1. Stefanie L. Drahuschak PharmD Candidate 2014 University of Pittsburgh School of Pharmacy HIV Infection in Solid Organ Transplant Patients

2. Objectives Identify diagnostic tools and important laboratory tests for Human Immunodeficiency Virus Describe appropriate therapeutic options for HIV-positive patients Describe the interactions between antiretroviral and anti- rejection medications Determine relative risk of interactions between patient’s antiretrovirals and post-transplantation regimen.

3. NR: History of Present Illness CC: End Stage Renal Disease Being evaluated for kidney and pancreas transplants on 8/27/13 42 year old Caucasian male No known medication allergies

4. NR: Past Medical History End Stage Renal Disease Human Immunodeficiency Virus Diabetes mellitus, Type 1 Hypertriglyceridemia (severe) Hypertension Gout Depression Hypothyrodism

5. NR: Family and Social History Family History Unknown Social History No tobacco use No alcohol use No substance abuse No compliance issues Single male living alone, is with his partner of 17 years

6. NR: Home medications MedicationDoseFrequency Abacavir (Ziagen)300 mg2 tabs once daily Allopurinol (Zyloprim)100 mg1 tab twice daily B complex-vitamin c-folic acid (Nephro-Vite) 0.8 mg1 cap once daily Benzoyl peroxide (Benzefoam)Apply as directed Calcitriol (Rocaltrol)0.25 mcg1 cap once daily Colchicine (Colcrys)0.6 mg1/2 tab 3 times per week Cyclobenzaprine (Flexeril)10 mg1 tab three times daily as needed Duloxetine (Cymbalta)60 mg1 cap once daily Ergocalciferol (Vitamin D2)50,000 units1 cap once weekly

7. NR: Home Medications MedicationDoseFrequency Fenofibrate (Antara)43 mg1 tab once daily Icosapent ethyl (Vascepa)1 gram2 cap every 12 hours Insulin aspart (Novolog)100 u/mLUses via pump Lamivudine (Epivir)10 mg/mL10 mL once daily Levothyroxine (Synthroid)125 mcg1 tab once daily Lisinopril (Prinivil)10 mg1 tab once daily Nebivolol (Bystolic)20 mg1 tab once daily Pitavastatin (Livalo)4 mg1 tab once daily Raltegravir (Isentress)400 mg1 tab twice daily Sevelamer (Renvela)800 mg4 tabs three times daily with meals

8. NR: Laboratory Results (8/27/13) Blood type: B negative HIV-1/HIV-2 Antibody: positive HIV serologic confirmation: positive C-peptide: 17.60 ng/mL (H) CMV: positive Epstein-Barr Virus: positive Lipase: 156 U/L (H; NR: 15-70 U/L) g-Glutamyl trans (gGTP): 270 IU/L (H) Uric acid: 9.1 mg/dL (H)

9. NR: Laboratory Results (8/27/13) Lipid panel TC: 119 mg/dL Triglycerides: 936 mg/dL (H) LDL: Cannot be calculated when Trig > 400 HDL: 16 mg/dL (L) CBC with differential RBC: 3.42 UNITS (L) Hgb: 10.9 g/dL (L) Hct: 30.7% (L)

10. NR: Laboratory Results (8/27/13) Metabolic panel Urea Nitrogen: 40 mg/dL (H) Creatinine: 5.7 mg/dL (H) Glucose: 218 mg/dL (H) Hemoglobin A1c: 6.9% (H) AST: 49 IU/L (H) Anion gap: 16 mEq/L (H)

11. Human Immunodeficiency Virus Background 35 million people living with HIV HIV is a single-stranded RNA virus Member of Lentivirinae (subfamily of viruses) Two distinct HIV viruses HIV-1: United States and HIV-2: Western Africa Three primary modes of infection 1) Sexual transmission (most common) 2) Perinatal (primary cause of pediatric infection) 3) Parenteral transmission (IV drug use, blood products, organ transplantation)

12. HIV Diagnosis Screening test: Enzyme-linked Immunosorbent Assay (ELISA) Inexpensive, highly sensitive (>99%) and specific (>99%) Detects the presence of HIV antibody in blood False positives do occur Confirmatory test: Western Blot Gold standard for diagnosis Uses gel electrophoresis to detect specific proteins for the HIV antigen

13. Baseline Testing for HIV Patients HIV diagnosis (ELISA then Western Blot) Drug resistance testing (before treatment) CD4+ T-cell count Plasma HIV RNA (viral load) Others STD testing, Tb skin test, routine CBC and liver enzymes, FBG and lipid levels, Hep A, B, and C.

