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7/5/2017
1
HIV Update 2017
Lori A. Gordon, PharmD, BCPS‐AQ ID, AAHIVP
Clinical Assistant Professor
Xavier University of Louisiana College of Pharmacy
LPA 2017.07.14
Disclosures• Lori A. Gordon, PharmD, reports the following disclosures:
– ViiV Healthcare (Regional Medical Advisory Board Expert)
2
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Pharmacists Learning Objectives• Following this presentation, the viewer should be able to:– Relate the steps of the HIV life cycle to targets of antiretroviral therapeutic classes
– Recommend appropriate complete regimens for treatment naïve HIV patients
– Identify common and unique adverse drug reactions within antiretroviral therapeutic classes
– Recognize potential mechanisms of drug‐drug interactions between antiretroviral agents and other concomitant medications
3
Technicians Learning Objectives• Following this presentation, the viewer should be able to:
– Identify antiretroviral therapeutic classes required for complete regimens in treatment naïve HIV patients
– Identify common adverse reactions within antiretroviral therapeutic classes
– Identify common drug‐drug interactions between antiretroviral agents and other concomitant medications
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Natural Course of HIV Infection
5
Rates of Diagnoses of HIV Infection among Adults and Adolescents, 2014—United States and 6 Dependent Areas
N = 44,609 Total Rate = 16.6
Note. Data include persons with a diagnosis of HIV infection regardless of stage of disease at diagnosis. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting.
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Louisiana Statistics (2014)• Persons living with HIV: 20,627
– 52% with AIDS
• 2nd highest state in nation for new HIV diagnoses– Baton Rouge ranked highest and New Orleans ranked 2nd
highest among large metropolitan areas in nation for new HIV diagnoses
– Major risk factors• Men who have sex with men (MSM): 70%• African‐American: 71%• Youth/young adult: 31% (25 – 34yo); 27% (13 – 24yo);
• 2nd highest state in nation for new AIDS diagnoses– Baton Rouge ranked 1st; New Orleans ranked 4th
7LA OPH SHP 2015, www.hiv411.orgwww.aidsvu.org
• On average, I provide care to ___ HIV+ patients on a weekly basis
– 0 – 5
– 5 – 10
– 10 – 20
– 20+
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Hands up! The HIV Hijack
Targets for Antiretroviral Therapy
Life Cycle of HIV: Pharmacological Targets
• Binding
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Life Cycle of HIV: Pharmacological Targets
• Binding
• Fusion/Penetration
Life Cycle of HIV: Pharmacological Targets
• Binding
• Fusion/Penetration
• Transcription
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Life Cycle of HIV: Pharmacological Targets
• Binding
• Fusion/Penetration
• Transcription
• Integration
Life Cycle of HIV: Pharmacological Targets
• Binding
• Fusion/Penetration
• Transcription
• Integration
• Translation
• Assembly/Budding/Maturation
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Life Cycle of HIV: Pharmacological Targets• Binding
– CCR5 antagonists
• Fusion/Penetration– Fusion inhibitors
• Transcription– Nucleoside/Non‐nucleoside
reverse transcriptase inhibitors (NRTI/nNRTI)
• Integration– Integrase strand transfer
inhibitors (InSTIs)
• Translation• Assembly/Budding/Maturation
– Protease inhibitors (PI)
Putting the cART before the horse
Recommended Antiretroviral Regimens
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Ms. Jones• Ms. Jones is a 26yo female who is newly diagnosed HIV+ patient.
– She is treatment‐naïve, with a baseline viral load of 893,000 copies/mL and CD4 count of 351 cells/mm3
• What would you select as an appropriate initial regimen for her?
17
Combination AntiRetroviral Therapy (cART)
18Courtesy of AS Fauci
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Stage 3 (AIDS) Classifications and Deaths of Persons with HIV Infection Ever Classified as Stage 3 (AIDS), among Adults and
Adolescents, 1985–2013—United States and 6 Dependent Areas
Note. All displayed data have been statistically adjusted to account for reporting delays, but not for incomplete reporting. Deaths of persons with HIV infection, stage 3 (AIDS) may be due to any cause.
