Kidney International Reports
Elsevier
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Ritonavir-Boosted Protease Inhibitors Do Not Significantly Affect the Performance of Creatinine-Based Estimates of GFR
Volume: 5, Issue: 5
DOI 10.1016/j.ekir.2020.01.020
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Wyatt, Chaudhari, Miao, Krishnasami, Hellinger, Levey, Ross, Ryom, Mocroft, Brunet, Fusco, and Inker: Ritonavir-Boosted Protease Inhibitors Do Not Significantly Affect the Performance of Creatinine-Based Estimates of GFR

Chronic kidney disease (CKD) is more common among HIV-positive individuals.S1–S4 Accurate estimation of glomerular filtration rate (GFR) is important for appropriate antiretroviral (ART) regimen selection and dose adjustment, and for the identification of patients with CKD who may benefit from more intensive modification of HIV-related and traditional CKD risk factors.1, 2 Commonly used estimates of GFR are based on serum creatinine, a product of skeletal muscle metabolism that is primarily eliminated by glomerular filtration. The generation of creatinine by muscle, with substantial variability in muscle mass between and even within individuals over time, is well recognized as an important limitation of creatinine-based GFR estimates (eGFRCr ) in HIV-positive individuals.1, 2

Until recently, the impact of active tubular secretion on eGFRCr has rarely been a clinically relevant concern. In early-phase clinical trials, the newer pharmacoenhancer cobicistat and the ART agents dolutegravir, raltegravir, and rilpivirine were observed to cause an early rise in serum creatinine and a corresponding decrease in eGFRCr .3, S5–S15In vitro studies have demonstrated that cobicistat and dolutegravir interfere with the tubular secretion of creatinine by inhibiting specific tubular transporters.4 As such, a small increase in serum creatinine is expected with the initiation of these agents and is not thought to reflect a decline in true kidney function. This can complicate the interpretation of eGFRCr or calculated creatinine clearance, particularly near dosing thresholds or in patients with or at risk for progressive CKD.

In the same series of in vitro experiments, ritonavir was also shown to inhibit the tubular transport of creatinine.4 Although the physiologic relevance is unknown, particularly with low-dose ritonavir used as a pharmacoenhancer, this raises the possibility that ritonavir-boosted protease inhibitors (PI/r) could also affect serum creatinine and eGFRCr independent of their effect on GFR. Because multiple prior studies have linked PI/r exposure to an increased risk of CKD as defined by decreased eGFRCr ,2, 5, 6 this could have implications both for epidemiologic research and for clinical practice. We sought to determine whether the performance of eGFRCr is affected by the use of PI/r, using a direct measure of GFR by plasma iohexol clearance as the reference standard.

We conducted a secondary analysis of a published cross-sectional study that compared the performance of available GFR estimates in 200 HIV-positive individuals on stable ART therapy.7, 8 Characteristics of the study population have been described previously.7 Briefly, 73% of participants were male, 52% were of self-reported black race, and 34% were older than 50 years (Table 1); 61% of participants had a suppressed HIV-RNA, and the median CD4+ cell count was 536 cells/μl. The ART regimen included a PI/r in 87 participants (44%), with the most common agents being atazanavir/r (n = 46), darunavir/r (n = 17), and lopinavir/r (n = 15). Among participants who were not taking a PI/r, 20 were taking an unboosted PI, most commonly atazanavir, and 23 were taking raltegravir. No participants were on cobicistat, dolutegravir, or rilpivirine. The most commonly used backbone was tenofovir disoproxil fumarate, in 63% of participants.

