Supplementary Data Statistical Analysis Due to the limited number of patients with acute kidney injury and concern for model overfitting, covariates included in multivariable logistic regression analyses were limited to main effects for baseline measures. Covariate selection was driven by available knowledge and biological plausibility of potential confounders, taking into consideration the hypothesis of interest. Tests for statistical interactions between covariates were not done. Before implementation of any specific statistical analysis for serum levels of creatinine (SCr) and creatinine clearance (CrCl), all assumptions were assessed (i.e., normality and homogeneity of variance). SCr required a natural logarithm transformation before analysis to help ensure statistical assumptions were not violated. Repeated-measures analyses for SCr and CrCl were performed with a mean model through the SAS MIXED Procedure (version 9.4) providing separate estimates of the mean by time on study (baseline, 1 to <4weeks,4to<8weeks,8to<12 weeks, 12 24 weeks, and >24 weeks) and treatment group [tenofovir disoproxil fumarate (TDF) or non-tdf]. A compound-symmetric variance covariance form in repeated measurements was assumed for each outcome and robust estimates of the standard errors of parameters were used to perform statistical tests and construct 95% confidence intervals. 1 The model-based means are unbiased with unbalanced and missing data, so long as the missing data are noninformative (missing at random). Specific statistical tests were done within the framework of the mixed-effects linear model. After analysis of the ln-transformed SCr outcome, the mean and 95% confidence intervals were back transformed to the usual arithmetic scale and reported as geometric mean along with the 95% confidence intervals. Reference 1. Diggle PJ, Liang KY, Zeger SL: Analysis of Longitudinal Data. Clarendon Press, Oxford, 1994. Supplementary Table S1. Nephrotoxic Medications and Medication Classes Antimicrobial agents Acyclovir Aminoglycosides, systemic Amphotericin B deoxycholate, liposomal, and lipid complex formulations Beta-lactams Foscarnet Sulfamethoxazole/trimethoprim Valacyclovir Vancomycin Antineoplastic agents Cisplatin Methotrexate Cardiovascular agents Angiotensin-converting enzyme inhibitors Angiotensin II receptor blockers Loop diuretics Thiazide diuretics Other Allopurinol Contrast dye Cyclosporine Lithium Nonsteroidal anti-inflammatory agents Tacrolimus Supplementary Table S2. Antiretroviral Therapies Taken with Ledipasvir/Sofosbuvir TDF (n = 86) Non-TDF (n = 31) ART administered with LDV/SOF, n (%) Darunavir/ritonavir 22 (25.6) 13 (41.9) Atazanavir/ritonavir 15 (17.4) 7 (22.6) Atazanavir 0 (0) 1 (3.2) Lopinavir/ritonavir 4 (4.7) 3 (9.7) Efavirenz 24 (27.9) 2 (6.5) Rilpivirine 10 (11.6) 0 (0) Etravirine 1 (1.2) 1 (3.2) Nevirapine 1 (1.2) 0 (0) Dolutegravir 9 (10.5) 8 (25.8) Raltegravir 13 (15.1) 9 (29) Elvitegravir/cobicistat 1 (1.2) 0 (0) Tenofovir disoproxil fumarate 86 (100) 0 (0) Abacavir 6 (7) 20 (64.5) Emtricitabine 75 (87.2) 2 (6.5) Lamivudine 5 (5.8) 24 (77.4) Zidovudine 1 (1.2) 3 (9.7) Didanosine 0 (0) 1 (3.2) Maraviroc 1 (1.2) 0 (0) ART, antiretroviral therapy; LDV, ledipasvir; SOF, sofosbuvir; TDF, tenofovir disoproxil fumarate.
