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Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis

Abstract

Introduction

Peritoneal dialysis (PD) is an effective renal replacement modality in people with HIV (PWH) with end-stage kidney disease (ESKD), particularly those with residual kidney function. Data on pharmacokinetics (PK) of antiretrovirals in patients on peritoneal dialysis are limited.

Methods

A single-participant study was performed on a 49-year-old gentleman with ESKD on PD and controlled HIV on once daily dolutegravir (DTG) 50 mg + tenofovir alafenamide (TAF) 25 mg / emtricitabine (FTC) 200 mg. He underwent serial blood plasma, peripheral blood mononuclear cell, and urine PK measurements over 24 h after an observed DTG + FTC/TAF dose.

Results

Plasma trough (Cmin) concentrations of TAF, tenofovir (TFV), FTC, and DTG were 0.05, 164, 1,006, and 718 ng/mL, respectively. Intracellular trough concentrations of TFV-DP and FTC-TP were 1142 and 11,201 fmol/million cells, respectively. Compared to published mean trough concentrations in PWH with normal kidney function, observed TFV and FTC trough concentrations were 15.5- and 20-fold higher, while intracellular trough concentrations of TFV-DP and FTC-TP were 2.2-fold and 5.4-fold higher, respectively. TFV and FTC urine levels were 20 times lower than in people with normal GFR.

Conclusions

In a single ESKD PWH on PD, daily TAF was associated with plasma TFV and intracellular TFV-DP trough concentrations 15-fold and 2-fold higher than those of people with uncompromised kidney function, potentially contributing to nephrotoxicity. This suggests that TFV accumulates on PD; thus, daily TAF in PD patients may require dose adjustment or regimen change to optimize treatment, minimize toxicity, and preserve residual kidney function.

Introduction

People living with HIV (PWH) are at a higher risk for developing chronic kidney disease (CKD) than the general population. In North America, up to 1 in 10 individuals living with HIV has CKD, due to both HIV-related factors and traditional risk factors [1,2,3,4]. Peritoneal dialysis (PD) is a form of kidney replacement therapy that has been increasing in use globally and in the USA, where up to 10% of people needing dialysis are on PD [5]. However, data on antiretroviral pharmacokinetics (PK) and dosing in this population are scarce. Descovy™ (fixed dose formulation of the nucleoside reverse transcriptase inhibitors emtricitabine (FTC) and tenofovir alafenamide (TAF) lacks an FDA label indication for people with severe kidney disease (creatinine clearance (CrCl) < 30 mL/min) who are not yet on dialysis, but can be used in individuals with CrCl < 15mL/min who are on hemodialysis (HD) without dose adjustment, with recommended dosing timed after HD [6,7,8].

TAF is a modified prodrug of tenofovir (TFV); it is administered at lower dosages than tenofovir disoproxil fumarate (TDF) and is associated with enhanced prodrug stability in plasma and lower systemic TFV exposures. Studies of healthy individuals switched from TDF to TAF showed 90% lower plasma TFV concentrations and 2- to 4-fold higher intracellular TFV-DP concentrations with TAF than with TDF [9]. The lower plasma TFV concentration is largely responsible for the improved kidney and bone toxicity profile of TAF [10]. Studies in individuals with severe CKD (CrCl of 15 to 29 mL/min) given TAF have shown that plasma peak concentration (Cmax) and area under the concentration-time curve extrapolated to infinity (AUCinf) of TAF and TFV are 79% and 92% higher, and 2.8-fold and 5.7-fold higher, respectively, than in individuals with normal kidney function given TAF [11].

Conversely, the integrase strand transfer inhibitor (INSTI) dolutegravir (DTG) may be used for people with severe CKD (CrCl < 30 mL/min) who tend to have lower plasma DTG concentrations for unexplained reasons [12], a small case series of the use of daily DTG in people on HD have found it to be safe and effective without dose adjustment [13].

