CADO/PADO: Update on 2015 WHO Consolidated guidelines Towards Treat All in the context of SDGs

CADO/PADO: Update on 2015 WHO Consolidated guidelines Towards Treat All in the context of SDGs Meg Doherty, Treatment and Care Coordinator WHO HQ

Outline What s new in ARV Guidelines Drug optimisation PADO priority list 2015 CROI 2016 Think Thank Meeting EOI 2016 list HIVDR Moving forward

Outline What s new in ARV Guidelines Drug optimisation PADO priority list 2015 CROI 2016 Think Thank Meeting EOI 2016 list HIVDR Moving forward

Key messages from the 2015 WHO ARV guidelines Treat all (at any CD4) - PLHIV across all ages, but the sickest remain a priority (symptomatic disease and CD4 < 350). Phased introduction of optimized regimens (new drug class; optimized dosing and formulations) Care packages to optimize the care cascade (reduce late presentation, improve retention). PrEP recommended as an additional prevention choice for all people at substantial risk of HIV infection.

PLHIV Evolution of global ART coverage and eligibility criteria according WHO guidelines (2003-2015) 40 000 000 35 000 000 30 000 000 25 000 000 at any CD4 not elegible 20 000 000 CD4 < 500 3 elegible but not on ART 15 000 000 CD4 < 350 2 on ART 10 000 000 5 000 000 0 CD4 < 200 3% CD4 < 200 1 7% 21% 36% 2003 2006 2010 2013 2015 1. At CD4 < 350: active TB disease and HIV+ pregnant women 2. At any CD4: active TB disease and HBV co-infection requiring HBV treatment 3. At any CD4: active TB disease, HBV co-infection with severe liver disease, HIV+ pregnant women and HIV serodiscordant couples 43% Source WHO rand UNAIDS reports

Global number of PLHIV Treatment gap based on 2013 WHO ART guidelines (CD4 < 500) PLHIV currently on ART Treatment Gap ~ 37 million +9 million +13 million 16 million +21 million Treatment gap with expanded eligibility criteria (Treat all) Cost 31 billion USD per year by 2020; 50% treatment cost

Summary of sequencing options for major first-, second- and third-line ART regimens in adults, adolescents, pregnant women and children Population 1 st line regimens 2 nd line regimens 3 rd line regimens Adults and adolescents Pregnant/breastf eeding women Children 2 NRTIs + EFV 2 NRTIs + DTG 2 NRTIs + EFV 2 NRTI + LPV/r 2 NRTIs + ATV/r or LPV/r DRV/r + DTG (or RAL) ± 1-2 2 NRTI + DRV/r NRTIs Adults and adolescents: Preferred 1 st and 2 nd line remains the same 2 NRTIs ; + new ATV/r options or LPV/r as DRV/r alternatives + 2 NRTIs ± in NNRTI 1 st line (DTG and EFV 400 ) and 2 nd line (RAL and DRV/r) 2 NRTI + EFV 2 NRTI + DRV/r 08/03/2016 7 Optimize regimen using genotype profile 2 NRTIs + ATV/r or LPV/r DRV/r + DTG (or RAL) ± 1-2 2 NRTI + DRV/r NRTIs Pregnant women: Like adults (except DTG & EFV 400 ) If less than 3 years: 2 NRTI + RAL If older than 3 years: DTG + 2 NRTIs DRV/r + 2 NRTIs 2 NRTI + EFV or RAL DRV/r + DTG ± 1-2 NRTIs Infants and children: No changes in 1 st line; more options for 2 nd line (RAL and expanded age for ATV/r) 2 NRTIs + ATV/r c or LPV/r

