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DTG transiiton - Marco Vitoria (Webex UKR) ENG

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WHO perspectives on transition to
dolutegravir in first-line regimens
Marco Vitoria
HIV Department, WHO, Geneva
October 2017
ON TRACK TO REACH 30 MILLION PEOPLE ACCESSING TREATMENT… BUT NEED MORE
WORK TO CLOSE THE GAP …
Number of PLHIV on ART, 2000–2016
Number of new HIV infections
↑ 95% since 2010
Number of new HIV infections, 2000–2016
↓ 18% since 2010
coverage on testing, treatment and viral suppression
New HIV infections
2020 target
Source: UNAIDS Global AIDS Update, 2017
Source: UNAIDS 2017 estimates. Global AIDS Monitoring, 2017.
*The 2020 target is fewer than 500 000 new HIV infections, equivalent to a 75% reduction since 2010.
Progress toward the 90-90-90 targets in Eastern
Europe and Central Asia (2016)
63%
45%
77%
[49-72%]
[35-52%]
[61-89%]
of PLHIV have been
diagnosed
of diagnosed PLHIV
receive treatment
of people on treatment are
virally suppressed
ART coverage and AIDS related deaths in EECA
(2000-2016)
Use of antiretroviral drugs in EECA, 2016
Distribution of ART regimens
Use of 1st line regimens
1%
7%
45%
28%
92%
1st line
2nd line
27%
3rd line
TDF+FTC/3TC+EFV
Regimen that includes LVP/r
Other
Slide includes data from 7 reporting countries (Armenia, Georgia, Kazakhstan, Kyrgyzstan, Republic of Moldova, Tajikistan and Ukraine).
Key treatment and care messages from the 2016
WHO ARV guidelines
• Treat all (at any CD4) - PLHIV across all ages, but the sickest remain a
priority
• Phased introduction of optimized regimens (new drug class; optimized
dosing and formulations) as fixed-dose-combination
• Task shifting, decentralization, integration to optimize the HIV care
cascade (reduce late presentation, improve retention). Use of differentiated
care packages.
• Routine viral load as preferred approach for monitoring ART response (CD4
monitoring can be discontinued if virally supressed)
WHO ARV Guidelines Evolution: 2002 to 2016
Topic
When to
start
2002
2003
2006
2010
2013
2016
CD4 ≤200
CD4 ≤ 200
CD4 ≤ 200
CD4 ≤ 350
CD4 ≤ 500
- consider 350
- TB at CD4 ≤ 350
- TB,HBV at any CD4
- CD4 ≤ 350 as priority
- TB, HBV, PW, SDC at
any CD4
Earlier initiation
1st Line ART
- CD4 ≤ 350 as priority
- Programmatic focus on
KPs
8 options
4 options
8 options
6 options (FDC)
1 preferred option (FDC)
1 preferred option (FDC)
- AZT preferred
- AZT preferred
- AZT/TDF preferred
- d4T dose reduction
- AZT/TDF preferred
- d4T phase out
- TDF/EFV preferred (all pops)
- TDF/EFV preferred (all pops)
- transition to new
alternative ARV options
Simpler treatment
2nd Line ART
Treat All
Boosted and
non-boosted PIs
Boosted PIs
-IDV/r LPV/r,
SQV/r
Boosted PIs
- ATV/r, DRV/r, FPV/r
LPV/r, SQV/r
(DTG, EFV400)
Boosted PIs
- Heat stable coformulation: ATV/r, LPV/r
Boosted PIs
-Heat stable co-formulation:
ATV/r, LPV/r
Boosted PIs
- Heat stable co-formulation:
ATV/r, LPV/r
- new alternative options
(DRV/r, LPV/r + RAL)
Less toxic, more robust regimens
3rd Line ART
None
None
None
DRV/r, RAL, ETV
DRV/r, RAL, ETV
DRV/r, RAL, ETV, DTG
Viral Load
Testing
No
No
(Desirable)
Yes
(Tertiary centers)
Yes
(Phase in approach)
Yes
(preferred for monitoring,
use of PoC, DBS)
Yes
(preferred for monitoring, scale
up all technologies)
Better and simpler monitoring
- CD4 monitoring can be stopped
if patient virally supressed
Vitoria et al , Curr Opin HIV/AIDS ,2013, 8: 12-18.
Treat All Policy: uptake & implementation, July 2017
What is new in treatment & care (2017) ?
Transition to new ARVs – clinical and programmatic considerations
Transition to new antiretroviral drugs in HIV programmes: clinical and programmatic considerations
is a available from the WHO webiste at:
http://www.who.int/hiv/pub/toolkits/transition-to-new-arv/en/
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
Summary of optimization profiles of new ARVs recommended in
2016 WHO ARV guidelines - comparative analysis
Optimization criteria
High virologic potency
Efficacy and safety Low toxicity
High genetic barrier to resistance
Simplification
Available as generic FDC
Low pill burden
Use in pregnant women
Harmonization
Use in children
Use in HIV-associated TB
Few drug interactions
Cost
Low price
 yes
 no
? ongoing studies
DTG
EFV400
DRV/r
RAL





?
?
?





