drug interactions in managing hiv/hcv...

Drug Interactions in Managing HIV/HCV Co-InfectionPresenter: Christopher Keeys, Pharm.D., BCPS

28 October 2015

Drug-Drug Interactions between Direct Acting Antiviral (DAA) and Antiretroviral Therapy (ART) in

HIV/HCV Co-infected Patients

October, 2015. Clinical Pharmacy Associates, Inc. All rights reserved.

P R E S E N T E R : C H R I S T O P H E R K E E Y S , P H A R M . D . , B C P S

P R E S I D E N T , C L I N I C A L P H A R M A C Y A S S O C I A T E S , I N C .C E O , M E D N O V A T I O N S , I N C .

P R E S E N T A T I O N B Y : X I R U I C H E N , P H A R M . D . , P R A C T I C E F E L L O W

Disclaimer

No conflict of interest to disclose by presenters


Objectives

Identify the basic epidemiology of chronic hepatitis C (CHC) infection and CHC/HIV coinfection in the population

Recognize the availability and clinical importance of newer direct acting antivirals (DAAs) in the medical management of CHC and CHC/HIV infections

Identify and discuss the importance of DAA and antiretroviral (ARV) drug drug interactions in the management of CHC and CHC/HIV

Identify and utilize basic pharmacologic and pharmacokinetic information to minimize drug interactions in care of patients

Recognize and support medication management strategies that limit drug interactions and adverse health outcomes for patients


Background on HCV

Epidemiology: An estimated 2.7 million persons in the United States have chronic hepatitis C virus infection (all genotypes). Approximately 75%–85% of people who become infected with Hepatitis C virus develop chronic infection1,2,3

Screening: people with risk factors and all patients with HIV infections3


Risk Factors2,3

Recipient of blood transfusions and organ transplants before July 1992 (no screening tools available prior to 1992)

IV drug use Sexual exposure Other, including occupational

exposure and perinatal exposure


HIV/HCV Co-infection4

Statistics: 50%–90% of HIV IV drug users are co-infected with HCV due to common route of transmission (IV drug use); 25% overall coinfection in population in the USA

Prognostics of co-infection: Lower rate of spontaneous clearance of virus during acute infection due to low CD4 counts HIV/HCV coinfection accelerates hepatic fibrosis in HCV infected patients, and poor outcomes

following transplantation Higher rate of liver decompensation in HIV/HCV co-infected patients, especially in the

absence of ART (e.g. ascites, spontaneous bacterial peritonitis, etc.) Higher liver-related mortality rates in HIV-infected patients.


Direct Acting Antivirals (DAAs)2,5,6


What’s the Holdup? Evidence?6

MANY drug interactions between DAA and antiretroviral therapy (ART) limit patient’s choice of treatment options By understanding the basic mechanism of

interactions will allow a healthcare provider to choose a therapy that is effective and safe for the patient

FDA approval USPHS, AASLD and IDSA guidance


HCV Life Cycle

http://fyeahmedlab.tumblr.com/post/37090103139/volextus-hepatitis-c-virus-life-cycle-thisOctober, 2015. Clinical Pharmacy Associates, Inc. All rights reserved.

HCV Pharmacological Targets2


http://fyeahmedlab.tumblr.com/post/37090103139/volextus-hepatitis-c-virus-life-cycle-this

Oral anti-HCV pharmacological agents

Name Mechanism of Action

Approved Indication Dosing

Simeprevir(OLYSIO®)7

NS3/4A protease inhibitors

CHC genotype 1 or 4 infection in combination with PEG-IFN alfa and ribavirin

150 mg daily with food

Not recommended in patients with moderate to severe hepatic impairment

Sofosbuvir (SOVALDI®)8

NS5B polymerase inhibitor

CHC genotypes 1, 2, 3, and 4 infection in combination with ribavirin and/or PEG-IFN alfa

HCV/HIV-1 co-infection

400 mg daily

No dose adjustment required for mild to moderate renal impairment (eGFR >30 ml/min/1.73m2)

