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

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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

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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%

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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)

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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

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ACQUIRED HIV DRUG RESISTANCE

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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)

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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

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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

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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

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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.

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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)

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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

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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

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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)

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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

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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

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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