DDIs, INSTIs, TB and Hepatitis

DDIs, INSTIs, TB and Hepatitis David Back University of Liverpool UK David Back University of Liverpool Rio de Janeiro August 2018

Disclosures Honoraria received for advisory boards and lectures from AbbVie, BMS, Gilead, Merck, ViiV, Janssen, Teva Educational grants for www.hep-druginteractions.org and www.hiv-druginteractions.org from AbbVie, BMS, Gilead, Janssen, Merck, ViiV

Overview 1 DDIs the Problem 2 Integrase Inhibitors: Similarities and Differences 3 Integrase Inhibitors and TB Therapy 4 Integrase Inhibitors and HCV Therapy

Overview 1 DDIs the Problem 2 Integrase Inhibitors: Similarities and Differences 3 Integrase Inhibitors and TB Therapy 4 Integrase Inhibitors and HCV Therapy

1. The Problem Relatively few formal DDI studies Increasing numbers of patients on ARVs Ageing Population Polypharmacy DDIs: Are not going away! Different prescribers Recreational drugs Increased use of Over the Counter Online access to drugs Adapted from Okoli C - with permission

Drug Concentration Does the ARV drug alter the exposure (concentration) of other drugs? Do other drugs alter the exposure of the ARV drug? If Yes what is the magnitude of the change in PK parameters? If Yes what is the clinical significance of the DDI? What is the appropriate management strategy for the DDI? AEs AEs ARV Perpetrator Comed Victim Loss of efficacy Loss of efficacy

Based on www.hiv-druginteractions.org The Potential of ARVs to Interact Highest potential Moderate Potential Lowest Potential Boosted PIs Perpetrators enzyme and transporter Inhibition Victims - absorption (ATV); induction EVG/cobi Perpetrator enzyme and transporter inhibition Victim - absorption; induction Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Raltegravir Victim of absorption and a few induction interactions Dolutegravir Victim of absorption and a few induction interactions. Perpetrator of renal interaction Bictegravir Victim of absorption and some induction/inhibition interactions. Also consider TAF Efavirenz Perpetrator enzyme and transporter induction NRTIs Victim of some transporter mediated interactions. TDF & TAF > ABC, 3TC, FTC

Selected Interactions for Boosted Regimens (PI/r; PI/c; EVG/c) - Perpetrator Drug class Corticosteroids Antidepressants Benzodiazepines Chemotherapy drugs Anticoagulants; Vit K antagonists Direct acting anticoagulant (DOAC) Calcium channel blockers Statins Comment Risk of Cushing syndrome.. Risk not just oral but inhaled, eye drops, injection, topical. Triamcinolone, budesonide, fluticasone, mometasone contra-indicated. Avoid tricyclics - can cause anticholinergic effects, sedation Caution. AEs increased. Use lowest dose for short duration. Midazolam, triazolam contraindicated. Increased risk of chemo related toxicities. Monitor INR. Dose adjustment may be required if switching from ritonavir to cobicistat. Significant effect expected (limited data). Recommended - avoid with boosted regimens Potential hypotensive effect. Start with lowest dose and titrate. Some statins increased. Simva-, lovastatin contraindicated. Pitavastatin can be used. Others start with low dose and titrate. Think about long term use of boosters particularly in older patients Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012, www.hiv-druginteractions.org

Drug-Drug Interactions With First-line ART and Lipid-Lowering Therapy Antiretroviral Contraindicated Titrate Dose No Dose Adjustment EFV RPV Atorvastatin Simvastatin Pravastatin Lovastatin Pitavastatin Rosuvastatin All DRV/RTV DRV/COBI Lovastatin Simvastatin Atorvastatin Pravastatin Rosuvastatin Pitavastatin EVG/COBI/FTC/TAF Lovastatin Simvastatin Atorvastatin Rosuvastatin Rosuvastatin Pitavastatin EVG/COBI/FTC/TDF Lovastatin Simvastatin Atorvastatin Rosuvastatin Rosuvastatin Pitavastatin DTG or RAL or BIC All From www.hiv-druginteractions.org and DHHS Adult Guidelines. October 2017. US Food and Drug Administration

Help is at hand!

