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Pharmacology considerations when choosing INSTIs
David Back
University of Liverpool
Salvador – August 2019
Disclosures
• Honoraria received for advisory boards and lectures from AbbVie, BMS, Gilead, Merck, ViiV, Janssen, Teva
• Educational grants for www.hiv-druginteractions.org, www.hep-druginteractions.org, and www.cancer-druginteractions.orgfrom AbbVie, BMS, Gilead, Janssen, Merck, ViiV, Astellas, AstraZeneca, Boehringer Ingelheim, BMS, Ipsen, Janssen, Pfizer, Roche, Sanofi
Google images
Since Salvador 2018!
Copa Americana Champions League
1. What are the Key Pharmacological Characteristics of
Integrase Inhibitors?
Google images
Spot the difference!
The Integrase Inhibitors – similar but different! STRUCTURE
Mg
Mg
Integrase
Inhibitor
Mechanism of Binding
White K,, CROI 2017 and Back D
The Integrase Inhibitors – similar but different! BINDING
Mg
Mg
Integrase
Inhibitor
Mechanism of Binding
White K,, CROI 2017 and Back D
Dissociation of INSTI from wild type IN-DNA Complexes
Note: A different method for estimating the dissociation half-life (by exponential decay) gives higher values (see Hightower et al AAC 2011; 55: 4552-4559.
The Integrase Inhibitors – similar but different! HALF LIFE
Podany A et al Clin Pharmacokinet 2017; 56: 25-40
Integrase Inhibitor Elimination Half-Life (hours)
Bictegravir ~18
Dolutegravir ~14
Raltegravir ~9
Elvitegravir/c ~12Time
Dru
g C
on
cen
trat
ion
in
Pla
sma
0 24(h)
Elimination half life
IQ = The number of times Ctrough is above the PA EC95
Time
Ctrough Ctrough
Dru
g C
on
ce
ntr
ati
on
in
Pla
sm
a
PA EC95
PA EC95
IQ
Drug Concentration Time-Curve at Steady State
Kabagambe et al. BHIVA 2019, O08; Podany AT et al Clin Pharmacokinet 2-17; 56: 25-40
Integrase Inhibitor Inhibitory Quotient (IQ)
Raltegravir 8
Elvitegravir/c 10
Bictegravir 16.1
Dolutegravir 17.0
The Integrase Inhibitors – similar but different! INHIBITORY QUOTIENT
The Integrase Inhibitors – similar but different! FORGIVENESS
Elliot E et al JAIDS 2016; 71:1031-1036
Dolutegravir
Elvitegravir
RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR
DOSE 400 mg BID*1200 mg QD
150 mg QD with cobi in FDC with F/TDF or F/TAF
50 mg QD alone or in FDC with ABC/3TC; also FDC with RPV
50 mg QD in FDC with FTAF
1. Isentress SmPC 29th Nov 2018; 2. Stribild SmPC 15th Nov 2018; 3. Tivicay SmPC 14th Feb 2019; 4. Biktarvy SmPC 2nd Nov 2018.
Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors - 1
BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl transferase 1A1.
RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR
DOSE 400 mg BID*1200 mg QD
150 mg QD with cobi in FDC with F/TDF or F/TAF
50 mg QD alone or in FDC with ABC/3TC; also FDC with RPV
50 mg QD in FDC with FTAF
METABOLISM UGT1A1 CYP3A (major), UGT1A1/3 (minor)
UGT1A1 (major), CYP3A (minor)
UGT1A1 and CYP3A (equal)
1. Isentress SmPC 29th Nov 2018; 2. Stribild SmPC 15th Nov 2018; 3. Tivicay SmPC 14th Feb 2019; 4. Biktarvy SmPC 2nd Nov 2018.
Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors - 1
BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl transferase 1A1.
RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR
DOSE 400 mg BID*1200 mg QD
150 mg QD with cobi in FDC with F/TDF or F/TAF
50 mg QD alone or in FDC with ABC/3TC; also FDC with RPV
50 mg QD in FDC with FTAF
METABOLISM UGT1A1 CYP3A (major), UGT1A1/3 (minor)
UGT1A1 (major), CYP3A (minor)
UGT1A1 and CYP3A (equal)
DRUG INTERACTION POTENTIAL (DDI)
Least Highest (due to booster)
Slightly greaterthan RAL
Slightly greater than RAL
1. Isentress SmPC 29th Nov 2018; 2. Stribild SmPC 15th Nov 2018; 3. Tivicay SmPC 14th Feb 2019; 4. Biktarvy SmPC 2nd Nov 2018.
Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors - 1
BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl transferase 1A1.
Comparative Tablet Size for Integrase Inhibitor-Containing Fixed Dose Regimens
Gaur A et al CROI 2018; Abs 844; Boston. USA
B/F/TAF 275 mg*; with or without food
E/C/F/TAF 510 mg*; with food
DTG/ABC/3TC 950 mg*; with or without food
*Active Drug
2. Are drug interactions really an issue in the Integrase era?
Antiretroviral Drug Approval 1987-2019
The Integrase Era
Back D; Personal communication
… when co-administration leads to safety, efficacy or tolerability issues greater than when drugs are administered alone.
When are Interactions of Concern?
Back DJ, personal communication
≈ 780 co-meds
No interaction Potential weak interaction
Interaction of clinical relevance Drugs should not be co-administered
n ≈ 780 Co-medications
Efavirenz Rilpivirine Doravirine
Boosted ARV BictegravirRaltegravir Dolutegravir
Etravirine
Interaction Profile of Antiretroviral Drugs: www.hiv-druginteractions.org
Available at: www.hiv-druginteractions.org.
▪ Retrospective, non-interventional cohort study.▪ DDI considered if ‘Do not co-administer’ statement in www.hiv-druginteractions.org▪ Annual healthcare costs were $16,219 for those without DDI and $19,784 for those
with DDI; unadjusted difference of $3564
Open Forum Infectious Diseases 2019 Mar 22;6(3):ofz051;.
Risk and Cost
Mechanisms of Interactions of Integrase Inhibitors
GI, gastrointestinal; P-gp, P-glycoprotein; BCRP, breast cancer resistance protein; OAT, organic anion transporter; MRP, multidrug resistance-associated protein; UGT, UDP-glucuronosyltransferase; PI, protease inhibitor; /r, ritonavir; /c, cobicistat.
Enzyme = CatalystTransporter = PumpVictim drugsPerpetrator drugs
Drug
Metabolite, M
Metabolite glucuronide, MG
Gut Lumen
Enterocyte
Portal Blood Hepatocyte Bile Duct
pH
BCRP
OATP1B1
OATP1B3
MRP3
MRP3
OATP1B3
OATP1B1
MRP2
MRP2
BCRP
P-gp
P-gp
BCRP
P-gp
CYP3A4
BCRP
P-gp
CYP3A4
M
M
CYPs M
UGTsMG
CYPsM
UGTs
MGChelation with
CationsIntegrase inhibitors
Induction, Inhibition of Hepatic Transporters; CYPs & UGTs
BIC, RAL; DTG; EVG
Induction, Inhibition of GITransporters, & CYP Enzymes
eg TAF + Rifampicin
Back DJ, personal communication
Some DDIs can Occur in the Kidney
OAT, organic anion transporter; OCT, organic cation transporter; MRP, multidrug resistance-associated protein; MATE, multidrug and toxin extrusion protein.
Song IH, et al. J Acquir Immune Defic Syndr 2016; 72(4):400–407;Custodio J, et al. Open Forum Infect Dis 2017; 4(Suppl1):S249.
