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

DDIs – the Problem

Integrase Inhibitors: Similarities and Differences

1

2

Integrase Inhibitors and TB Therapy3

Integrase Inhibitors and HCV Therapy4

Overview

DDIs – the Problem

Integrase Inhibitors: Similarities and Differences

1

2

Integrase Inhibitors and TB Therapy3

Integrase Inhibitors and HCV Therapy4

DDIs:Are not going away!

Ageing

Population

Polypharmacy

Increased use

of

‘Over the

Counter’

Online access to drugs

Different prescribers

Recreational drugs

Increasing

numbers of

patients on

ARVs

Adapted from Okoli C - with permission

1. The Problem

Relatively few formal

DDI studies

❑ 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?

Perpetrator

Victim

ARVCo-

med

Loss of

efficacy

Loss of

efficacy

AEs AEsD

rug

Co

nce

ntr

atio

n

Highest potential Moderate Potential Lowest Potential

Boosted PIsPerpetrators – enzyme and

transporter Inhibition

Victims - absorption (ATV);

induction

RilpivirineVictim of enzyme inhibition and

induction. Also absorption.

RaltegravirVictim of absorption and a few

induction interactions

EVG/cobiPerpetrator – enzyme and

transporter inhibition

Victim - absorption; induction

DolutegravirVictim of absorption and a few

induction interactions.

Perpetrator of renal interaction

Bictegravir

Victim of absorption and some

induction/inhibition interactions.

Also consider TAF

EfavirenzPerpetrator – enzyme and

transporter induction

NRTIsVictim of some transporter

mediated interactions.

TDF & TAF > ABC, 3TC, FTC

The Potential of ARVs to Interact

Based on www.hiv-druginteractions.org

Selected Interactions for Boosted Regimens

(PI/r; PI/c; EVG/c) - Perpetrator

Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012, www.hiv-druginteractions.org

Drug class Comment

Corticosteroids Risk of Cushing syndrome.. Risk not just oral but inhaled, eye drops,

injection, topical. Triamcinolone, budesonide, fluticasone, mometasone

contra-indicated.

Antidepressants Avoid tricyclics - can cause anticholinergic effects, sedation

Benzodiazepines Caution. AEs increased . Use lowest dose for short duration. Midazolam,

triazolam contraindicated.

Chemotherapy

drugs

Increased risk of chemo related toxicities.

Anticoagulants;

Vit K antagonists

Monitor INR. Dose adjustment may be required if switching from ritonavir to

cobicistat.

Direct acting

anticoagulant

(DOAC)

Significant effect expected (limited data). Recommended - avoid with

boosted regimens

Calcium channel

blockers

Potential hypotensive effect. Start with lowest dose and titrate.

Statins 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

Antiretroviral Contraindicated Titrate Dose No Dose Adjustment

EFV AtorvastatinSimvastatinPravastatinLovastatin

PitavastatinRosuvastatin

RPV All

DRV/RTVDRV/COBI

LovastatinSimvastatin

AtorvastatinPravastatin

Rosuvastatin

Pitavastatin

EVG/COBI/FTC/TAF LovastatinSimvastatin

AtorvastatinRosuvastatin

RosuvastatinPitavastatin

EVG/COBI/FTC/TDF LovastatinSimvastatin

AtorvastatinRosuvastatin

RosuvastatinPitavastatin

DTG or RAL or BIC All

Drug-Drug Interactions With First-line

ART and Lipid-Lowering Therapy

From www.hiv-druginteractions.org and DHHS Adult Guidelines. October 2017. US Food and Drug Administration

Help is at hand!

Overview

DDIs – the Problem

Integrase Inhibitors: Similarities and Differences

1

2

Integrase Inhibitors and TB Therapy3

Integrase Inhibitors and HCV Therapy4

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 (INI-

resistant)

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

Integrase Inhibitors:Profile

Selected DDI for Integrase Inhibitors

(RAL; DTG; EVG/c; BIC)

Smith JM et al. AIDS 2017, Burgess MJ et al. HIV AIDS 2015; Nachega JB et al. AIDS 2012, www.hiv-druginteractions.org

Drug Class Comment

Cations: ie

Antacids*,

Calcium; Iron

Integrase inhibitors bind to divalent cations in the g.i.tract which limits absorption.

Variable decrease in exposure with potential risk of

treatment failure.

Metformin 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 Rifampicin variably decreases DTG, EVG, BIC, RAL exposure.

Rifabutin Rifabutin decreases EVG and BIC exposure but no clinically

significant effect on DTG or RAL

*NOT omeprazole or other Proton pump inhibitors or H2 blockers

Victim

Victim

Victim

Perpetrator

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

Mechanism of Interaction specific to

Integrase Inhibitors: Chelation with Cations

Mg2+

Mg2+

Mg

MgIntegrase

Inhibitor

Binding of integrase

inhibitors

Dolutegravir + antacid 2h later

Dolutegravir alone

0 10 20 30 40 50 8060 70

2.0

1.8

1.6

1.4

1.2

1.0

0.8

0.6

0.4

0.2

0Mea

n D

TG

con

cent

ratio

n (µ

g/m

L)

26%

74%

Time (hrs)

Dolutegravir +antacid

Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Biktarvy SmPC 06/18

Impact of Mg++/Al++ Containing Antacid on the Plasma

Exposure (AUC and Cmin) of Integrase Inhibitors

Mg2+

Mg2+

RAL (bd)

AUC/Cmin

RAL (QD)

AUC/Cmin

EVG

AUC/Cmin

DTG

AUC/Cmin

BIC

AUC/Cmin

Antacid

(Al++/Mg++)

taken together

↓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;

Cmin = 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.

