amp HCV Therapy Larry Pineda PharmD PhC BCPS AAHIVP Visiting Assistant Professor UNM College of Pharmacy Conflicts of Interest Disclosure No conflicts of interest 2 Learning Objectives Pharmacist ID: 740607
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Slide1
Community Pharmacy Considerations for HIV & HCV Therapy
Larry Pineda,
PharmD
,
PhC
, BCPS, AAHIVP
Visiting Assistant Professor
UNM College of PharmacySlide2
Conflicts of Interest DisclosureNo conflicts of interest
2Slide3
Learning Objectives – PharmacistList the DHHS recommended HIV antiretroviral regimens
Describe current HCV direct-acting antivirals
Discuss the importance of adherence counseling for HIV
antiretrovirals
and HCV direct-acting antivirals
Recognize common prescription and nonprescription drug interactions with HIV
antiretrovirals and HCV direct-acting antivirals
3Slide4
Learning Objectives – Pharm TechIdentify common HIV
antiretrovirals
and HCV direct-acting antivirals
State the minimum number of antiretroviral drugs in an appropriate HIV antiretroviral regimen
Understand the importance of adherence counseling for HIV
antiretrovirals
and HCV direct-acting antiviralsDescribe the impact of drug-drug interactions with HIV and HCV medications
4Slide5
HIV therapy considerationsSlide6
HIV Antiretroviral TherapyInhibit viral replication
HIV life cycle
Antiretroviral drugs target key steps in replication
https://www.youtube.com/watch?v=odRyv7V8LAE
6
Figure: http://collections.infocollections.org/whocountry/en/d/Jh4325e/7.htmlSlide7
HIV Antiretroviral TherapyEntry inhibitors
Attachment
Selz
entry
(
maraviroc
)FusionFuzeon
(
enfuvirtide
)
Reverse transcriptase inhibitors
Nucleoside
Truvada
(
tenofovir
disoproxil
(TDF)/
emtricitabine
)Descovy (tenofovir alafenomide (TAF)/emtricitabine)Epzicom (abacavir/lamivudine)Non-nucleoside Sustiva (efavirenz)Edurant (rilpivirine)
7Slide8
HIV Antiretroviral TherapyIntegra
se strand transfer
inhibitors
Isentress
(
ral
tegravir)Vitekta (
elvi
tegravir
)
Always with
cobicistat
(booster)
Tivicay
(
dolu
tegravir
)
Protease inhibitorsPrezista (darunavir)Reyataz (atazanavir)Norvir (ritonavir)8Slide9
DHHS Recommended AgentsUpdated July 2016
Available at:
https://
aidsinfo.nih.gov/guidelines
5
recommended HAART regimens:
4 integrase-based regimens
1
protease inhibitor-based
regimen
9Slide10
Integrase-Based RegimensSingle tablet
Triumeq
(
dolutegravir
/
abacavir
/lamivudine)Genvoya (elvitegravir
/
cobicistat
/TAF/
emtricitabine
) or
Stribild
(
elvitegravir
/
cobicistat
/TDF/emtricitabine)Two tabletDolutegravir + TDF/emtricitabine or TAF/emtricitabineRaltegravir* + TDF/emtricitabine or TAF/emtricitabine
10
*Twice daily dosing
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/Slide11
Protease Inhibitor-Based Regimen Darunavir/ritonavir
+ TDF/
emtricitabine
or
TAF/
emtricitabineAtazanavir based regimens moved to alternative
Non-nucleoside reverse transcriptase inhibitor based regimens on alternative list
Entry inhibitors typically reserved for patients with resistance to recommended agents
11
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/Slide12
12Slide13
HAARTHighly
A
ctive
A
nti-
R
etroviral Therapy3 active antiretroviral drugs2 nucleoside reverse transcriptase inhibitors
Plus 3
rd
active agent:
Integrase strand transfer inhibitor
Non-nucleoside reverse transcriptase inhibitor
Protease inhibitor with pharmacokinetic enhancer (
cobicistat
, ritonavir)
Goal: undetectable HIV viral load
Adherence
critical for success
13
https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/Slide14
14Slide15
Virologic Impact of Adherence
15
Patterson DL et al. Ann Intern Med. 2000;133:21-30Slide16
Virologic Impact of Adherence
16
Low-Beer S et al. J Acquir Immune Defic Syndr. 2000; 23:360-1Slide17
Adherence ConsiderationsDo not assume prescriber has provided education
Monitor refill history
Offer
adherence devices
Pill box
Blister packaging
Reminders (alarms, logs, apps, visual med calendar)Recognize “outdated” regimens
Screen for polypharmacy
Avoid treatment gaps