No dose adjustment required for any degree of hepatic impairment





Ledipasvir/Sofosbuvir (HARVONI ®)9

NS5A protein inhibitor/NS5B polymerase inhibitor

CHC genotype 1 infection Ledipasvir/Sofosbuvir: 90/400 mg fixed dose, one tablet daily

No dose adjustment required for mild to moderate renal impairment (eGFR >30 ml/min/1.73m2)






Paritaprevir/rOmbitasvirDasabuvir(VIEKIRA PAK®)10

NS3/4Aprotease inhibitor/NS5A proteininhibitor/NS5Bpolymerase inhibitor

CHC genotype 1 infection with or without ribavirin

• Ombitasvir, paritaprevir, ritonavir: 12.5/75/50 mg fixeddose, one tablet daily in the morning

• Dasabuvir: 250 mg morning and evening

No dose adjustment required for any degree of renal impairment

No dose adjustment required for mild hepatic impairment. Contraindicated in patients with moderate tosevere hepatic impairment





Daclatasvir(DAKLINZA®)11

NS5A protein inhibitor

CHC genotype 3 infection in combination with sofosbuvir

60 mg once daily, taken with sofosbuvir



Ombitasvir/paritaprevir/ritonavir(TECHNIVIE®)12

NS5A protein inhibitor/NS3/4A protease inhibitor/CYP3A inhibitor

CHC genotype 4 infection in combination with ribavirin

Ombitasvir, paritaprevir, ritonavir: 12.5/75/50 mg fixed dose tablet, 2 tablets once daily in the morning with food


No dose adjustment required for mild hepatic impairment. Contraindicated in patients with moderate to severe hepatic impairment


Why so many DDI?

Protein (enzyme/transporter) induction and inhibition


https://en.wikipedia.org/wiki/Membrane_transport_protein#/media/File:Scheme_facilitated_diffusion_in_cell_membrane-en.svghttp://classes.midlandstech.edu/carterp/Courses/bio225/chap05/ss2.htm

Sample Pharmacokinetics Study13


Pharmacokinetics of DAA7-18

DDA Substrate of … Metabolized by … Inhibitor of …

Simeprevir (OLYSIO®) P-gp, BCRP, OATP1B1, MRP2 CYP3A CYP2A6, CYP2C8, CYP2D6CYP2C19, CYP3AP-gp, BCRP, OATP1B1, MRP2

Sofosbuvir (SOVALDI®) P-gp, BCRP (active metabolite not affected)

Not metabolized by CYP P-gp

Ledipasvir/Sofosbuvir(HARVONI®)

P-gp, BCRP Not metabolized by CYP P-gp, BCRP

Paritaprevir/rOmbitasvirDasabuvir(VIEKIRA PAK®)

P-gp, BCRP, OATP1B1/B3 CYP3A CYP3A (ritonavir), P-gp, BCRP,OATP1B1/B3

P-gp Amide hydrolysisoxidative metabolism

P-gp, BCRP CYP2C8, CYP3A P-gp, BCRP

Daclatasvir (DAKLINZA®) P-gp, BCRP, OATP1B1/B3 CYP3A P-gp,BCRP, OATP1B1/B3


Summary of DAA and ARV interactions7,14,15,17,18

DAA ARV Mechanism of Interaction

Effect on DAA Effect on ART Comment

Simeprevir(OLYSIO®)

Efavirenz, Etravirine, Nevirapine

CYP3A4 induction by ARV

↓ Simeprevir No significant effect on ART

Co-administration not recommended

Stribild (boosted with COBI)

CYP3A4 Inhibition by COBI

↑ Simeprevir

Ritonavir containing combination

CYP3A4 inhibition by ritonavir

↑ Simeprevir (AUC: ↑159%, Cmax:↑79%, Cmin: ↑358%)

In general, not recommended to coadminister with moderate to severe CYP3A inhibitors (e.g. anticonvulsants, dexamethasone, azoleantifungals, macrolide antibiotics etc.) of CYP3A inhibitors (e.g. phenytoin, carbamazepine, rifampin, St. John’s Worts). No significant interactions with tacrolimus or cyclosporine, therefore, it may be a good choice for patients who underwent liver transplants.