14. CD4+ T-cell Count Strongest predictor of disease progression and survival The total number of CD4+ T-lymphocytes Should be determined every 3-4 months Determines when to start therapy Assess response rate to therapy Adequate response rate is an increase of 50-150 cells/mm3 per year until steady state Assesses the need for start/stop of prophylatic medications

15. Plasma HIV RNA (Viral Load) Measures the number of copies of HIV RNA in plasma Most important indicator medication therapy Measured 2-8 weeks after the start or change of medication regimen Treatment goal: Undetectable viral load (<50 copies/mL)

16. Treatment: HAART Therapy NNRTI OR PI (boosted) 2-Drug NRTI OR INSTI

17. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) MOA: Inhibit reverse transcriptase by incorporation into the viral DNA Examples: Abacavir (Ziagen), didanosine (Videx EC), lamivudine (Epivir), tenofovir (Viread), zidovudine (Retrovir), emtricitabine (Emtriva) Combo NRTIs: Combivir, Trizivir, Truvada, Epzicom

18. Nucleoside Reverse Transcriptase Inhibitors (NRTIs) Mainly undergo renal elimination Must renally dose adjust NO CYP interactions Adverse events: Peripheral neuropathy and pancreatitis (with stavudine and didanosine only)-requires treatment Nephrotoxicity with tenofovir

19. Non-Nucleoside Reverse Transcriptase Inhibitors (NNRTIs) MOA: Inhibits reverse transcriptase by directly binding to the enzyme Examples: Delavirdine (Rescriptor), efavirenz (Sustiva), nevirapine (Virammune), etravirine (Intelence), rilpivirine (Edurant)

20. Non-Nucleoside Reverse Transcripase Inhibitors (NNRTIs) Hepatic metabolism-no renal adjustments MANY CYP interactions 3A4: delaviridine (inhibits), neviripine (strong inducer), efavirenz (stronger inducer), etravirine (strongest inducer), rilpivirine (substrate) Adverse events Hepatotoxicity (potentially fatal), rash (SJS, TENS), CNS events with Efavirenz only (confusion, vivid dreams, dizziness)

21. Protease Inhibitors (PIs) MOA: inhibit viral replication by selectively binding to HIV-1 protease and blocking protein cleavage therefore preventing the production of viral particles Examples: Amprenavir (Agenerase), atazanavir (Reyataz), darunavir (Prezista), fosamprenavir (Lexiva), indinavir (Crixivan), lopinavir/ritonavir (Kaletra), nelfinavir (RTV), saquinavir (Invirase), tipranavir (Aptivus)

22. Protease Inhibitors (PIs) Most potent class of antiretrovirals Most toxic class, can cause Hyperlipidemia, insulin resistance/diabetes, elevated LFTs, GI intolerances, lipodystrophy Most PIs are potent CYP3A4 inhibitors Ritonavir (most), saquinavir (least) Most PIs are boosted with ritonavir, the most potent PI

23. Integrase Inhibitor (INSTI) Inhibits integrase, which is the enzyme that integrates viral DNA into host cell DNA Raltegravir No CYP interactions Well tolerated Can be used in treatment naïve or experienced patients

24. Antiretrovirals and Immunosuppressants Frassetto, et al. Describes PK of CsA and TAC in 52 patients on both immunsuppression and NNRTIs or PIs Subjects had protocol-driven PK studies at weeks 2-4, and 3, 6, 12, and 24 months after transplantation and after a change in either their immunosuppression or antiretroviral therapies A total of 224 PK profiles were obtained during the study period Biopharm Drug Dispos. 2013; Not yet in print

25. Frassetto, et al. Cyclosporine When given with PIs required only 1/10 th the dose to achieve AUCs comparable to those in non-HIV transplant patients In patients receiving efavirenz (NNRTI), CsA AUCs increased nearly 40% despite lowering the CsA dose by more than 50%. Biopharm Drug Dispos. 2013; Not yet in print

26. Frassetto, et al. Tacrolimus Exposure to TAC increased more than 10-fold in the presence of PIs relative to NNRTIs (p=0.009), and more than 50-fold compared to non-HIV transplant patients Due to increases in bioavailability and decreases in clearance Dose of TAC needs decreased and dosing interval needs increased Biopharm Drug Dispos. 2013; not yet in print

27. Risks for NR’s Regimen Abacavir (Ziagen) NRTI-no CYP interactions Lamivudine (Epivir) NRTI-no CYP interactions Raltegravir (Isentress) INSTI-no CYP interactions No apparent risks for immunosuppressant interactions, but should be monitored very closely

28. References 1) Dipiro, J. (2011). Human Immunodeficiency Virus Infection. In Anderson, PL (Ed.). Pharmacotherapy (pp. 2169-90. New York, NY: The McGraw-Hill Companies 2) Frassetto L, Floren L, Barin B, et al. Changes in clearance, volume and bioavailability of immunosuppresants when given with HAART in HIV-1 infected liver and kidney transplant recipients. Biopharm Drug Dispos. 2013; not yet in print

29. Questions?