CADO/PADO: Update on 2015 WHO Consolidated guidelines

Towards Treat All in the context of SDGs

Meg Doherty,

Treatment and Care Coordinator

WHO HQ

• What’s new in ARV Guidelines

• Drug optimisation • PADO priority list 2015 • CROI 2016 Think Thank Meeting • EOI 2016 list • HIVDR

• Moving forward

Outline

• What’s new in ARV Guidelines

• Drug optimisation • PADO priority list 2015 • CROI 2016 Think Thank Meeting • EOI 2016 list • HIVDR

• Moving forward

Outline

Key messages from the 2015 WHO ARV guidelines

• Treat all (at any CD4) - PLHIV across all ages, but the sickest remain a priority (symptomatic disease and CD4 < 350).

• Phased introduction of optimized regimens (new drug class; optimized dosing and formulations)

• Care packages to optimize the care cascade (reduce late presentation, improve retention).

• PrEP recommended as an additional prevention choice for all people at substantial risk of HIV infection.

Evolution of global ART coverage and eligibility criteria according WHO guidelines (2003-2015)

0

5 000 000

10 000 000

15 000 000

20 000 000

25 000 000

30 000 000

35 000 000

40 000 000

2003 2006 2010 2013 2015

not elegible

elegible but not onART

on ART

CD4 < 200 CD4 < 2001

CD4 < 3502

CD4 < 5003

at any CD4

1. At CD4 < 350: active TB disease and HIV+ pregnant women

2. At any CD4: active TB disease and HBV co-infection requiring HBV treatment”

3. At any CD4: active TB disease, HBV co-infection with severe liver disease, HIV+ pregnant women and HIV serodiscordant couples Source WHO rand UNAIDS reports

3% 7%

21%

43%

36%

PL

HIV

Treatment Gap

16 million

+13 million

+9 million

PLHIV currently on ART

Treatment gap based on 2013 WHO

ART guidelines (CD4 < 500)

Treatment gap

with expanded

eligibility

criteria (Treat

all)

+21 million

~ 37 million Global number of

PLHIV

Cost 31 billion USD per year by 2020; 50% treatment cost

08/03/2016 7

Population 1st line regimens 2nd line regimens 3rd line regimens

Adults and adolescents

2 NRTIs + EFV 2 NRTIs + ATV/r or LPV/r DRV/r + DTG (or RAL) ± 1-2

NRTIs 2 NRTI + DRV/r

2 NRTIs + DTG 2 NRTIs + ATV/r or LPV/r DRV/r + 2 NRTIs ± NNRTI

2 NRTI + DRV/r Optimize regimen using genotype profile

Pregnant/breastfeeding women

2 NRTIs + EFV 2 NRTIs + ATV/r or LPV/r DRV/r + DTG (or RAL) ± 1-2 NRTIs 2 NRTI + DRV/r

Children

2 NRTI + LPV/r

If less than 3 years:

2 NRTI + RAL DTG + 2 NRTIs

DRV/r + 2 NRTIs

DRV/r + DTG ± 1-2 NRTIs

If older than 3 years:

2 NRTI + EFV or RAL 2 NRTI + EFV

2 NRTIs + ATV/r c or LPV/r

Summary of sequencing options for major first-, second- and third-line ART regimens in adults,

adolescents, pregnant women and children

Infants and children: No changes in 1st line; more options for 2nd line (RAL and expanded age for ATV/r)

Pregnant women: Like adults (except DTG & EFV400)

Adults and adolescents: Preferred 1st and 2nd line remains the same ; new options as alternatives in 1st line (DTG and EFV400 ) and 2nd line (RAL and DRV/r)

Safety and Efficacy of INSTIs and EFV400 in 1st line ART (using network metanalysis)

major outcomes

INSTI vs EFV 600

DTG vs other INSTI

DTG vs EFV600

DTG vs EFV400

EFV400 vs EFV 600

QUALITY OF EVIDENCE

Viral suppression

INSTI better DTG better DTG better comparable 1 comparable moderate

CD4 recovery INSTI better DTG better DTG better comparable EFV400 better moderate

