Drug Interactions of Antiretroviral Therapy

Ching-Yao Shih National Cheng Kung University Hospital 2018/1/14 Abbreviations ART Antiretroviral therapy NRTIs Nucleoside reverse transcriptase inhibitors 3TC Lamivudine ABC Abacavir AZT Zidovudine FTC Emtricitabine TAF Tenofovir alafenamide TDF Tenofovir disoproxil fumarate NNRTIs Non-nucleoside reverse transcriptase inhibitors EFV Efavirenz NPV Nevirapine RPV Rilpivirine PIs Protease inhibitors ATV/r Atazanavir/ ritonavir DRV/r Darunavir/ ritonavir LPV/r Lopinavir/ ritonavir INSTIs Integrase inhibitors RAL Raltegravir EVG/Cobi Elvitegravir/ cobicistat DTG Dolutegravir

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 2 Case discussion 8/20 27 y/o male, 167 cm, 34.5 kg HIV infection was diagnosed on August 2014 C.C.: Chronic cough & right chest pain Chest X-ray: Bilateral infiltration and pneumothorax at right lung Cefotaxime + doxycycline for pneumonia; Baktar inj. for PJP PJP PCR: Positive; Sputum AFS×3: Negative. 9/4 Biopsy on RUL lung: PJP and CMV pneumonia; CMV retinitis OS Valganciclovir for CMV infection 9/12 B/C: AFS(+) bacilli  susp. NTM bacteremia  Clarithromycin + ethambutol + rifampin for NTM infection  Biochip identification on 9/24: Mycobacterium avium complex 9/22 Clinical pharmacist was consulted for HAART selection. HIV virus load: 7.25×105 copies/mL, CD4 counts: 18 cells/ mL SCr: 0.42 mg/dL, ClCr: 67.7 mL/min, Hb: 9.9 g/dL

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 3 Outline

Drug-drug interaction between antiretroviral agents and non-antiretroviral agents

Useful tools to evaluate drug-drug interaction

Case discussion

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 4 The probability of experiencing clinically significant drug-drug interaction Clinically significant drug interactions have been reported in 27-40% of HIV patients.

Ann Pharmacother國立成功大學醫學院附設醫院., 2011, 45:317National-24 Cheng Kung University Hospital Can J Hosp Pharm., 2012, 65: 125-1455 Mechanisms of drug-drug interactions Enhancers (Boosters) Ritonavir (Non-selective CYP450 enzymes inhibitor) Cobicistat (Specific Inhibitor of CYP 3A) Affecting drug absorption Acid-reducing agents Polyvalent cations products Affecting hepatic metabolism Cytochrome P450 Uridine diphosphate glucuronosyltransferase (UGT) 1A1

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 6 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 7 Acid-reducing agents

PPIs or H2 blockers vs NNRTIs or PIs

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 8 Acid-reducing agents will decrease ATV plasma level

LPV: lopinavir; RTV: ritonavir;國立成功大學醫學院附設醫院 ATV: atazanavir; OME: omeprazole; RAN:National ranitidine Cheng Kung University Hospital J Clin Pharmacol., 2008, 48: 553-629 Polyvalent cations products Polyvalent cations products vs INSTIs

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 10 Different timing to take antacid makes dramatic difference!

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital S/GSK1349572: dolutegravir; MVI: multivitamin J Antimicrob Chemother., 2011, 66:1567-7211 Pharmacokinetic interactions affecting hepatic metabolism Cytochrome P450 enzyme system CYP3A4 substrate: NNRTIs, PIs, INSTIs: Elvitegravir, and maraviroc. CYP3A4 inhibitor: Most PIs CYP3A4 inducer: Most NNRTIs Uridine diphosphate glucuronosyltransferase (UGT) 1A1 INSTIs: Raltegravir, dolutegravir

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 12 TB or NTM and HIV co-infection

Ethambutol, isoniazid, pyrazinamide and rifamycin antibiotics (rifampin or rifabutin) are 1st line antitubercular agents

Ethambutol, rifampin, and macrolide antibiotics (clarithromycin or azithromycin) are usually used in NTM treatment, especially MAC infection. TB: Mycobacterium tuberculosis; NTM: Non-tuberculosis國立成功大學醫學院附設醫院 mycobacterium, MAC:NationalMycobacterium Cheng Kung avium Universitycomplex Hospital 13 Drug interaction between Macrolide and ART

Clarithromycin: CYP3A4 substrate and inhibitor When with PIs Clarithromycin concentration; May cause QTc prolongation! When with NNRTIs Clarithromycin concentration; Consider alternative agent. Shift to azithromycin, if MAC infection.

