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

Main Research findings

Background

Aim

Methodology

Results and Discussion

Conclusion and Recommendation

Presentation Outline

Main Message

Regardless of Rifampicin co-treatment in 263 HIV positive Ugandans,

Efavirenz autoinduction was prominent in

CYP2B6*1/*1 genotype

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

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%

Kasese

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

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).

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

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

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

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

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?

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