INTRODUCTIONEfavirenz is an inducer of drug metabolism enzymes. We studied the effect of efavirenz and ritonavir-boosted darunavir on serum unconjugated and conjugated bilirubin, as probes for UGT1A1 and bile transporters.

MATERIALS AND METHODSHealthy volunteers were enrolled in a clinical trial. There were 3 periods: Period 1, 10 days of darunavir 900 mg with ritonavir 100 mg once daily; Period 2, 14 days of efavirenz 600 mg with darunavir/ritonavir once daily; and Period 3, 14 days of efavirenz 600 mg once daily. Serum bilirubin (conjugated and unconjugated) concentrations were obtained at baseline, at the end of each phase and at exit.

RESULTSWe recruited 7 males and 5 females. One subject developed grade 3 hepatitis on efavirenz and was excluded. Mean serum unconjugated bilirubin concentrations were 6.09 μmol/L (95% confidence interval [CI], 4.99 to 7.19) at baseline, 5.82 (95% CI, 4.88 to 6.76) after darunavir/ritonavir, 4.00 (95% CI, 2.92 to 5.08) after darunavir/ritonavir with efavirenz, 3.55 (95% CI, 2.58 to 4.51) after efavirenz alone and 5.27 (95% CI, 3.10 to 7.44) at exit (P <0.01 for the efavirenz phases). Mean serum conjugated bilirubin concentrations were 3.55 μmol/L (95% CI, 2.73 to 4.36) at baseline, 3.73 (95% CI, 2.77 to 4.68) after darunavir/ritonavir, 2.91 (95% CI, 2.04 to 3.78) after darunavir/ritonavir with efavirenz, 2.64 (95% CI, 1.95 to 3.33) after efavirenz alone and 3.55 (95% CI, 2.19 to 4.90) at exit (P <0.05 for the efavirenz phases).

CONCLUSIONEfavirenz decreased unconjugated bilirubin by 42%, suggesting UGT1A1 induction. Efavirenz also decreased conjugated bilirubin by 26%, suggesting induction of bile efflux transporters. Ritonavir-boosted darunavir had no effect on bilirubin concentrations. These results indicate that efavirenz may reduce concentrations of drugs or endogenous substances metabolized by UGT1A1 or excreted by bile efflux transporters.

Adult ; Aged ; Anti-HIV Agents ; therapeutic use ; Benzoxazines ; pharmacology ; Biological Transport ; Confidence Intervals ; Darunavir ; Dose-Response Relationship, Drug ; Drug Interactions ; Enzyme Induction ; drug effects ; Female ; Glucuronosyltransferase ; biosynthesis ; blood ; HIV Infections ; drug therapy ; HIV Protease Inhibitors ; Humans ; Incidental Findings ; Male ; Membrane Transport Proteins ; drug effects ; metabolism ; Middle Aged ; Ritonavir ; pharmacology ; Sulfonamides ; pharmacology ; Young Adult

Abstract Diarrhoeal diseases are among the leading causes of morbidity and mortality in the Western Pacific Region. However, data on the major causes of infectious diarrhoea are limited in many countries within the Region, including Papua New Guinea. In 2013–2014, we conducted surveillance for acute diarrhoeal illness in four provinces in Papua New Guinea. One rural health clinic from each province participated in the surveillance activity. Samples were sent to central laboratories and batch analysed for bacterial and viral gastrointestinal pathogens that are commonly associated with diarrhoea. Across the four sites, the most commonly detected pathogens were Shigella spp., Campylobacter spp. and rotavirus. In this paper, we report the results of the surveillance activity and the challenges that we faced. The lessons learnt may be applicable to other parts of the Region with a similar socioeconomic status.