Active tubular secretion
Basolateral(Blood) Apical
(Urine)
Tenofovir (TFV)
Creatinine
DolutegravirBictegravir
Mitochondria
OAT-1
OAT-3
OCT-2
MRP2
MRP4
MATE1
CobicistatRitonavir
Proximal tubule
Metformin
M e t f o r m i n i n P l a s m a
T i m e , h
Me
tf
or
min
C
on
ce
nt
ra
tio
n, n
g/m
L
0 4 8 1 2 1 6 2 0 2 4
1 0
1 0 0
1 0 0 0
1 0 0 0 0
P l a c e b o
B / F / T A FAUC + 39%
Bictegravir on Metformin
Dolutegravir on Metformin
AUC + 79%
Agent USPI
Dofetilide Contraindicated
Carbamazepine 50 mg twice daily in INSTI naive
Oxcarbazepine Should be avoided
Phenobarbital Should be avoided
Phenytoin Should be avoided
SJW Should be avoided
Rifampicin 50 mg twice daily in INSTI naive
Efavirenz 50 mg twice daily in INSTI naive
Fosamprenavir/r 50 mg twice daily in INSTI naive
Cation containing antacids DTG 2 h before or 6 h after
Oral iron/calcium
supplements
DTG 2 h before or 6 h after
Etravirine Should not be used without
ATV/r, DRV/r, or LPV/r
Metformin Close monitoring; limit total daily
dose
Tivicay USPI; Tivicay SmPC; Tivicay JPI (all accessed January 2019);recommendations where there is known/considered interaction.
Dolutegravir is a VICTIM of interactions
except dofetilide and metformin
* Or absence of integrase resistance; ** Japan label differs from the USPI and the SmPC;SJW, St. John’s Wort; /r, ritonavir; INSTI, integrase strand transfer inhibitor; DTG, dolutegravir; ATV, atazanavir; DRV, darunavir; LPV, lopinavir; bPI, boosted-protease inhibitors.
Established and Other Potentially Significant DDIs: Dolutegravir
Note: ORANGE means an interaction of potential clinical relevance – need to do something! It does not mean do not give!
Agent USPI SmPC
Dofetilide Contraindicated Contraindicated
Carbamazepine 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive
Oxcarbazepine Should be avoided 50 mg twice daily in INSTI naive
Phenobarbital Should be avoided 50 mg twice daily in INSTI naive
Phenytoin Should be avoided 50 mg twice daily in INSTI naive
SJW Should be avoided 50 mg twice daily in INSTI naive
Rifampicin 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive
Efavirenz 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive
Fosamprenavir/r 50 mg twice daily in INSTI naive No dose adjustment in INSTI naïve*
Cation containing antacids DTG 2 h before or 6 h after Antacid 2 h after or 6 h before
Oral iron/calcium
supplements
DTG 2 h before or 6 h after Antacid 2 h after or 6 h before
Etravirine Should not be used without
ATV/r, DRV/r, or LPV/r
Use 50 mg twice daily without a bPI.
Should not be used without bPI in
INSTI resistant.
Metformin Close monitoring; limit total daily
dose
Dose adjustment should be considered
Tivicay USPI; Tivicay SmPC; Tivicay JPI (all accessed January 2019);recommendations where there is known/considered interaction.
Dolutegravir is a VICTIM of interactions
except dofetilide and metformin
* Or absence of integrase resistance; ** Japan label differs from the USPI and the SmPC;SJW, St. John’s Wort; /r, ritonavir; INSTI, integrase strand transfer inhibitor; DTG, dolutegravir; ATV, atazanavir; DRV, darunavir; LPV, lopinavir; bPI, boosted-protease inhibitors.
Established and Other Potentially Significant DDIs: Dolutegravir
Different wording/
recommendation
✓
✓
✓
✓
Agent USPI SmPC Japan PI
Dofetilide Contraindicated Contraindicated Pilsicainide – Caution**
Carbamazepine 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive
Oxcarbazepine Should be avoided 50 mg twice daily in INSTI naive – **
Phenobarbital Should be avoided 50 mg twice daily in INSTI naive Caution**
Phenytoin Should be avoided 50 mg twice daily in INSTI naive Caution**
SJW Should be avoided 50 mg twice daily in INSTI naive Caution**
Rifampicin 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive
Efavirenz 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive 50 mg twice daily in INSTI naive
Fosamprenavir/r 50 mg twice daily in INSTI naive No dose adjustment in INSTI naïve* Do not use in InH-resistant pts
Cation containing antacids DTG 2 h before or 6 h after Antacid 2 h after or 6 h before DTG 2 h before or 6 h after
Oral iron/calcium
supplements
DTG 2 h before or 6 h after Antacid 2 h after or 6 h before DTG 2 h before or 6 h after;
BUT with food at same time**
Etravirine Should not be used without
ATV/r, DRV/r, or LPV/r
Use 50 mg twice daily without a bPI.