TB: Mycobacterium tuberculosis; NTM: Non-tuberculosis國立成功大學醫學院附設醫院 mycobacterium; MAC:NationalMycobacterium Cheng Kung avium Universitycomplex Hospital 14 Drug interaction between rifampin and ART

ProductRifabutin information: only a moderate CYP 3A4 inducer Rifampin: a potent CYP 450 enzyme inducer including 3A4, 1A2, 2C9 and 2C19 Rifampin and EFV:

DHHS guideline 2017 Despite combination with rifampicin, sufficient plasma efavirenz concentrations can be achieved in HIV-infected Taiwanese with TB whoClin Pharmacokinetreceive efavirenz., 2002, 41:600 681 mg-90 daily.

PLoS One,國立成功大學醫學院附設醫院 2014, 9: e88497 National Cheng Kung University Hospital 15 Double-dose INSTIs in combination with rifampin Rifampin and INSTIs (RAL and DTG) Raltegarvir: 400 mg BID 800 mg BID Dolutegravir: 50 mg QD 50 mg BID

J Acquir Immune Defic Syndr., 2013, 62: 21-7 Antimicrobials Agents Chemother., 2009, 53: 2852-6 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 16 No dose adjustment of INSTIs in combination with rifabutin Rifabutin and INSTIs (RAL and DTG)

J Acquir Immune Defic Syndr., 2013, 62: 21-7 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 17 Decrease rifabutin dose in combination with PIs Rifabutin and PIs Rifabutin: 300 mg QD titrate down to  150 mg QOD (Guidelines for diagnosis and treatment of HIV/AIDS 4th ed, 2013)  150 mg QD or 300 mg TIW (DHHS guideline 2017)

+ LPV/r + LPV/r

+ LPV/r + LPV/r

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital PLoS One., 2014, 9: e84866 18 The most common concomitant medications by class in PLWHA

Neth J Med., 2017, 75: 235-240 AIDS, 2018, 32: 35-48 PLWHA: People living with HIV/ AIDS 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 19 Outline

Drug-drug interaction between antiretroviral agents and non-antiretroviral agents

Useful tools to evaluate drug-drug interaction

Case discussion

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 20 Drug-drug interaction table DHHS guideline

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 21 Drug-drug interaction table Immunodeficiency Clinic - Drug Interaction Summary Tables

國立成功大學醫學院附設醫院http://hivclinic.ca/drugNational-information/drug Cheng Kung University-interaction Hospital-tables/ 22 Drug-drug interaction database

UpToDate – Lexicomp Drug interactions Paid resource Multiple drugs cross comparison

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 23 Drug-drug interaction database

University of Liverpool – HIV Drug interactions Free Convenient – Apps: HIV iChart Only check interaction between HIV drugs and Co-medication

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 24 Drug-drug interaction database

NCBI – PubMed Free for search and abstract; Paid for article Primary studies Massive information!!!

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 25 Outline

Drug-drug interaction between antiretroviral agents and non-antiretroviral agents

Useful tools to evaluate drug-drug interaction

Case discussion

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 26 Case discussion 8/20 27 y/o male, 167 cm, 34.5 kg HIV infection was diagnosed on August 2014 C.C.: Chronic cough & right chest pain Chest X-ray: Bilateral infiltration and pneumothorax at right lung Cefotaxime + doxycycline for pneumonia; Baktar inj. for PJP PJP PCR: Positive; Sputum AFS×3: Negative. 9/4 Biopsy on RUL lung: PJP and CMV pneumonia; CMV retinitis OS Valganciclovir for CMV infection 9/12 B/C: AFS(+) bacilli  susp. NTM bacteremia  Clarithromycin + ethambutol + rifampin for NTM infection  Biochip identification on 9/24: Mycobacterium avium complex 9/22 Clinical pharmacist was consulted for HAART selection. HIV virus load: 7.25×105 copies/mL, CD4 counts: 18 cells/ mL SCr: 0.42 mg/dL, ClCr: 67.7 mL/min, Hb: 9.9 g/dL

