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Transcript
HIV Infection in Solid Organ
Transplant Patients
Stefanie L. Drahuschak
PharmD Candidate 2014
University of Pittsburgh School of Pharmacy
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 antirejection medications
 Determine relative risk of interactions between patient’s
antiretrovirals and post-transplantation regimen.
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
NR: Past Medical History
 End Stage Renal Disease
 Human Immunodeficiency Virus
 Diabetes mellitus, Type 1
 Hypertriglyceridemia (severe)
 Hypertension
 Gout
 Depression
 Hypothyrodism
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
NR: Home medications
Medication
Dose
Frequency
Abacavir (Ziagen)
300 mg
2 tabs once daily
Allopurinol (Zyloprim)
100 mg
1 tab twice daily
B complex-vitamin c-folic acid
(Nephro-Vite)
0.8 mg
1 cap once daily
Benzoyl peroxide (Benzefoam)
Apply as directed
Calcitriol (Rocaltrol)
0.25 mcg
1 cap once daily
Colchicine (Colcrys)
0.6 mg
1/2 tab 3 times per week
Cyclobenzaprine (Flexeril)
10 mg
1 tab three times daily as needed
Duloxetine (Cymbalta)
60 mg
1 cap once daily
Ergocalciferol (Vitamin D2)
50,000 units
1 cap once weekly
NR: Home Medications
Medication
Dose
Frequency
Fenofibrate (Antara)
43 mg
1 tab once daily
Icosapent ethyl (Vascepa)
1 gram
2 cap every 12 hours
Insulin aspart (Novolog)
100 u/mL
Uses via pump
Lamivudine (Epivir)
10 mg/mL
10 mL once daily
Levothyroxine (Synthroid)
125 mcg
1 tab once daily
Lisinopril (Prinivil)
10 mg
1 tab once daily
Nebivolol (Bystolic)
20 mg
1 tab once daily
Pitavastatin (Livalo)
4 mg
1 tab once daily
Raltegravir (Isentress)
400 mg
1 tab twice daily
Sevelamer (Renvela)
800 mg
4 tabs three times daily with meals
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)
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)
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)
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)
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
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.
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
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)
Treatment: HAART Therapy
 NNRTI
 OR
 PI (boosted)
 OR
 INSTI
2-Drug NRTI
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
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
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)
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)
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)
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
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
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
Frassetto, et al.
 Cyclosporine
 When given with PIs required only 1/10th 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
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
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
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
Questions?