Treatment discontinuation

INSTI better DTG better DTG better comparable EFV400 better moderate

Mortality comparable comparable comparable comparable comparable low

AIDS progression

comparable comparable comparable comparable comparable low

SAE comparable comparable comparable comparable comparable moderate

1 Estimated effects favored DTG but statistical analysis not significant

WHO, 2015

Safety and Efficacy of DRV/r and INSTI/PI

regimens in 2nd line ART (NMA)

major outcomes DRV/r vs

ATV/r or LPV/r

DRV800 OD vs DRV600 OD

DRV800/100 OD vs DRV600/100 BD

RAL + LPVr vs 2 NRTIs + ATVr or

LPV/r

QUALITY OF EVDIENCE

Viral suppression Comparable comparable 3 comparable 1 equivalent moderate

CD4 recovery comparable comparable comparable 2 comparable 4 low

Treatment discontinuation comparable comparable 3 comparable 2 comparable low

Mortality comparable comparable comparable 2 comparable low

AIDS progression comparable comparable comparable 2 comparable low

SAE comparable comparable comparable 2 comparable low

1 Confidence interval too large to establish equivalence

2 Estimated effects favored DRV/r 800/100 but statistical analysis not significant

3 Estimated effects favored DRV/r 800/100 but statistical analysis not significant

4 Estimated effects favored LPV/r + RAL but statistically not significant

WHO, 2015

• What’s new in ARV Guidelines

• Drug optimisation • PADO priority list 2015 • CROI 2016 Think Thank Meeting • EOI 2016 list • HIVDR

• Moving forward

Outline

ARV Drug Optimization: Key Principles

• Reduce toxicity

• Improve palatability/pill burden

• Increase durability

• Improve sequencing

• Harmonization across different age groups and populations

• Reduce cost

PADO 2 priorities

0-3 yrs 3-10 yrs 10 yrs +

FIRST LINE

Mid-term (5 yr) ABC/3TC/DTG TAF/3TC/DTG

Long term (10 yr) TAF/3TC/DTG

SECOND LINE

Mid-term (5 yr) AZT/3TC/RAL or LPV/r AZT/3TC/DRV/r TAF/3TC/DRV/r

Long term (10 yr) AZT/3TC/LPV/r RPV/DRV/r or AZT/3TC/DRVr

FORMULATIONS of existing ARVs

ABC/3TC/EFV

LPV r 4 in 1

DTG

NVP 20 mg

RAL

DRVr & ATVr

New formulations of existing drugs that already have registration for children or in advanced paediatric development

Identifying priority regimens for optimal sequencing which include newer compounds for which paediatric development has not been completed

LPVr 4-in-1: first line for under 3 years to address the lack of optimal formulations

EFV triple: first line 3-10 years to provide an FDC to maximise adherence and simplify procurement

ATVr and DRVr: use in 2nd and 3rd line formulations and overcome issue with separate administration of RTV

RAL better formulation: use in infants and young children to enable rapid introduction of INI for use in 1st line regimen

DTG single or FDCs: identified as key drug to introduce INI in first line with potential for harmonisation across the full age spectrum

NVP 20 mg: better dosage form to facilitate dosing for PnP

TAF: key drug for future use in 1st line to minimise toxicity with potential for harmonization across the full age spectrum

Rat

ion

ale

for

pri

ori

tisa

tio

n

Progress made since Dec 2014

• New Guidelines: more prominent role of integrase inhibitors and ATVr as an alternative to LPVr in 2nd line use.

• New products: LPVr pellets FDA approved

• Better access: Merck agreement with MPP on RAL

• Advances in FDC development: PHTI projects

• Progress of ongoing research: P1093 and new protocols

• More communication: SRAs consulted to advocate for PADO priorities and to explore regulatory pathways for key FDC

• More guidance: IATT policy briefs on LPVr pellets

• Impact in countries: PAPWG commitment has resulted in most countries with high burden to procure optimal products

MPP= Medicine Patent Pool; PHTI= Paediatric HIV Treatment Initiative; SRAs: stringent regulatory agencies; IATT= Interagency Task Team; PAPWG= Paediatric ARV Procurement Working Group; CTA=Commitment To Action.

