The role of Dolutegravir in first-line regimens WHO Satellite Session at IAS Paris: What’s new in HIV Treatment? 23 July 2017 Marco Vitoria HIV Department, WHO, Geneva No conflicts of interest to declare

ON TRACK TO 30 MILLION PEOPLE ACCESSING TREATMENT… BUT need more work to close the gap Number of people living with HIV ON antiretroviral therapy, global, 2000–2016 Knowledge of HIV status, treatment coverage and viral load suppression, global, 2016 Source: UNAIDS 2017 estimates. Global AIDS Monitoring, 2017.

WHO ARV Guidelines Evolution: 2002 to 2016 Topic 2002 2003 2006 2010 2013 2016 When to start CD4 ≤200 CD4 ≤ 200 consider 350 - TB at CD4 ≤ 350 CD4 ≤ 350 - TB,HBV at any CD4 CD4 ≤ 500 CD4 ≤ 350 as priority TB, HBV, PW, SDC at any CD4 Treat All Programmatic focus on KPs 1st Line ART 8 options - AZT preferred 4 options - AZT/TDF preferred - d4T dose reduction 6 options (FDC) - d4T phase out 1 preferred option (FDC) TDF/EFV preferred (all pops) - TDF/EFV preferred (all pops) - new alternative options (DTG, EFV400) 2nd Line ART Boosted and non-boosted PIs Boosted PIs -IDV/r LPV/r, SQV/r - ATV/r, DRV/r, FPV/r LPV/r, SQV/r - Heat stable co-formulation: ATV/r, LPV/r -Heat stable co-formulation: ATV/r, LPV/r Heat stable co-formulation: - new alternative options (DRV/r, LPV/r + RAL) 3rd Line ART None DRV/r, RAL, ETV DRV/r, RAL, ETV, DTG Viral Load Testing No (Desirable) Yes (Tertiary centers) (Phase in approach) (preferred for monitoring, use of PoC, DBS) (preferred for monitoring, scale up all technologies) - CD4 monitoring can be stopped if patient virally supressed Earlier initiation Simpler treatment Less toxic, more robust regimens Better and simpler monitoring Vitoria et al Curr Opin HIV/AIDS ,2013, 8: 12-18

ARV Drug Optimization: Key Principles Reduce toxicity Improve palatability/pill burden Increase resistance barrier Reduce drug interactions Safe use across different age groups and populations Reduce cost “Durability” “Durability” “Effectiveness” “Effectiveness” “Harmonization” “Harmonization”

Optimization criteria Summary of optimization profiles of new ARVs recommended in 2016 WHO ARV guidelines - comparative analysis Optimization criteria DTG EFV400 DRV/r RAL Efficacy and safety High virologic potency  Low toxicity High genetic barrier to resistance  Simplification Available as generic FDC Low pill burden Harmonization Use in pregnant women ? Use in children Use in HIV-associated TB Few drug interactions Cost Low price  yes  no ? ongoing studies

DTG in Clinical Practice: CNS Adverse Events Clinical trials (phase III) – SINGLE, SPRING-2, FLAMINGO, ARIA , SAILING (approximately 1700 patients on DTG) Low risk of severe adverse drug reactions Increased risk of insomnia but no increase of other CNS adverse events Depression and suicide ideation very rare Observational studies -Germany, Netherlands, UK, and Spain ( 5 studies - approximately 2800 patients on DTG ) Higher than expected rate of DTG discontinuation due intolerance(higher rates compared with RCTs) - primarily insomnia majority of cohorts (4/5) as retrospective studies Selection bias and confounding factors (“channelling”) CNS adverse events potentially associated with older age (>60 years), female gender , co-administration of ABC, use of fatty foods and higher plasma drug levels. Pending publication, other than Netherlands cohort -German and Netherlands were retrospective cohorts ? Role of fatty foods (known to increase absorption and drug levels of DTG) Bracchi et al, 2016 , de Boer et al, 2016; Postel et al, 2016; Hoffmann et al, 2017; Fettiplace et al, 2017

DTG in Clinical Practice: Increased Risk for Immune Reconstitution Inflammatory Syndrome (IRIS)? Risk of IRIS may be increased with use of INSTIs (vs PI/r or NNRTI) in presence of low CD4 counts at ART initiation faster rate of viral suppression and CD4 recovery limited data: RCTs excluded at risk patients (e.g.: low CD4, active OI, TB) Cohort studies (France and Netherlands - patients at high risk for IRIS - approximately 2500 patients) INSTI users with 2 fold risk when compared with NNRTI and PI users REALITY Trial: no significant risk detected in patients using RAL Pending publication -retrospective cohorts -mortality not reported Dutertre, 2017; Hakim, 2017; Wijting, 2017,

