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Virological response and resistance among HIV-infected children on first-line antiretroviral therapy without routine virological monitoring PowerPoint Presentation

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Description : Virological response and resistance among HIV-infected children on first-line antiretroviral therapy without routine virological monitoring

Tags : Pediatrics, Child Health, pediatric practice, pediatrician, health providers, HIV-infected infants, virological monitoring

Published on : Jul 16, 2020 | Views : 2823 | Downloads : 1

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Slide 1-

Andrew J. Prendergast, Alexander J. Szubert, Moira J. Spyer, Victor Musiime, Philippa Musoke, Mutsa Bwakura-Dangarembizi, Patricia Nahirya-Ntege, Margaret J. Thomason, Emmanuel Ndashimye, Immaculate Nkanya, Oscar Senfuma, Boniface Mudenge, Nigel Klein, Diana M. Gibb A. Sarah Walker and the ARROW trial team Virological response and resistance among HIV-infected children on first- line antiretroviral therapy without routine virological monitoring
Slide 2-

UNAIDS target of 90-90-90 51% of HIV-infected children are currently on ART and numbers will increase with universal treatment guidelines WHO guidelines recommend regular viral load monitoring 6 and 12 months after starting ART Every 12 months thereafter Virological failure defined as VL >1000 copies/mL However, VL availability remains limited in sub-Saharan Africa (estimated at 25% in 2014) Question: What are the long-term virological outcomes and resistance of children managed without regular VL? Background 2
Slide 3-

ARROW trial 1206 ART-naive children and adolescents (4 months -17 years) in Uganda and Zimbabwe, meeting WHO 2006 criteria for ART initiation Laboratory and Clinical Monitoring (LCM) 12 weekly biochemistry, FBC & CD4 (no VL) Other investigations & concomitant medications if clinically indicated Clinically Driven Monitoring (CDM) 12 weekly biochemistry, FBC & CD4 (no VL); FBC & biochemistry only returned if clinically requested (or grade 4 toxicity); CD4 never returned Other investigations & concomitant medications if clinically indicated Randomised Switch to second-line for • new/recurrent WHO 4 (or multiple WHO 3) • WHO CD4 criteria Switch to second-line for • new/recurrent WHO 4 or recurrent/persistent WHO 3 As per WHO guidelines, switching before 48 weeks discouraged in both groups 3
Slide 4-

ARROW trial 1206 ART-naive children and adolescents (4 months -17 years) in Uganda and Zimbabwe, meeting WHO 2006 criteria for ART initiation Laboratory and Clinical Monitoring (LCM) 12 weekly biochemistry, FBC & CD4 (no VL) Clinically Driven Monitoring (CDM) 12 weekly biochemistry, FBC & CD4 (no VL); d FBC & biochemistry only returned if clinically requeste (or grade 4 toxicity); CD4 never returned Other investigations & Other investigations & concomitant medications if concomitant medications if clinically indicated clinically indicated Randomised Viral loads were not measured in either group in real time or used for clinical management Switch to second-line for • new/recurrent WHO 4 (or multiple WHO 3) • WHO CD4 criteria Switch to second-line for • new/recurrent WHO 4 or recurrent/persistent WHO 3 As per WHO guidelines, switching before 48 weeks discouraged in both groups 4
Slide 5-

ARROW trial As well as monitoring randomization, factorial design with randomization to first-line ART strategies: Arm A: standard 3-drug ART throughout Arms B and C: Induction-maintenance (4 drugs for first 36 weeks) Thus long-term in ARROW, 2/3 children on standard 2NRTI + NNRTI and 1/3 were on 3NRTI 3TC+ABC+NNRTI 3TC+ABC+ZDV (3NRTI) 3TC+ABC+NNRTI 3TC+ABC+NNRTI+ZDV 3TC+ABC+NNRTI+ZDV Week 0 Week 36
Slide 6-

Retrospective viral load testing after 4 years ART and longitudinally in a subgroup Enrolled in ARROW and initiated ART containing ABC+3TC+NNRTI Managed with or without CD4 tests Followed for median 4 years (N=1206) Cross-sectional N=890 Longitudinal N=316 VL assayed at weeks 4, 24, 36 and 48 post-ART, then 24-weekly VL assayed in the 6 months before trial closure/death N=1127 with available viral load data
Slide 7-

Viral load and resistance testing 7 Viral loads tested with lower limit of <80 copies/ml Samples with VL >1000 copies/ml genotyped Reverse transcriptase only In-house assay at JCRC, Uganda Major NRTI and NNRTI mutations defined according to IAS 2013 Drug susceptibility predicted using Stanford algorithm v7
Slide 8-

Virological definitions in longitudinal substudy 8 Viral load response VL <10,000 copies/ml (or >1 log drop) at week 4 VL <5000 copies/ml at week 24 <80 copies/ml at all measurements thereafter [except slow responders, VL declining but >80 at week 36] Blips Single or dual measurement >80 copies/ml, provided prior and subsequent VL <80 copies/ml Persistent low-level viral load VL persistently detectable but <5000 copies/ml Rebound Confirmed VL >5000 copies/ml
Slide 9-

