The impact of antiretroviral drugs on renal function

1

Professor Bruce HendryRenal Medicine

Kings College London Kings College Hospital NHS Foundation Trust

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

1Consider 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

https://www.nice.org.uk/guidance/cg182

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 presenters expert opinion

HIV: Impact of CKD Stage G3-G5 (CRF)

p

HIV+ vs HIV-Onset of Age-Related Comorbidities

HIV+ individuals vs age-matched HIV- controls have more individual noninfectious comorbidities and at an earlier age (all P < 0.001)

7Guaraldi G, et al. Clin Infect Dis. 2011;53:1120-1126.

Prevalence of Individual Noninfectious Comorbidities HIV+ (N=2854) vs HIV- (N=8562)

Com

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s, %

40 Years

HIV+ HIV-

41 to 50 Years

HIV+ HIV-

51 to 60 Years

HIV+ HIV-

> 60 Years

HIV+ HIV-

Chart1

801631

9091

603181

801721

4235176

652861

213129154

40421520.25

No Age-Related Diseases

1 comorbidity

2 comorbidities

3 comorbidities

4 comorbidities

80

90

60

80

42

65

21

40

16

9

31

17

35

28

31

42

3

8

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6

29

15

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Sheet1

No Age-Related Diseases1 comorbidity2 comorbidities3 comorbidities4 comorbiditiesSeries 6

801631100

9091100

0

603181100

801721100

0

4235176100

652861100

0

213129154100

40421520.2599.25

To resize chart data range, drag lower right corner of range.

In the ageing HIV+ population the incidence of CKD CVD and related comorbidities is increasing

*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.

Comorbidities and risk factors, in 2004 and 2014

Bonnet. Glasgow 2016

Incident CKD in EuroSIDA

CKD defined as: Confirmed eGFR 60 >25% decline if baseline

eGFR

Factors associated with CKD in the EuroSIDA cohort

Mocroft et al. AIDS 2010

Renal Signal of ATV/r with TDFmedian change in creatinine clearance

Daar, E et al. 17th CROI 2010. Abstract 59LB

-4

-2

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Chan

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)

ATV/r EFV

ATV/r

EFV

ABC/3TC TDF/FTC

377 330 338 287 394 352 360 327n=

Wk 48, p=0.17

Wk 96, p=0.33

Wk 48, p=0.001

Wk 96, p

PI and renal riskRisk of CKD: multivariate analysis

*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.

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

Rockwood N, et al. Oral presentation IAS; 2011. Rome.

Patients on ATV/r or LPV/r were significantly more likely to develop eGFR

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

15ATV, 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.

Cumulative effects of ARVs on underlying CKD risk

Num

ber n

eede

d to

har

m

Years of ARV exposure

Low risk (

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 modification (TDF)

The information portrayed on this slide is attributed to the presenters expert opinion

http://www.chip.dk/TOOLShttp://hivinsite.ucsf.edu/InSite?page=md-calculator

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 valueeGFR decline >3 mL/min/1.73m2/year 69.6% 7.9% 5 mL/min/1.73m2/year 55.4% 3.5%

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): 18981906. 3. Birkus G, et al. Antimicrob Agents

Chemother 2007; 51(2): 543550. 4. Babusis D, et al. Mol Pharm 2013; 10(2): 459466.

https://www.medicines.org.uk/emc/medicine/31764

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-nave patients (GS-0104/0111)

TAF vs. TDF: P

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

28The author has permission to use this image

Dianummer 1DISCLOSURES: BRUCE HENDRYOverviewStratification of Renal RiskRenal Concerns in HIV careDianummer 6HIV+ vs HIV-Onset of Age-Related ComorbiditiesIn the ageing HIV+ population the incidence of CKD CVD and related comorbidities is increasingDianummer 9Dianummer 10Renal Signal of ATV/r with TDFmedian change in creatinine clearancePI and renal riskRisk of CKD: multivariate analysisDianummer 13Dianummer 14Some ARV therapies increase the risk of CKDRenal Risk Calculators in HIV careTubulopathy (acute tubular injury/Fanconi syndrome)TFV (TDF) exposure and kidney diseaseRapid eGFR decline and CKD in patients with subsequent TDF-associated Renal Tubulopathy Dianummer 20Dianummer 21Dianummer 22Dianummer 23eGFR through 96 weeks with ECF-TAF in patients with renal impairment (GS-0112) Dianummer 25Dianummer 26ART and the kidney KEY pointsDianummer 28