ART Update 2015
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In this downloadable slideset, Joel E. Gallant, MD, MPH, reviews the evidence behind the latest antiretroviral guidelines and offers a glimpse at upcoming agents currently under investigation. Format: Microsoft PowerPoint (.ppt) File size: 3.00 MB Date posted: 6/15/2015
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ART Update 2015
- 1. 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 ART Update 2015 Supported by educational grants from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen Therapeutics, Merck and ViiV.
- 2. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium About These Slides Users are encouraged to use these slides in their own noncommercial presentations, but we ask that content and attribution not be changed. Users are asked to honor this intent These slides may not be published or posted online without permission from Clinical Care Options (email permissions@clinicaloptions.com) Disclaimer The materials published on the Clinical Care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.
- 3. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Disclosures 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.
- 4. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium START: Immediate vs Deferred ART International, randomized phase IV study – 215 sites in 35 countries Study stopped by data and safety monitoring board following results of interim analysis – Risk of serious illness or death reduced by 53% with immediate ART – Rates of serious AIDS-related and non–AIDS-related events lower in immediate ART arm ART-naive adults with CD4+ cell count > 500 cells/mm3 (N = 4685) Immediate ART* Delayed ART* (until CD4+ cell count ≤ 350 cells/mm3 ) Randomized 1:1 Interim results: serious AIDS and non-AIDS events, n 41 86 *Any licensed ART allowed, according to national guidelines. ClinicalTrials.gov. NCT00867048. NIH Press Release, May 27, 2015.
- 5. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium When to Start Therapy: Balance Now Favors Early ART Drug toxicity Preservation of limited Rx options Risk of resistance (and transmission of resistant virus) ↑ potency, durability, simplicity, safety of current regimens ↓ emergence of resistance ↓ toxicity with earlier therapy ↑ subsequent treatment options Risk of uncontrolled viremia at all CD4 levels ↓ transmission Delayed ART Early ART
- 6. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium DHHS Guidelines, April 2015: What to Start NNRTIs and ATV/r, previously classified as “recommended,” are now “alternative regimens” DHHS Guidelines. April 2015. *Only for pts who are HLA-B*5701 negative. † Only for pts with pre-ART CrCl ≥ 70 mL/min. Recommended Regimens INSTI based DTG/ABC/3TC* DTG + TDF/FTC EVG/COBI/TDF/FTC† RAL + TDF/FTC PI based DRV/r + TDF/FTC
- 7. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium DHHS Guidelines, April 2015: What to Start DHHS Guidelines. April 2015. *Only for pts with pre-ART HIV-1 RNA < 100,000 copies/mL and CD4+ > 200 cells mm3 . † Only for pts with pre-ART CrCl ≥ 70 mL/min. ‡ Only for pts who are HLA-B*5701 negative. Alternative Regimens NNRTI based EFV/TDF/FTC RPV/TDF/FTC* PI based ATV/COBI + TDF/FTC† ATV/r + TDF/FTC DRV/COBI + ABC/3TC‡ DRV/r + ABC/3TC‡ DRV/COBI + TDF/FTC† An alternative regimen may be the preferred regimen for some pts
- 8. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Integrase Inhibitors
- 9. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Difference in 96-wk cumulative incidence (97.5% CI) -20 0-10 10 20 15% (10% to 20%) 7.5% (3.2% to 12%) 7.5% (2.3% to 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors RAL Favors DRV/r Lennox JL, et al. Ann Intern Med. 2014;161:461-471. *Plus TDF/FTC. ATV/r* RAL* DRV/r* ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure 1.00 0.75 0.50 0.25 0.00 CumulativeIncidence Wks Since Study Entry 0 24 48 64 80 96 112 128 144
- 10. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Toxicities Associated With Discontinuation, n (%) ATV/r† (n = 605) RAL† (n = 603) DRV/r† (n = 601) Any 95 (16%) 8 (1%) 32 (5%) Gastrointestinal toxicity 25 2 14 Jaundice/hyperbilirubinemia 47 0 0 Other hepatic toxicity 4 1 5 Skin toxicity 7 2 5 Metabolic toxicity 6 0 2 Renal toxicity (all nephrolithiasis) 4 0 0 Abnormal chem/heme (excl. LFTs) 0 0 2 Other toxicity 2 3 4 *Participants allowed to switch therapy for intolerable toxicity. † Plus TDF/FTC. Lennox JL, et al. Ann Intern Med. 2014;161:461-471. ACTG 5257: Tolerability Failure Toxicity-Associated Discontinuation of Randomized ART*
