Plasma cystatin C as a marker for estimated glomerular filtration rate assessment in HIV-1-infected patients treated with dolutegravir-based ART

Plasma cystatin C as a marker for estimated glomerular filtration rate assessment in... Abstract Objectives Inhibition of the organic cation transporter-2 renal tubule transporter by dolutegravir leads to serum creatinine increase. Serum cystatin C is a non-organic cation transporter-2-dependent marker, possibly enabling glomerular filtration rate (GFR) estimation under dolutegravir. Our goal was to evaluate the changes in creatinine- and cystatin C-based estimated GFR values before and after dolutegravir initiation. Methods Creatinine and cystatin measurements were carried out on frozen plasma samples from HIV-1-infected patients, before and after dolutegravir initiation, between October 2016 and March 2017 at Pitié-Salpêtrière Hospital. CKD-EPI equations were used to estimate mean GFR from creatinine and cystatin C values. Variations were analysed by paired t-test. Results Forty-four patients were included [median age = 48 years (IQR 36–58) and median CD4 count = 592 cells/mm3 (IQR 388–728)], including 6 ART-naive patients and 38 on switch strategies [72% with viral load <50 copies/mL and median ART duration = 13 years (IQR 5–20)]. Before dolutegravir initiation (median time = 41 days), 19 patients (43%) had creatinine-based estimated GFR <90 mL/min/1.73 m2 and 11 (25%) had cystatin C-based estimated GFR <90 mL/min/1.73 m2. After dolutegravir initiation, serum creatinine values significantly increased (+8.6 μmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated estimated GFR significantly decreased (−7.7 mL/min/1.73 m2, 95% CI −10.4; −5.1, P < 0.001). In contrast, there was no significant change in cystatin C value variation and associated estimated GFR. The same results were observed regardless of renal function at baseline. Conclusions Creatinine values increased after dolutegravir initiation, whereas no change was observed for cystatin C values. Use of cystatin C may enable better understanding of plasma creatinine fluctuations after dolutegravir initiation, particularly in high-risk renal patients. Introduction Dolutegravir is one of the most recent integrase inhibitors, having shown high efficacy in naive and pretreated HIV-1-infected patients.1 Triple and dual ART regimens including dolutegravir are increasingly being used.2 Dolutegravir inhibits the organic cation transporter (OCT)-2 and plasma creatinine is excreted through this transporter, leading to plasma creatinine increase at treatment initiation. Studies assessing dolutegravir efficacy have highlighted a stable plasma creatinine increase of ∼10 μmol/L as early as week 2–3.3 Estimated glomerular filtration rate (eGFR) is falsely decreased in this context when assessed with plasma creatinine-based equations (MDRD or CKD-EPIcreat). A Phase I study proved that measured GFR (mGFR) remained unchanged after dolutegravir initiation, using non-OCT-2-dependent isotopic markers.4 Monitoring renal function in patients on a dolutegravir-based ART regimen is a daily clinical concern. Cystatin C is a low molecular weight plasma protein freely filtered by the glomerulus. Its production is independent of gender, muscle mass, dietary influences and nyctohemeral period, and could be influenced by inflammation, thyroid dysfunction and smoking.5–8 Cystatin C is a non-OCT-2-dependent routinely available marker, which enables GFR estimation with a validated equation (CKD-EPIcyst).9 Our goal was to evaluate the changes in creatinine- and cystatin-based eGFR values after dolutegravir initiation, in HIV-infected patients from a French reference centre. Methods This study was conducted at Pitié-Salpêtrière Hospital, Paris, France, in March 2017. All HIV-1-infected patients were eligible if dolutegravir-based ART had been initiated between October 2016 and March 2017. They were included if at least one routine frozen plasma sample was available at the hospital laboratory before and after dolutegravir initiation (0–90 days before and 21–180 days after). Patients with systemic inflammation [C-reactive protein (CRP) >5 mg/L] or known thyroid dysfunction were not included. Plasma creatinine, cystatin C and CRP were measured from frozen plasma samples, as stability has been demonstrated after 6 months. Creatinine assay was performed on the Roche-Hitachi P-Module instrument using the Jaffe compensated method standardized against ID/MS. Cystatin C assay was performed on the Roche-Cobas 6000 instrument using the Diagam immunoturbidimetric method standardized against plasma reference material ERM-DA471/IFCC. CRP assay was performed on the Roche-Hitachi P-Module instrument using the particle-enhanced turbidimetric method standardized against the reference preparation CRM 470. CKD-EPIcreat and CKD-EPIcyst equations were used to estimate creatinine- and cystatin-based GFR, as described elsewhere.9 Plasma creatinine and cystatin C values, and creatinine- and cystatin C-based eGFR values were expressed as mean ± SD. Variations of these