1. WHO perspectives on dolutegravir
Optimal Satellite Session at IAS Paris: Accelerating Access to Dolutegravir and Other Optimal ARVs
26 July 2017
Marco Vitoria
HIV Department, WHO, Geneva
No conflicts of interest to declare

2. 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)
- transition to 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:

3. 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 (“Harmonization”)
Reduce cost
Gallant, 2002

4. 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

5. Knowledge gaps on clinical use of dolutegravir
HIV-associated TB: dose adjustment if rifampin is used (pK and clinical studies with ongoing)
Pregnant/BF women: Limited safety data. Very high DTG concentrations in blood cord at birth (pK and clinical studies ongoing)
CNS side effects: higher than expected rate of DTG discontinuation due insomnia in observational studies (compared with RCTs) but very low occurrence of other side effects.
Risk of IRIS in PLHIV with advanced HIV disease: increased risk observed in cohort studies but not detected in RCTs with other INSTIs (REALITY)

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

7. 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 DTG toxicity monitoring (in development)
At:
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)

8. Country transition to new ARVs: some programmatic considerations
New medication could mean new distributors, changes to supply chain, ART distribution, etc
Country drug regulation policy can be an important bottleneck for transition
Provider re-education for new ART protocol, medication side effects, etc
Complexities if cannot be prescribed to important subgroups such as TB/HIV co-infected, MTCT
Current status of procurement and stocks on currently used ARVs will influence the transition
“Bandwidth” capacity to develop multiple implementation polices (training, logistic management, monitoring capacity, quality)

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

10. *   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

11. 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

12. DTG transition in LMICs: Key messages
DTG has clinical and programmatic advantages and can help countries to move faster towards 90/90/90 targets.
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.
Pre treatment NNRTI resistance can be an accelerator to DTG transition in countries where this information is available.

13. Merci

14. BACKUP SLIDES

15. 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

16. Examples of scenarios and considerations for transition to new first-line ARV drugs
Potential country scenarios
Main factors that can prompt faster uptake of new ARVs*
Main country level actions needed to support introduction of new ARVs
Rapid transition to DTG-based 1st line ART
PDR to NNRTIs ≥10%
Country has a policy for introducing DTG
Adequate availability of DTG generic FDC
Supply chain prepared for the transition
DTG registered in the country
Phased transition to DTG-based 1st line ART
PDR to NNRTIs <10%
Country has a policy on introducing DTG
Low availability of DTG generic FDC
Supply chain not well prepared for the transition
High burden of TB/HIV and HIV in PW
Transition to DTG-based 1st line ART could be delayed
Pretreatment HIVDR to NNRTIs <10%
Country has no policy on introducing DTG
No availability of DTG generic FDCs
Supply chain not prepared for the transition
DTG not registered in the country
Transition to EFV400-based 1st line ART can be considered
pretreatment HIVDR to NNRTIs <10%
Supply chain system prepared for the transition
No availability of DTG generic FDC
EFV400 as FDC registered in the country
Transition to EFV400-based 1st line ART 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