Optimizing Paediatric and Adolescent ART: Challenges and Opportunities

Optimizing Paediatric and Adolescent ART: Challenges and Opportunities Dr Nandita Sugandhi ICAP at Columbia University PATA 2017 Continental Summit 24 October, 2017 Johannesburg South Africa

Overview What are our current challenges in ART for children and adolescents? What is optimization of ART for children and adolescent and what does it look like today? What is ahead for the optimization of ART for children and adolescents?

72% of all people living with HIV will know their HIV status of all people diagnosed with HIV will receive ARVs of all people receiving ARVs will be virally suppressed of all people living with HIV will be virally suppressed

We have committed to SUPER FAST TRACK TARGETS! AIDS Free: Provide 1.6 million children (aged 0 14) living with HIV with lifelong antiretroviral therapy by 2018. [Reach 95% of all children living with HIV]

Paediatric HIV Care and Treatment Trends Birth testing and EID Growing adolescent population

Courtesy of Prof. E.M. Obimbo, University of Nairobi

Initiating paediatric ART since 2013 Preferred Alternative Children < 3 years ABC + 3TC + LPV/r or AZT + 3TC + LPV/r ABC + 3TC + NVP AZT + 3TC + NVP Children 3 years to < 10 years ABC + 3TC + EFV ABC + 3TC + NVP AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP LPV/r a preferred drug for ALL infants and children <3 yrs AZT/3TC/NVP is suboptimal but included as an alternative option

LPV/r for 1 st line in < 3 years Age group Kaletra syrup Requires cold chain Bitter taste Toxic excipients Heavy to carry Hard to store Preferred 1 st Line <3 years ABC or AZT + 3TC + LPV/r

ABC + 3TC + EFV: Preferred for children 3-10 yrs Preferred Children 3 years to < 10 years ABC + 3TC + EFV Alternative ABC + 3TC + NVP AZT + 3TC + EFV AZT + 3TC + NVP TDF + 3TC (or FTC) + EFV TDF + 3TC (or FTC) + NVP ABC/3TC ABC/3TC Tab (disp, scored) 60/30mg Tab (disp, scored) 120/60mg 3-5.9kg 6-9.9kg 10-13.9kg 14-19.9kg 20-24.9kg 2 3 4 5 6 1 1.5 2 2.5 3 EFV Tab (scored) - - 1 1.5 1.5 Multiple tablets needed to provide a complete 3 drug regimen

% of children on 1st L. ART Main First line paediatric ART regimens among children 0-15 years old end 2015 in LMICs (n=748,638) 50 40 30 42 28 42% of all children in LMIC were still on AZT/3TC/NVP at the end of 2015 20 10 0 8 6 0 2 2 1 2 WHO ARV use survey in 2016

Adolescents: Harmonized with Adults First-line ART Adults Adolescents Preferred first-line regimens TDF + XTC + EFV TDF + XTC + EFV Alternative first-line regimens AZT + 3TC + EFV (or NVP) TDF + XTC + DTG TDF + XTC + EFV 400 TDF + XTC + NVP AZT + 3TC + EFV (or NVP) TDF (or ABC) + XTC + DTG TDF (or ABC) + XTC + EFV 400 TDF (or ABC) + XTC + NVP

Is this the best we can do?

Population-level HIV incidence assessments

ACTION QUALITY TRENDS Increasing levels of HIV Drug Resistance A systematic literature review of pretreatment drug resistance in children documented high rates of resistance in children starting ART, particularly those that had been exposed to NNRTI s during PMTCT In South Africa, one study showed that 63.7% of infants and children <18 months had HIVDR NNRTI resistance: 62.7% NRTI resistance: 13.9% At the end of 2015 only 14% of children 0-15 years across 66 LMIC were on boosted PI-based regimens HIV DRUGRESISTANCE REPORT 2017 http://apps.who.int/iris/bitstream/10665/255896/1/9789241512831-eng.pdf?ua=1

