HIV Alert: Best Practices in ART Following Recent Drug Approvals.2016
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In this downloadable slideset, Eric S. Daar, MD, and Joel E. Gallant, MD, MPH, review best practices and provide expert opinion in using newly approved ART options for treating patients with HIV. Format: Microsoft PowerPoint (.ppt) File size: 816 KB Date posted: 5/12/2016
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HIV Alert: Best Practices in ART Following Recent Drug Approvals.2016
- 1. HIV Alert: Best Practices in ART Following Recent Drug Approvals This program is supported by independent educational grants from Gilead Sciences and ViiV Healthcare.
- 2. Slide credit: clinicaloptions.com About These Slides Please feel free to use, update, and share some or all of these slides in your noncommercial presentations to colleagues or patients When using our slides, please retain the source attribution: These slides may not be published, posted online, or used in commercial presentations without permission. Please contact permissions@clinicaloptions.com for details
- 3. Faculty Eric S. Daar, MD Chief, Division of HIV Medicine Harbor-UCLA Medical Center Professor of Medicine David Geffen School of Medicine at UCLA Los Angeles, California Joel E. Gallant, MD, MPH Medical Director of Specialty Services Southwest CARE Center Santa Fe, New Mexico Adjunct Professor of Medicine Division of Infectious Diseases Johns Hopkins University School of Medicine Baltimore, Maryland
- 4. Faculty Disclosure Information Eric S. Daar, MD, has disclosed that he has received consulting fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Teva, and ViiV and funds for research support from Bristol-Myers Squibb, Gilead Sciences, Merck, and ViiV. Joel E. Gallant, MD, MPH, has disclosed that he has received consulting fees from Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, and ViiV and funds for research support from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck, Sangamo, and ViiV.
- 5. Slide credit: clinicaloptions.com Program Overview Indications and Supporting Data for FTC/TAF How FTC/TAF Compares With Other NRTI Backbones Expert Perspective – When I’ll Use FTC/TAF… and When I Won’t
- 6. Slide credit: clinicaloptions.com FTC/TAF Recently FDA Approved Label information: – Indicated in combination with other ARVs for the treatment of HIV infection – Not recommended for pts with CrCl < 30 mL/min – No dose adjustment necessary CrCl ≥ 30 mL/min; FTC/TDF requires dose adjustment CrCl 30-49 mL/min – Not indicated for PrEP or for pts coinfected with HBV – Dose: FTC 200 mg, TAF 25 mg Joins other approved TAF-containing fixed-dose combinations – EVG/COBI/FTC/TAF – RPV/FTC/TAF FTC/TAF [package insert]. April 2016. FTC/TDF [package insert]. April 2016.
- 7. Clinical Trials Supporting FTC/TAF Use Study Pt Population Treatment GS-104/111[1] Treatment naive (N = 1733) Pts randomized to EVG/COBI/FTC/TAF* or EVG/COBI/FTC/TDF GS-109[2] Virologically suppressed on TDF-based regimen (N = 1436) Pts switched to EVG/COBI/FTC/TAF* or remained on TDF-based regimen GS-1089[3] Virologically suppressed on FTC/TDF + third ARV (N = 663) Pts switched to FTC/TAF† + continued third ARV or remained on FTC/TDF + third ARV GS-112[4] Virologically suppressed on varied regimens; stable eGFRCG 30-69 mL/min (N = 242) Pts switched to EVG/COBI/FTC/TAF* Slide credit: clinicaloptions.com 1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. 4. Pozniak A, et al. J Acquir Immune Defic Syndr. 2016;71:530-537. *EVG/COBI/FTC/TAF dosing: 150/150//200/10 mg. † FTC/TAF dosing: 200/10 mg with boosted PIs; 200/25 mg with unboosted third drug.