DTG in Clinical Practice: HIV-associated TB & Pregnancy Rifampicin: lowers DTG AUC by 54% Increase dose of DTG to 50 mg BD (ongoing pK study on DTG 100 mg OD) Rifabutin: no significant interaction Use DTG at standard dose (50 mg once daily) Rifapentine: pK study in healthy volunteers stopped (toxicity reasons) Pregnancy Limited data (exclusion from RCTs - specific pK and clinical studies ongoing) No adverse events in animal studies (FDA class B) Very high DTG concentrations in blood cord at birth Same rate of birth defects as background risk based on pregnancy safety register data (and Botswana recent study) TB IRIS with ART 5-26% -TB-IRIS mortality 3.9% Dooley, 2013; Zash, 2017

Estimated timelines for completion of new clinical trials of DTG and EFV 400 Adapted from Vitoria et al, Curr Opin HIV/AIDS, 12: 369-76 2017

DTG for children: harmonization may be around the corner Dosing and safety (IMPAACT P1093 trial) Approval granted for ≥6 years and ≥ 15 kg (EMA) ≥30 kg (FDA) Enrolment ongoing for infants starting at 4 weeks-6 months Efficacy in 1st and 2nd line (Odyssey trial) Enrolled 329 (as of 19th July 2017) PK sub-studies to investigate RIF interaction and WHO weight-band dosing Expected completion May 2018 Extrapolation from adult efficacy appropriate Expected completion July 2020 (1st line by July 2018) WHO weight-band dose (as endorsed by PAWG based on available PK data and use of WHO generic tool) Number of tablets or capsules by weight band once daily 3–5.9 kg 6–9.9 kg 10–13.9 kg 14–19.9 kg 20–24.9 kg 25–34.9 kg 5 10 15 25 50 Dispersible Tablet 5 mg 1 ? 2 ? 3 ? - Dispersible scored Tablet 50 mg 0.5 1 Dosing and safety is being fully investigated within the P1093 trial that enabled approval of DTG from 6 years (with different weight for EMA and FDA) The trial is still ongoing and currently enrolling the smaller age cohort 4 weeks to 6 months with final expected results in May 2018 Efficacy both for 1st and 2nd line use is being investigated in Odyssey which is rapidly enrolling in the older age group and that will investigate TB co treatment as well as validate the WHO weight band dosing that the Paeditatric ARV working group has identified. As you can see results are expected by 2020 but interim data on fist line use are expected to arrive in a year from now. Click to have the animation Meantime we know that the paediatric community is aligned in extrapolating efficacy data from adults trials and with existing approvals by stringent regulatory authorities a scored 50 mg adult tablet could be used to provide DTG to children weighting at least 15 kg. So more work to do but reasons to be optimistic and harmonization might be around the corner.

Some programmatic factors that can influence the transition to DTG in 1st Line ART Regulatory issues: availability of low cost generic formulations (FDCs) Supply chain management (procurement preparedness, current stocks of EFV containing regimens) DTG introducing policy (eligibility criteria/priority populations) Pre-treatment levels of HIVDR to NNRTIs Programme monitoring for toxicity and pregnancy safety (pharmacovigilance) “Bandwidth” capacity to develop multiple implementation polices (training, logistic management, monitoring capacity, quality) 16/09/2018

Licensing and pricing of DTG in LMICs  Country DTG U$ price (pppy) LMICs (generic) 48 - 60 LMICs (originator) 396 - 1740 Botswana 272 Brazil 547 Mexico 2200 Belarus 2300 Ukraine 72 Sources: MSF, GFTAM, CHAI, MoH Brazil , Botswana, Mexico & Ukraine 9/16/2018

Surveillance approaches WHO supporting programmes Toxicity monitoring and pregnancy safety surveillance approaches recommended for DTG Populations Surveillance approaches WHO supporting programmes Adults, adolescents and children Active ARV toxicity monitoring (CNS, IRIS, long term toxicity) WHO global database for active dolutegravir toxicity monitoring (in development) http://who.int/tdr/research/tb_hiv/en/ Pregnant /breastfeeding women and infants ARV pregnancy registry and surveillance of congenital anomalies Mother–infant pairs monitoring during breastfeeding WHO/TDR global central database for the surveillance of drug safety during pregnancy At: http://who.int/tdr/research/tb_hiv/drug-safety-pregnancy/en/ *TDR Special Programme for Research and Training in Tropical Diseases (TDR)

