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CYP2B6 genotype but not Rifampicin co-administration explains variability in long term efavirenz clearance and plasma exposure
Presenter: Dr. Sarah Nanzigu
Authors: Jackson K. Mukonzo, Sarah Nanzigu, Qing Ma, Paul Waako, Jasper Ogwal –Okeng, Gene Morse, Lars L Gustafson, Eleni Aklillu
+ Efavirenz Rifampicin
Abstract O_04
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Main Research findings
Background
Aim
Methodology
Results and Discussion
Conclusion and Recommendation
Presentation Outline
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Main Message
Regardless of Rifampicin co-treatment in 263 HIV positive Ugandans,
Efavirenz autoinduction was prominent in
CYP2B6*1/*1 genotype
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Background CYP2B6*6 polymorphism predict Efavirenz Emax induction;*1/*1
exhibiting higher autoinduction
Rifampicin CYP2B6/CYP3A enzyme induction results in 20 – 25 % reduction in efavirenz concentrations.
Guidelines for Efv dose adjustment from 600 to 800mg for > 50kg
Rifampicin also induces ABCB1 encodes P-glycoprotein
A synergistic/ additive effect on enzyme induction is assumed in Efavirenz + Rifampicin co-treatment
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Background of Study site: Uganda
Area is 243,411 sq. km
Population estimated at 34 millions
HIV Prevalence 6.7% (15-49years)
TB incidence 144/ 100,000 population
• TB patients with known HIV status 80%
• HIV-positive TB patients 53%
• HIV-positive TB patients on ART
32%
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Previous Genetic studies on Healthy Ugandan
CYP2B6*6 and CYP2B6*11 mutations showed 21 &20% lower relative Clearance of Efavirenz
ABCB1 (rs3842) showed 26% higher relative oral bioavailability
A person homozygus for CYP2B6*6, CYP2B6*11 and ABCB1
(rs3842) predicted to have 1.5 times longer T1/2 AIM: We investigated the effect of genetics and rifampicin co-treatment on efavirenz autoinduction and apparent CLf
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Materials and Methods
263 patients ART naïve HIV positive Ugandans recruited 106 HIV only on Efavirenz + Lamivudine + Zidovidine (HAART)
157 HIV/TB on Efavirenz based HAART + Rifampicin based (2 EHRZ/4RH)
TB treatment started 2 weeks before ART Samples for plasma Efavirenz Concentrations collected on post
dosing on days 14, 56, 84, 112, 140, 168 and 224
Genotyped for CYP2B6*6 & *11, CYP3A5*3,*6 & *7, and ABCB1 (3435CT and rs3842).
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Baseline characteristics of the 263 HIV Infected Ugandans at ART Initiation
Participants All (n=263) HIV +TB (n=157)
HIV only (n=106) p-value
Females (%age) 52.9 47.1 60.4 0.08
Demographics Measures (mean ± SE)
Body weight (Kg) 52.2 ± 0.53 50.3± 0.66 54.9 ± 0.80 < 0.001
Age (years) 34.6 ± 0.49 32.5 ± 0.59 37.7± 0.75 < 0.001
CD4 cell count / µL 113.7 ± 5.5 87.77± 6.73 150.23± 8.0 < 0.001
ALT (U/l) 23.9± 1.25 28.15 ± 1.19 17.71 ± 0.99 < 0.001 ALB / (g/dl) 3.1 ± 0.06 2.76 ± 0.05 3.89 ± 0.08 < 0.001
Urea (mmol/l) 3.9± 0.28 4.53 ± 0.45 3.05 ± 0.16 0.015
Creatinine (µmol/l) 76.7 ± 1.95 70.86 ±2.80 84.11 ± 2.30 < 0.001
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Frequency of genotypes among HIV patients receiving HAART
CYP2B6*6 Genotype
Proportion of All 263 participants
Proportion out of 157 Efavirenz + Rifampicin
Proportion out of 107 Efavirenz only
*1/*1 43.4 50.7 33.7
*1/*6 46.6 42.0 52.8
*6/*6 10 13.5 7.3
Tanzania Zimbabwe S. Africa
37.5-47.7 30 36
38.6-45.8 44 41
13.6-16.7 27 23
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D14 Efavirenz CLf was higher for TB/HIV group (13.5l/h vs 11.6); p=0.01
No Rifampicin effect observed thereafter TB regimen given for 2 wks prior to ART
Increasing CLf from D14 to maximum by D168
0 30 60 90 120 150 180 210 240 0
5
10
15
20
EFV only RIF+EFV
Days on efavirenz based HAART
Efa
vire
nz C
L/F
(L/h
r)
p<0.05 p>0.05
Comparison of Efavirenz Apparent CLf between “Efavirenz only” and “Rifampicin co-treated” groups
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Comparison in efavirenz apparent oral clearance and concentration between “efavirenz only” and “Rifampicin-Cotreated” patients Stratified by CYP2B6 genotypes: line represents “efavirenz only” while line is “rifampicin co-treatment”
CYP2B6*1/*1
0 30 60 90 120 150 180 210 240 0
10
20
30
Efav
irenz
CL/
F (L
/hr)
CYP2B6*1/*6
0 30 60 90 120 150 180 210 240
10
20
30
CYP2B6*6/*6
0 30 60 90 120 150 180 210 240 0
10
20
30
0 30 60 90 120 150 180 210 240 3.0
3.2
3.4
3.6
3.8
4.0
Days on Efavirenz based ART
Log
efav
irenz
(ng/
mL)
0 30 60 90 120 150 180 210 240 3.0
3.2
3.4
3.6
3.8
4.0
0 30 60 90 120 150 180 210 240 3.0
3.2
3.4
3.6
3.8
4.0
Enzyme induction over time was highest among CYP2B6*1/*1 followed by *1/*6 while *6/*6 individuals exhibited no difference in clearance For the CYP2B6*1/*1 grp, the effect of enzyme induction on long term Efavirenz clearance was much higher with Efavirenz given alone
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Conclusion and Recommendations
Conclusion: CYP2B6 genotype but not rifampicin co-treatment
determines intra-individual variability in efavirenz autoinduction
Allay fears of Efavirenz-Rifampicin co-administration in this population Rather concentrate on effect of genotypes
Genotyping necessary for dose maximisation but expensive
But How about Sensitisation and TDM?
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Short Comings
SIDA Programme for funding
Support from Pharmacology departments at KI and MAK
Conference organizers and your attention are greatly
appreciated
Acknowledgements
Possible country genetic imbalance of study population