Transcript Conditional recommendation, very-low-quality evidence

Critical issues in
Children infected
with HIV
T.Puthanakit
Chulalongkorn University,
Bangkok, Thailand
Outline
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Key issues in 2013 guidelines
When to start ART
What to start as a first-line ART regimen
Treatment monitoring
Second-line ART regimen
Key issues for Treatment and Care
Programmatic Challenges
– EID coverage remains poor
– ART coverage only 34% (in 22 priority countries)
– Limited availability of pediatric formulations and
difficulties in harmonizing regimens with adults
– Poor retention of children on ART and in care
Technical Challenges
– Provide the most effective regimen to deal with high VL
and rapid disease progression
– Optimization of ART treatment sequencing
When to start ART
AGE
GROUP
2010 RECOMMENDATIONS
AGE
GROUP
2013 RECOMMENDATIONS
<1 YEARS
Treat ALL
Strong recommendation,
moderate-quality evidence
< 1 YEAR
Treat ALL
Strong recommendation, moderate-quality
evidence
1-2 YEARS
Treat ALL
Conditional recommendation,
very-low-quality evidence
1-5 YEARS
2-5 YEARS
Initiate ART with CD4 count ≤750
cells/mm3 or <25%, irrespective
of WHO clinical stage
Treat ALL
Conditional recommendation, very-lowquality evidence
Priority: children < 2 years or WHO stage 3-4
or CD4 count ≤ 750 cells/mm3 or < 25%
≥5 YEARS
Initiate ART with CD4 count ≤350 ≥5 YEARS
cells/mm3 (As in adults),
irrespective of WHO clinical stage
AND
WHO clinical stage 3 or 4
CD4 ≤ 500 cells/mm3
Conditional recommendation, very-lowquality evidence
CD4 ≤350 cells/mm³ as a priority (As in
Adults)
Strong recommendation, moderate-quality
evidence
What’s the evidence?
• CHER trial (young infant)
Early ART reduces mortality and HIV progression by 75%
• PREDICT trial (1-12 years)
AIDS-free survival did not differ between deferred and
early treatment group (median age 6.4 years).
• IeDea SA: (2-5 years)
Modelling of observational data showed no difference
in mortality between early and starting ART based on
current CD4 threshold. However, 75% of children with
CD4 > 25% (or 750 cells/mm3) become eligible by 3 years
from enrolment.
1 Violari A. NEJM 2008;359:2233-44.
2 Puthanakit T. Lancet Infect Dis 2012:933-941.
3 Schomaker M. IeDEA Southern Africa Collaboration 2012
Death 4% vs 16%
AIDS 6.3 % vs 25.6%
Move towards early ART
• Suggestions that Early ART:
– Improve immunological response
– Reduce barrier to ART initiation
– Improve retention in care
• Settings where access to immunological testing is limited, the
burden of paediatric HIV disease is high and paediatric ART
coverage still low are the most likely to benefit
• PLWA, caretakers and health care providers of HIV-infected
children think that earlier initiation is preferable to facilitate familybased care, prevent loss to follow up and improve adherence.
• Expanding ART to all children < 5 years will likely represent a small
increased burden on current systems
What ART to start: age < 3 years
Age group
<12 months
Prior exposure to
PMTCT ARV’s
Exposed
2010
recommendations
LPV/r + 2 NRTIs
Not Exposed
Exposure unknown
12 to <36
months
Regardless of exposure
NVP + 2 NRTIs
• AZT + 3TC
• ABC + 3TC
• d4T + 3TC
2013
recommendations
LPV/r plus 2 NRTIs
If LPV/r not available,
NVP-based
Plus
NRTI backbone:
• AZT or ABC + 3TC
• (d4T+3TC*)
• When HIV RNA monitoring is available, consider to substitute LPV/r with
NNRTI after virological suppression is sustained (conditional, low quality)
What to ART start: age < 3 years
• P1060 trial demonstrated that LPV/r is superior to NVP irrespective
of NNRTI exposure (Palumbo 2010, Violari 2012)
• Emerging evidence of high prevalence of NNRTI resistance
irrespective of PMTCT exposure history (Kuhn et al. CROI 2013, Apollo et al. IAS
2013)
• Low failure rate and good resistance profile at treatment failure
with limited selection of resistance to NRTIs (Violari et al. Glasgow 2012)
• Reduction of malaria incidence by 41% (Achan et al 2012)
LPV/r vs NVP: Virological failure or death
PROMOTE paeds
Achan 2012
3 mo- 6 year old children (median age 3.1 years, N= 185)
NNRTI-based versus PI-based ART and followed for 6 months to 2 years.
P1060 COHORT 1
Palumbo 2010
6 to 36 months of age who exposed to single dose NVP ( N=164)
AZT + 3TC +NVP versus AZT+3TC+ LPV/r
At week 24, VL > 400 copies/ml or death or discontinue: 39.6% vs 21.7%
P1060 COHORT 2
Violari 2012
2-36 months old children who never exposed to single-dose NVP (N=288)
NVP-based versus LPV/r-based ART.
At week 24, VL > 400 copies/ml or death rate: 41.5% vs 19.4%
Achan J. N Engl J Med 2012;367:2110-8; Palumbo P. N Eng J Med 2010; 363:1510-20;
Violari A. N Engl J Med 012;366:2380-9.
