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

2. 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

3. 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

4. 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

5. 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

6. Collaborative Partners
The New Horizons Advancing Pediatric HIV Care (New Horizons) Collaborative launched in 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)

7. Country Participants

8. 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

9. Donation Program Pilot Data
Pilot data collection in
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

10. 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: 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

11. 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 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)

12. 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

13. 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

14. 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

15. 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)

16. 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?

17. Journey continues……