Sofosbuvir (SOVALDI ®)

Tipranavir/r P-gp induction by tipranavir/r

↓ sofosbuvir No significant effect on ART

Co-administrationnot recommended

Ledipasvir/Sofosbuvir (HARVONI ®)

Tenofovir P-gp inhibition by ledipasvir

No significant effect on DAA

↑ Tenofovir Co-administrationwith Stribild® not recommended

Atazanavir/r P-gp inhibition by Atazanavir/r

↑ Ledipasvir ↑ Atazanavir Consider alternativetherapy

Tipranavir/r P-gp induction bytipranavir

↓ Ledipasvir/sofosbuvir

No significant effect on ART

Co-administrationnot recommended

In general, not recommended to coadminister with P-gp inducers (e.g. rifampin, St. John’s wort). SOVALDI® has relatively few significant interactions with ART, may be a good choice for HIV/HCV co-infected patients receiving ART. No significant interaction with tacrolimus or cyclosporine, therefore, it may be a good choice for patients who underwent transplants.





Paritaprevir/rOmbitasvirDasabuvir(VIEKIRA PAK®)

Protease Inhibitors (Atazanavir/r, Darunavir, Lopinavir/r)

CYP3A inhibition by Ritonavir

↑ Paritaprevir↑ or ↓ Ombitasavir↓ Dasabuvir

↑ Atazanavir↑ Lopinavir

Dose Atazanaviralone without COBI or Ritonavir boost

NNRTIs (Rilpivirine)

3A4 induction Predicted ↓ DAA ↑ Rilpivirine Co-administration not recommended

Elvitegravir, Stribild 3A4 inhibition by Ritonavir

Predicted ↑ ART

Maraviroc 3A4 inhibition by Ritonavir

Predicted ↑ ART

In general, not recommended to co-administer with CYP3A inducers (e.g. Phenytoin, Carbamazepine, Rifampin, etc.) or substrates. Co-administration with strong CYP2C8 inhibitor (e.g. Gemfibrozil) is contraindicated.


Summary of DAA and ARV interactions11



Daclatasvir(DAKLINZA®)

Atazanavir/r CYP3A4 inhibition ↑ Daclatasvir ↓ Raclatasvir dose to 30 mg daily

Efavirenz,Etravirine

CYP3A4 induction ↓ Daclatasvir ↑ Raclatasvir dose to 90 mg daily

In general, dose modification recommended when co-administering with strong CYP3A4 inhibitors/inducers. Monitor signs and symptomsof myopathy when co-administered with HMG-CoA reductase inhibitors.


Commonly co-prescribed drugs16

Oral contraceptives: metabolized by CYP3A, CYP2C9 Cyclosporine/Tacrolimus: metabolized by CYP3A, substrate for P-gp Selective Serotonin Reuptake Inhibitors : CYP2D6 inhibition Methadone: CYP3A4 substrate Digoxin: P-gp substrate “Statins”: CYP3A4 substrate Antimicrobials: CYP3A4 inhibitor P-gp inhibitor (e.g. azithromycin, azole

antifungal)


Prescribing (Selection of Agents )19

Efficacy- genotype (FDA, USPHS, guidelines) Comorbidities and HIV treatment status Prior Treatment Stage of fibrosis Route (e.g. injections vs oral/ both) Duration Contraindications/ Precautions/Warnings Adverse Drug Events Drug-Drug Interactions Access (Formulary status; insurance) and Cost


Dispensing

Pharmacist play pivotal role in evaluating the appropriateness of selection of agents, patient access and continuum of care Record and review COMPLETE and UP-TO-DATE list of patient’s medication,

including OTC products; especially at transitions in care (medication reconciliation) Timely communication with prescribers and other healthcare providers Patient education on adverse drug events and adherence Continuing education on newly approved DAA agents with better efficacy, safety and

fewer DDIs


Administration

DDI may alter oral absorption; check for …….. Avoidance of concomitant medication administrations Spacing of medications Taking with or without meals; special dietary adjustments Daily timing of medication administration to maximize treatment benefit Daily timing of medication administration to minimize adverse effects Special administration needs e.g., young children, tube feeding, impaired swallowing,

poor vision (look- alike/side alike medications)


Monitoring19

Adherence HCV RNA quantitative testing at week 4 Re-evaluate at week 6 if level was detectible at week 4 Week 12 level (end of therapy) level is unnecessary since most patient will achieve sustained

virologic response (SVR); exception is patients needing >/= 24 weeks Prescription fills, refills, mean possession rate (MPR), direct observation, etc.

