New Directions on WHO ARV Guidelines 2018

New Directions on WHO ARV Guidelines 2018 Elaine Abrams Co-chair WHO Guidelines Development Group ICAP at Columbia University, New York Martina Penazzato Paediatric lead for the HIV Department World Health Organization, Geneva

2016 WHO recommandations for 1st Line ART in Adults and Adolescents In 2017 WHO Recommendations: 1) Countries with national pretreatment HIVDR to EFV or NVP 10% should consider a RAPID transition to non-nnrti for all new ART starters 2) ART starters with reported prior exposure to ARVs: start a non-nnrti (i.e. DTG), regardless of level of PDR WHO Consolidated ARV Guidelines, 2016

PICO questions considered for the 2018 update 1. Should DTG (RAL for age groups where DTG is not approved) be recommended as the preferred first-line antiretroviral agent in combination with an age appropriate NRTI backbone for the treatment of HIV? 2. Should DTG (RAL for age groups where DTG is not approved) be recommended as the preferred second-line antiretroviral agent in combination with an age appropriate NRTI backbone for the treatment of HIV? 3. Should DTG (RAL for age groups where DTG is not approved) be antiretroviral agent in combination with an age appropriate NRTI backbone for HIV post-exposure prophylaxis (PEP)? 4. Should an indeterminate range be implemented for more accurate molecular diagnosis of infants under 18 months of age?

Safety and Efficacy of DTG and EFV600 in 1 st line ART (summary 2018 WHO Sys Review & NMA) Major Outcomes DTG vs EFV 600 Quality of Evidence Viral suppression (96 weeks) DTG better moderate Treatment discontinuation DTG better high CD4 recovery (96 weeks) DTG better moderate Mortality comparable low AIDS progression comparable low SAE comparable low Reference: Steve Kanters, For WHO ARV GDG, 16-18 May 2018

New Findings informed the safety profile in women of child bearing potential NIH funded study has identified a potential safety issue and reported it to the World Health Organization (WHO) and ViiV Healthcare. Observational study in Botswana, which has found 4 cases of neural tube defects out of 426 women who became pregnant while taking DTG. This rate of approximately 0.9% compares to a 0.1% risk of neural tube defects in infants born to women taking other antiretroviral medicines at the time of conception. See presentation from Rebecca Zash et al tomorrow

Direction of the recommendations Available clinical evidence as well as assessment of the risk and benefits support the use of DTG as a preferred 3 rd agent in all lines of antiretroviral treatment and post-exposure prophylaxis in adults and adolescents, including women and adolescents girls using consistent and reliable contraception. Concerns around the safety of DTG use during periconception period were acknowledged resulting in specific qualifications on the use of DTG in women and adolescents girls of childbearing potential

Note of caution for using DTG in women and adolescent girls of childbearing potential Exposure to DTG at the time of conception may be associated with NTD risk among infants. DTG appears to be safe when started after the period of risk of neural tube defects (ie, up to 8 weeks after conception). Adolescent girls and women of childbearing potential who do not currently want to become pregnant can receive DTG together with consistent contraception (hormonal contraception and DTG have no reported or expected drug drug interactions). An EFV-based regimen is a safe and effective first-line regimen and can be used among women of childbearing potential during the period of potential risk for developing NTDs. National programmes should consider the balance of benefits and risks when selecting the optimal ARV regimen for women and adolescent girls of childbearing potential (fertility levels, contraceptive availability and coverage, pre-treatment NNRTI resistance, drug availability, maternal and infant toxicity profile).

Implementation considerations for adolescents DTG is of particular benefit to adolescents (sub-optimal adherence, EFV side-effects, triple class failure). In LMIC, half of the estimated 23 million pregnancies in adolescent girls (2 million in below 15 years) were unintended. Policy decisions on DTG are an opportunity to review access SRHR services and current status of their integration with HIV services. Ensuring that adolescent girls living with HIV are well informed of their options to prevent unintended pregnancies, and provided with pre-pregnancy care to avoid use of DTG during preconception. A differentiated approach for integrated adolescent-friendly services is needed together with direct involvement of adolescents.

Focus on Infants and children

Background 1.8 million children were estimated to live with HIV in 2017 In 2017, only 51 % of HIV-exposed infants received EID (by 2 mo) Increasing exposure to maternal ARVs offers new challenges to ensure accurate EID Treatment coverage remains poor with only 52% receiving ART Almost half of those on ART continue to receive NVP based regimens HIVDR to NNRTI is as high as 60% as demonstrated by multiple national surveys Virological suppression remains poor particularly in younger children Lack of potent, tolerable ARVs in age appropriate formulations remains a critical barrier to scale up of paediatric treatment globally Introduction of new ARVs can happen when proven to be effective in adult population as soon as safety and PK are available to inform dosing.

