Tenofovir disoproxil treatment for a HIV-hepatitis B virus coinfected patient undergoing peritoneal dialysis: which dose do we need?

Abstract

Tenofovir disoproxil fumarate is the drug of choice for the treatment of HIV-hepatitis B virus (HBV)-coinfected patients [1]. Tenofovir is eliminated primarily by the kidneys through glomerular filtration and active tubular secretion. Therefore, patients with a reduced kidney function are treated with a less frequent dose regimen. Consequently, patients undergoing haemodialysis have to be treated with an adjusted dose regimen. The dialyzability of a drug depends on several factors, such as molecular weight, water solubility, protein binding and volume of distribution. Tenofovir is a relative small molecule (635.5 Da) and readily soluble in water, its protein binding is low (1–7%) and the volume of distribution is also relatively low (0.8 l/kg). On theoretical grounds, this makes tenofovir easily diffusible across membranes and therefore dialyzable. This has been confirmed by Izzedine et al.[2] and Kearney et al.[3], who investigated the pharmacokinetics of tenofovir in patients undergoing haemodialysis. On the basis of these findings, a dosing regimen of 245 mg tenofovir disoproxil (equimolar to 300 mg tenofovir disoproxil fumarate) once weekly is recommended in patients on haemodialysis (as compared with 245 mg daily in patients with adequate renal function). Surprisingly, for patients undergoing peritoneal dialysis, no specific dosing regimen has been established. Thus far, no data on pharmacokinetics of tenofovir disoproxil in patients undergoing peritoneal dialysis have been published. Therefore, we determined the tenofovir concentration in both serum and peritoneal dialysate in a patient undergoing peritoneal dialysis and treated with tenofovir disoproxil. A 46-year-old Afro-American man coinfected with HIV-1 and HBV with end-stage renal disease secondary to HIV-associated nephropathy had been treated for years abroad when he first presented at our clinic. He had no residual renal function and had been treated by continuous cycling peritoneal dialysis consisting of four nightly exchanges of 2.6 l peritoneal dialysis fluid containing 2.27% of glucose during 8.5 h and a long dwell of 1 l dialysis fluid containing glucose polymers during the day. HIV-HBV treatment consisted of lamivudine 50 mg once daily, atazanavir 150 mg once daily, ritonavir 100 mg once daily and abacavir 300 mg twice daily. His CD4+ cell count was 380 cells/μl. Serum HIV1-RNA was undetectable. Under lamivudine monotherapy for his HBV infection, there was a HBV viremia (9.9 × 108 copies/ml) with HBV mutations L180M and M204V. Therefore, tenofovir disoproxil 245 mg/week was started (based on the findings in patients undergoing haemodialysis), in combination with atazanavir 300 mg and ritonavir 100 mg. Steady-state tenofovir concentrations in serum and dialysis fluid were determined. Although no direct relation has been found between serum concentrations of tenofovir and the antiviral effect, a therapeutic range of 0.05–0.30 mg/l is generally accepted, based on previously investigated Cmax and Cmin values (0.30 and 0.05 mg/l, respectively) [4]. The trough tenofovir concentration in serum was 0.51 mg/l and 0.20 mg/l in the 24-h dialysis fluid. Samples were also measured during a standardized 4-h dwell of dialysis fluid intraperitoneally (Fig. 1).Fig. 1: Tenofovir dialysate concentrations and dialysate creatinine/plasma creatinine (D/Pcreatinine, y-axis) versus time (x-axis) in our patient during a standardized 4-h dwell of dialysis fluid intraperitoneally.Samples were taken at t = 0, 120 and 240 min.As expected, tenofovir is partially extracted by peritoneal dialysis. The tenofovir serum concentration of 0.51 mg/l in this patient was well above the accepted therapeutic window of 0.05–0.30 mg/l. This is most likely explained by the relatively small volume of dialysis fluids used in peritoneal dialysis; therefore, the absolute amount of tenofovir extracted in 24-h dialysate was very small (3.07 mg/24 h). In addition, there are several other factors that may influence the pharmacokinetics of tenofovir disoproxil and result in higher drug exposure, such as age, low BMI and ritonavir use [5], with the latter two being applicable for our patient. On the basis of these results, we decreased the dose to 245 mg every 2 weeks and measured the trough serum concentration at a steady state, being 0.20 mg/l, which is well within the earlier described therapeutic range. The HBV load in our patient decreased from 9.9 × 108 copies/ml before the start of tenofovir disoproxil to 7.8 × 104 copies/ml 6 months after the start of tenofovir disoproxil, indicating that tenofovir exposure was adequate. The HIV load was undetectable, both before and during treatment with tenofovir disoproxil. Our patient did not experience adverse events. We conclude that patients on peritoneal dialysis may be adequately treated for HIV-HBV coinfection with tenofovir disoproxil 245 mg on a 2-weekly regime. However, more data from patients undergoing peritoneal dialysis are needed to establish definitive guidelines on dose adjustments in this patient population both for viral suppression efficacy and for drug safety. Acknowledgements Conflicts of interest There are no conflicts of interest.