- 11. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium GS 102: EVG/COBI/TDF/FTC Noninferior to EFV/TDF/FTC Through Wk 144 1. Sax PE, et al. Lancet. 2012;379:2439-2448. 2. Zolopa A, et al. J Acquir Immune Defic Syndr. 2013;63:96-100. 3. Wohl D, et al. J Acquir Immune Defic Syndr. 2014;65:e118-e120. Wk 48 Wk 144 EVG/COBI/TDF/FTC (n = 348) EFV/TDF/FTC (n = 352) 80 75 88 84 8482 Wk 96 7 7 6 8 7 10 5 9 9 11 12 15 Wk 48 Wk 144 Wk 96 Wk 48 Wk 144 Wk 96 Virologic Success Virologic Failure No Data 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% 0 20 40 60 80 100 8.3%
- 12. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium GS 103: EVG/COBI/TDF/FTC Noninferior to ATV/r + TDF/FTC Through Wk 144 1. DeJesus E, et al. Lancet. 2012;379:2429-2438. 2. Rockstroh J, et al. J Acquir Immune Defic Syndr. 2013;62:483-486. 3. Clumeck N, et al. J Acquir Immune Defic Syndr. 2014;65:e121-e124. EVG/COBI/TDF/FTC (n = 353) ATV/RTV + TDF/FTC (n = 355) 7875 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 No Data 8382 5 5 57 7 78 8 1010 14 18 -12% 12%0 Favors ATV/RTV Favors EVG/COBI -3.2% 9.4% 3.1% 2.7% 7.5% 1.1% 6.7% -2.1% -4.5% Wk 48[1] Wk 96[2] Wk 144[3] 95% CI for Difference
- 13. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium SINGLE: DTG + ABC/3TC Superior to EFV/TDF/FTC in ART-Naive Pts to Wk 144 Open-label extension, excluding pts with HBV Emergent resistance in those with VF: 0/39 (DTG) vs 7/33 (EFV) Virologic Success* Virologic Nonresponse No Virologic Data Pts(%) Favors EFV/TDF/FTC 95% CI for Difference 0 Wk 48 Wk 96 Wk 144 7.4% 8.0% 8.3% 2.5% 2.3% 2.0% 14.6% 13.8% 12.3% Favors DTG + ABC/3TC 15% Pappa K, et al. ICAAC 2014. Abstract H-647a. 88 81 80 72 71 63 5 6 7 8 10 7 7 13 12 20 30 18 100 80 60 40 20 0 DTG + ABC/3TC QD (n = 414) EFV/TDF/FTC QD (n = 419) Wk 48 96 144 Wk 48 96 144 Wk 48 96 144 *HIV-1 RNA < 50 copies/mL as defined by FDA Snapshot algorithm. -10% noninferiority margin. -15%
- 14. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium FLAMINGO: DTG Superior to DRV/r in ART-Naive Pts to Wk 96 Virologic Success Virologic Nonresponse No Virologic Data Favors DRV/r 95% CI for Difference 0%-12% Wk 48 Wk 96 7.1% 12.4% 0.9% 4.7% 20.2% 13.2% Subjects(%) Favors DTG 25% DTG 50 mg QD + 2 NRTIs (n = 242) DRV/r 800 mg/100 mg QD + 2 NRTIs (n = 242) Molina et al. HIV Drug Therapy Glasgow 2014; Glasgow, UK. Slides O153. 0 20 40 60 80 100 W48 W48 W48W96 W96 W96 90 83 80 68 6 7 8 12 4 10 12 21
- 15. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Comparing the Integrase Inhibitors Agent Advantages Disadvantages Raltegravir Longest experience Fewer drug interactions than EVG, DTG Twice daily dosing (for now) No coformulation Elvitegravir Single-tablet regimen (STR) Once-daily dosing Requires COBI boosting COBI drug interactions similar to RTV Dolutegravir The only non-TDF–containing STR Once-daily dosing Higher barrier to resistance Few drug interactions Active against some RAL- and EVG-resistant virus Coformulated with ABC/3TC only Together, the results of STARTMRK, GS 102 and 103, SINGLE, FLAMINGO, and ACTG 5257 suggest that integrase inhibitor–based regimens are the preferred starting regimens in the majority of pts
- 16. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium PIs
- 17. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Difference in 96-wk cumulative incidence (97.5% CI) -20 0-10 10 20 15% (10% to 20%) 7.5% (3.2% to 12%) 7.5% (2.3% to 13%) ATV/r vs RAL DRV/r vs RAL ATV/r vs DRV/r Favors RAL Favors RAL Favors DRV/r Lennox JL, et al. Ann Intern Med. 2014;161:461-471. *Plus TDF/FTC. ATV/r* RAL* DRV/r* ACTG 5257: Cumulative Incidence of Virologic or Tolerability Failure 1.00 0.75 0.50 0.25 0.00 CumulativeIncidence Wks Since Study Entry 0 24 48 64 80 96 112 128 144
- 18. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium GS 114: ATV/COBI vs ATV/r With TDF/FTC Snapshot Wks 48, 96, 144 (ITT) *No data include: DC study drug due to AE/death; DC study drug (other reasons) and last available HIV-1 RNA < 50 c/mL; missing data during window. PercentageofSubjects(%) Virologic Success Virologic Failure No Data* 95% CI for Difference -7.4 3.0 Favors ATV + RTV -2.2 Favors ATV + COBI Wk 48 -7.6 4.7 -1.4Wk 96 4.5-8.7 -2.1Wk 144 Mean CD4 cell increase (cells/mm3 ) was 310 (COBI) vs 332 (RTV) 12%0-12% Gallant JE, et al. ICAAC 2014. Abstract H-647. 100 80 60 40 20 0 Wk48 Wk96 Wk144 Wk48 Wk96 W144 Wk48 Wk96 Wk144 85 87 78 79 72 74 6 4 7 5 8 5 9 9 15 16 20 21 COBI + TDF/FTC (n = 344) RTV + TDF/FTC (n = 348)
- 19. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Now Approved: New Boosted PI Fixed- Dose Combinations ATV/COBI 300/150 mg once daily[1] DRV/COBI 800/150 mg once daily[2] – Only for pts with no DRV resistance mutations Both FDCs added as “alternative regimen” options in DHHS guidelines[3] 1. Atazanavir/cobicistat prescribing information 2015. 2. Darunavir/cobicistat prescribing information 2015. 3. DHHS Guidelines. April 2015.
