DRUG INTERACTIONS IN HIV PATIENTS

DR SAMEER ABDUL SAMAD

DR JATIN AHUJA
DRUG INTERACTIONS IN HIV PATIENTS
▪ Absorption Interactions
▪ Drug-Drug Interactions
▪ Absorption
▪ Transport
▪ Metabolism
▪ Excretion

▪ Drug Interaction with Complementary & Alternative Medicines

▪ Ageing and Comorbidities
▪ Chemsex
TREND OF ANTI-RETROVIRAL THERAPY
 THE SWISS HIV COHORT STUDY
▪ Ongoing, multicentre longitudinal study
▪ Established in 1988
▪ 68% of patients (n = 1500) were receiving other types of medications in addition to
ART
▪ 40% of participants had atleast one potential drug- drug interaction
▪ Cardiovascular medications were among the most commonly co-administered
drugs(56%)

1. Foy M, Sperati C, Lucas G, Estrella M. Drug Interactions and Antiretroviral Drug Monitoring. Current
HIV/AIDS Reports. 2014;11(3):212-222.
COMMONLY USED ANTIRETROVIRAL
DRUGS
FIRST LINE ART SECOND LINE ART( 2NRTIS + PI)
NRTIs Ritonavir boosted Protease Inhibitors
 Tenofovir ▪ Atazanavir/ritonavir
 Zidovudine
▪ Lopinavir/ritonavir
 Lamivudine THIRD LINE ART( INSTI, PI, 2ND
GEN NNRTI)
 Abacavir
 Emtricitabine
Integrase Inhibitors
NNRTIs
 Efavirenz ▪ Raltegravir
 Nevirapine ▪ Dolutegravir
INSTI – Integrase Strand Transfer Inhibitors
1. www.naco.gov.in NRTIs – Nucleoside Reverse Transcriptase Inhibitors
NNRTI – Non-Nucleoside Reverse Transcriptase Inhibitors
2. www.who.in PI – Protease Inhibitors
ABSORPTION LEVEL INTERACTIONS
STOMACH ACIDITY & DRUG ABSORPTION
 Acidic environment
 Tenofovir - With Food
 Food
 Lamivudine – Food decreases Cmax but overall exposure unaffected
 Citrus juices - orange,
 Zidovudine - -------
lemon
 Abacavir – Food delays absorption (lowers Cmax but overall exposure unaffected)
 Didanosine is poorly
 Efavirenz – Fat increases absorption, leads to increased drug levels and toxicities
soluble in acidic
 Nevirapine - -------
environment
 Atazanavir, Lopinavir, Ritonavir – With Food
 “Empty stomach” – 2
 Raltegravir – Variable effects with food
hours before or 2 hours

www.nia.nih.gov after meals

www.nia.nih.gov
www.hiv.va.gov
www.hiv.va.gov
DRUG DRUG INTERACTIONS
IN HIV PATIENTS
DRUG-DRUG INTERACTIONS
▪ Level of Absorption
▪ Level of Transport
▪ Level of Metabolism
▪ Level of Excretion

Drug
B
#Absorption
#Transporter
#Metabolic
Enzymes
#Excretion
 ABSORPTION LEVEL INTERACTIONS
INVOLVING OTHER DRUGS
▪ Protease inhibitors need stomach acid to facilitate absorption

▪ Integrase inhibitors – absorption is inhibited by antacids due to chelation

▪ PPIs, Magnesium trisilicate increase didanosine absorption - ?toxicity

www.hiv-druginteractions.org
 LEVEL OF ABSORPTION
H2 RECEPTOR PROTON PUMP
DRUG ANTACID
ANTAGONISTS INHIBITORS
ATAZANAVIR REDUCE ABSORPTION REDUCE ABSORPTION REDUCE ABSORPTION
LOPINAVIR ( RAISED pH) ( RAISED pH)
RITONAVIR
RALTEGRAVIR,
DOLUTEGRAVIR
REDUCE ABSORPTION
(BY CHELATION)
DIDANOSINE INCREASE ABSORPTION INCREASE ABSORPTION INCREASES ABSORPTION

www.hiv.va.gov
www.hiv-druginteractions.org

ART – AntiRetroviral Therapy DDI – Drug Drug Interactions

 LEVEL OF TRANSPORT

Hoosain F, Choonara Y, Tomar L, Kumar P, Tyagi C, du Toit L et al. Bypassing P-Glycoprotein Drug
Efflux Mechanisms: Possible Applications in Pharmacoresistant Schizophrenia Therapy. BioMed
Research International. 2015;2015:1-21.
P-gp – P-glycoprotein BCRP – Breast Cancer Resistance Protein MRP – 2 – Multidrug Resistance associated Protein 2
Bailey D. Natural products and adverse drug interactions. Canadian Medical
Association Journal. 2004;170(10):1531-1532.
 P-GP (P-
GLYCOPROTE
IN) IS A KEY
EFFLUX PUMP
IN MOST
ORGANS

