Pharmacokinetics of anti-tuberculosis drugs in HIV-positive and HIV-negative adults in Malawi

J.J. van Oosterhout 1,2, F. Dzinjalamala 3, A. Dimba 4, D. Waterhouse 5, G. Davies 6,7, M. Molyneux 5,6, E. Molyneux 8, S. Ward7

1College of Medicine, Department of Medicine, Blantyre, Malawi,2Dignitas International, Zomba, Malawi,3 College of Medicine, Department of Biochemistry, Blantyre, Malawi, 4National Tuberculosis Control Program, Lilongwe, Malawi, 5Liverpool School of Tropical Medicine, Liverpool, United Kingdom, 6Malawi-Liverpool-Wellcome Trust Clinical Research Programme Unit, Blantyre, Malawi, 7University of Liverpool, Liverpool, United Kingdom, 8College of Medicine, Department of Pediatrics, Blantyre, Malawi

Background• High HIV prevalence and high TB-HIV co-infection rate in Malawi• High prevalence of malnutrition• Few pharmacokinetic studies of TB drugs sub-Saharan Africa• Some data suggest HIV infection affects TB drug levels

Aims• Pharmacokinetic profiles of 4 drugs of Malawi first line TB treatment

regimen (RHZE)• Impact of HIV status and other factors on TB drug pharmacokinetics

Methods• Intensive PK study adult Malawians • Sputum AFB smear positive PTB• Intensive phase TB treatment

• Exclusion: vomiting, diarrhea; Hb <8.0 g/dL; recent stop ART

• FDC formulations; dosing according to recommended weight bands

• Sampling: 0 – 0.5 – 1 – 2 – 3 – 4 – 6 – 8 – 24

• R and Z: high-performance liquid chromatography• H and E: mass spectrometry

Patient characteristics • N=47

• 51% male

• Mean age 34

• 30 (65%) HIV+

• Median CD4 = 167 (53% <200) cells/µL

• 14 (47%) on ART

• Median weight 54.5 kg

• Median BMI 19.2 (46% <18.5)

Results compatible with other studies from the region

A. Tostmann et al; AAC 2013. B. McIlleron et al; AAC 2006. C. Saleri et al; JAC 2012

No significant impact on main PK parameters:

•Dose, weight, weight-adjusted dose, gender, age

•HIV infection, being on ART

Potential causes of low rifampicin exposure

•Dose–weight •Malnutrition •HIV infection• Severe illness• Sample collection/transport

•Breakfast•Pharmaco-genetic factors• SLCO1B1 polymorphisms

•Quality of drug formulation

Conclusions:- PK results comparable to SSA studies low rifampicin exposure- No impact of HIV infection

Acknowledgements: National TB Control Programme; University of Liverpool

8-24 3-5 20-50 2-6