ART Resistance in treatment experienced Patients in Sub Saharan...
Transcript of ART Resistance in treatment experienced Patients in Sub Saharan...
ART Resistance in treatment experienced Patients in Sub Saharan Africa:
Resistance profile and consequences - virologic perspective
Pr Coumba Toure Kane Virologist, Cheikh Anta Diop University-Dakar Head of Molecular Biology, Bacteriology and Virology Lab, Le Dantec University Hospital-Dakar, Senegal
Outline
• Anti Retro Viral (ART) in resource-poor settings • HIV Drug Resistance (HIV DR) in Africa: epidemiology
and resistance profile • Consequences of late identification of failure -
virologic perspective • Managing HIV DR: what is needed?
ART in resource-poor settings
Unparalelled global progress in ART scale-up
GLOBAL HIV/AIDS RESPONSE Progress Report 2011
Host
Replication Drug resistance
Clinical & immune recovery
•Clinical monitoring •CD4 count •Viral load (VL)
•HIVDR genotyping
•Hematology •Liver function •Renal function •Metabolic disorders
ARVs Virus
Public health approach (WHO): Simplified guidelines & Limited laboratory monitoring
Toxicity
ART in poor-resource settings
• WHO approach in ART scaling-up : – successful when considering:
• ART coverage • Survival and immune recovery
– may be challenged for the identification of 1st line treatment failure
• Potential issue may be the risk of emergence of HIV
Drug Resistant strains
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Virologic outcomes of patients in 1st line regimens in SSA
• Comparable to those among subtype B infected patients in developed countries :
- Approximately 10% of patients experience Virologic failure after 12 months
- Up to 25% experience Virologic failure by two years on ART
• But Risk factors for HIV-DR emergence is higher for many reasons
Specific risk factors for HIV-DR in SSA
• Drug related - Procurement (intermittent supply, stock-outs) - Sub-optimal regimens (single dose NVP for PMTCT) - Drug quality : Use of less costly ARV’s with higher toxicity - Drug interactions (NVP-rifampicin, traditional medecines)
• Patient related - Preparation - Adherence
Specific risk factors for HIV-DR in SSA
• Related to the Health systems - Lack of HR - Quality systems - Lack of virological monitoring tools - Late reference of patients - Task shifting
• Virus - High viral genetic diversity HIVDR?
9 diffrent subtypes > 50 CRF and other recombinants
The situation of HIV-DR in Africa
Well-monitored cohorts
Walis et al. Ant Ther 2012 812 well-monitored patients 96 Wks (VL 12WKly)
• 83 experienced VF (10%) - Among them: switch in 61 (73%) with resistance
Well-monitored cohorts
Senegal (ANRS 1215) •12 years Follow-up
- VL: 2/years •367 patients included:
- 88% achieved an initial Virologic suppression
- cumulative risk of VF at - 12 months: 5% - 24 months: 16% - 60 months: 25%.
Monitoring according to WHO Approach
• TOGO (Dagnra AY et al., Int AIDS Soc (2011 June) • 188 patients on 1st line • No VL in routine monitoring • Retrospective VL showed: 58 (30.8%) VF
– DRM in 46 (24.5%) • All 46 patients were resistant to NNRTIs
– 12 were resistant only to NNRTIs – 25 to NNRTIs and NRTIs – 8 to all three drugs of their ARV regimens with predicted to be
resistant to etravirine • 3 patients harboured the K65R mutation, inducing major
resistance to tenofovir.