It is an ATP Binding
Cassette Protein
(“ABC”)

Borst P, Schinkel A. P-glycoprotein ABCB1: a

major player in drug handling by mammals.
Journal of Clinical Investigation.
2013;123(10):4131-4133.
 P-GLYCOPROTEIN SUBSTRATES, INDUCERS &
INHIBITORS

SUBSTRATES INHIBITORS INDUCERS

• Tenofovir INHIBITORS
• SUBSTRATES
• Ritonavir
• Itraconazole
• Rifampicin
Indinavir
• Ranitidine
• Nelfinavir • Saquinavir • Rifabutin
• Quinidine
• •Saquinavir
Tetracycline • Nelfinavir
• Verapamil • Carbamazepine
• •Dolutegravir
Verapamil • Carvedilol
• Ledipasvir
• •Itraconazole
Rifaximine • Atorvastatin • Phenytoin
• •Morphine
Fexofenadine • Rifaximine • Morphine
• •Methyl
Sofosbuvir
Prednisolone • Azithromycin • Dexamethasone
• Ledipasvir
• Dexamethasone • Clarithromycin • Clotrimazole
• Domperidone

1.Kim R. Drugs as P-glycoprotein substrates, inhibitors, and inducers. Drug Metabolism Reviews. 2002;34(1-2):47-54.
2.www.hiv-druginteractions.org
PLASMA PROTEIN BINDING
▪ Occurs with a combination of
▪ Albumin
▪ Glycoprotein
▪ Lipoprotein
▪ Globulins

▪ Protein bound drug cannot

▪ Distribute
▪ Be metabolised
▪ Excreted

▪ This binding is Non-Covalent and readily reversible

PLASMA PROTEIN BINDING
▪ The ratio of free to bound drug remains in a steady equilibrium

▪ As more drug is used, more drug is released from the plasma proteins

www.hiv-druginteractions.org
DRUG METABOLISM & EXCRETION
 Drug Metabolism & Excretion
HEPATIC RENAL
CLEARANCE CLEARANCE
Hepatic Clearance
Renal Clearance

1.Metabolism 1.Filtration
2.Transport 2.Active Transport
 Drug Metabolism & Excretion
Hepatic Clearance
Renal Clearance

Hepatic
Clearance

Metabolism Transporter

PHASE I PHASE II UPTAKE BILIARY

Eg. OATP1B1, TRANSPORT
Eg. CYP Eg. UDP Efflux out of
Glucuronyl OATP1B3
Hepatocyte
Transferase Eg. BCRP,
P-glycoprotein
 Drug Metabolism & Excretion
Hepatic Clearance
01 02

Renal Clearance
Renal Clearance

FILTRATION ACTIVE
Only unbound drug is TRANSPORT
- SECRETION &
readily filtered REUPTAKE FROM
Large Drugs like Heparin or PROXIMAL
Plasma protein bound drugs CONVOLUTED
Eg. Organic Cation Transporter
TUBULE
are not filtered Organic Anion Transporter
MRP2, MAT1, Pgp
 AT THE LEVEL OF METABOLISM
▪ Cytochrome P450 is a superfamily of Heme enzymes which catalyse a variety of
reactions Eg.Hydroxylation
? Peak absorption wavelength is 450nm

▪ So the drug can start getting metabolised in the Enterocyte

1.Bailey D. Natural products and adverse drug interactions. Canadian Medical Association Journal. 2004;170(10):1531-1532.
2.www.hiv-druginteractions.org
www.hiv-druginteractions.org
YP 3A INDUCERS AND INHIBITO
STRONG INDUCER
MODERATE INDUCER
CARBAMAZEPINE
BOSENTAN
PHENYTOIN
EFAVIRENZ
RIFAMPICIN

STRONG INHIBITOR
RITONAVIR MODERATE & WEAK
INHIBITOR
COBICISTAT
RANITIDINE
AZOLES
GRAPE FRUIT JUICE

www.hiv-druginteractions.org
 INDICATOR OF SEVERITY OF DRUG
INTERACTION

AUCdrug in presence of perpetrator

Severity of DDI =
AUCdrug alone

AUC – Area Under CurveDDI – Drug Drug Interaction www.hiv-druginteractions.org

KEY TO DRUG INTERACTIONS

No clinically significant interaction

expected
Potential weak interaction –
monitoring/dose adjustment unlikely to
be required

