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

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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

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

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

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

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

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

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 +++ - 3 - 10 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

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   +++ 3 - 10 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 14-19.9kg and TDF 200mg tab used for 20-24.9kg Source: WHO consolidated ARV use and prevention Guidelines 2016 and IATT Paediatric ARV Formulary and Limited-Use List 2016

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, 19-20 June 2018 (unpublished)

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, 19-20 June 2018 (unpublished)

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

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

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

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

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), ( 25-48 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.

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 2018. Poster 842. Andrieux-Meyer et al. CROI 2018; Poster 842

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

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

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

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.”

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!

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

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: