Clinical Pharmacology to Support HIV Clinicians in ... · College of Health Sciences, Makerere...
Transcript of Clinical Pharmacology to Support HIV Clinicians in ... · College of Health Sciences, Makerere...
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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
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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
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http://www.unaids.org
THE TREATMENT TARGET
diagnosed on treatment virally suppressed
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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
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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
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AID
S d
eath
s (
mil
lio
n)
AR
T c
overa
ge (
%)
UNAIDS, 2017
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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
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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
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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
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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
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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
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?▪ 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?
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Women and HIV
Non-pregnant
• Contraception plus ART?
Pregnancy/PMTCT
• Dose adjustments in pregnancy?
Post-partum/Breastfeeding
• How much drug gets to the baby?
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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%
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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
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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
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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
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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?
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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)
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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
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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.
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Concomitant Diseases
Tuberculosis
Malaria
Neglected Tropical Diseases
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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
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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
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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
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Seden et al. AIDS 2013
Interactions between ART and NTD drugs
Evidence for all recommendations: low quality or very low quality
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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