tenofovir disoproxil fumarate across the age spectrum: from...

Tenofovir disoproxil fumarate across the age spectrum:

from fetus to adolescent

Anna TurkovaPENTA-id

St Mary’s Hospital, ICHTMRC CTU at UCL, London

7th International Workshop on HIV Pediatrics

2015

Disclaimer

• I declare no conflict of interest

Overview

• Tenofovir disoproxil fumarate (TDF)

• Efficacy

• Toxicity

• Maternal TDF and its effect on infants

• Tenofovir Alafenamide

Tenofovir disoproxil fumarate

Advantages • Potent NRTI• Induction of a few RT

mutations • Long half-life (OD)• ‘Forgiving’• Favourable metabolic profile• Effective against Hep B• Available paediatric

formulations • FDC for adolescents

Aurpibul L, Puthanakit T. PIDJ 2015

CELL

Disadvantages: • Drug interactions:

– TDFddi– TDFATV, – PI/r TFV

• Renal and bone toxicity• Poor palatability of non-solid

formulations

Formulations for children and adolescents

Fixed dose combinations

Single Tablet Regimens

Eviplera®

Tenofovir disoproxil fumarate

The place of TDF in paediatric cART

US DHHS 2015 WHO 2013 PENTA 2015

Overview


• Efficacy

• Toxicity



TDF efficacy and safety in children and adolescents

• What’s new in 2015

Gilead 352 switch study4

• RCT, age 2-12y• N=97, supressed children • TDF vs ZDV/D4T • Randomisation phase 48 w• Extension phase 5.5 y

TDF efficacy

6.Aurpibul L, et al. PIDJ 2015

• Adult RCTs – excellent efficacy – TDF vs d4T1; TDF/FTC vs ZDV/3TC2; TDF/FTC vs ABC/3TC3

• Paediatric studies:

1. Gallant JE ,et al. JAMA 20042. Gallant JE ,et al. NEJM 20063. Sax PE, et al. NEJM 2009

THAI switch study6

• Non-randomised, age 3-18y • N=80, suppressed children• TDF vs ZDV/ddi• Wt-band dosing• 96w

Gilead 321 study5

• RCT, age 12-17y, • N=81, highly pre-treated• TDF vs PBO added to OBR• Randomisation phase 48 w• Extension phase 4.5 y

5. Della Negra M, et al. PIDJ 2015

4. Saez-Llorens X, et al. PIDJ 2015

Gilead 352 switch study1

• Supressed children, age 2-12y• Randomisation phase, w48

83% (TDF) v 85% (ZDV/d4T) VL<400

Non-inferiority not shown [M=F]• Extension phase: w144

(all TDF) 80.6% VL <400 [M=F]

TDF efficacy

1. Saez-Llorens X, et al. PIDJ 2015 2. Della Negra M, et al. PIDJ 2015 3.Aurpibul L, et al. PIDJ 2015

Gilead 321 study2

• Highly pre-treated, age 12-17y• Randomisation phase, w48

34% (TDF) v 44% (PBO) VL <400 [M=F]

• Extension phase: w144 (TDF/TDF) 30.4% VL <400 [M=F]high attrition

THAI non-randomised switch study3

• Suppressed children, age 3-18y • w96: • 98% (TDF) vs 85% (ZDV/ddi) VL<50

TDF toxicity

• Bone

– Bone mineral density (BMD)

– Fractures

• Renal

– Proximal tubular (PT) dysfunction

– Glomerular toxicity

• TDF – excreted via glomerular filtration and tubular secretion

• Proximal tubular dysfunction

– Likely mitochondrial toxicity

• Effect on eGFR

– Inhibition of tubular secretion of creatinine

• Dose dependent

• Duration dependent

• Co-administration with PI/r and ddi

• Reversible with prompt discontinuation

Tenofovir and kidneys

Hall A. Pediatr Nephrol 2013Bhimma et al. JIAS 2013

Genetic predisposition?Polymorphism ofABC-transporters

(TDF efflux)