While some scant data on TAF dosing in people with ESKD on HD are available [14, 15], the pharmacokinetics of TAF in people on PD have not been characterized. There is a single case report in the literature of a 46-year-old patient with HIV and HBV on PD who was taking TDF 245 mg once weekly + ritonavir-boosted atazanavir (r/ATZ). Plasma TFV concentrations were measured before and at 2 and 4 h into a peritoneal dialysis session with a 4-hour dwell; observed TFV trough concentrations were 510 ng/mL in serum and 200 ng/mL in the 24-hour dialysis fluid, confirming that TFV is partially extracted by PD. In order to lower concentrations to achieve target steady state concentrations (50–300 ng/mL), TDF dosing was decreased to 245 mg every 2 weeks; post-dose adjustment, observed serum TFV concentrations were 200 ng/mL [16].

To our knowledge, the current report is the first in the literature to describe the PK of TAF in a PWH on peritoneal dialysis.

Case presentation

A 49-year-old African American gentleman with past recovery from hepatitis B virus (HBV) infection and stably controlled HIV (CD4: 255 cells/mm3 (13.5%); HIV RNA: < 20 copies/mL) developed ESKD in the past 2 years due to type 1 diabetes and hypertension (he denied ingesting any nephrotoxins over this period.) He had been initiated one year prior on continuous 4-cycler PD nightly via an abdominal peritoneal dialysis catheter. At the time of PD initiation, he was found to be a low average transporter with the peritoneal equilibration test (PET). He was consented and brought into the Clinical Research Unit for sampling on two consecutive days. Eleven months prior to the study visit he had a hospitalization for bacterial peritonitis related to his PD catheter. At the time of study visit, his eGFR was 6 mL/min/1.73 m2 (eGFR CKD-Epi (2021) equation) and he was placed on the transplant list for a kidney-pancreas transplant. His overnight PD was followed by morning dosing of his ART. He had been on a TAF-containing regimen for 5 years and had initiated a regimen of once-daily 50 mg DTG/200 mg FTC/25 mg TAF 7 months prior to the described study visit. He was prompted daily to take his ART for 3 days prior to presenting to the clinical trials unit for pharmacologic sampling; pre-dose blood was collected, followed by his observed standard dose of DTG/FTC/TAF. Blood and urine were then collected over a 24-hour period.

Methods

The study was conducted at the Johns Hopkins University School of Medicine’s Drug Development Unit under an institutional review board (IRB)-approved protocol (NA_00031939); the participant provided informed consent. The study included a screening visit to determine eligibility based on the participant taking one of the protocol’s approved drugs, followed by the study visit. Blood was collected for plasma and PBMC isolation pre-dose, and 0.25, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, and 24 h after the observed dose. Urine was collected cumulatively over two time periods, 0–10 h, and 10–24 h post-dose with urine volume totals recorded. The participant’s plasma trough concentrations for all drugs were compared pre-dose and at 24 h after dose, to assess if he was at steady state on his ART. PK parameters were compared between the person included in this case report and cohorts of PWH, both with normal kidney function and on hemodialysis (HD). (Table 1). The PK parameters compared included time until maximum plasma concentration (Tmax), (Cmax), minimum plasma concentration (Cmin), and (AUClast). Renal dose was calculated from the 24-hour cumulative urine volume and the urine drug concentration. Renal clearance was then calculated as described before [17, 18]. KT/V and urea clearance values were calculated in his Nephrology chart with an online calculator where K is urea clearance, T is time on dialysis, and V is the urea volume of distribution where K is urea clearance, T is time on dialysis, and V is the urea volume of distribution [19, 20].

Table 1 Plasma and intracellular PK parameters for TAF, TFV, FTC, and DTG from a participant with HIV on PD & Comparison (ratio) of parameters to those in PWH with normal kidney function (normal CrCl)

Drug concentrations were determined via liquid chromatographic-mass spectrometric (LC-MS/MS) analysis using previously described methods by the Clinical Pharmacology Analytical Laboratory (CPAL) within the Johns Hopkins University School of Medicine [23,24,25]. Assay lower limits of quantification (LLOQ) were as follows: plasma TAF, 0.03 ng/mL; plasma TFV: 1 ng/mL; plasma FTC: 5 ng/mL; plasma DTG: 100 ng/mL; urine TFV, 50 ng/mL; urine FTC, 50 ng/mL; PBMC tenofovir diphosphate (TFV-DP), 5 fmol/sample; PBMC emtricitabine triphosphate (FTC-TP), 50 fmol/sample. Intracellular anabolite concentrations were normalized to cell counts and reported as fmol/million cells.

