HIV Drug Resistance S urveillance 2004-2010
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Transcript of HIV Drug Resistance S urveillance 2004-2010
HIV Drug Resistance Surveillance2004-2010
Satellite Session: HIV Drug Resistance Surveillance and Control: a Global Concern
Silvia Bertagnolio, MD
WHO, GenevaJuly 22, 2012
2www.who.int/hiv/pub/drugresistance/report2012
3
Overview of WHO's Global HIVDR Strategy
Surveillance of Transmitted Drug Resistance
Surveillance of Acquired Drug Resistance
Monitoring of Early Warning Indicators
4
TRANSMITTED HIV DRUG RESISTANCE
5
Transmitted HIVDR (WHO surveys) Overview of Methods
Method does not estimate point prevalence, but classifies levels in three categories*:– Low prevalence <5%– Moderate prevalence 5-15%– High prevalence >15%
Results not national or clinic-specific but apply to the geographic area surveyed within the country
*M.Myatt et al. Antiviral Therapy 2008D.Bennett et al. Antiviral Therapy 2008
ARV-naïve populations likely to have been recently infected
6
Transmitted HIVDR (WHO surveys) 2004-2010
Note:basedonthesub-setof72surveyswhoseHIVDRprevalenceresultscouldbeclassifiedaslow,moderateorhighforatleastonedrugclass;areassurveyeddifferbetweenthetwoperiods
- 72 surveys with results that could be classified as low, moderate or high to any drug class
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Transmitted HIVDR (WHO surveys) Surveys with Moderate Classification
2004 – 2010
- 20 (out of 72 surveys) reported moderate levels of resistance to any drug class
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Transmitted HIVDR (WHO surveys) Geographical Distribution (pooled
analysis)
CountryreportingresultsfromWHOsurveysoftransmittedHIVdrugresistance,2004–2010NodataavailableornotparticipatinginthesurveysNotapplicable
82 surveys covering a total of 3588 recently-infected individuals, 2004-2010
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Transmitted HIVDR (WHO surveys) Estimates by year and region (pooled
analysis)
Ifyoubreakdownbydrugclass…
2004 2005 2006 2007 2008 2009 2010 P-value*
ANY DRUG
AfricanRegion10.0
(2.8to23.7)0.2
(0.0to1.4)0.6
(0.0to2.4)1.2
(0.1to3.2)1.8
(0.1to4.8)4.5
(2.3to7.2)2.8
(0.1to7.7)0.04
South-EastAsiaRegion
…0.7
(0.0to4.8)2.2
(0.1to11.8)1.0
(0.2to3.8)… … … -
WesternPacificRegion
… …4.5
(1.0to9.6)4.4
(1.1to9.4)1.5
(0.0to4.3)2.4
(0.6to4.8)… 0.41
Americas8.5
(2.4to20.4)… … … … … … -
EuropeRegion … … … … …2.6
(0.1to6.9)… -
EasternMediterraneanRegion
… …7.7
(1.6to20.9)… … … … -
Overall9.2
(3.7to16.4)0.3
(0.2to1.4)1.6
(0.4to3.2)1.6
(0.5to3.1)1.6
(0.3to3.5)3.4
(2.1to5.1)2.8
(0.1to7.7)0.06
Note: *test for trend, adjusted for region; Source: 82 WHO surveys covering 3588 recently-infected individuals
10
Transmitted HIVDR (WHO surveys) Estimates by year, region and class of drug
2004 2005 2006 2007 2008 2009 2010 P-value*
NNRTI
AfricanRegion2.3
(0.1to12.0)0.0
(0.0to1.0)0.1
(0.0to0.9)0.0
(0.0to0.7)1.5
(0.1to3.9)3.4
(1.8to5.2)2.0
(0.2to5.0)<0.01
Overall0.7
(0.0to4.3)0.0
(0.0to0.8)0.2
(0.1to0.9)0.3
(0.0to1.3)0.9
(0.1to2.2)2.0
(1.1to3.2)2.0
(0.2to5.0)<0.01
NRTI
Overall6.5
(2.0to12.8)0.0
(0.0to0.8)0.5
(0.0to1.4)0.4
(0.0to1.4)0.4
(0.0to1.4)0.9
(0.3to1.7)0.6
(0.0to3.7)0.37
PI
Overall0.7
(0.0to5.3)0.1
(0.0to1.1)0.2
(0.0to1.0)0.3
(0.0to1.3)0.0
(0.0to0.7)0.5
(0.0to1.2)0.0
(0.0to1.1) -
…estimatedincreaseisonlystatisticallysignificantforNNRTIinAfrica.