Table 1
Characteristics of the study population
Participant characteristicsOverall (n = 200)PI/r (n = 87)No PI/r (n = 113)
Median age, yr48.0 (42.5, 53.0)48.0 (43.0, 54.0)47.0 (42.0, 52.0)
 > 50 yr68 (34)36 (41)32 (28)
Male145 (73)58 (67)87 (77)
Black104 (52)51 (59)53 (47)
Median weight, kg77.0 (67.6, 87.7)78.1 (69.1, 86.3)75.6 (66.9, 88.6)
Median BMI, kg/m226.1 (22.7, 29.1)26.4 (23.1, 29.4)25.7 (22.3, 28.7)
BMI <22 kg/m235 (18)13 (15)22 (19)
BMI >30 kg/m236 (18)18 (21)18 (16)
Hypertension60 (30)23 (26)37 (33)
Diabetes mellitus16 (8)5 (6)11 (10)
Hepatitis B–virus coinfection22 (11)11 (13)11 (10)
Hepatitis C–virus coinfection51 (26)24 (28)27 (24)
Ritonavir-boosted PI use
 Atazanavir/r46 (23)46 (53)
 Darunavir/r17 (9)17 (20)
 Lopinavir/r15 (8)15 (18)
 Fosamprenavir/r7 (4)7 (8)
 Saquinavir/r2 (1)2 (2)
 Tipranavir/r1 (1)1 (1)
Unboosted PI use20 (10)20 (18)
Raltegravir use23 (12)9 (10)14 (12)
Tenofovir (TDF) use125 (63)52 (60)73 (65)
Undetectable HIV-RNAa111 (61)53 (68)58 (56)
Median CD4+ cell count, cells/μl536 (354, 775)567 (312, 783)505 (359, 770)
Median C-reactive protein, mg/l1.6 (0.8, 4.8)1.4 (0.8, 5.5)1.6 (0.8, 4.4)
Median serum albumin, g/dl3.8 (3.6, 4.1)3.8 (3.6, 4.0)3.8 (3.6, 4.1)
Median serum creatinine, mg/dl1.1 (0.9, 1.3)1.1 (0.9, 1.4)1.1 (0.9, 1.3)
Median measured GFR, ml/min per 1.73 m286 (69, 105)82 (66, 100)90 (73, 106)
 < 60 ml/min per 1.73 m228 (14)14 (16)14 (12)
Median estimated GFR, ml/min per 1.73 m2
 CKD-EPI creatinine81 (62, 100)71 (55, 99)83 (66, 100)
 MDRD Study Equation75 (57, 91)67 (53, 91)77 (62, 91)
 Cockcroft-Gault CrCl81 (63, 96)77 (57, 93)82 (67, 99)
BMI, body mass index; CKD-EPI, Chronic Kidney Disease–Epidemiology Collaboration; Cockcroft-Gault CrCl, calculated creatinine clearance indexed to 1.73 m2 body surface area for consistency with measured GFR; GFR, glomerular filtration rate; MDRD, Modification of Diet in Renal Disease; PI/r, ritonavir-boosted protease inhibitor; TDF, tenofovir disoproxil fumarate.
Median values are expressed as median (25th percentile, 75th percentile). All other values are expressed as n (%).
a Eighteen participants had missing data for viral load status.

Overall, demographic and clinical characteristics were similar between participants on PI/r versus no PI/r regimens. The only statistically significant difference between groups was in measured GFR, which was lower in participants taking a PI/r versus no PI/r (median, 82 ml/min per 1.73 m2 vs. 90 ml/min per 1.73 m2, P = 0.04). Regardless of the GFR estimating equation used, eGFR also tended to be lower in participants taking a PI/r. Overall, 14% of participants had a measured GFR <60 ml/min per 1.73 m2.

As we have previously reported, all 3 creatinine-based GFR estimating equations underestimated the measured GFR in the study population (positive bias), and the CKD-EPICr equation had the smallest bias.7 In the current study, we demonstrate that the bias, accuracy, and precision of the CKD-EPICr were similar regardless of PI/r use (Figure 1 and Table 2); for example, 1-P30 was 16.1 (95% confidence interval, 9.2–23.0) for participants on a PI/r and 14.2 (95% confidence interval, 8.0–20.4) for those not on a PI/r (P  = 0.704). The results were qualitatively similar for the Modification of Diet in Renal Disease and Cockcroft-Gault equations (Figure 1 and Table 2) and in 2 sensitivity analyses: the first excluding participants with detectable plasma viral load or receiving an unboosted PI (Supplementary Table S1) and the second excluding participants on raltegravir (Supplementary Table S2). Tubular secretion, estimated as the difference between measured creatinine clearance and measured GFR, was highly variable, with a similar distribution regardless of PI/r use.