- 20. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium NRTIs
- 21. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Study Association? Description D:A:D[1] Cohort collaboration (prospective) Danish HIV Cohort[2] Cohort (linked with registries) Montreal study[3] Nested case-control study SMART[4] Post-hoc subgroup analysis of RCT (use of ABC not randomised) STEAL[5] Preplanned secondary analysis of RCT (use of ABC randomised) Desai et al[6] Cohort (retrospective) Swiss HIV Cohort[7] Cohort (retrospective) FHDH ANRS CO4[8] ? Nested case-control study NA-ACCORD[9] ? Cohort (retrospective) VA Clinical Case Registry[10] Cohort (retrospective) Brothers et al. analysis[11] Post-hoc meta-analysis of RCTs ACTG A5001/ALLRT[12] Post-hoc meta-analysis of RCTs FDA meta-analysis[13] Post-hoc meta-analysis of RCTs 1. Friis-Møller N, et al. N Engl J Med. 2003;349:1993-2003. 2. Obel N, et al. HIV Med. 2010;11:130-136. 3. Durand M, et al. J Acquir Immune Defic Syndr. 2011;57:245-253. 4. Phillips AN, et al. Antiv Ther. 2008;13:177-187. 5. Martin A, et al. AIDS. 2010;24:2657-2663. 6. Desai M, et al. Clin Infect Dis. 2015;[Epub ahead of print]. 7. Young J, et al. J Acquir Immune Defic Syndr. 2015;[Epub ahead of print]. 8. Lang S, et al. AIDS. 2010;24:1228-1230. 9. Palella F, et al. CROI 2015. Abstract 749LB. 10. Bedimo RJ, et al. Clin Infect Dis. 2011;53:84-91. 11. Brothers CH, et al. J Acquir Immune Defic Syndr. 2009;51:20-28. 12. Ribaudo HJ, et al. Clin Infect Dis. 2011;52:929-940. 13. Ding X, et al. J Acquir Immune Defic Syndr. 2012;61:441-447. Studies Addressing Abacavir and MI
- 22. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Nuke-Sparing and “Nuke-Lite” Regimens Regimen Results DRV/r + RAL (ACTG 5262)[1] Poor performance at high VL DRV/r + RAL (NEAT)[2] Less effective at high VL, low CD4 DRV/r + MVC (MODERN)[3] Less effective than standard ART ATV/r + RAL (HARNESS – switch)[4] Less effective than standard ART LPV/r + RAL (PROGRESS)[5] Small study; few pts with high VL LPV/r + EFV (ACTG 5142)[6] Poorly tolerated but effective LPV/r + 3TC (GARDEL)[7] As effective as standard ART LPV/r + 3TC or FTC (OLE – switch)[8] As effective as standard ART ATV/r + 3TC (SALT – switch)[9] As effective as standard ART 1. Taiwo B, et al. AIDS. 2011;25:2113-2122. 2. Raffi, et al. CROI 2014. Abstract 84LB. 3. Stellbrink HJ, et al. IAD 2014. Abstract MOAB0101. 4. Van Lunzen J, et al. IAC 2014. Abstract A-641-0126-11307. 5. Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29:256-265. 6. Daar ES, et al. Ann Intern Med. 2011;154:445-456. 7. Cahn P, et al. Lancet Infect Dis. 2014;14:572-580. 8. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Perez-Molina JA, et al. IAC 2014. Abstract LBPE18.
- 23. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium How to Select a Nuke-Sparing Regimen When You Need One? All NRTI-sparing regimens should include a boosted PI . . . for now – LPV/r + EFV was effective but poorly tolerated, but other PI/NNRTI combinations could be considered – Boosted PI + INSTI may not be enough My choices: – DRV/c + DTG + (3TC or FTC) – DRV/c + ETR (+/- 3TC or FTC) – DRV/c + (3TC or FTC)?
- 24. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium LATTE: NRTI-Sparing Maintenance With Cabotegravir + Rilpivirine 6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48 Margolis D, et al. CROI 2015. Abstract 554LB. VL<50c/mLbySnapshot Algorithm(%) 100 80 60 40 20 0 BL 4 12 24 28 36 48 72 96 Induction Phase Maintenance Phase (NRTI Sparing) CAB 10 mg + 2 NRTIs* CAB + RPV (n = 60) CAB 30 mg + 2 NRTIs* CAB + RPV (n = 60)† CAB 60 mg + 2 NRTIs* CAB + RPV (n = 61) EFV 600 mg + 2 NRTIs* (n = 62) 68% 63% 84% 75% Wks *TDF/FTC or ABC/3TC. † Cabotegravir 30 mg selected for future development. Induction Regimen Maintenance Regimen
- 25. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Virologic Success* Virologic Failure No Data Studies 104/111: TAF Noninferior to TDF at Wk 48 TAF also noninferior to TDF at Wk 48 in each study (104 and 111) Results similar across all baseline virologic and demographic subgroups 7 pts in TAF arm and 5 pts in TDF arm with NRTI resistance at VF – 1 in TAF arm and 2 in TDF arm with combined M184V/I + K65R 5 pts in TAF arm and 3 pts in TDF arm with INSTI resistance at VF 0.9% in TAF arm and 1.5% in TDF arm discontinued due to AE CD4+ increases greater in TAF arm: 211 vs 181 (P = .024) Pts(%) 92 90 Δ +2.0% (95% CI: -0.7% to +4.7) EVG/COBI/FTC/TAF (n = 866) EVG/COBI/FTC/TDF (n = 867) 0 20 40 60 80 100 4 4 4 6 n = *HIV-1 RNA < 50 c/mL as defined by FDA Snapshot algorithm. Discontinued for AE, death, or missing data. 800 784 Wohl DA, et al. CROI 2015. Abstract 113LB.
