Paediatric HIV Drug Resistance in African Settings Dr Cissy Kityo Mutuluuza INTEREST Meeting May 5-9, 2014 Lusaka, Zambia
Background: ART for children in sub- Saharan Africa 2.3 million children with HIV Treatment coverage estimated at 26% for Africa; 32% for Eastern and Southern Africa 2
HIVDR: Predisposing factors in children Exposure to antiretroviral medication for PMTCT Extended Nevirapine/Zidovudine Single dose nevirapine Higher baseline viral loads, longer time to suppression Inappropriate dosing because of limited paediatric formulations and weight changes Limited training of HCW in pediatric management 3 Adherence issues Reliance on adult caretakers Poorly palatable formulations (esp. liquids)
Pediatric HIVDR: extra challenges Life-long treatment with very limited number of regimens available HIVDR monitoring initiatives in Africa have limited pediatric cohorts
Countries showing resistance data in the HIV-1- infected paediatric population Rojas Sánchez P, and Holguín A J. Antimicrob. Chemother. 2014;jac.dku104
Resistance studies in HIV-1-infected paediatric populations over time including naive and pretreated patients Although majority of HIV infected children live in Sub Saharan Africa, HIVDR data in children only available in 11 (20.7%) of the 53 African countries Rojas Sánchez P, and Holguín A J. Antimicrob. Chemother. 2014;jac.dku104
Summary of TDR rates in drug-naive HIV-1-infected paediatric populations Country Sampling Period Naive Children Age Range Subjects with Resistance mutations to (%) NNRTI NRTI PI 2 Classes Cameroon 2009-11 41 0-12 5 2 0 2 Uganda 2004-06 39 2-12 0 0 0 0 Uganda (MARCH) 2010 372 0-12 7.5 5.7 0 3.2 Nigeria (MARCH) 2011 100 0-12 3 African countries out of 15 worldwide reporting TDR rates
HIVDR after treatment Monitoring initiatives in Africa have limited pediatric cohorts and mainly small numbers Published data Uganda(4), Mozambique (2), Camerron, Senegal, Kenya (2), South Africa, Ivory Coast, Malawi and Mali High proportion of children with drug-resistant HIV-1 infections after first-line ART failure in resource-limited settings (Sigaloff, Lancet Inf Dis 2011) Prevalence rates very variable NRTI 0-100%, NNRTI 0-100%, PI 0-37%, NRTI & NNRTI 0-100% NNRTI resistance most common: K103N, Y181C NRTI: M184V en TAMs 8 PI: only in certain regions (South America, South Africa)
Monitoring Emerging HIVDR and Associated Factors in Sentinel ART Sites Cohorts of approximately 130 ART-naive individuals beginning ART followed for 12 months Baseline assessment of HIVDR: Genotyping, ARV history 12-month assessment of HIVDR: Status (lost to follow-up, stop, switch, still on first-line ART) Viral load + genotyping at 12 months if still on first-line ART, or at regimen switch
have applied for WHO accreditation Implementation of the HIVDR strategy Country HIVDR WG 5yr plans EWI Surveys of Emerging Resistance HIVDR- Transmission TS HIVDR database Zimbabwe Accredited genotyping laboratories Zambia Kenya Malawi South Africa Tanzania Ethiopia Mozambique Paediatric Uganda Paediatric Namibia Paediatric Swaziland Paediatric Botswana
Single-dose NVP When prophylaxis fails, NNRTI resistance in up to 60% of infants < 6m (Hunt, AIDS 2011) Children with NVP exposure are less likely to achieve virological suppression on NNRTI-based regimens (Musiime AIDS Res Hum Retroviruses 2009) 11
Pediatric HIVDR after PMTCT Zimbabwe 232 children <18m Swaziland 201 children <18m Ugandan data underestimate pediatric HIVDR as compared to 100% PMTCT studies with younger children elsewhere in Africa Silvia Bertagnolio, Bloemfontein HIVDR workshop November, 2013
Treatment after PMTCT Virological failure after 24 weeks of AZT, 3TC, LPV/r vs. AZT, 3TC, NVP: 21.7% vs. 39.6% (Palumbo, N Eng J Med 2010) Baseline resistance to nevirapine was predictive of treatment failure Protease inhibitor preferred to nevirapine in children with exposure to single dose nevirapine 13