17Slide18
Antiretroviral ConsiderationsDo not dispense partial regimens
Question regimens with < 3 agents
Truvada
for
preexposure
prophylaxis (
PrEP) and nuc
-sparing regimens are exception
Recognize “outdated” regimens
Quality of life
Assist with prior authorizations
Facsimile response monitoring
Drug interactions
Alert fatigue
18Slide19
Drug InteractionsNew agents have less
drug interactions
Are
not
void of interactions
Keep in mind OTC/supplements/herbals
Bookmark key resourcesDon’t assume provider has checked
19Slide20
Integrase InhibitorsLow drug interactions
Polyvalent cations
Ca
++
, Fe
++
, Mg++, Zn++
, Al
+++
Chelate integrase inhibitors
Does not include food products
Maalox, Tums, multivitamins
Administer
2 hours before or 6 hours after taking
products containing
polyvalent
cations
20
http://www.hiv-druginteractions.org/Slide21
St. John’s Wort
Induction
of UGT1A1 and CYP3A4
Decreased
dolutegravir
exposureDecreased elvitegravir/cobicistat
concentrations
Potentially decreased
raltegravir
exposure
Decreased
darunavir
concentrations
http://www.hiv-druginteractions.org/
21Slide22
HerbalsInduce CYP3A4
Garlic supplements
Can induce CYP3A4 and/or P-
gp
Inconsistent
data on
allicin containing formulationsDoes not apply to dietary exposure
Dolutegravir
, ritonavir and
cobicistat
Ginkgo biloba
Inhibit CYP3A4
Grapefruit, goldenseal, ginseng
22Slide23
Pharmaceutical BoostersRitonavir
and
cobicistat
Inhibit CYP3A4, others vary
Anticoagulants
Warfarin (R enantiomer)
Monitor INRApixaban
, dabigatran, rivaroxaban,
ticagrelor
Avoid concomitant use
Anticonvulsants
Carbamazepine, phenobarbital, phenytoin
Decreases
dolutegravir
– UGT1A1, CYP3A4 induction
Alternative –
levetiracetam
(
Keppra
)23http://www.hiv-druginteractions.org/Slide24
CorticosteroidsInteraction with both ritonavir and
cobicistat
Cushing’s syndrome, adrenal suppression
Intranasal
Fluticasone (Flonase)*
Triamcinolone (Nasacort)*
Budesonide (
Rhinocort
)*
Inhaled
Fluticasone/salmeterol (Advair)
Budesonide/formoterol (
Symbicort
)
Alternative
Beclomethasone (QVAR, QNASL)
24
*available over the counter
http://www.hiv-druginteractions.org/Slide25
Serotonin Reuptake Inhibitor (SSRI)Paroxetine, fluoxetine, citalopram
Metabolized by CYP2D6
Ritonavir inhibits metabolism
Increased SSRI exposure
Sertraline
Metabolized
by CYP2B6
Ritonavir induces metabolism
Decreased SSRI exposure
25
http://www.hiv-druginteractions.org/Slide26
Drug Interaction Resource
26
http://www.hiv-druginteractions.org/
Also available as an app:
hivichartSlide27
Hcv
therapy considerationsSlide28
AbbreviationsSVR: sustained
virologic
response
IFN: interferon
RBV: ribavirin
Peg:
pegylated
BOC:
boceprevir
TPV:
telaprevir
SMV:
simeprevir
SOF:
sofosbuvir
PrOD
:
paritaprevir
/ritonavir +
ombitasvir + dasabuvirPrO
:
paritaprevir
/ritonavir +
ombitasvir
DCV:
daclatasvir
EBR/GZR:
elbasvir
/
grazoprevir
LDV/SOF:
ledipasvir
/
sofosbuvir
SOF/VEL:
sofosbuvir
/
velpatasvir
28Slide29
HCV TreatmentHistorically complex therapy
Gastroenterology, hepatology, infectious diseases
Severe side effects, injectable
Low cure rates
Advent of new direct acting all oral medications has simplified management
Less side effects
Shorter durationHigher cure rates
Goal of treatment is SVR
New agents highly effective SVR rates >90%
29Slide30
Slide courtesy Paulina Deming, PharmD, PhC
30
Evolution
of
HCV Treatment
SVR (%)
IFN
6
mos
PegIFN
RBV
12
mos
IFN
12 mos
IFN/RBV
12
mos
PegIFN
12
mos
2001
1998
2011
Standard
IFN
RBV
PegIFN
1991
BOC and TPV
PegIFN
/
RBV/
BOC or TPV
6-12
mos
IFN/RBV
6
mos
6
16
34
42
39
55
70+
0
20
40
60
80
100
2013
SOF
89+
SMV
80+
PegIFN
/
RBV/
SMV
24-48
wks
PegIFN
/
RBV/
SOF
12-24
wks
2014
LDV/SOF
>90
>90
PrOD
LDV/ SOF
8-12
wks
PrOD
+ RBV
12-24
wks
EBR/ GZR
12-16
wks
SOF + DCV
12
wks
DCV+ SOF
EBR/ GZR
2016
>90
>90
SOF/ VEL
>90
SOF/ VEL
12
wksSlide31
Key Differences in HCV TherapyPegIFN Based
Therapy
Injections
Significant laboratory abnormalities
Pancytopenias
Ribavirin
hemolytic
anemia
Substantial side effect profile
Limited use in advanced liver disease
