Transcript (1) The 6 th National Scientific Conference on HIV/AIDS

THE 6TH
NATIONAL SCIENTIFIC CONFERENCE ON HIV/AIDS
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
Outline
1. Background
2. Objectives
3. Methods
4. Results & Discussions
5. Conclusions
6. Recommendations
The 6th National Scientific Conference on HIV/AIDS
INTRODUCTION
1. Background
The biggest barrier in treatment for
HIV/AIDS patients is ARV drug
resistance problem
The 6th National Scientific Conference on HIV/AIDS
INTRODUCTION
The 6th National Scientific Conference on HIV/AIDS
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
The 6th National Scientific Conference on HIV/AIDS
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
The 6th National Scientific Conference on HIV/AIDS
2. Objectives
1. Identify specific HIVDR mutations and mutation
patterns in populations at initiation of first-line ART
2. 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
3. Identify specific HIVDR mutations and mutation
patterns in populations not achieving prevention of
HIVDR on first-line ART.
4. Identify programmatic factors potentially associated
with the prevention (or non-prevention) of HIVDR.
The 6th National Scientific Conference on HIV/AIDS
METHOD
3. Methods
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
The 6th National Scientific Conference on HIV/AIDS
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, pediatric
first-line ART regimen at a participating site.
The 6th National Scientific Conference on HIV/AIDS
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 .
The 6th National Scientific Conference on HIV/AIDS
PROCEDURE
Enrollment criteria
Agree
Consultant
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
HIVDR genotyping
<1000 cps/ml
Cont. as normal
Monitoring as normal
& HIVDR analysis
The 6th National Scientific Conference on HIV/AIDS
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).
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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
The 6th National Scientific Conference on HIV/AIDS
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
The 6th National Scientific Conference on HIV/AIDS
• 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
The 6th National Scientific Conference on HIV/AIDS
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 afterThe
ART
initation with HIV VL <3log cps/mL
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th
HIVDR at ART initiation
Number of children Prevalence
Mutation
with DR mutations
%
NRTI
2
1,47
T215A
NNRTI
1
0,74
N348I
M46L,
PI
4
2,94
K20I, T74S
Total
7
5,15
The 6th National Scientific Conference on HIV/AIDS
Mutation associated with resistance
Number of children Prevalence
Mutation
with DR mutations
%
NRTI
7
5.15
T69N, V75L
NNRTI
2
1.47
V179D/E
1
0.74
N348I
PI
5
3.68
L10I/V, L33I
Total
15
11.04
Both NRTI &
NNRTI
The 6th National Scientific Conference on HIV/AIDS
RESULTS
HIVDR outcomes after 12 months of ART
Number of children had
DR mutations
%
NRTIs
9
7,44
Dual resistance
to both NRTIs
& NNRTIs
6
4,96
PIs
0
0
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)
The 6th National Scientific Conference on HIV/AIDS
RESULTS
Drug Resistance Mutations
12/15 samples with VL ≥3log cps/mL
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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.
The 6th National Scientific Conference on HIV/AIDS
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)
The 6th National Scientific Conference on HIV/AIDS
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
The 6th National Scientific Conference on HIV/AIDS
Resistance to PIs
At ART initiation:
 Major mutation: M46L: nonpolymorphic PIselected 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
The 6th National Scientific Conference on HIV/AIDS
Resistance to PIs
After 12 months of ART:
 Major mutation: not detected.
 Minor mutation: only L10I/V recorded  not
effect on PI susceptibility
The 6th National Scientific Conference on HIV/AIDS
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.
The 6th National Scientific Conference on HIV/AIDS
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.
The 6th National Scientific Conference on HIV/AIDS
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
The 6th National Scientific Conference on HIV/AIDS
THANK YOU
The 6th National Scientific Conference on HIV/AIDS