Overview 1 DDIs the Problem 2 Integrase Inhibitors: Similarities and Differences 3 Integrase Inhibitors and TB Therapy 4 Integrase Inhibitors and HCV Therapy

Integrase Inhibitors:Profile Raltegravir Elvitegravir Dolutegravir Bictegravir Clinical dose 400 mg BID* OR 1200 mg QD 150 mg QD with cobi and FTDF or FTAF 50 mg QD 50 mg BID (INIresistant) 50 mg QD with FTAF Metabolism UGT1A1 CYP3A (major), UGT1A1/3 (minor) UGT1A1 (major), CYP3A (minor) UGT1A1 and CYP3A (equal) DDI Potential Least Highest Slightly greater than RAL Slightly greater than DTG 1. Tivicay SmPC July 2018. 2. Min S, et al. Antimicrob Agents Chemother 2010;54:254 8. 3. Min S, et al. AIDS 2011;25:1737 45 4. Isentress SmPC July 2018; 5. Stribild SmPC Aug 2018; 6. Ramanathan S, et al. Clin Pharmacokinet 2011;50:229 44; 7. Biktarvy SmPC June 2018

Drug Class Cations: ie Antacids*, Calcium; Iron Selected DDI for Integrase Inhibitors (RAL; DTG; EVG/c; BIC) Comment Integrase inhibitors bind to divalent cations in the g.i.tract which limits absorption. Variable decrease in exposure with potential risk of treatment failure. Victim Metformin Rifampicin DTG, EVG/c, BIC variably increase metformin exposure (inhibits OCT2/MATE-1 in kidney). RAL has no effect. Note: No DDIs with most other antidiabetic drugs. Rifampicin variably decreases DTG, EVG, BIC, RAL exposure. Perpetrator Victim Rifabutin Rifabutin decreases EVG and BIC exposure but no clinically significant effect on DTG or RAL Victim *NOT omeprazole or other Proton pump inhibitors or H2 blockers Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012, www.hiv-druginteractions.org

Mechanism of Interaction specific to Integrase Inhibitors: Chelation with Cations Mean DTG concentration (µg/ml) Binding of integrase inhibitors Mg Mg Integrase Inhibitor 2.0 1.8 1.6 1.4 1.2 1.0 0.8 0.6 0.4 0.2 0 74% Mg 2+ Mg 2+ 26% Dolutegravir alone Dolutegravir +antacid Dolutegravir + antacid 2h later 0 10 20 30 40 50 60 70 80 Time (hrs) Adapted from Patel P et al. JAC 2011, Pommier Y et al. Nat Rev 2005; Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18

Impact of Mg ++ /Al ++ Containing Antacid on the Plasma Exposure (AUC and C min ) of Integrase Inhibitors RAL (bd) AUC/C min RAL (QD) AUC/C min EVG AUC/C min DTG AUC/C min BIC AUC/C min Antacid (Al ++ /Mg ++ ) taken together Mg 2+ Mg 2+ 49%/ 63% NA/NA 45%/ 41% 74%/ 74% 79%/NA Antacid +/- 2h 51%/ 56% 14%/ 58%** / 26%/ 30% 13%/NA AUC = area under the plasma concentration time curve; C min = Minimum plasma concentration either 12 h for bd or 24 h for QD The values are the percentage decrease/change in the respective parameters. NOTE: Data with raltegravir qd was performed giving the antacid 12 h after raltegravir. Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Biktarvy SmPC 06/18