Limited drug interaction potential
Low
SVR
Direct Acting
Antivirals
All oral
Limited laboratory abnormalities
Ribavirin
hemolytic anemia Low side effect profileVariable drug interaction potentialVariable use in advanced liver diseaseHigh SVREmerging concerns for HCV resistance
31Slide32
HCV Treatment HighlightsGuided by HCV genotype
G1a most common in US
Finite
duration of
treatment
Typically ~12 weeks
Adherence vital for treatment successRetreatment
Lower SVR rates
Longer duration,
+
ribavirin
Cost of treatment
high
32
http://www.hepatitisc.uw.edu/
http://www.hcvguidelines.org
/Slide33
Cost of HCV Treatment
33
http://www.hepatitisc.uw.eduSlide34
HCV Drug TargetsSlide courtesy Monique, Dodd, PharmD, MLS(ASCP)
34
Core
E1
E2
P7
NS2
NS3
4A
NS4B
NS5A
NS5B
5’UTR
3’UTR
Ribavirin
NS3 Protease Inhibitors
NS5A Replication Complex Inhibitors
NS5B Polymerase
(Nucleotide) Inhibitors
NS5B Polymerase
(Non-nucleotide) Inhibitors
Boceprevir
(
BOC)
Telaprevir
(TVR)
Simeprevir
(SMV)
Paritaprevir
(PTV)
Grazoprevir
(GRZ)
Daclatasvir (DCV)
Ledipasvir
(LDV)
Ombitasvir
(OMV)
Elbasvir
(EBR)
Velpatasvir
(VEL)
Sofosbuvir
(SOF)
Dasabuvir
(DSV)
Pulled from marketSlide35
HCV Direct Acting Antivirals (DAAs)
Target
NS3/4A: Protease Inhibitors
(-
previr
)
NS5A: Replication Complex Inhibitors
(-
asvir
)
NS5B: Polymerase Inhibitors
(-
buvir
)
DAA
Boceprevir
*
Telaprevir
*
SimeprevirParitaprevir
Grazoprevir
Ledipasvir
Ombitasvir
Daclatasvir
Elbasvir
Velpatasvir
Nucleotide:
Sofosbuvir
Non-nucleoside:
Dasabuvir
35
* Pulled from marketSlide36
Treatment ResourcesJoint guidelines
of the American
Association for the Study of Liver Diseases (AASLD) and Infectious Diseases Society of America (IDSA)
Updated
frequently
– check online for most current version of guidelines
Available at: http://www.hcvguidelines.org
/
Hepatitis C Online (Univ. of Washington)
http://www.hepatitisc.uw.edu
/
HCV medication information, calculators, guidance
HCV course (modules)
36Slide37
Pharmacy ConsiderationsHigh cost – specialty pharmacy
High
copays, patient assistance networks
Avoid treatment gaps
Time it takes to order medication
Counseling:
Adverse effectsAdherence
Despite short, finite duration
Drug interactions
37Slide38
Side Effect Profile of DAAsMost commonly reported side effects:
Headache
Fatigue
Nausea
Most common laboratory abnormalities:
ALT elevations with
PrOD and ethinyl-estradiol use; ALT elevations with EBR/GZR
Anemia with concomitant use of ribavirin
Ribavirin causes hemolytic anemia
38
http://www.hepatitisc.uw.edu/Slide39
39Slide40
HCV Therapy AdherenceNo published literature on DAA adherence correlation to
SVR
Optimal adherence yet
to be determined
Recommend
100% adherent to
DAAsAdherence assessment and counseling at all healthcare encounters
40Slide41
Drug Interaction Concerns for DAAs
Overall have low potential for drug-drug interactions
Amiodarone with
sofosbuvir
and other DAA
Serious symptomatic bradycardia
Potential for other drugs to lower DAA concentrationsStrong CYP3A
inducers (e.g. carbamazepine
, oxcarbazepine, phenobarbital,
phenytoin)
Strong intestinal P-glycoprotein inducers (e.g. rifampin)
St. John’s wort (avoid
all
herbals/supplements)
Statins
Interactions vary by DAA and statin
www.hep-druginteractions.org
41Slide42
Acid Suppressive Therapy
Ledipasvir
and
velpatasvir
solubility decreases with increases in
pH
Requires acidity for absorption – greatest concern with velpatasvir
Antacids
S
eparate administration
by 4
hours
H2RAs
A
dministered
simultaneously with or 12 hours
apart
PPIs
C
an be administered simultaneously if medically necessary42www.hep-druginteractions.orgSlide43
Drug Interaction Resource
43
www.hep-druginteractions.org
Also available as an app:
hepichartSlide44
Patient CaseDD is a 48 year old HIV+ male with HCV coinfection. His provider has prescribed
Harvoni
(
ledipasvir
/
sofosbuvir
) x 12 weeks. Medications: famotidine prn heartburn, Tums prn heartburn, dolutegravir
,
emtricitabine
/TDF, acyclovir
No known drug allergies
44Slide45
45Slide46
Questions/considerations?