Could Praziquantel be sub-therapeutic for schistosomiasis in patients taking non-nucleotide reverse transcriptase inhibitors (NNRTIs) for HIV?

Janet Scott1, Amaya Bustinduy2, Bertie Squires2, Russell Stothard2. 1University of Liverpool, Liverpool, UK, 2Liverpool School of Tropical Medicine, Liverpool, UK

Introduction.

Human Immunodeficiency Virus (HIV) and Schistosomiasis are two of the most widespread infections in sub-Saharan Africa (SSA) where there is significant geographical overlap: Schistosomiasis infects about 25% of the population in SSA, with prevalence’s over 50% in high risk communities and HIV has a 15-28% prevalence in the same countries (1,2). Praziquantel (PZQ) is unlikely to impact on anti-retroviral (ART) efficacy; however it is also important to adequately treat schistosomiasis which is estimated to cause ~280000 deaths annually and serious morbidity (3). Extrapolating from the known pharmacology of PZQ, the dose in patients taking concurrent NNRTIs may need to be increased. Efficacy of PZQ treatment is not routinely assessed outwith research settings so any treatment failure is likely to be attributed to reinfection. We propose to assess whether there is a clinical need to alter the recommended dose of PZQ in people taking NNRTIs.

Current State of Knowledge PZQ is a pyrazinoisoquinoline derivative. Clearance predominantly occurs by first pass metabolism via CYP1A2, CYP2C19 and CYP3A4 with the dominance of CYP3A4 (4,5). Classic CYP3A4 inducers, carbamazepine and dexamethasone markedly reduce circulating PZQ concentrations (6,7) whereas CYP3A4 inhibitors e.g. ketoconazole, increase PZQ concentrations (3). Of clinical concern is whether known CYP3A4 and CYP2C19 inducers commonly used in ART, such as the NNRTI efavirenz will render PZQ less effective. There are no direct studies to date of efavirenz and PZQ interaction, however efavirenz can reduce plasma concentrations of methadone, which, like PZQ, is also 50-70% metabolised via CYP3A4 (8) and PZQ circulating concentrations are reduced below therapeutic concentrations in healthy volunteers taking rifampicin (3) indicating that CYP-mediated interactions may also be more than just theoretical.

Future Research. Treatment efficacy of PZQ for human schistosomiasis in patients taking concurrent NNRTIs could be studied in an area of high prevalence of both infections, and would be best sited in areas of high intensity of schistosomiasis infections. Should treatment efficacy prove to be sub-optimal, such studies should be followed by pharmacokinetic and dynamic studies to inform improved dosing of PZQ in patients taking NNRTIs.

References

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(2) Bustinduy A et al sub Lancet ID 2013

(3) Gryseels, Lancet 2006. p. 1106-18

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(8) Kharasch ED et al Clin Pharm &Therap 91, 673. 2012.