- 8. Wk 48 Efficacy: TAF-Based Treatment Noninferior to TDF-Based Treatment 1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. 100 80 60 40 20 0 Wk48HIV-1RNA <50c/mL(%) GS-104/111[1] Tx Naive* TAF-based regimen TDF-based regimen 92 90 97 93 94 93 Slide credit: clinicaloptions.com GS-109[2] Switch† GS-1089[3] Switch‡ 2.0% (-0.7% to 4.7%) Tx Difference (95% CI) 4.1% (1.6% to 6.7%) P = .0002 1.3% (-2.5% to 5.1%) *GS-104/111: EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF. † GS-109: Switched to EVG/COBI/FTC/TAF or remained on TDF-based ART. ‡ GS-1089: Switched to FTC/TAF + third ARV or remained on FTC/TDF + third ARV. n/N = 932/ 959 444/ 477 314/ 333 307/ 330 800/ 866 784/ 867
- 9. TAF Associated With Improvements in Renal Markers vs TDF In each of the GS-104/111,[1] GS-109,[2] and GS-1089[3] studies, FTC/TAF-based treatment was associated with each of the following (vs TDF-based treatment) at treatment Wk 48: – Higher eGFRCG – Less proteinuria (urinary protein, albumin, RBP, and β2-microglobulin to Cr ratio) No proximal renal tubulopathy or Fanconi syndrome associated with FTC/TAF-based treatment Slide credit: clinicaloptions.com 1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165.
- 10. TAF Associated With Improved BMD vs TDF GS-104/111[1] : smaller declines in spine and hip BMD associated with starting EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF at Wk 48 (P < .0001) GS-109[2] and GS-1089[3] : switching to FTC/TAF-based treatment improved spine and hip BMD vs remaining on FTC/TDF-based treatment at Wk 48 Slide credit: clinicaloptions.com 1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. Spine4 2 0 Mean%Change inBMD(95%CI) 1.5 -0.2 P < .001 BL Wk 24 Wk 48 Hip4 2 0 1.1 -0.2 BL Wk 24 Wk 48 GS-1089: Mean % BMD Change From BL FTC/TAF FTC/TDF P < .001
- 11. Lipid Increases Greater With TAF Than TDF TAF lacks lipid-lowering effects of TDF but does not have negative impact on lipids Similar lipid effects observed in GS-109[2] and GS-1089[3] Slide credit: clinicaloptions.com GS-104/111: Median Lipid Changes in Treatment-Naive Pts[1] 1. Sax PE, et al. Lancet. 2015;385:2606-2615. 2. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. 3. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. 200 150 100 50 0 5 4 3 2 1 0 189 160 177 163 115 101 109 104 51 44 44 48 114 95 108 100 3.7 3.6 3.7 3.6 TC:HDL Ratio P = .84 Triglycerides P = .027 HDL P < .001 LDL P < .001 TC P < .001 EVG/COBI/FTC/TAF Wk 48 Baseline EVG/COBI/FTC/TDF Wk 48 Baseline MedianValues(mg/dL)
- 12. GS-1249: Switching Pts With HIV/HBV Coinfection to EVG/COBI/FTC/TAF International, multicenter, single-arm, open-label phase IIIb trial (N = 72) – Pts with virologically suppressed HIV infection on any regimen, chronic HBV coinfection, and eGFR > 50 mL/min switched to EVG/COBI/FTC/TAF for 48 wks By Wk 48, 2/70 (3%) pts lost HBsAg/gained HBsAb; 2/30 (7%) pts had lost HBeAg; 1/30 (3%) pts gained HBeAb 20 Gallant J, et al. IAS 2015. Abstract WELBPE13. Pts(%) 94 92 Wk 24 Wk 48 100 80 60 40 20 0 HBV DNA < 29 IU/mL 86 92 HIV-1 RNA < 50 c/mL 100 80 60 40 0 Slide credit: clinicaloptions.com