Potential Interaction – may require close

monitoring or dose/timing adjustment

These drugs should not be coadministered

 ANTIRETROVIRAL VS ANTIBACTERIALS

P-gp inhibition
Decrease in
Zidovudine renal
clearance

Competition for
renal clearance QT Prolongation

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIFUNGALS

Fluconazole increases
N AUC of Nevirapine,
Zidovudine
E
P
H
R
O
T
O
X
I
C
I
T
Y

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTITUBERCULAR
DRUGS

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIPARASITE

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIVIRALS

Exacerbation of
anaemia

www.hiv-druginteractions.org
DRUG-DRUG INTERACTIONS AMONG ARVS

www.hiv-druginteractions.org ARVs – Anti RetroVirals www.hiv-druginteractions.org

AGEING AND COMORBIDITIES
AGE ASSOCIATED CHANGES IN
PHARMACOKINETICS
▪ As age advances
 Hepatic mass and Hepatic blood flow decrease Decreases Hepatic
Clearance

Decrease in Renal blood flow and GFR Decreases Renal Clearance

Changes in affinity of some drugs to receptors / changes in number of

receptors

Eg. Sensitivity to Benzodiazepines & opioids increases

Antihypertensives cause Orthostatic Hypotension

www.hiv-druginteractions.org
COMORBIDITIES
▪ In Chronic Kidney Disease – Uremic toxins accumulate in blood bind to
receptors which activate signalling pathways repress CYP transcription

Reduces CYP mediated metabolism

www.hiv-druginteractions.org
ANTIRETROVIRAL VS PROTON PUMP
INHIBITORS

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIDIABETIC
DRUGS

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIHYPERTENSIVES

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIPLATELETS,
ANTICOAGULANTS & FIBRINOLYTICS

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIEPILEPTICS

www.hiv-druginteractions.org
ANTIRETROVIRAL VS LIPID LOWERING
AGENTS

www.hiv-druginteractions.org
 ANTIRETROVIRAL VS STEROIDS,
CONTRACEPTIVES/HORMONE REPLACEMENT THERAPY

Adrenal axis suppression even with

ocular topical administration

www.hiv-druginteractions.org
ANTIRETROVIRAL VS ANTIARRHYTHMICS

www.hiv-druginteractions.org
COMPLEMENTARY & ALTERNATIVE
MEDICINES
INTERACTING WITH ART
HERBALS
▪ Can have interactions at transporter level or metabolism level

www.hiv-druginteractions.org
 • Synthetic prescription drugs as chemical adulterants
- potential interaction
• Eg. Sildenafil added to enhance sexual performance

C– interact with boosted PIs

B
megha”
increased concentration of sildenafil
A
• Mineral supplements: Ca , Mg , Fe , Cu , Se
2+ 2+ 2+ 2+ 2-
-
Impair absorption of Integrase inhibitors by forming
complexes
4 inhibition by
Cobicistat
• Integrase inhibitors administered 2 hours before
duction – no
raction with
d PIs mineral supplementation attenuates the interaction
CHEMSEX
 CHEMSEX
▪ “Party Drugs” or “Club Drugs”
▪ MDMA (Methylene Dioxy Methamphetamine “Ecstasy”)
▪ Ketamine
▪ Benzodiazepine
▪ Methamphetamine partially metabolized by CYP2D6
▪ GHB( Gamma Hydroxy Butyrate) Substrate of CYP3A4
▪ Mephedrone metabolized by CYP2D6
▪ Erectile Dysfunction Agents
▪ “Slamsex” - these drugs injected
▪ Smoking leads to decreased adherence to ART & decreased efficacy
of ART via CYP pathway
Kumar S, Rao P, Earla R, Kumar A. Drug–drug interactions between anti-retroviral therapies and drugs of
abuse in HIV systems. Expert Opinion on Drug Metabolism & Toxicology. 2014;11(3):343-355. www.hiv-druginteractions.org
 ANTIRETROVIRALS VS ILLICIT DRUGS

Methylene Dioxy MethAmphetamine GHB – Gamma Hydroxy Butyrate LSD – Lysergic Acid Diethylamide
www.hiv-druginteractions.org
 Drug-Drug Interactions
Unknown
Harmful Synergistic/
Effects Beneficial
Effects Effects
 Drug – Drug Interaction

Two major enzyme systems are most frequently responsible

for clinically significant drug interactions
1) Cytochrome P450 enzyme system : NNRTIs, PIs, MVC, and
the INSTI-EVG.
2) UGT 1A1 enzyme: INSTIs -DTG and RAL.