Results

The participant was initially non-oliguric and continued to produce urine throughout the 24-hour study visit. Dialysis dose delivered was quantified by the KT/V ratio and residual kidney function was quantified by the urea clearance (for reference, normal kidneys clear urea at a rate of 65 mL/min, equating to 655 L of blood per week). KT/V ratio and residual renal urea clearance were 1.82 and 0.58 L/week six weeks before the study visit, 1.84 and 0.07 L/week one month after the study visit, 1.84 and 0.43 L/week 4 months after the study visit, and 1.62 and 0.18 L/week six months after the study visit, respectively [19, 20]. Viral suppression was maintained.

Plasma concentration time profiles were plotted in relation to PK values in those with normal renal function (Fig. 1). Plasma pre-dose and 24-hour post-dose trough concentrations were 670 and 718 ng/mL for DTG, 147 and 164 ng/mL for TFV, and 888 and 1006 ng/mL for FTC, respectively, indicating that the participant may not have been at steady-state for his ART medications. The TAF Cmin was below the limits of quantitation of 0.05 ng/mL. When compared with concentrations in PWH with normal kidney function, (Tables 2 and 1) TAF Cmax and AUClast, were 1.92 and 1.40 times higher respectively; elevations were more pronounced for TFV, as Cmax and AUClast were 11.1 and 13.3-fold higher in the participant undergoing PD than in PWH with normal renal function. FTC Cmax and AUClast were 1.74 and 5.56-fold higher. Cmin was 15.5-fold and 20- fold higher for TFV and FTC, respectively. Lastly, DTG Cmin, Cmax and AUClast were 0.90-, 0.51-and 0.60-fold lower, respectively.

Table 2 Comparison of Plasma and Intracellular PK parameters for TAF, TFV, FTC, and DTG between the participant with HIV on PD and other populations with and without HIV and renal impairment
Fig. 1
figure 2

Plasma concentration: time plots of TAF, TFV, FTC, and DTG. Plasma drug concentration versus time plots for each of the four analytes related to the three drugs studied. Dotted reference lines indicate historical Cmax (long dash) and Cmin (short dash) for TAF, TFV, FTC, and DTG historical data. TFV plot includes additional historical Cmax (solid line) and Cmin (dotted line) from TDF dosing

Intracellular TFV-DP and FTC-TP concentrations were compared with historical and published data (Table 2); TFV-DP Cmax, AUClast, and Cmin were 1.74 times, 2.04 times, and 2.18 times higher in the participant receiving PD (Table 2). TFV-DP Cmax and AUClast were still within the range of concentrations observed in those with non-compromised renal function. For FTC-TP, Cmax was 4.68 times higher but within normal range, while AUClast, and Cmin were 4.17 and 5.44 times higher, respectively, and out of range when comparing his measurements with the median FTC-TP exposures of people with normal kidney function.

The participant produced 615 mL of urine over a 24-hour period. Total urine concentrations for FTC and TFV were 56,380 ng/mL and 6,743 ng/mL, respectively, for the first (0–10 h) period, and 27,970 ng/mL and 4,524 ng/mL, respectively, for the 10-24-hour period. Dose and renal clearance were calculated for both drugs. For TFV, the cumulative amount excreted (A0 − 24) was 3.3 mg, which makes up 22% of the 15 mg of TFV provided by 25 mg of TAF [26]. The TFV renal clearance was 14.1 mL/min. For FTC, (A0 − 24) was 23.86 mg, which is 11.9% of total 200 mg dose, with renal clearance 8.93 mL/min.

Discussion

We present the first report on TAF PK in a person with HIV with ESKD on chronic PD. Both Cmax and AUC of TAF in this participant were comparable with TAF concentrations in individuals with normal kidney function, likely due to the fact that TAF is not renally cleared to a significant degree [11, 27]. However, plasma TFV concentrations were higher in the setting of PD, ranging from 11-fold (Cmax) to 15-fold (Cmin) higher compared to individuals with normal kidney function. The elevated TFV trough observed in the participant on TAF in the setting of PD likely indicates plasma accumulation. Notably, the TFV trough concentration was also 3-fold higher than what would be expected with steady-state TDF dosing in someone with normal renal function (median trough concentration of ∼ 50 ng/mL (IQR 35–77) [28,29,30].