- 13. GS-119: Switch to EVG/COBI/FTC/TAF + DRV in Treatment-Experienced Pts Multicenter, open-label, randomized trial in which virologically suppressed, treatment-experienced pts on DRV-containing ART with history of drug resistance* switched to EVG/COBI/FTC/TAF + DRV (n = 89) or continued on baseline ART (n = 46) – 39% of pts receiving ≥ 6 pills/day at BL; median pills/day at BL = 5 2 100 Huhn G, et al. IDWeek 2015. Abstract 726. Slide credit: clinicaloptions.com *Resistance to ≥ 2 ARV classes, including ≤ 3 thymidine analogue mutations and K65R, but not integrase inhibitors, unless currently receiving raltegravir, and there is no DRV resistance. HIV-1 RNA < 50 c/mL 94 80 60 40 20 0 Virologic Failure No Data 76 11 3 13 EVG/COBI/FTC/TAF + DRV Baseline ART Treatment difference: 18.3% (95% CI: 3.5% to 33.0%; P = .004) Pts,Wk48(%)
- 15. Slide credit: clinicaloptions.com Considerations With NRTI Backbones and Associated Regimens NRTIs Considerations ABC/3TC DTG/ABC/3TC* only STR including unboosted INSTI Mixed data on CVD risk with ABC in high-risk pts Cannot be used in HLA-B*5701–positive pts Not recommended for pts with CrCl < 50 mL/min FTC/TDF STRs: EVG/COBI/FTC/TDF,* EFV/FTC/TDF, RPV/FTC/TDF Potential for renal toxicity and proximal tubulopathy EVG/COBI/FTC/TDF should not be initiated in pts with CrCl < 70 mL/min; discontinue in pts with CrCl < 50 mL/min EFV/FTC/TDF or RPV/FTC/TDF: not for use in pts with CrCl < 50 mL/min FTC/TDF must be dose adjusted when CrCl 30-49 mL/min Potential for decreases in BMD Lipid-lowering effects FTC/TAF STRs: EVG/COBI/FTC/TAF* and RPV/FTC/TAF Comparable efficacy and improved renal and bone profiles vs FTC/TDF No dose adjustment necessary when CrCl ≥ 30 mL/min *DHHS guideline–recommended initial regimen. References in slidenotes.
- 16. Expert Perspective: Selecting Therapy in the New Treatment Landscape
- 17. Slide credit: clinicaloptions.com Key Questions and Considerations Surrounding Use of FTC/TAF Should TDF-based regimens be dropped from consideration of “optimal” first-line regimens? When considering DTG, what are the pros and cons of DTG/ABC/3TC vs DTG + FTC/TAF? Are there specific pts for whom the FTC/TAF backbone should ALWAYS be used? Specific pts for whom it should NEVER be used? Should all pts on TDF-based regimens be switched proactively to TAF-based regimens?
- 18. Slide credit: clinicaloptions.com Should TDF-Based Regimens Still Be Considered as Initial Therapy? DHHS-Recommended First-line Regimens, January 2016 INSTI based DTG/ABC/3TC RAL + FTC/TDF DTG + FTC/TDF EVG/COBI/FTC/TDF EVG/COBI/FTC/TAF Boosted PI based DRV/RTV + FTC/TDF DHHS ART Guidelines. January 2016.
- 19. Slide credit: clinicaloptions.com Should TDF-Based Regimens Still Be Considered as Initial Therapy? EFV/FTC/TDF remains effective, economical, convenient choice for many pts in resource- constrained settings DHHS ART Guidelines. January 2016. DHHS-Recommended First-line Regimens With TAF Replacements INSTI based DTG/ABC/3TC RAL + FTC/TAF DTG + FTC/TAF EVG/COBI/FTC/TAF Boosted PI based DRV/RTV + FTC/TAF
- 20. Slide credit: clinicaloptions.com If DTG Is Your Preferred INSTI, How Do You Choose DTG/ABC/3TC vs DTG + FTC/TAF? Consideration Potential Choice DTG/ABC/3TC DTG + FTC/TAF Pt might benefit from STR vs MTR (adherence or preference) Pt has high CVD risk Pt is HLA-B*5701 positive Pt has osteopenia or osteoporosis Pt has renal impairment * *DTG/ABC/3TC not recommended for pts with CrCl < 50 mL/min as 3TC dose adjustment required. DTG/ABC/3TC [package insert]. September 2015. FTC/TAF [package insert]. April 2016.
