The impact of antiretroviral drugs on renal function Professor Bruce Hendry Renal Medicine King s College London King s College Hospital NHS Foundation Trust 1
DISCLOSURES: BRUCE HENDRY I have received research support and/or honoraria from Abbvie, AstraZeneca, Gilead Sciences, Otsuka and Viiv Pharmaceuticals The opinions expressed in this lecture are entirely my own
Overview Renal Disease: Basic Considerations Renal Disease in PLWHIV Anti Retroviral Therapy (ART) and the kidney Delivering Tenofovir: TAF versus TDF Key conclusions
Stratification of Renal Risk 1 Consider using egfrcystatinc for people with CKD G3aA1 ACR, albumin:creatinine ratio; CKD, chronic kidney disease; GFR, glomerular filtration rate NICE clinical guideline CG182. https://www.nice.org.uk/guidance/cg182. Accessed 07 February 2017
Renal Concerns in HIV care Present function egfr < 75 ml/min Proteinuria Future risk Age over 50 Diabetes Hypertension Cardiovascular disease (strong reciprocal relationship) Nephrotoxic medications Renal safety of ART The information portrayed on this slide is attributed to the presenter s expert opinion
HIV: Impact of CKD Stage G3-G5 (CRF) Overall patient survival Survival free of ESRF 1.00 No CRF (n=1824) 1.00 CRF not HIVAN (n=21) 0.75 CRF (n=36) 0.75 0.50 0.50 HIVAN (n=15) 0.25 0.25 p<0.00001 0.0 0.0 p<0.00001 p<0.0001 0 1 2 3 4 5 0 1 2 3 4 5 Years from inception Years since CRF diagnosis CRF = CKD stage G3-5 Campbell LJ et al. HIV Medicine 2009; 10(6): 329-336
HIV+ vs HIV- Onset of Age-Related Comorbidities Prevalence of Individual Noninfectious Comorbidities HIV+ (N=2854) vs HIV- (N=8562) Comorbidity Status, % 40 Years 41 to 50 Years 51 to 60 Years > 60 Years HIV+ HIV+ HIV+ HIV+ HIV- HIV- HIV- HIV- HIV+ individuals vs age-matched HIV- controls have more individual noninfectious comorbidities and at an earlier age (all P < 0.001) Guaraldi G, et al. Clin Infect Dis. 2011;53:1120-1126. 7
In the ageing HIV+ population the incidence of CKD CVD and related comorbidities is increasing Comorbidities and risk factors, in 2004 and 2014 Bonnet. Glasgow 2016 *Comorbidities were considered if the patients either had the diagnosis or current treatment Adapted from Bonnet F, et al. HIV Drug Therapy 2016; Glasgow, UK; #O212.
Incident CKD in EuroSIDA CKD defined as: Confirmed egfr <60 if baseline egfr >60 >25% decline if baseline egfr <60 21,482 PYFU median 3.7 years 225 (3.3%) progressed to CKD Incidence 1.1 (0.9-1.2) per 100py Mocroft A et al. AIDS 2010; 24: 1667-78
Factors associated with CKD in the EuroSIDA cohort Mocroft et al. AIDS 2010
Renal Signal of ATV/r with TDF median change in creatinine clearance 10 Wk 48, p=0.17 Wk 96, p=0.33 Week 48 Week 96 Wk 48, p=0.001 Wk 96, p<0.001 p-values: ATV/r vs. EFV Change in calculated creatinine clearance, (ml/min) 8 6 4 2 0-2 -4 n= ATV/r ATV/r EFV EFV ABC/3TC TDF/FTC 377 330 338 287 394 352 360 327 Daar, E et al. 17 th CROI 2010. Abstract 59LB
PI and renal risk Risk of CKD: multivariate analysis Hazard Ratio (95% CI) P value ATV/r 1.52 (1.14-2.03) 0.004 DRV/r 1.31 (0.94-1.81) 0.108 LPV/r 1.61 (1.1-2.6) 0.017 EFV 1 Patients on ATV/r or LPV/r were significantly more likely to develop egfr<60 ml/min/1.73m 2 compared with EFV. DRV/r was not significantly associated with renal impairment. * Adjusted for gender, age at start of HAART, baseline egfr, Hep B SAg, prior exposure to TFV and IND and total duration of TFV exposure. Rockwood N, et al. Oral presentation IAS; 2011. Rome.