HIV Treatment Regimens
nNRTI
InSTI
NRTI Backbone(2 NRTIs)
PI
Anchor Drug
Department of Health & Human Services 2016
InSTI = integrase strand transfer inhibitornNRTI = non‐nucleoside reverse transcriptase inhibitorNRTI = nucleoside reverse transcriptase inhibitorPI = protease inhibitor
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Recommended Initial Regimens
Department of Health & Human Services 2016
Emtricitabine/Tenofovir
(FTC/TDF or FTC/TAF)
Abacavir/Lamivduine
(ABC/3TC)
Darunavir/ritonavir(DRV/rtv) Raltegravir
(RAL)
Dolutegravir(DTG)
Elvitegravir/cobicistat(EVG/cobi)
DTG
TAF = tenofovir alafenamideTDF = tenofovir disoproxil fumarate
A Superior Anchor Drug:The SINGLE Trial
22Walmsley SL, et al. N Engl J Med 2013
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A Superior Anchor Drug:The SINGLE Trial
23Walmsley SL, et al. N Engl J Med 2013
Atazanavir/ritonavir(ATV/rtv)
Alternative Initial Regimens
Department of Health & Human Services 2016
Rilpivirine^(RPV)
Efavirenz(EFV)
^ Pre‐treatment viral load < 100,000 copies/mL & CD4 count > 200 cells/mm3
TAF = tenofovir alafenamideTDF = tenofovir disoproxil fumarate
Atazanavir/cobicistat(ATV/cobi)
Darunavir/cobicistat(DRV/cobi)
DRV/rtv DRV/cobi
Emtricitabine/Tenofovir
(FTC/TDF or FTC/TAF)
Abacavir/Lamivduine
(ABC/3TC)
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ECHO & THRIVE: RPV vs. EFV
25Cohen CJ, et al. J Acquir Immune Defic Syndr 2012
– N = 1368 (ITT population)– 84% (RPV) vs. 82% (EFV) [95 CI ‐2.0% to 6.0%] at 48 weeks
Rilpivirine Virologic OutcomesAccording to Baseline Viral Load & CD4
26Complera prescribing information 2016
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Other Regimens:When an NRTI Backbone Cannot Be Used
Department of Health & Human Services 2016
^ Pre‐treatment viral load < 100,000 copies/mL & CD4 count > 200 cells/mm3
NRTI = nucleotide reverse transcriptase inhibitor
Lopinavir/ritonavir(LPV/rtv)
Lamivduine(3TC)
Raltegravir(RAL)^
Darunavir/ritonavir (DRV/rtv)^
Dual Therapy in Healthy Patients: The NEAT Study
28Raffi F, et.al. Lancet 2014
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INSTIs
Single Tablet Regimens Reduce Pill Burden
• Genvoya® (EVG/cobi/FTC/TAF)
• Stribild® (EVG/cobi/FTC/TDF)
• Triumeq® (DTG/3TC/ABC)
• Atripla® (EFV/FTC/TDF)
• Complera® (RPV/FTC/TDF)
• Odefsey® (RPV/FTC/TAF)
29
NRTIs
NNRTIs
3TC = lamivudine; ABC = abacavir; cobi = cobicistat; DTG = dolutegravir; EFV = efavirenz; EVG = elvitegravir; FTC = emtricitabine; RPV = rilpivirine; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate
NRTIs
Fixed Dose Combination Tablets Reduce Pill Burden
• Epzicom® (ABC/3TC)
• Descovy® (FTC/TAF)
• Truvada® (FTC/TDF)
• Combivir® (3TC/AZT)
• Evotaz® (ATV/cobi)
• Prezcobix® (DRV/cobi)
• Kaletra® (LPV/rtv)
30
NRTIs
PIs
3TC = lamivudine; ABC = abacavir; ATV = atazanavir; AZT = zidovudine; cobi = cobicistat; DRV = darunavir; FTC = emtricitabine; LPV = lopinavir; rtv = ritonavir; TAF = tenofovir alafenamide; TDF = tenofovir disoproxil fumarate
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The Risk of Non‐Adherence• Genotype • Phenotype
31
Ms. Jones• Ms. Jones is a 26yo female who is newly diagnosed HIV+ patient.
– She is treatment‐naïve, with a baseline viral load of 893,000 copies/mL and CD4 count of 351 cells/mm3
• What would you select as an appropriate initial regimen for her?