Analysis 9 Cross-sectional study (n=1127) VL suppression and resistance compared between randomized monitoring and treatment arms, in the 6 months prior to trial closure/death, using chi-squared tests (ITT) Longitudinal study (n=316) Predictors of children with VL blips, persistent low-level viral load (pLLVL), rebound, and pLLVL/rebound identified using logistic regression Resistance summarized at the first VL in rebound, then at last subsequent genotype.
Slide 10-

Results 10 1206 children initiated ART Median age 6.0 years (IQR 2.4, 9.3) Median CD4 at initiation 12% (7, 17) Median follow-up 4.0 years (range 3.3-5.0) 5% with CD4 monitoring died vs 4% with clinical monitoring Only 63 (6%) switched to second-line ART At trial closure, 1132 (94%) alive and in follow-up Viral loads available for 1127 (99.6%)
Slide 11-

2 NRTI +NNRTI 3 NRTI 0 20 40 60 80 100 Percentage 2 NRTI +NNRTI 3 NRTI 0 20 40 60 80 100 Percentage VL outcomes at 4 years by randomized first-line ART 11 Viral load <80 copies/ml Viral load <1000 copies/ml 80% 65% 74% 52% P<0.001 P<0.001 Long-term 3NRTI first-line ART is virologically inferior to standard 2NRTI + NNRTI ART
Slide 12-

CD4 Clinical 0 20 40 60 80 100 e g a t n e c r e P CD4 Clinical 0 20 40 60 80 100 Percentage VL outcomes at 4 years by randomized monitoring strategy strategy (all on WHO-recommended 2NRTI + NNRTI) 12 Viral load <80 copies/ml Viral load <1000 copies/ml 81% 79% 75% 73% P=0.57 P=0.43 No difference in virological outcomes by monitoring
Slide 13-

0 20 40 60 80 100 LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM LCM CDM 3TC ABC ZDV DDI D4T FTC TDF NVP EFV ETR RPV Susceptible Potential low Low Intermediate High 3TC=lamivudine, ABC=abacavir, ZDV=zidovudine, DDI=didanosine, D4T=stavudine, FTC=emtricitabine, TDF=tenofovir, NVP=nevirapine, EFV=efavirenz, ETR=etravirine, RPV=rilpivirine Resistance data by monitoring strategy and first-line ART at 4 years (all with VL>1000) 13 2NRTI + NNRTI (n=110), majority on ABC + 3TC No difference in intermediate/high-level resistance to NRTIs and NNRTIs by monitoring strategy On WHO-recommended 2NRTI + NNRTI, only 15% had intermediate/high-level resistance to TDF and 9% to ZDV at 4 years 7% had K65R
Slide 14-

0 20 40 60 80 100 % Week 4 24 36 48 72 96 120 144 168 192 216 Week 4 24 36 48 72 96 120 144 168 192 216 Longitudinal viral load responses over 4 years by first- line ART 14 Arms A/B Arm-C Low level viral load Rebound Viral load response Died Current or previous blip Non responder N=311 children alive and achieving VL response by week 4
Slide 15-

Longitudinal viral load responses over 4 years by monitoring strategy Suppression Blips pLLVL 0 20 40 60 80 100 Percentage CD4 Clinical • Similar virological classification regardless of monitoring strategy throughout follow-up 37% 40% 35% 34% 11% 9% 17% 17% Rebound N=305 at week 144; P=0.94
Slide 16-

Longitudinal viral load responses over 4 years by monitoring strategy Suppression Blips pLLVL 0 20 100 CD4 80 Clinical e g a 60 t n e c 37% 40% r 40 35% 34% e P 11% 9% 17% 17% Rebound N=305 at week 144; P=0.94 Predictors of low-level viral load / rebound: 3 NRTI regimen compared to 2NRTI+NNRTI; P<0.001 ART initiated at older age; P=0.03 ART initiated with higher viral load; P=0.048 • Similar virological classification regardless of monitoring strategy throughout follow-up
Slide 17-

Development of resistance during 2 years of viral rebound (n=12 on 2NRTI + NNRTI) 17 0 20 40 60 80 100 3TCABCZDV DDI D4TFTCTDF NRTI NVPEFVETRRPV NNRTI (i) Arm A or Arm B (n=12) Percentage High (a) Stanford score at rebound: Susceptible Potential low Low Intermediate 0 20 40 60 80 100 3TCABCZDV DDI D4T FTCTDF NRTI NVPEFVETRRPV NNRTI (i) Arm A or Arm B (n=12) (b) Change in Stanford score between rebound and 2 years subsequently: -4 -3 -2 -1 Same +1 +2 +3 +4 After median 2.3 years of rebound, median 1 additional NRTI major mutation accumulated; P=0.009 Little impact on predicted drug susceptibility: only one child developed intermediate/high-level resistance to TDF and ZDV
Slide 18-

