Case 1 continued. Case 1 (cont) 12/8/16. MMAH Debate Panel Thursday, December 8, Case 1

Transcription

1 MMAH Debate Panel Thursday, December 8, 2016 Case 1 HPI 55 yo man with newly diagnosed HIV initiates care in your clinic. His CD4+ cell count is 600, with HIV VL=90,000 copies/ml. He is asymptomatic at today s visit, but anxious about his new HIV diagnosis. PMH He was previously not engaged in medical care. At the time of HIV diagnosis, he is also diagnosed with: Pre-diabetes (a1c=5.9) Hyperlipidemia Case 1 continued Medications He takes no other medications (yet). He is ARV naïve, and is ready to start ARVs at today s visit. Allergies NKDA He is HLAB5701 negative Social History He is housed, and lives alone. He identifies as a white gay man. He smokes cigarettes, but denies other drug use. Occasional alcohol use, but not to excess. Case 1 (cont) His baseline CBC and chem7 is normal, with a serum creatinine of 1.0 (egfr >60). Hep B and C negative He has a normal UA without proteinuria. He tells you that he is wary of side effects and of pharmaceutical companies. He asks you what you recommend for his initial ARVs. 1

2 ARS: Should everyone started on tenofovir-based ART start on TAF instead of TDF (initial therapy)? 1. Yes 2. No Parameter Efficacy (HIV RNA) Renal Safety Markers Bone Safety Markers TAF Better TAF TDF TAF vs TDF TDF Better Comments Sax. Lancet. 2015;385(9987): Gallant. Lancet HIV. 2016;3:e158-e165 Orkin International Congress of Drug Therapy in HIV Infection. Abstract O124. Sax. Lancet. 2015;385(9987): DeJesus. ASM Microbe Abstract LB-087 Sax. Lancet. 2015;385(9987): Orkin International Congress of Drug Therapy in HIV Infection. Abstract O124. Wohl D, et al. EACS Abstract 1091 Cost $ (to patient) Must check individual patient s plan Cost $ (to system) Based on WAC costs Efficacy in Hepatitis B Gallant. IAS Abstract WELBPE13 Convenience (single tablet) Drug-drug interactions Should TAF replace TDF? Reasons to choose TAF TAF is virologically as effective as TDF. Compared with TDF, TAF has more favorable effects on renal and bone markers. Don t have enough evidence on whether to use with existing renal or bone disease, but maybe those with high risk of these complications. Cost of TAF- and TDFregimens currently similar. Reasons to choose TDF Compared with TAF, more and longer-term data with TDF, particularly in treatment naïve More favorable lipid effects. Renal and bone marker advantages of TAF not yet known to translate into better clinical outcomes. TDF-regimens likely to be cheaper than TAF when TDF goes generic Patient on rifamycins (TB) For PrEP No data in pregnant women With boosted PIs (no data on 25mg TAF and boosted PIs) ARS: Should everyone started on tenofovir-based ART start on TAF instead of TDF (initial therapy)? 1. Yes 2. No 2

3 Case 1 (cont) He tolerates his new ARV regimen well (TAF/FTC/DTG) and his viral load is undetectable two months later. He has no adverse reactions to his new regimen initially, and follows up with you in clinic regularly. He is happy with his regimen, and relieved at the lack of side effects. Case 1 (cont) However, over the next two years, he develops chronic kidney disease (egfr=45) thought due to worsening diabetes and hypertension. Discussion question: Should this patient be continued on TAF? Should this patient be continued on TAF given his CKD? 1. Yes 2. No ARV Point 1: CrCl Cutoffs for ARVs FDA Approved CrCl cutoff, ml/min EVG/COBI/FTC/TDF 70 DRV/COBI + FTC/TDF 70 EFV/FTC/TDF 50 RPV/FTC/TDF 50 DTG/ABC/3TC 50 DRV/RTV, DTG, or RAL + FTC/TDF 50 EVG/COBI/FTC/TAF 30 RPV/FTC/TAF 30 DRV/COBI, DRV/RTV, DTG, or RAL + FTC/TAF 30 3