32
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A. Dolutegravir + abacavir + lamivudine
A. Darunavir + cobicistat + emtricitabine + tenofovir
A. Efavirenz + emtricitabine + tenofovir
A. Elvitegravir + cobicistat + abacavir + lamivudine
A. Rilpivirine + emtricitabine + tenofovir
33
A. Dolutegravir + abacavir + lamivudine
A. Darunavir + cobicistat + emtricitabine + tenofovir
A. Efavirenz + emtricitabine + tenofovir
A. Elvitegravir + cobicistat + abacavir + lamivudine
A. Rilpivirine + emtricitabine + tenofovir
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First, do no harm
Potential Adverse Drug Reactions
Nucleoside Reverse Transcriptase Inhibitors:The “d” Drugs & Mitochondrial Toxicity
• Inhibition of mitochondrial DNA polymerase (pol γ)– Decreased mitochondrial DNA copy number, diminished ATP pools– ddC ≥ ddI ≥ d4T > AZT ≥ TDF ≥ 3TC = FTC ≥ ABC
• Clinical Manifestations– Boxed warning: Lactic acidosis and severe hepatomegaly with hepatic
steatosis– Pancreatitis– Peripheral neuropathy– Lipodystrophy
• Clinical relevance?– Predominantly with “d‐drugs” ± AZT
• Stavudine, d4T (Zerit®)• Didanosine, ddI (Videx®)• Zalcitabine, ddC (Hivid®)
36Koczor CA, et.al Expert Opin Drug Metab Toxicol 2010
NRTIs
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Nucleoside Reverse Transcriptase Inhibitors
Drug Adverse Drug Reactions
3TC^/FTC#• Skin hyperpigmentation• Hepatitis B related hepatic flare
ABC• Hypersensitivity reaction (fever, rash, malaise, GI/respiratory
symptoms)• Increased risk of MI?
AZT*• Bone marrow suppression (macrocytic anemia, neutropenia)• GI intolerance• Nail hyperpigmentation
TAF*/TDF^
• Nephrotoxicity• Renal proximal tubulopathy (hypophoshatemia, glucosuria [with
normoglycemia], hypouricemia proteinuria, sCr elevation)• Decreased bone mineral density• Hepatitis B related hepatic flare
37
Department of Health & Human Services 2016Genvoya prescribing information 2017Vemlidy prescribing information 2017
^ Requires dose adjustment if CrCl < 50 mL/min# Requires dose adjustment if CrCl < 30 mL/min* Requires dose adjustment if CrCl < 15 mL/min
NRTIs
Abacavir Hypersensitivity: The PREDICT‐1 Study
• Comparison of HLA‐B*57:01 screening vs. abacavir skin patch test– Positive predictive value: 58%
• If you are HLA‐B*57:01(+) it is possible to develop hypersensitivity reaction (HSR)
• Likely additional genes involved in the development of HSR
– Negative predictive value: 100%• If you are HLA‐B*57:01(‐) it is unlikely to develop HSR
38Mallal S, et.al. N Engl J Med 2008
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Abacavir & Myocardial InfarctionThe D:A:D Collaboration
• International, prospective, observational cohort– 33,308 patients
• 178,835 person‐years (PYs)
– Evaluated incident cases of MI• Recent exposure to ABC associated with increased risk of MI (RR 1.70)
• Cumulative exposure to ABC associated with increased risk of MI (RR 1.07)
• Higher burden if pre‐existing cardiac risk factors
• Remains controversial– Studies with similar vs. weak/no association
39Sabin CA, et.al. Lancet 2008Worm SW, et.al. J Infect Dis 2010ABC = abacavir; MI = myocardial infarction; RR = relative risk
A Tale of Two Prodrugs: TDF vs TAF
40TAF = tenofovir alafenamideTDF = tenofovir disoproxil fumarate Callebaut C, et.al. Antimicrob Agents Chemother 2015
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Choose TAF over TDF: Renal Markers
41
Wohl D, et.al. J Acquir Immune Defic Syndr 2016
Choose TAF over TDF: Bone Mineral Density
42
Wohl D, et.al. J Acquir Immune Defic Syndr 2016
7/5/2017
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Integrase Strand Transfer Inhibitors
Drug ADRs
DTG• Non‐progressive sCr elevation (via OCT2 inhibition)• Neuropsychiatric symptoms (insomnia, depression)• Hypersensitivity reaction
EVG/cobi• Nausea• Diarrhea• Neuropsychiatric symptoms (depression)
RAL• Rash (including Stevens‐Johnson syndrome)• CPK elevation/muscle weakness• Neuropsychiatric symptoms (depression)
43Department of Health & Human Services 2016
INSTIs
Integrase Strand Transfer Inhibitors & Neuropsychiatric Events: The OPERA data
44
Fettiplace A, et.al. J Acquir Immune Defic Syndr 2017DRV = darunavir; DTG = dolutegravirEFV = efavirenz; RAL = raltegravir
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Protease Inhibitors: Out with the Old…
Drug ADRs
3TC/FTC• Skin hyperpigmentation• Hepatitis B related hepatic flare
ABC• Hypersensitivity reaction• Increased risk of MI?