Toxicity Lab work at baseline (CBC, BMP, liver enzyme and bilirubin levels) Routinely throughout the treatment (weeks 2,4,8,12 or more often if abnormal/concerning

lab results) Recommend treatment discontinuation for serious adverse effects, e.g., if AST >10x baseline,

or hyperbilirubinemia


Common Adverse Drug Reactions

DAA ADR (>5%) Labeled Warning

Simeprevir (OLYSIO®)7 Rash, pruritus, nausea, myalgia, dyspnea

Hepatic decompensation and hepatic failure. Usually within 1-4 weeks in therapy initiation. Not recommended in patients with severe cirrhosis.

Serious photosensitivity reactions resulting in hospitalization have been observed with OLYSIO in combination with Peg-IFN-alfa and RBV. Simeprevircontains sulfa-moiety, use caution in patients with sulfa allergy.

Paritaprevir/rOmbitasvir/ Dasabuvir(VIEKIRA PAK®)10

Fatigue, nausea, pruritus, skin reactions, insomnia, asthenia

Hepatic decompensation and hepatic failure. Usually within 1-4 weeks in therapy initiation. Not recommended in patients with severe cirrhosis.

Sofosbuvir (SOVALDI®)8 Headache, fatigue,diarrhea, nausea, insomnia, pruritus, decreased appetite

Serious symptomatic bradycardia has been reported in patients taking amiodarone who initiate treatment with sofosbuvir in combination with another HCV direct-acting antiviral.Ledipasvir/Sofosbuvir

(HARVONI®)9

Daclatasvir (DAKLINZA®)11


Case Example20 - #1Appreciation of the extent of potential DDI

Study Design: Cross sectional study among HIV/HCV co-infected patients Method:

1. Medications lists were collected from medical records2. Medication lists were entered into Lexi-Interact drug interaction software 3. Documented contraindicated DDI (XDDI) before/after the addition of either simeprevir or

sofosbuvir containing therapy Results: Before the addition of any HCV therapy: 20% patients had XDDIs Addition of simeprevir containing therapy: 88.4% (p<0.001) patients had XDDIs Addition of Sofosbuvir containing therapy: 24.5% (p<0.001) patients had XDDIs

NNRTI regimen (PR: 1.62; 95% CI: 1.38-1.91, p<0.001), PI regimen (PR: 1.64; 95% CI: 1.40-1.93, p<0.001), and ≥7 non-HIV medications (PR: 1.06; 95% CI: 1.00-1.14, p=0.09) were all associated with higher prevalence of XDDs.


Case Example21 - #2How to predict interactions

Many interactions can be predicted if healthcare professionals taking care of patients have an understanding of the mechanism of proposed interaction

DAA ART Mechanism of Interaction

Predicted Result Actual Result Recommend

Daclatasvir 60 mg daily

Atazanavir/Ritonavir

CYP3A4 inhibition ↑ Daclatasvir ↑ 3x AUC ↓ Daclatavir to 30 mg daily


Efavirenz CYP3A4 induction ↓ Daclatasvir ↓ 2x AUC ↑ Daclatavir to 90 mg daily


Tenofovir No effect on CYP3A4

No DDI No clinical significant DDI


Case Example22 - #3Pay attention to labeled warnings

Sofosbuvir has labeled warning regarding severe bradycardia when administered in combination with amiodarone.

Patient was on amiodarone and propranolol; 2 hours after the patient had received Sofosbuvir and Daclatasvir, the patient experienced severe bradycardia, heart rate was recorded as 27 beats/min. Amiodarone and propranolol were subsequently stopped, but DAA were continued for 3 days. Each time patient received DAA, he would demonstrate bradycardia. Upon discontinuation of Sofosbuvir and Daclatasvir, no bradycardic events were observed. Thirteen days after patient has stopped amiodarone and atenolol, patient was challenged with DAA, bradycardia was again recorded after 2 days. No bradycardic events were observed following a challenge 8 weeks after discontinuation of amiodarone.


