Optimizing 2 nd and 3 rd Line Antiretroviral Therapy in Children and Adolescents

Transcription

1 Optimizing 2 nd and 3 rd Line Antiretroviral Therapy in Children and Adolescents Victor Musiime, MBChB, MMED, PhD Senior Lecturer, Makerere University Investigator, Joint Clinical Research Centre (JCRC) Kampala, Uganda

2 Disclosure Dr. Musiime received speaker fees from Janssen Pharmaceutica NV.

3 Outline Second line ART and treatment failure Response to 2 nd line ART Factors associated with failure Drug resistance mutations associated with failure Options for 3 rd line ART WHO recommendations Approaches to optimization of response to 2 nd and 3 rd line regimens

4 Second-line ART regimens (WHO 2016) a ATV/r can be used as an alternative PI for children older than 3 months of age. b If ABC+ 3TC or TDF + 3TC (or FTC) was used in the first-line failing regimen, AZT + 3TC should be used in second-line and vice versa. c RAL + LPV/r can be used as an alternative second-line regimen in adults and adolescents. d DRV/r can be used as an alternative PI option in special situations. 3TC lamivudine, ABC abacavir, ATV atazanavir, AZT zidovudine, DTG dolutegravir, EFV efavirenz, FTC emtricitabine, LPV lopinavir, NRTI nucleoside reversetranscriptase inhibitor, NVP nevirapine, PI protease inhibitor, r or RTV ritonavir, RAL raltegravir. WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Second edition 2016.

5 Response to 2 nd line ART/ Virologic failure (VF) Various definitions of failure and durations of observations: Study Setting Population 1 (TREAT Asia) Sample size Asia Adolescents 1379 (22% on 2 nd line) Duration 2 CAR Children and Adolescents years (mean, range: ) Response - Incidence of VF: 3.4 per 100 p.yrs Being on 2 nd line ART a risk factor 64% developed VF 3 Uganda Children under 12 years months 20% had VL>1000 No PI mutations 4 (COHERE) Europe Adolescents and Young Adults years Risk of triple class failure: 9.6% in vertically infected 4.7% in horizontally infected 5 Kenya Children, Adolescents, Adults % failed 2 nd line ART 6 Thailand Adolescents months Risk of VF (VL>400 ) - 41% 50% failed after median 4.4yrs 7 Spain Children and Adolescents years (median) 48 children developed triple class failure (9% of total and 24% of the tested) 8 Uganda Children (Mean age 11 years) weeks Proportion with VL<400: 80% at 24 weeks, 85% at 48 weeks 1. Sudjaritruk et al. J Adolesc Health Mossoro-Kpinde et al. Medicine Boerma et al. J Trop Pediatr Judd et al. HIV Med Ochieng et al. Acquir Immune Defic Syndr Suaysod et al. Clin Infect Dis Rojas Sánchez et al. Clin Microbiol Infect Musiime et al. AIDS Res Hum Retroviruses 2013

6 Favorable response to 2 nd line ART in Uganda Boerma et al. J Trop Pediatr Study conducted at 3 JCRC sites in 3 regions of Uganda 60 children under 12 years 1 st line ART with 2NRTI and NNRTI 2 nd line ART with 2NRTI and LPV/r Virological suppression: Viral load < 1000 copies/ml

7 total NRTI M41L D67N K70R L210W T215F T215Y REV_215 K219E K219Q K65R L74V Y115F M184V total NNRTI K101E E138A E138G E138Q H221Y M230L K101P K103N V106A V108I Y181C Y181I Y181V Y188L G190A P225H total PI Q58E Resistance profiles of children on 2 nd line ART in Uganda: No PI mutations 100% 90% 80% 70% 60% 50% 40% 30% 20% 10% 0% NRTI NNRTI PI switch to second-line second-line failure Virological failure due to poor adherence Re-suppression expected with adherence counselling Boerma et al. J Trop Pediatr NRTI Nucleoside reverse transcriptase inhbitors; NNRTI Non-nucloeside reverse transcriptase inhibitors; PI Protease inhibitors

8 Factors associated with 2 nd line failure Patient factors Poor adherence Wasting at start of 2 nd line ART Having AIDS prior to 1 st line ART Baseline CD4<100 Having preadolescent virologic failure Initiating 1 st line ART as an adolescent Non disclosure Caregiver factors Grandparents Unavailability 1. Sudjaritruk et al. J Adolesc Health Boerma et al. J Trop Pediatr Judd et al. HIV Med Mossoro-Kpinde et al. Medicine Purchase et al. Afr J AIDS Res Wilhelmson et al. Glob Health Action Suaysod et al. Clin Infect Dis Kawuma et al. Afr J AIDS Res Musiime et al. AIDS Res Hum Retroviruses 2013

