Didactic Series. HIV-Associated Renal Disease. Christian B. Ramers, MD, MPH Family Health Centers of San Diego Ciaccio Memorial Clinic 10/9/14

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1 Didactic Series HIV-Associated Renal Disease Christian B. Ramers, MD, MPH Family Health Centers of San Diego Ciaccio Memorial Clinic 10/9/14 ACCREDITATION STATEMENT: University of California, San Diego School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The University of California, San Diego School of Medicine designates this educational activity for a maximum of one credit per hour AMA PRA Category 1 Credits. Physicians should only claim credit commensurate with the extent of their participation in the activity. 1

2 Disclosures Speaker s Bureau: Janssen Therapeutics (HIV), ViiV (HIV), Gilead Sciences (HIV, HCV), AbbVie (HCV) Scientific Advisor: Gilead Sciences (HIV, HIV/HCV) Grant/Research Support: CDC/HRSA, Northwest AETC, Pacific AETC, HealthHIV

3 Learning Objectives 1) Review basics of measuring renal function 2) List common causes of renal dysfunction in HIV-infected patients 3) Discuss renal toxicity of long-term antiretroviral therapy 3

4 The Basics How do we measure true renal capacity? - Iohexol (agfr) - Creatinine (CrCl) - egfr - Cockcroft-Gault - MDRD

5 Creatinine: a pretty good surrogate Cr = 1.4 mg/dl 25 yo WM, 210 lbs 86 yo AA woman, 115 lbs Cockcroft-Gault MDRD 66 46

6 CrCl: Less Precision at Higher Values Cockcroft-Gault Equation MDRD Equation Measured GFR minus egfr, ml/min per 1.73 m egfr = [140 Age (yrs)] x Weight (kg) x (0.85 if female)/(72 x SCr mg/dl) R 2 = (0.816 to 0.849) Measured GFR minus egfr, ml/min per 1.73 m egfr = 186 x SCr (mg/dl) x Age (yrs) x (0.742 if female) x (1.212 if African American) R 2 = (0.870 to 0.893) egfr Using the Cockcroft-Gault Equation Adjusted for Bias a, ml/min per 1.73 m egfr Using the MDRD Equation, ml/min per 1.73 m 2 Gupta SK, et al. Clin Infect Dis. 2005;40: ; Adapted from Levey AS, et al. Ann Int Med. 2006;145:

7 Creatinine: not a linear relationship with GFR 120 egfr (ml/min per 1.73 m 2 ) Black White Serum Creatinine Concentration (mg/dl) 10 Larger GFR change with Cr increase from 1-2 mg/dl than from 4-5 mg/dl Figure adapted from Levey AS, et al. Ann Intern Med. 1999;130:

8 CKD Stages & Definitions Stage Description GFR (ml/min/1.73 m 2 ) Action 1 At increased risk 60 (with CKD risk factors) Screen Reduce CKD risk 1 Kidney damage with normal or GFR 90 Diagnosis and treatment: Evaluate risk Treat comorbid conditions Slow progression Reduce CVD risk 2 Kidney damage with mild GFR Estimate progression 3 Moderate GFR Evaluate and treat complications 4 Severe GFR Prepare for kidney replacement therapy dialysis or transplantation 5 Kidney failure <15 (or dialysis) Replacement (if uremia present) 1 Levey AS, et al. Am J Kidney Dis. 2009;53:S4-S16. 2 NKF KDOQI Clinical Practice Guidelines for Chronic Kidney Disease. Accessed August 14, 2012.

9 Source: Leah Haseley, MD Evolution of Renal Disease in HIV

10 HIV-associated Renal Disease Pre-renal Diarrhea Sepsis Cachexia Vascular TTP Infiltrative KS Lymphoma GN HIVAN HIVIKDI KD Tubular Pentamidine Foscarnet Tenofovir AmphoB Rhabdo (AZT) ATN (Ischemic) Interstitium TMP-SMX Rifampin Plasmocytic IN CMV Post-Renal Crystalline - (ACV, IDV, ATZ) Tumors Source: Leah Haseley, MD

11 Relevance of HIV-associated Renal Disease Risk Factors Age HTN Diabetes Black race Hep B/C Low CD4 count/high viral load HAART (TDF, Indinavir, atazanivir?) Pre-existing CKD Among HIV+ pts: Up to 10% have impaired GFR Up to 30% have proteinuria Consequences Dose adjustment Change in ART Vascular disease Hemodialysis Increased Mortality