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 27 Drug list Drugs for opportunistic infection treatment CMV infection: Valganciclovir NTM infection: Clarithromycin, ethambutol, rifampin Antiretroviral candidates: ARVNRTIs: prescription Abacavir regulation, lamivudine, by Taiwan tenofovir CDC, zidovidine 2017 RecommendedNNRTIs: Efavirenz first line , nevirapine, rilpivirine TDF/ FTC/ EFV TDF/PIs: FTC/ Atazanavir RPV , lopinavir/ritonavir, darunavir ABC/IIs: 3TC/ Raltegravir DTG , dolutegravir TAF/ FTC/ Cobi/ EVG

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 28 Lexicomp drug interaction

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 29 Liverpool HIV drug interaction

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 30 Interpretation survey result (I)

Contraindication: Rifampicin and EVG/cobi/FTC/TAF Cobi and EVG concentration significantly Rifampicin and RPV RPV Cmax, AUC and Cmin by 69%, 80% and 89%

Recommended first line by Taiwan CDC TDF/ FTC/ EFV TDF/ FTC/ RPV ABC/ 3TC/ DTG TAF/ FTC/ Cobi/ EVG

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 31 Interpretation survey result (II)

Potential interaction Rifampicin and DTG: DTG AUC, Cmax and Ctrough by 54%, 43% and 72%  Titrate up DTG to 50 mg BID when combination with rifampicin  But drug price > 15,500 NTD/ month Prior approval needed

Recommended first line by Taiwan CDC TDF/ FTC/ EFV TDF/ FTC/ RPV ABC/ 3TC/ DTG TAF/ FTC/ Cobi/ EVG 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 32 Interpretation survey result (III)

Potential interaction Rifampicin and EFV: EFV AUC, Cmax and Cmin by 26%, 20% and 32%  Weight of this patient: 34.5 kg  No EFV dose adjustment, when combination with rifampicin

Recommended first line by Taiwan CDC TDF/ FTC/ EFV  TDF/ FTC/ RPV ABC/ 3TC/ DTG TAF/ FTC/ Cobi/ EVG

國立成功大學醫學院附設醫院 National Cheng Kung PLoSUniversityOne, Hospital 2014, 9: e88497 33 Interpretation survey result (IV)

Potential interaction: Ganciclovir and TDF: Compete with active tubular secretion. Both concentration  (Uptodate) Concurrent nephrotoxic agents use (Liverpool HIV)  Monitor patient condition

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 34 Interpretation survey result (V)

Potential interaction ClarithromycinBiochip identification: and EFV Clarithromycin Mycobacterium AUC and Cmax aviumby 39% andcomplex 26% ClarithromycinShift clarithromycin and TDF: to azithromycin is indicated. Liverpool HIV DDI database: No co-administration study. TDF is P-gp substrate; Clarithromycin is P-gp inducer. TDF conc.  Lexicamp DDI database: No drug interaction.

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 35 DDI interpretation result

For CMV infection: Keep valganciclovir For MAC infection: Keep ethambutol and rifampicin Shift clarithromycin to azithromycin HAART regimen: TDF/FTC/EFV 1# QD ABC/3TC/DTG 1# QD + DTG 1# QN  alternative choice, If EFV intolerance  monthly cost > 15,500 NTD, prior approval needed

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 36 Summary

To evaluate drug-drug interaction between ART and non-ART agents, and to advise a feasible regimen for clinicians are the duty of pharmacist. Either guideline or database would be useful tools to evaluate drug-drug interaction. Reassessment is necessary when a new agent is being initiated.