9 Factors associated with 2 nd line failure Medication / Regimen factors Adverse events Poor palatability Initial regimen NNRTI based as opposed to being PI based Drug-drug interactions Health System factors Stock outs Limited viral load monitoring Long waiting hours Health worker knowledge and attitudes 1. Sudjaritruk et al. J Adolesc Health Boerma et al. J Trop Pediatr Judd et al. HIV Med Mossoro-Kpinde et al. Medicine Purchase et al. Afr J AIDS Res Wilhelmson et al. Glob Health Action Suaysod et al. Clin Infect Dis Kawuma et al. Afr J AIDS Res Musiime et al. AIDS Res Hum Retroviruses 2013

10 Factors associated with 2 nd line failure Social/ community factors Stigma Fear of being seen by others Negative consequences of home visits Long distances and associated transport costs Lack of food, at times making medication side effects more pronounced 1. Purchase et al. Afr J AIDS Res Kawuma et al. Afr J AIDS Res 2014

11 Relationship between viral load levels and adherence to 2 nd line ART in CAR Mossoro-Kpinde et al. Medicine 2017

12 Drug resistance associated mutations on 2 nd line ART in CAR: PI Percent (%) Mossoro-Kpinde et al. Medicine 2017

13 Drug resistance associated mutations on 2 nd line ART in CART: RT Mossoro-Kpinde et al. Medicine 2017

14 3 rd line ART recommendations (WHO2016) a RAL + LPV/r can be used as an alternative second-line regimen in adults and adolescents. b In PI-experienced patients, the recommended DRV/r dose should be 600 mg/100 mg twice daily. c Safety and efficacy data on the use of DTG in adolescents younger than 12 years and pregnant women are not yet available. d If RAL is not available, no change is recommended unless in the presence of advanced clinical disease progression or lack of adherence, specifically because of poor palatability of LPV/r. In this case, switching to a second-line NVP-based regimen should be considered. Based on approval of the use of EFV in children less than 3 years of age, an EFV-based regimen could be considered as an alternative. However, more data are needed to inform how best to use EFV in this population (see Table 4.18). e ATV/r can be used as an alternative to LPV/r in children older than 3 months of age. However, the limited availability of suitable formulations for children younger than 6 years of age, the lack of an FDC and the need for separate administration of RTV booster should be considered when choosing this regimen. f RAL can be used in children failing PI-based second-line treatment when DTG is not available and when RAL has not been not used in a previous regimen. DTG is currently approved only for children 12 years and older; however, studies are ongoing to determine dosing in younger children, and approval for lower age groups is expected in the near future g DRV/r should not be used in children younger than 3 years of age WHO Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Second edition 2016.

15 Prevalence of DRMs and rate of predicted susceptibility of 3 rd line ART in Spain Favourable predicted susceptibility to DRV, TPV, ETR, RPV* ETR Clinical development only in treatment naïve patients Rojas Sánchez et al. Clin Microbiol Infect 2015 DRMs- Drug resistance mutations; NRTI Nucleoside reverse transcriptase inhbitors; NNRTI Non-nucloeside reverse transcriptase inhibitors; PI Protease inhibitors

16 The New Horizons donation program was launched in early 2014 by Janssen, Pharmaceutical Companies of Johnson & Johnson, together with the Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) as well as the Partnership for Supply Chain Management (PFSCM) and Imperial Health Sciences. PREZISTA (darunavir) and INTELENCE (etravirine) are being donated to eligible national HIV/AIDS programs in sub-saharan Africa and least-developed countries. PARTICIPATING COUNTRIES TO DATE: Kenya Lesotho Swaziland Uganda Zambia South Africa limited participation

17 3 rd line Experience JCRC Uganda 5 children (age range 9-15 years) with triple class ART failure Initiated on the following regimens 3 children on: RAL + DRV/r ETR + DRV/r + RAL TDF + 3TC + DRV/r + RAL Followed up for 6-54 months All had increments in CD4 count None developed new WHO III/IV events All virologically suppressed Kaudha et al. Abstract O_04, Global HIV Forum, Durban, South Africa, 2016.

18 Optimizing ART success: Adolescent and Caregiver perspectives Medication reminders Pill boxes Cell phone messaging Appointments Medication time Peer support groups Timely disclosure Socioeconomic support 1. Purchase et al. Afr J AIDS Res Kawuma et al. Afr J AIDS Res 2014

19 Summary Response to 2 nd line ART is influenced by several patient, caregiver, medication, health system and community factors Poor adherence is frequently associated with virologic failure Triple class failure is increasingly becoming common necessitating 3 rd line ART Newer generation PIs and Integrase inhibitors provide favourable response to 3 rd line ART Individual and group support needed to optimize outcomes on therapy

20 Acknowledgements Elizabeth Kaudha, JCRC Uganda Ragna S. Boerma and the MARCH study team