Treating HIV: When the Guidelines Don t Fit. Joel Gallant, MD, MPH. Southwest CARE Center Santa Fe, New Mexico

Transcription

1 Treating HIV: When the Guidelines Don t Fit Joel Gallant, MD, MPH Southwest CARE Center Santa Fe, New Mexico Johns Hopkins University School of Medicine University of New Mexico School of Medicine

2 Disclosures Consulting, Advisory Boards, and DSMBs Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. ViiV Healthcare Research Support AbbVie Bristol-Myers Squibb Gilead Sciences Janssen Therapeutics Merck & Co. Sangamo BioSciences ViiV Healthcare

3 When the Guidelines Don t Fit How to treat the patient who cannot take TDF or ABC How to safely switch or simplify therapy in a suppressed patient

4 DHHS Guidelines, April 2015: What to Start Recommended regimens Boosted PI based INSTI based Alternative regimens NNRTI based DRV/r + TDF/FTC RAL + TDF/FTC EVG/COBI/TDF/FTC DTG + TDF/FTC DTG + ABC/3TC EFV/TDF/FTC RPV/TDF/FTC (VL <100,000; CD4 >200) PI based ATV/c + TDF/FTC (CrCl >70) ATV/r + TDF/FTC (DRV/c or DRV/r) + ABC/3TC DRV/c + TDF/FTC (CrCl >70) DHHS Guidelines for Antiretroviral Therapy in Adults and Adolescents, April 2015.

5 IAS-USA Guidelines, July 2014 What to Start Class NNRTI Boosted PI INSTI Recommended Regimens EFV/TDF/FTC EFV + ABC/3TC* RPV/TDF/FTC ATV/r + TDF/FTC ATV/r + ABC/3TC* DRV/r + TDF/FTC DTG + ABC/3TC* DTG + TDF/FTC EVG/COBI/TDF/FTC RAL + TDF/FTC *Abacavir has been associated with increased cardiovascular risk, although data are conflicting; use with caution in patients with high cardiovascular risk. Günthard HF, et al. JAMA. 2014;312:

6 R.W. R.W. is a 49-yr-old executive Dx d with HIV 5 years ago He s been reluctant to take ART, but now has CD4 310, VL 156,000 c/ml, and agrees to start Had wild-type virus at time of Dx Medical problems: Diabetes (HbA1C 9.0% on metformin; refuses insulin) Hyperlipidemia (LDL 125 on atorvastatin, TG 350 on fibrate) Smokes 1/2 pack per day Non-nephrotic range proteinuria, creatinine 1.5, egfr 55 Liver enzymes normal, HLA B*5701 negative

7 Studies addressing association between abacavir and MI Study Association? Description D:A:D Cohort collaboration (prospective) Danish HIV Cohort Cohort (linked with registries) Montreal study Nested case-control study SMART Post-hoc subgroup analysis of RCT (use of ABC not randomised) STEAL Preplanned secondary analysis of RCT (use of ABC randomized) Brighton study Nested case-control study VA Clinical Case Registry Cohort (retrospective) FHDH ANRS CO4? Nested case-control study Boston Cohort Cohort (retrospective) GSK studies Post-hoc meta-analysis of RCTs ACTG A5001/ALLRT Post-hoc meta-analysis of RCTs FDA meta-analysis Post-hoc meta-analysis of RCTs Sabin C, et al. CROI 2013.

8 D:A:D 2014 use of ABC in cohort over time D:A:D presentation, March % of those with given CVD risk receiving ABC RR (1.68, 2.33) RR 1.97 (1.43, 2.72) Low CVD risk Mod CVD risk High CVD risk CVD risk U/K Total cohort 0 Sabin C, et al. CROI 2013.

