Renal Health in People Living

with HIV

1

Professor Bruce HendryRenal Medicine

King’s College London King’s 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

• Monitoring Renal Health

• Renal Disease in PLWHIV

• Anti Retroviral Therapy (ART) and the kidney

• 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

Distribution of chronic kidney disease in Japanese HIV cohort

Distribution of HIV-infected individuals

determined by the 2012 KDIGO classification

GFR

grade

eGFR

(mL/min/

1.73m2)

Categories of albuminuria

A1 A2 A3

G1 ≥ 90 35.8% 1.7% 0.0%

G2 60 – 89 50.1% 5.5% 0.3%

G3a 45 – 59 3.8% 1.5% 0.2%

G3b 30 – 44 0.3% 0.3% 0.1%

G4 15 - 29 0.1% 0.2% 0.1%

G5 < 15 0.0% 0.0% 0.0%

Albuminuria assessed via protein reagent dipstick: (A1) no proteinuria (dipstick - or +/-), (A2) mild

proteinuria (dipstick 1+ or 2+), (A3) heavy proteinuria (dipstick ≥3+)

Prevalence according to risk of poor

prognosis

Risk Prevalence

Low 85.9%

Moderately increased 11.0%

High 2.1%

Very high 1.0%

Prospective cohort (n=1,447) classified in line with 2012 KDIGO CKD

classification

Yanagisawa N. Clin Exp Nephrol (2014) 18:600–605

Monitoring renal function and pathology

Glomerular Filtration• Creatinine-based eGFR (CKD-EPI, MDRD, CG)

• Biomarker eGFR (cystatin C)

• Actual GFR (Cr-EDTA, iohexol clearance)

Glomerular Health• uACR (uPCR)

Tubule Function• LMW proteinuria (RBP, B2M, NGAL)

• Proteinuria (uPCR)

• Phosphate transport (TmPO4/GFR, serum phosphate)

• Renal glycosuria

Glomerular and Tubule Proteinuria

• Globally most proteinuria is glomerular(diabetes, HT, IgA nephropathy etc)

• In controlled HIV care, most proteinuria is from thetubules

• Dipstick of urine is a good screen for proteinuria as it is immediate and sensitive (and also carries more information e.g. glycosuria)

uACR and uPCR can be combined to estimate uAPR

An uAPR of 0.6 is typical of glomerular disease

APR< 0.4 indicates Tubule proteinuria (and vice versa)

King’s HIV proteinuria study mean APR was 0.1-0.2*

*Campbell at al. BMC Nephrol 2012,13:85

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)

p<0.00001

CRF (n=36)

No CRF (n=1824)

HIVAN (n=15)

p<0.0001

Survival free of ESRFOverall patient survival

CRF not HIVAN (n=21)

0 1 2 3 4 5 0 1 2 3 4 5

p<0.00001

Years from inception Years since CRF diagnosis

0.0

0.25

0.50

0.75

1.00

0.0

0.25

0.50

0.75

1.00

Campbell LJ et al. HIV Medicine 2009; 10(6): 329-336CRF = CKD stage G3-5

In PLWHIV reduced eGFR and proteinuria are risk factors for CV events

AIDS 2010; 24: 387-94

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)

11Guaraldi G, et al. Clin Infect Dis. 2011;53:1120-1126.

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

Com

orb

idit

y

Sta

tus,

%‡

≤ 40 Years

HIV+ HIV-

41 to 50 Years

HIV+ HIV-

51 to 60 Years

HIV+ HIV-

> 60 Years

HIV+ HIV-

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 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 TDFmedian change in creatinine clearance

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

-4

-2

0

2

4

6

8

10

Ch

ange

in c

alcu

late

dcr

eat

inin

e cl

ear

ance

, (m

L/m

in)

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<0.001

p-values:ATV/r vs. EFV

Week 48

Week 96

ARV exposure and chronic kidney disease

Lancet HIV. 2016; 3:e23-32

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<60 ml/min/1.73m2 compared with EFV.

• DRV/r was not significantly associated with renal impairment.

Risk factors for CKD: data from the D:A:D study

PLoS Med 2015; 12: e1001809

Some ARV therapies increase the risk of CKD

1

9ATV, 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

Nu

mb

er

ne

ed

ed

to

ha

rm

Years of ARV exposure

Low risk (<0)

Medium risk (0-4)

High risk (≥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 modification (TDF)

More accurate assessment

The information portrayed on this slide is attributed to the presenter’s expert opinion

Tubulopathy (acute tubular injury/Fanconi syndrome)

AIDS 2016; 30: 1311-3, HIV8, Glasgow 2008

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/1.73m2/year 69.6% 7.9% <0.0001

eGFR decline >5 mL/min/1.73m2/year 55.4% 3.5% <0.001

CKD (eGFR <60 mL/min/1.73m2 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.

Switching from TDF to TAF improves total and tubular proteinuria (GS-0112)

Post, F. Boston, USA, CROI 2016 (P680)

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

29

Thank you