Young person with multi-class resistance: follow-up and management
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Young person with multi-class resistance: follow-up and management (with perspectives from well-resourced and resource-limited settings). Gareth Tudor-Williams Imperial College London UK. Where would you prefer to be right now?. Langkawi resort?. Attending a workshop?.

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Gareth tudor williams imperial college london uk

Young person with multi-class resistance: follow-up and management(with perspectives from well-resourced and resource-limited settings)

Gareth Tudor-Williams

Imperial College London

UK


Where would you prefer to be right now

Where would you prefer to be right now?

Langkawi resort?

Attending a workshop?


Gareth tudor williams imperial college london uk

Young person with multi-class resistance: follow-up and management(with perspectives from well-resourced and resource-limited settings)

Gareth Tudor-Williams

Imperial College London

UK


Context

Context

  • In many resource-rich settings, young people with perinatally acquired HIV who are now in their mid-teens started on sub-optimal regimens in the pre-cART era.

  • Typically dual therapy, such as AZT + 3TC, or d4T and ddI were used.

  • Nelfinavir (unboosted) and ritonavir in therapeutic doses were our early PI’s.

  • NNRTI’s were added to failing regimens.


Thankfully the lessons have been learned

Thankfully, the lessons have been learned!

Less chance of selecting triple class resistance with today’s combination therapy


Case history

Case history

  • 15 year old girl, Zambian parents

  • VL 96,000 c/ml off treatment / CD4=280

  • Previous treatment:

    • AZT 3TC DDI TDF NFV RTV EFV

  • Can swallow tablets

  • Weighs 42 kg

  • No known allergies

  • Aware of her HIV status


Would you do a resistance test now

Would you do a resistance test now?

I would do a test:

I would not do a test now:


Hiv resistance mutations

HIV resistance mutations

  • Adherence has been a long-standing problem and she has never sustained an undetectable VL for any consistent length of time.

  • She has had a number of resistance tests over the years

  • Right now, not much point in repeating resistance test since she has been off treatment

  • Cumulative mutations from previous tests are more helpful, plugged into Stanford data base:

    http://sierra2.stanford.edu/sierra/servlet/JSierra?action=mutationsInput


15yrs triple class resistance

15yrs – triple class resistance

???


In a well resourced setting

In a well resourced setting:

  • More information required to help decide what else to offer:

    • Is she co-infected with HBV or HCV?


If she is hbv infected would you recycle lamivudine in next regimen

If she is HBV infected, would you recycle lamivudine in next regimen?

I would prescribe 3TC

I would not include 3TC


In a well resourced setting1

In a well resourced setting:

  • More information required to help decide what else to offer:

    • Is she co-infected with HBV or HCV? NO

    • HLA B*5701 status?


Where you work do you have access to hla b 5701 testing

Where you work, do you have access to HLA B*5701 testing?

I do have access

I do not have access


In a well resourced setting2

In a well resourced setting:

  • More information required to help decide what else to offer:

    • Is she co-infected with HBV or HCV? NO

    • HLA B*5701 status? Negative

    • HIV tropism?


Current co receptor binding inhibitors work best against which strain of hiv

Current co-receptor binding inhibitors work best against which strain of HIV?

CXCR4

CCR5


Gareth tudor williams imperial college london uk

Tropism = which co-receptor on the CD4+ lymphocyte

is being used by the virus to bind to the cell


Targets for currently available inhibitors

Targets for currently available inhibitors


In a well resourced setting3

In a well resourced setting:

  • More information required to help decide what else to offer:

    • Is she co-infected with HBV or HCV? NO

    • HLA B*5701 status? Negative

    • HIV tropism? X4


Virtual clinic recommendation 2010

‘Virtual clinic’ recommendation, 2010

Virtual clinic = our HIV team, plus virologist / lab scientist, monthly meeting

  • Darunavir600mg twice daily

  • Ritonavir 100mg twice daily

  • Raltegravir400mg twice daily

  • Truvada1 tablet once daily


Management

Management

  • Multi-disciplinary support for adherence

  • Seen every two weeks for first month, plus phone calls from clinical nurse specialist

  • No significant adverse effects

  • Viral load tested 4 weeks after starting new regimen – excellent response, which reinforces her ability to adhere

  • Follow-up visits gradually extended to 3m.


2012 vl 50 for 1 year would like once daily regimen

2012: VL<50 for 1 year - would like once daily regimen….

???