4 Point 1: CrCl Cutoffs for ARVs Point 1: CrCl Cutoffs for ARVs ARV FDA Approved CrCl cutoff, ml/min EVG/COBI/FTC/TDF 70 DRV/COBI + FTC/TDF 70 EFV/FTC/TDF 50 RPV/FTC/TDF 50 DTG/ABC/3TC 50 DRV/RTV, DTG, or RAL + FTC/TDF 50 EVG/COBI/FTC/TAF 30 RPV/FTC/TAF 30 DRV/COBI, DRV/RTV, DTG, or RAL + FTC/TAF 30 ARV FDA Approved CrCl cutoff, ml/min EVG/COBI/FTC/TDF 70 DRV/COBI + FTC/TDF 70 EFV/FTC/TDF 50 RPV/FTC/TDF 50 DTG/ABC/3TC 50 DRV/RTV, DTG, or RAL + FTC/TDF 50 EVG/COBI/FTC/TAF 30 RPV/FTC/TAF 30 DRV/COBI, DRV/RTV, DTG, or RAL + FTC/TAF 30 GS-112: Switching to a TAF-Based Regimen in Pts With Renal Impairment Multicenter, open-label phase III trial Virologically suppressed, HIV-positive pts with mild-moderate renal impairment (stable egfrcg [30-69 ml/min]) (N = 242) Outcomes: TDF-Based ART (n = 158) Non-TDF Based ART (n = 84) Virologic suppression: Maintained (92%) CrCl: Stable through 96 weeks Proteinuria, albuminuria, BMD (hip & spine): Improved Posniak,. JAIDS Apr 15; 71(5): Post FA, et al. CROI Abstract 680. Wk 24 Wk 48 EVG/COBI/FTC/TAF (N = 242) Wk 96 Characteristic D:A:D Risk Score for CKD in HIV-Infected Patients Mocroft A, et al. PLoS Med. 2015;12:e Addition to D:A:D Score Diabetes +2 IDU +2 HCV coinfection +1 Aged yrs +4 Aged yrs +7 Aged > 60 yrs +10 BL egfr > 60 to 70* +6 BL egfr > 90* -6 Female +1 Nadir CD4+ cell count > 200 cells/mm 3-1 Hypertension +1 Prior CVD +1 *ml/min/1.73 m 2 Low risk: < 0 Medium risk: 0-4 High risk: 5 4

5 GS-104/111: Renal Outcomes With TDF vs TAF by D:A:D Risk Score Renal Outcome High Risk for CKD Medium Risk for CKD Low Risk for CKD E/C/F/TAF (n = 56) E/C/F/TDF (n = 84) E/C/F/TAF (n = 107) E/C/F/TDF (n = 129) E/C/F/TAF (n = 697) E/C/F/TDF (n = 648) Incident CKD, n (%) 0 4 (4.8) 0 3 (2.3) 1 (0.1) 7 (1.1) Renal AE d/c, n (%) 0 3 (2.4) 0 3 (0.8) 0 0 Overall incident CKD: 1 (0.1%) E/C/F/TAF vs 14 (1.6%) E/C/F/TDF Wohl D, et al. CROI Abstract 681. Wohl D, et al. J Acquir Immune Defic Syndr. 2016;72: Unclear significance of renal biomarkers Better rush out to measure my retinol binding protein and beta 2 microglobulin in urine We don t have the clinical experience GUT PLASMA CELL with TAF TDF out since 2001; TAF since 2015 What are long-term clinical implications of the changes in renal markers? TAF gives 4-7x higher intracellular TFV-DP concentrations than TDF what does that mean for kidney? 25mg of TAF is being given with boosted PIs v FDA only approved 25mg/200mg TAF/FTC tablet v We know that 25mg TAF gives same exposure to TFV-DP as 10mg TAF + cobicistat Case 2 5