Should not be used without bPI in
INSTI resistant.
Use 50 mg twice daily without a bPI.
Do not use without either ATV/r,
DRV/r, or LPV/r in INSTI resistant.
Metformin Close monitoring; limit total daily
dose
Dose adjustment should be considered;
particularly in renal impairment
Administer with care; reduce dose
as necessary**
Tivicay USPI; Tivicay SmPC; Tivicay JPI (all accessed January 2019);recommendations where there is known/considered interaction.
✓
Dolutegravir is a VICTIM of interactions
except dofetilide and metformin
* Or absence of integrase resistance; ** Japan label differs from the USPI and the SmPC;SJW, St. John’s Wort; /r, ritonavir; INSTI, integrase strand transfer inhibitor; DTG, dolutegravir; ATV, atazanavir; DRV, darunavir; LPV, lopinavir; bPI, boosted-protease inhibitors.
Established and Other Potentially Significant DDIs: Dolutegravir
✓
CPT 2019; 105: 505-514
38 drugs selected – approved between 2008-2016;1727 co-meds documented in at least one label (average or 45 per study drug).
Message
DDIs
↑ Pill burden↓ Medication adherence↑ Prescribing cascade errorMultimorbidity
Polypharmacy(Inc non-prescription
drugs/supplements etc)
‘Polydoctory’
Reduced efficacy of HIV agent?
Reduced efficacy of co-medications?
Adverse effect?Perpetrator
Victim
Co-medARV
Cost
• DDIs may still be an issue in some patients on INSTIs – (older patients; polypharmacy; EVG/c).
Back DJ, personal communication
3. Which co-meds should we be alert for?
Integrase Inhibitors: Contraindications or Do Not Coadminister*
Raltegravir (n=1) Dolutegravir (n = 7) E/C/F/TAF (n= 55) B/F/TAF (n= 15)
Al++/Mg++ antacids Dofetilide; Eslicarbazepine; Oxcarbazepine; Phenobarbitone;Phenytoin; Primidone; St John’s Wort
Dextropropoxyphene;Amiodarone; Disopyramide; Quinidine; Dofetilidie; Rifampicin; Rifapentine; Apixaban; Clopidogrel; Dabigatran; Rivaroxaban; Ticagrelor; Carbamazepine; Phenobarbitone; Phenytoin; Primidone; Astemizole; Terfenadine; Dihydorergotamine; Ergotamine; Halofantrine; Pimozide; Quetiapine; Adefovir; Boceprevir; Elbasvir/Grazoprevir; OBV/PTV/r;OBV/PTV/r + DSV; Simeprevir; Telaprevir; TAF (HBV); Midazolam; Everolimus; Avanafil; Cisapride; Domperidone; St John’s Wort; Aliskiren; Eplerenone; Ivabradine; Lercanidipine; Ranolazine; Sildenafil; Sirolimus; Lovastatin; Simvastatin; Alfuzosin; Fibanserin; Darifenacin; Ergometrine; Budesonide; Fluticasone; Mometasone; Triamcinolone
Dofetilide; Rifabutin; Rifampicin; Rifapentine; Carbamazepine; Oxcarbazepine; Phenobarbitone;Phenytoin; Primidone; St John’s Wort; Adefovir; Boceprevir; Telaprevir;
Relevant prescribing information and www.hiv-druginteractions.org
* Excluding ARV-ARV
Top 20 Global Co-medication Searches 2018: Liverpool database
PPI, proton-pump inhibitor.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Perpetrator Victim
No
of
Qu
erie
s
Statins
PPIs/H2 blockers
Antidiabetics
Analgesics
Antihypertensives
Anti-infectives
Psychotropic drugs
AntiplateletsAnticoagulants
HIV DDIs searched: 2018
Website 3.08M;76%
App955K24%
60,000
50,000
40,000
30,000
20,000
10,000
Top 20 Co-medications Generating the Most DDI Queries in www.hiv-druginteractions.org (MixPanel Analytics).