Recent fda approval

Recent FDA approval

  • Darunavir once daily for ARV naïve without DRV resistance mutations:

  • ARV-naive children 3 to under 12 :

    • 10 to under 15 kg: 35/7 mg/kg once daily

    • 15 to under 30 kg: 600/100 mg once daily

    • 30 to under 40 kg: 675/100 mg once daily

  • ARV-naive adolescents 12 to <18 yrs:

    • 40 kg or more: 800/100 mg once daily 

      http://www.natap.org/2013/Pharm/Pharm_13.htm


Gareth tudor williams imperial college london uk

(I54S, V82A)

DRV susceptible


Gareth tudor williams imperial college london uk

Virtual Clinic discussion 2012

?? OD DRV/r +Truvada + Third agent ? – potential low level R to rilpivirine (2nd generation NNRTI)

? Wait elvitegravir / dolutegravir

?? OD Raltegravir

Decided to go for once daily DRV 800 / RTV 100 plus Truvada, with close monitoring of viral load… so far, so good!


Resource limited setting

Resource-limited setting

  • 15 year old girl

  • VL 96,000 c/ml off treatment / CD4=280

  • Previous treatment:

    • AZT 3TC DDI TDF NFV RTV EFV

  • Can swallow tablets

  • Weighs 42 kg

  • No known allergies

  • Aware of her HIV status


Resource limited setting1

Resource limited setting:

  • More information required to help decide what else to offer:

    • Is she co-infected with HBV? NO

    • HLA B57*01 status? Know your population!

    • HIV tropism? Not (currently) relevant


Prevalence of hla b 5701 varies according to ethnic background

Prevalence of HLA B*5701 varies according to ethnic background


Hla b 5701 prevalence

HLA B*5701 prevalence


Hla b 5701 prevalence in african populations

HLA B*5701 prevalence in African populations


Would you treat her with 3tc monotherapy

Would you treat her with 3TC monotherapy?

Yes, I would

No, I wouldn’t


Hiv resistance

HIV resistance

  • Much can be inferred without access to resistance testing

  • Need to know what regimens she has had, and how long she was on a failing regimen

  • Failure on 3TC – expect M184V mutation

  • Failure on NNRTI – predictable resistance

  • Trials such as the PENPACT 1 study provide some insights:


Penpact 1 penta 9 pactg 390

PENPACT 1 (PENTA 9 / PACTG 390)

Lancet Infect Dis 2011; 11: 273-283

Antiretroviral therapy initiation with a PI versus an NNRTI combination and switch at higher versus low viral load in HIV-infected children: an open randomised controlled phase 2/3 trial


Penpact 1 trial penta impaact

A long-term comparison in ART naïve children of:

PI-based versus NNRTI-based initial therapy

two different viral load criteria for switching from 1st to 2nd line therapy:>1,000 versus >30,000 copies/ml

PENPACT 1 trial (PENTA / IMPAACT)


Time to switch by drug class

Time to Switch by Drug Class

1.00

0.75

PI

0.50

Proportion of children not switched

NNRTI

0.25

p=0.64

0.00

0

24

48

72

96

120

144

168

192

216

240

264

288

Weeks from randomisation

Only 4 (2%) children switched to 3rd line


Time to switch by viral load switch point

Time to Switch by Viral Load Switch-point

1.00

0.75

1,000

30,000

0.50

Proportion of children not switched

p=0.04

0.25

0.00

0

24

48

72

96

120

144

168

192

216

240

264

288

Weeks from randomisation


Resistance testing

Resistance testing

  • Samples tested for resistance:

  • Last sample with viral load >1000c/ml

  • before switch

  • at confirmed viral load >1000c/ml before re-suppression (to ensure a fair comparison between the 1000 and 30000 groups)

  • at 4 years

  • at trial end


Gareth tudor williams imperial college london uk

If she was ‘failing’ on NVP for a year, would she have accumulated more NVP resistance than if she had switched as soon as VL reached 1,000 c/ml?

