Transcript Future ART options for HIV-infected children exposed to

Future ART options for HIV-infected
children exposed to maternal HAART
Lee Kleynhans
Experts Roundtable
23-24 June 2008
Overview
• Current WHO recommendations
• Problems
• Solutions
Current WHO guidelines
Report of WHO technical working group 10-11 April 2008
Population
Up to 12
months
Up to 12
months
1-4 years
≥ 5 years
Start ART
NVP
exposed:
PI- regimen
Not NVP
exposed:
NVPregimen
NVP/EFV +
2NRTI
NVP/EFV +
2NRTI
Strong
Strong
Strong
Strength of
Conditional
recommendati
on
All children diagnosed HIV-infected, <12 months to be started on
HAART, regardless of WHO or immunological staging
Based on CHER data from Violari et al showing 75% reduction in
mortality when treatment started early
Arrivé et al, Int Journ Epid 2007 Oct 36(5):1009-21
Prevalence of resistance to nevirapine in mothers and children after
single-dose exposure to prevent vertical transmission of HIV 1: A metaanalysis
• NVP resistance detected after single dose
NVP for PMTCT
– 35.7% resistance in women
– Over half of infants 52.6% (studies range between
40-90% babies)
• In adults started on NVP-based regimen
after 12 months 70% HIV RNA suppression
(Weidle P et al CROI 2008)
Effectiveness of NVP-Based HAART in Infected Children With and Without
SD NVP Exposure
Barlow-Mosha L et al. 15th CROI, Boston, MA 2008 Abs 583
Data from 92 Ugandan
children (median age
1.7 years)
Median Values
24
weeks
36 weeks
Baseline
12
weeks
48
weeks
8.5%
14.4%
17.5%
19.0%
22.5%
14.0%
23.5%
27.5%
39.5%
33.0%
CD4% trends
NVP unexposed (N=48)
NVP exposed (N=44)
HIV RNA trends
NVP unexposed (N=48)
239,027
ND
ND
ND
ND 80% <400
NVP exposed (N=44)
650,568
ND
ND
ND
ND 76% <400
ND = non-detectable <400 copies/mL
• But no study results yet on a head to head
comparison between NVP-based and OI-based
regimens in infants in low-income settings.
• Awaiting data from NEVEREST study- Coronation
Hospital South Africa
• PACTG 1060 underway
Zidovudine with Nevirapine for PMTCT reduces
Nevirapine resistance in mothers from the Western
Cape, South Africa GU Van Zyl et al; Journal of
medical Virology 80:942-946
• Recently reported from Western Cape
• 17.1 % NNRTI resistance if dual therapy
given as PMTCT
• Reduction compared to single dose NvP
• Confirmed by Arrivé et al
• Reduced to 4% (mother) and 16% (infant)
respectively
Antiretroviral Drug Penetration into
Breast Milk and Infant Plasma: BAN Study
Corbett A et al. 15th CROI Boston, MA, 2008 Abs 648
• While 3TC concentrations in breast milk was 2.6-fold
higher than maternal plasma, infant plasma exposure
was relatively low (1% of breast milk).
• NVP concentrations in breast milk were 70% of
maternal plasma, with infant exposure 20% of breast
milk.
• NFV concentration in breast milk is very low, 8%, with
no drug found in the infant.
• Conclusion: Risk for toxicity in the infant appears low
but low drug levels in infant from drug passage from
breast milk for NVP (possibly 3TC) may suggest risk
of resistance if infant becomes infected.
KIBS Maternal HAART Prophylaxis study
Zeh C et al. 15th CROI, Boston, MA, 2008 Abs 84LB
• Women receiving lamivudine, zidovudine and
either nevirapine or nelfinavir
• 5.8% transmission rate
• Genotypic resistance in infants:
• 43% of women taking NVP
• 100% of women taking nelfinavir
• No PI resistance but 100% NRTI resistance in
nelfinavir group and 100% NNRTI resistance
in NVP group
KIBS Maternal HAART Prophylaxis study
Zeh C et al. 15th CROI, Boston, MA, 2008 Abs 84LB
• Resistance mutations included:
– NRTI: M184V in 13, K65R in 4, D67N in 2 and T215Y
in 2
– NNRTI: Y181C in 3, K103N in 2, G190A in 2, K101E
in 1
• Among NVP-exposed infants:
– 4/6 had NRTI and 6/6 NNRTI resistance
• Among NFV-exposed infants:
– 10/10 had NRTI and 0/10 had PI resistance
Cont….
• Cumulative risk of resistance…not detected
initially
• Emerged week 14-24
• Most of resistance risk during breastfeeding
• 69% babies tested PCR + by 6 weeks
• Unknown maternal VL
Potential problems in infant
• High viral load if HIV-infected in face of low drug
levels
• 3TC and NVP have highest plasma levels
• These are the drugs with low genetic barrier for
resistance
• Atripla: FTC presumably similar to 3TC but no data.
• No data found on EFV levels in infants
• Resistance testing prohibitively expensive
therefore not possible in low income settings
• Many countries still using NVP as 1st line due to
cost compared with kaletra®
• 3TC excellent drug…cheap and minimal side
effects
Solutions
• EARLY INFANT TESTING
• At 6 week EPI visit, results at week
10
• EARLY INFANT DIAGNOSIS
• EARLY INFANT TREATMENT
Solutions
• Use WHO treatment guidelines BUT need to
be aware of possible resistance and
virological failure
• ? Motivate for at least 1 viral load within 6
months to assess HIV RNA supression as
may miss failure if only using clinical and
immunological criteria-> Risk TAMs and other
NRTI resistance mutations and decrease
future options
• Stop interventional HAART as soon as child
diagnosed HIV-infected (given for 1st 24
weeks not for maternal health)