Stanley Luchters, Centre for International Health, Burnet Institute

1. WHO guideline development using
GRC standards; a practice example
from the Kesho Bora study
Stanley Luchters MD MPH PhD
Centre for International Health – Burnet Institute
April 4th 2012

2. 1 0 0 p r e g n a n t H I V p o s it iv e w o m e n O n a v e r a g e 3 5 b a b ie s w ill b e in f e c t e d w it h H I V
About 7
become
infected during
the pregnancy
About 15
become
infected at
the time
of delivery
About 13
become
infected
through
breastfeeding

3. Efficacy of MTCT prevention interventions
• MTCT rates in developing countries without ARV
intervention = 35%
• MTCT rates in developing countries with ARV
prophylactic regimens = 20%
– single-dose NVP or “AZT short course”
• MTCT rates in developed countries = 1 - 2%
– combination ARV regimens or treatment
(ART), elective CS, no breastfeeding
 more effective regimens needed

4. Kesho Bora overall goal
• To optimize the use of ARV drugs before, during
and after delivery to prevent MTCT of HIV and
preserve the health of the mother in settings
where the majority of HIV-positive women are
breastfeeding.

5. Study Rationale
• Efficacy of MTCT prevention interventions in
developing countries needs to be improved
• Alternatives to replacement feeding for children
born to HIV-infected mothers need to be
identified
• Health of HIV-infected mothers needs more
attention
Triple-ARV prophylaxis during
pregnancy and breastfeeding
may achieve all 3 purposes

6. General study outline
Disease status in Intervention mother
pregnancy
CD4+ cell count < 200 cells/mm3 PROSPECTIVE COHORT:
or HIV stage 4 Lifelong antiretroviral therapy
CD4+ cell count 200-500 RANDOMIZED TO:
cells/mm3 • “triple ARV prophylaxis” up to 6 months
post partum during BF
OR
• “AZT short course” up to 1 weeks post
delivery (WHO 2006 recommended
regimen)
CD4+ cell count >500 cells/mm3 PROSPECTIVE COHORT:
“AZT Short-course”

7. Participating sites
Bobo Dioulasso
.
• Bobo-Dioulaso, Burkina-Faso Nairobi
• Durban, South Africa Mombasa
• Mtubatuba, South Africa
• Nairobi, Kenya
Mtubatuba
• Mombasa, Kenya
Durban

9. Infant HIV-free rates to 12 months of age.RCT, by study stratum
1.00
HIV-free survival of
0.95
Propotion not infected
infants from mothers
0.90
with CD4 200-500 Short
0.85
Triple
0.80
Log rank test p = 0.017
0.75
(stratified on centre and intention to BF) 0 1 2 3 4 5 6 7
Age (in months)
8 9 10 11 12
Triple-ARV
prophylaxis AZT short course
Rate Rate Reduction
(95% CI) (95% CI)
Birth 2.8 (1.5-4.9) 3.0 (1.7-5.2) 7%
6 weeks 4.8 (3.1-7.4) 6.2 (4.2-9.1) 23%
6 months 8.4 (6.0-11.6) 12.6 (9.7-16.3) 33%
12 months 10.2 (7.6-13.6) 16.0 (12.7-20.0) 36%

10. Subgroup analysis: mothers with
CD4 350-500 cells/uL
Triple-ARV prophylaxis AZT short course
Rate Rate Reduc
(95% CI) (95% CI) -tion
Birth 1.7 (0.6-5.2) 1.7 (0.5-5.1) 0%
6 weeks 2.9 (1.2-6.7) 3.4 (1.5-7.4) 15%
6 months 4.1 (2.0-8.3) 5.8 (3.1-10.5) 29%
12 months 4.7 (2.4-9.3) 7.1 (4.1-12.2) 34%
Log rank test p = 0.33
(stratified on centre and intention to BF)

11. Results
• Statistically significant reduction in HIV-free
survival at 12 months among infants in “triple ARV
prophylaxis” arm as compared to “AZT short
course”
• However, no statistically significant effect was
seen among women with CD4 350-500 cells/mm3.

