Durham E-Theses The long-term eectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients SARFO, FRED,STEPHEN How to cite: SARFO, FRED,STEPHEN (2013) The long-term eectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients, Durham theses, Durham University. 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Academic Support Oce, Durham University, University Oce, Old Elvet, Durham DH1 3HP e-mail: [email protected] Tel: +44 0191 334 6107 http://etheses.dur.ac.uk 2 TITLE The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin- based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients Dr. Fred Stephen Sarfo Doctor of Philosophy University of Durham School for Health 2013 1 Dedication To Maame and Jason. Love always. 2 Acknowledgements This dissertation has been possible because of the tireless and sacrificial inputs of several individuals. I am particularly grateful to all the doctors, nurses, allied health workers, pharmacists, laboratory technicians and public and social health workers who have cared for the patients whose data made this study possible. I am grateful to my supervisors Dr. David Chadwick of the James Cook University Hospital, Middlesbrough, UK, Dr. Mark Booth of Unversity of Durham, Wolfson Research Institute and Dr. Richard Phillips of the School of Medical Sciences, Kumasi, Ghana for their guidance, patience and insightful contributions throughout this endeavour. I would like to thank Prof. George Bedu-Addo, head of Department, Internal Medicine, Kumasi, Ghana and Dr. Betty Norman who is the head of the HIV clinic, Kumasi whose helpful suggestions helped in creating a database for assessing the effective of cART among Ghanaian HIV-infected patients. Dr. Lambert Appiah of KATH, and Dr. Mark Ankcorn were instrumental in recruitment, sampling and running the pharmacokinetic study of artesunate and efavirenz. Prof Saye Khoo, Prof. Andrew Owen, Mrs. Eghan Deirdre, Dr. John Tia and Ms Zhang all of the Department of Pharmacology and Therapeutics of the University of Liverpool provided immense support for genotyping of SNPs and plasma efavirenz concentration measurements. Further thanks to Dr. Steve Ward for assistance in measuring plasma artesunate and dihydroartemisinin concentrations at the Liverpool School of Tropical Medicine. Thank you Dr. Kasim Adetayor of the University of Durham, Wolfson Research Institute for help in statistical modelling of CD4 and BMI changes on cART. A special thank you Mr. Shadrack Asibey and Mr. George Bush for toiling through the nights in inputting the data from study proforma into excel format for this analysis. Hey it would not have been possible without you guys! Thanks be to God for His abundant grace, inspiration and strength to carry out this work. 3 Abbreviations A- adenine ACTG- AIDS Clinical Trialists Group AIDS- Acquired Immunne deficiency Syndrome ALT- Alanine transaminase ARTS- artesunate AST- Aspartate transaminase AUC- Area Under the Curve AZT- Zidovudine BENCHMRK- Blocking Integrase in Treatment Experienced patients with a novel compound against HIV, Merck BHIVA- British HIV Association C- cytosine CAR- Constitutive Androstane Receptor cART- combination antiretroviral therapy CDC – Centre for Disease Control CKD-EPI- Chronic Kidney Disease- Epidemiological Collaboration Cmax- Maximum concentration Cmin- Minimum concentration CYP – Cytochrome P450 CYP 2B6- cytochrome P450 isoform 2B6 CYP 2A6 – cytochrome P450 isoform 2A6 DART- Development of Antiretroviral therapy in Africa D4T- stavudine DHA- Dihydroartemisinin DNA- deoxyribonucleic acid DUET- Demonstrate Undetectable viral load in patients Experienced with ARV Therapy 4 EFV- Efavirenz ELISA- Enzyme linked Immunosorbent assay EMEA- European Medicines Agency eGFR- estimated glomerular filtration rate FDA- Food and drug administration FOTO- Five-days on, two-days off FSS- Fred Stephen Sarfo G- guanine HBV- hepatitis B virus HBSAg- hepatitis B surface antigen HCV- hepatitis C virus HIV- Human Immunodeficiency Virus HPLC- high performance liquid chromatography HR- Hazards ratio INCAS - Italy, the Netherlands, Canada and Australia Study IRIS- Immune reconstitution inflammatory syndrome IQR- Interquartile range KATH- Komfo Anokye Teaching Hospital LDL- low density