MARCH-Uganda study Prospective cohort study of 360 children in Uganda on ART PASER junior ART initiation or switch ~75% first-line ~15% second-line ARV-naive PMTCT
MARCH - objectives - Measure baseline HIVDR prevalence in children initiating first- or second-line ART - Monitor virological response to treatment - Determine prevalence and patterns of HIVDR in children with detectable viral load - Identify risk factors for virologic failure and HIVDR
Study design Prospective, observational cohort study of 120 HIV positive children 12 years at @ of the 3 JCRC sites Eligible when initiating first-line ART or switching to second-line ART due to treatment failure Follow-up 2 years, VL testing every 6 months HIVDR test if VL >1000 copies/ml at Reference Laboratory in Kampala
MARCH (sub-)study results Research question: What are the factors influencing the timing of pediatric ART initiation? Methods Both quantitative and qualitative data analysis 17
18 Baseline characteristic of children initiating first-line ART
HIVDR among children initiating first-line ART % 25 20 15 10 5 Any mutation NRTI NNRTI 2-class 0 First-line (n=279) ARV-naive (n=233) ARV-exp (n=46) 19 Frequencies (%) of HIVDR mutations in patients initiating firstline treatment either ARV-naïve or with previous PMTCT (n=14) or unknown exposure status (n=32)
HIVDR among ARV-naïve children initiating first-line ART, per site 20 Frequencies (%) of HIVDR mutations in ARV-naïve children initiating first-line treatment at the three JCRC sites.
Resistance patterns before first-line ART initiation 21
22 Factors associated with HIVDR before first-line ART initiation
Resistance in children switching to secondline ART 50 children enrolled in MARCH at time of failure of NNRTI-based first-line ART: 29 in Kampala, 18 in Mbale, 3 in Fort Portal Baseline characteristics: Median age (IQR), years 5.5 (4.0-10.1) WHO clinical stage 3 or 4 23 (46%) PMTCT-exposure 13 (26%) Median duration of first-line ART, months 29.8 (25.1-48.4) 1 previous ART regimen 24 (48%) Last ( failing ) ART regimen AZT+3TC+EFV/NVP 35 (70%) Triomune 10 (20%) 23 ABC-containing 5 (10%)
24 Resistance patterns at switch (n=44)
MARCH-Uganda: Susceptibility to RTinhibitors at time of switch Predicted HIV susceptibility to nucleoside and nonnucleoside reverse transcriptase inhibitors in children with first-line antiretroviral therapy failure (n = 44) 25 Sigaloff et al, AIDS research and human
Resistance patterns at switch TAM-2 pathway preferred? 26
Conclusions Important barriers to care remain for children, accounting for< 35% ART coverage in most African regions Even among reportedly ARV-naïve children, drug-resistant virus was present in 8% (MARCH) Besides PMTCT exposure, maternal ART use and breastfeeding may be important risk factors for baseline HIVDR The PMTCT practices of the last decade (non-use of Maternal HAART) have contributed to early virologic failure. The use of Maternal HAART scale up needs to be monitored for pediatric HIVDR
Conclusions Extensive resistance at switch (46% multiple TAMs) due to delayed switching fear of exhausting treatment options in children? These high HIVDR rates necessitate continued national surveillance programs to monitor trends. Affordable viral load & drug resistance testing and improved access to alternative combinations of ARVs are urgently needed
Acknowledgements All participants and their parents/caregivers JCRC, Uganda Cissy Kityo Peter Mugyenyi Victor Musiime Joshua Kayiwe Elizabeth Khauda Lillian Nakatudde Andrew Mukuye Bernard Ayebazibwe Michael Owor European Developing Countries Trial Partnership PharmAccess, AIGHD, AMC Tobias Rinke de Wit Kim Sigaloff Job Calis Sonia Boender Raph Hamers Sibyl Geelen Michèle van Vugt Michael Boele van Hensbroek University Medical Center, Utrecht Rob Schuurman 29 World Health Organization (WHO) Sylvia Bertagnolio