Thinking strategically about 1st line

0-4 weeks

RAL

DTG single or DTG/ABC/3TC

DTG/TAF/XTC

4 wks-3 years

LPVr 4-in-1

RAL better formulation

DTG single or DTG/ABC/3TC

DTG/TAF/XTC

3-10 years

EFV/ABC/3TC

DTG single or DTG/ABC/3TC

DTG/TAF/XTC

10-18 years

DTG/ABC/3TC or

DTG/TDF/XTC

DTG/TAF/XTC

NOW

FUTURE

Short term (1-2 years)

Mid term (2-5 years)

June 2010: Conference on dose optimization ("CADO I") April 2011: Priorities for ART optimization ( Tx 2.0 short term priorities) Nov 2011: ART sequencing meeting May 2012: Think Tank for ART optimization ( Tx 2.0 medium term

priorities) April 2013: Conference on drug optimization ("CADO II") Mar 2014: “Think Tank" for HIV treatment optimization (implications

for future reviews of WHO guidelines) Mar 2015: “Think Tank" for treatment optimization of HIV and Hepatitis C Feb 2016: “Think Tank" for treatment optimization of HIV (AAWG and

PAWG joint meeting)

Adult ART optimization - key events (2010-2016)

WHO ARV Guidelines Evolution from 2002 to 2015 Topic 2002 2003 2006 2010 2013 2015

When to start

CD4 ≤200 CD4 ≤ 200 CD4 ≤ 200 - Consider 350 - CD4 ≤ 350 for TB

CD4 ≤ 350 -Regardless CD4 for TB and HBV

CD4 ≤ 500 - Regardless CD4 for TB, HBV PW and SDC - CD4 ≤ 350 as priority

ART initiation

at any CD4

cell count

1st Line ART

8 options - AZT preferred

4 options - AZT preferred

8 options - AZT or TDF preferred - d4T dose reduction

6 options & FDCs - AZT or TDF preferred - d4T phase out

1 preferred option & FDCs - TDF and EFV

preferred across all pops

Continue with

FDC approach

and phased

introduction of

new options

(DTG, EFV400)

2nd Line ART

Boosted and non-boosted PIs

Boosted PIs -IDV/r LPV/r, SQV/r

Boosted PI - ATV/r, DRV/r, FPV/r LPV/r, SQV/r

Boosted PI - Heat stable FDC: ATV/r, LPV/r

Boosted PIs - Heat stable FDC: ATV/r, LPV/r

Add more heat

stable PI

options (DRV/r)

and new

strategies

(NRTI sparing

regimens)

3rd Line ART

None None None DRV/r, RAL, ETV DRV/r, RAL, ETV Encourage HIV

DR to guide

Viral Load Testing

No No (Desirable)

Yes (Tertiary centers)

Yes (Phase in approach)

Yes (preferred for monitoring, use of PoC, DBS)

Support for

scale up of VL

using all

technologies

Earlier initiation

Simpler treatment

Less toxic, more robust regimens

Better and simpler monitoring WHO, 2015

2015 Consolidated ARV Guidelines

New drug options • Phased introduction of new alternative ARV

options in 1st and 2nd line (dolutegravir, low dose efavirenz and heat stable darunavir/ritonavir )

Lower toxicity Better resistance profile Pill size and cost reduction potential

• Safety and efficacy in PLHIV with TB and

pregnant women still under evaluation • Generic single formulations and FDCs

expected to be available in 2017/2018

Current Role of New ARV Options in 2015 WHO Guidelines

ARV Population 1st line 2nd line 3rd line Comments

EFV400 Adult/Adol • No dose reduction studies in

children is needed (already pK adjusted).

DTG

Adult/Adol • Not approved in children less than 12 years old .

• Twice daily dose probably needed in TB patients using RMP

Children

RAL

Adult/Adol • Currently preferred as 3rd line option in adults and as 2nd line option in children

• Limited use as alternative 2nd line option in adults. (RAL+ LPV/r)

Children

DRV/r

Adult/Adol • Currently preferred as 3rd

line option . Children

What are the challenges that prevented further innovation in 2015 Consolidated Guidelines?

EFV400 • lack of efficacy data in TB and PW

DTG

• lack of safety data in PW • lack of efficacy in TB • lack of safety and efficacy in children • lack of efficacy data in 2nd line (adult and children)

RAL

• lack of efficacy data in 1st line for children • lack of generic production of age appropriate

formulations

DRV/r

• lack of heat stable formulations • harmonization in DRV/RTV ratio among adults and

children (6:1 in children vs 8:1 in adults)

TAF

• Lack of efficacy and safety data in TB, PW and children

2016 WHO Think Tank on Treatment Optimization: Key Messages

Safety and efficacy of DTG, EFV400 and TAF in pregnant women, children and TB coinfection

• trials with DTG and EFV400 ro provide evidence by 2017/2018.

