1. Clinical significance and challenges for transition to new ARVs
Satellite symposium at IAS Paris: Accelerating access to new HIV medicines in LMICs
25 July 2017
Marco Vitoria
HIV Department, WHO, Geneva
No conflicts of interest to declare

2. Temporal evolution of ARV drug pipeline: moving towards smarter and better HIV treatment options
Tenofovir alfenamide
2015          
withdrawn or no longer recommended ARVs

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. Major Areas for ARV Optimization in HIV Therapy
efficacy and safety
simplification
harmonization
cost
Co-formulations ↔ ↑
↑ or ↔ ↓
New drug class
↓ or ↑
Dose adjustment
Drug manufacturing process
New formulations
↑ or ↔
New strategies
↑ = increased ↔ = not affected ↓ = decreased

5. Summary of optimization profiles of major new ARVs
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
WHO policy brief transition to new ARVs in HIV programmes, Jul 2017

6. Major gaps on clinical use of dolutegravir
HIV-associated TB: need to adjust dose 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 observational studies but not detected in RCTs with other INSTIs (REALITY study)

7. Toxicity monitoring and pregnancy safety surveillance approaches
Populations
Surveillance approaches
WHO supporting programmes
Adults, adolescents and children
Active ARV toxicity monitoring
WHO global database for active ARV 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. Estimated timelines for completion of new clinical trials of DTG and EFV 400
Adapted from Vitoria et al, Curr Opin HIV/AIDS, 12:

9. 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. 39

10. TRANSITIONING to new formulations can be REALLY challenging…particularly for children
Demand is there BUT manufacturing capacity cannot address the demand.
Children < 3 years continue to receive NVP based regimens which is suboptimal particularly in light of high level of NNRTI resistance
We need urgent commitment by generic manufacturers to ensure that demand is addressed!
LPV/r Oral Pellet Packs in Order
12K pk/mo.
Source: APWG data as of Mar country intelligence
Does not include GF donation of 3K packs/mo. for 6 mo. for India

11. 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)

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

13. Major Clinical and Programmatic Challenges with New ARVs
Gaps in safety & efficacy info
(specific populations)
Gaps on how to promote programmatic transition
Limitations on drug regulations, formulations and price
Expected availability of generic formulations
Potential actions to address the knowledge gaps
DTG 
end 2016 (single)
early 2018 (FDC)
Clinical & pK studies (PW, TB, children, advanced HIV disease)
Catalytic procurement projects (UNITAID), programmatic data (Brazil, Botswana)
Adequate peds formulations
EFV400
early 2017 (FDC)
Clinical & pK studies (PW, TB,)
DRV/r
mid 2018 ?
(HS co-formulation)
Optimization chemistry synthesis
dose reduction?
RAL
available (but current price higher than originator)
Generic competition
dose reduction? New formulation?
Adequate peds formulation

14. 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

15. Merci

16. BACKUP SLIDES

17. 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

18. 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