?

?
























Major gaps on clinical use of dolutegravir
CNS side effects: higher than
expected rate of DTG
discontinuation due insomnia
in cohort studies (higher rates
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 trial)
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)
DTG for children: harmonization may be around the corner
• Dosing and safety (IMPAACT P1093 trial)
Expected completion
May 2018
– Approval granted for ≥6 years and ≥ 15 kg (EMA) ≥30 kg (FDA)
– Enrolment ongoing for infants starting at 4 weeks-6 months
Extrapolation from adult
efficacy appropriate
• 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
Number of tablets or capsules by weight band once daily
WHO weight-band dose
(as endorsed by PAWG based on
available PK data and use of
WHO generic tool)
Dispersible Tablet 5 mg
Dispersible scored
Tablet 50 mg
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
25
50
1?
2?
3?
-
-
-
-
-
-
0.5
0.5
1
Expected completion
July 2020
(1st line by July 2018)
Estimated timelines for completion of new
clinical trials of DTG and EFV 400
ARV
2017
2018
Q3-Q4
DTG
RADIO
DAWNING
ADVANZ-4
EFV400
SSAT 062
SSAT 063
Q1-Q2
IMPAACT 1093
Pregnant women
2019
Q3-Q4
DOLPHIN 1
NAMSAL
Q1-Q2
2020
Q3-Q4
DOLPHIN 2
D2EFT
INSPIRING
Q1-Q2
VESTED
ODYSSEY
ADVANCE
Q3-Q4
PANNA
ING200336
NAMSAL
Children
TB
Adults
Adapted from Vitoria et al, Current Opinion HIV/AIDS, 12: 369-76 2017
Licensing and pricing of DTG in LMICs
Country
DTG U$ price (pppy)
LMICs (generic)
48 - 60
396 - 1740
272
547
2200
2300
72
LMICs (originator)
Botswana
Brazil
Mexico
Belarus
Tentative SRA Approval Timeline for DTG, TDF/3TC/DTG and TDF/3TC/EFV400 formulations*
(2016-2019)
Ukraine
Sources: MSF, GFTAM, CHAI, MoH Brazil , Botswana, Mexico & Ukraine
ARV
2016
H2
2017
H1
2018
H2
H1
2019
H2
H1
H2
DTG
TDF/3TC/DTG
TDF/3TC/EFV400
*Assumes SRA approval received 12 months after filing date
Expected SRA approval of product by generic suppliers
SRA approval received by generic suppliers
TDF/3TC/DTG in 92 LMICs = 75 U$ pppy
(Sep/2017)
Toxicity monitoring and pregnancy safety surveillance approaches
recommended for DTG
Populations
Adults, adolescents
and children
Pregnant/breastfeeding
women and infants
Surveillance approaches WHO supporting programmes


Active ARV toxicity
monitoring (CNS,
IRIS, long term
toxicity)
ARV pregnancy
registry and
surveillance of
congenital
anomalies

WHO global database for
active DTG toxicity
monitoring (in development)
At: http://who.int/tdr/research/tb_hiv/en/

WHO/TDR global central
database for the surveillance
of drug safety during
pregnancy
At: http://who.int/tdr/research/tb_hiv/drug-
safety-pregnancy/en/