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

Genvoya SmPC 03/18; Tivicay SmPc 03/18.; Isentress SmPC 02/18; Biktarvy SmPC 04/18

Current Recommendations for Integrase Inhibitors

and Ca++ Containing Antacids/Supplements

Mg2+

Mg2+

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

Can be taken

together without

regard to food2.

1Important to note the difference in recommendation for the bd and QD dosing of raltegravir. The

QD dose gives a lower Cmin value than bd and the decrease in exposure with the calcium is ~50%.

2Note: 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)

The Calcium Content of Preparations can

be Highly VariablePreparation Calcium Carbonate1 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; 1Other forms of calcium include calcium citrate (better

absorbed) and calcium succinate.

Integrase Inhibitors and Metformin

1. GLUCOPHAGE SMPc 01/17; Tivicay SMPc 03/18; Song IH et al JAIDS 2016; 72: 400-407.

• Metformin for type-2 diabetes requires titration to optimize dosing.1

Blood UrineActive Tubular Secretion

OCT2

MATE1

Inhibition by:

Dolutegravir

Metformin

Metformin

Renal

tubular cell

Basolateral Apical

79%

Consider dose adjusting metformin when starting and stopping administration of

dolutegravir with metformin. Also dose adjust in moderate renal impairment.

Eur J Clin Pharmacol 2017; 73: 981-990

Metformin 15-30 ml/min 30-60 ml/min 60-90 ml/min 90-120 ml/min

IRDose (mg/12h)

AUC0-12h

(mg/L/h)

250

19

500

20

1000

26

1500

18

XRDose (mg/24h) 500 1000 2000*

*Max daily dose for XR

❑ 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.

Int J STD & AIDS 2017; 28: 1229-1233.

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

DDIs – the Problem

Integrase Inhibitors: Similarities and Differences

1

2

Integrase Inhibitors and TB Therapy3

Integrase Inhibitors and HCV Therapy4

Integrase Inhibitors and anti-TB Therapy

Co-administered

DrugRaltegravir Dolutegravir Elvitegravir/c Bictegravir

Rifampicin ↓RAL AUC 40%

Consider doubling

dose

↓DTG AUC 54%

Double dose of DTG

(+2NRTIs) in

absence of integrase

resistance

Not Triumeq

Contraindicated Contraindicated

(Also TAF

interaction)

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

Dooley KE et al CROI March 4-7 2018

Conclusion:

❑ DTG 50 mg BID during concomitant RIF-based TB therapy demonstrated high

efficacy and good immunological response through week 24.

❑ DTG Ctau was similar to DTG 50 mg QD without RIF

❑ 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 C24h (↓ 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 Cmin 72%;

Add additional

dose of DTG in

absence of

integrase

resistance.

↓DTG Cmin 54%;

↓RPV Cmin 80%;

Contra

indicated

↓RPV Cmin 80%;

↓CAB Cmin ~40%*;

Contra

indicated

Rifabutin

RFB 3 times per

week

RFB AUC: ↑

5.7-fold

RFB 3 times per

week

↓DTG Cmin 30%;

No dose

adjustment

necessary

↓DTG Cmin 30%;

↓RPV Cmin 48%;

Add additional

RPV 25mg

↓CAB Cmin 26%;

↓RPV Cmin ‘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 Ctrough is still

markedly reduced (by 80%).

Custodio J et al; CROI 2018; Abs 34.

Overview

DDIs – the Problem

Integrase Inhibitors: Similarities and Differences

1

2

Integrase Inhibitors and TB Therapy3

Integrase Inhibitors and HCV Therapy4

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 Protease

Inhibitors

Nucleos(t)ide

Polymerase

Inhibitors

Non-nucleoside

Polymerase

Inhibitors

NS5A Inhibitors

Specific Agents Simepravir

Paritaprevir

Grazoprevir

Glecaprevir

Voxilaprevir

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

HIV Drug Interactions. Available at: www.hiv-druginteractions.org (accessed Aug 2018).

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.

HCV DAAs and HIV Antiretrovirals: NRTIs and NNRTIs

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

SOF DAC 3D G/P SOF/VEL

NR

TIs

Abacavir ◆ ◆ ◆ ◆ ◆

Emtricitabine ◆ ◆ ◆ ◆ ◆

Lamivudine ◆ ◆ ◆ ◆ ◆

Tenofovir (TDF)◼

◆ ◆ ◆ ◆ ◼

NN

RT

Is

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.

HCV DAAs and HIV Antiretrovirals: Protease Inhibitors

and Entry/Integrase Inhibitors

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

SOF DAC 3D G/P SOF/VEL

Pro

tease

inh

init

ors

ATV/r ◆ ◼ ◼ ⚫ ◆

DRV/r ◆ ◆ ◼ ⚫ ◆

DRV/c ◆ ◼ ⚫ ◼ ◆

Lopinavir/r ◆ ◆ ⚫ ⚫ ◆

Inte

gra

se

inh

ibit

ors

Dolutegravir ◆ ◆ ◆ ◆ ◆

E/C/F/TDF ◆ ◼ ⚫ ◆ ◼

E/C/F/TAF ◆ ◼ ⚫ ◆ ◆

Raltegravir ◆ ◆ ◆ ◆ ◆

Bictegravir ◆ ◆ ◼ ◼ ◆

EI

Maraviroc ◆ ◆ ◼ ◆ ◆

❑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

C, cobicistat; E, elvitegravir; F, emtricitabine; RBV, ribavirin; SOF, sofosbuvir; TAF, tenofovir alafenamide.

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

Potential Interactions of the 3D regimen

with other drugs the patient is taking.

HEP Drug Interactions. Available at: www.hep-druginteractions.org (accessed Aug 2017).

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?

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.