- 26. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium TAF vs TDF: Renal Safety EVG/COBI/ FTC/TAF (n = 866) EVG/COBI/ FTC/TDF (n = 867) Events, n (%) Renal adverse events leading to discontinuation 0 4 (0.5) Tubulopathy/Fanconi syndrome 0 0 -6.6 P < .001 -11.2 Sax P, et al. CROI 2015. Abstract. 143LB. 20 10 0 -10 -20 Mean(SD)Change FromBaselineeGFR* 0 Time (Wks) 12 24 36 48 EVG/COBI/FTC/TAF EVG/COBI/FTC/TDF
- 27. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium TAF vs TDF: Quantitative Proteinuria Median%ChangeFromBaseline (Q1,Q3) β2- microglobulin P < .001 for all Baseline 44 mg/g 44 mg/g 5 mg/g 5 mg/g 64 μg/g 67 μg/g 101 μg/g 103 μg/g Protein (UPCR) Albumin (UACR) Retinol-binding protein Sax P, et al. CROI 2015. Abstract. 143LB. 76* 133* 168* -57* *Upper or lower limit of error bar. EVG/COBI/ FTC/TAF EVG/COBI/ FTC/TDF 75 50 25 0 -25 -50 -3 20 -5 7 9 51 -32 24
- 28. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Switch to EVG/COBI/FTC/TAF in Renal Impairment Change in eGFR (Cockcroft-Gault) 0 4 8 12 16 24 36 48 -10 -5 0 5 10 15 0.6 -1.4 Primary Endpoint Median(Q1,Q3)eGFR ChangeFrom Baseline(mL/min) Baseline eGFR < 50 mL/min (n = 80) ≥ 50 mL/min (n = 162) Retinol Binding Protein/Creatinine Ratio Wks -40 -20 0 Median%Changein RBP/CreatinineRatio(µg/g) P < .001 at all time points (for all pts combined) -80 -60 -100 01 4 12 24 482 β2-Microglobulin/Creatinine Ratio -40 -20 0 Median%Changein ß2-M/CreatinineRatio(µg/g) -80 -60 -100 P < .001 at all time points (for all pts combined) Wks 01 4 12 24 482 Pozniak A, et al. CROI 2015. Abstract 795. Baseline eGFRCG < 50 mL/min ≥ 50 mL/min 65% receiving TDF at baseline
- 29. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium EVG/COBI/TAF/FTC TAF/FTC RPV/TAF/FTC
- 30. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium In the Pipeline DRV/COBI/TAF/FTC: STR Doravirine[1] : NNRTI – Active against K103N, Y181C Ibalizumab[2] : entry inhibitor – Monoclonal antibody binds CD4 – Being studied for treatment and prevention BMS-663068[3] : entry inhibitor – Blocks attachment by binding to gp120 BMS 955176[4] : maturation inhibitor – Disrupts processing of gag protein – Trial in naive pts planned 1. Morales-Ramirez J, et al. CROI 2014. Abstract 92LB 2. Ernst J, et al. ICAAC 2014. Abstract H-995. 3. Lalezari J, et al. CROI 2014. Abstract 86. 4. Hwang C, et al. CROI 2015. Abstract 114LB.
- 31. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium What to Start? (My personal recommendations) No comorbidities or interacting medications – DTG/ABC/3TC – EVG/COBI/FTC/TDF High cardiac risk – DTG + TDF/FTC – EVG/COBI/FTC/TDF Kidney disease (low cardiac risk) – DTG/ABC/3TC (expect fall in eGFR) – RAL + ABC/3TC RTV or COBI interactions – DTG/ABC/3TC – DTG + TDF/FTC – RAL + TDF/FTC
- 32. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium How to Choose? (My personal recommendations) Adverse effects or desire for simplification on a suppressive regimen – DTG/ABC/3TC (no switch data yet, but why not?) – EVG/COBI/TDF/FTC – RPV/TDF/FTC Known or predicted nonadherence – DRV/COBI + TDF/FTC (compare with DHHS) – DTG/ABC/3TC (?) Likelihood of pregnancy – ATV/r + TDF/FTC HCV coinfection – DTG/ABC/3TC (or TDF/FTC) – RAL + TDF/FTC
- 33. Switching and Simplifying Therapy in Suppressed Patients
- 34. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Switching Regimens Rationale for switching in setting of virologic suppression To simplify therapy (reduce pill burden, dosing frequency, improve adherence) To enhance tolerability, decrease short- and long-term toxicity To change food or fluid requirements To avoid parenteral administration (enfuvirtide) To minimize or address drug interactions To allow for optimal use of ART during or in event of pregnancy To reduce cost Other reasons (mine) To avoid embarrassment To prevent boredom DHHS Guidelines. April 2015.
- 35. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Recent Switch Studies: Suppressed Trial From To Outcome GS-123 [1] RAL + TDF/FTC EVG/TDF/FTC/COBI ✔ GS-264[2] EFV/TDF/FTC TDF/FTC/RPV ✔ Strategy-NNRTI[3] NNRTI + TDF/FTC EVG/TDF/FTC/COBI ✔ Strategy-PI[4] PI/r + TDF/FTC EVG/TDF/FTC/COBI ✔ SPIRIT[5] PI/r + 2 NRTI RPV/TDF/FTC ✔ SPIRAL[6] PI/r + 2 NRTI RAL + 2 NRTI ✔ SALT[7] ATV/r + 2 NRTI ATV/r + 3TC ✔ OLE[8] LPV/r + 2 NRTIs LPV/r + 3TC ✔ SWITCHMRK[9] LPV/r + 2 NRTI RAL + 2 NRTI ✗ HARNESS[10] 3rd agent + 2 NRTI RAL+ ATV/r ✗ 1. Mills A, et al. HIV Clin Trials. 2014;15:51-56. 2. Mills A, et al. HIV Clin Trials. 2013;14:216-223. 3. Pozniak A, et al. Lancet Infect Dis. 2014;14:590-599. 4. Arribas JR, et al. Lancet Infect Dis. 2014;14:581-589. 5. Brunetta J, et al. Patient. 2015;[Epub ahead of print]. 6. Martínez E, et al. AIDS. 2010;24:1697-1707. 7. Perez-Molina JA, et al. AIDS 2014. Abstract LBPE18. 8. Gatell J, et al. AIDS 2014. Abstract LBPE17. 9. Eron JJ, et al. Lancet. 2010;375:396-407. 10. van Lunzen J, et al. AIDS 2014. Abstract LBPE19.
