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MONITORING OF HIV DRUG RESISTANCE IN CHILDREN RECEIVING FIRST LINE ANTIRETROVIRAL THERAPY AT TWO CHILDREN HOSPITALS NHI ĐỒNG 1 AND NHI ĐỒNG 2 IN HO CHI MINH CITY,VIETNAM.

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  1. MONITORING OF HIV DRUG RESISTANCE IN CHILDREN RECEIVING FIRST LINE ANTIRETROVIRAL THERAPY AT TWO CHILDREN HOSPITALS NHI ĐỒNG 1 AND NHI ĐỒNG 2 IN HO CHI MINH CITY,VIETNAM Ton Tran(1), Anh Q. Luong(1), Khanh Thu H. Huynh(1), Ngoc Thao T. Do(1), Nghia V. Khuu(1), Thinh X. Vu(1), Khanh H. Truong(2), Quy T. Du(2), Kim Thoa P. Le(2), Viet C. Do(3), An T. Vu(3), Thanh Thuy T. Le(3), Xuan Lien T. Truong(1).(1)Pasteur Institute, Ho Chi Minh City, (2)Nhi Dong 1 hospital, Ho Chi Minh City, (3)Nhi Dong 2 hospital, Ho Chi Minh City

  2. Outline Background Objectives Methods Results & Discussions Conclusions Recommendations

  3. INTRODUCTION Background The biggest barrier in treatment for HIV/AIDS patients is ARV drug resistance problem

  4. INTRODUCTION

  5. INTRODUCTION • Early detection of HIVDR and changing appropriate ARV regimens helps prevent: • Accumulation of resistance mutations   • Poor response or non-response to HAART   • Serious clinical events and mortality • Prolonged viremia and risk of transmission

  6. INTRODUCTION In Vietnam: On adult patients (1) Early Warning Indicator of HIVDR (EWI): từ 2010 (2) Mornitoring of HIVDR: 2009 - 2012 (3) HIVDR threshold survey: from 2011. (4) Cross-sectional studies on HIVDR on ARV- naive patients, ART patients, . . . Lack of HIVDR data on pediatrics

  7. Identify specific HIVDR mutations and mutation patterns in populations at initiation of first-line ART Estimate the proportion of the ART site population achieving HIVDR prevention, as measured by viral load suppression, in populations after one year of first-line ART Identify specific HIVDR mutations and mutation patterns in populations not achieving prevention of HIVDR on first-line ART. Identify programmatic factors potentially associated with the prevention (or non-prevention) of HIVDR. 2. Objectives

  8. METHOD 1- Study design: cohort study 2- Study subjects:HIV/AIDS children at initiation of first line anti-retroviral therapy at two children hospitals Nhi Đồng 1 and Nhi Đồng 2 in Ho Chi Minh city 3- Duration: 12/2011 – 03/2014 3. Methods

  9. METHOD • Enrollment criteria • Patients attending the selected OPCs who meet the following criteria: • ≤ 15 years old • Children whose parents or eligible guardians consent following the written informed consent process and who provide assent (for children 7 years old or older), and • Who are eligible to initiate, and do initiate, pediatricfirst-line ART regimen at a participating site.

  10. METHOD • Exclusion criteria: • Individuals enrolled in a clinical trial or clinical research study (either at the monitoring site or another location). • Individuals who are part of an observational cohort for whom more follow-up efforts are made than for other ART patients treated at the site (Patients enrolled in an observational cohort for whom no additional follow-up procedures are included may be eligible). • Individuals restarting ART, who have previously started and stopped ART at the sentinel survey site. • Individuals transferring in  from another paediatric ART site who are at the time of transfer currently taking a three- or four-drug first-line ART regimen .

  11. PROCEDURE Enrollment criteria Consultant Agree Disagree Data + sample Cont. as normal HIV VL testing HIVDR genotyping Data entry and analysis for baseline Monitoring as normal Stop 1st line regimens or after 12 months Data + sample for HIV VL ≥1000 cps/ml <1000 cps/ml Cont. as normal HIVDR genotyping Monitoring as normal & HIVDR analysis

  12. Testing at HIV/AIDS laboratory of Pasteur Institute: • HIV-1 Viral load by Real time PCR (Generic HIV Charge Virale of Biocentric – France, LOD: 250 cps/mL) • HIVDR genotyping: • Sequencing of Pol gen (1800 bp) => coding for proteins which are targets of NRTIs, NNRTIs & PIs being used in Vietnam. • Sequence analysis by DNAStar Lasergene 12 Core Suite • Sequence interpretation with HIVdb program of Stanford HIV drug resistance database (USA).