Pre-treatment HIVDR to EFV or NVP in first-line ART initiators in selected countries

*   DTG transition protocols in five early adopter countries Country DTG eligibility criteria Pregnancy during DTG use TB during DTG use Use VL for DTG substitution Follow up of DTG exposed pregnant women/babies until delivery/birth Standard IRIS definition ART naive NNRTI intolerance NNRTI exposure/contra indication PW TB Botswana   Stay on DTG Stay on DTG (double dose) Brazil Switch to RAL * Kenya Switch to EFV Stay on DTG, (double dose) Nigeria Switch to EFV or ATV/r Switch to EFV or LPV/r Uganda * Also provide follow up of DTG exposed babies after birth. Source: MoH Brazil, MoH Botswana & CHAI, 2017

How WHO support countries in transitioning to new ARV drugs? evaluating efficacy and safety data in clinical studies with new drugs providing guidance and tools for monitoring drug toxicity and HIVDR providing advice on how to phase in new drugs sharing country experiences http://www.who.int/hiv/pub/toolkits/transition-to-new-arv-technical-update/en/

DTG transition in LMICs: Key messages DTG has clinical and programmatic advantages and can help countries to move faster towards 90/90/90 targets. Some knowledge gaps in specific populations need to be solved to broad implementation of DTG as preferred option. Several countries already started the transition to DTG using different strategies and their implementation process need to be closely monitored. DTG transitioning programmes need to consider: local regulatory issues, importance of specific populations, supply chain readiness, drug toxicity and HIVDR monitoring capacity and country HIV policy priorities. Pretreatment NNRTI resistance can be an accelerator to DTG transition in countries where this information is available. And where needed additional experts, e.g. in the co-morbidity section

Merci

Backup slides

DTG containing regimens EFV400 containing regimens Key items that programmes need to consider for a safe transition to new first- line ARVs Optimization criteria DTG containing regimens EFV400 containing regimens Preferred Choice Efficacy Highly efficacy in context of NNRTI resistance (cost saving ), Efficacy data on PW and TB co-infection pending Efficacy data on PW and TB co-infection pending Concerns with rising NNRTI resistance Favours DTG Safety Limited safety data in young children, pregnancy , TB co-infection and advanced HIV disease (IRIS risk) Used for decades in LMICs and is proved safe in PW and PLHIV with TB. Lower doses are better tolerated. Favours EFV 400 Simplification Generic single formulation available, but FDC expected only in 2018 Need dose adjustment in TB co-treatment (twice daily dose) Generic FDC already available No dose adjustment needed and maintenance of once daily dose Favours EFV400 Harmonization Strategically preferred choice in long term Limitations for use in all populations (young children, IDU ) some important drug interactions Cost Cheaper than EFV600 and higher potential for further cost reduction (strong generic competition) Cheaper than EFV600 but less potential for further cost reduction WHO technical update on transition to new ARVs, 2017

Examples of scenarios and considerations for transition to new first-line ARV drugs Potential country scenarios Factors that can prompt faster uptake of new ARVs* Country level actions needed to support introduction of new ARVs Rapid transition to DTG PDR to NNRTIs ≥10% Country has a policy for introducing DTG DTG generic FDC largely available DTG registered in the country Supply chain prepared for the transition Phased transition to DTG PDR to NNRTIs <10% Country has a policy on introducing DTG DTG generic FDC available but limited High burden of TB/HIV and HIV in PW Supply chain not well prepared for the transition Transition to DTG could be delayed PDR to NNRTIs <10% Country has no policy on introducing DTG DTG generic FDCs not available DTG not registered in the country Supply chain not prepared for the transition Transition to EFV400 can be considered EFV400 generic FDC available Supply chain system prepared for the transition DTG generic FDC not available EFV400 as FDC registered in the country Transition to EFV400 should be reconsidered * Other programmatic factors : patient and clinician readiness to accept the new drugs, viral load suppression rates among those on ART, ability to monitor drug toxicity and supervision and monitoring of programme quality. WHO technical update on transition to new ARVs, 2017