AZT• Bone marrow suppression (macrocytic anemia, neutropenia)• GI intolerance• Nail hyperpigmentation
TDF
• Renal proximal tubulopathy (hypophoshatemia, glucosuria (with normoglycemia, hypouricemia proteinuria, sCr elevation)
• Decreased bone mineral density• Hepatitis B related hepatic flare
45Department of Health & Human Services 2016
Drug ADRs
Fosamprenavir (FPV)• Rash (sulfonamide moiety)• Nephrolithiasis
Indinavir (IDV) • Nephrolithiasis
Lopinavir/ritonavir (LPV/r)• GI intolerance• Hyperlipidemia (hyperTG)• PR/QT prolongation
Nelfinavir (NFV)• Diarrhea• LFTs elevation
Saquinavir (SQV)• PR/QT prolongation• LFTs elevation
Tipranavir (TPV)• Hepatotoxicity• Rash (sulfonamide moiety)• Intracranial hemorrhage
PIs
Protease Inhibitors:…In With the New
Drug ADRs
Atazanavir(ATV) rtv
• GI intolerance• Hyperlipidemia• Hyperglycemia
• Indirect hyperbilirubinemia• Nephrolithiasis• Cholethiaisis• Rash (sulfate moiety)• PR prolongation/1° AV block
Darunavir(DRV)
• Hepatotoxicity/LFTs elevation• Rash (sulfonamide moiety)
46Department of Health & Human Services 2016
PIs
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Non‐Nucleoside ReverseTranscriptase Inhibitors
Drug ADRs
EFV
• Neuropsychiatric symptoms (vivid dreams/nightmares, dizziness, suicidal ideation/attempt/completion)
• Rash• Teratogenicity (D/C/C)• False positive tests (cannabinoid, benzodiazepine)
RPV• Rash• Neuropsychiatric symptoms (depression, insomnia, headache)
Etravirine(ETR)
• Rash• Hypersensitivity reaction
47Department of Health & Human Services 2016
NNRTIs
DDI… not ddI
Drug‐Drug Interactions
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Mr. Smith• Mr. Smith is a 54yo patient who has been living with HIV for the past 10 years. – He is currently virologically suppressed on DRV/cobi + FTC/TAF with a high CD4 count.
– His past medical history includes:• GERD
• Hyperlipidemia (ASCVD 10‐yr risk = 13.5%)
• HCV
• Seasonal allergies
• How would you appropriately manage his other chronic co‐morbidities?