While FTC Cmax was modestly higher in our PD patient compared to patients with normal renal function, both FTC AUClast and FTC trough (Cmin) were many-fold higher—6-fold and 20-fold higher, respectively. This suggests FTC accumulation in the plasma, however, this may not add substantial toxicity risk given the overall tolerability of FTC [31]. Lastly, DTG peak, trough, and AUClast, measurements were lower in this participant than in people with normal kidney function. This might indicate that DTG is either (1) better cleared by PD (compared to HD where it is only minimally cleared, with a median extraction ratio of 7%) or (2) not being absorbed as well, or (3) another mechanism that is not yet characterized [13]. Regardless, the DTG trough concentrations, while low, are above the protein-adjusted in vitro IC90 of 64 ng/mL and also above 300 ng/mL, the median plasma trough concentrations established to be sufficient for viral suppression from 10 mg DTG once daily,, which showed equivalent viral suppression to recommended 50 mg once daily in the phase 2 efficacy trial SPRING-1) [32].

Despite the high plasma TFV concentrations, TFV-DP Cmax and AUC last were within the normal range, while Cmin was slightly above the range, 2.18 times the average historical data. For FTC-TP, Cmax was within range, while AUClast and Cmin were higher compared with historic data, with Cmin being 5.44-fold higher than the historical average. The molar relationship between plasma FTC and intracellular FTC-TP (0.1) is higher than previously reported (0.034) [33, 34, 22] and may be attributed to the 20-fold higher plasma FTC trough concentrations, or the saturation of one of the molecular mechanisms responsible for the conversion of FTC to FTC-TP [8, 35, 36].

Comparing the participant’s urine data to a recent study of people with normal renal function taking FTC/TDF [37], the TFV A0 − 24 was 38 mg, which made up 28% of the 136 mg TFV provided by 300 mg TDF, while the clearance was 289 mL/min, which is 20-fold higher than the clearance in the participant. This supports that TFV is not getting sufficiently cleared in the participant by his kidneys nor by his PD, causing the accumulation. As for FTC, in those with normal renal function, the A0 − 24 was 114 mg, making up 57% of the 200 mg dose of the FTC. Clearance was 216 mL/min, 24-fold the clearance in the participant.

The factors that determine whether a given drug is likely to be removed via PD include drug specific factors like molecular weight, protein binding, water solubility, and volume of distribution, as well as patient specific factors like their peritoneal membrane transport function [38, 39]. TFV it is cleared by HD, with an extraction ratio of around 54%, and has factors that suggest it should be easily dialyzable via PD [14, 40]. However, since plasma TFV concentrations were quite elevated in this participant on PD, the amount of TFV removed with PD is likely insufficient to overcome the accumulation that occurs in the absence of renal elimination. And although the TFV concentrations were lower compared with historical HD data, those were from people dosed with TDF. Bloodstream TFV concentrations in the setting of daily adherence to TAF might be even higher, given that this individual was not at steady state. Further, the TFV accumulation observed in our PD patient led to TFV plasma trough concentration threefold those seen with daily TDF dosing, possibly mitigating any renal safety advantages conferred by TAF compared to TDF, as concentrations in this range have previously been linked to potential nephrotoxicity [41, 42].

Between the time of the study visit and the publication of this report, the patient’s residual kidney function had declined further, fluctuating around a low baseline. We do not know if this resulted from continued progression of his underlying renal disease or elevated plasma TFV concentrations. Regardless, based on data from this single individual on PD, we conclude that once daily TAF dosing results in plasma trough TFV concentrations 15-fold higher than those in individuals with normal kidney function, and 3-fold higher than trough TFV concentrations in individuals with normal kidney function on TDF. Notably, we do not judge any of the observed PK changes in the participant on PD to have resulted in any loss of antiviral efficacy; he has remained suppressed. But while more research is needed, it may be reasonable at present to avoid daily TAF in people with ESKD receiving PD where preservation of residual kidney function is strongly desired.

Data availability

The deidentified data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.

