Paediatric HIV Research: Status, priorities and ethical considerations

1
Paediatric HIV ResearchStatus, priorities and
ethical considerations

• Dr Nigel Rollins
• Child and Adolescent Health and Development,
• World Health Organization, Geneva

2
Acknowledgements

• Siobhan Crowley, Department of HIV
• Ying Lo Ru, Department of HIV
• Alasdair Reid, UNAIDS

3
2007 global HIV and AIDS estimates Children (lt15
years)

• Children living with HIV 2.0 million 1.9 2.3
  million
• New HIV infections in 2007 370 000 330 000 410
  000
• Deaths due to AIDS in 2007 270 000 250 000 290
  000

4
Progress has been made in treating children
Estimated need as of 2006

• More children are receiving ART
• Increased from 75,000 in 2005 to almost 200,000
  in 2007
• 19 of 20 countries with highest PMTCT burden are
  in sub-Saharan Africa

Great variance within countries
5
ART outcomes - good news across the globe

• National programmes reporting good outcomes
• 1 year survival estimated as 93-95
• 2 year survival 91

6
1 ADULT FDC AM PM
Revised simplified dosing
1 ADULT FDC AM 0.5 PM
0.5 ADULT FDC AM PM
2 BABY FDC AM PM
2 BABY FDC AM 1 PM
Same dosing irrespective of FDC, or same dosing
for all three single ARV agents
1 BABY FDC AM 1 PM
Most dose adjustments done in 1st year
Adapted from T. NUNN
7
Children everywhere are Starting Treatment Late
Baseline Median Age Baseline Median CD4
Janssens/Cambodia 2007 N212 6.0 yrs 6
George/Haiti 2007 N100 6.3 yrs 12
Wamawala/Kenya 2007 N67 4.4 yrs 6
Reddi/S Africa 2007 N151 5.7 yrs 8
Puthanakit/Thailand 2007 N107 7.7 yrs 5
Kamya/Uganda 2007 N250 9.2 yrs 8.6
Rouet/Cote dIvoire 2006 N78 6.5 yr 8
Meta-analysis 1,195 children from 8 African
clinical trials 53 gt5 years of age, 70 severe
immune deficiency, 12 aged lt 12 months
(KIDS-ART-LINC) Arrive 2008
8
Starting late increases mortality
Months from ART start Probability of Death After Starting ART Probability of Death After Starting ART
Immune Deficient at Start ART Not Immune Deficient at Start ART
6 months 7.8 1.8
12 months 8.2 2.2
Arrive E et al. 14th CROI, Los Angeles, CA, 2007
Abs. 727

• 73 median age gt 5 years of age, gt 50 start with
  severe immune deficiency, most deaths within 6
  months of starting ART
• Risk factors for death
• low CD4
• lt 18 months age
• WHO stage 3/4
• viral load greater than 60 log
• severe malnutrition

Sutcliffe et al. Lancet Infect Dis 20088 47789
9
Research priorities

• Early identification of infected children
• Diagnostic / screening algorithms e.g. in IMCI
• HIV testing algorithms
• Universal screening at immunisation clinics
• Monitoring of disease progression / ART response
  in settings with minimal / intermittent lab
  support
• Target weight gain
• Clinic-based technology
• Feasibility of nurse-led ART initiation /
  management
• Type and methods of support

10
Tuberculosis

• 1/3 of the worlds population is infected with TB
• Only 5-10 actually develop TB disease during
  their lifetime
• Risk of progression highest in young children and
  soon after infection
• Increased risk with HIV, malnutrition,
  immunocompromise
• One fifth of all TB cases occur in children and
  young people
• Approximately 11 of all TB cases occur in
  children lt15

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TB/HIV

• Children living with HIV are up to 20 times more
  likely to develop TB than HIV negative children
• Increased risk of exposure
• Increased risk of progression from infection to
  disease
• TB is commonest cause of illness death in
  people living with HIV in Africa
• Data on the situation in children are scant
• The burden of HIV in confirmed and clinical
  cases of TB in children ranges from 11-70
• Main challenge is making a definitive diagnosis
  of TB in children