- 21. Slide credit: clinicaloptions.com Opinion: For Which Pts Will I Always/ Never Use TAF-Based Therapy? Always/usually – Pts with high CVD risk Relative contraindications – Pts with potential COBI drug interactions (EVG/COBI/FTC/ TAF) – Pt receiving PPIs or H2 blockers (RPV/FTC/TAF) – Pt with CD4+ cell count < 200 c/mm3 (RPV/FTC/TAF) Never/unlikely – Pt with CrCl < 30 mL/min – Pt with severe hepatic impairment (EVG/COBI/FTC/ TAF) – Pt with HIV-1 RNA > 100,000 copies/mL (RPV/FTC/TAF) – Pt receiving rifamycin – Pregnant pt – As PrEP References in slidenotes.
- 22. Slide credit: clinicaloptions.com Should All Pts on TDF-Based Regimens Be Switched to TAF-Based Regimens? Considerations for switching to TAF-based regimen – Efficacy maintained – Renal and bone improvements Considerations for maintaining therapy – Does switch require adjustment from STR to MTR? – Relevant for pts on EFV/FTC/TDF – Long-term data with TDF-based regimens
- 23. Slide credit: clinicaloptions.com Take-Home Points Guideline-recommended regimens for first-line therapy likely to evolve to FTC/TAF + an INSTI or DRV/RTV or DTG/ABC/3TC TAF-based treatment noninferior to TDF-based treatment in terms of efficacy in first-line and switch settings – TAF-based treatment associated with improved BMD and renal function vs TDF-based treatment TAF-based regimens should be considered: – To replace TDF-based regimens as optimal agents in the first-line setting – As switch options for pts on TDF-based regimens Use of FTC/TAF-containing vs ABC/3TC-containing regimens should be considered for each individual pt
- 24. Go Online for More CCO Coverage of HIV! Timely Webinars with expert faculty that address important developments in HIV care as they occur Downloadable Webinar slides and audio for self-study and use in your own presentations clinicaloptions.com/hiv
Editor's Notes
- These slides include notes based on commentary provided by Joel E. Gallant, MD, MPH.
- Disclaimer: The materials published on the Clinical Care Options Web site reflect the views of the authors of the CCO material, not those of Clinical Care Options, LLC, the CME providers, or the companies providing educational grants. The materials may discuss uses and dosages for therapeutic products that have not been approved by the United States Food and Drug Administration. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or using any therapies described in these materials.
- FTC, emtricitabine; TAF, tenofovir alafenamide.
- ARV, antiretroviral; COBI, cobicistat; CrCl, creatinine clearance; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; HBV, hepatitis B virus; PrEP, pre-exposure prophylaxis; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; WT, wild type. FTC/TAF has recently been FDA approved and is indicated for use in combination with other antiretrovirals for HIV treatment. It is not recommended for patients with creatinine clearances lower than 30 mL/min. However, a difference from FTC/TDF—which requires dose adjustment at creatinine clearances of 30 to 49 mL/min—is that with FTC/TAF, you do not have to reduce or adjust the dose with creatinine clearances down to 30 mL/min. It is not indicated for PrEP or yet for patients coinfected with HBV, and the dose is the same for everybody: FTC 200 mg with TAF 25 mg. FTC/TAF now joins 2 other approved TAF-containing fixed-dose combinations: EVG/COBI/FTC/TAF with elvitegravir and cobicistat and RPV/FTC/TAF with rilpivirine.
- ARV, antiretroviral; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. This slide highlights some of the most important trials supporting FTC/TAF use. GS-104 and -111 were 2 identical trials conducted simultaneously to compare EVG/COBI/FTC/TAF with EVG/COBI/FTC/TDF in a large number of treatment-naive patients; these were the most important studies to get EVG/COBI/FTC/TAF approved. Then in GS-109, virologically suppressed patients on TDF-containing regimens were randomized to stay on their preexisting regimens or to switch to EVG/COBI/FTC/TAF. Another switch study just presented at CROI this year was GS-1089. Patients who were virologically suppressed on FTC/TDF with a third agent were randomized to either continue their current regimen or to switch to FTC/TAF plus a third agent in a placebo-controlled, blinded fashion.
- ARV, antiretroviral; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RNA, ribonucleic acid; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; Tx, treatment. Here are the efficacy results for GS-104/111, -109, and -1089. Clearly, noninferiority is established. Quite frankly, efficacy here is reassuring, but not really the most interesting part of any of these studies, because the efficacy is similar between arms in each study. What is more interesting with these studies, of course, is looking at differences in toxicity between TAF and TDF, which will be discussed in the following slides.
