1. VIRTUAL MEDZONE Your Resource for HIV Related Innovative Medical Communication

2. HIV CASE PRESENTATIONS Alice Tseng Pharm.D., FCSHP, AAHIVP David Fletcher MD FRCPC

3. CASE 1 54 yo Caucasian woman, Dx HIV & HCV in 2002 ARV treatment (CD4 280, VL 40,526) DATEARV REGIMENVLCD4 10/02AZT/3TC/NFV<50477 10/07AZT/3TC/LPVr<50727 09/09TDF/FTC/LPVr<50819

4. CASE 1 HCV 1a (gr 3-4 fibrosis, RNA 1.32E+6 IU/mL) DATETREATMENTOUTCOME 02/03RBV+peg-IFNd/c after 2 doses ( ↓ Hgb, ANC) 06/03Amitriptyline, RBV+peg- IFN, EPO, GCSF d/c after 2 weeks 09/05 LFTs still  pre-RBV, peg- IFN 2A d/c after wk 12 (supoptimal response)

5. CASE 1 Considerations with HCV protease inhibitors: Telaprevir: LPVr: 54%  AUC, 52%  Cmin of TVR DRVr: 35%  AUC, 32%  Cmin of TVR; also 40%  AUC, 42%  Cmin of darunavir ATVr: 20%  AUC, 15%  Cmin of TVR; least impact of all current PIs  ongoing evaluation in HIV/HCV Tenofovir:  AUC (relevance?). Monitor Scr. Boceprevir: minimal effects of RTV 100 mg QD and BID on BOC AUC

6. CASE 1 So how should we manage this patient on TDF /FTC/LPVr?...switch ARVs Telaprevir RTV/ATZ EFV Raltegravir Boceprevir…stay tuned

7. CASE 2 50 yo, Caucasian male, HIV+ since 1992 VL suppressed since 1996, CD4 720 some NRTI mutations, no PI mutations, R5+ on 3TC, SQV 600/RTV 300 mg BID, RAL BID since 2008

8. CASE 2 Asthma: prev. on Symbicort (budesonide/formoterol) inhaler interaction with RTV/SAQ  adrenal suppression/ insufficiency, Cushings Syndrome (2010) also has osteoporosis, hyperlipidemia, autoimmune retinopathy How do you manage his asthma?

9. CASE 3 62 yo male, HIV+ 1992 extensive ARV history with AEs & resistance CAD, CHF, HTN, hyperlipidemia, NIDDM, gout, chronic renal insufficiency

10. CASE 3 Meds: ABC, 3TC, LPVr, T20 TMP/SMX DS, allopurinol, metoprolol, furosemide, Aggrenox (dipyridamole 200 mg/ASA 25 mg), amlodipine, rosuvastatin Dx pulmonary arterial hypertension (PAH) 2003, respirologist Rx bosentan… How do you manage this patient?

11. PAH THERAPIES Substrate P450 Substrate (other)Inducer/ Inhibitor Endothelin Receptor Antagonists: Bosentan (Tracleer®)3A4, 2C92C9, 3A4 (inducer) Ambrisentan (Volibris®)CYP3A4, 2C19 UGT1A9S, 2B7S, 1A3S, Pgp Phosphodiesterase inhibitors: Sildenafil (Revatio®)3A4>>2C 9 1A2, 2C9, 2C19, 2D6, 2E1, 3A4 (weak inhibitor) Tadalafil (Adcirca®)3A4

12. POTENTIAL INTERACTION BETWEEN BOSENTAN & PIS Possibility of  bosentan and/or  lopinavir/r concentrations via CYP450 inhibition/induction Usual bosentan dose: 62.5 mg BID x 4 weeks, then 125 mg BID

13. POTENTIAL INTERACTION BETWEEN BOSENTAN & PIS May 2004: Rx bosentan 62.5 mg BID,  LPV/r to 5 capsules BID 1 month later developed recurrent anemia requiring transfusions despite iron supplementation & EPO

14. POTENTIAL INTERACTION BETWEEN BOSENTAN & PIS anemia associated with bosentan is dose- related in controlled studies,  Hgb of at least 10 g/L observed in 57% bosentan-tx subjects vs. 29% placebo group

15. ADMINISTERING BOSENTAN WITH PROTEASE INHIBITORS Management: if already on stable PI tx: initiate bosentan 62.5 mg q1-2days if on stable bosentan and require PI: d/c bosentan for >36 h, start PI x 10 days, re-start bosentan at 62.5 mg q1-2days [DHHS Guidelines, Oct 14/11; Tracleer monograph, June 2011; Reyataz monograph, May 2011.]

16. ADMINISTERING BOSENTAN WITH PROTEASE INHIBITORS Monitoring parameters: efficacy: improvement in exercise tolerance, NYHA functional status severity and hemodynamic measures via right heart catheterization. Also suggest PI TDM & VL. [DHHS Guidelines, Oct 14/11; Tracleer monograph, June 2011; Reyataz monograph, May 2011.]

17. ADMINISTERING BOSENTAN WITH PROTEASE INHIBITORS Monitoring parameters: toxicity: headache, flushing, GI effects, anemia, liver injury, worsening CHF (wt gain, leg edema) and pulmonary edema (SOB, painful/difficult breathing) Atazanavir: do not use unboosted atazanavir with bosentan (may  ATV) [DHHS Guidelines, Oct 14/11; Tracleer monograph, June 2011; Reyataz monograph, May 2011.]

18. CASE 4 66 yo male, HIV+ 1992 NIDDM, hyperlipidemia, HTN, renal dysfunction (multifactorial), peripheral neuropathy, depression, BPH, chronic pain

19. CASE 4 Medications DRV/r BID, RAL BID, ETV BID ASA, amlodipine, ramipril, coenzyme Q10, fenofibrate, ezetimibe, atorvastatin, metformin, Prandase (acarbose), Januvia (sitagliptin), Cymbalta (duloxetine), ACV, Detrol (tolterodine), dulcolax, colace, metamucil, Flonase prn, testosterone cream Urologist wants to add daily tadalafil: Interaction with DRV/r?

20. IMPACT OF PIS ON PDE5 INHIBITORS SildenafilTadalafilVardenafil Darunavir/r 300%  Fosamprenavir/rPriapism (case) Lopinavir/r 100%  Ritonavir 1000%  (500mg BID) 124%  (200 mg BID) 49-fold  (600 mg BID) Saquinavir/r 210% 

21. DOSING OF PDE5 INHIBITORS WITH PIS *if on stable tadalafil and starting PI therapy: d/c tadalafil for at least 24 h, start PI, restart tadalafil after 7 days at 20 mg QD with  to 40 mg QD prn For PAHSildenafilTadalafilVardenafil Usual Dose20 mg TID40 mg QD With PI/rContraindicated 20mg QD,  to 40 mg QD if tolerated For EDSildenafilTadalafilVardenafil Usual Dose50-100 mg QD10-20 mg QD prn 2.5-5 mg OD (daily dosing) With PI/r25 mg q48h10 mg q48h, max 3x/wk No change NB: Vardenafil is contraindicated with ritonavir, indinavir, ketoconazole and itraconazole