Safety and Efficacy of INSTIs and EFV 400 in 1 st line ART (using network metanalysis) major outcomes INSTI vs EFV 600 DTG vs other INSTI DTG vs EFV 600 DTG vs EFV 400 EFV 400 vs EFV 600 QUALITY OF EVIDENCE Viral suppression INSTI better DTG better DTG better comparable 1 comparable moderate CD4 recovery INSTI better DTG better DTG better comparable EFV 400 better moderate Treatment discontinuation INSTI better DTG better DTG better comparable EFV 400 better moderate Mortality comparable comparable comparable comparable comparable low AIDS progression comparable comparable comparable comparable comparable low SAE comparable comparable comparable comparable comparable moderate 1 Estimated effects favored DTG but statistical analysis not significant WHO, 2015

Safety and Efficacy of DRV/r and INSTI/PI regimens in 2 nd line ART (NMA) major outcomes DRV/r vs ATV/r or LPV/r DRV 800 OD vs DRV 600 OD DRV 800/100 OD vs DRV 600/100 BD RAL + LPVr vs 2 NRTIs + ATVr or LPV/r QUALITY OF EVDIENCE Viral suppression CD4 recovery Comparable comparable 3 comparable 1 equivalent moderate comparable comparable comparable 2 comparable 4 low Treatment discontinuation comparable comparable 3 comparable 2 comparable low Mortality AIDS progression SAE comparable comparable comparable 2 comparable low comparable comparable comparable 2 comparable low comparable comparable comparable 2 comparable low 1 Confidence interval too large to establish equivalence 2 Estimated effects favored DRV/r 800/100 but statistical analysis not significant 3 Estimated effects favored DRV/r 800/100 but statistical analysis not significant 4 Estimated effects favored LPV/r + RAL but statistically not significant WHO, 2015

Outline What s new in ARV Guidelines Drug optimisation PADO priority list 2015 CROI 2016 Think Thank Meeting EOI 2016 list HIVDR Moving forward

ARV Drug Optimization: Key Principles Reduce toxicity Improve palatability/pill burden Increase durability Improve sequencing Harmonization across different age groups and populations Reduce cost

PADO 2 priorities DRVr & ATVr ABC/3TC/EFV FORMULATIONS of existing ARVs LPV r 4 in 1 Identifying priority regimens for optimal sequencing which include newer compounds for which paediatric development has not been completed RAL DTG 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

Rationale for prioritisation LPVr 4-in-1: first line for under 3 years to address the lack of optimal formulations EFV triple: first line 3-10 years to provide an FDC to maximise adherence and simplify procurement ATVr and DRVr: use in 2 nd and 3 rd line formulations and overcome issue with separate administration of RTV RAL better formulation: use in infants and young children to enable rapid introduction of INI for use in 1 st line regimen DTG single or FDCs: identified as key drug to introduce INI in first line with potential for harmonisation across the full age spectrum NVP 20 mg: better dosage form to facilitate dosing for PnP TAF: key drug for future use in 1 st line to minimise toxicity with potential for harmonization across the full age spectrum

Progress made since Dec 2014 New Guidelines: more prominent role of integrase inhibitors and ATVr as an alternative to LPVr in 2 nd line use. New products: LPVr pellets FDA approved Better access: Merck agreement with MPP on RAL Advances in FDC development: PHTI projects Progress of ongoing research: P1093 and new protocols More communication: SRAs consulted to advocate for PADO priorities and to explore regulatory pathways for key FDC More guidance: IATT policy briefs on LPVr pellets Impact in countries: PAPWG commitment has resulted in most countries with high burden to procure optimal products MPP= Medicine Patent Pool; PHTI= Paediatric HIV Treatment Initiative; SRAs: stringent regulatory agencies; IATT= Interagency Task Team; PAPWG= Paediatric ARV Procurement Working Group; CTA=Commitment To Action.