Mother–infant pairs
monitoring during
breastfeeding
*TDR Special Programme for Research and Training in
Tropical Diseases (TDR)
Pre-treatment HIVDR to EFV or NVP in first-line
ART initiators in selected countries
countries should consider using an alternative 1st-line non-NNRTIs
regimen when national levels of NNRTI DR reach 10%
DTG vs EFV vs LPV/r: brief comparative analysis
Parameters
DTG
EFV
LPV/r
Tolerability
Comments
LPV/r : GI symptoms, dyslipidaemia ; EFV: CNS side effects ( depression) ; DTG: insomnia
Risk of drug interactions
DTG and LPV/r need dose adjustment in TB treatment using rifampicin
Efficacy in TB
Safe use in PW
Poor outcomes with TDF/XTC + bPIs in PROMISE study
DTG pK safety studies ongoing (FDA class B drug). BW programme and small cohorts showing similar
outcomes when compared with EFV
Safe for use in infants/children
EFV approved for children >3 years. DTG approved in children > 6 years. LPV/r pellets formulations
for infants recently approved.
High genetic barrier to HIVDR
Once daily regimen
DTG registration in process in 24 countries in 2017 and expected in + 50 in 2018
Wide availability in LMICs
Generic TDF/3TC/DTG available since Sep 2017.
Availability as FDC
Impact on ART sequencing
DTG= 44 USD ppy; EFV= 55 USD ppy, LPV/r = 220 USD ppy
TDF/3TC/DTG = 75 USD ppy TDF/3TC/EFV= 95 USD ppy
Lower prices as generics



Some programmatic factors that can influence the
transition to DTG in 1st Line ART

DTG introducing policy (eligibility
criteria/priority populations)

Regulatory issues: availability of low cost
generic formulations (FDCs)

Supply chain management (procurement
preparedness, current stocks of EFV containing
regimens)

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)
18
Key items that programmes need to consider for a safe transition to
new first- line ARVs
Optimization criteria
Efficacy
Safety
Simplification
Harmonization
DTG containing regimens
EFV400 containing regimens
•
Highly efficacy in context of NNRTI
resistance (cost saving ),
•
Efficacy data on PW and TB co-infection
pending
•
Efficacy data on PW and TB coinfection pending
•
Concerns with rising NNRTI resistance
•
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.
•
Generic FDC already available
•
No dose adjustment needed and
maintenance of once daily dose
•
Limitations for use in all populations (young
children, IDU )
some important drug interactions
Favours DTG
Cheaper than EFV600 but less potential for
further cost reduction
Favours DTG
•
Generic single formulation available,
but FDC expected only in 2018
•
Need dose adjustment in TB cotreatment (twice daily dose)
•
Strategically preferred choice in long
term
•
Cost
Preferred Choice
•
Cheaper than EFV600 and higher
potential for further cost reduction
(strong generic competition)
•
Favours DTG
Favours EFV 400
Favours EFV400
WHO technical update on transition to new ARVs, 2017
Examples of scenarios and considerations for transition to new first-line ARV drugs
Potential country scenarios
Rapid transition to DTG
Phased transition to DTG
Factors that can prompt faster uptake
Country level actions needed to support
of new ARVs*
introduction of new ARVs
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
PDR to NNRTIs <10%
Country has a policy on introducing DTG
DTG generic FDC available but limited
DTG registered in the country
High burden of TB/HIV and HIV in PW Supply chain not well prepared for the transition
Transition to DTG could be
delayed
Transition to EFV400 can be
considered
PDR to NNRTIs <10%
DTG generic FDCs not available
EFV400 generic FDC available
Country has no policy on introducing DTG
PDR to NNRTIs <10%
Supply chain system prepared for the transition
EFV400 as FDC registered in the country
DTG not registered in the country
DTG generic FDC not available
Transition to EFV400 should
be reconsidered
Country has no policy on introducing DTG
DTG not registered in the country
Supply chain not prepared for the transition
PDR to NNRTIs ≥10%
* 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
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
http://www.who.int/hiv/pub/toolkits/transition-to-new-arv-technical-update/en/
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.
Other policy briefs released by WHO in July 2017
HIV drug resistance
viral load and CD4
testing
point-of-care tools
for EID
person-centred HIV
patient monitoring
Thank you
PrEP implementation
tool
Advanced HIV
disease
Backup slides
Advantages of DTG in context of IDU epidemic
•
Better tolerated (low incidence of side effects , including CNS side effects)
•
Higher genetic barrier and better sequencing potential
•
Low pill burden and OD schedule (generic FDC available)
•
Lower risk of drug interactions (safe use with opiods, anti-neoplastic, anti-depressive, oral contraceptives, hep C
drugs, new anticonvulsants , recreational drugs) - major drug interactions: rifampin, carbamazepin, fenitoin,
metformin
•
Can be used in TB co-infection (pK studies and emerging programme data showing efficacy with DTG dose
adjustment)
•
FDA class B drug (emerging programme and cohort data suggest no clinical outcome differences when compared
with EFV)
•
Included in WHO, EACS and DDHS guidelines, WHO EML, PEPFAR and GFTAM procurement lists
•
Lower price ( with potential for further reduction)
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