Vigano et al. Clin Drug Investig 2015

TDF renal toxicity – monitoring

Measures

Serum creatinine

eGFR

Serum phosphate

Fractional Excretion phosphate

Glycosuria

Urine Albumin Creatinine ratio

Urine Protein Creatinine ratio

Urine tubular proteins (RBP, β2 microglobulin)

1. Hall AM. Pediatr Nephrol 2013

Blo

od

Uri

ne

Renal toxicity – long term safety

Gilead 352, age 2<16y1

• 87.7% on boosted PI

• Median eGFR Δ -28.7 • 5% (4/79) discontinued TDF

due to tubulopathy (w 84-156)

1. Saez-Llorens, et al. PIDJ 2015 2. Della Negra M, et al. PIDJ 2015 3. Aurpibul L, et al. PIDJ 2015

Gilead 321, age 12-17y2

• 52% on boosted PI

• Median eGFR Δ -38.1 • n=2 developed proteinuria

– n=1 TDF-related • n=1 acute renal failure (AmB)

THAI study, age 3-18y3

• 3rd agent – NNRTI 86%

• TDF group: no significant change in mean eGFR from baseline, small but significant increased Ca excretion, no change in phosphate excretion

• No significant difference between groups reported

Renal toxicity in children

NO N, TDF-exposed

Years of TDF

YES N, TDF-exposed

Years of TDF

Hazra 2005 18 1 Andiman 2009 255 6

Vigano 2007 27 2 Judd 2010 132 Mean 2.1

Vigano 2011 26 5 Soler-Palacin2011

40 6

Pontrelli 2012* 31 2 Purswani 2013 95 3

Della Negra 2012(Gilead 321)

45 1 Riordan 2009 159 n/a


81 2-3 Saez-Llorens2015 (Gilead 352)

97 6.5

Lim 2015 70 ~2

Giacomet 2015 26 11

Aurpibul 2015 40 2* No difference between TDF-exposed and not exposedAurpibul L, Puthanakit T. PIDJ 2015

Summary: renal toxicity in paediatric studies

• Mixed results

• Renal dysfunction associated with TDF mg/kg dose and prolonged TDF use

• Co-administration of boosted PI


Lim et al. Clin Drug Investig 2015

Giacomet V et al. Clin Drug Investig 2015

Andiman WA. PIDJ 2009

Large cohorts report 2.3-4.8 times higher risk in children treated with TDF

Judd et al. AIDS 2010

• Decline of proximal tubular function– Proteinuria 0-22% – Hypophosphataemia 0-65%– Discontinuation treatment 0-10%

• Decline of eGFR– Significant (<60 mL/min/1.73m2) in 0 - 0.6%– Any decrease of eGFR in 0-15%

Pathogenesis

• Phosphate wasting secondary to PT dysfunction

Increased bone turnover / bone de-mineralisation

• Decreased Vit D activation, which takes place in PT

• Elevation of PTH

• Direct mitochondrial toxicity in bone tissue (?)

Bone disease - multifactorial:

• HIV (advanced stages), ART, lifestyle,

immune activation, vitamin D deficiency

Tenofovir and bones

Puthanakit T, Siberry GK. JIAS 2013Hall AM. Pediatr Nephrol 2013

• Critical periods for bone accrual: 3rd trimester & puberty

• Concern: diminished accrual may lead to low peak bone mass, associated with bone fragility (osteoporosis and fractures) in adulthood

Tenofovir and bones: concern for children

Age, years

Lumbar Spine BMD changes

Puthanakit T, Siberry GK. JIAS 2013

Bone toxicity – long-term safety


• 87.7% on boosted PIBMD results: • R (w48): similar spine, but

lower total body BMD gain in TDF group (difference bwgroups?)

