine protein.[7,8] If patients are at risk of renal impairment, a serum phosphorus level should also be obtained. Coformulated drugs containing cobicistat should not be initiated in patients who have impaired renal function, that is, estimated glomerular filtration rate (GFR) &lt; 70 mL/min. There are ongoing studies evaluating cobicistat as a pharmacologic booster in patients with estimated GFR &lt; 70 mL/min, but those studies have not been completed yet.
- BL, baseline; CrCl, creatinine clearance; Cr, creatinine; IQR, interquartile range. When the cobicistat regimen is started, there is an increase almost immediately—generally measured by 2 weeks and certainly present by 4 weeks—in the serum creatinine level. The median increase is approximately 0.14 mg/dL.[9-11]
- BL, baseline; COBI, cobicistat; CrCl, creatinine clearance; Cr, creatinine; EVG, elvitegravir; FTC, emtricitabine; IQR, interquartile range; TDF, tenofovir; UA, urinalysis. At the 4-week mark (denoted by the vertical hashed line), one should not expect any additional increases in serum creatinine. This level should provide the “new baseline” by which further creatinine levels are measured.[12,13] One would expect no progressive increases beyond this point; if such occur, they require investigation. In fact, the phase III studies of elvitegravir, which now report data out to 3 years, show that after that initial increase, the curve is generally flat. Serum creatinine should be measured at regular intervals, in general every 3-6 months.[13] Urinalysis should be done regularly to check for potential toxicity that might be associated with other drugs in the combination, for example, TDF. There is the potential that interpretation of renal function may be problematic or confusing to practitioners when assessing patients receiving coformulations that include both cobicistat and tenofovir DF. As noted previously, cobicistat blocks tubular secretion of creatinine, and TDF can cause tubular defects, but this has happened in only a small number of patients. The practitioner should be able to distinguish between the prompt (but small and nonprogressive) increase in creatinine related to cobicistat following the initiation of a cobicistat-containing regimen and the more progressive decline in renal function with increased creatinine often associated with other markers of tubulopathy (eg, proteinuria and or glycosuria) that occurs in a small minority of TDF-treated patients. The fixed-dose combinations that include drugs such as TDF and cobicistat should not be used with other nephrotoxic drugs as these combinations can increase the risk of renal toxicity.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; MVC, maraviroc; OCP, oral contraceptive pil This slide includes a partial list of important drug–drug interactions that can occur with cobicistat.[14] Again, these are similar to those associated with ritonavir. An important distinction, however, is that there is no interaction between cobicistat and methadone. ls; TDF, tenofovir.
- ART, antiretroviral therapy; COBI, cobicistat; EMEA, European Medicines Agency; EVG, elvitegravir; FTC, emtricitabine; PK, pharmacokinetic; TDF, tenofovir. In July 2013, the European authorities approved cobicistat as a stand-alone pharmacokinetic enhancer for once-daily atazanavir 300 mg or once-daily darunavir 800 mg when these drugs are used as part of a complete antiretroviral regimen.[15] In the United States, cobicistat is currently only available and approved as part of the coformulated single-tablet regimen of TDF/emtricitabine/elvitegravir/cobicistat. Approval as a single stand-alone pharmacoenhancing agent is still pending in the United States.[16]
- ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; QD, once daily; RTV, ritonavir; TDF, tenofovir. Turning now to data that support the use of newer fixed-dose combinations that contain approved agents, this slide outlines the 2 phase III trials for elvitegravir/cobicistat/TDF/emtricitabine.[17,18] In Study 102, this combination was compared head to head with coformulated efavirenz/TDF/emtricitabine, and in Study 103, elvitegravir/cobicistat/TDF/emtricitabine was compared head to head with atazanavir/ritonavir plus TDF/emtricitabine. These were registration trials that included large numbers of patients—more than 700 in each trial, which translates into a total of 700 patients randomized to elvitegravir/cobicistat/TDF/emtricitabine. The primary endpoint in both studies was the percentage of patients with HIV-1 RNA &lt; 50 copies/mL at Week 48 using the US Food and Drug Administration (FDA) snapshot analysis. Importantly, eligibility for these trials was limited to patients with baseline estimated GFR ≥ 70 mL/min.
