Integrating human immunodeficiency virus and tuberculosis drug treatment.
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Date
2014
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Abstract
The human immunodeficiency virus (HIV) and tuberculosis (TB) epidemics are major
global public health challenges. Worldwide, approximately 42% of TB patients are also
co-infected with HIV, and sub-Saharan Africa (SSA) is home to the majority of the world’s
infections of both HIV and TB. Dual infection has been shown to be associated with a
higher risk of death. Integrating drug treatment for both diseases is therefore essential to
improve survival. However, drug interactions between antiretroviral therapy (ART) and
anti-TB medication remain a challenge to effective treatment integration. Although
several drug interactions have been identified, only some are clinically relevant. The
impact of significant interactions on public health outcomes is expected to be greatest
when large numbers of patients are prescribed interacting drugs.
Efavirenz (EFV) is the most commonly prescribed nucleoside reverse transcriptase
inhibitor (NNRTI) component of first line ART in sub-Saharan Africa, particularly when
rifampicin (RIF) based TB treatment is co-administered. RIF is known to up-regulate
cytochrome P450 (CYP450) drug metabolizing enzymes resulting in decreased exposure
to concomitantly administered drugs that utilize similar metabolic pathways. Therefore,
the concomitant use of EFV with RIF would be expected to increase EFV clearance while
absorption of TB drugs may also be compromised by advanced HIV disease. The
efficacy of both TB and HIV treatment may thus be compromised by pharmacokinetic
interactions, while more recent evidence also implicates genetic variation in drug
metabolism as a predictor of drug exposure.
To understand the significance of the EFV-RIF interaction better in a South African
population, the pharmacokinetics of EFV during and after RIF-based TB treatment were
investigated as an ancillary study of the ‘Starting Tuberculosis and Antiretroviral Therapy’
(START) trial (CAPRISA 001: NCT00091936). Participants were randomized to receive
both ART and TB treatment simultaneously (integrated arm) or to initiate ART only on
completion of TB treatment (sequential arm). In both arms, the ART regimen included
once daily enteric-coated didanosine (400 mg for participants >60 kg; 250 mg for
participants <60 kg), lamivudine 300mg and efavirenz. Based on the expected drug
interactions, when EFV was administered in the presence of TB treatment, participants
weighing less than 50kg received 600mg and those weighing 50kg or more received
800mg daily. After TB treatment was successfully completed, all patients received EFV
600mg.
Blood samples for trough EFV plasma concentrations were obtained at the end of months
1, 2 and 3 during TB treatment and at the same time points after TB treatment was
successfully completed. Additionally, approximated peak RIF concentrations were
measured 2.5 hours post-dose at the end of months 1, 2 and 3 of TB treatment. The
influence of single nucleotide polymorphisms, in CYP2B6, CYP2A6, and UGT2B7 on
EFV concentrations, and in drug transporter genes (SLCO1B1) on RIF concentrations,
was assessed post-trial from stored peripheral blood mononuclear cell (PBMC) samples.
EFV concentration-time data were analyzed using a population pharmacokinetic nonlinear
mixed effects model (NONMEM) to quantify the impact of RIF-based TB treatment
on EFV clearance. Unexpectedly, there was an overall 29.5% reduction in EFV clearance
during TB treatment. A bimodal distribution of EFV apparent clearance (CL/F) was
evident and indicated that slow EFV metabolisers accounted for 21.9% of the population.
EFV clearance after oral administration in fast metabolisers was 11.5 L/h/70kg off TB
treatment and 7.6 L/h/70kg when on TB treatment. In slow metabolisers, however, the
clearance estimates were 2.9 and 4.3 L/h/70kg in the presence and absence of TB
treatment respectively.
Building on the findings of the NONMEM analysis and in response to the US FDA
prescribing change in 2012, that approved an EFV dose increase from 600mg to 800mg
in patients weighing 50kg and more when on concomitant RIF, the presence and
influence of pharmacogenetic polymorphisms of the CYP450 enzyme system on NNRTI
plasma exposure during and after TB co-treatment and the effect of increasing the EFV
dose was investigated. During TB treatment, median (IQR) EFV Cmin was 3.2 (2.6-6.3)
μg/mL and 3.3 (2.4-9.5) μg/mL in the EFV 800mg and 600mg groups respectively, while
off TB treatment Cmin was 2.0 (1.4 - 3.5) μg/mL. The frequency of the CYP2B6 *1, *6
and *18 haplotypes was 18.5%, 38.9% and 25.9% respectively. Polymorphisms in all
three CYP2B6 genes studied (516T-785G-983C) were present in 11.1% of patients.
Median (IQR) EFV concentrations in patients with the three mutations were 19.2 (9.5-20)
μg/mL and 4.7 (3.5-5.6) μg/mL when on and off TB treatment. TB treatment, composite
genotypes CYP2B6 516 GT/TT, CYP2B6 983 TC/CC or being a CYP2A6*9B carrier
predicted median EFV Cmin > 4 μg/mL. Therefore, increasing the EFV dose to 800mg
during TB treatment is unnecessary in African patients with these polymorphisms.
As a critical component of first line TB treatment concerns about sub-optimal TB drug
bioavailability were examined for RIF. The influence of drug transporter gene
polymorphisms on RIF concentrations was also assessed. Median RIF (IQR) C2.5hr was
found to be 3.6 (2.8-5.0) μg/mL while polymorphism frequency of the SLCO1B1
(rs4149032) drug transporter gene was high (0.76) and was associated with low RIF
concentrations as was male gender and having a low haemoglobin. Increased RIF
dosage warrants urgent consideration in African TB-HIV co-infected patients.
In conclusion, concomitant RIF-containing TB treatment unexpectedly reduced EFV CL/F
with a corresponding increase in EFV exposure. Polymorphisms of EFV metabolizing
enzymes were frequent in this population and contribute to this outcome. While in South
Africa where TB-HIV co-treatment is associated with elevated EFV concentrations, peak
RIF concentrations were alarmingly low and well below the recommended target range of
8 to 24 μg/mL. Increased RIF dosage may be warranted in African TB-HIV co-infected
patients whilst the need for EFV dose increase is not supported by these data. Recommendations for public health benefit, in this generalized epidemic in South Africa,
include the consideration of an EFV dose reduction as a cost saving to improve life-long
treatment sustainability, and a RIF dose increase to curb TB treatment failure and future
development of multiple-drug resistant (MDR) TB.
Description
Ph. D. University of KwaZulu-Natal, Durban 2014.
Keywords
HIV infections--Treatment., Tuberculosis--Treatment., Therapeutics., Medicine--Management., Theses--Therapeutics and medicine management.