1. Treatment Approaches to Achieve the 2nd 90: Child Friendly Formulations
Victor Musiime, MBChB, MMED, PhD
Senior Lecturer, Makerere University
Investigator, Joint Clinical Research Centre
Kampala, Uganda

2. Disclosure statement Johnson and Johnson ViiV Health Care Mylan
Payment or other (financial) remuneration
Johnson and Johnson
ViiV Health Care
Mylan

3. Outline The missing link in ending Pediatric AIDS
Testing and treatment
Challenges faced in treating children
Tackling the formulation challenge
Novel formulations (focus on lopinavir/ritonavir)
Summary

4. New Infections: Progress made!
2 million infections among children averted since 2000
Source: UNICEF. Children and AIDS Update: statistical update. December 2017

5. The critical gap: testing and treatment!
Only 43% of HIV exposed infants were tested within 2months of life
Only 43% of the 2.1 million HIV infected children received antiretroviral therapy
120,000 died of AIDS related causes
1.2 million children (the 57%) to be identified and started on treatment
Source: UNICEF. Children and AIDS Update: statistical update. December 2017

6. Where are the children?
Points where HIV exposed/ infected children and adolescents can be identified for testing
Courtesy Figure

7. Challenges of treating children
Limited appropriate drug formulations
Child factors
Non disclosure
Poor adherence
Advanced disease at presentation
Caregiver factors
Advanced age
Unavailability
Health system factors
Health care worker knowledge and attitudes
Community factors
Stigma
Socioeconomic issues

8. Formulation challenges
Unpalatability
Requirement for refrigeration
Storage and handling issues
Requirement for accurate measurement
Pill burden
Relationship with food
Courtesy Images

9. WHO 2016 recommendations and available paediatric formulations
WHO Guideline 2016 PREFERRED first line
Formulation
Child and caregiver friendliness
< 3 years
ABC or (AZT) + 3TC + LPV/r
ABC/3TC 60/30mg dispersible tab
ABC/3TC 120/60mg dispersible tab
AZT/3TC 60/30mg dispersible tab
LPV/r 80/20mg solution
LPV/r 40/10mg pellets
+++ -
years
ABC + 3TC + EFV
ABC/3TC 60/30mg dis tab
ABC/3TC 120/60mg disp tab
EFV 200mg tab +
LPV/r solution for infants and young children requires refrigeration and contains 40% alcohol
ABC+3TC+EFV is once a day regimen but not available in FDC and EFV 200mg tab not dispersible
Source: WHO consolidated ARV use and prevention Guidelines 2016 and IATT Paediatric ARV Formulary and Limited-Use List 2016

10. WHO 2016 recommendations and available paediatric formulations
WHO Guideline 2016 ALTERNATIVE first line
Formulation
Child and caregiver friendliness
< 3 years
ABC (or AZT) + 3TC + NVP
AZT/3TC/NVP 60/30/50 mg dispersible tab
+++
years
ABC + 3TC + NVP
AZT + 3TC + EFV (or NVP)
TDF* + 3TC (or FTC) + EFV (or NVP)
ABC/3TC 60/30mg dispersible tab
ABC/3TC 120/60mg dispersible tab
EFV 200mg tab
TDF 40mg oral powder
TDF 150mg
TDF 200mg tab + -
TDF is approved for children older than 2 years and opportunity to harmonise with adult treatment
TDF oral powder has poor palatability; TDF 150mg tab used for kg and TDF 200mg tab used for kg
Source: WHO consolidated ARV use and prevention Guidelines 2016 and IATT Paediatric ARV Formulary and Limited-Use List 2016

11. WHO 2018 recommendations and available paediatric formulations
WHO Guideline 2018 PREFERRED first line
Formulation
Child and caregiver friendliness
Neonates
AZT + 3TC + RAL
AZT/3TC 60/30mg dispersible tab
RAL 100mg granules for suspension
+++ -
1st line for 4 weeks to 6years
ABC + 3TC + DTG
ABC/3TC 60/30mg dispersible tab
ABC/3TC 120/60mg dispersible tab
DTG dosing not approved yet
N/A
6 - 10years
DTG 10mg tab
DTG 25mg tab +
RAL 100mg granules preparation is a 12 step process
DTG dosing for <6 years not yet approved
DTG 10mg and 25mg tab are non dispersible
Source: IATT Paediatric ARV Formulary meeting, June 2018 (unpublished)

