Critical issues in Children infected with HIV

T. Puthanakit

Chulalongkorn University,Bangkok, Thailand

Outline

• 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 CareProgrammatic 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

GROUP2010 RECOMMENDATIONS

<1 YEARS Treat ALLStrong recommendation, moderate-quality evidence

1-2 YEARS Treat ALLConditional recommendation, very-low-quality evidence

2-5 YEARS Initiate ART with CD4 count ≤750 cells/mm3 or <25%, irrespective of WHO clinical stage

≥5 YEARS Initiate ART with CD4 count ≤350 cells/mm3 (As in adults), irrespective of WHO clinical stageANDWHO clinical stage 3 or 4

AGE GROUP

2013 RECOMMENDATIONS

< 1 YEAR Treat ALLStrong recommendation, moderate-quality evidence

1-5 YEARS Treat ALLConditional recommendation, very-low-quality evidencePriority: children < 2 years or WHO stage 3-4 or CD4 count ≤ 750 cells/mm3 or < 25%

≥5 YEARS CD4 ≤ 500 cells/mm3 Conditional recommendation, very-low-quality evidenceCD4 ≤350 cells/mm³ as a priority (As in Adults)Strong recommendation, moderate-quality 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.

What’s the evidence?

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 family-based 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 Prior exposure to PMTCT ARV’s

2010 recommendations

2013 recommendations

<12 months Exposed LPV/r + 2 NRTIs LPV/r plus 2 NRTIs

If LPV/r not available, NVP-based

PlusNRTI backbone:

• AZT or ABC + 3TC• (d4T+3TC*)

Not Exposed

NVP + 2 NRTIs• AZT + 3TC• ABC + 3TC• d4T + 3TC

Exposure unknown

12 to <36 months

Regardless of exposure

• 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 paedsAchan 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 1Palumbo 2010

6 to 36 months of age who exposed to single dose NVP ( N=164) AZT + 3TC +NVP versus AZT+3TC+ LPV/rAt week 24, VL > 400 copies/ml or death or discontinue: 39.6% vs 21.7%

P1060 COHORT 2Violari 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• 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 co-treatment (Arrow trial 2013)

Age group 2010 recommendations

Age group 2013 recommendations

3-19 years

NVP or EFV

plus

2 NRTIs in preferential order:

AZT + 3TCABC + 3TCd4T + 3TC

TDF + FTC + EFV to be used as preferred regimen if HIV/HBV coinfection and >12 years and > 35 Kg

3-10 years

(Including > 10 yrs who weighing <35kg)

NNRTI EFV is preferredNVP as alternative

2NRTIs In preferential order:ABC + 3TC AZT or TDF + 3TC or FTC

10-19 years

(weighing ≥35 kg)(align with adults)

NNRTI EFV is preferredNVP as alternative

2NRTIs In preferential order:TDF + FTC or 3TCABC + 3TCAZT + 3TC

What to start in > 3 years

What to start in > 3 yearso Opportunity for harmonization with adults – improve

children’s access to ARTo 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 Considerationso Experience with TDF in children is limited and long term impact is unknowno Feasibility highly dependent on the toxicity monitoring

requiredo TDF-containing FDCs needs to be made available

o To provide an early and more accurate indication of treatment failure, reducing the accumulation of HIVDR mutations and improving clinical outcomes.

o Can also help to discriminate between treatment failure and non-adherence

o Can serve as a proxy for the risk of transmission at the population level

o Harmonized monitoring approaches between adults and children

o Lack of viral load or CD4 capacity should not prevent starting ART

o If VL availability limited, phase in use of targeted approach (or CD4 / clinical monitoring)

Targeted viral load monitoring (suspected clinical or

immunological failure)

Routine viral load monitoring (early detection of virological failure)

Switch to second-line therapy

Maintain first-line therapy

Viral load ≤1000 copies/ml

Viral load >1000 copies/ml

Repeat viral load testing after 3–6 months

Evaluate for adherence concerns

Viral load >1000copies/ml

Test viral load

Rationale: Viral load Monitoring

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 + 3TCAZT or d4T + 3TC (or FTC) TDF + FTC or ABC + 3TC (Strong recommendation, low-quality evidence)