parameters after dolutegravir initiation were analysed by paired t-test. The analyses of creatinine-based eGFR and plasma viral load (pVL) at baseline were conducted for all patients and then in different subgroups. Routine clinical data were recorded in the Nadis database and informed consent was obtained from all patients. Results Patient characteristics One hundred and seventy-six patients were eligible (dolutegravir initiation in the last 6 months) and 44 patients were included (two available frozen plasma samples, as described earlier), after exclusion of 10 patients with CRP >5 mg/L (Table 1). No one had thyroid dysfunction. Six patients were ART-naive, with a median pVL of 4.8 log10 copies/mL (IQR 4.3–5.2). Thirty-eight were pretreated, with a median ART duration of 13 years (IQR 5–20), and among them 28 (74%) had pVL <50 copies/mL. Data on microalbuminuria or proteinuria were not available. After dolutegravir initiation, the number of patients with tenofovir-, cobicistat- and rilpivirine-based ART was equal or lower than before dolutegravir initiation (Table 1). Reasons for ART switch were: simplification for single tablet regimen in 13 patients (34%); renal, metabolic or bone toxicity in 9 (24%); virological failure in 8 (21%); and prevention of toxicity in 8 (21%). Renal toxicity affected three patients, of whom the first received tenofovir/emtricitabine + rilpivirine and the other two received tenofovir/emtricitabine + elvitegravir/cobicistat. Table 1. Patient characteristics (n = 44) Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Table 1. Patient characteristics (n = 44) Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Plasma creatinine and cystatin C values and associated eGFR at baseline Samples were assessed for a median of 9 days (IQR 2–17) before dolutegravir initiation and 41 days (IQR 29–72) after dolutegravir initiation. The mean plasma creatinine value was 85.6 μmol/L (±21.5), with a mean associated eGFR of 91.5 mL/min/1.73 m2 (±22.8), whereas the mean plasma cystatin C value was 0.80 mg/L (±0.29), with a mean associated eGFR of 106.2 mL/min/1.73 m2 (±30.0) (Table 2). Table 2. Variation in serum creatinine and cystatin C values and associated eGFR after dolutegravir initiation   Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)    Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)  DTG, dolutegravir; NS, statistically not significant. a Statistical test used: paired t-test. Table 2. Variation in serum creatinine and cystatin C values and associated eGFR after dolutegravir initiation   Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)    Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)  DTG, dolutegravir; NS, statistically not significant. a Statistical test used: paired t-test. Nineteen patients (43%) had a creatinine-based eGFR of <90 mL/min/1.73 m2 and 11 (25%) had a cystatin C-based eGFR of <90 mL/min/1.73 m2. Three and two patients had a creatinine- and cystatin C-based eGFR of <60 mL/min, respectively. Variations in plasma creatinine and cystatin C values and associated eGFR After dolutegravir initiation, plasma creatinine values significantly increased (+8.6 μmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated eGFR significantly decreased (−7.7 mL/min/1.73 m2, 95% CI −10.4; −5.1, P < 0.001) (Figure 1 and Table 2). In contrast, there was no significant variation in cystatin C values (−0.03 mg/L, 95% CI −0.12; +0.06, P = 0.50) or associated eGFR (+2.5 mL/min/1.73 m2, 95% CI −6.3; +11.3, P = 0.57) (Figure 1 and Table 2). Figure 1. View largeDownload slide Variation in plasma creatinine- and cystatin-based estimated GFR (eGFR) after dolutegravir initiation. Data are presented as mean eGFR with standard deviation. (a) In all patients (n = 44). (b) In patients with creatinine-based eGFR <90 mL/min/1.73 m2 before dolutegravir initiation (n = 19). (c) In patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before dolutegravir initiation (n = 25). (d) In patients with pVL >50 copies/mL at baseline (n = 16). *Statistically significant after performing paired t-test. DTG, dolutegravir. Figure 1. View largeDownload slide Variation in plasma creatinine- and cystatin-based estimated GFR (eGFR) after dolutegravir initiation. Data are presented as mean eGFR with standard deviation. (a) In all patients (n = 44). (b) In patients with creatinine-based eGFR <90 mL/min/1.73 m2 before dolutegravir initiation (n = 19). (c) In patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before dolutegravir initiation (n = 25). (d) In patients with pVL >50 copies/mL at baseline (n = 16). *Statistically significant after performing paired t-test. DTG, dolutegravir. Variations in creatinine values and associated eGFR were statistically significant in the subgroups of patients with creatinine-based eGFR <90 mL/min/1.73 m2 or ≥90 mL/min/1.73 m2 and in the subgroup of patients with pVL >50 copies/mL (Figure 1 and Table 2). There were no significant changes in cystatin C values and associated eGFR in any of these subgroups (Figure 1 and Table 2). Discussion Our results showed that plasma