References

  1. Valdivia-Cerda V, Alvarez-Zavala M, Sánchez-Reyes K, Cabrera-Silva RI, Ruiz-Herrera VV, Loza-Salazar AD, et al. Prevalence and risk factors of chronic kidney disease in an HIV positive Mexican cohort. BMC Nephrol. 2021;22(1):317.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Ekrikpo UE, Kengne AP, Bello AK, Effa EE, Noubiap JJ, Salako BL, et al. Chronic kidney disease in the global adult HIV-infected population: a systematic review and meta-analysis. PLoS ONE. 2018;13(4):e0195443.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Wyatt CM. Kidney disease and HIV infection. Top Antivir Med. 2017;25(1):13–6.

    PubMed  PubMed Central  Google Scholar 

  4. Swanepoel CR, Atta MG, D’Agati VD, Estrella MM, Fogo AB, Naicker S, et al. Kidney disease in the setting of HIV infection: conclusions from a kidney disease: improving global outcomes (KDIGO) Controversies Conference. Kidney Int. 2018;93(3):545–59.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Zimmerman AM. Peritoneal dialysis: increasing global utilization as an option for renal replacement therapy. J Glob Health 9(2):020316.

  6. FDA. DESCOVY FDA Package Insert. 2016.

  7. Dosing Recommendations for Drugs Used to Treat or Prevent Opportunistic Infections That Require Dosage Adjustment in Patients with Renal Insufficiency| NIH [Internet]. 2023 [cited 2023 Apr 30]. https://clinicalinfo.hiv.gov/en/guidelines/hiv-clinical-guidelines-adult-and-adolescent-opportunistic-infections/dosing-recommendations-drugs-used-full

  8. Gilead Sciences Inc. FDA CLINICAL PHARMACOLOGY AND BIOPHARMACEUTICS REVIEW, -. SUMMARY OF BIOPHARMACEUTICAL STUDIES AND ASSOCIATED ANALYTICAL METHODS. 2014.

  9. Podany AT, Bares SH, Havens J, Dyavar SR, O’Neill J, Lee S, et al. Plasma and intracellular pharmacokinetics of tenofovir in patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide. AIDS. 2018;32(6):761–5.

    Article  CAS  PubMed  Google Scholar 

  10. Gupta SK, Post FA, Arribas JR, Eron JJ, Wohl DA, Clarke AE, et al. Renal safety of tenofovir alafenamide vs. tenofovir disoproxil fumarate: a pooled analysis of 26 clinical trials. AIDS. 2019;33(9):1455–65.

    Article  CAS  PubMed  Google Scholar 

  11. Custodio JM, Fordyce M, Garner W, Vimal M, Ling KHJ, Kearney BP, et al. Pharmacokinetics and safety of Tenofovir Alafenamide in HIV-Uninfected subjects with severe renal impairment. Antimicrob Agents Chemother. 2016;60(9):5135–40.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. FDA. TIVICAY FDA Package Insert. 2013.

  13. Moltó J, Graterol F, Miranda C, Khoo S, Bancu I, Amara A, et al. Removal of Dolutegravir by Hemodialysis in HIV-Infected patients with end-stage renal disease. Antimicrob Agents Chemother. 2016;60(4):2564–6.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Eron JJ, Wilkin A, Ramgopal M, Osiyemi O, McKellar M, McKellar M, et al. A daily single tablet regimen (STR) of Bictegravir/Emtricitabine/Tenofovir alafenamide (B/F/TAF) in virologically-suppressed adults living with HIV and End Stage Renal Disease on Chronic Hemodialysis. Open Forum Infect Dis. 2020;7(Suppl 1):S529–30.

    Article  PubMed Central  Google Scholar 

  15. Eron JJ, Lelievre JD, Kalayjian R, Slim J, Wurapa AK, Stephens JL et al. Safety of elvitegravir, cobicistat, emtricitabine, and tenofovir alafenamide in HIV-1-infected adults with end-stage renal disease on chronic haemodialysis: an open-label, single-arm, multicentre, phase 3b trial. Lancet HIV. 2018;S2352-3018(18)30296-0.

  16. Aleman J, van den Berk GEL, Franssen EJF, de Fijter CWH. Tenofovir disoproxil treatment for a HIV-hepatitis B virus coinfected patient undergoing peritoneal dialysis: which dose do we need? AIDS. 2015;29(12):1579–80.