49ASCVD = atherosclerotic cardiovascular disease; cobi = cobicistat; DRV = darunavir; FTC = emtricitabine; GERD = gastroesophageal reflux disease; HCV = hepatitis C; TAF = tenofovir alafenamide
The Pharmacokinetics of An Oral Dose of Medication
50Courtesy of SR Penzak
7/5/2017
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The Pharmacokinetics of Therapy: Concentration vs Time Curve
51Courtesy of A Pau
OVERALL DRUG EXPOSURE
TROUGH
CMAX
Food & Antiretroviral Interactions• Take with food
– elvitegravir
– etravirine
– rilpivirine
– atazanavir
– darunavir
– lopinavir/ritonavir
• Take on an empty stomach
– efavirenz
52
DRUG LEVELS
SIDE EFFECTS
SIDE EFFECTS
Department of Health & Human Services 2016
7/5/2017
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Acid Reducing Agents & Antiretrovirals
53
* without concomitant TDF
ATV
Directions Treatment‐Naïve Treatment‐Experienced
AntacidsGive ATV 2h before/1h after
ATV 400mgATV 300mg + RTV 100mg
ATV 400mgATV 300mg + RTV 100mg
H2RAsGive ATV simultaneously or 2h before/10h after
ATV 400mgNot to exceed famotidine 20mg PO bid‐‐‐ATV 300mg + RTV 100mgNot to exceed famotidine 40mg PO bid
ATV 300mg + RTV 100mg*
ATV 400mg + RTV 100mg
Not to exceed famotidine 20mg PO bid
PPIs Give ATV 12 afterATV 300mg + RTV 100mgNo to exceed omeprazole 20mg PO daily
Do not co‐administer
RPV
AntacidsGive RPV 4h before/2h after
RPV 25mg
H2RAsGive RPV 4h before/12h after
RPV 25mg
PPIs ‐‐‐ Do not co‐administer
Department of Health & Human Services 2015
Integrase Strand Transfer Inhibitors & Polyvalent Cations
• Al3+, Ca2+, Fe2+/3+, Mg2+, Zn2+
– Give INSTI 2h before (4 – 6 hours after) polyvalent cations*^&
• Potential sources:
– Antacids
– Laxatives
– Multivitamins/supplements
54
^ no need to separate DTG from Ca2+ or Fe2+/3+ if given with food* no need to separate administration of RAL and Ca2+& do not co‐administer RAL and Al3+ Department of Health & Human Services 2016
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Types of Metabolism• Phase I/Oxidation
– Increases water solubility
– Mediated by Cytochrome P450 (CYP450) enzyme family
• CYP3A4 responsible for 82% of CYP‐mediated drug elimination
• Phase II/Conjugation
– Renders pharmacologically inactive
• Attach additional chemical group to drug
– Mediated by uridine diphosphateglucuronosyltransferase (UGT)
55Galetin et.al. Exp Opin Drug Metab Toxicol 2008
CYP Inhibition
56Courtesy of SR Penzak
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CYP Induction
57Courtesy of SR Penzak
Exploiting CYP3A Inhibition
58van Heeswijk RPG, et.al. AIDS 1999
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Pharmacokinetic Boosting Agents:Ritonavir & Cobicistat
59Mathias A, et.al. IWCPHT 2010GS‐9350 = cobicistat; RTV = ritonavir
COBI Considerations: ATV/c & DRV/c
60Gallant JE et.al. J Infect Dis 2013
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ARV CYP Mechanism of Interactions
61
InducersInhibitors Substrates
3A4ATV cobi*
DRV EFVETR EVGRPV rtv
2B6 2D6 2C9/2C19EFV rtv ETR
3A4EFVETR
1A2RTV2B6
EFV, rtv2C9/2C19
rtv
3A4ATVcobi*DRVrtv
2C9/2C19EFV, ETR2D6COBI*
* COBI is not an antiretroviral Department of Health & Human Services 2016
Anti‐infectives: Rifamycins• asda
62
ARV Rifampin Rifabutin Dosing Recommendations
Protease Inhibitors
PI Cmin: >75% Rif AUC: > 100%Rifampin: Do not co‐administerRifabutin: 150mg/day or 300mg 3x/week
EFV EFV AUC: 26% Rif AUC: 38%Rifampin: 600mg/day; EFV 600mg/day Rifabutin: 450 – 600 mg/day; EFV 600mg/day
ETR ETR possibleRif AUC: 17%ETR AUC: 37%
Rifampin: Do not co‐administerRifabutin: 300 mg/day*; ETR 200mg BID
RPV RPV AUC: 80% RPV AUC: 46%Rifampin: Do not co‐administerRifabutin: 300mg/day; RPV 50mg/day
RAL RAL AUC: 40% RAL AUC: 19%Rifampin: 600mg/day; RAL 800mg BIDRifabutin: 300mg/day; RAL 400mg BID
EVG/c EVG possibleEVG Cmin: 67%
Rif’ AUC: > 600%Rifampin: Do not co‐administerRifabutin: Do not co‐administer
DTG DTG AUC: 54% DTG Cmin: 30%Rifampin: 600mg/day; DTG 50mg BID^Rifabutin: 300mg/day; DTG 50mg/day^
MVC MVC AUC: 64% MVC possibleRifampin: Use only if necessary; MVC 600mg BID (MVC 300mg BID#)Rifabutin: 300mg once daily (MVC 150mg BID#)
* without concomitant PI# with concomitant PI^ unless certain INSTI RAMs ‘ 25‐O‐desacetyl‐rifabutin (metabolite)
Department of Health & Human Services 2016Complera prescribing information 2016
7/5/2017
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Anti‐infectives: Azolesand CYP 3A4 Modulators
63
CYP3A4 Metabolism
SubstrateMinor Moderate Major
Voriconazole Itraconazole Isavuconazonium
RecommendationVoriconazole 400mg BID + EFV 300mg/day
Monitor itraconazolelevels^ (especially if
>200mg/day)
Caution in co‐administration
(consider alternative?)