cystatin C levels were not affected by dolutegravir use in HIV-infected patients, whereas plasma creatinine levels significantly increased over the same period. Consequently, cystatin-based eGFR could be a better option to assess renal function in dolutegravir-treated patients. These results confirm recent findings from Japan.10–12 Dolutegravir is increasingly being prescribed as it is included in a fixed combination without tenofovir (abacavir/lamivudine + dolutegravir) and in several effective dual therapies (particularly lamivudine + dolutegravir and rilpivirine + dolutegravir).13 Our study population reflects the changes in prescriptions over time. Accuracy of renal function monitoring under ART is an important clinical issue in patients with a high risk of worsening renal function. HIV-infected patients are an ageing population, with a growing number of comorbidities leading to renal impairment, and cancers, with sometimes the need for nephrotoxic treatments (such as chemotherapies).14 Our study population reflects the current dolutegravir-treated population, with 10 patients >60 years old and a significant prevalence of high blood pressure and diabetes. This population is poorly represented in clinical trials. Here, the variation in markers of renal function was not dependent on the eGFR at baseline. Assessment of renal function at baseline highlighted discrepancies between creatinine- and cystatin C-based eGFR. Mean cystatin C-based eGFR was higher than the mean creatinine-based eGFR. Relevance of cystatin C measurement to estimate GFR in HIV-infected patients is unclear. Several studies have compared the performance of creatinine- and cystatin C-based equations (CKD-EPIcreat and CKD-EPIcyst, respectively) regarding mGFR and shown better or equivalent accuracy for the cystatin C-based equation in HIV-infected patients,15–17 including populations of HIV-positive patients on dolutegravir.11 However, other authors have shown that cystatin C levels are dependent on HIV replication (increase in cystatin C levels in the case of high pVL, high immune activation or low CD4 count).18,19 Here, we showed that our findings remained identical in the subgroup of patients with HIV replication at baseline (pVL >50 copies/mL). Data from literature show that tenofovir-, rilpivirine- and cobicistat-based regimens can also disrupt renal outcomes.3,20 Despite the fact that some drugs can inhibit active tubular transport, overall, in our study, modifications of drugs combined with dolutegravir did not impact cystatin C marker variation. Plasma cystatin C is a routinely accessible and available marker, which can be used in clinical practice. In France, it is much more expensive than plasma creatinine and not yet available in all laboratories, but it is not uncommon for clinicians to be concerned about a decrease of creatinine-based eGFR, involving many supplementary dispenses for eliminating renal impairment in high-risk renal patients (biological controls, consultations, radiological exams), in case of subnormal plasma creatinine. Our study presents some limitations, including a small sample size, large range of sample timings and limited number of patients with eGFR <60 mL/min/1.73 m2. A specific and prospective study centred on such patients could show the relevance of plasma cystatin C use in patients on dolutegravir with advanced renal failure. On the other hand, plasma creatinine and cystatin C were measured only once after dolutegravir initiation. However, it has been shown that the plasma creatinine increase after dolutegravir initiation occurs early and remains stable.3,10 To conclude, we suggest that plasma cystatin C could be used to estimate GFR variations in HIV-positive patients with a dolutegravir-based regimen, particularly for patients with multifactorial renal dysfunction. Acknowledgements We thank Fiona McBrearty for proofreading this article prior to submission. Funding This study was supported by internal funding. Transparency declarations None to declare. References 1 Osterholzer DA, Goldman M. Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection. Clin Infect Dis  2014; 59: 265– 71. Google Scholar CrossRef Search ADS PubMed  2 European AIDS Clinical Society. Guidelines for Management of People Living With HIV in Europe. 2017. http://www.eacsociety.org/files/guidelines9.0-english.pdf. 3 Maggi P, Montinaro V, Mussini C et al.   Novel antiretroviral drugs and renal function monitoring of HIV patients. AIDS Rev  2014; 16: 144– 51. Google Scholar PubMed  4 Koteff J, Borland J, Chen S et al.   A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol  2013; 75: 990– 6. Google Scholar CrossRef Search ADS PubMed  5 Randers E, Kornerup K, Erlandsen EJ et al.   Cystatin C levels in sera of patients with acute infectious diseases with high C-reactive protein levels. Scand J Clin Lab Invest  2001; 61: 333– 5. Google Scholar CrossRef Search ADS PubMed  6 Cimerman N, Brguljan PM, Krasovec M et al.   