9 NA-ACCORD: recent abacavir use and risk of MI Retrospective analysis of pts in 7 clinical cohorts with recent ABC use (prescribed in previous 6 mos) from 1/1/1995 to 12/31/2010 ABC initiators (n = 1948) vs noninitiators (n = 14,785): Full study population: all ART users excluding those on ABC at entry Restricted population: ART-naive pts who started ART in the cohort Endpoint of incident MIs: presence of clinical diagnosis or elevation of cardiac enzymes Adjusted HRs for MI in Those With Recent ABC Use D:A:D Replication Full Study Restricted Study Recent ABC use significant in restricted population and D:A:D replication Significant predictors: Both: age 60+, HTN, egfr < 30, AIDS Full: smoking, DM Palella F, et al. CROI Abstract 749LB.

10 NRTI-Sparing Regimens

11 NEAT 001: DRV/r + either RAL or TDF/FTC: Primary endpoint at W96 by baseline characteristics RAL + DRV/r TDF/FTC + DRV/r Overall n = % 13.7 % Baseline HIV-1 RNA < 100,000 c/ml n = % 7 % > 100,000 c/ml n = % 27 % P = 0.09 Baseline CD4+ < 200/mm 3 n = % 21.3 % > 200/mm 3 n = % 12.2 % P = Difference in estimated proportion (95% CI) RAL TDF/FTC; adjusted Raffi et al, CROI2014, Abstract 84LB.

12 MODERN: MVC QD + DRV/r not noninferior to TDF/FTC + DRV/r Pts With HIV-1 RNA < 50 copies/ml [1] BL Wk 86.8% TDF/FTC + DRV/r (n = 401) 77.3% Adjusted treatment difference (95% Cl): -9.5% (-14.8% to -4.2%) MVC + DRV/r (n = 396) Similar rates of VL suppression at Week 48 by screening assay type Assay Type MVC + DRV/r (n = 396) TDF/FTC + DRV/r (n = 401) Phenotypic Genotypic Δ (95% CI) 6.9% (1.3% to 15%) Stellbrink H-J, et al. AIDS Abstract MOAB0101.

13 GARDEL: LPV/r + 3TC noninferior to LPV/r + 2 NRTIs at Wk 48 Patients (%) Δ 4.6 (95% CI: -2.2 to 11.8; P =.171) Dual ART (n = 214) Triple ART (n = 202) n = Virologic success* Virologic nonresponse D/C due to AE or death *VL< 50 c/ml by FDA Snapshot algorithm. Cahn P, et al. Lancet Infect Dis 2014;14: D/C for other reasons CD4 count increase similar Grade 2-3 AEs more frequent in triple-art arm (88 vs 65 events) VF in 22 pts, of whom 2 had resistance (M184V) Both on dual ART

14 OLE: switching suppressed pts to LPV/r + 3TC noninferior to triple ART at Wk 48 Patients (%) Δ -0.6% (95% CI: -6.9% to 8.1%) Dual ART (n = 118) Triple ART (n = 121) New grade 3-4 AEs in 9 pts in each arm Numerically greater increases in lipids, decreases in creatinine in triple-art arm VF in 3 pts in each arm 20 n = 0 Therapeutic Response* Virologic Failure *VL < 50 c/ml at Wk 48 (mitt). 3.3 D/C Due to AE D/C for Other Reasons 1 pt (dual-art) tested for resistance; had K103N and M184V Gatell J, et al. AIDS Abstract LBPE17.

15 NRTI-sparing regimens Regimen DRV/r + RAL (ACTG ) DRV/r + RAL (NEAT 2 ) DRV/r + MVC (MODERN 3 ) ATV/r + RAL (HARNESS 4 switch) LPV/r + RAL (PROGRESS 5 ) LPV/r + EFV (ACTG ) LPV/r + 3TC (GARDEL 7 ) LPV/r + 3TC or FTC (OLE 8 switch) ATV/r + 3TC (SALT 9 switch) Results Poor performance at high VL Less effective at high VL, low CD4 Less effective than standard ART Less effective than standard ART Small study; few pts with high VL Poorly tolerated but effective As effective as standard ART As effective as standard ART As effective as standard ART The best nuke-sparing regimens contain nukes (or NNRTIs) 1. Taiwo B, et al. AIDS. 2011;25: Raffi et al. CROI 2014, Abstract 84LB. 3. Stellbrink H-J, et al. IAD Abstract MOAB Van Lunzen J et al. IAC Abstract A Reynes J, et al. AIDS Res Hum Retroviruses. 2013;29: Daar ES et al. Ann Intern Med Cahn P, et al. Lancet Infect Dis 2014;14: Gatell J, et al. AIDS Abstract LBPE Perez-Molina, JA, et al. IAC Abstract LBPE18..