Integrase Inhibitors and Mg ++ /Al ++ Containing Medications: Recommendations Coadministered Drug Raltegravir Dolutegravir Elvitegravir/c Bictegravir Mg/Al containing antacid Not recommended (NR) bd & qd Separate well (DTG 2h before or 6h after antacid) Separate by least 4h Take BIC under fasting conditions 2h before Genvoya SmPC 08/18; Tivicay SmPc 07/18.; Isentress SmPC 07/18; Bictarvy PI 06/18

Current Recommendations for Integrase Inhibitors and Ca ++ Containing Antacids/Supplements Cation Raltegravir Dolutegravir Elvitegravir/c Bictegravir Calcium containing antacid/ supplement No dose adjustment (bd) 1 Not recommended (qd) 1 Separate well (DTG 2h before or 6h after) Ca ++ Not specifically stated Mg 2+ Can be taken together without regard to food 2. Mg 2+ 1 Important to note the difference in recommendation for the bd and QD dosing of raltegravir. The QD dose gives a lower C min value than bd and the decrease in exposure with the calcium is ~50%. 2 Note: The USPI gives different recommendation ie can be taken together with food (supplement) and should be administered at least 2h before, under fasting condition (antacid) Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Biktarvy SmPC 04/18

The Calcium Content of Preparations can be Highly Variable Preparation Calcium Carbonate 1 content (mg) Gaviscon 187.5 TUMS 500 TUMS Ultra strength 1000 Calcichew 1250 Calcichew Forte 2500 Multivitamins (Forceval) 108 Glass of milk* 300 Cheese (per 30g)* 100-200 *Elemental calcium; 1 Other forms of calcium include calcium citrate (better absorbed) and calcium succinate.

Integrase Inhibitors and Metformin Metformin for type-2 diabetes requires titration to optimize dosing. 1 Inhibition by: Dolutegravir Renal tubular cell Metformin OCT2 79% Metformin MATE1 Blood Basolateral Apical Active Tubular Secretion Urine Consider dose adjusting metformin when starting and stopping administration of dolutegravir with metformin. Also dose adjust in moderate renal impairment. 1. GLUCOPHAGE SMPc 01/17; Tivicay SMPc 03/18; Song IH et al JAIDS 2016; 72: 400-407.

Metformin 15-30 ml/min 30-60 ml/min 60-90 ml/min 90-120 ml/min IR Dose (mg/12h) AUC 0-12h (mg/l/h) 250 19 500 20 1000 26 1500 18 XR Dose (mg/24h) 500 1000 2000* *Max daily dose for XR Eur J Clin Pharmacol 2017; 73: 981-990

Int J STD & AIDS 2017; 28: 1229-1233. Retrospective case series of pts prescribed DTG and metformin (n=19) GI distress (n=3) and hypoglycaemic symptoms (n=3) reported leading to Metformin dose reduction (n=2) and/or discontinuation (n=2) No cases of lactic acidosis. Raltegravir Elvitegravir/c Bictegravir No interaction expected RAL does not inhibit OCT2 Caution metformin concentrations may be increased due to effect of cobicistat Metformin exposure increased by 39%. Assess benefit:risk

Overview 1 DDIs the Problem 2 Integrase Inhibitors: Similarities and Differences 3 Integrase Inhibitors and TB Therapy 4 Integrase Inhibitors and HCV Therapy

Integrase Inhibitors and anti-tb Therapy Co-administered Drug Raltegravir Dolutegravir Elvitegravir/c Bictegravir Rifampicin RAL AUC 40% Consider doubling dose DTG AUC 54% Double dose of DTG (+2NRTIs) in absence of integrase resistance Contraindicated Contraindicated (Also TAF interaction) Not Triumeq Rifabutin No dose adjustment No dose adjustment Not recommended Not recommended Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Bictarvy PI 02/18; www.hiv-druginteractions.org

Conclusion: DTG 50 mg BID during concomitant RIF-based TB therapy demonstrated high efficacy and good immunological response through week 24. DTG C tau was similar to DTG 50 mg QD without RIF Dooley KE et al CROI March 4-7 2018