• Overall: modest change in BMD-HAZ

0

1. Saez-Llorens, et al. CROI 2015, #954 2. Della Negra M, et al. PIDJ 2015

Median BMD-HAZ


• 52% on boosted PIBMD results:• R (w48): larger decline of

BMDZ in TDF group (non-sig. difference bw groups)

• Overall: modest decline of BMD-Z, no significant change in BMD-HAZ



• 87.7% on boosted PIBMD results: • R (w48): similar spine, but

lower total body BMD gain in TDF group (non-sig. difference bw groups?)

• Overall: modest change in BMD HAZ

0

1. Saez-Llorens, et al. CROI 2015, #954 2. Della Negra M, et al. PIDJ 2015


• 52% on boosted PIBMD results:• R (w48): larger decline of

BMDZ in TDF group (non-sig. difference bw groups)

• Overall: modest decline of BMD-Z, no significant change in BMD-HAZ

Median HA-BMD Z scores

• At 96 weeks - 9% had low BMDZ but no difference between the groups (p=0.395)


Z-Scores

*Aurpibul L, et al. PIDJ 2015

THAI study, age 3-18y* • N=80 (40 on TDF), 3rd agent NNRTI 86%

96 wks (2yrs), excellent retention

• At 24 wks - significant in spine BMDZ in TDF group but not in the control group

Mean spine BMDZ

TDF

No-TDF

Bone toxicity in children

• Only three comparative studies (2 RCTs 48w)• Mixed reporting measures: BMD gain and loss, mean & median BMD Z-

scores, BMD Ht adjusted Z-scores

NO N, TDF-exposed

Years of TDF

YES N, TDF-exposed

Years of TDF

Giacomet 2005 16 1 Hazra 2005 18 1

Vigano 2011 21 5 Gafni 2006 15 2

Della Negra 2012(Gilead 321, RCT)

45 1 Schtscherbyna2012

74 Cross-section

Gilead 352 2012(RCT)

92 1

Saez-Llorens 2015(Gilead 352, 2015)

97 6.5


81 5.5

Aurpibul 2015 40 2


Summary: bone toxicity in paediatric studies

• Mixed data, variable results

• Longitudinal studies: initial decline with subsequent stabilisation

• Children with higher TDF exposure are at higher risk

– young, pre-pubertal,higher TDF dose (mg/kg), concomitant use of PI

• No effect on growth or fracture rates

• Unknown long-term consequences of modest BMD decline

• Monitoring


? DEXA? Frequency of monitoring? Clinical relevance

Resource poor setting

• The largest burden of HIV infection in the world

• High prevalence of pre-existing chronic kidney disease

• Prevalence of low BMD may be higher

• TDF is a part of first and second line ART in children >10y/>35kg

• Toxicity monitoring is difficult, and the need and feasibility has not been established

Bhimma et al. JIADS 2013 Hall AM. Pediatr nephrol 2013

Puthanakit T, Siberry GK. JIAS 2013 Stöhr W, et al. Antivir Ther 2011

*Adult DART trial – severe decline of eGFR rare; routine lab monitoring didn’t improve renal outcomes compared to clinical monitoring

Overview


• Efficacy

• Toxicity



TDF in pregnant women

• TDF included in the 1st line ART for pregnant1,2,3 and

breastfeeding1 women

• TFV – high placental transfer (60%) and long half-life

• Pregnancy registry database – no increased

congenital abnormalities

• In pre-term labour, addition of double-dose TDF

given to mother to load the baby is recommended2

• Not recommended in neonates

– Have been studied in ANRS 12109 trial as single dose4

– Used off label in cases with high risk of transmission

of resistant virus5

1. WHO 2013 2. BHIVA 2014 3.US DHHS 2014 4. Hirt D, et al. AAC 2011 5. St Marys, London

PROMISE1

• Lower MTCT on triple ARV

• Significantly higher risk of infant death for

TDF/FTC vs ZDV/3TC (+ LPV/r):– 4.4%(15/341) vs. 0.6% (2/346)

(p=0.001)

• The difference in death - in infants <34 w gestation

• Unexpected results

• Further investigation needed

1. Mary Glenn Fowler, CROI 2015, 31LB 2. Gibb DM. PLOS Med 2012

*DART (n=390 pregnancy outcomes, cohort analysis) showed no difference in preterm deliveries, low birth weights or deaths in infants exposed to TDF2 (No LPV/r)