6 Case 2 CB is a 38yo woman with HIV diagnosed 4 years ago Baseline labs: CD4 267 (27%) HIV RNA 18,000 HIV Genotype: wild type Hepatitis B and C negative Cr 0.89 HLA-B57*01 negative Initial regimen: TDF/FTC/EFV Had relapse of heroin and was poorly compliant for 4 months Now in residential treatment and returning to care Current lab results CD4 312 (32%) HIV RNA 1400 CASE 2 (continued) HIV Genotype: RT: M184V, K103N; PR: No mutations Strong preference for single-tablet regimen ARS: What would you start now? 1. Start DTG/3TC/ABC (Triumeq) 2. Start EVG/Cobi/TAF/FTC or TDF/FTC (Genvoya or Stribild ) 3. Start DRV/c-r + TDF-TAF/FTC 4. Start DTG + TDF-TAF/FTC 5. Start DRV/c-r + DTG + TDF-TAF/FTC CASE 2 Start DRV/c-r + TDF-TAF/FTC VF due to non-adherence on Atripla à M184V, K103N Patient wants a single tablet option. What are the options? RPV/TAF or TDF/FTC c/evg/taf or TDF/FTC DTG/3TC/ABC Sub-optimal because: - Low barrier to resistance of RPV - Same low barrier w/ EVG - 184V causes low-level ABC Resist 3 active drugs (DRV/r/DTG/TDF/FTC) = most conservative What about 2 drugs: DRV/c-r vs. DTG + TDF-TAF/FTC DTG DRV/r Boosted DRV: 1. Stronger evidence (than DTG) for efficacy of dual therapy with boosted PIs (e.g. GARDEL: LPV/r/3TC non-inferior to LPV/r/3TC+NRTI); and switch to DRV/r monotherapy (e.g. MONET) 2. Longer clinical experience 6

7 96 week results of FLANGO trial DTG/TDF vs DRV/r/TDF Difference 12 4, 95% CI ; p=0 002) DTG 80% DRV/r 68% Remember that neither of these have been studied as dual therapy ( NOT-1 and 2 ) But not a single case of treatment emergent resistance in the naïve DTG trials (SINGLE, SAILING, FLANGO) (4 in ARTES-DRV/r naïve trial, but not major 1 ) Rare emergence of resistance with DTG in experienced patients; more common with DRV (POWER 1, 2 2 ) Increasing data on INSTI + 2 nd drug 1 Orkin. HIV Med 2013; 2 Clotet Lancet 2007 Case 3 Case 3 56 yo man with HIV diagnosed in 2015 naïve to therapy HTN (BP 145/95) DM (HbA1c 9.8) Coronary artery disease Chronic kidney disease Osteoporosis 7

8 Labs Case 3 (continued) CD4 count 580 cells/mm 3 ; viral load 140,000 cp/ml HIV genotype wild type HLA-B5701 negative Estimated CrCl 45 ml/min ARS: What would you do now? 1. Opt for NRTI-including regimen 2. Opt for NRTI -sparing regimen Case 3 Opt for NRTI-including regimen NRTI-sparing regimens as initial Rx? Not yet Several trials of Nuc-sparing (+/- 3TC) Rx Almost all have been problematic*: Failure to meet non-inferiority in virologic suppression SPARTAN (ATV/RAL vs. ATV/r/RAL/TDF/FTC) >Rx failure in ATV/RAL ACTG 5262: single arm study of DRV/r + RAL -> unexpectedly high rates of virologic failure w/ resistance (esp baseline HIV VL >100K) Met non-inferiority for virologic failure... but, ACTG 5142: Greater rates of failure with resistance NEAT001: Concerning sub-groups (CD4<200 inferior; VL>100,000) PROGRESS: LPV/r/3TC (2 M184V mutations) vs. LPV/r/3TC+NRTI (no mutations) PADDLE = small study; too soon to say * Especially NRTI-free vs. NRTI-sparing (3TC) Case 3 Opt for NRTI-including regimen In this case: TAF/FTC vs. ABC/3TC as NRTI backbone both options TAF: CrCl = 45 (ie. >30) ABC: Can reduce /CV risk by addressing modifiable risk factors Virologic suppression important for reducing CV risk Mostly based on observational (cohort) data; FDA metaanalysis of RCTs: no e/o association w/ Absolute risk of associated with ABC use is low 8