Thinking strategically about 1st line 0-4 weeks 4 wks-3 years 3-10 years 10-18 years NOW RAL DTG single or DTG/ABC/3TC LPVr 4-in-1 RAL better formulation DTG single or DTG/ABC/3TC EFV/ABC/3TC DTG single or DTG/ABC/3TC DTG/ABC/3TC or DTG/TDF/XTC DTG/TAF/XTC DTG/TAF/XTC DTG/TAF/XTC DTG/TAF/XTC FUTURE

Short term (1-2 years)

Mid term (2-5 years)

Adult ART optimization - key events (2010-2016) June 2010: Conference on dose optimization ("CADO I") April 2011: Priorities for ART optimization ( Tx 2.0 short term priorities) Nov 2011: ART sequencing meeting May 2012: Think Tank for ART optimization ( Tx 2.0 medium term priorities) April 2013: Conference on drug optimization ("CADO II") Mar 2014: Think Tank" for HIV treatment optimization (implications for future reviews of WHO guidelines) Mar 2015: Think Tank" for treatment optimization of HIV and Hepatitis C Feb 2016: Think Tank" for treatment optimization of HIV (AAWG and PAWG joint meeting)

WHO ARV Guidelines Evolution from 2002 to 2015 Topic 2002 2003 2006 2010 2013 2015 When to start CD4 200 CD4 200 CD4 200 - Consider 350 - CD4 350 for TB CD4 350 -Regardless CD4 for TB and HBV CD4 500 - Regardless CD4 for TB, HBV PW and SDC - CD4 350 as priority ART initiation at any CD4 cell count 1 st Line ART 2 nd Line ART 3 rd Line ART Viral Load Testing 8 options - AZT preferred Boosted and nonboosted PIs 4 options - AZT preferred Boosted PIs -IDV/r LPV/r, SQV/r 8 options - AZT or TDF preferred - d4t dose reduction Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r 6 options & FDCs - AZT or TDF preferred - d4t phase out Boosted PI - Heat stable FDC: ATV/r, LPV/r 1 preferred option & FDCs - TDF and EFV preferred across all pops Boosted PIs - Heat stable FDC: ATV/r, LPV/r Continue with FDC approach and phased introduction of new options (DTG, EFV 400 ) Add more heat stable PI options (DRV/r) and new strategies (NRTI sparing regimens) None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Encourage HIV DR to guide No No (Desirable) Earlier initiation Simpler treatment Less toxic, more robust regimens Yes (Tertiary centers) Yes (Phase in approach) Better and simpler monitoring Yes (preferred for monitoring, use of PoC, DBS) Support for scale up of VL using all technologies WHO, 2015

2015 Consolidated ARV Guidelines New drug options Phased introduction of new alternative ARV options in 1 st and 2 nd line (dolutegravir, low dose efavirenz and heat stable darunavir/ritonavir ) Lower toxicity Better resistance profile Pill size and cost reduction potential Safety and efficacy in PLHIV with TB and pregnant women still under evaluation Generic single formulations and FDCs expected to be available in 2017/2018

Current Role of New ARV Options in 2015 WHO Guidelines ARV Population 1 st line 2 nd line 3 rd line Comments EFV 400 Adult/Adol DTG RAL Adult/Adol Children No dose reduction studies in children is needed (already pk adjusted). Not approved in children less than 12 years old. Twice daily dose probably needed in TB patients using RMP Adult/Adol Currently preferred as 3 rd line option in adults and as 2 nd line option in children Children Limited use as alternative 2 nd line option in adults. (RAL+ LPV/r) DRV/r Adult/Adol Currently preferred as 3 rd Children line option.

What are the challenges that prevented further innovation in 2015 Consolidated Guidelines? EFV 400 lack of efficacy data in TB and PW DTG RAL DRV/r TAF lack of safety data in PW lack of efficacy in TB lack of safety and efficacy in children lack of efficacy data in 2 nd line (adult and children) lack of efficacy data in 1 st line for children lack of generic production of age appropriate formulations lack of heat stable formulations harmonization in DRV/RTV ratio among adults and children (6:1 in children vs 8:1 in adults) Lack of efficacy and safety data in TB, PW and children