12. WHO 2018 recommendations and available paediatric formulations
WHO Guideline 2018 ALTERNATIVE first line
Formulation
Child and caregiver friendliness
Neonates
AZT + 3TC + NVP
AZT/3TC/NVP 60/30/50 mg dispersible tab
+++
1st line for 4 weeks to 6years
ABC + 3TC + LPV/r
ABC + 3TC + RAL
ABC/3TC 60/30mg dispersible tab
ABC/3TC 120/60mg dispersible tab
LPV/r 80/20mg solution
LPV/r 40/10mg pellets
RAL 25mg chewable tab -
6 - 10yo
RAL 100mg chewable tab
Alternative 1st line becomes default 1st line for 4 weeks to 6 years due to availability of paediatric dosing and formulations
Source: IATT Paediatric ARV Formulary meeting, June 2018 (unpublished)

13. More needs to be done….
WHO guidelines ahead of the paediatric formulation development
Paediatric ARV market small; 1/10 of adult market
disincentive for product development
Innovation needed for paediatric formulation
adherence to treatment key for viral suppression
Not to “throw the baby out with the bathwater”; move away from NNRTIs but use alternative regimen - NRTIs + LPV/r or RAL

14. Optimal formulations: Heat stable LPV/r
Heat stable; not requiring refrigeration
LPV/r exposure from pellets was comparable with syrup
Pellets were more acceptable than syrup for younger children
Viral load <50copies/ml at wk 48 was 74%; all were <1000c/ml

15. Prospective study of lopinavir based ART for HIV infected children globally (LIVING study)
Aim: evaluate the effectiveness of LPV/r pellets plus NRTI tablets (ABC or AZT and 3TC) under field conditions in HIV infected infants and young children in Africa
Primary effectiveness endpoint; composite : viral load <1000 copies/ml; being alive and on study drug
LPV/r pellets
NRTI tablets

16. Study setting and enrolment status (June 2008)
Tunisia
Morocco
Algeria
Libya
Western Sahara
(Morocco)
Egypt
Mauritania
Senegal
Niger
Sudan
Eritrea
The Gambia
Mali
Chad
Djibouti
Burkina
Faso
Guinea-Bissau
Guinea
Benin
Sierra Leone
Côte
d'Ivoire
Togo
Nigeria
Ethiopia
Liberia
Ghana
Central African
Republic
South Sudan
Cameroon
Somalia EG
Uganda
São Tomé
and Príncipe
Kenya
Gabon
Congo Republic
DR Congo R B
Tanzania
Comoros
Angola
Mayotte (France)
Enrolled participants (June 2018)
Zambia
Malawi
Mozambique
Zimbabwe
Country
Nº trial sites
Nº enrolled
Kenya (n=350) 5
444
Uganda (n=350)
350
Tanzania (n=215) 2
207
Total
1001
Namibia
Madagascar
Botswana S L
South Africa

17. Viral load changes by age band at baseline, week24 and week 48 [266 children included in analysis]
*** I.Andrieux-Meyer, O.Salami, R.Omollo, T. Egondi, F.Simon, M.Lallemant et all. Pellets’s formulation of lopinaivr/ritonaivr in children: 48 weeks evolution of viral suppression across age categories in the Living study. Submitted IAS 2018.
Number of participants per age categorie: (5-11months, n=21), (12-24 months, n= 40), ( months, n= 95), (49+ months, n= 110), total 266 children included in this analysis.median age at enrolment 43 months( 95% CI: 25-62)
Abstract no WEAB0204: Pellets’ Formulation Of Lopinavir/Ritonavir In Children: 48-week Evolution Of Viral Suppression Across Age Categories In The Living Study.