Twenty-four hour variations of cystatin C and total cysteine proteinase inhibitory activity in sera from healthy subjects. Clin Chim Acta  2000; 291: 89– 95. Google Scholar CrossRef Search ADS PubMed  7 Schanz M, Pannes D, Dippon J et al.   The influence of thyroid function, inflammation, and obesity on risk prediction of acute kidney injury by cystatin C in the emergency department. Kidney Blood Press Res  2016; 41: 604– 13. Google Scholar CrossRef Search ADS PubMed  8 Knight EL, Verhave JC, Spiegelman D et al.   Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int  2004; 65: 1416– 21. Google Scholar CrossRef Search ADS PubMed  9 Inker LA, Schmid CH, Tighiouart H et al.   Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med  2012; 367: 20– 9. Google Scholar CrossRef Search ADS PubMed  10 Yoshino Y, Koga I, Seo K et al.   The clinical value of cystatin C as a marker of renal function in HIV patients receiving dolutegravir. AIDS Res Hum Retroviruses  2017; 33: 1080– 2. Google Scholar CrossRef Search ADS PubMed  11 Yukawa S, Watanabe D, Uehira T et al.   Clinical benefits of using inulin clearance and cystatin C for determining glomerular filtration rate in HIV-1-infected individuals treated with dolutegravir. J Infect Chemother  2018; 24: 199– 205. Google Scholar CrossRef Search ADS PubMed  12 Hikasa S, Hideta K, Shimabukuro S et al.   Utility of estimated glomerular filtration rate based on cystatin C in patients receiving combination antiretroviral therapy including dolutegravir. Infect Dis (Lond)  2018; 50: 77– 9. Google Scholar CrossRef Search ADS PubMed  13 Katlama C, Ghosn J, Murphy RL. Individualized antiretroviral therapeutic approaches: less can be more. AIDS  2017; 31: 1065– 71. Google Scholar CrossRef Search ADS PubMed  14 Smit M, Brinkman K, Geerlings S et al.   Future challenges for clinical care of an ageing population infected with HIV: a modelling study. Lancet Infect Dis  2015; 15: 810– 8. Google Scholar CrossRef Search ADS PubMed  15 Seape T, Gounden V, van Deventer HE et al.   Cystatin C- and creatinine-based equations in the assessment of renal function in HIV-positive patients prior to commencing highly active antiretroviral therapy. Ann Clin Biochem  2016; 53: 58– 66. Google Scholar CrossRef Search ADS PubMed  16 Inker LA, Wyatt C, Creamer R et al.   Performance of creatinine and cystatin C GFR estimating equations in an HIV-positive population on antiretrovirals. J Acquir Immune Defic Syndr  2012; 61: 302– 9. Google Scholar CrossRef Search ADS PubMed  17 Gagneux-Brunon A, Delanaye P, Maillard N et al.   Performance of creatinine and cystatin C-based glomerular filtration rate estimating equations in a European HIV-positive cohort. AIDS  2013; 27: 1573– 81. Google Scholar CrossRef Search ADS PubMed  18 Mauss S, Berger F, Kuschak D et al.   Cystatin C as a marker of renal function is affected by HIV replication leading to an underestimation of kidney function in HIV patients. Antivir Ther  2008; 13: 1091– 5. Google Scholar PubMed  19 Bhasin B, Lau B, Atta MG et al.   HIV viremia and T-cell activation differentially affect the performance of glomerular filtration rate equations based on creatinine and cystatin C. PLoS One  2013; 8: e82028. Google Scholar CrossRef Search ADS PubMed  20 Casado JL. Renal and bone toxicity with the use of tenofovir: understanding at the end. AIDS Rev  2016; 18: 59– 68. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Journal of Antimicrobial Chemotherapy Oxford University Press

Plasma cystatin C as a marker for estimated glomerular filtration rate assessment in HIV-1-infected patients treated with dolutegravir-based ART

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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0305-7453
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1460-2091
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10.1093/jac/dky112
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Abstract

Abstract Objectives Inhibition of the organic cation transporter-2 renal tubule transporter by dolutegravir leads to serum creatinine increase. Serum cystatin C is a non-organic cation transporter-2-dependent marker, possibly enabling glomerular filtration rate (GFR) estimation under dolutegravir. Our goal was to evaluate the changes in creatinine- and cystatin C-based estimated GFR values before and after dolutegravir initiation. Methods Creatinine and cystatin measurements were carried out on frozen plasma samples from HIV-1-infected patients, before and after dolutegravir initiation, between October 2016 and March 2017 at Pitié-Salpêtrière Hospital. CKD-EPI equations were used to estimate mean GFR from creatinine and cystatin C values. Variations were analysed by paired t-test. Results Forty-four patients were included [median age = 48 years (IQR 36–58) and median CD4 count = 592 cells/mm3 (IQR 388–728)], including 6 ART-naive patients and 38 on switch strategies [72% with viral load <50 copies/mL and median ART duration = 13 years (IQR 5–20)]. Before dolutegravir initiation (median time = 41 days), 19 patients (43%) had creatinine-based estimated GFR <90 mL/min/1.73 m2 and 11 (25%) had cystatin C-based estimated GFR <90 mL/min/1.73 m2. After