N = 3523

• Human studies: mixed results 1-4

• Systematic review 20135: 4/5 studies showed no

relationship bw TFV exposure and growth, bone, or renal

outcomes

– Siberry 2012: lower mean infant length and head

circumference at 1 year2

• 2013-2015: Two studies showed small negative effect:

– Ransom 2013: lower sex-adjusted WZ at 6 m2

– Siberry 2015: lower BMC at birth6

Maternal TDF: effect on infant growth and bone

1. Siberry G, et al. AIDS 2012 2. Ransom CE, et al. JAIDS 2013 3. GibbDM, et al. PLOS 2012 4. Vigano A, et al. Antivir Ther 20115. Wang L, et al. CID 2013

• Maternal TDF associated with lower neonatal whole body BMC 5.3g lower BMC in TDF arm, p=0.013 (95%CI: -9.5, -1.2)

• No difference in length or weight Z-scores at birth

Effect of maternal TDF on fetal bone

• Cross-sectional substudy of SMARTT• HIV-uninfected infants, GA ≥ 36 weeks, n=143• Whole-body bone mineral content (BMC), age <1m• No-TDF vs TDF exposed

Siberry GK. CROI 2014; CID 2015

• Clinical significance?• Further studies

– Serial DXA (IMPAACT, P1084)– Comparative studies with HIV-/ART-

George Siberry, et al. CID 2015

Overview


• Efficacy

• Toxicity



Tenofovir Alafenamide

Gilead studies 104&111, combined analysis, w48

• TAF – intracellular

conversion to TFV

• 90% lower circulatory

plasma tenofovir (TFV)1,2

2. Wohl D, CROI 2015, 113LB1. Ruane P et al, JAIDS 2013 2. Sax PE, CROI2015, 143LB;

Adults: E/C/F/TAF vs E/C/F/TDF, w48

• TAF is virologically non-inferior to TDF

– VL< 50 c/ml: 92.4% vs. 90.4% 3

• TAF w48: much better renal and bone safety profile

Adolescents:E/C/F/TAF

• Single arm

• N=23, W24 results

PK

• (AUC, Cmax, Cmin) similar to adults

Efficacy

• 91.3% achieved VL<50c/ml

• 2 subjects with detectable VL had <20 c/ml on re-test

Kizito H, et al. CROI 2015 #953

Efficacy

Gilead Study 106

mea

n +

/-SD

Study week

Mean AUCtau

Renal:

• serum Cr consistent with COBI inhibition of Cr tubular secretion

• Minimal changes in tubular proteins

– Β-2 microglobulin

Bone:

• Positive change in median BMD

• BMD Z-scores (unadjusted and HA) improved

– 2/23 had ≥4% decrease of BMD

• No discontinuations to side effects

Serum creatinine

Study week

eGFR

Kizito H, et al. CROI 2015 #953

Gilead Study 106

Adolescents:E/C/F/TAF

Safety

Adolescents and children: other TAF formulations

F/TAF1: Ongoing: age 6-18 y

D/C/F/TAF2 – phase II adult study published: plans for children?

Planned (PIP): age 4w to 6 y

Gilead Study 1269

1.Erin Quirk, PENTAid , San Servolo 2015

• United States• Panama• South Africa• United Kingdom

2. Mills A, et al. JAIDS 2015

Concluding remarks

• TDF is widely used in paediatrics

• Severe renal toxicity is rare, but proximal tubulopathy is not uncommon, discontinuation in ~3-10%

• Severe BMD loss in minority; modest BMD loss is well reported; long-term consequences of is unknown

• In resource-limited countries -monitoring is a logistical challenge; the feasibility needs evaluation

• Recent studies raised concerns regarding increased infant mortality and effect on bone

• New formulations (TAF) offer effective and safer options and are likely to supersede TDF in coming years

Concluding remarks

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