Drug Treatment Regimens:

How and why WHO makes its global recommendations

Prof Charles Gilks

Director, Co-ordinator

Antiretroviral Treatment and Care

Department of HIV/AIDS

WHO Geneva.

WHO Drug Treatment Regimens

• Why WHO needed to make recommendations and to set global norms and standards

• How WHO set about doing this

• Consider how successful or not WHO's work has been in ART scale-up so far

• Revised (2008) WHO processes for making recommendations and issuing guidance

“Three by Five”

2002 / 2003: GFATM and PEPFAR established and resourced

The target: three million people on

treatment by the end of 2005

The goal : universal access to anti- retroviral therapy (ART) as a

human right to health to all in need

The treatment gap was declared a global health emergency

Sept 22nd, 2003 at UN General Assembly

•

Filling the treatment gap

• WHO entered "emergency mode"

• Defined the extent of the problem– end 2002, estimated 300,000 on ART– 91% of treatment gap in 34 countries

• Recognised the extent of the challenge– New intervention with limited experience– Countries most in need had weakest health systems– Prevailing view: ART was complex and specialised

Delivering on 3 x 5

WHO’s strategy: to catalyse rapid uptake of ART in communities where it is needed now but not widely accessible by adopting a two-pronged approach:

Supporting countries to recognise and respond to their HIV/AIDS treatment gap and leveraging the necessary resources to enable ART to be scaled up rapidly in line with 3x5 target

Simplifying and standardizing ART as far as possible without compromising effectiveness so it can be universally scaled up and delivered in resource constrained settings

Public Health ART StrategyVision: Universal access to ART

Elements: • One global standard of care for ART

– One first-line then one second-line regimen (then stop)

– Sequential use of 3 drug classes– Simple recommendations for when to

start switch & toxicity substitutions – Tiered laboratory support for clinical

decision-making– Standard population-based HIVDR

monitoring and surveillance– Pharmacovigilance/toxicity monitoring

• Chronic disease management• Integrated and decentralised care

Process: Evidence-based Simplification Standardisation

Harmonised ART Policy Guidance

Audience for guidelines

• Primarily national planners and policy makers engaged in public sector ART and in target-setting– What ARVs to make available in public sector

first and second-line regimens– How to use: the four Ss of clinical management:

when to start, substitute, switch and stop

• Care implementers - basic knowledge to use ARVs effectively according to national policy recommendations

• Trainers, M&E experts – to design appropriate tools and materials to support national policy recommendations

1st and 2nd line ARVs for adults

Start Substitute Switch Stop

1st Line 2nd line

AZT, d4T, 3TC,

NVP; EFV

ABC, TDF

ddI

PI/r

Recommended 1st Line ARV Drugs

Recommended as 2nd Line Drugs

Frequently Recommended as 2nd line drugs, but also as alternative drugs in 1st

line regimens

Table 4 - Recommendations for initiating ART in adults and adolescents based on clinical stage and availability of immunological markers

WHO Clinical StagingCD4 testing not

availableCD4 testing available

1 Do not treat [A-III]

Treat if CD4 cell count < 200/mm3[A-III] a

2 Do not treat b [B-III]

3 Treat [A-III]Consider treatment if CD4 cell count < 350/mm3 a c and initiate

ART before CD4 cell count drops below 200/mm3 d [B-III]

4 Treat [A-III] Treat irrespective of CD4 cell count [A-III]

a CD4 cell count advisable to assist with determining need for immediate therapy for situations as pulmonary TB and severe bacterial infections, which may occur at any CD4 level.b A total lymphocyte count of ≤ 1,200/mm3 can be substituted for the CD4 count when the latter is unavailable and mild HIV disease exist. It is not useful in the asymptomatic patients. Thus, in the absence of CD4 cell count and TLC, patients with WHO Adult Clinical Stage 2 should not be treated.c Initiation of ART is recommended in all HIV-infected pregnant women with WHO Clinical Stage 3 disease and CD4< 350 cells/mm3.d The precise CD4 cell level above 200/mm3 at which ARV treatment should be started has not been established.

When to Start - adults

Virologic ClinicalImmunologic

Viral load CD4 countClinicalcriteria

"Early Switch" "Late Switch"

Failure / When to Switch

WHO Clinical Staging

Clinical Failure(CD4 and VL not

available)

Immunologic Failure

(VL not available)

Immunologic and Virologic Failure(CD4 and VL available)

1 N/A Do Not Switch Consider

Switch

2 N/A Do Not Switch Consider Switch

3Consider Switch

Switch Switch

4Switch Switch Switch

When to Switch from 1st Line to 2nd Line ARV Regimens for Treatment Failure

Clinical failure is defined as a occurrence of new or recurrent WHO clinical stage 3 or 4 event (excluding IRIS).

