1. Future ART options for HIV-infected children exposed to maternal HAART Lee Kleynhans Experts Roundtable 23-24 June 2008

2. Overview Current WHO recommendations Problems Solutions

3. Current WHO guidelines Report of WHO technical working group 10-11 April 2008 PopulationUp to 12 months 1-4 years≥ 5 years Start ARTNVP exposed: PI- regimen Not NVP exposed: NVP- regimen NVP/EFV + 2NRTI Strength of recommendati on ConditionalStrong 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

4. 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 meta- analysis 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)

5. Effectiveness of NVP-Based HAART in Infected Children With and Without SD NVP Exposure Barlow-Mosha L et al. 15 th CROI, Boston, MA 2008 Abs 583 Data from 92 Ugandan children (median age 1.7 years) Median Values Baseline 12 weeks 24 weeks 36 weeks48 weeks CD4% trends NVP unexposed (N=48) 8.5%14.4%17.5%19.0%22.5% NVP exposed (N=44) 14.0%23.5%27.5%39.5%33.0% HIV RNA trends NVP unexposed (N=48) 239,027ND ND 80% <400 NVP exposed (N=44) 650,568ND ND 76% <400 ND = non-detectable <400 copies/mL

6. 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

7. 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

8. Antiretroviral Drug Penetration into Breast Milk and Infant Plasma: BAN Study Corbett A et al. 15 th 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.

9. KIBS Maternal HAART Prophylaxis study Zeh C et al. 15 th 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

10. KIBS Maternal HAART Prophylaxis study Zeh C et al. 15 th 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

11. 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

12. 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

13. Resistance testing prohibitively expensive therefore not possible in low income settings Many countries still using NVP as 1 st line due to cost compared with kaletra® 3TC excellent drug…cheap and minimal side effects

14. Solutions EARLY INFANT TESTING At 6 week EPI visit, results at week 10 EARLY INFANT DIAGNOSIS EARLY INFANT TREATMENT

15. 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 1 st 24 weeks not for maternal health)