9 Summary of Key Analyses Showing ABC Associated With Risk of Study Study Design Age, Yrs (Range) Event (n) Pts, N ABC CV Effect Time on ABC, Mos Risk of (95% CI) D:A:D Cohort 40 (35-47), validated (387) 22,625 Yes ( ) D:A:D 2015 Cohort 39 (33-46) (493) 32,663 Yes Current 1.47 ( ) SMART RCT 45 (39-51), validated (19) 2752 Yes Current 4.3 ( ) STEAL RCT 45.7 ±8.8 (4) 357 Yes * ( ) QPHID CC 47 (22-67) (125) 7053 Yes Any 1.79 ( ) Danish Cohort 39 (33-47) (67) 2952 Yes > ( ) VA (Choi) Cohort 46 CVD event (501) 10,931 Yes Recent 1.64 ( ) Swiss Cohort Not given CVD event (365) 11,856 Yes Recent 4.06 ( ) MAGNIFICENT CC 50 ( ) CVD event (571) 1875 Yes Current 1.56 ( ) NA-ACCORD Cohort, validated (301) 16,733 Yes Recent 1.33 *Risk for serious non-aids events (most common was CVD, including ); HR for CVD with TDF vs ABC: 0.12 (95% CI: ; P =.048). Risk for CVD event, including, invasive CV procedure, or CV-related death. Summary of Key Analyses Showing ABC NOT Associated With Risk of Study FHDH ALLRT/ ACTG Study Design CC Cohort Age, Yrs (Range) 47 (41-54) 37 (26-51) VA Cohort 46 FDA NA- ACCORD Metaanalysis of RCTs Cohort Event (n) (289) (36) (278) (46), validated (301) *Without adjustment for cocaine use OR: 2.01 ( ). Pts, N ABC CV Effect 74,958 No Time on ABC, Mos < 12/ recent 5056 No 72 19,424 No Per No 19 Adj Risk of (95% CI) 1.27* ( ) 0.6 ( ) 1.18 ( ) 1.02 ( ) 16,733 No Recent 1.33 Study Novel TDF- and ABC-Sparing ART Strategies Initial or Switch From Suppr. ART N Regimen Results GARDEL [1] Initial 426 LPV/RTV + 3TC Similar efficacy as LPV/RTV + 2 NRTIs PADDLE [2] Initial 20 DTG + 3TC Small study; encouraging efficacy NEAT001/ Initial 805 DRV/RTV + RAL Similar efficacy as DRV/RTV + TDF/FTC ANRS143 [3] SALT [4] Switch 286 ATV/RTV + 3TC Similar efficacy as ATV/RTV + 2 NRTIs ATLAS-M [5] Switch 266 ATV/RTV + 3TC Similar (improved in post hoc analysis) efficacy vs ATV/RTV + 2 NRTIs OLE [6] Switch 250 LPV/RTV + 3TC Similar efficacy as cont. standard ART NA [7] Switch 48 DRV/RTV + 3TC Small study; encouraging efficacy LATTE [8] Switch 243 CAB + RPV Similar efficacy as cont. standard ART LATTE-2 [9] Induction- Maintenance 309 Induct: CAB + ABC/3TC PO; Mainten: LA CAB + LA RPV IM Q4W or Q8W Similar efficacy as cont. oral CAB + ABC/3TC; injection-site rxns frequent but high pt satisfaction 1. Cahn P, et al. EACS Abstract Raffi F, et al. Lancet. 2014;384: Figueroa, et al. EACS Abstract Perez-Molina JA, et al. Lancet Infect Dis. 2015;15: Di Giambenedetto S, et al. EACS Abstract Arribas JR, et al. Lancet Infect Dis. 2015;15: Casado JL, et al. J Antimicrob Chemother. 2015;70: Margolis DA, et al. Lancet Infect Dis. 2015;15: Margolis DA, et al. CROI Abstract 31LB. NEAT-001/ANRS 143: DRV/RTV + RAL vs DRV/RTV + TDF/FTC in Naive Pts Randomized, open-label phase III study ART-naive pts with HIV-1 RNA > 1000 c/ml CD4+ cell count 500 cells/mm 3 (N = 805) Raffi F, et al. CROI Abstract 84LB. DRV/RTV 800/100 mg QD + RAL 400 mg BID (n = 401) DRV/RTV 800/100mg QD + TDF/FTC 300/200 mg QD (n = 404) Wk 96 9