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 37 Thanks for your attention

Any Question? 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 39 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 40 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 41 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 42 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 43 Boosters

Ritonavir (RTV or /r) Non-selective CYP450 enzymes inhibitor Anti-HIV activity at high doses (1200 mg/ day) Cobicistat (Cobi or /c) Specific Inhibitor of CYP 3A Without anti-HIV activity

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 44 Pharmacokinetic of ART given with and without boosting agents

Clin Pharmacokinet., 2014, 53: 865-72 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 45 Conclusion

Either Lexicamp drug interaction database or Liverpool HIV drug interaction database would be useful tools to evaluate drug-drug interaction. Reassessment is necessary whether a new ARV drug is being initiated in a patient on a stable concomitant medication or if a new concomitant medication is being initiated in a patient on a stable ARV regimen.

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 46 Glucocorticoids vs HAART Triamcinolone, fluticasone and budesonide are metabolized by CYP3A4. When co-administered with protease inhibitors, ritonavir or cobicistat, there are reports of each of these drugs accumulating and causing hypercortisolism or itrogenic Cushing’s syndrome, which often begin within weeks of starting co-administered. Not only systemic exposure (oral or intravenous), but also topical use (inhaled, nasal, topical, ocular, or intra-articular) should be considered this drug interaction.

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 47 Glucocorticoids vs HAART

Inhaled/intranasal: Switch to beclometasone or steroid sparing agent Oral: Ensure only physiological (replacement) dose is administered Topical: Discuss with dermatology for steroid sparing agents Injected: Stop further administrations, consider disease modifying agents

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital Clin Med (Lond)., 2016, 16: 412-418 48 Antifungals vs HAART

Fluconazole: Minimal DDI with HAART  The preferred azole antifungal

Itraconazole: Substrate of CYP 3A4  Concentration, when co-administer with NNRTIs; Concentration, when co-administer with PIs

Voriconazole: Substrate of CYP 2C19  Ritonavir is CYP2C19 inducer. Additional dose would be necessary!

國立成功大學醫學院附設醫院 NationalExpert Opin ChengDrug Kung Metab UniversityToxicol., 2014,Hospital 10: 561-580 49 Antifungals vs HAART

 Azole antifungals are generally considered to be CYP 3A4 inhibitors  Concentration of NNRTIs and PIs , when co-administration.  Interpretation DDI case by case!! And use with caution!!

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital J Antimicrob Chemother., 2010, 65: 31650-9 Drug-drug interaction and HIV treatment In addition to antiretrovirals for their HIV infection, many patients require treatment for concomitant conditions. Prophylaxis or treatment of opportunistic infections Hepatitis coinfection Illicit substance use Psychiatric illness Comorbidities of ageing patients such as cardiovascular disease, hyperlipidemia, hypertension, diabetes mellitus, gastrointestinal conditions, osteoporosis, renal disease, and non–AIDS-related cancers Solid-organ transplantation Vitamins, food supplements, complementary or alternative medicine agents Recreational agents, either regularly or occasionally

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital Can J Hosp Pharm., 2012, 65: 125-14551 Pharmacodynamic drug interactions (NRTIs class) Lamivudine (3TC) and emtricitabine (FTC) minimal additive antiviral activity similar resistance profiles FTC Stavudine (d4T) and didanosine (ddI) additive or synergistic activity potentially serious overlapping toxicities such as peripheral neuropathy, pancreatitis, and lactic acidosis 3TC

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 52 Pharmacokinetic interactions affecting drug absorption

Drugs that induce or inhibit the enzyme efflux transporter p-glycoprotein in the intestines

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 53 Case discussion Drugs for opportunity infection treatment CMV infection: Ganciclovir NTM infection: Clarithromycin, ethambutol, rifampin Antiretroviral candidates: NRTIs: Abacavir, lamivudine, tenofovir, zidovidine NNRTIs: Efavirenz, nevirapine, rilpivirine PIs: Atazanavir, lopinavir/ritonavir, darunavir IIs: Raltegravir, dolutegravir, elvitegravir Booster: Cobicistat

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 54 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 55 About this case

10/2 To ER C.C.: 1. Intermittent fever; 2. Mild dyspnea; 3. Watery diarrhea(>10 times/day); 4. Skin rash over chest, back and extremities ADR report: Valganciclovir induced leucopenia (WBC: 1500; ANC: 870) Empirical antibiotics use: Tazocin 10/3 Symptoms no improvement Tazocin shift to ceftriaxone HAART rearrangement 3TC 150 mg BID TDF 300 mg QD RAL 800 mg BID 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 56 Drug-drug interaction between HAART and anti-NTM regimen