Note: *test for trend, adjusted for region; Source: 82 WHO surveys covering 3588 recently-infected individuals; all other regions omitted due to lack of statistical significance. Areas surveyed variec considerably among countries and over time..
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any m
utation
NNRTINRTI
NRTI & N
NRTI PI
K103NS
K101EPY1
81C
G190A
Y188CL
M184IV
D67GN
T215DFIS
K219ENQR
K70RM41L
T69D
L210W
-1.000%
.000%
1.000%
2.000%
3.000%
4.000%
5.000%
6.000%
Perc
enta
ge o
f Gen
otyp
es
Transmitted HIVDR (WHO surveys)Mutation Prevalence
(n=3588, pooled analysis from 82 surveys)
Note: drug resistance mutations as defined by WHO 2009 Surveillance Drug Resistance Mutation (SDRM) list
Overall prevalence: 3.1%
K103N or S: 0.8%
D67N/G, K101E/P, Y181C and M184V: between 0.3 – 0.4%
12
0% 5% 10% 15% 20% 25% 30% 35% 40%0%
2%
4%
6%
8%
10%
12%
14%
16%
18%
20%
Eastern AfricaSouthern AfricaWestern and Central AfricaSouth-East Asia RegionWestern Pacific Regionother
Antiretroviral therapy coverage: % of people living with HIV receiving ART
Prev
alen
ce o
f NN
RTI r
esis
tanc
e m
uta-
tions
: % o
f gen
otyp
esTransmitted HIVDR (WHO surveys)
Relationship between transmitted resistance to NNRTI and ART coverage
Notes: p-value adjusted for region: 0.039. Odds-ratio = 1.49 (95% CI 1.07-2.08)
13
Transmitted HIVDR - Conclusions
More recent surveys reported higher average levels of transmitted resistance, particularly to NNRTI in the areas surveyed in the African region
As expected, higher HIVDR prevalence is associated with higher ART coverage
14
ACQUIRED HIV DRUG RESISTANCE
15
Acquired HIVDR – WHO surveys
Objectives
– To describe HIVDR in cohorts at start and 12 months after ART initiation
– To estimate viral load suppression 12 months after ART initiation at the clinic level
Populations starting 1st-line ART at select clinics (naïve- and ARV-exposed)
16
Acquired HIVDR (WHO surveys)40 surveys, 12 countries, 2006 – 2010
17
.000%
1.000%
2.000%
3.000%
4.000%
5.000%
6.000%
Perc
enta
ge o
f Gen
otyp
es
Acquired HIVDR (WHO surveys) Mutation Prevalence at ART initiation (N = 5094)
Any SDRM: 5%
NNRTI: 3.7%
NRTI: 1.4%
NNRTI & NRTI: 0.6%
Note: drug resistance mutations as defined by WHO 2009 Surveillance Drug Resistance Mutation (SDRM) list
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Acquired HIVDR (WHO surveys)HIVDR in Patients before ART Initiation (N =
5094)
Year of Implementation
2007 2008 2009 2010 p-valueAny drug class
Africa 4.6 (3.6–5.8) 3.7 (2.8–4.8) 4.6 (2.2–7.8) 6.8 (4.8–9.0) 0.04South-East Asia 7.9 (4.0–13.7) 5.4 (2.9–8.6) … … 0.34
Overall 4.8 (3.8–6.0) 3.9 (3.0–4.9) 4.6 (2.2–7.8) 6.8 (4.8–9.0) 0.06NRTI Africa 1.1 (0.6–1.7) 1.0 (0.5–1.6) 1.1 (0.3–2.2) 1.0 (0.3–2.0) 0.75
South-East Asia 3.6 (1.2–8.2) 4.3 (2.0–7.2) … … 0.74
