# Presentation: 788892

## 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 22****nd****, 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 Strategy

**Vision: **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

## Slide 9

## 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

## When to Start - adults

| Table 4 - Recommendations for initiating ART in adults and adolescents based on clinical stage and availability of immunological markers |  |  |
| --- | --- | --- |
| WHO Clinical Staging | CD4 testing not available | CD4 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**

## Failure / When to Switch

- Viral load

- CD4 count

- Clinical
- criteria

- "Early Switch"

- "Late Switch"

**Failure / When to Switch**

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

| 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 |
| 3 | Consider Switch | Switch | Switch |
| 4 | Switch | 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.

## Slide 14

## WHO HIVResNet

** ****Steering Committee**

**Time-Limited **
**Subject Matter**
**Working Groups**

- WG

- WG

- WG

- WG

**WHO HIVResNet**
**Laboratory Network**
**Surveillance and Monitoring Network**

**WHO Secretariat**

**Modeling of**
**The emergence and transmission of resistance**

**HIVDR database development**
**and support**

**Public Health Assessment Tool**
**For evaluation of country HIVDR data**

**Global Laboratory**
**Network: 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**

- WG

**Operational Research**

- WG

**Mutation lists for**
**Surveillance and monitoring**

## Universal Access

## Slide 17

## Progress has been made with children 

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

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

- Progress has been made with children

**Notes:**
The number of children receiving ART increased form about 75,000 in 2005 to almost 200,000 in 2007, However, many children living with HIV are still not receiving treatment, and mortality among them remains high.

The estimation of need for ART will need to be revised based on these recent revised criteria for eligibility for ART in infants , hence coverage is not provided
Most children receiving ART are older  and the mortality in the first few months of starting ART remains high, retention in care continues to decline beyond the first year , and most children are starting ART very late 
Average age of children starting ART in the KIDS-ART-LINC Cohort Collaboration (17 participating clinics) was 4.9 years ( with only 12% <12-month)
70% -  had severe immunodeficiency, 
60% - started on a NNRTI based regimen
The 2-year risk of death on ART was 6.9% (95% confidence interval [CI]: 5.9-8.1), 
And was independently associated with:
baseline severe anaemia (adjusted hazard ratio [aHR]: 4.10 [CI: 2.36-7.18]), 
immunodeficiency (aHR: 2.95 [CI: 1.49-5.83]) 
advanced clinical disease (aHR: 3.65 [CI: 1.95-6.83]); 
Risk of LTFU was 9.5% (CI: 8.3-10.9), higher in children with severe clinical status.  And persists out through the second year. 
Only 8% of infants born to pregnant women with HIV in 2007 were tested for
HIV within the first two months of birth. In addition, only 4% of infants born
to women living with HIV initiated co-trimoxazole prophylaxis as indicated in
WHO guidelines.

## Revised simplified dosing 

## WHO FDC ARV tablet regimen superimposed

**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 dosing**
**irrespective of FDC, or same dosing for all three single ARV agents **

**Most dose adjustments done in 1****st**** year **

- Adapted from T. NUNN

## Revised (2008) WHO process

- New WHO Guideline review committee
- Revised WHO guidelines for guidelines
- Minimum standards for:
- Reporting
- Processes
- Use of evidence
- Different types of guidance documents recognised to fit different purposes:
- E.g. Emergency, Standard, Full , 'Books ' joint guidelines?

## Quality of evidence – GRADE approach

| Quality 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 recommendation

| Factors | 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 effects | Larger 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