Many reasons for lack of LPVr uptake in young children but NNRTI resistance is rising 100% 80% 60% 79% 72% Zimbabwe Swaziland In young infants HIVDR levels are very high 40% 44% 48% Most of this is NNRTI resistance ~40% Y181 20% 22% 25% 23% 13% Even children who are not exposed to PMTCT had high levels 0% 0-3 months 4-6 months 7-12 months 13-18 months Source: WHO 2011 HIV DR surveys in PCR positive infants

Viral resistance in sexually active youth with HIV RNA>5000 copies/ml (n=38) Slide courtesy of Theodore Ruel 42% of 92 sexually active 1 VL >5000 copies/ml 81 % had resistance to 1 ARV class 24% had some resistance to drugs in all 3 classes 63% with resistance reported unprotected sex Tassiopoulos, CID, 2013.

What is ART Optimization? Potent Low toxicity Well tolerated and easy to take/administer High generic barrier to resistance/durable Improve sequencing/switching options Can be harmonized across special populations Reduce cost

There are options for neonates diagnosed in the 1 st month of life Dealing with limited options for newborns Optimizing options with the best formulation available Monitoring closely and adjusting dosing 0-2 weeks 2 weeks - 3 months 3 36 months Preferred Alternative Special circumstances AZT + 3TC + NVP AZT + 3TC + NVP* AZT + 3TC + NVP ABC or AZT + 3TC + LPV/r syrup ABC or AZT + 3TC + LPV/r pellets ABC or AZT + 3TC + LPV/r pellets ABC or AZT + 3TC + RAL (from 4 weeks)

LPV/r 40mg/10mg oral pellets LPV/r oral pellets tentatively approved by USFDA Safety and acceptability established in infants 6 months, limited evidence in infants 3-6 months of age Field evaluation is ongoing to determine if very young infants are able swallow pellets LPV/r oral pellets may provide a better alternative to deliver the preferred 1 st line ART regimen for infants and young children <3 years.

Offering better options for 2 nd line Children including adolescents LPV/r-based first line Younger than 3 years NNRTI-based firstline regimen First-line ART regimen Second-line ART regimen ABC + 3TC + LPV/r AZT or ABC + 3TC + AZT + 3TC + LPV/r RAL 3 years and older ABC + 3TC + LPV/r AZT + 3TC + EFV or RAL AZT + 3TC + LPV/r ABC or TDF + 3TC + EFV or RAL All ages ABC + 3TC + EFV (or NVP) AZT + 3TC + ATV/r or TDF + 3TC + EFV (or NVP) LPV/r AZT + 3TC + EFV (or NVP) ABC or TDF + 3TC + ATV/r or LPV/r Introducing more potent options for children failing on LPVr Promoting use of once daily bpi such as ATV Alternatives for adults and adolescents include DRV/r or LPV/r + RAL

Raltegravir (RAL) Twice daily integrase inhibitor We have dosing and approval down to 4 weeks We have pediatric formulations (chewable tab) for >10kg but powder for suspension for <10kg Low genetic barrier as compare to DTG Currently limited availability Limited interest for adults Weight band (kg) RAL Dose using chewable tablet 3 to <6 25mg BID* 6 to <10 50mg BID* 10 to < 14 75mg BID (consistent with USPI) 14 to < 20 100mg BID (consistent with USPI) 20 to < 25 150mg BID (consistent with USPI) * Chewable tablets currently only approved for children 2 yrs and 10kg

BREATHER ( PENTA 16) Non-inferiority randomized trial of 199 children aged 8-24 years who were suppressed (viral load < 50 c/ml for > 12 months) and receiving EFV plus two NRTIs. RESULTS at 48 weeks: 6 (short cycle) vs 7 (continuous) had a confirmed VL > 50 copies/ml [difference -1.2%, 90% confidence interval (CI) - 7.3% to 4.9%]. no evidence of increased inflammation in the SCT arm. Participants expressed a strong preference for SCT in a qualitative substudy and pre/post-trial questionnaires Slide courtesy of Theodore Ruel Butler, et al. Health Technol Assess, 2016.