    Article  PubMed  Google Scholar 

  17. Tucker GT. Measurement of the renal clearance of drugs. Br J Clin Pharmacol. 1981;12(6):761–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Rowland M, Tozer TN. Clinical pharmacokinetics: concepts and applications. 3rd ed. Baltimore: Williams & Wilkins; 1995. p. 601.

    Google Scholar 

  19. Touchcalc - Programmed by Stephen Z Fadem. PD KT/V CALCULATOR [Internet]. [cited 2023 Jul 26]. http://touchcalc.com/calculators/ktv_pd

  20. NIH. Hemodialysis dose and adequacy - national kidney and Urologic Diseases Information Clearinghouse - National Institute of Diabetes and Digestive and kidney diseases. NIH Publication No; 2009. pp. 09–4556.

  21. Min S, Sloan L, DeJesus E, Hawkins T, McCurdy L, Song I, et al. Antiviral activity, safety, and pharmacokinetics/pharmacodynamics of dolutegravir as 10-day monotherapy in HIV-1-infected adults. AIDS. 2011;25(14):1737.

  22. Thurman AR, Schwartz JL, Cottrell ML, Brache V, Chen BA, Cochón L et al. Safety and Pharmacokinetics of a Tenofovir Alafenamide Fumarate-Emtricitabine based Oral Antiretroviral Regimen for Prevention of HIV Acquisition in Women: A Randomized Controlled Trial. eClinicalMedicine [Internet]. 2021 Jun 1 [cited 2023 Jul 5];36. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(21)00173-5/fulltext

  23. Hummert P, Parsons TL, Ensign LM, Hoang T, Marzinke MA. Validation and implementation of liquid chromatographic-mass spectrometric (LC–MS) methods for the quantification of tenofovir prodrugs. J Pharm Biomed Anal. 2018;152:248–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Hendrix CW, Andrade A, Bumpus NN, Kashuba AD, Marzinke MA, Moore A, et al. Dose frequency ranging pharmacokinetic study of Tenofovir-Emtricitabine after directly observed dosing in healthy volunteers to establish adherence benchmarks (HPTN 066). AIDS Res Hum Retroviruses. 2016;32(1):32–43.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dooley KE, Savic R, Gupte A, Marzinke MA, Zhang N, Edward VA, et al. Once-weekly rifapentine and isoniazid for tuberculosis prevention in patients with HIV taking dolutegravir-based antiretroviral therapy: a phase 1/2 trial. Lancet HIV. 2020;7(6):e401–9.

    Article  PubMed  Google Scholar 

  26. Kawuma AN, Wasmann RE, Sinxadi P, Sokhela SM, Chandiwana N, Venter WDF, et al. Population pharmacokinetics of tenofovir given as either tenofovir disoproxil fumarate or tenofovir alafenamide in an African population. CPT: Pharmacometrics Syst Pharmacol. 2023;12(6):821–30.

    CAS  PubMed  Google Scholar 

  27. Di Perri G. Tenofovir alafenamide (TAF) clinical pharmacology. Infez Med. 2021;29(4):526–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. FDA. TRUVADA FDA Package Insert. 2016.

  29. Barditch-Crovo P, Deeks SG, Collier A, Safrin S, Coakley DF, Miller M, et al. Phase I/II trial of the Pharmacokinetics, Safety, and antiretroviral activity of Tenofovir Disoproxil Fumarate in Human Immunodeficiency Virus-infected adults. Antimicrob Agents Chemother. 2001;45(10):2733–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Calcagno A, Gonzalez de Requena D, Simiele M, D’Avolio A, Tettoni MC, Salassa B, et al. Tenofovir plasma concentrations according to Companion drugs: a cross-sectional study of HIV-Positive patients with normal renal function. Antimicrob Agents Chemother. 2013;57(4):1840–3.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wood BR, Pozniak AL. Dosing lamivudine or emtricitabine in renal impairment: new data confirm it’s time for updated guidance! AIDS. 2021;35(8):1305–7.

    Article  PubMed  Google Scholar 

  32. van Lunzen J, Maggiolo F, Arribas JR, Rakhmanova A, Yeni P, Young B, et al. Once daily dolutegravir (S/GSK1349572) in combination therapy in antiretroviral-naive adults with HIV: planned interim 48 week results from SPRING-1, a dose-ranging, randomised, phase 2b trial. Lancet Infect Dis. 2012;12(2):111–8.