2016 WHO Think Tank on Treatment Optimization: Key Messages Safety and efficacy of DTG, EFV 400 and TAF in pregnant women, children and TB coinfection trials with DTG and EFV400 ro provide evidence by 2017/2018. Lack of safety and efficacy data for TAF use in PW and children Concerns about drug interactions between TAF and RIF- Studies needed Impact of HIVDR in transition to new regimens Moderate support to move away from NNRTI to INSTIs in presence of >15% prevalence resistance to NNRTIs among ART starters Achieving moderate to high national viral load coverage more important than individual HIVDR testing Treatment Optimization of HIV (2016 AAWG and PAWG Joint Meeting) Feb 21, 2016 (18:00-22:00 hs) Westin Copley Hotel Boston USA Two drug treatment strategies (switching & long acting ARVs) Lower support for switch /simplification strategies using PI+3TC and DTG+RIL; moderate support for DTG+3TC. Highlights need for 2 nd line ART studies with new combinations as DRV/r+ DTG Confidence that long acting ARV treatments containing two drugs seems to be sufficient access programmes in the future

Long acting ARVs - The emergence of Long Acting ARVs is exciting & great interest to the HIV community - Main focus on prevention but interest also in treatment - 2 drugs currently in clinical trials (PK and PK-PD): - Rilpivirine LA - Cabotegravir - Particular use in special/vulnerable populations with poor adherence or difficult to treat - Administration at least monthly but preferably longer - Need to understand mechanisms of entry from depot into systemic circulation and reasons for variability.

NEW RATIONALE TO SIMPLIFY /OPTIMIZE THE EOI LIST FOR ANTIRETROVIRAL DRUGS AND FORMULATIONS For inclusions in EoI-HIV: New ARV drugs or new formulations of existing drugs: drugs and formulations that are newly included in the most recent WHO guidelines or prioritized by adult and paediatric ARV optimization working groups (AAWG and PAWG) For deletions in EoI-HIV: Adult ARVs: a) products with five or more of manufacturers already prequalified by WHO b)standalone formulations and co-blister packs of ARVs currently recommended in WHO consolidated guidelines which already exist in dual and /or triple fixed dose combinations Paediatrc ARVs: a) products not included in the Optimal and Limited use list as defined by the 2016 IATT formulary b) products with three or more of manufacturers already WHO prequalified

HIV Drug Resistance (HIVDR) Surveillance data from 2004-2010 revealed pre-treatment (PDR) HIVDR increased over time in LMIC and estimated that to be 6.8% in 2010. Increase levels of NNRTI PDR have emerged in several LMIC including: Angola (16%), Cuba (22%), Papua New Guinea (16%), Argentina (11%), Mexico (11%), Botswana (10%). A recent survey from another African country show NNRTI PDR >15%. Wide implementation of newly released WHO HIV Consolidated Guidelines on Treat All and PrEP, while reducing HIV incidence, are likely to further increase HIVDR prevalence. While the concern of HIVDR should not stop from providing ARVs to all in need, the long-term implications of earlier initiation on adherence and HIVDR need to be closely monitored. WHO recommends that ART scale up should be accompanied by routine HIVDR Surveillance; no indication for individual HIVDR

WHO HIVDR Surveillance and Monitoring Early Warning Indicators Pretreatment HIVDR HIVDR surveillance and Monitoring Acquired HIVDR Infants <18 months ART-naive

Outline What s new in ARV Guidelines Drug optimisation PADO priority list 2015 CROI 2016 Think Thank Meeting EOI 2016 list HIVDR Moving forward

Moving forward Opportunity for innovation in mid-2017 DTG could become preferred first-line regimen across age groups and as an option for second line Rethink the role of TAF in drug optimization (if indeed important rifampicin drug interaction) Need to review study design and inclusion criteria to enable more rapid uptake of innovations in WHO guidelines (ie. TB co-infection, PW) Advance the drug optimization agenda (CADO 3 and PADO3 in 2016)

http://www.who.int/hiv/pub/arv/policy-brief-arv-2015/en/ 08/03/2016 30