^ Do not co‐administer with EFV Department of Health & Human Services 2016
Inhibitor
Weak Moderate Strong
Fluconazole IsavuconazoniumPosaconazoleVoriconazole
RecommendationNo adjustment
necessary(see recommendation
above)
Monitor for ARV‐related toxicities; co‐administer if benefit outweighs risk^
Anti‐infectives: Hepatitis C
64Department of Health & Human Services 2016Harvoni prescribing information 2017
ATV = atazanavir; cobi = cobicistat; DCV = daclatasvir; DRV = darunavir; DTG = dolutegravir; EFV = efavirenz; ETR = etravirine; EVG = elvitegravir; LPV = lopinavir; RAL = raltegravir; RPV = rilpivirine; TAF = tenofoviralafenamide; TDF = tenofovir disoproxil fumarate; rtv = ritonavir
Anti‐retrovirals
Direct Acting Antivirals
DaclatasvirElbasvir/
GrazoprevirLedipasvir/ Sofosbuvir
Ombitasvir/Paritaprevir/rtv +
DasabuvirSimeprevir
Velpatasvir/ Sofosbuvir
ATVdecrease DCV dose
✗ ✔ use ATV 300mg(no additional booster)
✗ ✔
DRV✔ ✗ ✔ ✗ ✗ ✔
DTG ✔ ✔ ✔ ✔ ✔ ✔
EFVincrease DCV dose
✗ ✔ ✗ ✗ ✗
ETRincrease DCV dose
✗ ✔ ✗ ✗ ✗
EVG/cobidecrease DCV dose
✗ ✔ ✗ ✗ ✔
LPV/rtv ✔ ✗ ✔ ✗ ✗ ✔
RAL ✔ ✔ ✔ ✔ ✔ ✔
RPV ✔ ✔ ✔ ✔ ✔
TAF ✔ ✔ ✔ ✔ ✔ ✔
TDF ✔ ✔ caution ✔ ✔ caution
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HMG‐CoA Reductase Inhibitors (“statins”) and CYP 3A4 Inhibitors
65
CYP Metabolism
3A4 (3A4) Mixed Non‐CYP (UGT)
LovastatinSimvastatin
PravastatinAtorvastatin (3A4, UGT)
Fluvastatin (3A4, 2C9, 2D6)Rosuvastatin (3A4, 2C9)
Pitavastatin
Do not co‐administer
No adjustment necessary
Titrate carefully and use lowest necessary dose
No adjustment necessary
Department of Health & Human Services 2016
Phosphodiesterase‐5 (PDE‐5) Inhibitors and CYP 3A4 Inhibitors
66
PDE‐5 Inhibitor
Recommendation
Avanafil • Do not co‐administer
Sildenafil• 25mg q48h (erectile dysfunction)• Do not co‐administer (for PAH)
Tadalafil• 5 10mg q72h (erectile dysfunction)• 20 40mg once daily (PAH)• 2.5mg once daily (BPH)
Vardenafil • 2.5mg q72h (erectile dysfunction)
Benign prostatic hyperplasia (BPH); Pulmonary arterial hypertension (PAH) Department of Health & Human Services 2016
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Neuropsychiatric Medications &and CYP 3A4 Modulators
67
CYP Metabolism
Only non‐3A4 3A4 (minor) 3A4 (major)
Substrate
LamotriginePhenobarbitalValproic acidOxazepamParoxetineLorazepam
AmitriptylinePhenytoin*BupropionSertaline
Temazepam
AlprazolamDiazepam
CarbamazepineClonazepamEthosuximideQuetiapine#
RecommendationNo adjustment
necessaryTitrate dose of substrate based on clinical response
Consider alternative or monitor levels/effectiveness
of substrate
Induction Valproic acid
CarbamazepinePhenobarbitalPhenytoin
Oxcarbazepine
RecommendationNo adjustment
necessaryConsider alternative or monitor levels of ARV^
^ Do not co‐administer with PI without RTV, ETR, or RPV* Consider alternative/levels (narrow therapeutic index)# Reduce quetiapine dose by 1/6 if starting PI Department of Health & Human Services 2016
