Drug-drug interaction between dolutegravir and artemether-lumefantrine in HIV and malaria mono- and co-infections: a pharmacogenetic analysis from Ghana.

Background: Human Immunodeficiency Virus and malaria are significant public health challenges in sub-Saharan Africa, contributing substantially to morbidity and mortality in the region. The trajectory of HIV and malaria mono- and coinfections may be different with presentations of drug-drug and disease-disease interactions. Current medications of artemether-lumefantrine and dolutegravir (DTG) -based anti-retroviral therapy which are the preferred drugs are metabolised by CYP2B6, CYP3A4/5 and UGTs which are polymorphic and may contribute to drug disposition and clinical outcomes. This study investigated the pharmacogenetic effects of co-administration of arthemeter-lumfantrine and DTG in HIV-malaria mono and coinfection.

Methods: Malaria and HIV mono- and coinfected participants were recruited from health facilities in the Central region of Ghana. Blood samples were taken at pre-defined time points during malaria and HIV mono- and coinfection. Plasma drug concentrations of artemether-lumefantrine and dolutegravir and their metabolites of dihydroartemisinin and desbutyl-lumefantrine were determined by liquid chromatography-mass spectrometry (LC-MS/ MS). Genotyping for CYP2B6, UGT1A, CYP3A4 and CYP3A5 was undertaken using PCR-RFLP, TaqMan assays and Iplex GOLD SNP genotyping protocol.

Results: Two hundred and sixty-one participants were involved in this study, with a male to female ratio of 1:2. Median parasitaemia for malaria monoinfection and HIV-malaria coinfection was 947.34 parasites/µL of whole blood and 5287.36 parasites/µL of whole blood respectively on day 1. By days 3 and 7, the parasitaemia had decreased to 0 for both malaria monoinfection and HIV-malaria coinfections. Plasma median C_{day 7} for lumefantrine was 741.5 (496.0, 1276.0) ng/mL for malaria monoinfection and 426.0 (254.5, 803) ng/mL for malaria and HIV coinfection (MHC) showing a decreased plasma concentration during coadministration with DTG. There was a decrease in the plasma concentration of DTG in MHC cases compared to HIV monoinfection. This trend is observed in CYP3A5 rs776746, CYP3A rs10264272, CYP3A4 rs2740574, UGT1A1 rs4148323 and CYP2B6 rs28399499 genetic variations.

Conclusions: There is an observed decrease in plasma drug concentrations during the co-administration of artemether-lumefantrine and dolutegravir. Possible long-term effects from non-adherence may include sub-optimal levels that could result in clinical differences and outcomes.