16 How to select a nuke-sparing regimen when you need one No NRTI-sparing regimen is recommended in guidelines. DHHS: The Panel does not recommend any of these strategies for initial therapy except in patients in whom both TDF and ABC are contraindicated. 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/r or DRV/c) + DTG + (3TC or FTC) (DRV/r or DRV/c) + ETR (+/- 3TC or FTC) (DRV/r or DRV/c) + (3TC or FTC)?

17 LATTE: virologic success through maintenance Week 96 VL < 50 c/ml by Snapshot algorithm (%) Induction phase Maintenance phase CAB 10 mg (n = 60) CAB 30 mg (n = 60)* CAB 60 mg (n = 61) EFV 600 mg (n = 62) 0 BL Wks 84% 75% 68% 63% 6 pts in CAB arms with PDVF at Wk 96; 4 additional pts since Wk 48 Margolis D, et al. CROI Abstract 554LB. *Cabotegravir 30 mg selected for future development

18 At next year s course will anyone talk about NRTI-sparing regimens?

19 TAF vs TDF: renal safety 20 E/C/F/TAF E/C/F/TDF Mean (SD) change from baseline egfr* P < Time (Weeks) Events n (%) Renal adverse events leading to discontinuation E/C/F/TAF n = 866 E/C/F/TDF n = (0.5) Tubulopathy/Fanconi syndrome 0 0 Sax P, et al. 22nd CROI; Seattle, WA; February 23-26, Abst. 143LB.

20 TAF vs TDF: quantitative proteinuria Urine [protein]:creatinine ratio Median % change from baseline (Q1, Q3) Protein (UPCR) Albumin (UACR) 7 9 RBP 51 Beta2- microglobulin E/C/F/TAF E/C/F/TDF P <0.001 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 Sax P, et al. 22nd CROI; Seattle, WA; February 23-26, Abst. 143LB.

21 Switch to E/C/F/TAF in mild-moderate kidney disease Median (Q1,Q3) egfr change from baseline (ml/min) Change in egfr (Cockcroft-Gault) Primary Endpoint Baseline egfr CG <50 ml/min 50 ml/min Median % change in RBP/creatinine ratio (µg/g) Retinol binding protein/creatinine ratio Weeks P <0.001 at all time points (for all patients combined) Median % Change in ß2MG/Creatinine Ratio (µg/g) Beta-2 microglobulin/creatinine ratio Weeks P <0.001 at all time points (for all patients combined) Baseline egfr <50 ml/min (n = 80) 50 ml/min (n = 162) Pozniak, A, et al. 22nd CROI; Seattle, WA; February 23-26, Abst. 795.

22 Switching and Simplifying Therapy in Suppressed Patients

23 Case: J.B. J.B. is a 63-year-old man with longstanding HIV infection, diagnosed in 1987 He has been treated by multiple doctors on a variety of regimens since the early 1990s. He does not have old records and does not know his treatment history He remembers being told he has some resistance He is now on DRV/r (600/100 mg twice daily) + RAL + ETR + TDF/FTC He wants a simpler regimen, once-daily with fewer pills

24 Switching Regimens

25 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 for Antiretroviral Therapy in Adults and Adolescents, May 2014.

26 Recent switch studies: suppressed Trial From To Outcome GS-123 TDF/FTC + RAL TDF/FTC/EVG/Cobi GS-264 TDF/FTC/EFV TDF/FTC/RPV Strategy- NNRTI TDF/FTC + NNRTI TDF/FTC/EVG/Cobi Strategy-PI TDF/FTC + PI/r TDF/FTC/EVG/Cobi SPIRIT 2 NRTI + PI/r TDF/FTC/RPV SPIRAL 2 NRTI + PI/r 2 NRTI + RAL SWITCHMRK 2 NRTI + LPV/r 2 NRTI + RAL HARNESS 2 NRTI + 3rd agent TDF/FTC + ATV/r ATV/r + RAL SALT ATV/r + 2 NRTI ATV/r + 3TC OLE LPV/r + 2 NRTIs LPV/r + 3TC Slide courtesy of David Wohl.