Overall 1.2 (0.7–2.0) 1.3 (0.8–2.0) 1.1 (0.3–2.2) 1.0 (0.3–2.0) 0.70NNRT
I Africa 3.4 (2.4–4.5)2.3 (1.4–
3.3)3.3 (1.8–
5.0)5.4 (3.7–
7.4) 0.03South-East Asia 7.9 (4.0–13.7) 3.0 (1.2–5.6) … … …
Overall 3.7 (2.5–4.9) 2.4 (1.6–3.3) 3.3 (1.8–5.0) 5.4 (3.7–7.4) 0.06PI Africa 0.3 (0.1–0.8) 0.5 (0.1–0.9) 0.5 (0.1–1.7) 0.0 (0.0–0.4) 0.82
South-East Asia 0.0 (0.0–2.6) 0.0 (0.0–0.7) … … …
Overall 0.3 (0.0–0.7) 0.4 (0.1–0.8) 0.5 (0.1–1.7) 0.0 (0.0–0.4) 0.97Note:"…"notavailableorapplicable;selectp-valuescouldnotbecalculatedduetocollinearity,lackofdataand/orvariability
19
Acquired HIVDR (WHO surveys)HIVDR in Patients Before ART Initiation (N =
5094)
Year of Implementation
2007 2008 2009 2010 p-valueAny drug class
Africa 4.6 (3.6–5.8) 3.7 (2.8–4.8) 4.6 (2.2–7.8) 6.8 (4.8–9.0) 0.04South-East Asia 7.9 (4.0–13.7) 5.4 (2.9–8.6) … … 0.34
Overall 4.8 (3.8–6.0) 3.9 (3.0–4.9) 4.6 (2.2–7.8) 6.8 (4.8–9.0) 0.06NRTI Africa 1.1 (0.6–1.7) 1.0 (0.5–1.6) 1.1 (0.3–2.2) 1.0 (0.3–2.0) 0.75
South-East Asia 3.6 (1.2–8.2) 4.3 (2.0–7.2) … … 0.74
Overall 1.2 (0.7–2.0) 1.3 (0.8–2.0) 1.1 (0.3–2.2) 1.0 (0.3–2.0) 0.70NNRT
I Africa 3.4 (2.4–4.5) 2.3 (1.4–3.3) 3.3 (1.8–5.0) 5.4 (3.7–7.4) 0.03South-East Asia 7.9 (4.0–13.7) 3.0 (1.2–5.6) … … …
Overall 3.7 (2.5–4.9) 2.4 (1.6–3.3) 3.3 (1.8–5.0) 5.4 (3.7–7.4) 0.06PI Africa 0.3 (0.1–0.8) 0.5 (0.1–0.9) 0.5 (0.1–1.7) 0.0 (0.0–0.4) 0.82
South-East Asia 0.0 (0.0–2.6) 0.0 (0.0–0.7) … … …
Overall 0.3 (0.0–0.7) 0.4 (0.1–0.8) 0.5 (0.1–1.7) 0.0 (0.0–0.4) 0.97Note:"…"notavailableorapplicable;selectp-valuescouldnotbecalculatedduetocollinearity,lackofdataand/orvariability
20
Acquired HIVDR (WHO surveys) – Three 12-Month Outcomes (n=3834)
(1) HIV drug resistance prevented: - VL <1000 copies/ml
(2) HIV drug resistance detected: - VL > 1000 copies/ml and HIVDR
(3) HIV drug resistance possible:- LTFU, stops and VL > 1000 copies/ml but no HIVDR observed
21
Acquired HIVDR (WHO Surveys) Summary of 12-Month Outcomes (pooled,
n=3834)
Region
HIV drug resistance prevention
(% of people initiating therapya)
Any HIV drug resistance at endpointb
Possible HIV drug resistance
(% of people initiating therapya)
% of people initiating therapya
% of people genotyped at treatment failure
Eastern Africa 79.4% 4.3% 63.7% 16.4%
Southern Africa 80.3% 4.7% 73.3% 15.0%Western/central Africa 59.9% 6.0% 74.5% 34.1%African Region 76.6% 4.7% 69.5% 18.8%
South-East Asia 71.4% 8.9% 93.3% 19.7%
Overall 76.1% 5.1% 72.1% 18.8%aExcludespeoplewhodiedorwhoweretransferredtoanotherantiretroviraltherapyfacility.bHIVdrugresistancedefinedasadrugresistancepredictionoflow,intermediateorhighlevelusingtheStanfordHIVdatabasealgorithm.Alternatively,ifcalculatedbasedonthenumberofsurveillancedrugresistancemutationsatendpoint,subregional,regionalandoverallproportionsremainidentical.