    Article  PubMed  Google Scholar 

  33. Anderson PL, Kiser JJ, Gardner EM, Rower JE, Meditz A, Grant RM. Pharmacological considerations for tenofovir and emtricitabine to prevent HIV infection. J Antimicrob Chemother. 2011;66(2):240–50.

    Article  CAS  PubMed  Google Scholar 

  34. Seifert SM, Chen X, Meditz AL, Castillo-Mancilla JR, Gardner EM, Predhomme JA, et al. Intracellular tenofovir and Emtricitabine anabolites in Genital, rectal, and blood compartments from first dose to steady state. AIDS Res Hum Retroviruses. 2016;32(10–11):981–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Paff MT, Averett DR, Prus KL, Miller WH, Nelson DJ. Intracellular metabolism of (-)- and (+)-cis-5-fluoro-1-[2-(hydroxymethyl)-1,3-oxathiolan-5-yl]cytosine in HepG2 derivative 2.2.15 (subclone P5A) cells. Antimicrob Agents Chemother. 1994;38(6):1230–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Painter GR, Rimsky LT, Furman PA, Liotta DC, Schinazi RF, Quinn JB. Preclinical and clinical development of the anti-HIV, anti-HBV oxathiolane nucleoside analog emtricitabine. Front Viral Hepat. 2003;451–84.

  37. Coleman JS, Diniz CP, Fuchs EJ, Marzinke MA, Aung W, Bakshi RP, et al. Interaction of Depot Medroxyprogesterone acetate and Tenofovir Disoproxil Fumarate/Emtricitabine on Peripheral Blood mononuclear cells and cervical tissue susceptibility to HIV infection and pharmacokinetics. JAIDS J Acquir Immune Defic Syndr. 2023;92(1):89.

    Article  CAS  PubMed  Google Scholar 

  38. Kidney Disease Clinic [Internet]. [cited 2023 Apr 30]. https://kidneydiseaseclinic.net/dialyzers/kidneydiseaseclinic.net

  39. Misra M, Khanna R. Peritoneal equilibration test. UpToDate. Retreived July 3rd, 2023, from https://www.uptodate.com/contents/peritoneal-equilibration-test#:~:text=The peritoneal equilibration test (PET,peritoneal capillary blood and dialysate. In 2022.

  40. Ueaphongsukkit T, Gatechompol S, Avihingsanon A, Surintrspanont J, Iampenkhae K, Avihingsanon Y, et al. Tenofovir alafenamide nephrotoxicity: a case report and literature review. AIDS Res Ther. 2021;18(1):53.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Avihingsanon A, Sophonphan J, Thammajaruk N, Chaihong P, Burger D, Cressey TR, et al. Plasma tenofovir concentrations and proximal tubular dysfunction in HIV-Infected adults receiving tenofovir in Thailand. J AIDS Clin Res. 2015;6(7):1–7.

    Article  Google Scholar 

  42. Kunimoto Y, Ikeda H, Fujii S, Kitagawa M, Yamazaki K, Nakata H, et al. Plasma tenofovir trough concentrations are associated with renal dysfunction in Japanese patients with HIV infection: a retrospective cohort study. J Pharm Health Care Sci. 2016;2(1):22.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors would like to acknowledge and thank the research participant for his time and participation in the study.

Funding

EDW reports receiving funding through the NIH Career Development K23 Grant.

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Contributions

SAM, EJF, and RPB performed the research. SAM, EJF, EDW, CWH, and MAM designed the research study. RPB and MAM contributed essential reagents and tools. SAM and EDW analyzed the data. All authors contributed equally in writing the paper.

Corresponding author

Correspondence to Ethel D. Weld.

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MGA is involved in litigation involving Gilead Sciences Inc.

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Massih, S.A., Atta, M.G., Thio, C.L. et al. Pharmacokinetics of tenofovir alafenamide, emtricitabine, and dolutegravir in a patient on peritoneal dialysis. AIDS Res Ther 21, 34 (2024). https://doi.org/10.1186/s12981-024-00616-5

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  • DOI: https://doi.org/10.1186/s12981-024-00616-5

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