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Community Pharmacy Considerations for HIV & HCV Therapy Larry Pineda, PharmD, PhC, BCPS, AAHIVP

Visiting Assistant Professor UNM College of Pharmacy

Conflicts of Interest Disclosure

• No conflicts of interest

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Learning Objectives – Pharmacist

• List 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

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Learning Objectives – Pharm Tech

• Identify 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 antivirals

• Describe the impact of drug-drug interactions with HIV and HCV medications

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HIV THERAPY CONSIDERATIONS

HIV Antiretroviral Therapy

• Inhibit 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.html

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HIV Antiretroviral Therapy

• Entry inhibitors – Attachment

• Selzentry (maraviroc)

– Fusion • Fuzeon (enfuvirtide)

• Reverse transcriptase inhibitors – Nucleoside

• Truvada (tenofovir disoproxil (TDF)/emtricitabine) • Descovy (tenofovir alafenomide (TAF)/emtricitabine) • Epzicom (abacavir/lamivudine)

– Non-nucleoside • Sustiva (efavirenz) • Edurant (rilpivirine)

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HIV Antiretroviral Therapy

• Integrase strand transfer inhibitors – Isentress (raltegravir)

– Vitekta (elvitegravir) • Always with cobicistat (booster)

– Tivicay (dolutegravir)

• Protease inhibitors – Prezista (darunavir)

– Reyataz (atazanavir)

– Norvir (ritonavir)

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DHHS Recommended Agents

• Updated July 2016

• Available at: https://aidsinfo.nih.gov/guidelines

• 5 recommended HAART regimens:

– 4 integrase-based regimens

– 1 protease inhibitor-based regimen

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Integrase-Based Regimens

• Single tablet

– Triumeq (dolutegravir/abacavir/lamivudine)

– Genvoya (elvitegravir/cobicistat/TAF/emtricitabine) or

Stribild (elvitegravir/cobicistat/TDF/emtricitabine)

• Two tablet

– Dolutegravir + TDF/emtricitabine or TAF/emtricitabine

– Raltegravir* + TDF/emtricitabine or TAF/emtricitabine

10 *Twice daily dosing https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-treatment-guidelines/0/

Protease Inhibitor-Based Regimen

• Darunavir/ritonavir + TDF/emtricitabine or TAF/emtricitabine

– Atazanavir 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/ 12

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HAART

• Highly Active Anti-Retroviral Therapy

• 3 active antiretroviral drugs – 2 nucleoside reverse transcriptase inhibitors

– Plus 3rd 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/ 14

Virologic Impact of Adherence

15

78.3

45.4

33.3 28.6

17.9

>95 90-94.9 80-89.9 70-79.9 <70

% w

ith

VL

<400

co

pie

s/m

L

% PI Adherence (MEMS caps)

Patterson DL et al. Ann Intern Med. 2000;133:21-30

Virologic Impact of Adherence

16

84

64

47

24

12

>95 90-94.9 80-89.9 70-79.9 <70

% w

ith

VL

<500

co

pie

s/m

L

% Adherence (refill history)

Low-Beer S et al. J Acquir Immune Defic Syndr. 2000; 23:360-1

Adherence Considerations

• Do 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

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Antiretroviral Considerations

• Do 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

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Drug Interactions

• New agents have less drug interactions

– Are not void of interactions

• Keep in mind OTC/supplements/herbals

• Bookmark key resources

• Don’t assume provider has checked

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Integrase Inhibitors

• Low 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/

St. John’s Wort

• Induction of UGT1A1 and CYP3A4

• Decreased dolutegravir exposure

• Decreased elvitegravir/cobicistat concentrations

• Potentially decreased raltegravir exposure

• Decreased darunavir concentrations

http://www.hiv-druginteractions.org/ 21

Herbals

• Induce CYP3A4

– Garlic supplements

• Can induce CYP3A4 and/or P-gp – Inconsistent data on allicin containing formulations