12. Participating Institutions Financial Support
UNIVERSITY OF NAIROBI
COLLEGE OF HEALTH SCIENCES
SCHOOL OF MEDICINE

13. The Kesho Bora Team
STUDY SITES STUDY COORDINATION
Bobo Dioulasso, Burkina-Faso (Centre Muraz) World Health Organization, Switzerland
• Nicolas Meda – Principal Investigator • Isabelle de Vincenzi – Study Coordinator
• Paulin Fao, Clarisse Gouem – Study Coordinators • Philippe Gaillard – Site Coordinator
• Paulin Somda, Hervé Hien, Elysée Ouedraogo – Investigators • Tim Farley – Project Manager
• Diane Valea – Laboratory Coordinator • Ndema Habib – Statistician
• Roselyne Toure – Data manager • Sihem Landoulsi – Data Management
Durban, South Africa (University of KwaZulu-Natal)
• Nigel Rollins, Kevi Naidu – Principal Investigators SUPPORTING INSTITUTIONS
• Lynne McFetridge – Study Coordinator Université Montpellier 1, EA 4205 and CHU Montpellier, Laboratoire
• Johannes Viljoen – Laboratory Coordinator de Bactériologie-Virologie, Montpellier, France
Mombasa, Kenya (International Centre for Reproductive Health) • Philippe Van de Perre – Laboratory Coordination
• Stanley Luchters, Marcel Reyners – Principal Investigators Centre Muraz, Burkina-Faso
• Eunice Irungu – Study Coordinator • Francois Rouet – Site Laboratory Coordination and Quality
Assurance
• Christine Katingima, Mary Mwaura, Gina Ouattara – Investigators
Institut de Recherche pour le Développement, France
• Kishor Mandaliya – Laboratory Coordinator
• Cecile Cames, Amandine Cournil, Kirsten Simondon – Nutrition
• Mary Thiongo – Data manager
Coordination
Nairobi, Kenya (University of Nairobi)
National Institute of Child Health and Human Development, National
• Ruth Nduati – Principal Investigator Institutes of Health, USA
• Judy Kose – Study Coordinator • Jennifer Read – Sponsor Representative and Co-investigator
• Ephantus Njagi – Laboratory Coordinator Agence Nationale de Recherche sur le SIDA, France
• Peter Mwaura – Data Manager • Brigitte Bazin, Claire Rekacewicz – Sponsor Representatives and
Somkhele, South Africa (Africa Centre) Co-investigators
• Marie-Louise Newell – Principal Investigator Centers for Disease Control and Prevention, USA
• Steven Mepham, Thembi Blose – Study Coordinator • Mary Glenn Fowler, Denise Jamieson, Allan Taylor, Michael
• Londiwe Mthethwa – Data Manager Thigpen – Sponsor Representatives and Co-investigators
International Centre for Reproductive Health, Belgium
• Patricia Claeys , Marleen Temmerman – Sponsor Representative
and Co-investigator

14. WHO guideline development using
GRC standards

15. World Health Organization
• WHO has a mandate to:
– define evidence-based global health norms
and standards and
– help countries adapt international
recommendations according to their national
circumstances

16. The problem with WHO guidelines before
2009
• Limited transparency about judgments
• Limitations in evidence base
– Review of evidence not always systematic
– Often expert opinion
• Long delay between time taken and when
advice needed
• Other issues (few country adaptations)
Oxman et al, Lancet 2007;369:1883-9

17. WHO response
• Revised WHO handbook for guidelines
• Guideline Review Committee (GRC)
• Standards for
– Use of evidence
– Processes
– Reporting

18. Revised WHO recommendations
(2010)
Antiretroviral drugs for treating
pregnant women and preventing
HIV infection in infants;
Recommendations for a public
health approach

20. Step 1-3 Scoping the document, group
composition, conflict of interest
• Identify need for policy adaptations: reasons for
choosing the topic, problems with existing
guidelines, new evidence emerged, etc
• WHO convened an expert consultation in
November 2008 to review new evidence since
the 2006 guidelines
• Core writing group (7 members)
• 2 WHO
• 2 guideline writers
• 3 other experts

22. Step 4 - WHO prepared four key questions
(PICOT)
• When to start ART in pregnant women; and what
regimen to give to pregnant women eligible for ART
• When to start ARV prophylaxis for prevention of MTCT in
pregnant women, and what regimen to give HIV-infected
pregnant women for ARV prophylaxis?
• What ARV prophylaxis regimen to give newborn infants
born to HIV-infected mothers in the immediate
postpartum period?
• What regimen to use for preventing breastfeeding
transmission of HIV beyond the immediate postpartum
period?