*Enhancers (Boosters): RTV/COBI

US Pharm. 2008;33
1) 45 year male, HIV infection diagnosed in 2006

• Currently on ATV/r + TDF/3TC

• Last CD4 = 560 cells/mm3 ,HIV RNA < 50 cpm
• Other medical history:
◦ IDU – last use 2005
◦ HBsAg +
◦ BMI = 29 kg/m2
• He presented to clinic in the past couple of months with BP around 150/90 mm Hg,
HR 70-80 per min.
Which of the following antihypertensive agents has the greatest potential for
interaction with his ART regimen (ATV/r + TDF/3TC)?

a. Telmisartan

b. Hydrochlorothiazide

c. Atenolol

d. Amlodipine

e. Diltiazem
 Atazanavir (+/- ritonavir) + Diltiazem

• Atazanavir +/- ritonavir – potent CYP3A4 inhibitor

• Diltiazem – CYP3A4 substrate
• When combined – > 2-fold inc. in diltiazem AUC
• Report of 2nd and 3rd degree AV block when ATV added to a stable diltiazem
regimen
• Use lowest diltiazem dose with close monitoring
Which of the following antihypertensive agents has the greatest potential for
interaction with his ART regimen (ATV/r + TDF/3TC)?

a. Telmisartan

b. Hydrochlorothiazide

c. Atenolol

d. Amlodipine

e. Diltiazem
2 ) 45 year Male, HIV infection diagnosed in 2006

• Currently on ATV/r + TDF/3TC

• Started on Telmisartan 20mg per day with good BP response

• 3 months later, he presented for follow-up, reported that a

couple of months ago, he has been suffering from acid reflux

• He bought some over-the-counter omeprazole with good

symptom relief

• CD4 remains stable at 600, but HIV RNA has increased to

7,000 copies/mL
 Reason for virological failure is

a) Interaction b/w Telmisartan and ATV/r

b) Omeprazole inhibiting the absorption of TDF and 3TC

c) Omeprazole decreased the ATV/r Cmax by 75%

d) Poor compliance to the ART

e) All of the above

Effect of decrease in drug absorption on ARV pharmacokinetics

Atazanavir w/
normal gastric ↑ Oral bioavailability
pH
(F)
↑ Cmax, ↑ Cmin
↔ T1/2

Atazanavir +
omeprazole
IC50

Time (Hours)
 Reason for virological failure is

a) Interaction b/w Telmisartan and ATV/r

b) Omeprazole inhibiting the absorption of TDF and 3TC

c) Omeprazole decreased the ATV/r Cmax by 75%

d) Poor compliance to the ART

e) All of the above

 3)
42 year old male, with h/o Type 2 DM, recently started on EFV/TDF/3TC

• Pre-ART CD4 = 100 cells/mm3 , HIV RNA = 150,225 copies/mL

• Tolerated ART x 4 weeks

• Presented with fever up to 102 F, eventual diagnosis was disseminated

histoplasmosis

• Received liposomal amphotericin B x 2 weeks, then switched to oral itraconazole

• Other medications: dapsone, telmisartan, metformin

 42/M with histoplasmosis

• The patient was discharged on Itraconazole 200mg twice daily

• Returned to clinic one week later with complaints of fever, fatigue, and shortness of
breath

• Urine histoplasma Ag rose from 2.5 IU at discharge to 10.5 IU

• Itraconazole conc. (trough) = 0.2 mcg/mL

What potential significant interaction would you expect?

a) Itraconazole may increase telmisartan concentration.

b) Itraconazole may significantly decrease efavirenz concentration.

c) Efavirenz may significantly reduce itraconazole concentration

d) Itraconazole may increase dapsone concentration

e) None of the above

Annals of pharmacology 43(5):908-13 · April 2009
What potential significant interaction would you expect?

a) Itraconazole may increase telmisartan concentration.

b) Itraconazole may significantly decrease efavirenz concentration.

c) Efavirenz may significantly reduce itraconazole concentration

d) Itraconazole may increase dapsone concentration

e) None of the above

 4) 45/M with HIV, stable on ARV of DRV/r + TDF/3TC

Despite changing to a healthier diet and increasing his exercise, lipid values remain
elevated:
TC: 268 mg/dL
LDL: 198 mg/dL
HDL: 35 mg/dL
TG: 220 mg/dL
Strong family history of CAD and his father had a myocardial infarction at age 52.
The patient does not want to consider modifying his antiretroviral regimen, but
agrees to start lipid-lowering therapy.
Which one of the following statins is/are contraindicated for use in this patient?

a) Simvastatin

b) Pravastatin

c) Atorvastatin

d) Lovastatin

e) Rosuvastatin
 PIs with statins (Simvastatin/Lovastatin)

1) To some degree, all PIs undergo metabolism via the CYP450 system and all inhibit
CYP system enzymes.