- AE, adverse event; COBI, cobicistat; d/c, discontinued; EFV, efavirenz; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; TDF, tenofovir. When elvitegravir/cobicistat/TDF/emtricitabine was compared with efavirenz/TDF/emtricitabine, the virologic response rate at Weeks 48, 96, and 144, was comparable between the arms.[19-21] In fact, the criterion for noninferiority was met at all 3 time points. Numerically, the rates of viral suppression at each time point all favored elvitegravir/cobicistat/TDF/emtricitabine, but the CIs all cross 0, meaning that superiority was never achieved at any of these time points. Importantly, the number of patients failing with confirmed virologic failure—HIV-1 RNA &gt; 50 copies/mL—was quite small for both arms, and comparable between the 2 arms during the 3 years of follow-up.
- ATV, atazanavir; BL, baseline; CI, confidence interval; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. The results were very similar in the study comparing elvitegravir/cobicistat/TDF/emtricitabine and atazanavir/ritonavir plus TDF/emtricitabine. Again, quite comparable efficacy rates were seen between the 2 arms, with elvitegravir/cobicistat/TDF/emtricitabine demonstrating noninferiority at all time points.[22-24] The number of virologic failures was once again quite low in both arms and quite comparable.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; TDF, tenofovir. There is much interest in using new coformulated single-tablet regimens as switch agents. A sampling of some the switch studies involving elvitegravir/cobicistat/TDF/emtricitabine is listed on this slide.[25-27] Whereas many of these are switches to improve the simplicity of patient regimens, some of these are also evaluating metabolic parameters and tolerability profiles that might improve with these switches. Of note, the first study listed on this slide reported results at the 2013 European AIDS Clinical Society meeting. All 48 patients remained virologically suppressed through 48 weeks with no relevant changes in serum creatinine or in serum lipids after the switch.[25]
- The DHHS guidelines for first-line antiretroviral therapy were updated in October 2013 and all 3 agents of the INSTI class are now included in preferred regimens for treatment-naive patients.[28,29] Of note, the regimen comprising dolutegravir with abacavir/lamivudine is currently the only preferred regimen in this guideline that includes abacavir/lamivudine as the NRTI backbone.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BID, twice daily; CrCl, creatinine clearance; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; QD, once daily; RAL, raltegravir; RTV; ritonavir; TDF, tenofovir; VL, viral load. There have been 3 phase III studies of dolutegravir in treatment-naive patients.[30-32] Note that a proportion of dolutegravir patients in each trial—and all of the dolutegravir patients in the SINGLE trial—used abacavir/lamivudine as the NRTI backbone. This combination is now being studied as a coformulated single-tablet regimen. As was observed in the elvitegravir/cobicistat trials, high proportions of patients in each arm of each trial achieved the primary endpoint of HIV-1 RNA &lt; 50 copies/mL. The far right column of this slide shows this endpoint in patients on dolutegravir plus abacavir/lamivudine, attesting to the high levels of viral suppression with this regimen.
- 3TC, lamivudine; ART, antiretroviral; ABC, abacavir; ATV, atazanavir; FDC, fixed-dose combination; FTC, emtricitabine; TDF, tenofovir. An ongoing phase IIIB study is evaluating coformulated dolutegravir/abacavir/lamivudine compared with atazanavir/ritonavir plus TDF/emtricitabine in treatment-naive HIV-infected women.[33] Primary endpoint results for this study are expected in July 2015. In October 2013, this single-tablet regimen was submitted to regulatory authorities in the United States, Europe, and Canada for consideration of approval.
- ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; RTV, ritonavir; TDF, tenofovir. Turning now to novel boosted PI coformulations, cobicistat has been studied as a boosting agent for both darunavir and atazanavir. A phase III study in nearly 700 patients compared ritonavir-boosted atazanavir and cobicistat-boosted atazanavir, each on a backbone of TDF/emtricitabine.[34] This was the first time that pharmacologic boosters rather than antiretrovirals were the focus of a study in HIV-infected patients. At Week 48, 85% of patients in the cobicistat arm vs 87% in the ritonavir arm had virologic success—HIV-1 RNA &lt; 50 copies/mL by the FDA snapshot analysis—meeting the criteria for noninferiority between these 2 agents
- COBI, cobicistat; DRV, darunavir; FDC, fixed-dose combination; PK, pharmacokinetic; QD, once daily; RTV, ritonavir; SD, standard deviation. The coformulation of cobicistat with darunavir has been studied and the pharmacokinetic parameters assessed. This slide shows 2 studies in healthy volunteers. The figure on the left shows data from a comparison of darunavir 800 mg boosted with ritonavir as single agents vs darunavir boosted with cobicistat 150 mg in a coformulation in a dosing/washout study. The curves over 24 hours are overlapping at all time points, suggesting that cobicistat is effective as a booster, comparable to ritonavir.[35] The figure on the right shows a difference in darunavir concentration when boosted with cobicistat based on whether the patient is fed. The pharmacokinetic curves are better—higher peak and higher area under the concentration curve —in the fed state vs the fasted state; this was true whether darunavir and cobicistat were administered as single agents or in a fixed-dose combination.[36] The difference is undoubtedly important. In October 2013, the coformulation of darunavir/cobicistat was submitted to regulatory authorities in the Europe for consideration of approval.
