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

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

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

4. 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

5. 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

6. 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)

7. 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.

8. 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?

9. 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

10. 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

11. 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

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

13. 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

14. 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

15. 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 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], 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.

16. 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%)

17. 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

18. 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

19. 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

20. 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

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