- 36. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Switching: Caveats Know the treatment and resistance history Avoid switching from high barrier to lower barrier agents when you don’t
- 37. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Switching and Simplifying Therapy: “Horizontal” vs “Vertical” Switches Vertical Switches: switch to drug with lower resistance barrier Most drug discontinuations Boosted PI → NNRTI Boosted PI → INSTI Boosted PI → any STR DRV/r twice daily → once daily Horizontal Switches: switch to drug with equal or higher resistance barrier RTV → COBI (boosters) Switches within INSTI class in previously INSTI-naive pts EFV or NVP → RPV or ETR LPV/r or ATV/r → DRV/r ABC or AZT → TDF TDF → TAF
- 38. clinicaloptions.com 25th Annual CCO HIV and Hepatitis C Symposium Conclusions Initial therapy – Due to a combination of efficacy, safety, and tolerability, 4 of the 5 DHHS recommended regimens are now INSTI-based combinations – DRV/r is the only recommended PI – ATV/r, ETR, and RPV are now alternative agents Some pts still need “nuke-sparing” or “nuke-lite” regimens – DHHS guidelines list no NRTI-sparing regimen as “Recommended” or “Alternative” – TAF may make this less necessary in the near future Switching therapy in virologically suppressed pts is appropriate and safe, provided resistance profile and resistance barrier are considered
- 39. Go Online for More CCO Coverage of HIV! Multimedia modules featuring video of expert faculty discussions of controversies and challenging cases Downloadable slidesets for your own study or presentations clinicaloptions.com/hiv
Editor's Notes
- These are the results of the START trial, which randomized people with CD4 counts above 500 to either start therapy immediately or to wait until their CD4 was below 350. And, as you know, the DSMB recommended that the study be opened and the results be revealed when they found about a 53% reduction in serious illness or death with immediate ART. In addition, rates of serious AIDS-related and non-AIDS–related events were also lower in the immediate arm. Now, of course, this won’t change US guidelines because both the guidelines panels had already decided that there was sufficient evidence to recommend treatment regardless of CD4 count. But none of the other countries had jumped on our bandwagon. And so this is probably going to have an important global impact.
- ART, antiretroviral therapy. Okay, and I think you’ve seen versions of this slide before, but I think that clearly the evidence had already strongly supported earlier therapy, and now we have confirmation from a large randomized clinical trial. And I suspect that even if you’re not that interested in this trial because you’d already assumed that it was a good thing to start therapy, there’s no doubt we’re going to get lots of additional information from substudies over the years, just like we did in an earlier study, the SMART study.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; COBI, cobicistat; CrCl, creatinine clearance; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; r, ritonavir; RAL, raltegravir; TDF, tenofovir. So these are the new DHHS guidelines on what to start. And I’m going to focus much more on that issue of initial therapy, and as we discussed at lunch today, all but one of the recommended regimens are now integrase inhibitor–based regimens. The NNRTIs and atazanavir have been moved to alternative. This was discussed in the lunch debate, and I’m definitely on the side that approves of this decision because, frankly, in looking at patients over the last several years, it’s been really hard for me to think of a patient who wouldn’t be best treated with either an integrase inhibitor or a protease inhibitor. And I really haven’t found a place for NNRTIs as an initial therapy anymore given the choices that we have available to us.
- 3TC, lamivudine; ART, antiretroviral therapy; ATV, atazanavir; COBI, cobicistat; CrCl, creatinine clearance; DHHS, US Department of Health and Human Services; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; r, ritonavir; TDF, tenofovir. These are the alternative regimens in the DHHS guidelines. And the guidelines do point out that an alternative regimen may be the preferred regimen for some patients. The alternative regimens now include efavirenz, rilpivirine, atazanavir, and the cobicistat-boosted PIs. It’s important to remember that it doesn’t mean that COBI boosting is inferior to ritonavir boosting. It’s just that these are very new drugs, and very new drugs often will go onto the alternative list until we have longer-term data.
- ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; r, ritonavir; RAL, raltegravir; TDF, tenofovir. All right, so let’s start with a discussion of the integrase inhibitors and why we’re at the state that we’re in. Of course, one of the very important studies in our field lately has been ACTG 5257, which compared 2 boosted PIs, atazanavir and darunavir, with raltegravir, for treatment-naive patients. I won’t go through all of the different analyses they did. I’ll just show the cumulative analysis that looked at combined virologic and tolerability endpoints and showed that raltegravir was superior to both of the PIs, and that among the PIs, darunavir was superior to atazanavir.
- ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; LFT, liver function test; r, ritonavir; RAL, raltegravir; TDF, tenofovir. Now of course, no one was surprised about the difference between darunavir and atazanavir because we know that some people develop jaundice on atazanavir and end up switching. And so that was not particularly surprising. But what was unexpected, I think, was differences in GI toxicity, since all 3 of these drugs are really felt to be pretty well tolerated. But raltegravir was significantly better tolerated from a GI standpoint. and interestingly, darunavir was better tolerated than atazanavir, excluding the hyperbilirubinemia and jaundice toxicities. And so this was largely what drove these differences, much more than virologic endpoints.
- COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; TDF, tenofovir. Then we have the GS 102 study looking at the elvitegravir/quad combination compared to efavirenz/tenofovir/FTC. And what you can see here is that the differences are not significant, although there were numerical differences favoring the elvitegravir combination. And most of the differences are not in terms of virologic failure, which is in that middle group. What differences there were tended to be more in terms of tolerability and toxicity, but overall, both arms performed very well.
- ATV, atazanavir; COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; r, ritonavir; RTV, ritonavir; TDF, tenofovir. And here’s a similar study comparing elvitegravir/quad with boosted atazanavir. Again, no significant differences; maybe a little bit of numerical difference favoring elvitegravir, but it met the noninferiority criteria with very low rates of virologic failure in both arms.
- 3TC, lamivudine; ABC, abacavir; ART, antiretroviral therapy; DTG, dolutegravir; EFV, efavirenz; FDA, US Food and Drug Administration; FTC, emtricitabine; HBV, hepatitis B virus; QD, once daily; TDF, tenofovir; VF, virologic failure. Then we have the SINGLE study, which was sort of an historic study, because it was the first time that any regimen was superior to efavirenz at a primary endpoint. These results show the data out to 144 weeks, but the superiority was noted at 48 weeks. And again, it was not superiority based on virologic response, as you can see in that middle group of bars. It was mainly superiority based on higher discontinuation due to adverse events in the efavirenz arm compared to the dolutegravir arm.