• Lack of safety and efficacy data for TAF use in PW and children

• Concerns about drug interactions between TAF and RIF- Studies needed

Impact of HIVDR in transition to new regimens

• Moderate support to move away from NNRTI to INSTIs in presence of >15% prevalence resistance to NNRTIs among ART starters

• Achieving moderate to high national viral load coverage more important than individual HIVDR testing

Two drug treatment strategies (switching & long acting ARVs)

• Lower support for switch /simplification strategies using PI+3TC and DTG+RIL; moderate support for DTG+3TC.

• Highlights need for 2nd line ART studies with new combinations as DRV/r+ DTG

• Confidence that long acting ARV treatments containing two drugs seems to be sufficient access programmes in the future

Treatment Optimization of HIV (2016

AAWG and PAWG Joint Meeting) Feb 21 , 2016 (18:00 - 22:00 hs)

Westin Copley Hotel Boston USA

Long acting ARVs

- The emergence of Long Acting ARVs is exciting & great interest to the HIV community - Main focus on prevention but interest also in treatment - 2 drugs currently in clinical trials (PK and PK-PD):

- Rilpivirine LA - Cabotegravir

- Particular use in special/vulnerable populations with poor

adherence or difficult to treat

- Administration at least monthly but preferably longer

- Need to understand mechanisms of entry from depot into systemic circulation and reasons for variability.

NEW RATIONALE TO SIMPLIFY /OPTIMIZE THE EOI LIST FOR ANTIRETROVIRAL DRUGS AND FORMULATIONS

For inclusions in EoI-HIV:

New ARV drugs or new formulations of existing drugs: drugs and formulations that are newly included in the most recent WHO guidelines or prioritized by adult and paediatric ARV optimization working groups (AAWG and PAWG)

For deletions in EoI-HIV:

Adult ARVs:

a) products with five or more of manufacturers already prequalified by WHO

b)standalone formulations and co-blister packs of ARVs currently recommended in WHO consolidated guidelines which already exist in dual and /or triple fixed dose combinations

Paediatrc ARVs:

a) products not included in the Optimal and Limited use list as defined by the 2016 IATT formulary

b) products with three or more of manufacturers already WHO prequalified

• Surveillance data from 2004-2010 revealed pre-treatment (PDR) HIVDR increased over time in LMIC and estimated that to be 6.8% in 2010.

• Increase levels of NNRTI PDR have emerged in several LMIC including: Angola (16%), Cuba (22%), Papua New Guinea (16%), Argentina (11%), Mexico (11%), Botswana (10%). A recent survey from another African country show NNRTI PDR >15%.

• Wide implementation of newly released WHO HIV Consolidated Guidelines on Treat All and PrEP, while reducing HIV incidence, are likely to further increase HIVDR prevalence.

• While the concern of HIVDR should not stop from providing ARVs to all in need, the long-term implications of earlier initiation on adherence and HIVDR need to be closely monitored.

• WHO recommends that ART scale up should be accompanied by routine HIVDR Surveillance; no indication for individual HIVDR

HIV Drug Resistance (HIVDR)

HIVDR surveillance

and Monitoring

Early Warning

Indicators

Acquired HIVDR

Infants

<18 months

ART-naive

Pre-treatment

HIVDR

WHO HIVDR Surveillance and Monitoring

• What’s new in ARV Guidelines

• Drug optimisation • PADO priority list 2015 • CROI 2016 Think Thank Meeting • EOI 2016 list • HIVDR

• Moving forward

Outline

Moving forward • Opportunity for innovation in mid-2017

• DTG could become preferred first-line regimen across age groups and as an option for second line

• Rethink the role of TAF in drug optimization (if indeed important rifampicin drug interaction)

• Need to review study design and inclusion criteria to enable more rapid uptake of innovations in WHO guidelines (ie. TB co-infection, PW)

• Advance the drug optimization agenda (CADO 3 and PADO3 in 2016)

08/03/2016 30

http://www.who.int/hiv/pub/arv/policy-brief-arv-2015/en/