Clinical Pharmacology to Support HIV Clinicians in ... · College of Health Sciences, Makerere University, Uganda Investing In The Future –Impacting Real Lives Lamorde M, FRCP,

Infectious Diseases InstituteCollege of Health Sciences, Makerere University, Uganda

Investing In The Future – Impacting Real Lives

Lamorde M, FRCP, PhD

Clinical Pharmacology to Support HIV Clinicians in Developing Countries

2

▪ Few standardized antiretroviral therapy (ART) regimens

▪ Task shifting or task sharing • Nurse-led HIV clinics

• Pharmacy visits

• Peer HIV support including contact tracing, peer counseling, community drug distributions

▪ Minimal laboratory monitoring• Viral load prioritized over CD4 counts for ongoing monitoring after initiation of antiretroviral

therapy

• Limited role for resistance testing

Public health approach to HIV treatment

http://www.unaids.org

THE TREATMENT TARGET

diagnosed on treatment virally suppressed

PREFERRED REGIMEN TDF + 3TC (or FTC) + EFV

ALTERNATIVEREGIMENS

AZT + 3TC + EFV (NVP)TDF + 3TC + DTG*TDF + 3TC + EFV400*TDF + 3TC + NVP

Global guidance…first-line therapy

* Caveat: Inadequate data in pregnancy for DTG, inadequate data in pregnancy and TB for EFV400

PREFERRED REGIMEN TDF + 3TC (or FTC) + EFV

ALTERNATIVEREGIMENS

AZT + 3TC + EFV (NVP)TDF + 3TC + DTG*TDF + 3TC + EFV400*TDF + 3TC + NVP

Global guidance…first-line therapy

Commentary: PK studies often difficult to interpret in LMICs due to differences

in patient factors

DDI studies relevant to LMICs lacking for relevant comorbidities

First-line ART in LMICs include ARVs with high propensity for

DDIs

Seden et al. Curr Opin HIV 2017

* Caveat: Inadequate data in pregnancy for DTG, inadequate data in pregnancy and TB for EFV400

AID

S d

eath

s (

mil

lio

n)

AR

T c

overa

ge (

%)

UNAIDS, 2017

Ethnic Factors and Impact on Drug Therapy

Intrinsic factors

• Gender

• Age

• Race

• Polymorphism

• Height

• Body weight

• Diseases

• Food habits

Extrinsic factors

• Culture

• Socioeconomic factors

• Medical practice

• Drug compliance

ICH E5

Ethnic Factors and Impact on Drug Therapy

Intrinsic factors

• Gender

• Age

• Race

• Polymorphism

• Height

• Body weight

• Diseases

• Food habits

Extrinsic factors

• Culture

• Socioeconomic factors

• Medical practice

• Drug compliance

ICH E5

BRIDGING STUDIES

Uganda

* UPHIA report, UNAIDS

National HIV prevalence: 6.2% (5.8 -6.7)

• Infectious Diseases Institute, Makerere University, Kampala • Supporting >150,000 patients with HIV nationally• Main clinic in national referral hospital 7500 (6000 on first-line ART)

Clinical research site for ART for relevant drug-drug interactions and ART optimization studies

• DolACT: Dolutegravir antimalarial interactions• DolPHIN-1 & 2: Dolutegravir in late pregnancy• SSAT062: Efavirenz 400 mg in tuberculosis• SSAT063: Efavirenz 400 mg in pregnancy

High prevalence and long duration of nervous system and psychiatric adverse drug reactions in Ugandan patients taking efavirenz (EFV) 600mg daily

• 43% patients on EFV reported a nervous system or psychiatric disorder side effect

• 61% patients rated symptoms as severe ≥5/10

• 75% symptoms were experienced for ≥18 months

Majority not disclosed to doctors

Seden K, et al. 18th International Workshop on Clinical Pharmacology of Antiviral Therapy 14 - 16 June 2017, Chicago, USA

Nurse triage for CNS ADRs in all patients taking EFV ≥3 months

Doctor ADR causality assessmentAssessment of contra-indicationsDecision to switch

Doctor detects issue -LFTs deranged-CNS disorder-Hypersensitivity reaction

Viral load suppressed within 3 months

Switch to DTGFollow up at usual visits for 6 monthsADR assessment

Patient counselling and consent

Suspected Medication Problem

(What happens? Always present?)