- ART, antiretroviral therapy; DRV, darunavir; DTG, dolutegravir; QD, once daily; r, ritonavir. And then FLAMINGO, an open-label trial comparing dolutegravir with boosted darunavir, again, achieved superiority. Dolutegravir was superior to boosted darunavir based primarily on tolerability and toxicity differences.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DTG, dolutegravir; EVG, elvitegravir; RAL, raltegravir; RTV, ritonavir. So, let’s compare the integrase inhibitors. We have 3 of them. Raltegravir is the one with which we have the longest experience. And it probably has fewest drug interactions. The disadvantages are that, for now, it’s twice-daily dosing. There is a once-daily formulation being developed. And it is not available in a coformulated product. Elvitegravir is a single-tablet regimen, once-a-day dosing. The disadvantages are mainly the cobicistat boosting, which causes drug interactions similar to what you would see with ritonavir. And then, dolutegravir has the advantage of being available in the only non-tenofovir–containing STR, which is useful for those who can’t take tenofovir; once-daily dosing. Probably a higher barrier to resistance than the other integrase inhibitors, with relatively few drug interactions. And there is activity against some raltegravir- and elvitegravir-resistant virus. If it has any disadvantages, it’s just that the coformulation contains abacavir, and abacavir is not appropriate for all patients. But, of course, dolutegravir doesn’t have to be used in that coformulation. So I think, together—and the results of STARTMRK, which I didn’t discuss—102, 103, single FLAMINGO, ACTG 5257 all really suggest that integrase inhibitor–based regimens are probably the preferred starting regimens for a vast majority of patients. We’ll come back where protease inhibitors fit in, since, remember, that they’re still on that recommended list. But I think this is sort of what persuaded the DHHS committee that 4 out of the 5 recommended regimens now contain integrase inhibitors.
- ATV, atazanavir; DRV, darunavir; FTC, emtricitabine; r, ritonavir; RAL, raltegravir; TDF, tenofovir. Not a whole lot to say about PIs except to remind you again about ACTG 5257—superiority of darunavir over atazanavir, which is why, now, darunavir is the only PI on the recommended list in the guidelines.
- ATV, atazanavir; COBI, cobicistat; FTC, emtricitabine; ITT, intent to treat; r, ritonavir; RTV, ritonavir; TDF, tenofovir. And then we now have cobicistat boostings. So this was the GS 114 study comparing COBI-boosted atazanavir with ritonavir-boosted atazanavir, really showing absolutely no difference in terms of efficacy or tolerability between the two. And of course, I’ve heard people say, well, what’s the point of COBI if it doesn’t have any advantages? Well, it does have one advantage: the advantage of being able to be coformulated, and that is a huge advantage.
- ATV, atazanavir; COBI, cobicistat; DHHS, US Department of Health and Human Services; DRV, darunavir; FDC, fixed-dose combination. So we now have boosted—we have an atazanavir/COBI combination, and we have a darunavir/COBI combination. As I said before, both are listed now as alternatives in the DHHS guidelines, but I wouldn’t be surprised if that changed to recommended with a little more experience and more data.
- ABC, abacavir; MI, myocardial infarction; RCT, randomized controlled trial. So this whole question of abacavir and MI—here are a bunch of studies that have shown an association between abacavir and MI. Many people think it’s just D:A:D, but it’s more than that. Here are some studies that have not shown an association between abacavir and MI. And then the ones in the middle, the French one first showed an association, then it didn’t, and that’s why it got a question mark. And then the NA-ACCORD does show at least a signal, but even the authors of the study don’t agree whether it’s confirming an association or not. So it’s a very confusing picture, but it leads us to this problem where sometimes we can’t use tenofovir—kidney disease, osteoporosis. And we also can’t use nuc-sparing regimens because of a positive HLA-B*5701 or a very high cardiac risk.
- 3TC, lamivudine; ART, antiretroviral therapy; ATV, atazanavir; DRV, darunavir; EFV, efavirenz; FTC, emtricitabine; LPV, lopinavir; MVC, maraviroc; r, ritonavir; RAL, raltegravir; VL, viral load. So what do we do? So these are lists of either nuc-sparing or what I’ll call nuc-lite regimen meaning that they contain nucs, but it’s lamivudine or emtricitabine, which don’t really count in terms of toxicity. And you can see at the top are some problematic studies or problematic regimens. They’re all boosted PIs plus either an integrase inhibitor or, in one case, maraviroc. And none of them really were home runs. If anything, they had weaknesses, poor performances at high viral loads, less effectiveness than standard ART, or, in the case of the PROGRESS study, it was just a small study that didn’t have many people that had high viral loads. But in the bottom, you see regimens that did pretty well. And what do they have in common? They all have a reverse transcriptase inhibitor in them. In the case of the lopinavir with efavirenz, it was a very large study, a very effective regimen, but very poorly tolerated probably because of the drugs chosen. But the bottom 3, a boosted PI plus 3TC have all done quite well either as an initial regimen, as in the case of the GARDEL study, or as a switch regimen. So what does this mean? The best nuc-sparing regimens have nucs. Why is that somehow better than a boosted PI plus an integrase inhibitor? I don’t know. Is there something intrinsically wrong about that combination or is it just the studies that have been done to date?
- 3TC, lamivudine; c, cobicistat; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; ETR, etravirine; FTC, emtricitabine; LPV, lopinavir; r, ritonavir. So how do you select a nuc-sparing regimen when you need one? Well, the problem with the guidelines—they do address this question, but they can only talk about the regimens that have been studied, all of which have problems. They’re not really in the business of speculating on unstudied regimens, which I can freely do up here with the microphone. So here’s my take on it, because sometimes this comes up, and you have to do it. All nuc-sparing regimens should include a boosted PI, at least for now. That may change soon with new data, but for now, I think that’s a safe bet. We know that a boosted PI plus a nonnuc was effective in one study, but poorly tolerated. But what about a different combination, boosted darunavir and etravirine, for example? We have plenty of data on that, but not in this particular population. I think it’s fair to say that a boosted PI plus an integrase inhibitor should at least give you pause. It may not be enough, based on the data we have to date. So my own choice is, when I’m forced into this position, would be to use boosted darunavir—and I tend to do it with cobicistat acknowledging that that’s currently an alternative—plus either an integrase inhibitor like dolutegravir or a nonnuc like etravirine. But I would typically add lamivudine or emtricitabine because of the concern that we’ve seen about these 2-drug regimens that weren’t working very well, especially at high viral loads. Now what about just using a boosted PI plus lamivudine? It’s not something that we’ve been doing much in the US, but I think there’s growing data to support that approach. And we’ll have to see what happens with additional studies.