27 SWITCHMRK 1 & 2: from LPV/r + NRTIs to RAL + NRTIs Wk 12 lipid analysis Wk 24 efficacy analysis HIV+ pts with viral suppression on LPV/rbased ART for 3 mos. (not required to be initial regimen) (N = 702) (SWITCHMRK 1: 348 SWITCHMRK 2: 354) Switch to RAL + other BL ARVs* (SWITCHMRK 1: n = 174 SWITCHMRK 2: n = 176) Continue LPV/r + other BL ARVs* (SWITCHMRK 1: n = 174 SWITCHMRK 2: n = 178) *All patients continued background regimen including 2 NRTIs. Eron JJ, et al. Lancet. 2010;375:

28 SWITCHMRK: prior failure predicts failure Inferior efficacy of RAL appeared driven by more failure among pts with previous virologic failure Outcome Patients without previous virologic failure SWITCHMRK1 SWITCHMRK 2 RAL (n = 174) LPV/r (n = 174) RAL (n = 176) LPV/r (n = 178) VL < 50 at Wk 24, % Treatment difference, % (95% CI) -0.7 (-9.9 to 8.6) -1.0 (-8.5 to 6.3) Patients with previous virologic failure VL < 50 at Wk 24, % Treatment difference, % (95% CI) (-33.0 to -2.5) (-26.5 to -2.6) Eron JJ, et al. Lancet. 2010;375:

29 Switching: Caveats Know the treatment and resistance history Avoid switching from high-barrier to lowerbarrier agents when you don t know

30 Switching and simplifying therapy: No brainers and switches that require a brain Horizontal Switches : switch to drug with equal or higher resistance barrier RTV COBI (boosters) Switches within INSTI class EFV or NVP RPV or ETR LPV/r or ATV/r DRV/r ABC or AZT TDF 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 Anything boosted PI

31 Switching: know what you need to know to maintain suppression Viral Load Adapted from David Wohl. Time

32 Case: J.B. J.B. is a 63-year-old man with longstanding HIV infection, diagnosed in 1987 He has been treated by multiple doctors on a variety of regimens since the early 1990s. He does not have old records and does not know his treatment history He remembers being told he has some resistance He is now on DRV/r (600/100 mg bid) + RAL (400 mg bid) + ETR (200 mg bid) + TDF/FTC He requests a simpler regimen, once-daily with fewer pills

33 Options for J.B.: The good, the bad, and the iffy Switch OK? Comments RAL DTG Yes Reduces pill burden DTG superior in ART-exp d pts (SAILING) ETR 200 bid 400 QD Yes Not approved dose but supported by PK Discontinue TDF/FTC Maybe NRTIs unnecessary if >2 fully active agents (OPTIONS) His complex salvage regimen suggests that he probably has TDF and FTC resistance already DRV/r BID QD Risky DRV mutations? (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) APV and FPV most likely to cause DRV crossresistance Change to ABC/3TC/DTG Risky DTG resistance barrier may be as high as a boosted PI NRTI resistance unknown Change to any other STR No way! Remember SWITCHMRK!

34 Provides drug resistance data when standard resistance testing cannot be performed due to inadequate plasma viral load. Interrogates the viral archive [amplifies cell-associated proviral DNA] using next-generation sequencing methods to provide a list of the archived mutations.

35 Conclusions Guidelines cannot provide specific recommendations for every patient or clinical scenario Some patients need NRTI-sparing regimens (at least for now). Clinicians may need to choose regimens based on extrapolations from existing data rather than using studied but suboptimal combinations We can make our patients lives easier and better by updating or simplifying their regimens if we do it carefully. Viral suppression is not the only criterion for success.

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