Relevant for unboosted INI
Out of the Top 20 searches – 2 relevant for non-boosted INSTIs
Therefore, we suggest that physicians remain vigilant in monitoring for toxicity and limit the total daily dose of metformin to 1000 mg when metformin is taken concomitantly with dolutegravir, and suggest avoidance of this combination in patients at highest risk for metformin-associated lactic acidosis, such as elderly patients with suboptimal renal function.
Gervasoni C et al JAIDS 2017; 75: e24-26
Cattaneo D et al AIDS 2018; 32: 532-533
Naccarato M et al AIDS 2017; 31: 2176-2177.
#1. Drug Interactions with Statins
ATV, atazanavir; DRV, darunavir; EFV, efavirenz; DOR, doravarine; RAL raltegravir; DTG, Dolutegravir; BIC, bictegravir; EVG, elvitegravir; /c, cobicistat; /r, ritonavir; F, FTC; TAF, tenofovir alafenamide
www.hiv-druginteractions.org.
• Statins are Victims of DDIs.
• Increased exposure (eg boosted regimens) gives potential statin-associated muscle symptoms plus other side effects; reduced exposure (eg EFV) possible loss of efficacy
Agent ATV/r DRV/r DRV/c EFV DOR RAL DTG BIC/F/TAF EVG/c
Atorvastatin
Fluvastatin
Pitavastatin
Pravastatin
Rosuvastatin
Simvastatin
No interaction Potential weak interaction
Interaction of clinical relevance Drugs should not be co-administered
#1. However…
NRTI, nucleoside reverse transcriptase inhibitor; TC, total cholesterol . Myers J, et al. HIV Med 2018; 13:190–192
• Note: raltegravir, dolutegravir, bictegravir, doravarine & NRTIs do not interact with statins.
• Be careful re suboptimal dosing due to concern of DDI.
#2. DDIs with Proton Pump Inhibitors
No interaction Drugs should not be co-administered
Agent ATV/r DRV/r or DRV/c
RPV EFV DOR RAL DTG BIC/F/TAF EVG/c
Omeprazole *
Pantoprazole *
ATV, atazanavir; DRV, darunavir; EFV, efavirenz; DOR, doravarine; RAL raltegravir; DTG, Dolutegravir; BIC, bictegravir; EVG, elvitegravir; /c, cobicistat; /r, ritonavir; F, FTC; TAF, tenofovir alafenamide www.hiv-druginteractions.org.
* But note Dolutegravir/Rilpivirine!
#2. DDIs with Proton Pump Inhibitors + H2 Antagonists
No interaction Drugs should not be co-administered
Agent ATV/r DRV/r or DRV/c
RPV EFV DOR RAL DTG BIC/F/TAF EVG/c
Omeprazole *
Pantoprazole *
Ranitidine *
Interaction of clinical relevance
www.hiv-druginteractions.org.
* But note Dolutegravir/Rilpivirine!
#2. DDIs with PPIs + H2 Antagonists + Antacids
No interaction Drugs should not be co-administered
Agent ATV/r DRV/r or DRV/c
RPV EFV DOR RAL DTG BIC/F/TAF EVG/c
Omeprazole
Pantoprazole
Ranitidine
Antacids
(cations)
Interaction of clinical relevance
www.hiv-druginteractions.org.
• All the integrase inhibitors are affected by cation containing antacids BUT there are different recommendations dependent on the integrase inhibitor and the cations (Al++/Mg++ vs Ca++) and food effect.