lipoprotein LTFU- Lost-to-follow up MDRD- Modified Diet in Renal Disease MERIT- Maraviroc versus Efavirenz Regimens as Initial Therapy MOTIVATE- Maraviroc versus optimised therapy in viraemic antiretroviral treatment- experienced patients MVC- Maraviroc NA-ACCORD- North American AIDS Cohort Collaboration on Research and Design NADE- Non-AIDS defining events NFV- Nelfinavir 5 NRTI- Nucleoside (-tide) Reverse Transcriptase Inhibitor NNRTI- Non-nucleoside reverse transcriptase inhibitor NVP- nevirapine OR- Odds ratio PCR- polymerase chain reaction PD- pharmacodynamics PI- protease inhibitor PK- pharmacokinetics PMTCT- Prevention of Mother to Child Transmission pVL- plasma viral load PXR- pregnane X receptor RAL- raltegravir RNA- ribonucleic acid ROP- Richard Odame Phillips RXR - 9-cis retinoic acid receptor SEM- standard error of mean SMART- Strategies for Management of Antiretroviral Therapy SNPs- Single Nucleotide polymorphisms SSA- sub-Saharan Africa START- Strategic Timing of Antiretroviral Treatment T- thymidine TB- tuberculosis TDM- Therapeutic drug monitoring TORO- T-20 versus Optimised Regimen Only UGT – UDP-glucuronosyltransferase ULN- upper limit of normal WHO- World Health Organisation 3TC- lamivudine 6 Abstract Dr. Fred Stephen Sarfo, The long-term effectiveness of efavirenz-based combination antiretroviral therapy, the impact of pharmacogenomics and pharmacokinetic interaction of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV- infected patients. PhD dissertation, Durham University, January 2013. Introduction: In sub-Saharan Africa, HIV treatment is initiated with combination of antiretroviral medications comprising of a backbone of either stavudine or zidovudine plus lamivudine with a non-nucleoside reverse transcriptase inhibitor of either efavirenz or nevirapine. Efavirenz is highly efficacious, durable and well tolerated. The risk for toxicity of efavirenz is determined by several factors including single nucleotide polymorphisms in the hepatic enzymes responsible for its metabolism and concurrently administered medications such as antimalarials, which share common metabolic pathways. The aims of this dissertation are to assess the long-term effectiveness of efavirenz-based antiretroviral therapy and the impact of pharmogenomics and pharmacokinetic interactions of artemisinin-based antimalarial therapy on efavirenz exposure among Ghanaian HIV-infected patients. Methods: The effectiveness of efavirenz- compared with nevirapine-based antiretroviral therapy was assessed retrospectively in nearly 4000 patients starting treatment between 2004 and 2010. The main outcome measure was a composite of toxicity, disease progression and attrition, and CD4 count changes. A prospective pharmacokinetic study of artesunate and efavirenz was conducted among 22 HIV-infected and 21 controls. Plasma efavirenz and artesunate/ dihydroartemisinin concentrations were measured using validated and standardised methods. Genotyping for single nucleotide polymorphisms in CYP2B6 G516T, T983C; CYP2A6*9B, UGT2B7*735 and *802 as well as CAR rs2307424 were performed for 800 patients with real-time polymerase chain reaction with allelic discrimination. Results: Antiretroviral therapy was associated with robust CD4 increases. Efavirenz was comparable with nevirapine in composite outcomes but better tolerated. Artesunate was well tolerated when administered to HIV-infected patients on efavirenz. Single nucleotide polymorphisms in the CYP2B6 G516T and T983C were associated with increased plasma efavirenz concentrations. Conclusions/Recommendation: Among this Ghanaian cohort, both efavirenz and nevirapine- based antiretroviral therapy were effective. The better tolerability of efavirenz compared with nevirapine means it can be safely used as the preferred first line non-nucleoside reverse transcriptase inhibitor in sub-Saharan Africa. 7 Contents Dedications………………………………………………………………………………2 Acknowledgements……………………………………………………………………...3 Abbreviations……………………………………………………………………...…….4 Abstract……………………………………………………………………...…………..7 Contents…………………………………………………………………………………8 Table of tables………………………………………………………………………….11 Table of figures…………………………………………………………………………15 Table of appendixes…………………………………………………………………….19