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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?. - PowerPoint PPT Presentation

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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-WilliamsImperial College LondonUK

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 LondonUK

ContextIn 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 PIs.NNRTIs were added to failing regimens.Thankfully, the lessons have been learned!Less chance of selecting triple class resistance with todays combination therapyCase history15 year old girl, Zambian parentsVL 96,000 c/ml off treatment / CD4=280Previous treatment: AZT 3TC DDI TDF NFV RTV EFVCan swallow tabletsWeighs 42 kgNo known allergiesAware of her HIV statusPrevious treatment in various combinationsWould you do a resistance test now?I would do a test:I would not do a test now:

HIV resistance mutationsAdherence 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 yearsRight now, not much point in repeating resistance test since she has been off treatmentCumulative mutations from previous tests are more helpful, plugged into Stanford data base:http://sierra2.stanford.edu/sierra/servlet/JSierra?action=mutationsInput

Pool all resistance data ever detected

15yrs triple class resistance???Many questions about whether and what to restart! Level of motivation to restart treatment is crucial.In a well resourced setting:More information required to help decide what else to offer:

Is she co-infected with HBV or HCV?

HBV co-infection will require TDF to be included in subsequent regimen. Any active hepatitis may modify the choice of drugs avoid those that are associated with higher risk of hepatotoxicity.13If 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?

3TC resistance may have already been selected TDF would be a better choice.HLA B*5701 - Predicts abacavir hypersensitivity.15Where you work, do you have access to HLA B*5701 testing?I do have accessI 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?CXCR4CCR5

Tropism = which co-receptor on the CD4+ lymphocyte is being used by the virus to bind to the cell19R5 vs X4

stageBlocked by 1Binding & FusionCCR5 co-receptor inhibitor (Maraviroc)Fusion inhibitor (Enfuvirtide = T20)2Reverse transcriptnNRTIs (3TC, ABC)NNRTIs (NVP, EFV)3IntegrationIntegrase inhibitors(Raltegravir)4Transcription5Assembly Protease inhibitors(Lopinavir / ritonavir)6Budding and maturationMaturation inhibitorsTargets for currently available inhibitors20MaravirocIn 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

So maraviroc is not an option which is something we see too frequently in later stages of infection. Case for deploying this class of drugs earlier in the course of infection?21Virtual clinic recommendation, 2010 Virtual clinic = our HIV team, plus virologist / lab scientist, monthly meeting

Darunavir 600mg twice dailyRitonavir 100mg twice dailyRaltegravir 400mg twice dailyTruvada 1 tablet once dailyA twice daily regimen is a challenge, but no once daily choiceManagementMulti-disciplinary support for adherenceSeen every two weeks for first month, plus phone calls from clinical nurse specialistNo significant adverse effectsViral load tested 4 weeks after starting new regimen excellent response, which reinforces her ability to adhereFollow-up visits gradually extended to 3m.2012: VL30,000 copies/ml PENPACT 1 trial (PENTA / IMPAACT)Just to remind people:2 x 2 factorial design - double randomisation at baselineTime to Switch by Drug ClassAt trial endPI (N=131)NNRTI (N=132)On 1st regimen 9673%9270%0.000.250.500.751.00Proportion of children not switched024487296120144168192216240264288Weeks from randomisationp=0.64 PINNRTIOnly 4 (2%) children switched to 3rd lineJust to remind people: n = 263 randomised188 (71%) overall still on 1st line regimen at trial end. Only 4 (2%) children switched to a 3rd line regimen.

Switch defined as: change of 3 drugs OR change of 2 drugs with the reason virological or clinical failure (including resistance)

Time to Switch by Viral Load Switch-point0.000.250.500.751.00Proportion of children not switched024487296120144168192216240264288Weeks from randomisationp=0.041,00030,000HIV-1 RNA at switchc/ml, median (IQR)1,00030,000 p-value6,720 (1,380; 26,100)35,712 (8,060; 72,800)1000c/ml

before switchat confirmed viral load >1000c/ml before re-suppression (to ensure a fair comparison between the 1000 and 30000 groups)at 4 yearsat trial endRe-cap of the main trial results:We tested samples available at the last viral load >1000 prior to switch, at 4 years and at end of follow-up. Additionally, to ensure a fair comparison between the 1000 and 30000 arms, we tested the last sample >1000 in anyone who confirmed >1000 (but did not switch).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 resistanceNo, no greater resistance

Cumulative Resistance at end of follow-up1,00030,000P-value*Total childrenNumber expected to have testsNumber with tests13460511294840PI resistance1 or 2 mutations

11 (9%)

5 (4%)0.27NNRTI resistance1 or 2 mutations3 or more mutations

18 (14%)3 (2%)

16 (13%)5 (4%)0.50High-level etravirine resistance1 (1%)2(2%)**Analysis assumes those without tests were not resistant. *Poisson regression ** score 5 on Stanford scaleThis is what we published: By the end of the trial, major PI resistance mutations were infrequent with no difference between the 1000 and 30000 arms.Major NNRTI mutations were common, but there was no difference between the 1000 and 30000 arms, suggesting they were selected early during viral rebound. Only 3 children had high-level resistance to etravirine (score of 5 on Stanford system)Cumulative Resistance at end of follow-upPI 1,000PI 30,000NNRTI 1,000NNRTI30,000P valueTotal childrenNumber expected to have testsNumber with tests6633

286523

186827

236425

22NRTI resistance1 or 2 mutations3 or more mutations9 (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 armFor NRTI resistance, there was an interaction between initial ART and switching level, with more major mutations in the NNRTI 30k group. Also, more TAMS and M184 in NNRTI 30k groupInteraction p-value 0.02Start 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 susceptible43Start 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