1. 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

2. 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.

3. 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

4. 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”

5. Optimization criteria
Summary of optimization profiles of new ARVs recommended in 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

6. DTG in Clinical Practice: CNS Adverse Events
Clinical trials (phase III) – SINGLE, SPRING-2, FLAMINGO, ARIA , SAILING (approximately 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 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

7. 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,

8. 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

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

10. 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.

11. 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

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

14. 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)
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:
*TDR Special Programme for Research and Training in Tropical Diseases (TDR)

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

16. *   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

17. 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

18. 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

20. Merci

21. Backup slides

22. 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

23. 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