- 3TC, lamivudine; ABC, abacavir; CAB, cabotegravir; EFV, efavirenz; FTC, emtricitabine; PDVF; cobicistat, RPV, rilpivirine; TDF, tenofovir; VL, viral load. Now I said always use the boosted PI for now, we have the LATTE study that’s looking at a nuc-sparing maintenance regimen with cabotegravir and rilpivirine. I think you’re going to hear more about that later. So far, it looks pretty good in the maintenance phase, so you get people suppressed, and then you switch to this combination not currently available, of course. And the reason for this study is because, you know, after this they’ll do the “cappuccino” study or whatever it’s called to look at long-acting injectables of these 2 drugs, because they’re both going to be available as long-acting injectables. One thing to be aware of, cabotegravir is a dolutegravir-like drug, but it isn’t dolutegravir. We have seen drug resistance to cabotegravir, which we have not yet seen with dolutegravir.
- AE, adverse event; COBI, cobicistat; EVG, elvitegravir; FDA, US Food and Drug Administration; FTC, emtricitabine; TAF, tenofovir alafenamide; TDF, tenofovir DF; VF, virologic failure. So I guess the question is, next year, will we still care about nuc-sparing regimens? So there’s a couple of things that could happen by next year. One is we could get more data on abacavir showing that it doesn’t increase your risk of MI. That would certainly help, if we did. The other, of course, is tenofovir alafenamide, which is another prodrug of tenofovir, but unlike the TDF that we use now, it gets higher intracellular levels and lower plasma levels, which is thought to possibly decrease the risk of nephrotoxicity and bone toxicity, but perhaps increase activity against drug-resistant virus. And we’ve seen data presented by our own David Wohl showing that TAF was not noninferior to TDF at Week 48. And of course, that was not necessarily surprising. I think there was some concern. There was the hope that the higher intracellular levels would decrease the risk of resistance. That didn’t turn out to happen. You saw resistance in both arms. But certainly it was noninferior to TDF from an efficacy standpoint.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; SD, standard deviation; TAF, tenofovir alafenamide; TDF, tenofovir DF. Renal safety—this is the same study looking at the effect on EGFR in TAF vs TDF. And you can see that you get less of a decline in EGFR with TAF than TDF. Many people look at this and say, well then clearly it’s safer to kidneys. But remember that this dramatic decline that you see EGFR in those first few weeks is a cobicistat effect. It’s the effect of blocking tubular excretion of creatinine. So both of these regimens, they both contained cobicistat at the same dose. Why would there be a difference? I haven’t heard really a satisfactory explanation. But I don’t think you can use this slide to say that TAF is safer to kidneys since this is not a true nephrotoxicity; it’s sort of a pseudo-nephrotoxicity due to cobicistat.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; UACR, urine albumin-to-creatinine ratio; UPCR, urine protein-to-creatinine ratio; TAF, tenofovir alafenamide; TDF, tenofovir DF Maybe a little more compelling is the effect on proteinuria. And this is looking at both overall proteinuria, but also at retinol-binding protein and β2-microglobulin, which are markers of tubular toxicity. And you can see that there’s less proteinuria of all kinds with TAF vs TDF. Again, it’s interesting; this is an effect seen fairly quickly, and yet we don’t expect to see tenofovir nephrotoxicity very quickly. Could this be some kind of a marker of future tubulopathy? Perhaps. At least it’s certainly not bad news.
- COBI, cobicistat; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; RBP, retinol binding protein; TAF, tenofovir alafenamide; TDF, tenofovir DF. Maybe the best news comes from this study presented by Anton Pozniak where they took people who already had kidney disease, whether due to tenofovir or something else, and switched them from whatever it was they were taking to the elvitegravir/TAF coformulation and found that the kidney function, rather than continuing to decline, stabilized. And that there was a reduction in proteinuria. And that, to me, may be the most convincing argument that there is less tenofovir renal toxicity with TAF compared to TDF. Because you would assume that, with TDF, you would have seen continued decline in renal function.
- COBI, cobicistat; EVG, elvitegravir; FTC, emtricitabine; RPV, rilpivirine; TAF, tenofovir alafenamide; TDF, tenofovir DF. So coming soon, probably by the end of this year, we will have this new elvitegravir/TAF quad pill. And then early next year, we’ll have a TAF/FTC and a rilpivirine/TAF/FTC.
- COBI, cobicistat; DRV, darunavir; FTC, emtricitabine; STR, single-table regimen; TAF, tenofovir alafenamide. And we also have a pipeline. It’s encouraging that the pipeline still exists. This is “pipeline” in the good sense of the word pipeline, not the controversial political sense. We’ll probably in a couple of years have a darunavir/COBI/TAF/FTC STR. That’ll be the very first protease inhibitor STR. Doravirine, a nonnuc that is active against K103N and Y181C. So if you’re worried that the guidelines have removed all nonnucs from recommended lists, who knows—doravirine may be there someday. Ibalizumab—a lot of fun to say—ibalizumab, I’ll say it again, it’s an entry inhibitor monoclonal antibody that binds to CD4 and is being studied for treatment and prevention. And then BMS-663068—not as much fun to say—another entry inhibitor that blocks attachment by binding to gp120. And we have a maturation inhibitor that disrupts processing of the gag protein and is being studied in naive patients as well, I believe, as in experienced patients.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DTG, dolutegravir; eGFR, estimated glomerular filtration rate; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; RTV, ritonavir; TDF, tenofovir. So what to start? Now I’m going to leave the guidelines behind and just go through categories and give you my own personal thoughts. So the generic patient: no comorbidities, interacting medications, adherent. I think you can’t go wrong with either of these single-tablet regimens. And I should probably have added dolutegravir plus tenofovir/FTC even though it’s not a single-tablet regimen. But I think these make a lot of sense for patients like that. High cardiac risk: I would say I don’t know whether abacavir increases the risk of MI, but until I do, I think it’s best to follow the guidelines and be cautious about it and avoid abacavir. And for that reason I’ve listed 2 good choices for that category. Now, for the—I don’t know if such a patient exists, but if you had a patient with kidney disease who is at low cardiac risk, you’d probably want to avoid tenofovir and could easily use an abacavir-based regimen. I’ve listed 2 of them here, but remember, with dolutegravir, it also blocks tubular excretion of creatinine. So you are going to see a fall in EGFR when you use dolutegravir just as you would with cobicistat. But remember, it’s not really true nephrotoxicity. Problems with drugs that interact with ritonavir or COBI: I think the most commonly seen are the inhaled steroids, fluticasone; people who are getting joint injections with steroids, etc. And here you want to avoid a COBI and ritonavir, and so I’ve listed 3 integrase inhibitor–based regimens that you could use.