Probability of resuppressing a detectable viral load 18% of single viral loads >1000 copies/ml (and 8% of confirmed VL >1000) were immediately followed by VL<1000 0 .1 .2 .3 .4 .5 .6 1000 5000 10000 100000 1000000 VL measurement (x) (copies/ml) Probability of single VL measurement =x copies/ml returning <5000 copies/ml Probability of confirmed VL measurement =x copies/ml returning <5000 copies/ml Probability of single VL measurement =x copies/ml returning <1000 copies/ml Probability of confirmed VL measurement =x copies/ml returning <1000 copies/ml 18 Logistic regression to explore probability of single VL>1000 returning to <1000 copies/ml
Slide 19-

Discussion Virological outcomes in children from Zimbabwe and Uganda in the ARROW trial were very good Almost 3/4 fully suppressed (<80) after 4 years of ART Only 6% switched to second-line ART No difference in virological failure or resistance between children managed with CD4 monitoring and clinical monitoring 3NRTI regimen was virologically inferior to standard 2NRTI + NNRTI first-line ART 19
Slide 20-

Discussion Virological blips are common Persistent viraemia/rebound occurs in a minority – Only 20% of those on standard 2NRTI + NNRTI regimens Intermediate-high level drug resistance only found in a minority of children with virological failure Children with virological rebound (>5000 copies/ml) developed slight increase in NRTI resistance over 2 years, suggesting there should not be a substantial delay in switching at this level. 20
Slide 21-

Programme implications 21 Excellent virological outcomes are achievable even without routine VL monitoring Reassuring in low-level health facilities where VL not available Single VL >1000 copies/ml should be interpreted with caution Blips are common Low-level viraemia may be followed by resuppression, even without adherence counselling Confirmed viral rebound >5000 copies/ml may lead to resistance mutations and should prompt consideration of switch to second-line.
Slide 22-

Acknowledgments We thank all the patients and staff from all the centres participating in the ARROW trial. MRC/UVRI Uganda Research Unit on AIDS, Entebbe, Uganda: P Munderi, P Nahirya-Ntege, R Katuramu, J Lutaakome, F Nankya, G Nabulime, I Sekamatte, J Kyarimpa, A Ruberantwari, R Sebukyu, G Tushabe, D Wangi, M Musinguzi, M Aber, L Matama, D Nakitto-Kesi. Joint Clinical Research Centre, Kampala, Uganda: P Mugyenyi, V Musiime, R Keishanyu, VD Afayo, J Bwomezi, J Byaruhanga, P Erimu, C Karungi, H Kizito, WS Namala, J Namusanje, R Nandugwa, TK Najjuko, E Natukunda, M Ndigendawani, SO Nsiyona, R Kibenge, B Bainomuhwezi, D Sseremba, J Tezikyabbiri, CS Tumusiime, A Balaba, A Mugumya, F Nghania, D Mwebesa, M Mutumba, E Bagurukira, F Odongo, S Mubokyi, M Ssenyonga, M Kasango, E Lutalo, P Oronon. University of Zimbabwe, Harare, Zimbabwe: KJ Nathoo, MF Bwakura-Dangarembizi, F Mapinge, E Chidziva, T Mhute, T Vhembo, R Mandidewa, M Chipiti, R Dzapasi, C Katanda D Nyoni, GC Tinago, J Bhiri, S Mudzingwa, D Muchabaiwa, M Phiri, V Masore, CC Marozva, SJ Maturure, S Tsikirayi, L Munetsi, KM Rashirai, J Steamer, R Nhema, W Bikwa, B Tambawoga, E Mufuka. Baylor College of Medicine Children’s Foundation Uganda, Mulago Hospital, Uganda: A Kekitiinwa, P Musoke, S Bakeera-Kitaka, R Namuddu, P Kasirye, A Babirye, J Asello, S Nakalanzi, NC Ssemambo, J Nakafeero, J Tikabibamu, G Musoba, J Ssanyu, M Kisekka. MRC Clinical Trials Unit, London, UK: DM Gibb, MJ Thomason, AS Walker, AD Cook, B Naidoo-James, MJ Spyer, C Male, AJ Glabay, LK Kendall, J Crawley, AJ Prendergast. Economics Group: P Revill, T Mabugu, F Mirimo, S Walker, MJ Sculpher. Independent ARROW Trial Monitors: I Machingura, S Ssenyonjo. Trial Steering Committee: I Weller (Chair), E Luyirika, H Lyall, E Malianga, C Mwansambo, M Nyathi, F Miiro, DM Gibb, A Kekitiinwa, P Mugyenyi, P Munderi, KJ Nathoo, AS Walker; Observers S Kinn, M McNeil, M Roberts, W Snowden. Data and Safety Monitoring Committee: A Breckenridge (Chair), A Pozniak, C Hill, J Matenga, J Tumwine. Endpoint Review Committee (independent members): G Tudor-Williams (Chair), H Barigye, HA Mujuru, G Ndeezi; Observers: S Bakeera-Kitaka, MF Bwakura-Dangarembizi, J Crawley, V Musiime, P Nahirya-Ntege, A Prendergast, M Spyer. Funding: ARROW was funded by the UK Medical Research Council and the UK Department for International Development (DFID). ViiV Healthcare/GlaxoSmithKline donated first-line drugs for ARROW and provided funding for VL assays. 22

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