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Research priorities

• Acute need for more research on TB in children,
  esp those living with HIV
• True burden of disease
• Better diagnostics that dont rely on sputum
• Clarity on optimal regimens for treatment of TB
  and MDR TB in combination with ARVs
• TB vaccine
• safety of BCG in children on ARVs
• New more effective TB vaccine

13
Preventing HIV infection in infants and children
Total 370 000 (330 000 410 000)
14
Pregnant women with HIV who received ARV drugs
to reduce mother-to-child transmission increased
- 49 still received only single dose nevirapine
Distribution of ARV regimens, 2007
Percentage of pregnant women with HIV receiving
ARVs for PMTCT in low- and middle-income
countries, 2004-2007
Towards Universal Access Scaling up priority
HIV/AIDS interventions in the health sector.
WHO/UNAIDS/UNICEF, June 2008
15
Provider-initiated HIV testing and counselling
increases access for PMTCT
Percentage of pregnant women receiving an HIV
test by region, 2004-2007 (low- and middle-income
countries)
Towards Universal Access Scaling up priority
HIV/AIDS interventions in the health sector.
WHO/UNAIDS/UNICEF, June 2008
16
Preventing HIV infection in infants and children

• Primary prevention of HIV
• Prevention of unwanted pregnancies
• Prevention of transmission from HIV-infected
  women to their infants
• Appropriate treatment, care and support

Source Strategic approaches to the prevention of
HIV infection in infants. WHO 2002.
17
Recommended first-line ART regimens for eligible
pregnant women
Mother
Antepartum AZT 3TC NVP twice daily
Intrapartum AZT 3TC NVP twice daily
Postpartum AZT 3TC NVP twice daily
Infant AZT x 7 days
If the mother receives lt 4 wks of ART during
pregnancy, give 4 wks of infant AZT
Source Antiretroviral drugs for treating
pregnant women and preventing HIV infection in
infants. WHO 2006
18
Recommended ARV-prophylaxis for pregnant women
not eligible for ART
Mother
Antepartum AZT
Intrapartum Sd-NVP AZT/3TC
Postpartum AZT/3TC for 7 days
Infant Sd-NVP AZT for 7 days
If the mother receives lt 4 wks of ART during
pregnancy, give 4 wks of infant AZT
Source Antiretroviral drugs for treating
pregnant women and preventing HIV infection in
infants. WHO 2006
19
Initiating ART is based on clinical and/or
immunological assessment - only 12 of pregnant
women were assessed for ART
Recommendations for initiating antiretroviral treatment in pregnant women based on clinic stage and availability of immunological markers1 Recommendations for initiating antiretroviral treatment in pregnant women based on clinic stage and availability of immunological markers1 Recommendations for initiating antiretroviral treatment in pregnant women based on clinic stage and availability of immunological markers1
WHO Clinical Staging CD4 testing not available CD4 testing available
1 Do not treat Treat if CD4 cell count lt 200/mm3
2 Do not treat Treat if CD4 cell count lt 200/mm3
3 Treat Treat if CD4 cell count lt 350/mm3
4 Treat Treat irrespective of CD4 cell count
1 Women have lower CD4 cell counts during
pregnancy compared to postpartum, partly due to
pregnancy-related haemodilution. The impact of
this on using CD4 350 threshold in pregnant women
is not known.
Source Antiretroviral drugs for treating
pregnant women and preventing HIV infection in
infants. WHO 2006 Towards Universal Access
Scaling up priority HIV/AIDS interventions in the
health sector. WHO/UNAIDS/UNICEF, 2008
20
HIV and infant feeding technical
consultationGeneva, October 25-27,
2006CONSENSUS STATEMENT

• The most appropriate infant feeding option for an
  HIV-infected mother should continue to depend on
  her individual circumstances 
• Exclusive breastfeeding is recommended for
  HIV-infected women for the first 6 months of life
  unless replacement feeding is acceptable,
  feasible, affordable, sustainable and safe
  (AFASS) for them and their infants before that
  time. 
• When replacement feeding is acceptable, feasible,
  affordable, sustainable and safe, avoidance of
  all breastfeeding by HIV-infected women is
  recommended.

