Young person with multi-class resistance: follow-up and management

(with perspectives from well-resourced and resource-limited settings)

Gareth Tudor-WilliamsImperial College London

UK

Where would you prefer to be right now?

Langkawi resort?Attending a workshop?

Young person with multi-class resistance: follow-up and management

(with perspectives from well-resourced and resource-limited settings)

Gareth Tudor-WilliamsImperial College London

UK

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!

Less chance of selecting triple class resistance with today’s

combination therapy

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?

I would do a test: I would not do a test now:

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

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?I would prescribe

3TCI would not include

3TC

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?I do have access I do not have access

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?CXCR4 CCR5

Tropism = which co-receptor on the CD4+ lymphocyte is being used by the virus to bind to the cell

stage Blocked by 1 Binding &

FusionCCR5 co-receptor inhibitor (Maraviroc)Fusion inhibitor (Enfuvirtide = T20)

2 Reverse transcript’n

NRTI’s (3TC, ABC)NNRTI’s (NVP, EFV)

3 Integration Integrase inhibitors(Raltegravir)

4 Transcription

5 Assembly Protease inhibitors(Lopinavir / ritonavir)

6 Budding and maturation

Maturation inhibitors

Targets for currently available inhibitors

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

• Darunavir 600mg twice daily• Ritonavir 100mg twice daily• Raltegravir 400mg twice daily• Truvada 1 tablet once daily

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….

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

(I54S, V82A)

DRV susceptible

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

• 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 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

HLA B*5701 prevalence

Ethnicity n = % positive

White / Eurasian 654 8

Niger / Congo 573 0.5

Black Caribbean 82 0

South Asian 42 5

East Asian 12 0

HLA B*5701 prevalence in African populations

Would you treat her with 3TC monotherapy?

Yes, I would No, I wouldn’t

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)

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

Lancet Infect Dis 2011; 11: 273-283

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

At trial end PI (N=131) NNRTI (N=132)

On 1st regimen 96 73% 92 70%

0.00

0.25

0.50

0.75

1.00

Pro

porti

on o

f chi

ldre

n no

t sw

itche

d

0 24 48 72 96 120 144 168 192 216 240 264 288

Weeks from randomisation

p=0.64

PINNRTI

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

Time to Switch by Viral Load Switch-point

0.00

0.25

0.50

0.75

1.00

Pro

porti

on o

f chi

ldre

n no

t sw

itche

d

0 24 48 72 96 120 144 168 192 216 240 264 288

Weeks from randomisation

p=0.04

1,000

30,000

HIV-1 RNA at switchc/ml, median (IQR)

1,000 30,000 p-value

6,720 (1,380; 26,100)

35,712 (8,060; 72,800)

<0.01

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

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

1,000 30,000 P-value*

Total childrenNumber expected to have testsNumber with tests

1346051

1294840

PI resistance1 or 2 mutations 11 (9%) 5

(4%)

0.27

NNRTI resistance1 or 2 mutations3 or more mutations

18 (14%)3 (2%)

16 (13%)5 (4%)

0.50

High-level etravirine resistance

1 (1%)

2(2%)

**

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

Cumulative Resistance at end of follow-up

PI 1,000

PI 30,000

NNRTI 1,000

NNRTI30,000

P value

Total childrenNumber expected to have testsNumber with tests

6633

28

6523

18

6827

23

6425

22

NRTI resistance1 or 2 mutations3 or more mutations

9 (15%)3 (5%)

6 (10%)3 (5%)

14 (22%) 0 (0%)

12 (20%)7 (11%)

0.001**

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

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

susceptiblepot . 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 susceptibleORABC ddI LPV/r : 5 fully susceptible

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 susceptiblepot . 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 susceptibleORABC ddI LPV/r :1 fully susceptible

Start LPV/r: 30000 group 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.

Example

7 children started on 3TC ZDV/d4T + LPV/r

WHO recommends second-line:

ABC 3TC EFV : 4 fully susceptibleORABC ddI EFV : 4 fully susceptible

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 toDr Caroline Foster

and my colleagues in the HIV Family Clinic,Imperial College Healthcare NHS Trust,

London UKand colleagues in

Paediatric European Network for Treatment of AIDS (PENTA)

especially Linda Harrison for PP1 analyses