24. Step 5 – Evidence retrieval, evaluation and
synthesis
• The HIV/AIDS Cochrane Collaborative Review
Group search strategy was used for each of the
four key questions
– Protocol developed for each question
– Systematic review of peer-reviewed
literature, abstracts, conference proceedings
and ongoing trials
• For each of the selected studies, an assessment
of the risk of bias using standard Cochrane
format was completed

25. Step 5 – Evidence retrieval, evaluation and
synthesis (continued)
• Formal assessment of the quality of the
evidence (GRADE)
• GRADE is the Grading of Recommendations
Assessment, Development and Evaluation
• Review outcomes for each question as defined
in the PICO tables as high, moderate, low or
very low

27. Example of a GRADE table
PICOT: Are triple-ARV regimens during pregnancy and continued during breastfeeding (intervention)
more effective than regimens using antepartum AZT (comparator) for PMTCT among HIV-1 infected
pregnant women (population)?

28. 1 eligible study?
• Triple has been used for over a decade in
developed countries.
• Studies in developing countries available, but
largely observational
• Sometimes regimen not specified…

30. Step 6 - Risk-benefit profile
• Risk-benefit tables
– Draft recommendations (incl. strength)
– Evidence (incl. quality)
– Benefits and risks (AEs; drug resistance)
– Values and acceptability (complexity;
adherence)
– Cost
– Feasibility (integration)

31. Step 7 - Guideline review meeting
• 2-day expert meeting (50 participants)
• Final recommendations formulated, taking into
consideration quality of evidence, balance between
benefits and harms, balance between values and
preferences, cost, feasibility, and related factors.
• Final agreement on recommendations was
achieved by active consensus of the participants in
the guidelines meeting.

33. Step 8 – Additional feasibility assessment
• Various meetings and presentations addressed
the feasibility of potential new
recommendations.
– An informal two-day meeting was held in
September 2009 with implementing agencies
and other key stakeholders
– rapid assessment of relevant country-specific
policies and barriers (structured
questionnaire to 12 selected WHO country
offices)
– Review of health systems issues of PMTCT
programmes

34. Step 9 – Formulating additional research
needs
• Predominantly done by Guideline review
meeting and the core writing group

35. Step 10 - Peer review
• The summary recommendations and Grade
Evidence Profile Tables were sent for peer
review to six independent peer reviewers and
the WHO regional offices.

36. Revised WHO recommendations (2010)
Antiretroviral drugs for treating “ triple ARV prophylaxis"
pregnant women and preventing (Option B)
HIV infection in infants; Mother
Recommendations for a public Maternal triple ARV prophylaxis starting from as early
health approach as 14 weeks gestation and continued until delivery, or
if breastfeeding, continued until one week after all
infant exposure to breast milk has ended.
Recommended regimens include:
AZT+3TC+LPV/r or
AZT+3TC+ABC or
AZT+3TC+EFV or
TDF+3TC(or FTC)+EFV
Infant
Daily NVP or twice daily AZT from birth until 4 to 6
weeks of age (irrespective of mode of infant feeding).
"For the first time, WHO recommends that HIV-positive mothers or their infants
take ARVs while breastfeeding to prevent HIV transmission"

37. Eligibility criteria for initiating antiretroviral treatment
(ART) or prophylaxis in HIV-infected pregnant women
based on CD4 cell count and WHO clinical stage.

38. Eligibility criteria for initiating antiretroviral treatment
(ART) or prophylaxis in HIV-infected pregnant women
based on CD4 cell count and WHO clinical stage.

39. The problem with WHO guidelines before
2009
• Limited transparency about judgments
• Limitations in evidence base
– Review of evidence not always systematic
– Often expert opinion
• Long delay between time taken and when
advice needed
• Other issues (few country adaptations)
Oxman et al, Lancet 2007;369:1883-9

40. Conclusions
• Transparency about judgments?
• Evidence based recommendations?
– Review of evidence systematic – yes
– Often expert opinion – still yes
• Time between need and availability reduced?

41. Conclusions (2)
• Important to have standardized process for
developing evidence-based guidelines
• More formal consideration of observational and
other relevant data would be helpful
• Allow forward thinking recommendations
• Countries are implementing the 2010 PMTCT
guidelines (PNG is currently doing country
adaptation)

42. Thank you