2) Use of PIs and statins can result in an increase in the level of the statin and enhance
the risk for statin-related adverse effects, such as rhabdomyolysis.
Which one of the following statins is/are contraindicated for use in this patient?

a) Simvastatin

b) Pravastatin

c) Atorvastatin

d) Lovastatin

e) Rosuvastatin
5) A 35/M with EPTB, recently diagnosed with HIV

• He was already on HRZE regimen for last 2 months and started

on TLE (ART) 3 weeks back
• Presented with symptoms of mental cloudiness, blurry vision
and ataxia.
• MRI of the brain showed nodular perivascular space
enhancement with surrounding vasogenic oedema and midline
shift

JC virus PCR positive in CSF

• His ART was changed from TLE to TDF/3TC/MVC

Which one of the following is TRUE regarding drug interactions between ART and
medications used to treat tuberculosis?

a) Maraviroc 300 mg twice daily can be used with rifampicin

b) Maraviroc 600 mg twice daily can be used with rifampicin

c) Maraviroc 150 mg twice daily can be used with rifampicin

d) None of the above

 Maraviroc (MVC)
• Elimination or metabolic pathway: CYP3A4 substrate

• Without Potent CYP3A Inhibitors or Inducers: 300 mg BID; reduce to 150 mg BID if
postural hypotension occurs.

• Dose increased to 600 BID when used with an enzyme inducer such as Rifampicin.

AIDSinfo (Last updated

May 30, 2018)
Which one of the following is TRUE regarding drug interactions between ART and
medications used to treat tuberculosis?

a) Maraviroc 300 mg twice daily can be used with rifampicin

b) Maraviroc 600 mg twice daily can be used with rifampicin

c) Maraviroc 150 mg twice daily can be used with rifampicin

d) None of the above

6) A 52-year-old woman with HIV infection

• is receiving an antiretroviral regimen of DRV/r + TDF/3TC.

• She has HCV coinfection with genotype 1

• Plan is to treat HCV with ledipasvir-sofosbuvir.

 What is the main concern related to potential drug interactions
if ledipasvir-sofosbuvir is used concomitantly with the
antiretroviral medications being taken by this woman?

a) Tenofovir levels may increase

b) Sofosbuvir levels may decrease

c) Ledipasvir levels may decrease

d) Darunavir levels may decrease

e) None of the above

 What is the main concern related to potential drug interactions
if ledipasvir-sofosbuvir is used concomitantly with the antiretroviral
medications being taken by this woman?

a) Tenofovir levels may increase

b) Sofosbuvir levels may decrease

c) Ledipasvir levels may decrease

d) Darunavir levels may decrease

e) None of the above

• Ledipasvir/sofosbuvir increases tenofovir levels when given as TDF

• Leading to increase risk of tenofovir associated renal toxicity

• Ledipasvir absorption is pH dependent

• Should be avoided if eGFR is <60 ml/min

ERADICATE trial, ION-4 study AASLD:

www.hcvguidelines.org
 7) interactions, the coadministration of glecaprevir-pibrentasvir should be
Due to drug
avoided with which HIV antiretroviral medications?

a) Ritonavir-boosted atazanavir

b) Raltegravir

c) Dolutegravir

d) Tenofovir DF

e) None of the above

 HIV/HCV
• Atazanavir inhibits OATP 1B and CYP 450

• So Glecaprevir Cmax increased by 4 fold

• Increased in AST levels as well as risk of hepatotoxicity

• Glecaprevir absorption is also pH dependent

Expedition 2 study AASLD:

www.hcvguidelines.org
 7) interactions, the coadministration of glecaprevir-pibrentasvir should be
Due to drug
avoided with which HIV antiretroviral medications?

a) Ritonavir-boosted atazanavir

b) Raltegravir

c) Dolutegravir

d) Tenofovir DF

e) None of the above

AASLD:
www.hcvguidelines.org
AASLD:
www.hcvguidelines.org
 SUMMARY
• Assessment of drug-drug interactions should be a critical part of patient
management :
- starting a regimen
- stopping any drug

• Drugs are to be stopped

- when patients are experiencing toxicities at normal doses
- when suboptimal clinical response is seen despite medication adherence
Whenever in doubt?