Dolutegravir (DTG) A best in class integrase inhibitor Well tolerated Low toxicity High genetic barrier to resistance Small pill size Can be dosed twice daily in patients on TB treatment Emerging safety data on use in pregnancy Available as 50mg tab TDF/3TC/DTG 300mg/300mg/50mg (aka TLD) ABC/3TC/DTG 600mg/300mg/50mg Lower cost than currently preferred 1 st line of TDF/XTC/EFV

Multiple countries have already adopted dolutegravir in their guidelines Senegal Western Sahara Gambia Guinea Bissau Sierra Leone Liberia Mauritania Guinea Ivory Coast Morocco Mali Burkina Faso** Ghana Togo Algeria Benin Equatorial Guinea Niger Nigeria Tunisia Cameroon** Gabon Congo Libya Chad Angola Namibia Not pictured: Armenia, Belarus, Brazil, Cambodia, Georgia, Jamaica, Syria, Ukraine DRC Egypt** Sudan Central African Republic Rwanda Burundi Zambia Botswana South Africa Swaziland Lesotho Uganda Malawi Zimbabwe Tanzania Ethiopia Kenya Eritrea Djibouti Somalia Mozambique Madagascar Included or plan to include DTG in national guidelines Initiated procurement plan for DTG singles Botswana, Cambodia, Cote d Ivoire, DR Congo, Lesotho, Kenya, Nigeria, Uganda, South Africa, Tanzania, Zimbabwe Armenia**, Belarus**, Botswana*, Burkina Faso**, Cambodia*, Cameroon**, Cote d Ivoire*, DR Congo*, Egypt**, Georgia**, Jamaica**, Kenya*, Nigeria*, Syria**, Uganda* Ukraine**, Zimbabwe *indicates APWG country **indicates APWG country with initiated procurement plan but guidelines may not be updated DTG/TLD Adoption DTG not included in guidelines or no data DTG/TLD included in national guidelines (or confirmed plans) DTG included in national guidelines and procurement initiated 28

Eligibility for DTG containing regimens: Initiating Patients 2016 WHO Consolidated guidelines include DTG as an alternative WHAT to start Evidence of superiority of DTG-containing regimens for treatment-naïve patients SINGLE: DTG with ABC/3TC superior to TDF/FTC/EFV over 144 weeks with faster virologic suppression and no drug resistance FLAMINGO: DTG with 2 NRTI s superior to DRV/r with 2 NRTI s over 48 weeks SPRING 2: DTG non-inferior to RAL over a 96 week period regardless of baseline VL and NRTI back bone and Adolescents

Evidence for DTG use in Patients already on ART Stable First-line patients STRIIVING: non-inferiority of switch to ABC/3TC/DTG v. continuing current regimen in adults with stable viral suppression Second-line patients DAWNING: DTG superior to LPV/r when combined with 1 fully active NRTI Third-line patients SAILING: In patients with viral failure and resistance to 2 drug classes DTG superior to RAL when combined with 1-2 other fully active drugs VIIKING: In patients with viral failure and INSTI resistance, DTG BD effective when combined with 1 fully active drug.

DTG is still active even in heavily treatment experienced patients High suppression rates in STRIIVING regardless to genotypic susceptibility score after switching to dolutegravir-based regimen in patients with VL suppression ACTG A5353: DTG + 3TC for initial treatment of of patients with VL <500,000 DOLULAM: DTG+ 3TC maintains virological suppression even in heavily treatment experienced patients

There s more work to be done on optimization for children and adolescents Diagnosis Tx targets by 2018 Monitor and evaluation AIDS free Drug optimiz ation Service delivery Community engagement AIDS Free Thematic Areas Diagnosis Drug Optimization Service Delivery Community Engagement Monitoring and Evalution

