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