  13. RESULTS 4. Results & Discussions Baseline Characteristics • 136 eligible children consecutively initiating first line ART were enrolled; male/female: 69/67 • 31,62 % were HIV diagnosed before 18 months of age. 72,06% were detected after 18-month old. • 75,21 % of children >18 months of age, 39,67 % of children >5 years old at ART initation

  14. RESULTS 6/136 of patients‘mothers joined in PMTCT program, including 3 ones were HIV detected at labor Number of children having ARV in PMTCT program was 11/136 (8,09%) 47/136 (34,55%) had advanced disease – WHO clinical stages III and IV at ART initation 65/136 (47,79%) were severely immunocompromised (LT CD4 <15%) at ART initation

  15. 100% had HIV VL > 3log cps/ml, of whom 81,62% had HIV VL > 5log cps/ml at ART initation 32 (37,21%) had OIs, of whom 58,54% had tuberculosis at ART initation. 5,15 % (7/136) had HBsAg (+), 3,68% (5/136) had anti HCV (+) & 2,20% (3/136) had Cryptococcus Antigen (+). 134/136 (98,53%)had HIV-1 subtype CRF01-AE

  16. RESULTS Outcomes at 12 months 7 (5%) were dead, 8 (6%) were loss-follow up Most of 121 children continued to be monitored had clinical and immunological status well changed (p< 0,001) • 97,52% (119/121) had WHO clinical stage I after 12 months of ART • 92,56% (112/121) had LT CD4 ≥ 15% 87,6% of patients had suppressed HIV RNA at 12 months after ART initation with HIV VL <3log cps/mL

  17. HIVDR at ART initiation

  18. Mutation associated with resistance

  19. RESULTS HIVDR outcomes after 12 months of ART Of 9 of children with TB and TB treatment in parallel with ART, there were 5 cases (55.56%) had DRMs => 6 times compared with the proportion of non-TB patients B had DRMs (p = 0.01)

  20. RESULTS Drug Resistance Mutations 12/15 samples with VL ≥3log cps/mL

  21. DRM Interpretation • Resistance to NRTIs • At ART initiation: T215A, T69N và V75L. • T215A: low-level resistance to D4T & AZT, potential low-level resistance to ABC & DDI (ART naive). • T69N: potential low-level resistance to DDI • V75L: potential low-level resistance to D4T & DDI. • None of TAMs were recorded.

  22. DRM Interpretation • After 12months of ART: D67N, K70R, L74V, V75M, V75T, Y115F, Q151M, M184V, T215F, T215S & T215N. • M184V: detected in 6/12 cases (50%), selected by 3TC and reduces susceptibility to this drugs >1000-fold. It is also selected by, and causes low-level resistance to, ABC and ddI • V75M: high-level resistance to d4T and medium-level resistance to ddI. • Q151M: intermediate/high-level resistance to AZT, ddI, d4T and ABC and low-level resistance to TDF, 3TC and FTC. In combination with mutations at the associated positions 62, 75, 77, and 116, Q151M confers high-level resistance to AZT, ddI, d4T and ABC and intermediate-level resistance to TDF, 3TC and FTC. PED1-025 had Q151M, F77L and F116FY. • TAMs: D67N, K70R, T215F, K219Q. PED2-003 had 3 TAMs (D67N, K70R and K219Q)

  23. Resistance to NNRTIs • Low genetic barrier, 1 primary mutation  reduced susceptibility to the relevant NNRTIs. • At ART initiation: • Primary mutation : N348I  low-level resistance to NVP, potential low-level resistance to EFV and AZT, D4T. • V179D/E potential low-level resistance to all of 4 NNRTIs • After 12months of ART: 5/9 of primary mutation to NNRTIs were detected: K101E, K103N, Y181V, Y188L and G190A => multi DR with all regimens of NNRTIs

  24. Resistance to PIs • At ART initiation: • Major mutation: M46L: nonpolymorphic PI-selected mutations that reduce susceptibility to IDV, NFV, FPV, LPV and ATV when present with other mutations. M46L also reduces susceptibility to TPV. • Minor mutations: K20I is a PI-selected mutation that appears to reduce NFV susceptibility; T74S is a polymorphic mutation weakly selected by most PIs and associated with low-level resistance to NFV. • L10I/V, L33I not effect on PI susceptibility 

  25. Resistance to PIs • After 12 months of ART: • Major mutation: not detected. • Minor mutation: only L10I/V recorded  not effect on PI susceptibility 

  26. CONCLUSION (1) 5. Conclusions & Recommendations (1) • Most of HIV-infected children were detected late with high viral load, compromised immunity, late clinical stage due to accessing testing, care and treatment services late.  Need more interventions to increase accessibility to care - treatment programs for children born to HIV infected mothers.

  27. CONCLUSION (2) 5. Conclusions & Recommendations (2) • Low level of HIVDR were observed among children after 12 months of ART. • HIVDR associated mutations related to multi - drug resistance were recorded and dual class resistance, including combined NRTI and NNRTI, was present after only 12 months of ART  Continue to monitor HIVDR in children to provide the information needed to contribute to the HIV treatment guidelines for children in the actual conditions of Vietnam.

  28. CONCLUSION (3) 5. Conclusions & Recommendations (3) • Having TB and TB treatment in parallel with ART seemed to relate to the emergence of HIV drug resistance  Need to be considered in the National ARV treatment guidelines

  29. THANK YOU

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