Paediatric HIV Drug Resistance 26th-International-Workshop-on-HIV-Drug-Resistance-programme- 20171031[2].tiff Mo Archary King Edward VIII Hospital / UKZN Paediatric Infectious Diseases Unit
Overview State of Pediatric HIV Epidemic Pre-treatment HIV Drug resistance (HIVDR) Drivers of Paediatric HIVDR Acquired HIVDR First-line treatment responses First-line treatment HIVDR Second-line treatment HIVDR
Global PaediatricEpidemic Vast majority of HIVinfected children reside in the African region. Majority of children on cart reside in the African region
Rapid expansion of global access to Antiretroviral treatment including children/adolescents. Estimated 21.7 million people receiving ART globally, however only 50% of children access ART globally UNAIDS Estimate, 21 countries, 2015
Global PaediatricEpidemic -Successes 700,000 600,000 Number of new HIV infections among children in low- and middle-income countries, 2001 2012 and 2015 target New HIV infections 500,000 400,000 300,000 200,000 100,000-52% 2001 2012-35% 2009 2012 0 2001 2009 2012 2015 40,000-90% UNAIDS report on the global AIDS epidemic 2013. Available at: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/unaids_global_report_2013_en.pdf
Projected impact on new child HIV infections by programmes to prevent mother-to-child transmission, 21 Global Plan priority countries in sub-saharan Africa, 2009 2015 New HIV infections 350,000 300,000 250,000 200,000 150,000 100,000 50,000 0 2012 coverage maintained ARV coverage scaled up to 90% Eliminate unmet need for family planning Reduce incidence by 50% Target 2009 2012 2015 UNAIDS 2015: 150 000 (110 000-190 000) UNAIDS report on the global AIDS epidemic 2013. Available at: http://www.unaids.org/en/media/unaids/contentassets/documents/epidemiology/2013/gr2013/unaids_global_report_2013_en.pdf
Some countries are doing better than others
What is EMTCT
Is this goal achievable? 2015 2016 2018 8 countries have attained the criteria
How far away in SA from achieving EMTCT
How is this relevant to a resistance talk?
Pre-treatment Resistance in children 30.8% had drug associated mutation T74S, L10V, T69N, E138G 6.8% - clinically relevant drug associated mutations Drug Resistance and Coreceptor Usage in HIV Type 1 Subtype C-Infected Children Initiating or Failing Highly Active Antiretroviral Therapy in South Africa Taryn N. Green et al AIDS RESEARCH AND HUMAN RETROVIRUSES Volume 28, Number 4, 2012 2008
Pre-treatment Resistance in children Jordan MR. HIV Drug resistance in African Infants and Young children newly diagnosed with HIV: A multi-country analysis; CID, 2017:65
What has changed? Few mothers on cart (short course single or dual maternal ART PMTCT regimen Infant prophylaxis single dose NVP at birth with erratic implementation Majority of mothers on cart either pre-conception or during delivery. Many mothers have had prior exposure to ART for PMTCT single or multiple ART regimens Infant prophylaxis given either NVP or NVP/AZT 2008 2018
National PaediatricPre-treatment surveillance HIV Drug Resistance report 2017. Geneva: WHO;2017 South African survey: Prevalence of HIVDR = 63.7% (95% CI 59-68.4%) NNRTI resistance = 62.7% (95% CI 58-67.4%) NRTI resistance = 13.9% (95% CI 10.5 17.3%)
Drivers of PaediatricPre-treatment resistance Frequency of adults with unsuppressed HIV VL (U=U) HIVDR in adults of child-bearing potential Infant prophylaxis regimens Implications for NNRTI Firstline Regimen in children
Post ART initiation -Early Cohort from Malawi: Virological failure occurred in 66% of children by 12 months HIV DR was detected in 44% - all had NNRTI mutations/ 12% NNRTI and NRTI mutations 41% - had a GSS <3 to their current first line regimen High level resistance to NVP (26%) High Failure rates on first line NNRTI regimens Huibers MHW, 2018; Journal of Antimicrobial Chemotherapy
Post ART initiation -Late Cohort from Benin, West Africa Median age 10 yrs (IQR 6-13)/ duration on therapy 5 years (IQR 3-7) Regimens: 76% NNRTI based regimen / 24% PI based regimen Resistance: 71% (NRTI mutation), 84% (NNRTI mutation), 65% (dual-class resistance) 4% PI resistance 25% had undetectable ARV concentrations Drivers of Acquired HIVDR Fofana, 2018; Journal of Antimicrobial Chemotherapy
Drivers of Acquired PaediatricHIVDR Interrupted drug supply Drug-drug interactions Failure to change dose with increasing weight Inadequate drug dosing Suboptimal Formulations Characteristics of an Ideal Paediatric Formulation Palatable Infrequent dosing Ease of administration (dispersible table) Fixed dose combination Limited side-effects Limited drug-drug interactions
Acquired HIV Drug Resistance Surveillance HIV Drug Resistance report 2017. Geneva: WHO;2017
Acquired HIVDR Protease Inhibitors Cohort from Western Cape, South Africa Median age 8.8 yrs (IQR 5.5-11)/ duration on therapy 6.9 years (IQR 5-9.9) Regimens: Failing a PI based regimen Resistance Outcomes at 2 years: 96.7% had a KIV VL < 400c/mL Nuttal J, 2018;SAMJ, 2018
Acquired HIVDR Protease Inhibitors Cohort from Western Cape, South Africa Median age 8.8 yrs (IQR 5.5-11)/ duration on therapy 6.9 years (IQR 5-9.9) Regimens: Failing a PI based regimen Resistance 3 rd line regimens following PI failure is associated with good outcomes Outcomes at 2 years: 96.7% had a HIV VL < 400c/mL Nuttal J, 2018;SAMJ, 2018
Conclusions The goal of the Paediatric ART program is the elimination of vertical transmission. These efforts maybe jeopardized by poor suppression rates and HIVDR in adults. Limited value of a NNRTI based-regimen in paediatrics. Efforts to attain the last 90 hampered by poor paediatric formulations? Impact of the Introduction of Dolutegravir