12 HIV-associated Nephropathy (HIVAN) Initially described in 1984 (New York, Miami) To date: 90% cases reported in blacks Requires Renal Biopsy for definitive diagnosis HIV infects glomerular and tubular cells Collapsing FSGS and cystic tubules Source: Charles Alpers, MD UWMC

13 HIV Nephropathy: large echogenic kidneys

14 HIV associated Nephropathy (HIVAN) Most common biopsy finding among HIV- infected patients Almost exclusively in Blacks (4 th most common cause of ESRD in AA men age 20-64) An indication to start HAART regardless of CD4 or viral load

15 HIVAN: Management BIOPSY!! START ART!! HIVAN has long been an indication: Dramatic reduction in incidence and reversibility of CKD, ACE inhibitors Nephrotic hygiene watch for hypercoaguable events, encapsulated organisms, hyperlipidemia Optimize co-existing disease: DM II, smoking, cocaine use, Treat HTN to < 130/80

16 HIV immune kidney disease (HIVIKD) IgA Nephropathy - IgA levels commonly elevated in HIV - Autopsy studies among Caucasian Europeans with HIV show 8% have mesangial IgA Postinfectious gomerulonephritis Lupus-Like glomerulonephritis MPGN (HCV) Membranous GN (HBV) IgA-IgG-gp120 Mesangial deposits of IgA Workup: UA (protein, cells), ANA, RF, Cryoglobulins, HBV/HCV

17 HAART Nephrotoxicity Indinivir: Stones, interstitial nephritis Tenofovir: Fanconi Syndrome, AKI, CKD Indinavir crystals Atazanavir: Stones

18 Tenofovir Nephrotoxicity Proximal Tubular Toxicity Subclinical tubular defects Fanconi Syndrome (glycosuria, phosphaturia, proteinuria) ATN (reversible) CKD Randomized control trials Industry sponsored Observational What does the literature show? NO NO YES 0-2.8%

19 Rates of D/C Due to Renal Impairment in early TDF Studies Study TDF Pts (N) Percent (%) Discontinuation TDF Control Follow-up (weeks) Reference Overall Discontinuation Due to TDF Renal Events (0-1%)

20 Top Antiviral Med 2012; 20(3):

21 San Francisco VA: TDF Toxicity Study 10,8421 HAART naïve veterans Exclude: advanced CKD 4303 exposed to TDF for mean of 1.3 years (max 6.3 years) 30% increased risk of proteinuria per year of exposure 11% increase risk of rapid decline in renal function 10% increased risk of creatinine doubling 33% increased risk of GFR < 60. NO increased risk of GFR < 30 Scherzer, AIDS, 2012

22 Working up Suspected TDF-Nephrotoxicity Hall et al AJKD 2011

23 Many Drugs Affect Tubular Secretion of Creatinine Cr Cr Cr Cr Cr Cr Cr Creatinine OCT2 MATE 1 Urine Drugs affecting Tubular Secretion of Cr: TMP/SMX Ritonavir Cobicistat Dolutegravir Rilpivirine Blood Vessel Proximal Tubule Source: Gilead Sciences 23

24 COBI Inhibits Active Tubular Secretion of Creatinine, Resulting in Increased SCr 1,2 Creatinine SCr mg/dl Cobicistat Proximal Tubule Cell Blood Vessel Urinary Space For illustrative purposes only. MATE1, multidrug and toxin extrusion 1; OCT2, organic For cation illustrative For transporter illustrative purposes 2. purposes only. only. 1 Lepist EI, et al. ICAAC Abstract A1-1724; 2 German P, et al. J Acquir Immune Defic Syndr. 2012;61:32-40; 3 Lepist EI, Ray AS. Expert Opin Drug Metab Toxicol. 2012;8: ; 4 Stray KM, et al. Antimicrob Agents Chemother. 2013;57: van Acker BA, et al. Lancet. 1992;340: ; 6 Naderer O, et al. Antimicrob Agents Chemother. 1997;41:

25 Tenofovir and Creatinine Utilize Distinct Renal Transport Pathways Creatinine Tenofovir Cobicistat Proximal Tubule Cell Blood Vessel For illustrative purposes only. Urinary Space MRP4, multidrug resistance protein 4; OAT1/3, organic anion transporter 1/3; TFV, tenofovir. German P, et al. J Acquir Immune Defic Syndr. 2012;61:32-40; Lepist EI, Ray AS. Expert Opin Drug Metab Toxicol. 2012;8: Stray KM, et al. Antimicrob Agents Chemother. 2013;57:

