Dealing with Treatment Failure….. Challenges and Opportunities Natella Rakhmanina, EGPAF

Adherence Challenges Adherence to HIV treatment - major challenge in adolescence Multiple barriers to ART among adolescents include: Denial and fear of the HIV infection Concerns with stigma and discrimination Distrust in ART and treatment fatigue Lack of confidence and self-management skills Lack of family and social, peer support Inconsistent access to care Risk of inadvertent disclosure Mental health and substance use problems

Adherence Challenges % of time spent with VL >400 cp/ml Proportion of time spent with CD4 <200 cells/mm3 Rate of CDC-C and WHO 4 events,/100 PY 7-12 years 22% 2% 0.7 13-17 years 30% 5% 0.9 18-30 years 44% 18% 2.1 Monitoring of VL did not decline with increasing age, indicating ongoing engagement with care 1446 PHIV young people, mean age 14.6 years, 6548 PY of follow-up (PHACS AMP and/or IMPAACT P1074) Adherence has been shown to decline as children enter adolescence and transition into adulthood Neilan, JAMA Ped 2017, slide courtesy of Heather Bailey, UK

Treatment Approach for Adolescents with HV Singe tablet regimen (STR) with Fixed Dose Combinations (FDC) of antiretroviral drugs given once daily - preferred regimen – but pill size matters! Simplification strategies are slow to scale up Estimated treatment failure rate is 10-30%, though it is most likely to increase with viral load scale up More complex regimens are recommended for the treatment-experienced adolescent patients with treatment failure

The aim is to catalyze improved and scaled-up pediatric and adolescent care and treatment through advocacy, resource leveraging across multi-sector partnerships, increased awareness, research, health system strengthening, and improved access to second- and third-line medications

Collaborative Partners The New Horizons Advancing Pediatric HIV Care (New Horizons) Collaborative launched in 2014 by Janssen Pharmaceuticals Partners include: Elizabeth Glaser Pediatric AIDS Foundation (EGPAF) Supply Chain Management System (SCMS) of the Partnership for Supply Chain Management (PFSCM) Relevance Network Right to Care Collaborative Initiative for Paediatric HIV Education and Research (CIPHER) of the International AIDS Society (IAS)

Country Participants

New Horizons Funded Projects Donation Program A darunavir (DRV)/etravirine (ETR) donation program currently rolled out in Zambia, Kenya, Swaziland, Lesotho, and Uganda Technical Assistance and Training Activities such as country specific technical assistance, resource and tool development for national HIV/AIDS programs, and assessment of current national data systems Data Collection Collection of demographic and clinical characteristics of patients on donated product

Donation Program Pilot Data Pilot data collection in 2015-2016 Zambia, Swaziland, Kenya and Lesotho Respective IRB approvals in each country Conducted by EGPAF with MOH support Data analyzed, manuscript under review Multi-year, prospective/prospective data collection protocol in development for NH participating countries

Results: Demographics Four countries – eight sites 48 records 45.8% female (n=22) Median age at initiation on DRV and/or ETR = 15 years (IQR: 17.7-10.3 years) Age groups: - 34/48 > 10 years - 11/48 ≥5 years - ≤10 years 3 < 5 years 87.5% had ≥2 documented regimens prior to DRV and/or ETR initiation Median duration of most recent regimen - 23 months

Results: Viral Suppression and ART 81.2% of patients had prior lopinavir/ritonavir (LPV/r) based regimen, and others were exposed to non-nucleoside reverse transcriptase inhibitors Viral Load: 48 total tests obtained at median 138 days prior (IQR 280-58 days) Median HIV RNA - 56,653 copies/mL in 46/48 patients Viral genotype: 47 patients New regimen consisted on average of 4 ARVs DRV and integrase inhibitor raltegravir (RAL) – most frequently prescribed (83.3%; n=40 started on DRV/rtv and RAL, each)

Results: Genotype Resistance Mutations Protease Inhibitor (PI) 63.8% had ≥ 3 PI mutations 42.6% of those with PI mutations had ≥ 1 DRV-associated mutation I54V (36.2%) and M46I (38.3%) and V82A (38.3%) were most predominant PI mutations Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) 65.9% had ≥ 1 NNRTI mutation(s) 57.4% of those with NNRTI mutations had ≥ 1 ETR-associated mutation K103N (23.4%) , Y181C (17.0%) , and G190A (23.4%) were most predominant NNRTI mutations Nucleoside Reverse Transcriptase Inhibitor (NRTI) 87.2% of patients had ≥ 1 NRTI mutation(s) M184V (76.6%) was most predominant D67N (51.1%) and M41L (38.3%) were most predominant NRTI TAM mutations

Summary of Study Findings Treatment-experienced African children and adolescents underwent viral load testing prior to the 2nd and 3rd line ART switch Treatment-experienced children with viral failure had high rates of multidrug resistance DRV was primarily used in pediatric patients with treatment failure and prior exposure to a PI-based regimen (LPV/r) Limited, unstandardized documentation in medical charts regarding reasons for ART switch and justifications for the new ART regimen

Summary of Study Findings There were different approaches to 3rd line ART management: Centralized national 3rd line ART expert committee or center of excellence Decentralized 3rd line management Clinical officers and nurses managing 3rd line ART vs. doctors and specialists Practitioners in all countries expressed desire to gain more expertise for management of treatment failure and interest in support tools and capacity building especially in era of the viral load scale up

CIPHER Global Cohort Collaboration Switch to Second Line ART Collins IJ et al. IAS 2016 Durban S Africa, Abs. TUAB0105LB Cumulative Incidence 3 Yr Switch by Monitoring Strategy and Region Cumulative Incidence 3 Yr Switch by Monitoring Strategy in SSA Trend to higher switch with routine VL and CD4 monitoring and lowest with clinical monitoring (see SSA data)

Looking ahead We need to learn how to best help adolescents and young adults to stay in care and be adherent to ART We need to strengthen our capacity to evaluate and diagnose treatment failure We need specific national guidance for the 2nd and 3rd line ART management among pediatric and adolescent populations Will differentiated service delivery models help achieve better adherence and viral suppression in adolescents?

Journey continues……