The additional dose of dolutegravir may be difficult to implement in high burden settings where nurses often prescribe ART, making complex regimens undesirable. Pharmacies would also need to stock dolutegravir as a single tablet and the fixed dose combination formulation, increasing the risks of stock outs. The potential impact on adherence with twice daily administration. Curr Opin HIV AIDS 2017; 12: 355-358

Adjusting the dolutegravir dose might be challenging in public sector programmes and would negate the benefits of a once-daily regimen, meaning that further work is needed to assess the clinical effect of rifampicin co-administered with once daily dolutegravir. www.thelancet.com/hiv Vol 5 July 2018

Although there were substantial reductions in the DTG key PK parameter C 24h ( 76%) when co-administered with RIF, concentrations of DTG 100mg OD with RIF were still above the protein binding-adjusted IC of 64 ng/ml, suggesting the need for further study of this dose. Antiviral PK Workshop May 2018

2-Drug Regimens and anti-tb Therapy TB Drug DRV/r + 3TC LPV/r + 3TC DTG + 3TC DTG/RPV CAB + RPV Rifampicin Large decrease in PI exposure Contra indicated Large decrease in PI exposure Not recommended DTG C min 72%; Add additional dose of DTG in absence of integrase resistance. DTG C min 54%; RPV C min 80%; Contra indicated RPV C min 80%; CAB C min ~40%*; Contra indicated Rifabutin RFB 3 times per week RFB AUC: 5.7-fold RFB 3 times per week DTG C min 30%; No dose adjustment necessary DTG C min 30%; RPV C min 48%; Add additional RPV 25mg CAB C min 26%; RPV C min X %; Add additional RPV 25mg? Prezista SmPC 03/18; Tivicay SmPc 03/18.; Kaletra SmPC 02/18; Juluca SmPC; 05/18; *PBPK modelling Rajoli RFR et al CROI 2018; Ford SL et al AAC; 2017: 61: e00487-17

Giving BFTAF BD does not overcome the RIF effect. The C trough is still markedly reduced (by 80%). Custodio J et al; CROI 2018; Abs 34.

Overview 1 DDIs the Problem 2 Integrase Inhibitors: Similarities and Differences 3 Integrase Inhibitors and TB Therapy 4 Integrase Inhibitors and HCV Therapy

HIV-HCV Co-infection When treating a co-infected patient it is important to recognize that there are important and clinically significant interactions between antiretroviral drugs and many of the DAA regimens. 1. May need to change the ARV regimen to allow for prescribing of first-line HCV agent. 2. If this is not possible then have to find a DAA that works around the drug interactions. 3. Always review all the drug interactions.

Characteristics of HCV Drugs Characteristic Specific Agents Protease Inhibitors Simepravir Paritaprevir Grazoprevir Glecaprevir Voxilaprevir Nucleos(t)ide Polymerase Inhibitors Non-nucleoside Polymerase Inhibitors NS5A Inhibitors Sofosbuvir Dasabuvir Ledipasvir Daclatasvir Ombitasvir Elbasvir Velpatasvir Pibrentasvir Predominant Elimination Hepatic Renal Hepatic Hepatic Potential for DDIs Highest Low Low to moderate Low to moderate Modified from Schaefer EA et al Gastroenterology 2012; 142: 1340-1350

Case Study: Patient JK 49-year-old MSM diagnosed with HIV and HCV in 2013 HIV: Currently on DRV/r + F/TDF CD4 count 560 cells/μl Viral load < 40 copies/ml Normal renal function HCV: Genotype 1a HCV PCR 437,987 IU/mL Fibroscan 14.2 kpa (F4) Child Pugh A Previously failed SOF + pegifn + RBV in 2014

Co-Medications Amlodipine, 5 mg Metformin 500 mg bd mg Atorvastatin 20 mg Omeprazole, 40 mg DRVr + TDF/FTC 800/100 + 300/200 mg HIV Provider has already needed to assess the DDIs between ARV regimen and the co-meds

Potential Drug Drug Interactions Note: The patient is on: i) a low dose of Amlodipine (5 mg) ii) A dose of Atorvastatin that with the PI boosting should not be exceeded. HIV Drug Interactions. Available at: www.hiv-druginteractions.org (accessed Aug 2018).