18. Viral suppression at week 48
HIV RNA VL
Patient type N
Median
IQR
<1.7 (<50cp/ml)
<2.6
(<400 cp/ml)
<3
(<1000 cp/ml)
>3
(>1000cp/ml)
Data available
(log10 copies/mL)
Enrollment
Naive 58
5.4
4.8 – 5.8
2 (3.8%)
5 (9.5%)
6 (11.4%)
47 (88.7%) 53
NNRTI+LPV/r
514
2.2
1.6 – 3.9
142 (29.5%)
279 (57.9%)
306 (63.5%)
177 (36.5%)
483
NNRTI 38
4.7
4.3 – 5.5
2 (5.3%)
4 (10.6%)
33 (89.4%) 37
Overall
610
2.5
1.7 – 4.6
146 (25.5%)
288 (50.3%)
316 (55.2%)
257 (44.8%)
573
WEEK 24 31 2
1.3 – 3.5
11 (35.5%)
18 (58.1%)
20 (64.6%)
11 (35.4%)
322
1.7
1.3 – 2.5
160 (51.2%)
239 (76.6%)
250 (80.1%)
62 (19.9%)
312 25
1.8
11 (45.8%)
18 (75%)
20 (83.3%)
4 (16.7%) 24
378
1.3 – 2.6
182 (49.6%)
275 (74.9%)
290 (79%)
77 (21%)
367
WEEK 48 23
2.1
1.3 – 3.8
10 (43.5%)
15 (65.2%)
16 (69.6%)
7 (30.4%)
188
1.6
1.3 – 2.1
105 (56.8%)
152 (82.1%)
157 (84.9%)
28 (15.1%)
185 12
1.5
7 (58.3%)
9 (75%)
10 (83.3%)
2 (16.7%)
223
1.3 – 2.3
122 (55.4%)
176 (80.0%)
183 (83.2%)
37 (16.8%)
220
I.Andrieux-Meyer, O.Salami, R.Omollo, T.Eggondi, M.Lallemant et all. Effectiveness and safety of LPV/r pellets-based ART in children: 48 weeks analysis. CROI Poster 842.
Andrieux-Meyer et al. CROI 2018; Poster 842

19. Acceptability of LPV/ pellets (RE-LIVING study)
Sub-study of LIVING to assess the acceptance and adherence of LPV/r pellets
In-depth interviews conducted
42 in-depth interviews with care-givers
16 with health care providers
Observations of pellet administration
17 observations at home
17 observations in clinic
Onyango-Ouma et al, ICASA 2017; Poster presentation

20. RE-LIVING: acceptability findings
Caregivers found the pellets highly acceptable due to
the ease of storage (no refrigeration required)
the packaging (discreet, secure closing, no spillage)
administering with liquids
taste: lack of bitterness
Children accepted the LPV/r pellets very well
If mix was given quickly; avoiding development of a bitter taste
Onyango-Ouma et al, ICASA 2017; Poster presentation

21. RE-LIVING: Adherence findings
Better acceptability of the new formula contributes to initiation of adherence
Visible positive outcomes (of the child’s health) of giving the new formula stimulates maintaining adherence
Easy administration empowers caregivers and stimulates their commitment to the treatment and becomes a pre-condition to adherence maintenance
Onyango-Ouma et al, ICASA 2017; Poster presentation

22. Re-LIVING: the words of caregivers
“He has never gotten sick. The changes I have seen is that he has gotten stronger and now he can walk. I have never taken my child to the hospital because he is sick.” “The pellets are easy to administer compared to the other one, the syrup. The syrup required a lot of work because you had to put it in a syringe, measure a particular quantity and give it to the child but this does not require a lot of work.”

23. Pipeline of Paediatric Formulations
Supplier(s)
Usage for WHO 2018 Guideline
Timeline for SRA filing
Comments
ABC/3TC/LPV/r 40/15/40/10mg granules (4-in-1)
Cipla
Alternative first line for 4 weeks to 6 years
Q4 2018
Will ease current supply constraints of LPV/r pellets
DTG 10mg scored dispersible tab
Mylan,
Macleods
Preferred first line for 4 weeks to 6 years
Q2 2019
Awaiting dosing studies/ approval for <6years
More work still needed for second line and FDCs!

24. Summary
Inspite of remarkable progress in prevention of HIV in children, critical gaps remain in HIV diagnosis and treatment
There is need for innovative approaches both in identification and treatment, including appropriate formulations, if we expect to end Pediatric AIDS
LPV/r pellets a step in the right direction
4-in-1 and DTG in the pipeline

25. Acknowledgements Janice Lee and Olawale Salami (DNDi)
Participants and caregivers in LIVING study
LIVING study team in Kenya, Tanzania, and Uganda
Donors who funded the studies: