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The Aurum Vision - 81KB - Aurum Health Research

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									      The Aurum Vision
    Aurum Health intends to be an
internationally recognised, independent
and self sustaining research and health
    systems organisation, aiming to
 improve the health of individuals and
         communities in Africa.
Rationale
• Efavirenz is widely used in first-line antiretroviral
  therapy
   – severe central nervous system (CNS) neuropsychiatric side-effects,
     including dizziness, disturbed sleep, nightmares, headaches, mood
     disturbance and psychosis

• The therapeutic range is 1-4mg/l
   – increased rate of virological failure with levels below 1mg/l,

   – increased central nervous system (CNS) side-effects with
     levels above 4mg/l
…rationale
•   Tuberculosis occurs commonly in HIV-infected patients
•   Rifampicin, a key component of tuberculosis treatment
     – is a potent inducer of hepatic cytochrome P450 enzymes, including
         isoenzyme 2B6 (CYP2B6), the main route of efavirenz metabolism.
     – decrease efavirenz plasma levels by enhancing hepatic metabolism
     – may lead to ART failure and development of viral resistance
•   Concerns about prescribing efavirenz at standard doses together with rifampicin
     –   CDC guidelines increase EFV to 800mg



•   The cytochrome P450 2B6 G516T polymorphism may lead to increased
    efavirenz levels
Objectives
• To describe efavirenz mid-dosing interval levels in
  HIV-infected patients taking efavirenz-based ART in
  South Africa.
• To identify risk factors for efavirenz levels outside the
  therapeutic range in this population.
• To investigate the association between the CYP2B6
  G516T polymorphism and efavirenz levels.
• To compare efavirenz levels in the presence of
  concomitant rifampicin to levels in participants not
  taking rifampicin.
Methods
• Participants taking efavirenz-based
  antiretroviral therapy
• Blood for efavirenz level was sampled 12-20
  hours after last dose
• A sample for genetic analysis
• 2 Arms
  – those on rifampicin : sampled twice - whilst on
    rifampicin, and 1 month or more after stopping
    rifampicin
  – Efavirenz-only participants were sampled once
Analysis
• EFV-only participants with EFV-RIF
  participants at 1st sampling occasion (sample
  1)

• EFV-only participants with EFV-RIF
  participants at 2nd sampling occasion
  (sample 2)

• EFV-RIF participants during and on
  discontinuation of RIF
Results
• 142 participants
  – 40 on RIF
     • 17 had 2nd specimen off RIF
• Mean age 41 years
• Females 27%
• Median efavirenz level was 1.9mg/l (IQR 1.4-
  3.8)
  – 39/159(24.5%) in 38/142(26.7%) were > 4mg/l
  – 27/159(17.0%) in 25/142(17.6%) were < 1mg/l.
• The G516T polymorphism was common:
  – 48/129(37.2%) had the wild-type G/G genotype,
  – 36/129(27.9%) were G/T heterozygotes
  – 45/129(34.9%) T/T homozygotes
Effect of RIF on EFV levels
• Median efavirenz level
  – 2.4 (IQR 1.3-3.1) in the 40 participants on
    EFV-RIF
  – 1.8 (IQR 1.4-4.4) in 102 participants on
    EFV-only
  – A Wilcoxon signed-rank test on paired
    efavirenz levels on and off rifampicin in 17
    participants, confirmed this finding (p=0.113)
Effect of genotype on EFV levels

•   Genotype G/G - 1.6mg/(IQR 1.0-2.6)
•   Genotype G/T - 2.4mg/l(IQR 1.4-4.8)
•   Genotype T/T - 2.3mg/l(IQR 1.6-5.5)
•   strong evidence for a difference
    between genotypes (Kruskal-Wallace
    p= 0.0083).
 Risk factor analysis
• G516T polymorphism was strongly associated
  with efavirenz levels above 4mg/l
  – odds ratios
     • GG = 1
     • GT = 6.61 (95%CI 1.82-24.01 Wald test p=0.004)
     • TT = 5.19 (95%CI 1.46-18.35 Wald test p=0.011)
• No association between high levels and CNS
  side-effects, except severe sleep disturbance
• In those on ART for ≥ 6 months, efavirenz levels
  below 1mg/l were associated with virological
  failure (> 400 copies/ml)
Conclusion
• Efavirenz can be used at standard 600mg
  doses together with rifampicin in this
  population, without dose adjustment.

• The G516T polymorphism was common and
  associated with efavirenz levels above 4mg/l.

• High levels were not associated with CNS
  side-effects, except for insomnia.

								
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