• Separation of the antacid by +/- 2 hours (or greater) reduces the interaction for DTG, EVG and BIC but doesnot reduce interaction for RAL (qd). RAL (bid) can be used with Ca++ antacid.
Refer to the USPI or SmPC for full prescribing information
#2. However…
4. What about these drugs?
Gender Affirming Steroids
www.hiv-druginteractions.org.
5. What about these patients?
Case: Clinical Characteristics
Nationality Caucasian
Age 62 years
BMI 20.1
HIV History Recently diagnosed with HIV; VL 105,000 cps/ml
CD4 520 cell/ul
HLA-B*5701 Negative
Chronic HBV No
Any history of drug resistance No
Renal function eGFR 50 ml/min
ComorbiditiesComplex medical history, multiplewell-controlled comorbidities, including hypertension, atrial fibrillation, diabetes, GERD
♂
GERD: Gastroesophageal reflux disease
Case: Co-medications
www.ncmedsoc.org; www.fda.gov.
Calcium channel blockers Amlodipine 10 mg
Lipid-lowering agent Atorvastatin 20 mg
New Oral Anticoagulant Dabigatran 150 mg twice daily
Antiarrthyhmic Digoxin 125µg/day
Antidiabetic Sitagliptin 50 mg
Proton-pump inhibitor Omeprazole 20 mg
Antidepressant Quetiapine 300 mg/day
Are you concerned about the DDIs with a first line integrase based regimen?
Case: Interactions of Integrase Inhibitors with the co-meds
No interaction Interaction of clinical relevance Drugs should not be co-administered
www.hiv-druginteractions.org
44
Case: Interactions of Integrase Inhibitors with the co-meds
▪ Other considerations:
• ABC/3TC/DTG not recommended (renal function);
• Also need to consider abacavir and cardiovascular risk.
• Recommend BIC/F/TAF or DTG + F/TAF or RAL + F/TAF
Expert opinion of the presenter
What would you do?
A 48 year old male has recently been referred to your clinic. His HIV viral load has been
suppressed on DTG/ABC/3TC for more than 1 year. He is receiving the following co-
medications for depressive psychosis; quetiapine, risperidone, olanzapine, mirtazapine,
oxcarbazepine. You immediately note that the recommended dosing for dolutegravir is
bd when oxcarbazepine is present. However his VL is suppressed and there are no
recorded blips. What do you do?
A.Nothing. It’s not broke – no need to fix it!
B.Add an additional DTG so that the regimen is now BID.
C.Consider an alternative to oxcarbazepine.
D.Switch to B/F/TAF
Always refer to the SmPC for all products for recommendations on managing potential DDIs
What would you do?
A 54 year old male with HIV who is well controlled on once daily
Dolutegravir, TAF/FTC has now developed Hansen’s disease and requires
rifampicin once a month. What do you do?
A.Nothing! Maintain HIV regimen without change.
B.Maintain QD DTG but switch TAF/FTC to TDF/FTC
C.Increase the DTG dose to 50 mg twice daily.
D.Increase the DTG dose to 50 mg twice daily for 1 week and then
continue on 50 mg once daily for the rest of the month.
E.Not at all sure!
Hansen’s disease (also known as leprosy) is an infection caused by bacteria called Mycobacterium leprae. These bacteria grow very slowly and it may take up to 20 years to develop signs of the infectionref: https://www.cdc.gov/leprosy/about/about.html accessed July 2019
Advice for Clinicians• DDIs are practically unavoidable in HIV care – there are many more with boosted
regimens and efavirenz.
• Be aware of the relatively few interactions with unboosted integrase inhibitors..
• Older patients particularly at risk: age-related co-morbidities and physiological changes.
• Managing interactions is the key
• Searchable online Drug Interaction checkers are a vital resource.
• Other key areas going forward:
Determine impact of eliminating medications
not essential for quality of life in older PLWH
1
Understand the implications for DDIs of
Long acting ARVs
2
Its all about Teamwork!