- Additional clinical data on the outcomes associated with cobicistat-boosted darunavir are anticipated from an ongoing phase IIIb study evaluating the combination of darunavir, cobicistat, and 2 NRTIs in treatment-naive patients or as a switch option for patients virologically suppressed on another regimen who do not have darunavir-associated resistance mutations.[37] Results from this study are expected in the near future.
- ART, antiretroviral; COBI, cobicistat; DP, diphosphate; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; MP, monophosphate; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; TFV, tenofovir. Finally, studies of several coformulated regimens including the investigational drug tenofovir alafenamide fumarate (TAF) are currently ongoing. TAF is a new prodrug of tenofovir that has been compared with TDF, the currently used tenofovir prodrug. In a phase II study, these NRTIs were compared in patients with CD4+ cell counts &gt; 50 cells/mm³ and estimated GFRs ≥ 70 mL/min, as components of regimens that also included elvitegravir, cobicistat, and emtricitabine.[38,39] This was a small study of 170 patients; twice as many received the investigational drug TAF as the currently used drug TDF. Before I discuss the results of this study, it is important to differentiate the metabolism of TAF from TDF. Tenofovir itself is not bioavailable, and it therefore requires the administration of a prodrug. This prodrug—currently TDF—allows the tenofovir to be delivered to the plasma. TDF is rapidly hydrolyzed, releasing free tenofovir that then diffuses into cells. With TAF, on the other hand, the prodrug delivers tenofovir into the cell, where it is then metabolized by the protease cathepsin A, after which the tenofovir is phosphorylated to the active state. Cells that are rich in cathepsin A include lymphoid cells and hepatocytes, suggesting that TAF is likely to be an active drug to treat both HIV and hepatitis B virus.
- BMD, bone mineral density; COBI, cobicistat; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. In the phase II study, the fixed-dose combination containing TAF was noninferior to the coformulation containing TDF, with 88.4% vs 87.9% of patients achieving HIV-1 RNA &lt; 50 copies at Week 48, respectively.[40] There were very few virologic failures in either arm. There were smaller changes in bone mineral density at both Week 24 and Week 48 with TAF compared with TDF. The difference between the 2 arms was statistically significant at Week 48. This implies that there may be less toxicity associated with this new formulation. Since TAF is concentrated in cells, a smaller dose may be used. TAF is dosed at 10 mg/day vs 300 mg/day for TDF. That lower dose facilitates coformulation and may contribute to the lower levels of toxicity.
- ART, antiretroviral; COBI, cobicistat; DRV, darunavir; eGFR, estimated glomerular filtration rate; FTC, emtricitabine; MP, monophosphate; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. The small dose of TAF has already enabled the development of a fixed-dose coformulation with darunavir. (Given that the once-daily dose of darunavir is 800 mg, a coformulation that also contained 300 mg of TDF would not be possible.) An ongoing study of this, the first coformulated boosted-PI regimen, in treatment-naive patients is currently under way.[41] This study is scheduled to be completed in 2013, and the results are keenly awaited.
- ART, antiretroviral therapy. Conclusions In conclusion, coformulated drugs and regimens offer opportunities for simpler dosing for ART for our patients. Many patients favor these simple regimens for HIV treatment, considering that at the current time, they must assume that they will be receiving ART for a lifetime. This simplicity may result in benefits for adherence over the long term, and there may be some financial considerations for patients as well. Cobicistat is a new pharmacologic booster that has been investigated with the use of the integrase inhibitor elvitegravir and the PIs darunavir and atazanavir. It does appear to be effective at increasing the exposure of these drugs to an extent similar to that seen with low-dose ritonavir. Importantly, cobicistat has no antiviral activity, so there is no concern that it might select for antiretroviral resistance. It does however have an impact on serum creatinine. We understand the physiology, and this is not due to actual toxicity. However, use of cobicistat does require renal function monitoring, particularly when cobicistat is used with other drugs that might cause renal toxicity. That renal monitoring should include not only serum creatinine measurements but also urinalysis. Finally, other coformulated regimens that do not require boosting are also being developed. These may also be quite favorable for patients, and it is possible that regimens containing TAF may be better tolerated than those containing TDF.