21
Maternal ARV prophylaxis studies antepartum and
postpartum (Triple ARVs/ART) Between age 4-6
weeks and 6-7 months HIV transmission rates
4 observational studies showed reduced HIV
breastfeeding transmission rates
TR at 6 months
6 mos EBF
6 mos EBF
6 mos EBF
6 mos EBF
Courtesy Lynne Mofenson
22
Two randomized controlled infant ARV prophylaxis
studies Negative at birth and 6 mos (SWEN) and 9
mos. (PEPI) HIV TR
RR 0.80, p0.16
AHR 0.56, plt0.001
6 wks NVP
Control sd NVP AZT x 7
Control sd NVP
14 wks NVP
Swen Study Team, Lancet 2008 372300-13,
Kumwenda NI et al NEJM 200810.1056,
23
Research priorities

• Maternal triple ARV regimens for prophylaxis
• Impact of stopping triple ARVs on women's health
• Optimal regimens differentiated by maternal CD4
• Safety for the mother and the infant
• Transmitted HIV drug resistance to the infant
• Optimum duration of ARV prophylaxis (?until EBF
  discontinued or lifelong)
• Feasibility and cost

24
Research priorities

• Extended infant ARV prophylaxis
• Optimal duration and safety of prolonged
  nevirapine, or other ARVs e.g. 3TC,
  administration to HIV negative infants
• Resistance and impact on prophylaxis and future
  treatment options in infants who become infected
  despite prophylaxis
• Feasibility under what circumstances would
  infant prophylaxis be preferred to maternal
  prophylaxis
• Infant feeding
• Under what circumstances to recommend a woman to
  stop breastfeeding at about 6 months?
• Can an infant be adequately fed from 6-12 months
  without any milk and still achieve normal growth
  and development?

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PMTCT

• As a term it has
• Constrained our understanding of what is needed
• Focussed the outcome of value to be what happens
  to the child
• Partitioned service delivery
• Greater understanding of the relationship between
  treatment and prevention
• Requires a different way of thinking, and
  organisation of services
• To achieve HIV-free survival of the child, it is
  essential to protect maternal health and survival
• Integrated Care of Women and Children in the
  context of HIV

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Integration
ANC PMTCT and family planning
PMTCT and A/N services
PMTCT and Prevention services
Integrated mother and child health cards
ANC PMTCT and postnatal services
PMTCT and ART services
6 characters in search of an author. Luigi
Pirandello. 1921
27
How can effective interventions be scaled up to
reduce infections to children and protect women?
28
From proof of principle to implementation

• Cannot simply extrapolate practices implemented
  at one pilot site (even 2-3 sites) and expect the
  same outcomes
• Promotion of exclusive breastfeeding

29
Implementation Research How do we get
transmission below 5 at scale?
30
Why do academics and funders not, more commonly,
engage these questions?

• Implementation research not seen as a serious
  science
• Requires a different way of looking at problems -
  unfamiliar territory
• Out there not in here
• Not in control (of the system)
• Needs to work with non-researchers and DoH
• multidisciplinary team
• Different skills and perspectives

31
Other ethical challenges in paediatric HIV
research

• How to balance the childs interests (survival)
  vs. the mothers interests (confidentiality)?
• Developing models of care that might place child
  at risk because of dependency e.g. hospital or
  home for MDR / XDR TB Rx.
• How to assess understanding in the assent
  process?
• If effective vaccines are identified, how can
  these be given to infants or children in order to
  prevent infections in adolescence?
• How to respect the sexual and reproductive rights
  of HIV-infected adolescents in order to achieve
  risk-reduction interventions for other?

32
Other ethical challenges in paediatric HIV
research

• What responsibility do research centres have to
  help local services improve their quality of care
  vs. setting up parallel structures?
• Is it reasonable to research models of care that
  cannot be scaled-up to address the greater need?