Clinical considerations for the introduction of DTG Nandita Sugandhi ICAP at Columbia University No conflicts of interest to declare

Overview Introducing DTG in guidelines now Special Populations Programmatic Context Eligible patient populations Special Populations Advanced disease TB Co-infection Pregnancy Pediatrics

Overview Introducing DTG in guidelines now Special Populations Programmatic Context Eligible patient populations Special Populations Advanced disease TB Co-infection Pregnancy Pediatrics

Programmatic Context Other new recommendations under consideration: “Test and treat” Intro of other first- line “alternative” regimens (eg TLE400) Differentiated Service Delivery Introduction of new lines of treatment (eg. 3rd line) Practicalities: Availability of resources Existing stock and supply chain management Access to diagnostics (Viral Load and Genotyping) Reason/Urgency for change

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

At the end of 2016, 53% of PLHIV were accessing ART: What about them? Patients needing drug substitution (i.e. intolerance, drug interactions) Patients needing regimen switch (treatment failure) Patients wanting regimen optimization (stable but want a “better” drug)

DTG for 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 (TUAB0105LB): 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.

Real world sequencing is not always so straightforward Initiating patients may be re-initiating patients Existing 1st line patients May have been exposed to multiple NRTI backbones (e.g. d4T or AZT TDF) May not have had VL before prior substitutions Existing 2nd line patients May not have been switched to ≥ 2 active drugs Existing 3rd line patients May have archived drug resistance Is VL and/or Resistance Testing needed for Patients Already on ART?

DTG is still active in the presence of underlying NRTI drug resistance MOPEB0316- High suppression rates in STRIIVING regardless of genotypic susceptibility score after switching to dolutegravir-based regimen in patients with VL suppression MOAB0107LB- ACTG A5353: DTG + 3TC for initial treatment of of patients with VL <500,000 MOPEB0322- DOLULAM: DTG+ 3TC maintains virological suppression even in heavily treatment experienced patients

What about DTG monotherapy? DOMONO DTG monotherapy in Pts with no prior h/o treatment failure and VL<100,000 at baseline 8/77 patients at wk 48 had VF 3/6 patients had INSTIR (155H, 263K, S230R1) Blanco J et al2 122 tx experienced patients with no h/o INSTIR changed to DTG monotherapy 11/122 (9%) had viral failure 7/11 developed ≥ 1 INSTIR mutations(92Q, 97A, 118R 148R/K/H, 155H) MOPEA0011 CROI 2017

Eligibility Considerations Emerging evidence for use of DTG for Initiating patients Stable first line patients Second line patients Third line patients When making a single drug substitution, VL is recommended to ensure viral suppression However, there is residual activity of NRTI’s even with NRTIR in combination with DTG More data needed from real world settings Effectiveness, Safety, Tolerability

Overview Introducing DTG in guidelines now Special Populations Programmatic Context Eligible patient populations Special Populations Advanced disease TB Co-infection Pregnancy Pediatrics

Advanced Disease and Coinfection Concerns about IRIS Significant percent of patients present with advanced disease IRIS is not a new phenomenon but may become more common with use of DTG TB is the leading cause of mortality in PLHIV Co-administration of DTG with rifampicin significantly decreases DTG plasma concentrations Limited evidence that 50mg DTG BD is sufficient to overcome this interaction PK study in HIV negative volunteers1 Limited data from observational studies Ongoing and planned studies INSPIRING: DTG 50mg BD v. EFV600 in treatment-naïve patients during TB treatment (results expected December 2017) RADIO: PK of DTG 50mg and 100mg once daily with rifampicin (Results expected Jan 2018) 1 Dooley K. JAIDS, 2012

Current guidance on use of DTG in pregnancy WHO Rec DTG for alternative 1st line in adults but insufficient studies in pregnant women to make a recommendation Advises that DTG should not be used in pregnancy unless the perceived benefits outweigh the potential risks DHHS DTG-containing regimens are one of the preferred 1st line regimens for adults and adolescents Recommends that if a woman is on a suppressive regimen she should continue without change

Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir MOPEB0283 Dolutegravir use during pregnancy and birth outcomes: data from the Antiretroviral Pregnancy Registry (APR) As of 31 January 2016 -61 pregnancy with exposure to DTG prospectively reported 51 live births 3 (4.9%) with induced Ab, 7 (11.5%) with spontaneous Ab, 0 stillbirths MOPECO609 Pregnancy and neonatal outcomes following prenatal exposure to dolutegravir: real world safety of DTG use in pregnancy in Europe EPPICC A total of 81 pregnancies in 81 women were identified. Median maternal age at conception was 33.1 years (interquartile range [IQR], 26.7-37.1 years), and 44/81 (54.3%) born in sub-Saharan Africa. Most (62/74, 83.8%, 7 unknown acquisition) women had heterosexual acquisition of HIV, 9 women were vertically infected and 3 had injecting drug use acquisition. Most women had been diagnosed with HIV before conception (70/75, 6 unknown), 48 conceived whilst on any ART and 28 conceived on a DTG-based regimen. There were two twin pregnancies (all live births). Pregnancy outcomes were known for 64 pregnancies (1 moved to another country before delivery, 16 continuing): 61 ended in live births (29 with 1st trimester DTG exposure), 1 in stillbirth (without 1st trimester DTG exposure), 1 in termination (with 1st trimester DTG exposure) and 1 in spontaneous abortion (with 1st trimester DTG exposure). Birth outcomes for the 63 delivered liveborn infants (including 2 twin pairs) and 1 stillborn infant (62 pregnancies) are in the Table. The congenital abnormalities with 1st trimester DTG exposure were: patent foramen ovale; bilateral hexadactyly of hands (familial) and hypospadias (both in 1 child); in 2nd trimester: ankyloglossia.

MOAX0202LB: DTG/TDF/FTC started in pregnancy is as safe as EFV/TDF/FTC in nationwide birth outcomes surveillance in Botswana Tsepamo study: Ongoing birth surveillance in Botswana covering 45% of births in the country Previously demonstrated that EFV/TDF/FTC is safer than older regimens in pregnancy Found similar risk of adverse birth outcomes compared to EFV/TDF/FTC Only 33 women on DTG since conception- more data expected in 2-3 years DTG/TDF/FTC n=845 EFV/TDF/FTC n=4593 Any Adverse Outcome 291 (34.4%) 1206 (35%) Severe Adverse Outcome 92 (10.9%) 519 (11.3%) Stillbirth 18 (2.1%) 105 (2.3%) Neonatal death (<28 days) 11 (1.3%) 60 (1.3%) Preterm brith (<37 wks) 149 (17.8%) 844 (18.5%) SGA (<10th%tile for GA) 35 (4.2%) 160 (3.5%) VSGA (<3rd%tile for GA) 51 (6.1%) 302 (6.7%)

Dolutegravir for Pediatric Patients Now Pediatric Formulations available: 10mg + 25mg tab for patients ≥30kg DTG 50mg can be used for adolescents ≥40kg Included as 3rd line option in WHO 2016 guidelines

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 withint the 1093 trial that enbaled approval of DTG from 6 yeaes (with different weight for EMA and FDA) The trial is still ongoing and currently enroling 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 orlder 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 lien use are expected to arrive in a year from now. Click to have the animation Menatime we know that the paediatric community is aligned in extrapolating efficacy data from adults trials and with existing approvals by stringent regulatory aouthorities 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. Slide courtesy of Martina Penazzato

Variety of approaches: 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 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 http://www.who.int/hiv/pub/toolkits/transition-to-new-arv-technical-update/en

Summary New programmatic and clinical recommendations must be integrated with planning for the introduction of DTG Multiple patient populations may be eligible but must be carefully considered in the context of available evidence Viral load may be needed for single drug substitutions Careful review of treatment history is necessary for regimen switches in absence of viral load or genotyping (good history beats a genotype) Close monitoring is still needed to understand real world effectiveness, safety and tolerability Sequencing of regimens must be considered when introducing a new drug class Additional evidence is accumulating on DTG use in special populations TB coinfection Pregnant and breastfeeding women Pediatrics Multiple approaches may be possible according to country context- one size does not fit all

Merci Acknowledgements: Wafaa El-Sadr Elaine Abrams Maureen Syowai Marco Vittoria Martina Penazatto Herb Harwell