Database of Antiretroviral Drug Interactions


http://arv.ucsf.edu/

References

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2. Hepatitis C. http://emedicine.medscape.com/article/177792-overview#a5. Medscape. Updated August 03, 2015. Accessed October 20, 20153. HCV Guidance: Recommendations for Testing, Managing, and Treating Hepatitis C. HCV Testing and Linkage to Care. IDSA and AASLD and IAS-USA.

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October 18, 2015.8. Prescribing Information for SOVALDI®. Gilead Sciences. http://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/sovaldi/sovaldi_pi.pdf. Updated

August 2015. Accessed October 18, 2015. 9. Prescribing Information for HARVONI®. Gilead Sciences. https://www.gilead.com/~/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf.

Updated March 2015. Accessed October 18, 2015. 10. Prescribing Information for VIEKIRA PAK®. AbbVie. http://www.rxabbvie.com/pdf/viekirapak_pi.pdf. Updated October 2015. Accessed October 18, 2015. 11. Prescribing Information for DAKLINZA®. Bristol-Myers Squibb. http://packageinserts.bms.com/pi/pi_daklinza.pdf. Updated July 2015. Accessed October 18,

2015.12. Prescribing Information for TECHNIVIE®. AbbVie. http://www.rxabbvie.com/pdf/technivie_pi.pdf. Updated October 2015. Accessed October 18, 2015.


http://www.cdc.gov/hepatitis/hcv/cfaq.htm

http://emedicine.medscape.com/article/177792-overview

http://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care

http://www.uptodate.com/contents/treatment-regimens-for-chronic-hepatitis-c-virus-genotype-1?source=search_result&search=hepatitis+C&selectedTitle=3%7E150

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https://www.gilead.com/%7E/media/Files/pdfs/medicines/liver-disease/harvoni/harvoni_pi.pdf

http://www.rxabbvie.com/pdf/viekirapak_pi.pdf

http://packageinserts.bms.com/pi/pi_daklinza.pdf

http://www.rxabbvie.com/pdf/technivie_pi.pdf

References


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19. Kim Y. Epidemiology, natural history, and diagnosis of hepatitis C in the HIV-infected patient. UpToDate. http://www.uptodate.com/contents/epidemiology-natural-history-and-diagnosis-of-hepatitis-c-in-the-hiv-infected-patient?source=search_result&search=hepatitis+c+hiv&selectedTitle=2~150. Updated December 2014. Accessed October 19, 2015.

20. Patel N, Nasiri M, Koroglu A, Amin R, McGuey L, McNutt LA. Prevalence of drug-drug interactions upon addition of simeprevir- or sofosbuvir-containing treatment to medication profiles of patients with HIV and hepatitis C coinfection. AIDS Res Hum Retroviruses. 2015;31(2):189-97

21. Bifano M, Hwang C, Oosterhuis B, Hartstra J, Grasela D, Tiessen R. Assessment of pharmacokinetic interactions of the HCV NS5A replication complex inhibitor daclatasvir with antiretroviral agents: ritonavir-boosted atazanavir, efavirenz and tenofovir. Antivir Ther. 2013;18(7):931-40

22. Renet S, Chaumais MC, Antonini T, Zhao A, Thomas L, Savoure A. Extreme Bradycardia After First Doses of Sofosbuvir and Daclatasvir in Patients Receiving Amiodarone: 2 Cases Including a Rechallenge. Gastroenterology. 2015; In Press.

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http://www.ncbi.nlm.nih.gov/pubmed/?term=dosing+recommendations+for+concomitant+medications+druing+3D+anti+hcv+therapy



http://www.aidsinfo.nih.gov/ContentFiles/AdultandAdolescentGL.pdf

http://www.uptodate.com/contents/epidemiology-natural-history-and-diagnosis-of-hepatitis-c-in-the-hiv-infected-patient?source=search_result&search=hepatitis+c+hiv&selectedTitle=2%7E150




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