DRUG CLASS: Anti‐depressant; Anti‐epileptic; Anti‐psychotic; Benzodiazepine
Hormonal Contraceptives
68
ARV Contraceptive Dosing Recommendations
Estrogen
ATV/r & DRV/r Ethinyl estradiol AUC: 19 – 44%^
Recommend alternative/additionalcontraception
EFV Ethinyl estradiol AUC: no change
EVG/c/FTC/TDF Ethinyl estradiol AUC: 25%
ETR Ethinyl estradiol AUC: 22%No adjustment necessary
RPV Ethinyl estradiol AUC: 14%
Progesterone
ATV/r & DRV/r Norethindrone AUC: 14 – 34%^
Recommend alternative/additionalcontraception
EFV Levonorgestrel AUC: 58 – 83%*
EFV Etonogestrel AUC: 63%
EVG/c/FTC/TDF Norgestimate AUC: > 200%
^ Without RTV boosting, AUC increase* Case reports of contraceptive failure with implants
Department of Health & Human Services 2016Scarsi KK, et.al. CROI 2014Perry SH, et.al. AIDS 2014
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Local Corticosteroidsand CYP 3A4 Inhibitors
69
Ramanathan R, et.al. Clin Infect Dis 2008
Local Corticosteroidsand CYP 3A4 Inhibitors
70Boyd SD et.al. J Acquir Immune Defic Syndr 2013
7/5/2017
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Types of Transport
Ayrton A, et.al. Xenobiotica 2001
Breast cancer resistance protein (BCRP); Multi‐drug resistance‐associated protein (MRP); Organic anion transporting polypeptide (OATP); Organic anion transport (OAT); Organic cation transport (OCT); P‐glycoprotein (P‐gp, also ABC)
Limit Metformin Dose with Dolutegravir
72
Song IH, et.al. J Acquir Immune Defic Syndr 2016
7/5/2017
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Mr. Smith• Mr. Smith is a 54yo patient who has been living with HIV for the past 10 years. – He is currently virologically suppressed on DRV/r + FTC/TDF with a high CD4 count.
– His past medical history includes:• GERD
• Hyperlipidemia (ASCVD 10‐yr risk = 13.5%)
• HCV
• Seasonal allergies
• How would you appropriately manage his other chronic co‐morbidities?
73
• Can Mr. Smith receive a PPI with his cART?– Yes
• Which HMG‐CoA reductase inhibitor would be best for Mr. Smith?– Atorvastatin– Rosuvastatin
• Which HCV medications should Mr. Smith avoid?– Ledipasvir– Paritepravir (+ Ombitasvir + Dasabuvir)– Simeprevir
• Which corticosteroid intranasal spray would you recommend for Mr. Smith?– Beclomethasone
74
7/5/2017
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Conclusions• Combination antiretroviral therapy results in HIV virologic suppression, leading to increased longevity and quality of life
• Recommended and alternative antiretroviral regimens are generally well tolerated– Patients should be educated regarding hallmark adverse drug reactions that may commonly or rarely occur
• As patients age with HIV, it is important to conduct a comprehensive medication review to reconcile potential drug‐drug interactions.
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Questions?
Lori A. Gordon, PharmD, BCPS, AAHIVP
Xavier University of Louisiana College of Pharmacy