NNRTIs NRTIs HCV DAAs and HIV Antiretrovirals: NRTIs and NNRTIs SOF DAC 3D G/P SOF/VEL Abacavir Emtricitabine Lamivudine Tenofovir (TDF) Efavirenz Etravirine Nevirapine Rilpivirine No clinically significant interaction expected. Potential interaction that may require a dosage adjustment, altered timing of administration, or additional monitoring. These drugs should not be co-administered. 3D, ombitasvir/paritaprevir/ritonavir plus dasabuvir; DAA, direct-acting antiviral; DCV, daclatasvir; DDI, drug drug interaction; EBR, elbasvir; GZR, grazoprevir; LDV, ledipasvir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside/nucleotide reverse transcriptase inhibitor; SIM, simeprevir; SOF, sofosbuvir * Known or anticipated increase in tenofovir concentrations. : www.hep-druginteractions.org

EI Integrase inhibitors Protease inhinitors HCV DAAs and HIV Antiretrovirals: Protease Inhibitors and Entry/Integrase Inhibitors SOF DAC 3D G/P SOF/VEL ATV/r DRV/r DRV/c Lopinavir/r Dolutegravir E/C/F/TDF E/C/F/TAF Raltegravir Bictegravir Maraviroc 3D, ombitasvir/paritaprevir/ritonavir plus dasabuvir; ATV, atazanavir; C, cobicistat; DCV, daclatasvir; DRV, darunavir; E, elvitegravir; EBR, elbasvir; F, emtricitabine; GZR, grazoprevir; LDV, ledipasvir; PI, protease inhibitor; r, ritonavir; SOF, sofosbuvir; TAF, tenofovir alafenamide; TDF, tenofovir disoproxil fumarate; VEL, * Known or anticipated increase in tenofovir concentrations. : www.hep-druginteractions.org

Ombitasvir/Paritaprevir/r + Dasabuvir (3D) should not be used in patients on efavirenz, etravirine, nevirapine, darunavir/c, lopinavir/r, E/C/F/TDF and E/C/F/TAF. Daclatasvir requires dose modification to 90 mg in patients on efavirenz, etravirine and nevirapine and to 30 mg in patients on atazanavir/r, atazanavir/c, E/C/F/TDF and E/C/F/TAF.

Case Study: Outcome HIV Therapy switch to Dolutegravir But note patient is on Metformin 500 mg bid. HCV Therapy start OBV/PTV/r + DSV (3D) No interactions with ARV therapy However need to check the interactions with co-meds being taken C, cobicistat; E, elvitegravir; F, emtricitabine; RBV, ribavirin; SOF, sofosbuvir; TAF, tenofovir alafenamide.

Potential Interactions of the 3D regimen with other drugs the patient is taking. Note: The patient is on: i) a low dose of Amlodipine (5 mg) we can monitor ii) Atorvastatin could possibly be stopped - or switched iii) Omeprazole 40 mg? HEP Drug Interactions. Available at: www.hep-druginteractions.org (accessed Aug 2017).

Finally.

MixPanel Stats: Top Searches for Co-meds used with ART: Global in 2017 www.hiv-druginteractions.org

MixPanel Stats: Top Searches for Co-meds used with ART: Brazil in 2017 www.hiv-druginteractions.org

In Management of HIV positive patients it is essential to: Remember the different DDI potential of ARVs Review all the co-meds particularly when starting or stopping Resources - available Key points / Take home message Is the drug really needed? Is there an alternative with less potential for DDIs? Start with lowest dose if drug necessary and monitor the patient.