PADO priorities ABC/3TC/EFV (Paediatric ARV Drug Optimization) DRVr & ATVr RAL FORMULATIONS of existing ARVs LPV r 4 in 1 DTG Identifying priority regimens for optimal sequencing which include newer compounds for which paediatric development has not been completed 0-3 yrs 3-10 yrs 10 yrs + NVP 20 mg FIRST LINE Mid-term (5 yr) ABC/3TC/DTG TAF/3TC/DTG New formulations of existing drugs that already have registration for children or in advanced paediatric development Long term (10 yr) TAF/3TC/DTG SECOND LINE Mid-term (5 yr) AZT/3TC/RAL or LPV/r AZT/3TC/DRV/r TAF/3TC/DRV/r Long term (10 yr) AZT/3TC/LPV/r RPV/DRV/r or AZT/3TC/DRVr

Dolutegravir (DTG) for younger children Low dose/kg is good for infants and children High genetic barrier ideal for poorly adherent children and adolescents OD and good toxicity profile Currently approved in 30kg and above (FDA) and 6 yrs/ 15kg (EMA) P1093 dose-finding study is ongoing Paediatric FDC planned for coformulation with abacavir and lamivudine Available in 50mg, 25mg and 10mg tablets Paediatric Dosing (EMA) Body weight (kg) Dose 15 to less than 20 20mg OD 20 to less than 30 25mg OD 30 to less than 40 35mg OD 40 or greater 50mg OD

ABC/3TC/EFV STR for preferred paediatric 1 st line for children >3 years Final TPP: Dispersible, scored tablet, 150/75/150 Following recent confirmation of ALE dosage, generic manufacturers have started development ABC/3TC/EFV 150mg/75mg/150mg scored dispersible tablet Weight Band 10kg - 13.9kg 1.5 14kg - 19.9kg 2 20kg - 24.9kg 2.5 25kg - 35kg 3 # tablets daily

4 in 1 = 2 NRTI s + LPV/r LPV/r oral pellets tentatively approved by USFDA in 2015 but 4 in 1 still in development LIVING study- Field implementation using LPV/r pellets before availability of better-adapted 4-in-1 LPV/r based FDCs, in order to : provide better treatments to infants today and promote in-country registration & adoption provide supportive clinical data on the feasibility, effectiveness, safety, and PK of the new products in routine treatment settings The patients will switch to 4-in-1 LPV/r/AZT/3TC (40/10/30/15mg) or LPV/r/ABC/3TC (40/10/30/15mg) granules (heat stable) as soon as the products become available. A protocol amendment will be done at that time

Darunavir with ritonavir boosting (DRV/r) Lifelong treatment requires consideration for treatment after failure on LPV/r DRV/r can be sequenced after both LPV/r and ATV/r failure Currently no paediatric co-formulation of DRV + RTV available Priority for development Dosage form 120mg/20mg capsules for twice-daily dosing Granules may also be feasible Other potential technologies (freeze drying)

Tenofovir Alafenamide (TAF) Current alignment with adults on the NRTI backbone is only down to adolescents >35 kg due to concerns around TDF bone toxicity and limitations with available formulations TAF has potential for reduced toxicity and wider use than TDF Currently investigated only in 6 years and older TAF full PIP has only been planned in co-formulation, lack of single strength approval is a barrier to development of alternative promising formulations such as DTG/TAF/XTC

Long acting formulations a game changer? Cabotegravir and rilpivirine Phase II LATTE 1/2 look good Phase III underway in adults Antiretroviral Therapy as Long Acting Suppression (ATLAS) - switch First Long-Acting Injectable Regimen (FLAIR) - ART naïve Phase II studies for young adults in development Concern for long tail and development of resistance with nonadherence RPV detected over 500 days from last dose in 7/8 subjects * Slide courtesy of Theodore Ruel *McGovern I et al. AIDS 2016, Durban. TUAC0103 http://programme.aids2016.org/abstract/abstract/4652

Conclusion Suboptimal formulations and increasing levels of drug resistance are threats to reaching the last 90 for children and adolescents Recent developments offer some improvement. This includes: LPV/r oral pellets New treatment strategies (SCT) Integrase inhibitors Raltegravir Dolutegravir But we can (and should) do better! Acknowledgements Shaffiq Essajee (UNICEF) Theodore Ruel (UCSF) Elaine Abrams (ICAP) Martina Penazzato (WHO) Dolutegravir is rapidly becoming a preferred drug for adults and adolescents