- Cr, creatinine; eGFRCG, estimated glomerular filtration rate by Cockcroft-Gault formula; FTC, emtricitabine; RBP, renal-binding protein; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. In terms of kidney issues, we know that TAF is associated with improvements in renal markers compared to TDF. Compared with FTC/TDF in GS-104/111, -109, and -1089, FTC/TAF-based treatment was associated with higher estimated GFRs (using the Cockcroft-Gault equation) and less proteinuria; that includes both overall proteinuria, as measured by urine protein or albumin to creatinine ratios, and tubular proteinuria, as measured by retinol-binding protein and β2-microglobulin to creatinine ratios. There has not been, so far, proximal renal tubulopathy or Fanconi syndrome seen in patients on FTC/TAF, whereas that is sometimes seen with TDF.
- BL, baseline; BMD, bone mineral density; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. TAF is also associated with improved bone mineral density compared to TDF in all of the aforementioned studies. In the GS-104/111studies of treatment-naive patients, there were smaller declines in spine and hip BMD for EVG/COBI/FTC/TAF vs EVG/COBI/FTC/TDF. In the GS-109 and -1089 switch studies, BMD for patients who remained on TDF stayed fairly stable because they had presumably already experienced their decline early on when starting TDF, but those who switched from TDF to TAF had a significant bone mineral density increase over 48 weeks.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; HDL, high density lipoprotein, LDL, low density lipoprotein; TAF, tenofovir alafenamide; TC, total cholesterol; TDF, tenofovir disoproxil fumarate. Lipids tend to rise when you switch from TDF to TAF, and they tend to be higher on TAF than TDF if you start with TAF. The reason is not because TAF increases lipids. The reason is that TDF—tenofovir, in general—has lipid-lowering effects, and TDF achieves greater plasma levels of tenofovir than TAF. So, TAF does not have a negative impact; it just fails to have the positive impact, but these differences are fairly small. Also, notice that the total cholesterol to HDL ratio is really no different between TAF and TDF, and though this particular graph is from the GS-104/111 studies, you see the same effects with GS-109 and GS-1089.
- COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; HBeAb, hepatitis B e antibody; HBeAg, hepatitis B e antigen; HBsAb, hepatitis B surface antibody; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; RNA, ribonucleic acid; TAF, tenofovir alafenamide. The GS-1249 study switched HIV/HBV coinfected patients who were already HIV suppressed, but not necessarily HBV suppressed, to EVG/COBI/FTC/TAF. Post-switch, these patients maintained HIV suppression. Interestingly, by Week 48, 3% of patients had lost their HBV surface antigen and gained surface antibody; 7% had lost E antigen; and 3% had gained E antibody. It is hard to know what to make of that because we do not have a comparison group; we do not know what would have happened to them had they stayed on their existing regimen.
- ART, antiretroviral therapy; ARV, antiretroviral; COBI, cobicistat; DRV, darunavir; eGFR,, estimated glomerular filtration rate; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; TAF, tenofovir alafenamide. The GS-119 study randomized treatment-experienced patients (in some cases fairly highly treatment-experienced patients) to either stay on their existing salvage regimen or to switch to a 2-pill regimen of EVG/COBI/FTC/TAF plus darunavir. Now, what is important to note is resistance. To get into the study, patients had to have resistance to at least 2 classes of drugs, but they could not have more than 3 thymidine analogue mutations; they could not have integrase resistance unless they were currently receiving raltegravir and suppressed; and they could not have darunavir resistance, so this is a selected group. Still, 39% of these patients were on 6 or more pills per day at baseline, and the median number of pills was 5. You can see that switching to EVG/COBI/FTC/TAF plus darunavir was actually associated with a better outcome than remaining on previous therapy. The better outcome was not just due to easier regimens and less toxicity, because you do see that there was a difference between the 2 regimens in virologic failure. Thus, a switch to EVG/COBI/FTC/TAF may be an option for some heavily-treated, experienced patients, but remember that this cannot be applied to all of them because of the restrictions on resistance.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; BMD, bone mineral density; COBI, cobicistat; CrCl, creatinine clearance; CVD, cardiovascular disease; DHHS, US Department of Health and Human Services; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; INSTI, integrase strand-transfer inhibitor; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. References: DHHS ART Guidelines. January 2016. DTG/ABC/3TC [package insert]. September 2015. FTC/TAF [package insert]. April 2016. FTC/TDF [package insert]. April 2016. EVG/COBI/FTC/TAF [package insert]. March 2016. Sax PE, et al. Lancet. 2015;385:2606-2615. Mills A, et al. Lancet Infect Dis. 2016;16:43-52. Gallant JE, et al. Lancet HIV. 2016;3:e158-e165. Let&apos;s talk about the NRTI backbones that we are currently using. I would say that there are 3. The first one is abacavir/lamivudine. Considerations here are that there is a single-table regimen (STR), with dolutegravir, and this is the only STR right now to not include a tenofovir component and to include an unboosted integrase inhibitor. Lingering controversy about the risk of cardiovascular disease and MI with abacavir still exists, so DHHS guidelines recommend avoiding it in high-risk patients with multiple risk factors or with known cardiovascular disease, and, of course, you cannot use it in HLA-B*5701-positive patients. The ABC/3TC NRTI backbone is also not recommended for patients with creatinine clearances lower than 50 mL/min because technically you&apos;re supposed to reduce the dose of lamivudine, which means breaking up the combination. Next, there&apos;s FTC/TDF, which we&apos;ve been using for a long time. It&apos;s available in 3 different single-tablet regimens, but there is the potential for nephrotoxicity and proximal tubulopathy, and so you should not use these STRs in patients with creatinine clearances lower than 70 mL/min, and you should discontinue use when the creatinine clearance is below 50 mL/min. Remember that FTC/TDF itself is supposed to be dose adjusted if the creatinine clearance is between 30 and 49 mL/min. Again, there are potentials for decreases in bone mineral density that are greater than what we see with other nucleoside-based regimens, and there is the advantage of the lipid-lowering effects, which sort of came as a surprise to people after we started using TDF. Then, finally, we now have FTC/TAF, which is available as a single-tablet regimen with elvitegravir and cobicistat or with rilpivirine. It has comparable efficacy compared to TDF-based regimens but improved kidney and bone profiles, and you don&apos;t have to adjust doses down to a creatinine clearance of 30 mL/min.
- 3TC, lamivudine; ABC, abacavir; DTG, dolutegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Let&apos;s talk about how we select therapy given the new availability of TAF-based agents. Some of the key questions we will want to talk about are: if TDF-based regimens should be dropped from the recommended regimens and guidelines and replaced by TAF; when considering dolutegravir, the pros and cons of using it in the single-tablet formulation with abacavir/lamivudine vs using it with FTC/TAF; if there are specific patients for whom the FTC/TAF backbone should always be used or never be used; and if all patients on TDF-based regimens should be switched proactively regardless of whether they are having any trouble with TDF.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Should TDF-based regimens still be considered? These are the current DHHS guidelines as of January 2016. Right now, everything has either abacavir or TDF with the exception of EVG/COBI/FTC/TAF, which is now a recommended regimen. I&apos;m told that there may be an update maybe in July based on these new regimens.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. This is what the DHHS guidelines would look like if we replaced all of the TDF-based regimens with TAF-based regimens. Efavirenz/FTC/TDF is no longer a recommended regimen, but it is on the alternative list, and it is still an effective, relatively economical, and convenient choice, especially for patients in resource-constrained settings where it is the most widely used regimen. Keep in mind that this single-tablet regimen containing TDF will not have an equivalent TAF-containing version.
- 3TC, lamivudine; ABC, abacavir; CVD, cardiovascular disease; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine; MTR, multiple-tablet regimen; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Let&apos;s say that dolutegravir is your preferred integrase inhibitor. How do you choose between using it as a coformulation with abacavir/lamivudine or as a separate tablet with FTC/TAF? Clearly, in patients who really want or who would really benefit from a single-tablet regimen from an adherence standpoint, your choice is going to be DTG/ABC/3TC. In patients who have multiple cardiac risk factors or who are HLA-B*5701 positive, FTC/TAF is likely going to be your choice. Osteopenia and osteoporosis are harder; I don&apos;t know that we know which one is better. The 2 have not yet been compared, although studies are ongoing. I think we need a head-to-head comparison to know that, so either regimen would be acceptable here. In patients with renal impairment, you could also use either one. Keep in mind that the abacavir/lamivudine regimen would not be recommended for creatinine clearances lower than 50 mL/min.
- COBI, cobicistat; CrCl, creatinine clearance; CVD, cardiovascular disease; EVG, elvitegravir; FTC, emtricitabine; HBV, hepatitis B virus; PPI, proton pump inhibitor; PrEP, pre-exposure prophylaxis; RNA, ribonucleic acid; RPV, rilpivirine; TAF, tenofovir alafenamide. References: DTG/ABC/3TC [package insert]. September 2015. EVG/COBI/FTC/TDF [package insert]. March 2016. FTC/TAF [package insert]. April 2016. FTC/TDF [package insert]. April 2016. RPV/FTC/TAF [package insert]. March 2016. Are there patients for whom you would always use TAF? For hepatitis B coinfection, you clearly should be using tenofovir of some kind; TDF is currently indicated for hepatitis B, but there are data supporting TAF as an HBV drug, and I suspect that TAF will eventually get an approval for that indication. In patients with high cardiovascular risk, you&apos;re going to want to avoid abacavir. There are very few contraindications to TAF itself, but there are relative contraindications to some of the TAF-containing regimens. For example, cobicistat in EVG/COBI/FTC/TAF has a lot of drug interactions, so that is an important consideration. Patients using proton pump inhibitors or H2 blockers should avoid use of RPV/FTC/TAF; similarly, patients with CD4 counts below 200 probably should not be on RPV/FTC/TAF either. Are there patients for whom you would never use TAF at all? We have discussed not using TAF in patients with creatinine clearances lower than 30 mL/min, but you might also avoid EVG/COBI/FTC/TAF use in patients with severe hepatic impairment and RPV/FTC/TAF use in patients with viral loads above 100,000 copies/mL.
- EFV, efavirenz; FTC, emtricitabine; MTR, multiple-tablet regimen; STR, single-tablet regimen; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Should all patients on TDF-based regimens be switched to TAF? The considerations in favor of that approach are that we know that efficacy is maintained with TAF in multiple switch studies, and we see renal and bone improvements vs TDF. Why would you consider not switching? Well, in one case, if you have somebody who really, really likes being on efavirenz/FTC/TDF, you are not going to be able to switch them to TAF without breaking up the single-tablet regimen, so that may be a consideration in some patients. Of course, we also have longer-term data with TDF-based regimens, but I would say that the overall benefit of switching seems to outweigh the risk. This is especially true because we saw, in many of those studies, that even though patients may not have had clinically significant kidney disease on TDF, they did have more proteinuria, including proximal tubular proteinuria. You have to wonder whether, over time, this would lead to an increased risk of tubulopathy and kidney disease.
- 3TC, lamivudine; ABC, abacavir; BMD, bone mineral density; DRV, darunavir; DTG, dolutegravir; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate. Here are some take-home points for this HIV Alert program. Guideline-recommended regimens for first-line therapy are very likely to evolve to FTC/TAF. I&apos;m fairly confident that FTC/TAF with a third agent will become a recommended regimen. The question is whether TDF will be removed or whether they&apos;ll both just be there. TAF-based treatment is noninferior to TDF-based treatment in terms of efficacy, both in first-line and switch settings, and TAF-based treatment has been associated with improvements in bone mineral density and renal function compared to TDF-based treatment. I think that TAF-based regimens should be considered to replace TDF-based regimens as optimal agents in first-line settings and as switch options for patients currently on TDF-based regimens. Whether or not to use FTC/TAF vs abacavir/lamivudine depends on the patient. There are very good arguments for both, and these 2 nucleoside backbones will and should become the 2 that we use in the vast majority of our patients.