Considerations for use of DTG Extrapolation from adult efficacy data 1 Safety and PK from P1093 2 and ODYSSEY 3 Some limited experience in clinical practice from CHIPS cohort 4 High genetic barrier integrase inhibitor Acceptability of once daily administration Feasibility in the context of simplified dosing Need for clarity on dosing during TB cotreatment Approved dosing below 15 kg to become available in late 2019 Need for strengthening of toxicity monitoring alongside introduction References: 1. Kanters et al 2018; 2. Viani et al 2015, Wiznia et al 2016, Ruel et al 2017; 3. Turkova et al 2018; 4 Collins et al 2018; 5. Archary

Considerations for use of RAL Extrapolation from adult efficacy data 1 Safety and PK from birth based on P1066 trial 2 Dosing for TB cotreatment available from P1101 trial 3 Limited experience with use in first line for young children 4 Low genetic barrier compared to DTG with potential selection of INSTI resistance (BD DTG following use of RAL) Feasibility and acceptability of granules 5 Recommendation for use of time-limited provision while possible is not desirable for procurement and supply 6 Need to provide a non NNRTI alternative for neonates and for settings where LPVr pellets might not be available References: 1. Kanters et al 2018; 2. Nachman et al 2014, Clarke et al. 2017; 3. Meyers et al 2018; 4. Personal communication IeDea/CIPHER; 5. Archary et al 2018; 6. APWG 2018.

Overall messages Move away from NNRTI-based regimens Introduce DTG as soon as possible Use the most potent non-nnrti option

Direction of the recommendations for 1st line NEONATES CHILDREN Preferred AZT+3TC+RAL 1 ABC+3TC+DTG 2 Alternatives Special circumstances 4 AZT+3TC+NVP AZT+3TC+LPV/r ABC+3TC+LPV/r ABC+3TC+RAL 2 ABC (or AZT)+3TC+EFV 3 ABC (or AZT)+3TC+RAL AZT+3TC+LPV/r AZT+3TC+RAL AZT+3TC+NVP 1 For the shortest time possible, until a solid formulation of LPV/r or DTG can be used 2 For age and weight groups with DTG approved dosing and where LPV/r is not available 3 In cases where no other alternatives are available 4 From 3 years of age

Direction of the recommendation for 2 nd and 3 rd line Population 1 st line 2 nd line 3 rd line Children 2 NRTI + LPV/r 2 NRTIs + DTG** 2 NRTIs + EFV 2 NRTIs + DTG*** 2 NRTI + DTG 2 NRTIs + (ATV/r or LPV/r) DRV/r + DTG**** ± 1-2 NRTIs Where possible consider optimization using genotyping * Optimized NRTI backbone should be used: AZT following TDF or ABC failure, and viceversa. **This applies to children for whom approved DTG dosing is available. RAL should remain the preferred 2 nd line for those children for whom approved DTG is not available ***This applies to children for whom approved DTG dosing is available. ATV/r or LPV/r should remain the preferred 2nd line for those children for whom approved DTG is not available. ****DTG based 3rd line following use of INSTI must be administered with DTG BD.

Support for implementation Guiding product selection in line with Global Guidelines Supporting transition to optimal regimens Soon available online at http://www.who.int/hiv/pub/paediatric/aids-free-toolkit/en/

PICO questions considered for the 2018 update 1. Should DTG (RAL for age groups where DTG is not approved) be recommended as the preferred first-line antiretroviral agent in combination with an age appropriate NRTI backbone for the treatment of HIV? 2. Should DTG (RAL for age groups where DTG is not approved) be recommended as the preferred second-line antiretroviral agent in combination with an age appropriate NRTI backbone for the treatment of HIV? 3. Should DTG (RAL for age groups where DTG is not approved) be antiretroviral agent in combination with an age appropriate NRTI backbone for HIV post-exposure prophylaxis (PEP)? 4. Should an indeterminate range be implemented for more accurate molecular diagnosis of infants under 18 months of age?

As MTCT rate decreases, so does the confidence on a positive EID result (positive predictive value) 20% MTCT 5% MTCT x 400 x 1,900 10% MTCT 1% MTCT True positive False positive True negative x 900 x 9,900

Several EID technologies exist Qualitative technologies generally report detected or not detected, which is interpreted as positive or negative, respectively. HOWEVER Low levels of viremia may not be due to infection but rather contamination at the point of collection or at the lab. THEREFORE An indeterminate range could minimize unnecessary All tests with WHO-PQ have high sensitivity > 98% treatment by having the sample repeat tested before treatment initiation.

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Acknowledgements Treatment and Care team (WHO) Meg Doherty Nathan Ford Marco Vitoria Lara Vojnov Silvia Bertagnolio Chantal Migone Ajay Rangaraj Anisa Ghadrshenas Serena Brusamento Wole Ameyan Vindi Singh Systematic reviewers Guidelines Development Group members External Review Committee

The AIDS Free Working Group Is pleased to announce the launch of a new AIDS FREE TOOLKIT FOR THE ACCELERATION OF TESTING AND TREATMENT SCALE-UP IN CHILDREN AND ADOLESCENTS LIVING WITH HIV Coming soon at: http://www.who.int/hiv/pub/paediatric/aids-free-toolkit/en/

Toolkit for research and development of paediatric antiretroviral drugs and formulations In collaboration with experts from the Paediatric Antiretroviral Working Group Soon available at http://www.who.int/hiv/pub/research-dev-toolkit-paediatric-arv-drug-formulation/en/ https://globalhealthtrainingcentre.tghn.org/research-toolkit-paediatric-antiretroviral-drug-and-formulationdevelopment/