CD4 failure is defined as a fall to (or below) the pre-treatment baseline or a 50% drop from the on-treatment peak level or persistent levels < 100 cells/mm3.

Virological failure is provisionally defined as a plasma HIV-1 RNA level >10,000 copies/ml after a minimum of 6 months on therapy.

Steering Committee

Time-Limited Subject Matter

Working Groups

WG

WG

WG

WG

WHO HIVResNet•Laboratory Network•Surveillance and Monitoring Network

WHO Secretariat

Modeling ofThe emergence and transmission of resistance

HIVDR database developmentand support

Public Health Assessment ToolFor evaluation of country HIVDR data

Global LaboratoryNetwork: Criteria,Protocols, Training,QA

The WHO HIVResNet is a global group of experts, laboratories, and organizations constituted to support HIVDR prevention, surveillance, and monitoring as antiretroviral treatment (ART) is rolled out worldwide.

Country HIVDR Committees

HIVDR monitoring & surveys

WGOperational Research

WGMutation lists forSurveillance and monitoring

Universal Access2005 G8 Summit at Gleneagles, Final Communiqué:“…working with WHO, UNAIDS and other international bodies to develop and implement a package of HIV prevention, treatment and care, with the aim of as close as possible to universal access to treatment for all those who need it by 2010.”

More children are receiving ART

Increased from 75,000 in 2005 to almost 200,000 in 2007

0

50,000

100,000

150,000

200,000

250,000

End 2005 End 2006 End 2007

Child

ren <1

5 rec

eiving

ART

East, South & South East Asia

Eastern Europe & Central Asia

Latin America & Caribbean

West and Central Africa

Eastern and Southern Africa

Total=75,000 Total=197,600Total=127,300

78% increase from 2005-2006

55% increase from 2006-2007

Towards Universal Access: Scaling up priority HIV/AIDS interventions in the health sector, WHO/UNAIDS/UNICEF 2008

Progress has been made with children

Revised simplified dosing

1 ADULT FDC AM & PM

1 BABY FDC AM & 1 PM

1 ADULT FDC AM & 0.5 PM

2 BABY FDC AM & PM

2 BABY FDC AM & 1 PM

0.5 ADULT FDC AM + PM

WHO FDC ARV tablet regimen superimposed

Same dosingirrespective of FDC, or same dosing for all three single ARV

agents

Most dose adjustments done in 1st

year Adapted from T. NUNN

Revised (2008) WHO process

• New WHO Guideline review committee• Revised WHO guidelines for guidelines• Minimum standards for:

Reporting ProcessesUse of evidence

• Different types of guidance documents recognised to fit different purposes:E.g. Emergency, Standard, Full , 'Books ' joint

guidelines?

Quality of evidence – GRADE approachQuality of

evidence(summary

score)

Study design Lower if * Higher if *

High (4) Randomized trial

Study quality:-1 Serious

limitations-2 Very serious limitations-1 Important inconsistency Directness:-1 Some uncertainty-2 Major uncertainty-1 Sparse or

imprecise data-1 High probability of reporting bias

Strong association:

+1 Strong, no plausible confounders, consistent and direct evidence+2 Very strong, no major threats to validity and direct evidence+1 Evidence of a Dose response gradient

Moderate (3)

Low (2) Observational study

Very low (1)

Strength of a recommendationFactors Comments

Quality of the evidence Higher the quality of the evidence the more likely

a strong recommendation can be made Balance between desirable

and undesirable effectsLarger the gap or gradient between these then more likely a strong recommendation will be made

Values and preferences If there is a great deal of variability or strong reasons that the recommended course of action is unlikely to be accepted then it is more likely a weak recommendation will be made.

Costs/financial implications (resource use)

Higher the cost both financial and in terms of infrastructure, equipment or requirements, and more resource intensive requirements, then less likely to make a strong recommendation

Feasibility Where intervention is possible and practical in the settings where greatest impact is likely to be attained or is being sought, strong recommendation is more likely

Conclusions

• Developing WHO drug treatment regimens is challenging – but can have great impact

• Balance between – being permissive; driving ART agenda forward – maintaining relevance to all countries

• Processes updated in WHO (GRADE)– Even more rigorous and transparant– Costs and feasibility