- 3TC, lamivudine; ABC, abacavir; COBI, cobicistat; DHHS, US Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EVG, elvitegravir; FTC, emtricitabine; RAL, raltegravir; r, ritonavir; RPV, rilpivirine; RTV, ritonavir; TDF, tenofovir. Patients who simply want to switch either because of side effects or desire to simplify therapy, we have 2 drugs where there’s very good data: the elvitegravir/quad and rilpivirine combination. I’m sure we’ll have data with dolutegravir soon, but there’s no reason that you couldn’t use that. They’re all certainly reasonable choices. Now the question is patients who could be nonadherent, and this is why they left darunavir in the recommended category. We have really strong data saying that you can’t really screw up a PI-based regimen. And so that makes perfect sense. And nowadays you can do it with 2 pills a day so it’s not difficult. Dolutegravir is widely being used for this purpose, and it may be a great choice. We have not yet seen resistance to dolutegravir. But then again, we don’t have nearly as much experience as we do with PIs. So, you know, my own practice is to let you all do those experiments. I give my patients a boosted PI, if they’re going to be nonadherent. So I’m waiting for that first case of resistance to be reported. But the longer we go without reported resistance, the more comfortable I think we all will be using it for that purpose. Likelihood of pregnancy: my own choice, boosted atazanavir with tenofovir/FTC. Boosted atazanavir is a preferred agent. Tenofovir/FTC is an alternative agent. But the last thing a pregnant woman needs is AZT to make her more nauseated than she already is. And hep C: I think we generally want to be careful about drug interactions, especially with ledipasvir. And for that reason, dolutegravir- and raltegravir-based regimens probably make the most sense.
- Now what about switching? I used to talk about treatment-experienced patients in terms of drug resistance, but nowadays, the reason we tend to switch is not drug resistance. It tends to be just simplifying therapy.
- ART, antiretroviral therapy. So here’s what the guidelines say about good reasons to switch: all the usual things that you can guess. I have also added my own reasons to switch. One is avoiding embarrassment. You don’t want your patient to be on AZT/3TC and nelfinavir and tell people at a cocktail party that he’s your patient, right? And the other is to prevent boredom because if every day you go to work and just keep refilling the same regimens, you’ll get bored and burn out and quit your job. But those have not been viewed as legitimate reasons to add to the guidelines.
- 3TC, lamivudine; ATV, atazanavir; COBI, cobicistat; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TDF, tenofovir. Switch studies can be boring because most of the time you show the data, and you say the people either switched or they didn’t, and they all do fine. So I won’t go through all those, but I want to focus on the 2 switch studies at the bottom that didn’t do so well. One was HARNESS where people switched to boosted atazanavir plus raltegravir and didn’t do well. And again, that’s the yet another PI plus integrase that didn’t have a good outcome. And then there is the SWITCHMRK study where people on 2 nucs plus lopinavir or ritonavir either stayed or switched to raltegravir, regardless of their past treatment experience and regardless of resistance. And they didn’t do so well either. So I think we have to be really cognizant of that SWITCHMRK data when we switch. When we’re really being careful to not go from a high barrier drug or regimen to a low barrier without knowing past resistance data.
- Caveats for switching: Know the treatment and resistance history. Avoid switching from a high barrier to a low regimen if you don’t know the treatment history. Now there is a new test out where you’re supposed to be able substitute for medical records. It’s an archived genotype that’s supposed to tell you about resistance that’s been present in the past. You know, I think it’s an interesting test. I like playing with it, but you have to be careful because it really hasn’t been clinically validated yet.
- ABC, abacavir; ATV, atazanavir; AZT, zidovudine; COBI, cobicistat; DRV, darunavir; EFV, efavirenz; ETR, etravirine; LPV, lopinavir; NVP, nevirapine; r, ritonavir; RPV, rilpivirine; RTV, ritonavir; STR, single-table regimen; TAF, tenofovir alafenamide; TDF, tenofovir DF. So I sort of separate horizontal from vertical switches. The horizontal switches are the no brainers—the ones where you’re not sacrificing any resistance barrier, and you can see examples there. The more difficult ones are these vertical switches, often going from a boosted PI to something with a lower barrier. And those are the ones where I think you really have to have a good sense of the patient’s treatment history and, hopefully, their resistance profile.
- ATV, atazanavir; DHHS, US Department of Health and Human Services; DRV, darunavir; ETR, etravirine; r, ritonavir; RPV, rilpivirine; TAF, tenofovir alafenamide. So to conclude, for initial therapy, I think it’s appropriate that most of the recommended regimens are now integrase inhibitor–based combinations, with darunavir being the only recommended PI. I think there will still, for a little while at least, be a patients who need nuc-sparing or nuc-lite regimens. And none of them are currently recommended in the guidelines, but TAF may make this less necessary in the future. And finally, switching therapy in suppressed patients is perfectly appropriate and safe, provided that you’re considering the resistance profile and the resistance barrier of the new regimen. Thank you very much.