Supplementary Table S3. Nephrotoxic Medication and Medication Class Use According to Study Group from Start of Ledipasvir/Sofosbuvir Therapy Through 48 Weeks After Completing Ledipasvir/Sofosbuvir Therapy Medication/medication class a TDF, n (%), n = 86 Non-TDF, n (%), n = 31 ACEi/ARB 27 (31.4) 14 (45.2) Acyclovir/valacyclovir 11 (12.8) 2 (6.5) Allopurinol 1 (1.2) 2 (6.5) Beta-lactam antibiotics 14 (16.3) 6 (19.4) Contrast, intravenous 16 (18.6) 4 (12.9) Loop diuretics 2 (2.3) 1 (3.2) NSAID 50 (58.1) 19 (61.3) Sulfonamide antibiotics 10 (11.6) 3 (9.7) Thiazide diuretics 17 (19.8) 9 (29) Vancomycin, intravenous 2 (2.3) 1 (3.2) a Receipt of medication was determined based upon retrospective chart review of the electronic medical records available at the study site. ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; NSAID, nonsteroidal anti-inflammatory drug. Supplementary Table S4. Baseline Laboratories Assessing for Proximal Renal Tubule Dysfunction TDF (n = 87) Non-TDF (n = 31) Serum potassium, meq/l, mean (SD) 4.1 (0.43) 4.1 (0.41) Serum bicarbonate, meq/l, mean (SD) 28.7 (3.1) 27.6 (2.9) Serum phosphorus, mg/dl, median (IQR) (n) 3.1 (2.4 3.4) (26) 3.6 (3 3.8) (9) Glycosuria 250 mg/dl, n/total (%) 0/40 (0) 2/19 (10.5) Proteinuria 100 mg/dl, n/total (%) 4/40 (10) 4/19 (21.1) IQR, interquartile range; SD, standard deviation.
Supplementary Table S5. Summary of Study Patients with Acute Kidney Injury That Did Not Resolve by the End of the Study Period Baseline demographic A 34-year-old black male, no comorbid conditions A 54-year-old black male, A 35-year-old black male, A 59-year-old black male, A 61-year-old black male, A 47-year-old black male, A 52-year-old black male, A 52-year-old black male, A 61-year-old black male, Antiretroviral therapy LDV/SOF treatment duration, weeks Baseline SCr, mg/dl (CrCl, ml/min) Maximum SCr, mg/dl (CrCl, ml/min) Last recorded SCr for study period a, mg/dl (CrCl, ml/min) Time, days, between LDV/SOF initiation and AKI Time, days, between LDV/SOF initiation and last recorded SCr for study period a DTG, TDF/FTC 12 1.1 (114) 1.4 (89) 1.4 (89) 8 218 DRV/r, TDF/FTC 12 1 (85) 1.3 (65) 1.3 (65) b 298 298 ATV/r, TDF/FTC 12 0.8 (>120) 1.2 (95) 1.2 (95) 66 314 DRV/r, ABC, 3TC 12 2 (46) 2.4 (38) 2.4 (38) b 316 316 DRV/r, ABC/3TC 8 c 0.9 (91) 1.3 (63) 1.2 (69) 29 286 EFV, ABC/3TC 12 1.7 (43) 2.2 (33) 2.2 (33) 47 257 ABC/3TC, RAL 12 1 (>120) 1.4 (90) 1.3 (97) 30 274 ATV/r, ABC/3TC 12 3.1 (27) 5.4 (15) 5.4 (15) 46 179 ABC, 3TC, DTG 12 1.3 (48) 1.6 (39) 1.6 (39) b 354 354 a Study period was defined as the day of initiating LDV/SOF therapy through 48 weeks after completing LDV/SOF therapy. b This was the first documented AKI for the patient during the study period. c Intended 12 weeks of LDV/SOF, but patient only received 8 weeks of therapy. 3TC, lamivudine; ABC, abacavir; AKI, acute kidney injury; ATV, atazanavir; CKD, chronic kidney disease; CrCl, creatinine clearance; DRV, darunavir; DTG, dolutegravir; EFV, efavirenz; FTC, emtricitabine;, hypertension; r, ritonavir; RAL, raltegravir; SCr, serum creatinine.