Challenges of using LPV/r
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Cold chain requirements
Low adherence due to poor palatability
Lack of FDC available
Lack of second line options in RLS
Interaction with TB drugs
• Sprinkles soon available and “4in1”FDC are under development
• Simplification by switching to NVP once virological suppression is
achieved is safe in children without baseline resistance to NNRTI
(Coovadia et al 2010)
• 3NRTI regimen to be considered as an option for the duration of TB cotreatment (Arrow trial 2013)
What to start in > 3 years
Age group
2010
Age group
recommendations
3-10 years
2013
recommendations
NNRTI
NVP or EFV
plus
3-19 years
2 NRTIs
in preferential order:
AZT + 3TC
ABC + 3TC
d4T + 3TC
TDF + FTC + EFV to be
used as preferred
regimen if HIV/HBV
coinfection and >12
years and > 35 Kg
(Including > 10 yrs
who weighing <35kg) 2NRTIs
EFV is preferred
NVP as alternative
In preferential order:
ABC + 3TC
AZT or TDF + 3TC or FTC
10-19 years
(weighing ≥35 kg)
(align with adults)
NNRTI
EFV is preferred
NVP as alternative
2NRTIs
In preferential order:
TDF + FTC or 3TC
ABC + 3TC
AZT + 3TC
What to start in > 3 years
o Opportunity for harmonization with adults – improve
children’s access to ART
o Convenience of once daily regimens and FDC where
available (EFV preferred)
o Better sequencing of therapy: non-thymidine analogues
(ABC and TDF) as 1st line followed by AZT as 2nd line.
Implementation Considerations
o Experience with TDF in children is limited and long
term impact is unknown
o Feasibility highly dependent on the toxicity monitoring
required
o TDF-containing FDCs needs to be made available
Rationale: Viral load Monitoring
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Targeted viral load monitoring
(suspected clinical or
immunological failure)
To provide an early and more accurate indication of
treatment failure, reducing the accumulation of
HIVDR mutations and improving clinical outcomes.
Can also help to discriminate between treatment
failure and non-adherence
Can serve as a proxy for the risk of transmission at
the population level
Harmonized monitoring approaches between
adults and children
Lack of viral load or CD4 capacity should
not prevent starting ART
If VL availability limited, phase in use of
targeted approach (or CD4 / clinical
monitoring)
Routine viral load monitoring
(early detection of
virological failure)
Test viral load
Viral load >1000
copies/ml
Evaluate for adherence
concerns
Repeat viral load testing
after 3–6 months
Viral load ≤1000
copies/ml
Viral load >1000
copies/ml
Maintain first-line
therapy
Switch to second-line
therapy
Second line ART
 Failure of a first-line NNRTI-based regimen
a boosted PI plus two NRTIs (LPV/r is the preferred boosted PI)
(Strong recommendation, moderate-quality evidence)
 Failure of a first-line LPV/r-based regimen in children < 3 years old
Remain on the same regimen plus improve adherence
(Conditional recommendation, very-low-quality evidence)
 Failure of a first-line LPV/r-based regimen in children > 3 years
NNRTI plus two NRTIs; EFV is the preferred NNRTI
(Conditional recommendation, low-quality evidence)
 NRTIs backbone substitution after treatment failure
ABC or TDF + 3TC (or FTC)
AZT + 3TC
AZT or d4T + 3TC (or FTC)
TDF + FTC or ABC + 3TC
(Strong recommendation, low-quality evidence)
MCH Guideline Development Group
Co-chairs: Elaine Abrams (International Center for AIDS Care and Treatment Programs (ICAP), Columbia
University, USA) and Denis Tindyebwa (African Network for the Care of Children Affected by AIDS, Uganda).
Members: Joerg Meerpohl (German Cochrane Centre, University Medical Center, Freiburg, Germany). Renaud
Becquet (Internationale Institut de Santé Publique d’Epidémiologie et de Développement, Université Bordeaux
Segalen, France), Deborah Birx (United States Centers for Disease Control and Prevention, USA), Benjamin Chi
(Centre for Infectious Disease Research in Zambia, Zambia), Mark Cotton (Stellenbosch University, South Africa),
Nonhlanhla Dlamini (National Department of Health, South Africa), René Ekpini (United Nations Children’s Fund,
New York), Carlo Giaquinto (Paedatric Infectious Disease Unit and Clinical Trials Unit of Azienda Ospedaliera di
Padua, Italy), Diana Gibb (Medical Research Council Clinical Trials Unit, United Kingdom), Sabrina Bakeera-Kitaka
(Makerere University and Mulago National Referral Hospital, Uganda), Louise Kuhn (Columbia University, USA),
Evgenia Maron (Charitable Women’s Foundation Astra, Russian Federation), Babalwa Mbono (mothers2mothers,
South Africa), James McIntyre (University of Cape Town, South Africa), Lynne Mofenson (National Institutes of
Health, USA), Angela Mushavi (Ministry of Health and Child Welfare, Zimbabwe), Ryan Phelps (United States
Agency for International Development, USA), Jorge Pinto (Federal University of Minas Gerais, Brazil), Andrew
Prendergast (Queen Mary University of London, United Kingdom), Thanyawee Puthanakit (Chulalongkorn
University, Thailand), Atiene Sagay (Unversity of Jos, Nigeria), Roger Shapiro (Harvard School of Public Health,
USA), George Siberry (National Institutes of Health, USA), Landry Tsague (United Nations Children’s Fund,
Zambia), Thorkild Tylleskar (University of Bergen, Norway), Paula Vaz (Fundação Ariel Glaser contra o SIDA
Pediátrico, Mozambique), Evgeny Voronin (Russian AIDS Pediatric Center, Russian Federation) and Linhong Wang
(Chinese Center for Disease Control and Prevention, China).
WHO Facilitators : Nathan Shaffer and Lulu Muhe
WHO consultants: Martina Penazzato, Shaffiq Essaje, April Baller