– Does not apply to dietary exposure

• Dolutegravir, ritonavir and cobicistat

– Ginkgo biloba

• Inhibit CYP3A4

– Grapefruit, goldenseal, ginseng

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Pharmaceutical Boosters

• Ritonavir and cobicistat – Inhibit CYP3A4, others vary

• Anticoagulants – Warfarin (R enantiomer)

• Monitor INR

– Apixaban, dabigatran, rivaroxaban, ticagrelor • Avoid concomitant use

• Anticonvulsants – Carbamazepine, phenobarbital, phenytoin – Decreases dolutegravir – UGT1A1, CYP3A4 induction – Alternative – levetiracetam (Keppra)

23 http://www.hiv-druginteractions.org/

Corticosteroids

• Interaction 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)

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*available over the counter http://www.hiv-druginteractions.org/

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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/

Drug Interaction Resource

26 http://www.hiv-druginteractions.org/ Also available as an app: hivichart

HCV THERAPY CONSIDERATIONS

Abbreviations

• SVR: sustained virologic response

• IFN: interferon

• RBV: ribavirin

• Peg: pegylated

• BOC: boceprevir

• TPV: telaprevir

• SMV: simeprevir

• SOF: sofosbuvir

• PrOD: paritaprevir/ritonavir + ombitasvir + dasabuvir

• PrO: paritaprevir/ritonavir + ombitasvir

• DCV: daclatasvir

• EBR/GZR: elbasvir/grazoprevir

• LDV/SOF: ledipasvir/sofosbuvir

• SOF/VEL: sofosbuvir/ velpatasvir

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HCV Treatment

• Historically 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 duration – Higher cure rates

• Goal of treatment is SVR – New agents highly effective SVR rates >90%

29 Slide courtesy Paulina Deming, PharmD, PhC 30

Evolution of HCV Treatment

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/RB

V

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 wks

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Key Differences in HCV Therapy

PegIFN 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 profile • Variable drug interaction

potential • Variable use in advanced liver

disease • High SVR • Emerging concerns for HCV

resistance

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HCV Treatment Highlights

• Guided by HCV genotype – G1a most common in US

• Finite duration of treatment – Typically ~12 weeks

• Adherence vital for treatment success

• Retreatment – Lower SVR rates

– Longer duration, + ribavirin

– Cost of treatment high

32 http://www.hepatitisc.uw.edu/ http://www.hcvguidelines.org/

Cost of HCV Treatment

33 http://www.hepatitisc.uw.edu

HCV Drug Targets

Slide 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 market

HCV Direct Acting Antivirals (DAAs)

Target NS3/4A: Protease Inhibitors (-previr)

NS5A: Replication Complex Inhibitors (-asvir)

NS5B: Polymerase Inhibitors (-buvir)

DAA Boceprevir* Telaprevir* Simeprevir Paritaprevir Grazoprevir

Ledipasvir Ombitasvir Daclatasvir Elbasvir Velpatasvir

Nucleotide: Sofosbuvir Non-nucleoside: Dasabuvir

35 * Pulled from market

Treatment Resources

• Joint 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)

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Pharmacy Considerations

• High cost – specialty pharmacy – High copays, patient assistance networks

• Avoid treatment gaps – Time it takes to order medication

• Counseling: – Adverse effects

– Adherence • Despite short, finite duration

– Drug interactions

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Side Effect Profile of DAAs

• Most 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/

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HCV Therapy Adherence

• No published literature on DAA adherence correlation to SVR

– Optimal adherence yet to be determined

– Recommend 100% adherent to DAAs

• Adherence assessment and counseling at all healthcare encounters

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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 concentrations – Strong 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 41

Acid Suppressive Therapy

• Ledipasvir and velpatasvir solubility decreases with increases in pH

• Requires acidity for absorption – greatest concern with velpatasvir – Antacids

• Separate administration by 4 hours

– H2RAs • Administered simultaneously with or 12 hours apart

– PPIs • Can be administered simultaneously if medically necessary

42 www.hep-druginteractions.org

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Drug Interaction Resource

43 www.hep-druginteractions.org Also available as an app: hepichart

Patient Case

• DD 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

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QUESTIONS/CONSIDERATIONS?