Anti-NTM regimen Azithromycin  10~12 mg/ kg/ day × 34.5 kg = 345~414 mg QD ≒ 500 mg (2#) QD (UptoDate) Ethambutol  15 mg/ kg × 34.5 kg QD = 517.5 mg QD ≒ 600 mg (1.5#) QD Rifampin  10 mg/ kg × 34.5 kg QD = 345 mg QD ≒ 300 mg (1#) QD

HAART regimen - NNRTI base (Due to low body weight(34.5 kg), pediatric dose were used to modify his dose) 3TC  4 mg/ kg × 34.5 kg BID = 138.8 mg BID ≒ 150 mg (1#) BID TDF  210 mg/ m2 × 1.27 m2 QD = 266.7 QD ≒ 300 mg (1#) QD EFV  32.5~40 kg  400 mg HS ≒ 600 mg (1#) HS

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 57 HAART rearrangement due to skin rash

1. Due to possible efavirenz induced skin rash, to shift to nevirapine would be contraindicated. 2. Due to diarrhea, protease inhibitors would not be considered. 3. Raltegravir might be an alternative choice!! (1) > 25 kg: 400 mg (1#) BID (2) Drug-drug interaction between rifampin and raltegravir: Rifampin decrease level of raltegravir(400 mg BID). (AUC40%) The recommended dose of raltegravir for this patient is 800 mg (2#) BID.

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 58 If MAC treatment complete…

No potential drug-drug interactions. To titrate dose of raltegravir would be necessary!! To shift to PI-base regimen might be considered.

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 59 Valganciclovir induced leukopenia

4000 3730 3653 3500 3312 3000 3056 Bone marrow

L) survey m 2500 2328

2000 1556 1500 1520

1576 ANC counts (cells/ counts ANC 1100 987 1152 1000 844 870 840 892

500 540 547 572 576 340 0 8/20 8/27 9/3 9/10 9/17 9/24 10/1 10/8 10/15 10/22 10/29 11/5 11/12 Valganciclovir regimen 900 mg BID 900 mg QD 900 mg QD (9/4~25) (9/26~10/15) (11/5~)

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 60 Boosters

Ritonavir (RTV or /r) Non-selective CYP450 enzymes inhibitor Anti-HIV activity at high doses (1200 mg/ day) Cobicistat (Cobi or /c) Specific Inhibitor of CYP 3A Without anti-HIV activity

國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 61 Pharmacokinetic of ART given with and without boosting agents

Clin Pharmacokinet., 2014, 53: 865-72 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 62 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 63 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital 64 Drug-drug interaction between HAART and anti-NTM regimen

NTM Clarithromycin Rifampin Ethambutol Azithromycin HAART AZT     3TC     TDF     ABC     EFZ     NVP     PIs     : No drug interaction; : Mild drug interaction; : Avoid combination 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital Drug-drug interaction between HAART and anti-NTM regimen

NTM Rifampin decrease level of AZT. Rifampin (AUC47%) HAART Uptodate: Possible drug interaction! AZT  PubMed: No effect in health volunteer. 3TC 

TDF  Rifampin decrease level of EFZ. (AUC47%) 國內愛滋病治療指引根據台大的研究發現兩者併用 ABC  時，efavirenz 600 mg/ day對於wild-type HIV仍有效

EFZ  Rifampin decrease level of NVP to lower than that of the minimum therapeutic NVP  concentration. PIs  Rifampin increase liver toxicity of lopinavir, and decrease level of lopinavir and ritonavir.

國立成功大學醫學院附設醫院: No drug interaction; :National Mild drug Cheng interaction; Kung University : Avoid Hospital combination Drug-drug interaction between HAART and anti-NTM regimen

NTM Clarithromycin decrease level of AZT. (AUC25%) Clarithromycin Increase of myelosuppressive effect of AZT. HAART AZT  3TC  TDF  Both EFZ and NPV decrease level of clarithromycin. ABC  EFZ  NVP  Highest risk QT prolonging PIs  : No drug interaction; : Mild drug interaction; : Avoid combination 國立成功大學醫學院附設醫院 National Cheng Kung University Hospital