Monitoring according to WHO Approach
0,0% 20,0% 40,0% 60,0% 80,0%100,0%
ETR
NNRTI
TAMs
M184
NRTI
NRTI+NNRTI
PI
Any DRM
CV>1000 cp/mlM12 (n=55)
M24 (n=77)
Avelin et al CROI 2012
• Cross sectional study in 5 African countries (BF, CM, CI, SN, TG) and 2 Asiatic countries (VN et TH)
•2 groups 1st line: M12 and M24
•Results:
•VF at M12:
•BF and TH (≤ 5%)
•CM, SN and VN (≤ 10%)
•CI and TG (>15%)
•M24: similar trend at M24
TOGO (M12 and M24)
The consequences in a virologic perspective
Early Failure (12 months) Late Failure (> 24 months)
NRTIs
HIV replication under treatment failure Accumulation of mutations (NRTIs)
M184V
M41L D67N K70R
L210W
K219Q T215Y
TAMs Q151M INSERTION
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MDR
NNRTIS
Early failure: M12 Late failure: M24
PIs
Early failure: M12 Late failure: M24
Lack of viral load monitoring
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•Acquired HIV-DR
•Accumulation of mutations after prolonged failure
•Reduced efficacy of second line regimen
•Eventually, transmission of HIV-DR mutations
Country Geographic Area Surveyed
Year ART
Roll-Out Survey Year Survey
Population NNRTI NRTI PI
Angola Luanda 2004 2009 Pregnant Women <5% <5% <5%
Botswana
Gaborone
2002
2005 Pregnant Women <5% <5% <5%
Francistown 2005 Pregnant Women <5% <5% <5%
Gaborone 2007 Pregnant Women <5% <5% <5%
Francistown 2007 Pregnant Women <5% <5% <5%
Burkina Faso Bobo Doulasso
2003 2005 Pregnant
Women <5% <5% <5%
Ouagadougou 2009 Pregnant Women 5-15% 5-15% <5%
Cameroon Douala
2000 2006 Pregnant
Women <5% 5-15% <5%
Yaoundé 2006 Pregnant Women 5-15% <5% <5%
Chad N'Djamena 2000 2006 Pregnant Women <5% <5% <5%
Cote d'Ivoire Abidjan 1998 2007 Pregnant Women <5% <5% <5%
Ethiopia Addis Ababa 2003 2005 Pregnant Women <5% <5% <5%
Malawi
Lilongwe
2003
2006 Pregnant Women <5% <5% <5%
Lilongwe 2009 Pregnant Women 5-15% <5% <5%
Blantyre Region 2009 Pregnant Women <5% <5% <5%
Senegal Dakar 1998 2007 VCT Attendees <5% <5% <5%
CROI 2011 Bertagnoli et al TDRM
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AIDS 2011
Sensitivity Specificity PPV NPV
CIF criteria 17% (12-23)
43% (30-58)
52% (39-65)
12% (8-18)
CIF criteria with confirmatory VL
83% (77-88)
57% (42-70)
88% (82-92)
48% (35-61)
Sigaloff et al. JAIDS2011;58(1):23 Second-line ART: unnecessary switching
Table: Performance of clinico-immunological criteria versus confirmatory VL to diagnose VF (HIVRNA >1000 c/ml)
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Lack of viral load: inappropriate switch
N=268
46.9%
12.4%
0
20
40
60
80
100
clinical+CD4 clinical+CD4+VL
unecessary switch (VL<1000cp/mL)appropriate switch
Sigaloff et al. JAIDS2011;58(1):23
Management of HIV DR what is needed?
Current approach of national ART programmes (in the given context) carries the risk for the development of HIVDR in Africa A tale of two failures: - Treatment failure - Failure to identify it
slide from Dr Pascale Ondoa communication HIV DR policy meeting, Kampala 19th of April 2012
What is needed (1)
• Virological monitoring – Implement pVL testing to avoid:
• incremental cost of unnecessary switching (confirmatory testing) • accumulation (routine testing)
– Access to VL technologies • Alternative tools for virological monitoring VL on DBS • Development of POC
• Reduction of Viral Load test prices • Increasing variety and innovation among supplier
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• Strengthening Health system – National Health Authorities and laboratory capabilities
national HIV treatment programs – preserve drug options by reducing resistance – Access to alternative drugs without cross-resistance to
(N)NRTIs – Robust supply chains
• Implement WHO HIVResNet strategies – Population-based for resistance assessment. – Early warning indicator – HIV-DR monitoring
What is needed (2)
In the context of more patients needing ART and less funding available !!!
Conclusion
• Improving monitoring of treatment failure is needed to avoid HIV-DR and maintain the clinical benefit and the cost effectiveness of ART
• Strategies to prevent HIV-1 resistance become a priority