Performance of creatinine-based glomerular filtration rate (GFR) estimates stratified by ritonavir-boosted protease inhibitor use. Left: bias (median difference between measured and estimated GFR). Positive bias indicates an underestimation of measured GFR. Right: accuracy (percentage of estimates greater than 30% of measured GFR; 1-P30). Error bars represent interquartile ranges. CG, creatinine clearance estimated by the Cockcroft-Gault equation indexed to 1.73 m2 body surface area for comparison with the other equations; CKD-EPICr, glomerular filtration rate estimated by the Chronic Kidney Disease–Epidemiology Collaboration creatinine equation; MDRD, GFR estimated by the Modification of Diet in Renal Disease Study equation; PI/r, ritonavir-boosted protease inhibitor.
Figure 1
Performance of creatinine-based glomerular filtration rate (GFR) estimates stratified by ritonavir-boosted protease inhibitor use. Left: bias (median difference between measured and estimated GFR). Positive bias indicates an underestimation of measured GFR. Right: accuracy (percentage of estimates greater than 30% of measured GFR; 1-P30). Error bars represent interquartile ranges. CG, creatinine clearance estimated by the Cockcroft-Gault equation indexed to 1.73 m2 body surface area for comparison with the other equations; CKD-EPICr, glomerular filtration rate estimated by the Chronic Kidney Disease–Epidemiology Collaboration creatinine equation; MDRD, GFR estimated by the Modification of Diet in Renal Disease Study equation; PI/r, ritonavir-boosted protease inhibitor.
Table 2
Performance of GFR estimating equations stratified by ritonavir-boosted protease inhibitor use (n = 200)
EquationsBoosted PIMedian bias (95% CI)IQR (95% CI)1-P30 (95% CI)
CKD-EPICrPI/r5.5 (2.2–11.4)21.9 (16.5–30.0)16.1 (9.2–23.0)
No PI/r5.4 (0.5–9.3)22.7 (17.3–30.5)14.2 (8.0–20.4)
MDRD StudyPI/r11.4 (6.0–16.8)20.8 (16.8–26.9)18.4 (11.5–26.4)
No PI/r10.8 (7.3–15.6)22.4 (17.5–29.3)21.2 (14.2–29.2)
Cockcroft-GaultPI/r6.9 (2.4–11.0)22.6 (16.5–28.7)17.2 (10.3–25.3)
No PI/r7.9 (3.0–11.1)24.4 (19.4–29.7)17.7 (10.6–24.8)
CI, confidence interval; CKD-EPICr, glomerular filtration rate (GFR) estimated by the Chronic Kidney Disease–Epidemiology Collaboration creatinine equation; Cockcroft-Gault, creatinine clearance estimated by the Cockcroft-Gault equation indexed to 1.73 m2 body surface area; IQR, interquartile range; MDRD Study, GFR estimated by the MDRD Study equation; PI, protease inhibitor; P30, accuracy indicated as percent of estimates within 30% of the measured GFR (mGFR), with large errors indicated by 1-P30.
Statistical significance of the difference for the median of errors for each equation was tested using the Wilcoxon 2-sample test with t-approximation and for differences of 1-P30 using the χ2 test. None of the P values were less than alpha level of 0.05 and are, hence, not listed here. Bias (median difference between measured and estimated GFR). Positive numbers indicate an underestimate of mGFR and negative numbers indicate an overestimate of mGFR.

In this study of HIV-positive adults on stable ART, the use of low-dose ritonavir as a pharmacoenhancer did not have a clinically or statistically significant impact on the performance of commonly used creatinine-based GFR estimates as compared with a direct measure of GFR. This finding is consistent with a more recent in vitro study suggesting that exposure of proximal tubular epithelial cells to ritonavir at low levels consistent with its use as a pharmacoenhancer does not inhibit the relevant tubular transporter for creatinine.9 We previously reported no difference in the performance of GFR estimates with the use of tenofovir disoproxil fumarate in this population,7 suggesting that the observed declines in eGFR with cumulative exposure to PI/r and tenofovir disoproxil fumarate alone or in combination likely reflect a true change in GFR rather than a change in tubular secretion of creatinine or other non-GFR effect.

Key strengths of the current analysis include use of a direct measure of GFR as the gold standard, use of a creatinine assay traceable to reference standards, and inclusion of a generalizable patient sample from 3 unique clinical sites, across a range of body composition, HIV disease control, and kidney function. Although we used a convenience sample with measured GFR available from a prior study, the sample included adequate numbers of participants receiving PI/r and alternative third-agent ART regimens to allow for comparison between the groups. The relatively small sample of participants on PI/r did not allow for comparisons between specific PI/r, some of which have been more strongly linked to decreased eGFR. In addition, data on duration of ART exposure were not collected; however, all participants had been on a stable ART regimen for at least 3 months before enrollment. We were also unable to validate the reported impact of the newer pharmacoenhancer cobicistat or the antiretroviral agents dolutegravir and rilpivirine, as these agents were not approved for use at the time of the original study. Nonetheless, the absence of these agents simplifies the interpretation of our results. Sensitivity analyses excluding participants on raltegravir or an unboosted PI yielded similar results, suggesting that their inclusion did not influence the results. Finally, the original study was not specifically designed to evaluate differences in tubular creatinine secretion between groups. Creatinine clearance was measured using a short timed urine collection, and the resulting measure of estimated tubular secretion varied widely across the study population regardless of PI/r use.