How long

(eg. since ARVs

started, 3 weeks, 2

years etc)

Severity

(see scale

below)

Ask the patient to rate on a scale of 1-10 how severe the side effect is, with 1 being the mildest, and 10 being the most severe:

Active (Screening tool)

Passive

?▪ 42 year old man in a food pharmacokinetic study in 2013

▪ Switched from efavirenz to study drug (rilpivirine) for 56 days and then back to efavirenz

▪ Actively checked for efavirenz central nervous system side effects before switch (none reported)

▪ After 42 days, one patient sent a letter…..he felt better

What if people don’t know that they have adverse events?

Women and HIV

Non-pregnant

• Contraception plus ART?

Pregnancy/PMTCT

• Dose adjustments in pregnancy?

Post-partum/Breastfeeding

• How much drug gets to the baby?

Levonorgestrel implant versus ART

0

200

400

600

800

1000

1200

1400

1600

0 5 10 15 20 25 30 35 40 45

LN

G P

las

ma

Co

nc

en

tra

tio

n (

pg

/mL

)

Weeks (post-implant insertion)

No ART

NVP-based ART

EFV-based ART

Over 48 weeks of combined LNG-NVP use:

• LNG concentrations were not different

than the control group

Over 48 weeks of combined LNG-EFV use:

• LNG concentrations were reduced by

45-57%

Unintended pregnancies3 pregnancies observed in the EFV group; none in the Control group

• 2 identified at study week 48; the EFV study arm was then halted

• 1 identified at an early discontinuation visit

Pregnancy 1

(pg/mL)

Pregnancy 2

(pg/mL)

Pregnancy 3

(pg/mL)

Week 1 693 501 185

Week 4 631 411 201

Week 12 348 363 125

Week 24 297 268 150

Week 36 299 303 122

Study visit

pregnancy was

detected

Week 48,

≈ 2 weeks post-

conception

Week 48,

≈ 10 weeks post-

conception

Week 43,

≈ 2 weeks post-

conception

Scarsi et al. Clin Infect Dis. 2016

Etonogestrel contraceptive implant + ART

Chappell CA et al, AIDS 2017

Study

week

NVP:

ART-Naïve1

EFV:

ART-Naïve1

10.78

(0.74-0.81)

0.16

(0.16-0.17)

40.90

(0.88-0.91)

0.17

(0.17-0.17)

121.03

(1.02-1.04)

0.14

(0.14-0.14)

240.94

(0.90-1.01)

0.18

(0.17-0.20)

AUC0-24

0.94

(0.94-0.94)

0.16

(0.16-0.16)

1Geometric mean ratio (GMR), with 90% CI

0

100

200

300

400

500

600

700

800

900

1000

0 4 8 12 16 20 24

ART-Naïve

NVP

EFV

Efficacy Threshold

Weeks

Scarsi KK et al. Drug-Drug Interactions, Effectiveness, and Safety of Hormonal Contraceptives in Women Living with HIV. Drug Saf. 2016 Nov;39(11):1053-1072

▪ DOUBLNG

• Double dose LNG versus efavirenz-based ART

▪ DOUBLET

• Double dose ENG versus efavirenz-based ART

▪ DRIVE I

• Standard dose ENG versus rilpivirine-based or darunavir-based ART

▪ DRIVE II RPV, DRV v ENG or LNG

• Standard dose ENG versus rilpivirine-based or darunavir-based ART

Planned/Ongoing studies

Review

Antiretroviral drug

T3 reduction Dose adjustment? Reference

EFV NA No Hill et al. AIDS 2014

NVP 20% (AUC) No Lamorde et al. JAIDS 2012

LPV NA No* Cressey et al. JAC 2015

ATZ 34% (AUC) No+ Colbers et al. Antivir Ther2014

DTG NA No PANNA, PK workshop 2017

* Increased doses may be needed for >100kg, adherence problems, prior use of LPV/r+ Some subjects may require increase of ATZ/r 400/100 mg.