Liverpool Website Team & Editorial Board
Katie MossLiverpool
Katie McAllisterLiverpool
Justin ChiongLiverpool
Jasmine MartinLiverpool
Fiona MaraGlasgow
Jonathan SchapiroTel Aviv - Glasgow
Charles FlexnerBaltimore
Mohammed LamordeKampala
David BurgerNijmegen
Mas ChapondaLiverpool
Catia MarzoliniBasel
David BackLiverpool
Saye KhooLiverpool
Sara GibbonsLiverpool
Marta BoffitoLondon
Spanish and Portuguese versions of the website coming SOON
In Numbers: www.hiv-druginteractions.org
• Accessed from 188 countries across the world
• In the past 3 years around 8.5M DDIs have been downloaded,~ 4M in 2018
• Year-on-year increase in usage (+ ~20%)
• UK Standards require every GP letter to carry the URL
• Recommended tool for over 30 national or international HIV guidelines
• Translations: Japanese (HEP) in 2017, Spanish (HIV) version to launchDec 2019 and Portuguese (HIV) in Q1 2020.
• Database linkage for electronic prescribing in Uganda and Australia
Back Ups
Summary of Bictegravir Concentration (C24) Changes After Various Antacid/Supplement Co-administration Conditions
The effects on BIC PK and IQ were limited when antacids/supplements were administered either simultaneously with B/F/TAF under fed conditions or staggered from B/F/TAF administration by ± 2 h under fasted conditions
511. Lutz JD, et al. International Workshop on Clinical Pharmacology of Antiviral Therapy 2018, poster 6. Kabagambe, BHIVA, 2019, O08
0
20
0
25
50
75
100
125
Fasted Fed 2 hBefore
2 hAfter
Fasted Fed Fasted Fed%G
LS
M R
atio
(9
0%
CI)
fo
r B
IC C
24
47
16.1
7.6
Ca + B/F/TAFAI/Mg + B/F/TAF Fe + B/F/TAF
Pre
dic
ted IQ
in H
IV-1–In
fecte
d P
atie
nts
Refer to the SmPC for prescribing advice
RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR
RENAL
ELIMINATION
RENAL
ELIMINATION
~32% of dose (mainly glucuronide)
No dose
adjustment
Minimal; ~7%
eGFR > 30 (Genvoya)
eGFR > 70 (Stribild)
~31% of dose(primarily metabolites)
No dose adjust
(DTG)
eGFR > 50
(Triumeq)
~35% of dose (primarily metabolites)
eGFR > 30
(Biktarvy)
1. Isentress SmPC 29th Nov 2018; 2. Stribild SmPC 15th Nov 2018; 3. Tivicay SmPC 14th Feb 2019; 4. Biktarvy SmPC 2nd Nov 2018.
Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors - 1
BID, twice daily; QD, once daily. CYP3A, cytochrome P450 3A4; UGT1A1; uridine glucuronyl
transferase 1A1.
RALTEGRAVIR ELVITEGRAVIR DOLUTEGRAVIR BICTEGRAVIR
CSF/Plasma
ratio
0.03a - 0.06b 0.003c 0.02d 0.003e
Semen/Plasm
a ratio
1.6-6.5f
1.8g
0.4h 0.08i No data
Breast Milk
/Plasma ratio
No data No data 0.02k No data
Other Key Pharmacological Characteristics of the Individual Integrase Inhibitors – 2. PENETRATION
aJohnson DH et al; PLOS ONE 2013; 8: e82672; bCalcagno A et al AIS Res Hum Retro 2016; 32: 409-411. c Croteau D et al AAC 2010; 56: 5156-5160; d Greener BN et al JAIDS 2013; 64: 39-44; e Tiraboschi J et al CROI 2019
Abs 474; f Calcagno A et al AAC 2010; 54: 2744-2745; g Le MP et al Pharmacotherapy 2019; [ahead of print]; h Imaz A et al HIV Med 2017; 18: 225-230; i Imaz A et al; JID 2016; 214: 1512-1519; k Kobbe R et al AIDS 2016; 30:
2731-2735;