22
Region
HIV drug resistance prevention
(% of people initiating therapya)
Any HIV drug resistance at endpointb
Possible HIV drug resistance
(% of people initiating therapya)
% of people initiating therapya
% of people genotyped at treatment failure
Eastern Africa 79.4% 4.3% 63.7% 16.4%
Southern Africa 80.3% 4.7% 73.3% 15.0%Western/central Africa 59.9% 6.0% 74.5% 34.1%African Region 76.6% 4.7% 69.5% 18.8%
South-East Asia 71.4% 8.9% 93.3% 19.7%
Overall 76.1% 5.1% 72.1% 18.8%27.9%ofpatientsfailingtherapyhadnoHIVDR27.9%ofpatientsfailingtherapyhadnoHIVDR
Acquired HIVDR (WHO Surveys) Summary of 12-Month Outcomes (pooled,
n=3834)
23
Acquired HIVDR (WHO Surveys) Prevalence of Mutations in People Failing ART
at 12 Months (pooled) (n=269)
M184V: 58.7%K65R (10.4%)D67N (7.1%)T215 (multiple): 5.6%K219 (multiple): 4.8%
≥ 3 TAMs: 3.3%
NNRTI NRTI NNRTI & NRTI
24
any d
rug*NNRTI
NRTI
NRTI & N
NRTINVP
EFV
RPVET
R
3TC/FT
CABC ddI
d4TTD
FAZT
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Perc
enta
ge o
f Gen
otyp
es
*PIresistancewasonlyobservedfornelfinavir,resultingfromthepresenceofmultiplepolymorphicmutations,especiallyinsubtypesC,GandCRF02_AG.NelfinavirresistancewasneverobservedinspecimenswithoutpredictedNRTIorNNRTIresistance.Nodrugresistancewaspredictedforanyritonavir-boostedPI.BasedontheStanfordalgorithmusingresistanceinterpretationof"low-level"orhigher.
Acquired HIVDR (WHO Surveys)Predicted HIVDR in people failing ART at 12
months (pooled) (n=269)
NRTIs commonly used in 2nd-line regimens
Currently-recommended second-line regimens likely to be effective for the majority of patients failing
first-line ART
25
Region
HIV drug resistance prevention
(% of people initiating therapya)
Any HIV drug resistance at endpointb
Possible HIV drug resistance
(% of people initiating therapya)
% of people initiating therapya
% of people genotyped at treatment failure
Eastern Africa 79.4% 4.3% 63.7% 16.4%
Southern Africa 80.3% 4.7% 73.3% 15.0%Western/central Africa 59.9% 6.0% 74.5% 34.1%African Region 76.6% 4.7% 69.5% 18.8%
South-East Asia 71.4% 8.9% 93.3% 19.7%
Overall 76.1% 5.1% 72.1% 18.8%
Acquired HIVDR (WHO Surveys) Summary of 12-Month Outcomes (pooled,
n=3834)
26
Acquired HIVDR (WHO Surveys) –Summary of Key 12-Month Outcomes (by
clinic)
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
HIVDR Possible Any HIVDR HIVDR prevention
Note:Possibledrugresistanceincludes75patientswithviralloadgreaterthan1000copies/mlat12monthsandnoresistance,13whostoppedantiretroviraltherapy,599whowerelosttofollow-up,34withviralloadgreaterthan1000copies/mlat12monthsbutwithspecimensfailingtoamplifyand1withviralloadgreaterthan1000copies/mlatswitchbutfailingtoamplifyPCRproducts
27
Acquired HIVDR (WHO surveys) Conclusions
AT ART INITIATION:
5% of individuals had any HIVDR-associated mutation
Currently recommended first-line ART regimens will be effective for most people initiating treatment.
AT 12 MONTHS:
Of individuals initiating therapy: (i) 5.1% had any DR, (ii) 76.6% had no drug resistance, but (iii) 18.8% had possible DR
Of individuals failing therapy at 12 months: 72.1% had any DR (69.5% NNRTI, 62.5% NRTI, 59.9% NNRTI and NRTI)
Currently recommended second-line ART regimens will be effective for most people failing therapy if they were switched soon after virological failure
28
CONCLUSIONS
As ART roll out continues, increased rates of HIVDR may occur
ART programs must be informed by routine programmatic evaluation to minimize first-line failure and HIVDR emergence and transmission
Routine, standardized, population-based surveillance of HIVDR is imperative and must be in place to detect potential future increase of HIVDR in a timely manner
Funders and national governments must step up to support and sustain a global approach to assessing HIVDR