Pregnancy dose adjustments?

DolPHIN Studies

AIM• PK of DTG in T3, BM and infants• Define optimal dose of DTG in T3• Safety data• Preliminary data on VL compared with EFV• 28-34w gestation• DTG continued for 2w PP

DolPHIN-1 pilot

DolPHIN-2

AIM

• RCT, maternal VL is primary endpoint

• Safety data

• 28w – labour

• DTG continued until 72 weeks post-

partum

ViiV funded

UNITAID funded

Optimal Dosing in T3 and PPInfant exposures (IP and BF)

Preliminary efficacy data (mother)Preliminary safety data (mother, infant)

C. Waitt et al. Is infant exposure to antiretroviral drugs during breastfeeding quantitatively important? A systematic review and meta-analysis of pharmacokinetic studies J Antimicrob Chemother 2015 Jul;70(7):1928-4

WHO and Uganda recommend exclusive breastfeeding for 6 months

Breastfeeding

Tenofovir, FTC and lamivudine in breast milk

Waitt JAC 2018

Study in 30 Ugandan and 29 Nigerian mothers receiving first-line ART and their infants

FTC also present in breastmilk Tenofovir low concentrations in breastmilk and undetectable in infants.

Concomitant Diseases

Tuberculosis

Malaria

Neglected Tropical Diseases

Tuberculosis

Can we use lower doses of EFV with rifampicin in TB patients?

Two stage PK study• Efavirenz 400 in HIV patients without TB (n=15)

• Efavirenz 400 in HIV-TB co-infected patients in Kampala (n=10)

SSAT062 Trial

Tuberculosis

What if efavirenzcannot be used?

0

2,0

00

4,0

00

6,0

00

8,0

00

200/400 400/400

n=7 n=9

Day 7 nevirapine C12 ng/mL

CARINEMO RCT for TB/HIV Co-infectionWeek 48 VL <50 copies/ml • NVP (no-lead in) 60% • EFV 68.4%

2013 CDC Guidelines: efavirenz is preferred but if

nevirapine must be used, avoid lead-in dosing

Lamorde et al. JAC 2011

Bonnet et al. Lancet ID 2013

Malaria

Co-administered

drugEffect on artemether-lumefantrine exposure

artemether DHA lumefantrine

rifampicin1 89% 85% 68%

nevirapine2 72% 37% 21%

efavirenz2 77% 75% 55%

LPV/r3 43% Not affected 386

1Lamorde et al AIDS 2013 2Byakika-Kibwika et al JAC 2012 3 Byakika-Kibwika JAC 2012 4 Hoglund BJCP 2014

Simulations suggest artemether-lumefantrine dose increases required4

• 250% dose increase with efavirenz

• 75% dose increase with nevirapine

Review: ART versus artemisinin derivatives. Kiang et al. Clin Pharmacokinet. 2014

Seden et al. AIDS 2013

Interactions between ART and NTD drugs

Evidence for all recommendations: low quality or very low quality

Acknowledgements

• National AIDS Control Program

• Kim Scarsi, University of Nebraska Medical Center

• Saye Khoo, University of Liverpool

• Kay Seden, University of Liverpool

• Catriona Waitt, University of Liverpool

• Catherine Chappell, University of Pittsburgh

• Marta Boffito, St Stephens AIDS Trust

• Ceppie Merry, Trinity College Dublin