26 Source: DHHS Guidelines 2014 Gupta CID 2005; 40(11): Recommended Renal Monitoring Test Entry ART Initiation BMP (BUN/Cr) Urinalysis (Prot, Glu) Serum Phos RBP Prot:Cr Renal U/S 2-8 wks after ART Initiation Every 3-6 months thereafter As Clinically Indicated X X X X X X X X (if on TDF) X X (if on TDF) **More frequent monitoring may be indicated for patients with evidence of renal disease (proteinuria, decreased egfr), or those at risk (e.g. co-existing DM II, HTN). X X X X X

27 Hamada et al CID 2012; 55(9):

28 HAART in Patients with Renal Impairment HAART is curative in pts with renal dysfunction due to HIVAN At first sign of Renal Dysfunction, initiate workup! - UA (glucose, protein), Serum BUN/Cr, Serum Phos, Urine Phos, (RBP?) ART to avoid: - Tenofovir dose adjustment < 50 ml/min; could contribute toxicity - Cobicistat (FTC/TDF/COBI/ELV) alters egfr by inhibiting Cr secretion Renally Friendly ART: - NNRTI s/pi s/insti s No Dose Adjustment - Abacavir No Dose Adjustment - Lamivudine/3TC Dose adjust < 50 but little toxicity - Maraviroc No Dose Adjustment > 30 ml/min

29 Summary Remember the limitations of Cr as the sole measure of renal dysfunction Most important renal pathologies through time have been HIVAN, ART toxicity, and now DM II and HTN ART must be used cautiously in patients with moderate renal impairment Newer agents recognized to influence serum Cr without truly altering actual GFR

30 ADDITIONAL SLIDES 31

31 Expected Renal Changes When Initiating STRIBILD Median Change (IQR) From Baseline in SCr, mg/dl Based on clinical trials, the expectations when initiating a patient on STRIBILD are 1 - A modest increase in SCr (mean, mg/dl) Study A modest decline in estimated CrCl (mean, ml/min) STRIBILD SCr increase occurs early and soon stabilizes Week ATV + RTV + FTC/TDF 0.4 At Week 96, median changes in SCr (mg/dl[iqr]) were EFV/FTC/TDF 0.12 ( ) for STRIBILD and 0.08 ( ) for ATV + RTV + FTC/TDF in Study ( ) for STRIBILD and 0.01 ( ) for EFV/FTC/TDF in Study The COBI component of STRIBILD has been shown to decrease estimated CrCl due to inhibition of tubular secretion of creatinine without affecting renal glomerular function (as confirmed by iohexol) 6 A SCr change of >0.4 mg/dl from baseline with STRIBILD should be closely monitored (mmol/l) Study Week (mmol/l) IQR, interquartile range. 1 STRIBILD Prescribing Information. Gilead Sciences, Inc. 2013; 2 Rockstroh J, et al. HIV11. Glasgow, UK. O424b; 3 Zolopa A, et al. HIV11. Glasgow, UK. O424a; 4 Rockstroh JK, et al. J Acquir Immune Defic Syndr. 2013;62: ; 5 Zolopa A, et al, J Acquir Immune Defic Syndr. 2013;63:96-100; 6 German P, et al. J Acquir Immune Defic Syndr. 2012;61:

32 GS-7340 Novel TFV Prodrug: Greater in vitro Potency Tenofovir (TFV) Viread (TDF) GS-7340 (TAF) EC 50 HIV-1 [µm] Compound MT-2s PBMCs Macrophages Tenofovir TDF GS Lee WA, et al. Antimicrob Agents Chemother. 2005;49(5): Ruane P, et al. CROI; Seattle, WA; March 5-8, Oral #

33 GS-7340 Dose-Ranging Study 104: Lower Plasma TFV and Higher Intracellular TFV-DP Plasma Concentrations Intracellular PBMC Concentrations TFV Plasma Concentration (ng/ml) TDF 300 mg GS mg GS mg GS mg AUC Cmax reference 79% 89% 86% 94% 96% 98% Intracellular TFV-DP (µm*h) Ref TDF >20X ~7X ~1X GS-7340 GS-7340 GS-7340 Time (hour) 300 mg 8 mg 25 mg 40 mg Ruane P, et al. CROI; Seattle, WA; March 5-8, Oral #