Yes, more resistance

No, no greater resistance


Cumulative resistance at end of follow up

Cumulative Resistance at end of follow-up

Analysis assumes those without tests were not resistant. *Poisson regression ** score 5 on Stanford scale


Cumulative resistance at end of follow up1

Cumulative Resistance at end of follow-up

** Driven by more children with ≥ 3 NRTI mutations in NNRTI switch at 30,000 c/ml arm


Start nnrtis 1000 group

Start NNRTIs: 1000 group

Potential NRTIs for second-line

n first-line ZDV ddI 3TC ABC

1 3TC ABC EFZ low - - -

2 3TC ABC EFZ - - high pot. low

3 3TC ABC EFZ - inter. high high

4 3TC d4T EFZ - - - -

5 ZDV 3TC EFZ - - - -

6 ZDV 3TC EFZ - - - -

7 ZDV 3TC EFZ - - - -

8 ZDV 3TC EFZ - - - -

9 ZDV 3TC EFZ - - high pot. low

10 ZDV ddI EFZ inter. low - low

11 3TC d4T NVP - low high low

12 3TC d4T NVP - - high pot. low

13 3TC d4T NVP - - high pot. low

14 ZDV 3TC NVP - - high pot. low

15 ZDV 3TC NVP - - - -

16 ZDV 3TC NVP - - high pot. Low

17 ZDV 3TC NVP low low high inter.

18 ZDV 3TC NVP - - high pot. low

19 ZDV ABC NVP inter. low - low

20 ZDV ddI NVP - - - -

  • Stanford score

  • = 1 fully susceptible

  • pot . low = 2 potential low

  • low = 3 low

  • Inter. = 4 intermediate

  • high = 5 high

Example

14 children start on

3TC ZDV/d4T + NNRTI

WHO 2010 recommends 2nd line:

ABC 3TC LPV/r : 5 fully susceptible

OR

ABC ddI LPV/r : 5 fully susceptible


Start nnrtis 30000 group

Start NNRTIs: 30000 group

Potential NRTIs for second-line

n first-line ZDV ddI 3TC ABC

1 3TC ABC EFZ - - high pot. low

2 3TC ABC EFZ - high high high

3 ZDV 3TC EFZ - - high pot. low

4 ZDV 3TC EFZ - - high pot. low

5 ZDV 3TC EFZ - pot. low high pot. low

6 ZDV 3TC EFZ - - high pot. low

7 ZDV 3TC EFZ inter. inter. high inter.

8 ZDV 3TC EFZ - pot. low high low

9 ZDV 3TC EFZ inter. pot. low high low

10 ZDV 3TC EFZ low high high high

11 ZDV ddI EFZ inter. inter. - low

12 ZDV ddI EFZ - - - -

13 ZDV ddI EFZ low - - -

14 ZDV ddI EFZ inter. low - low

15 3TC ABC NVP - - high pot. low

16 3TC d4T NVP - - high pot. low

17 3TC d4T NVP pot. low - - -

18 3TC d4T NVP - - high pot. low

19 3TC d4T NVP inter. pot. low high low

20 3TC d4T NVP high inter. high inter.

21 ZDV 3TC NVP - - high pot. low

22 ZDV 3TC NVP high high high high

  • Stanford score:

  • = 1 fully susceptible

  • pot . low = 2 potential low

  • low = 3 low

  • inter. = 4 intermediate

  • high = 5 high

Example

15 children start on

3TC ZDV/d4T +NNRTI

WHO 2010 recommends second-line:

ABC 3TC LPV/r :1 fully susceptible

OR

ABC ddI LPV/r :1 fully susceptible


Start lpv r 30000 group

Start LPV/r: 30000 group

Example

7 children started on

3TC ZDV/d4T + LPV/r

WHO recommends second-line:

ABC 3TC EFV : 4 fully susceptible

OR

ABC ddI EFV : 4 fully susceptible

Potential NRTIs for second-line

n 1st line ZDV ddI 3TC ABC

1 3TC d4T LPV - - - -

2 ZDV 3TC LPV - - - -

3 ZDV 3TC LPV - - - -

4 ZDV 3TC LPV inter. low - pot. low

5 ZDV 3TC LPV - - - -

6 ZDV 3TC LPV - - high pot. low

7 ZDV 3TC LPV inter. inter. high inter.


Management1

Management

  • Use boosted PI (i.e. Kaletra, if that’s what is available)

  • Recycle available options

  • Push for access to newer agents – darunavir / atazanavir / raltegravir and in due course dolutegravir….

  • GOOD LUCK!


With many thanks to dr caroline foster

With many thanks toDr Caroline Foster

and my colleagues in the HIV Family Clinic,

Imperial College Healthcare NHS Trust, London UK

and colleagues in

Paediatric European Network for Treatment of AIDS (PENTA)

especially Linda Harrison for PP1 analyses


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