10 NEAT: RAL + DRV/RTV Noninferior to TDF/FTC + DRV/RTV at 96 Weeks LATTE-1: GSK (Cabotegravir) as Part of ART in Naive Pts Overall, regimens noninferior by % reaching composite primary endpoint of 6 virologic and clinical endpoints at Wk 96 RAL: 17.4%; TDF/FTC: 13.7% Inferior response in pts with BL CD4 < 200 and a trend toward more primary endpoints in pts with BL VL 100K Similar numbers of pts with PDVF (RAL: n = 66; TDF/FTC: n = 52) No pts with resistance in TDF/FTC arm vs 5 with integrase mutations and 1 with K65R in RAL arm Overall N = 805 BL HIV-1 RNA < 100,000 c/ml 100,000 c/ml BL CD4+ cell count n = 530 n = 275 < 200/mm 3 n = /mm 3 n = 682 Raffi F, et al. CROI Abstract 84LB. Reproduced with permission. Primary Endpoint at Wk 96: Adjusted Difference Estimate (95% CI) RAL - TDF/FTC RAL TDF/FTC Significantly greater mean increases in fasting lipids in RAL arm 7 27 (P =.09) (P =.02) GSK (744), DTG analogue with long half-life, oral or injectable formulations Randomized, dose-ranging phase IIb study of oral formulation Primary endpoint: HIV-1 RNA < 50 c/ml at Wk 48 Stratified by HIV-1 RNA Wk 48 ( vs > 100,000 c/ml) and NRTI Wk 24 primary analysis Induction Phase* Maintenance Phase mg QD + 2 NRTIs (n = 60) mg QD + RPV 25 mg QD ART-naive pts, HIV-1 RNA > 1000 c/ml (N = 243) mg QD + 2 NRTIs (n = 60) mg QD + 2 NRTIs (n = 61) mg QD + RPV 25 mg QD mg QD + RPV 25 mg QD EFV 600 mg QD + 2 NRTIs QD (n = 62) *Pts with HIV-1 RNA < 50 c/ml at Wk 24 continued to maintenance phase. TDF/FTC or ABC/3TC. Margolis D, et al. EACS Abstract PS7/1. Margolis D, et al. CROI Abstract 91LB; Margolis D Lancet ID HIV-1 RNA < 50 c/ml by Snapshot Algorithm (%) LATTE-1: Virologic Success During Induction and Maintenance Phases Induction Phase Maintenance Phase 0 BL Wks 2 pts with PDVF during maintenance; both with INSTI mutations at BL 96% 94% 92% 91% Cabotegravir 10 mg (n = 60) Cabotegravir 30 mg (n = 60) Cabotegravir 60 mg (n = 61) EFV 600 mg (n = 62) Margolis D, et al. EACS Abstract PS7/1. Margolis D, et al. CROI Abstract 91LB; Margolis D Lancet ID Dolutegravir Monotherapy in Treatment-Naive Pts N = 9 pts who refused NRTIs and initiated DTG monotherapy All pts had baseline HIV-1 RNA < 100,000 copies/ml No baseline NRTI, NNRTI, PI, or INSTI resistance Pt HIV-1 RNA, copies/ml CD4+ Cell Count, cells/mm 3 Mos on DTG Baseline After 4 Wks DTG At Last Visit Baseline At Last Visit 1 20,400 Undetectable Undetectable ,400 Undetectable < , Undetectable , Undetectable ,300 < 20 Undetectable , < ,200 < 20 Undetectable ,900 Undetectable Undetectable ,000 < 20 Undetectable Lanzafame M, et al. J Acquir Immune Defic Syndr. 2016;72:e12-e14. 10