ARV exposure and chronic kidney disease Lancet HIV. 2016; 3:e23-32
Risk factors for CKD: data from the D:A:D study PLoS Med 2015; 12: e1001809
Some ARV therapies increase the risk of CKD Low risk (<0) Medium risk (0-4) High risk ( 5) Cumulative effects of ARVs on underlying CKD risk Number needed to harm Years of ARV exposure ATV, atazanavir; ATV/r, atazanavir/ritonavir; BPI, other ritonavir-boosted protease inhibitor (excluding lopinavir/ritonavir and atazanavir/ritonavir); LPV/r, lopinavir/ritonavir; TDF, tenofovir. 1. Mocroft A et al. PLoS Med 12(3): e1001809. 1 5
Renal Risk Calculators in HIV care Copenhagen University http://www.chip.dk/tools (D:A:D) Simple binary input (e.g. diabetes yes or no) Risk of CKD within 5 years Underestimates risk if moderate or severe comorbidity Includes ART risk modification (TDF etc) UCSF http://hivinsite.ucsf.edu/insite?page=md-calculator (VA) More sophisticated input (continuous variable) Includes proteinuria Less quick and easy Risk of CKD within 5 years Includes ART risk The information modification portrayed on this (TDF) slide is attributed to the presenter s expert opinion
Tubulopathy (acute tubular injury/fanconi syndrome) AIDS 2016; 30: 1311-3, HIV8, Glasgow 2008
TFV (TDF) exposure and kidney disease Scherzer et al, AIDS 2012
Rapid egfr decline and CKD in patients with subsequent TDF-associated Renal Tubulopathy egfr pattern on TDF Cases Controls P value egfr decline >3 ml/min/1.73m 2 /year 69.6% 7.9% <0.0001 egfr decline >5 ml/min/1.73m 2 /year 55.4% 3.5% <0.001 CKD (egfr <60 ml/min/1.73m 2 for >3 months 43.5% 9.5% <0.0001 Hamzah et al, J Infect. 2017 Jan 25. pii: S0163-4453(17)30029-4
egfr slopes in patients who discontinued TDF JID 2014; 210: 363-373
Factors associated with incomplete recovery of renal function after TDF discontinuation JID 2014; 210: 363-373
Pharmacokinetics of Tenofovir alafenamide (TAF) 10/25 mg 1. SmPC DESCOVY. Available at https://www.medicines.org.uk/emc/medicine/31764. Accessed 3 May 2016. 2. Lee WA, et al. Antimicrob Agents Chemother 2005; 49(5): 1898 1906. 3. Birkus G, et al. Antimicrob Agents Chemother 2007; 51(2): 543 550. 4. Babusis D, et al. Mol Pharm 2013; 10(2): 459 466.
Plasma tenofovir concentrations (TDF vs. TAF)
egfr through 96 weeks with ECF-TAF in patients with renal impairment (GS-0112) Primary end point was egfr change at Week 24 (primary endpoint met; no statistically significant difference in ecrcl) Post, F. Boston, USA, CROI 2016 (P680)
Switching from TDF to TAF improves total and tubular proteinuria (GS-0112) Post, F. Boston, USA, CROI 2016 (P680)
Comparison of renal events with ECF-TAF vs. ECF- TDF in ART-naïve patients (GS-0104/0111) TAF vs. TDF: P<0.0001 for each biomarker Ward, D. HIV & Aging 2016, Washington, USA, (P33)
ART and the kidney KEY points PLWHIV should have baseline and ongoing assessment of renal function and risk (egfr and proteinuria) Signals of renal toxicity have been associated with certain ART notably TDF, ATV, LPV/r and boosted PI regimes in general. ART not associated with renal risk include ABV, TAF, NNRTI and Integrase Inhibitors Renal Risk assessment should be used to guide choice of ART using national and international guidelines For patients with established CKD the future use of unboosted ART is of great potential benefit in avoiding DDI Bruce Hendry, personal communication,
Thanks The author has permission to use this image 28