dolutegravir initiation, serum creatinine values significantly increased (+8.6 μmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated estimated GFR significantly decreased (−7.7 mL/min/1.73 m2, 95% CI −10.4; −5.1, P < 0.001). In contrast, there was no significant change in cystatin C value variation and associated estimated GFR. The same results were observed regardless of renal function at baseline. Conclusions Creatinine values increased after dolutegravir initiation, whereas no change was observed for cystatin C values. Use of cystatin C may enable better understanding of plasma creatinine fluctuations after dolutegravir initiation, particularly in high-risk renal patients. Introduction Dolutegravir is one of the most recent integrase inhibitors, having shown high efficacy in naive and pretreated HIV-1-infected patients.1 Triple and dual ART regimens including dolutegravir are increasingly being used.2 Dolutegravir inhibits the organic cation transporter (OCT)-2 and plasma creatinine is excreted through this transporter, leading to plasma creatinine increase at treatment initiation. Studies assessing dolutegravir efficacy have highlighted a stable plasma creatinine increase of ∼10 μmol/L as early as week 2–3.3 Estimated glomerular filtration rate (eGFR) is falsely decreased in this context when assessed with plasma creatinine-based equations (MDRD or CKD-EPIcreat). A Phase I study proved that measured GFR (mGFR) remained unchanged after dolutegravir initiation, using non-OCT-2-dependent isotopic markers.4 Monitoring renal function in patients on a dolutegravir-based ART regimen is a daily clinical concern. Cystatin C is a low molecular weight plasma protein freely filtered by the glomerulus. Its production is independent of gender, muscle mass, dietary influences and nyctohemeral period, and could be influenced by inflammation, thyroid dysfunction and smoking.5–8 Cystatin C is a non-OCT-2-dependent routinely available marker, which enables GFR estimation with a validated equation (CKD-EPIcyst).9 Our goal was to evaluate the changes in creatinine- and cystatin-based eGFR values after dolutegravir initiation, in HIV-infected patients from a French reference centre. Methods This study was conducted at Pitié-Salpêtrière Hospital, Paris, France, in March 2017. All HIV-1-infected patients were eligible if dolutegravir-based ART had been initiated between October 2016 and March 2017. They were included if at least one routine frozen plasma sample was available at the hospital laboratory before and after dolutegravir initiation (0–90 days before and 21–180 days after). Patients with systemic inflammation [C-reactive protein (CRP) >5 mg/L] or known thyroid dysfunction were not included. Plasma creatinine, cystatin C and CRP were measured from frozen plasma samples, as stability has been demonstrated after 6 months. Creatinine assay was performed on the Roche-Hitachi P-Module instrument using the Jaffe compensated method standardized against ID/MS. Cystatin C assay was performed on the Roche-Cobas 6000 instrument using the Diagam immunoturbidimetric method standardized against plasma reference material ERM-DA471/IFCC. CRP assay was performed on the Roche-Hitachi P-Module instrument using the particle-enhanced turbidimetric method standardized against the reference preparation CRM 470. CKD-EPIcreat and CKD-EPIcyst equations were used to estimate creatinine- and cystatin-based GFR, as described elsewhere.9 Plasma creatinine and cystatin C values, and creatinine- and cystatin C-based eGFR values were expressed as mean ± SD. Variations of these parameters after dolutegravir initiation were analysed by paired t-test. The analyses of creatinine-based eGFR and plasma viral load (pVL) at baseline were conducted for all patients and then in different subgroups. Routine clinical data were recorded in the Nadis database and informed consent was obtained from all patients. Results Patient characteristics One hundred and seventy-six patients were eligible (dolutegravir initiation in the last 6 months) and 44 patients were included (two available frozen plasma samples, as described earlier), after exclusion of 10 patients with CRP >5 mg/L (Table 1). No one had thyroid dysfunction. Six patients were ART-naive, with a median pVL of 4.8 log10 copies/mL (IQR 4.3–5.2). Thirty-eight were pretreated, with a median ART duration of 13 years (IQR 5–20), and among them 28 (74%) had pVL <50 copies/mL. Data on microalbuminuria or proteinuria were not available. After dolutegravir initiation, the number of patients with tenofovir-, cobicistat- and rilpivirine-based ART was equal or lower than before dolutegravir initiation (Table 1). Reasons for ART switch were: simplification for single tablet regimen in 13 patients (34%); renal, metabolic or bone toxicity in 9 (24%); virological failure in 8 (21%); and prevention of toxicity in 8 (21%). Renal toxicity affected three patients, of whom the first received tenofovir/emtricitabine + rilpivirine and the other two received tenofovir/emtricitabine + elvitegravir/cobicistat. Table 1. Patient