Despite evidence that ritonavir interferes with the tubular secretion of creatinine in vitro, the results of the current study suggest that the use of low-dose ritonavir as a pharmacoenhancer does not have a clinically or statistically significant impact on the performance of creatinine-based GFR estimates.

Disclosure

All the authors declared no competing interests.

References

1 

    Lucas G.M., Ross M.J., Stock P.G.. Clinical practice guideline for the management of chronic kidney disease in patients infected with HIV: 2014 update by the HIV Medicine Association of the Infectious Diseases Society of America. Clin Infect Dis 59: 2014. , pp.e96-e138

2 

    Swanepoel C.R., Atta M.G., D'Agati V.D.. Kidney disease in the setting of HIV infection: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference. Kidney Int 93: 2018. , pp.545-559

3 

    German P., Liu H.C., Szwarcberg J.. Effect of cobicistat on glomerular filtration rate in subjects with normal and impaired renal function. J Acquir Immune Defic Syndr 61: 2012. , pp.32-40

4 

    Lepist E.I., Zhang X., Hao J.. Contribution of the organic anion transporter OAT2 to the renal active tubular secretion of creatinine and mechanism for serum creatinine elevations caused by cobicistat. Kidney Int 86: 2014. , pp.350-357

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    Mocroft A., Lundgren J.D., Ross M.. Cumulative and current exposure to potentially nephrotoxic antiretrovirals and development of chronic kidney disease in HIV-positive individuals with a normal baseline estimated glomerular filtration rate: a prospective international cohort study. Lancet HIV 3: 1 2016. , pp.e23-e32

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    Mocroft A., Kirk O., Reiss P.. Estimated glomerular filtration rate, chronic kidney disease and antiretroviral drug use in HIV-positive patients. AIDS 24: 2010. , pp.1667-1678

7 

    Inker L.A., Wyatt C., Creamer R.. Performance of creatinine and cystatin C GFR estimating equations in an HIV-positive population on antiretrovirals. J Acquir Immune Defic Syndr 61: 2012. , pp.302-309

8 

    Okparavero A.A., Tighiouart H., Krishnasami Z.. Use of glomerular filtration rate estimating equations for drug dosing in HIV-positive patients. Antivir Ther 18: 2013. , pp.793-802

9 

    Kikuchi R., Chiou W.J., Kasai M.A.. No inhibition of MATE1/2K-mediated renal creatinine secretion predicted with ritonavir or cobicistat. J Pharm Sci 108: 2019. , pp.3118-3123

Acknowledgments

The original study was supported by 10.13039/100005564Gilead Sciences, Inc. under an investigator-initiated protocol NCRR L1RR025752 and by the 10.13039/100000002National Institutes of Health/10.13039/100006108National Center for Advancing Translational Sciences UL1 RR025752 (10.13039/100006954Tufts Medical Center), UL1 RR029887 (Mount Sinai School of Medicine), and UL1 RR025777 (10.13039/100008333University of Alabama at Birmingham). The investigators received additional support for the current analysis from the 10.13039/100000062National Institute of Diabetes and Digestive and Kidney Diseases R01DK112258 and P01DK056492.

Notes

Supplementary File (PDF)

Supplementary Methods.:

Table S1.: Sensitivity analysis in participants with suppressed HIV-RNA, excluding participants on unboosted PIs (n = 100∗).

Table S2.: Sensitivity analysis excluding participants on raltegravir (n = 177∗).

https://www.researchpad.co/tools/openurl?pubtype=article&doi=10.1016/j.ekir.2020.01.020&title=Ritonavir-Boosted Protease Inhibitors Do Not Significantly Affect the Performance of Creatinine-Based Estimates of GFR&author=Christina M. Wyatt,Juhi Chaudhari,Shiyuan Miao,Zipporah Krishnasami,James Hellinger,Andrew S. Levey,Michael Ross,Lene Ryom,Amanda Mocroft,Laurence Brunet,Jennifer Fusco,Lesley A. Inker,&keyword=&subject=Research Letter,