Supplementary Table S6. Univariable Logistic Regression of Risk Factors Potentially Associated with Acute Kidney Injury Among Patients Coinfected with Human Immunodeficiency Virus/Hepatitis C Virus Risk factor Incidence of AKI, n/total (%) OR 95% CI p Treatment TDF 13/86 (15) Reference <.001 Non-TDF 19/31 (61) 8.89 3.50 22.60 Age, years 55 15/62 (24) Reference.67 <55 17/55 (31) 1.40 0.62 2.71 Sex Male 23/92 (25) Reference.28 Female 9/25 (36) 1.69 0.66 4.33 Race (n = 113) White 2/14 (14) Reference.34 a Black 30/99 (30) 2.61 0.55 12.38 CD4 count <500 17/60 (28) Reference.81 500 15/57 (26) 0.90 0.40 2.04 Use of boosted HIV PI No 12/53 (23) Reference.30 Yes 20/64 (31) 1.55 0.68 3.57 Chronic kidney disease No 20/94 (21) Reference.004 Yes 12/23 (52) 4.04 1.55 10.50 Hypertension No 9/47 (19) Reference.11 Yes 23/70 (33) 2.07 0.86 4.99 Diabetes mellitus No 29/100 (29) Reference.40 a Yes 3/17 (18) 0.53 0.14 1.96 Proteinuria (n = 59) No 18/51 (35) Reference 1.00 a Yes 3/8 (38) 1.10 0.24 5.14 Use of other nephrotoxic agents ACEi/ARB No 19/76 (25) Reference.44 Yes 13/41 (32) 1.39 0.60 3.22 Acyclovir/valacyclovir No 29/104 (28) Reference 1.00 a Yes 3/13 (23) 0.78 0.20 3.02 Beta-lactam No 25/97 (26) Reference.40 Yes 7/20 (35) 0.55 0.56 4.32 Contrast, intravenous No 25/97 (26) Reference.40 Yes 7/20 (35) 1.55 0.56 4.32 NSAID No 12/48 (25) Reference.64 Yes 20/69 (29) 1.22 0.53 2.82 Sulfonamide No 28/104 (27) Reference.75 a Yes 4/13 (31) 1.21 0.34 4.23 Thiazide diuretic No 26/91 (29) Reference.58 Yes 6/26 (23) 0.75 0.27 2.08 a Fisher s exact test. CI, confidence interval; HIV, human immunodeficiency virus; OR, odds ratio; PI, protease inhibitor.
Supplementary Table S7. Multivariable Logistic Regression of Creatinine Clearance Per 10 ml/min Decrease and Its Potential Association with Acute Kidney Injury Among Patients Coinfected with Human Immunodeficiency Virus/Hepatitis C Virus Factor AKI No AKI Adjusted OR 95% CI p All patients, n (%) 32 (27) 85 (73) Treatment (non-tdf/tdf) a, n/total (%) 19/32 (59) 12/85 (14) 7.36 2.77 19.52 <.001 CrCl, ml/min, mean (SD) 72.6 (25.2) 85.3 (21.6) 1.14 0.92 1.41.24 a n (%) where the numerator of the fraction is the at risk category (i.e., the number of patients treated with non-tdf ART). Supplementary Table S8. Multivariable Logistic Regression of Serum Creatinine Per 0.1 mg/dl Increase and Its Potential Association with Acute Kidney Injury Among Patients Coinfected with Human Immunodeficiency Virus/Hepatitis C Virus Factor AKI No AKI Adjusted OR 95% CI p All patients, n (%) 32 (27) 85 (73) Treatment (non-tdf/tdf) a, n/total (%) 19/32 (59) 12/85 (14) 7.60 2.90 19.91 <.001 SCr, mg/dl, mean (SD) 1.20 (0.44) 1.04 (0.25) 1.10 0.93 1.29.27 a n (%) where the numerator of the fraction is the at risk category (i.e., the number of patients treated with non-tdf ART).