characteristics (n = 44) Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Table 1. Patient characteristics (n = 44) Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Men  28 (64%)  Women  16 (36%)  Caucasian subjects  29 (66%)  Black subjects  15 (34%)  Age (years), median (IQR)  48 (36–58)  Comorbidities   smoking  12 (27%)   treated high blood pressure  13 (30%)   treated diabetes  3 (7%)   HBV coinfection  0 (0%)   cured HCV coinfection  4 (9%)  CD4 count at baseline (cells/mm3), median (IQR)  592 (388–728)  CD4/CD8 ratio at baseline, median (IQR)  0.82 (0.60–1.09)  Antiretroviral regimen at baseline   naive patients     more than three drugs  1/38 (3%)   triple therapy  32/38 (84%)   dual therapy  5/38 (13%)   tenofovir-based regimen  20/38 (53%)   rilpivirine-based regimen  8/38 (21%)   cobicistat-based regimen  2/38 (5%)  Antiretroviral regimen after dolutegravir introduction   more than three drugs  1/44 (2%)   triple therapy  27/44 (61%)   dual therapy  16/44 (37%)   tenofovir-based regimen  9/44 (20%)   rilpivirine-based regimen  8/44 (18%)   cobicistat-based regimen  0/44 (0%)  Plasma creatinine and cystatin C values and associated eGFR at baseline Samples were assessed for a median of 9 days (IQR 2–17) before dolutegravir initiation and 41 days (IQR 29–72) after dolutegravir initiation. The mean plasma creatinine value was 85.6 μmol/L (±21.5), with a mean associated eGFR of 91.5 mL/min/1.73 m2 (±22.8), whereas the mean plasma cystatin C value was 0.80 mg/L (±0.29), with a mean associated eGFR of 106.2 mL/min/1.73 m2 (±30.0) (Table 2). Table 2. Variation in serum creatinine and cystatin C values and associated eGFR after dolutegravir initiation   Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)    Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)  DTG, dolutegravir; NS, statistically not significant. a Statistical test used: paired t-test. Table 2. Variation in serum creatinine and cystatin C values and associated eGFR after dolutegravir initiation   Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)    Before DTG initiation, mean ± SD  After DTG initiation, mean ± SD  Before/after difference, mean value (95% CI), Pa  All patients (n = 44)   creatinine (μmol/L)  85.6 ± 21.5  94.2 ± 24.8  +8.6 (+5.8; +11.4), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  91.5 ± 22.8  83.8 ± 22.3  −7.7 (−10.4; −5.1), P < 0.001   cystatin (mg/L)  0.80 ± 0.29  0.77 ± 0.26  −0.03 (−0.12; +0.06), P = 0.50 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  106.2 ± 30.0  108.7 ± 28.7  +2.5 (−6.3; +11.3), P = 0.57 (NS)  Patients with creatinine-based eGFR <90 mL/min/1.73 m2 before DTG initiation (n = 19)   creatinine (μmol/L)  101.4 ± 22.0  111.0 ± 27.2  +9.6 (+4.1; +15.2), P = 0.002   creatinine-based eGFR (mL/min/1.73 m2)  71.3 ± 13.8  65.2 ± 16.1  −6.1 (−9.8; −2.4), P = 0.003   cystatin (mg/L)  0.92 ± 0.32  0.84 ± 0.33  −0.08 (−0.11; +0.26), P = 0.40 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  92.1 ± 29.0  98.4 ± 30.7  +6.2 (−23.6; +11.1), P = 0.46 (NS)  Patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before DTG initiation (n = 25)   creatinine (μmol/L)  73.7 ± 10.6  81.4 ± 11.9  +7.8 (+4.8; +10.7), P < 0.001   creatinine-based eGFR (mL/min/1.73 m2)  109.6 ± 15.0  98.0 ± 14.7  −8.9 (−12.8; +5.0), P < 0.001   cystatin (mg/L)  0.71 ± 0.22  0.71 ± 0.19  0.00 (−0.09; +0.08), P = 0.92 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  117.0 ± 26.1  116.6 ± 24.3  −0.3 (−9.1; +9.7), P = 0.94 (NS)  Patients with pVL >50 copies/mL at baseline (n = 16)   creatinine (μmol/L)  78.4 ± 17.6  87.6 ± 18.2  +9.2 (+4.2; +14.1), P = 0.001   creatinine-based eGFR (mL/min/1.73 m2)  99.3 ± 27.4  89.7 ± 25.7  −9.6 (−15.2; −4.0), P = 0.002   cystatin (mg/L)  0.82 ± 0.29  0.74 ± 0.21  −0.08 (−0.14; +0.29), P = 0.44 (NS)   cystatin-based eGFR (mL/min/1.73 m2)  104.4 ± 29.9  110.4 ± 25.8  +6.1 (−25.7; +13.6), P = 0.52 (NS)  DTG, dolutegravir; NS, statistically not significant. a Statistical test used: paired t-test. Nineteen patients (43%) had a creatinine-based eGFR of <90 mL/min/1.73 m2 and 11 (25%) had a cystatin C-based eGFR of <90 mL/min/1.73 m2. Three and two patients had a creatinine- and cystatin C-based eGFR of <60 mL/min, respectively. Variations in plasma creatinine and cystatin C values and associated eGFR After dolutegravir initiation, plasma creatinine values significantly increased (+8.6 μmol/L, 95% CI +5.8; +11.4, P < 0.001) and associated eGFR significantly decreased (−7.7 mL/min/1.73 m2, 95% CI −10.4; −5.1, P < 0.001) (Figure 1 and Table 2). In contrast, there was no significant variation in cystatin C values (−0.03 mg/L, 95% CI −0.12; +0.06, P = 0.50) or associated eGFR (+2.5 mL/min/1.73 m2, 95% CI −6.3; +11.3, P = 0.57) (Figure 1 and Table 2). Figure 1. View largeDownload slide Variation in plasma creatinine- and cystatin-based estimated GFR (eGFR) after dolutegravir initiation. Data are presented as mean eGFR with standard deviation. (a) In all patients (n = 44). (b) In patients with creatinine-based eGFR <90 mL/min/1.73 m2 before dolutegravir initiation (n = 19). (c) In patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before dolutegravir initiation (n = 25). (d) In patients with pVL >50 copies/mL at baseline (n = 16). *Statistically significant after performing paired t-test. DTG, dolutegravir. Figure 1. View largeDownload slide Variation in plasma creatinine- and cystatin-based estimated GFR (eGFR) after dolutegravir initiation. Data are presented as mean eGFR with standard deviation. (a) In all patients (n = 44). (b) In patients with creatinine-based eGFR <90 mL/min/1.73 m2 before dolutegravir initiation (n = 19). (c) In patients with creatinine-based eGFR ≥90 mL/min/1.73 m2 before dolutegravir initiation (n = 25). (d) In patients with pVL >50 copies/mL at baseline (n = 16). *Statistically significant after performing paired t-test. DTG, dolutegravir. Variations in creatinine values and associated eGFR were statistically significant in the subgroups of patients with creatinine-based eGFR <90 mL/min/1.73 m2 or ≥90 mL/min/1.73 m2 and in the subgroup of patients with pVL >50 copies/mL (Figure 1 and Table 2). There were no significant changes in cystatin C values and associated eGFR in any of these subgroups (Figure 1 and Table 2). Discussion Our results showed that plasma cystatin C levels were not affected by dolutegravir use in HIV-infected patients, whereas plasma creatinine levels significantly increased over the same period. Consequently, cystatin-based eGFR could be a better option to assess renal function in dolutegravir-treated patients. These results confirm recent findings from Japan.10–12 Dolutegravir is increasingly being prescribed as it is included in a fixed combination without tenofovir (abacavir/lamivudine + dolutegravir) and in several effective dual therapies (particularly lamivudine + dolutegravir and rilpivirine + dolutegravir).13 Our study population reflects the changes in prescriptions over time. Accuracy of renal function monitoring under ART is an important clinical issue in patients with a high risk of worsening renal function. HIV-infected patients are an ageing population, with a growing number of comorbidities leading to renal impairment, and cancers, with sometimes the need for nephrotoxic treatments (such as chemotherapies).14 Our study population reflects the current dolutegravir-treated population, with 10 patients >60 years old and a significant prevalence of high blood pressure and diabetes. This population is poorly represented in clinical trials. Here, the variation in markers of renal function was not dependent on the eGFR at baseline. Assessment of renal function at baseline highlighted discrepancies between creatinine- and cystatin C-based eGFR. Mean cystatin C-based eGFR was higher than the mean creatinine-based eGFR. Relevance of cystatin C measurement to estimate GFR in HIV-infected patients is unclear. Several studies have compared the performance of creatinine- and cystatin C-based equations (CKD-EPIcreat and CKD-EPIcyst, respectively) regarding mGFR and shown better or equivalent accuracy for the cystatin C-based equation in HIV-infected patients,15–17 including populations of HIV-positive patients on dolutegravir.11 However, other authors have shown that cystatin C levels are dependent on HIV replication (increase in cystatin C levels in the case of high pVL, high immune activation or low CD4 count).18,19 Here, we showed that our findings remained identical in the subgroup of patients with HIV replication at baseline (pVL >50 copies/mL). Data from literature show that tenofovir-, rilpivirine- and cobicistat-based regimens can also disrupt renal outcomes.3,20 Despite the fact that some drugs can inhibit active tubular transport, overall, in our study, modifications of drugs combined with dolutegravir did not impact cystatin C marker variation. Plasma cystatin C is a routinely accessible and available marker, which can be used in clinical practice. In France, it is much more expensive than plasma creatinine and not yet available in all laboratories, but it is not uncommon for clinicians to be concerned about a decrease of creatinine-based eGFR, involving many supplementary dispenses for eliminating renal impairment in high-risk renal patients (biological controls, consultations, radiological exams), in case of subnormal plasma creatinine. Our study presents some limitations, including a small sample size, large range of sample timings and limited number of patients with eGFR <60 mL/min/1.73 m2. A specific and prospective study centred on such patients could show the relevance of plasma cystatin C use in patients on dolutegravir with advanced renal failure. On the other hand, plasma creatinine and cystatin C were measured only once after dolutegravir initiation. However, it has been shown that the plasma creatinine increase after dolutegravir initiation occurs early and remains stable.3,10 To conclude, we suggest that plasma cystatin C could be used to estimate GFR variations in HIV-positive patients with a dolutegravir-based regimen, particularly for patients with multifactorial renal dysfunction. Acknowledgements We thank Fiona McBrearty for proofreading this article prior to submission. Funding This study was supported by internal funding. Transparency declarations None to declare. References 1 Osterholzer DA, Goldman M. Dolutegravir: a next-generation integrase inhibitor for treatment of HIV infection. Clin Infect Dis  2014; 59: 265– 71. Google Scholar CrossRef Search ADS PubMed  2 European AIDS Clinical Society. Guidelines for Management of People Living With HIV in Europe. 2017. http://www.eacsociety.org/files/guidelines9.0-english.pdf. 3 Maggi P, Montinaro V, Mussini C et al.   Novel antiretroviral drugs and renal function monitoring of HIV patients. AIDS Rev  2014; 16: 144– 51. Google Scholar PubMed  4 Koteff J, Borland J, Chen S et al.   A phase 1 study to evaluate the effect of dolutegravir on renal function via measurement of iohexol and para-aminohippurate clearance in healthy subjects. Br J Clin Pharmacol  2013; 75: 990– 6. Google Scholar CrossRef Search ADS PubMed  5 Randers E, Kornerup K, Erlandsen EJ et al.   Cystatin C levels in sera of patients with acute infectious diseases with high C-reactive protein levels. Scand J Clin Lab Invest  2001; 61: 333– 5. Google Scholar CrossRef Search ADS PubMed  6 Cimerman N, Brguljan PM, Krasovec M et al.   Twenty-four hour variations of cystatin C and total cysteine proteinase inhibitory activity in sera from healthy subjects. Clin Chim Acta  2000; 291: 89– 95. Google Scholar CrossRef Search ADS PubMed  7 Schanz M, Pannes D, Dippon J et al.   The influence of thyroid function, inflammation, and obesity on risk prediction of acute kidney injury by cystatin C in the emergency department. Kidney Blood Press Res  2016; 41: 604– 13. Google Scholar CrossRef Search ADS PubMed  8 Knight EL, Verhave JC, Spiegelman D et al.   Factors influencing serum cystatin C levels other than renal function and the impact on renal function measurement. Kidney Int  2004; 65: 1416– 21. Google Scholar CrossRef Search ADS PubMed  9 Inker LA, Schmid CH, Tighiouart H et al.   Estimating glomerular filtration rate from serum creatinine and cystatin C. N Engl J Med  2012; 367: 20– 9. Google Scholar CrossRef Search ADS PubMed  10 Yoshino Y, Koga I, Seo K et al.   The clinical value of cystatin C as a marker of renal function in HIV patients receiving dolutegravir. AIDS Res Hum Retroviruses  2017; 33: 1080– 2. Google Scholar CrossRef Search ADS PubMed  11 Yukawa S, Watanabe D, Uehira T et al.   Clinical benefits of using inulin clearance and cystatin C for determining glomerular filtration rate in HIV-1-infected individuals treated with dolutegravir. J Infect Chemother  2018; 24: 199– 205. Google Scholar CrossRef Search ADS PubMed  12 Hikasa S, Hideta K, Shimabukuro S et al.   Utility of estimated glomerular filtration rate based on cystatin C in patients receiving combination antiretroviral therapy including dolutegravir. Infect Dis (Lond)  2018; 50: 77– 9. Google Scholar CrossRef Search ADS PubMed  13 Katlama C, Ghosn J, Murphy RL. Individualized antiretroviral therapeutic approaches: less can be more. AIDS  2017; 31: 1065– 71. Google Scholar CrossRef Search ADS PubMed  14 Smit M, Brinkman K, Geerlings S et al.   Future challenges for clinical care of an ageing population infected with HIV: a modelling study. Lancet Infect Dis  2015; 15: 810– 8. Google Scholar CrossRef Search ADS PubMed  15 Seape T, Gounden V, van Deventer HE et al.   Cystatin C- and creatinine-based equations in the assessment of renal function in HIV-positive patients prior to commencing highly active antiretroviral therapy. Ann Clin Biochem  2016; 53: 58– 66. Google Scholar CrossRef Search ADS PubMed  16 Inker LA, Wyatt C, Creamer R et al.   Performance of creatinine and cystatin C GFR estimating equations in an HIV-positive population on antiretrovirals. J Acquir Immune Defic Syndr  2012; 61: 302– 9. Google Scholar CrossRef Search ADS PubMed  17 Gagneux-Brunon A, Delanaye P, Maillard N et al.   Performance of creatinine and cystatin C-based glomerular filtration rate estimating equations in a European HIV-positive cohort. AIDS  2013; 27: 1573– 81. Google Scholar CrossRef Search ADS PubMed  18 Mauss S, Berger F, Kuschak D et al.   Cystatin C as a marker of renal function is affected by HIV replication leading to an underestimation of kidney function in HIV patients. Antivir Ther  2008; 13: 1091– 5. Google Scholar PubMed  19 Bhasin B, Lau B, Atta MG et al.   HIV viremia and T-cell activation differentially affect the performance of glomerular filtration rate equations based on creatinine and cystatin C. PLoS One  2013; 8: e82028. Google Scholar CrossRef Search ADS PubMed  20 Casado JL. Renal and bone toxicity with the use of tenofovir: understanding at the end. AIDS Rev  2016; 18: 59– 68. Google Scholar PubMed  © The Author(s) 2018. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For permissions, please email: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

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Journal of Antimicrobial ChemotherapyOxford University Press

Published: Apr 24, 2018

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