World Health Organization World Health Organization Surveys of Transmitted and Surveys of Transmitted and

Acquired HIV Drug Resistance in Acquired HIV Drug Resistance in Resource Limited SettingsResource Limited Settings

CROI 2011

S Bertagnolio*, K Kelley*, A Saadani Hassani*, Y Obeng-Aduasare**, M Jordan*°

*World Health Organization, HIV Department, Geneva**Dartmouth College, NH, USA°Tufts University School of Medicine, MA, USA

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Goal of the WHO HIVDRSurveillance Strategy

Standardized survey methods

Inform population-based selection of 1st and 2nd line ART regimens

Support national programs in minimizing the emergence and transmission of HIVDR

Gilks et al. Lancet, 2006

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Elements of the WHO HIVDRSurveillance Strategy

1. Monitoring HIVDR "Early Warning Indicators" * at ART sites

2. Surveillance of acquired HIVDR

3. Surveillance of transmitted HIVDR

*Jordan et al. Poster # 626; Poster Discussion Weds 1 pm

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Surveys of Acquired HIVDR

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

– Use results for programmatic adjustments

Populations starting 1st line ART at sentinel clinics (naive and ARV exposed)

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Surveys of Acquired HIVDR Using WHO

Methods (Feb 2011)

15 surveys conducted in 15 clinics in 5 countries– Burundi, India, Malawi, Mozambique, Nigeria

~140 naïve or ARV exposed adults or pediatric patients consecutively initiating first-line ART enrolled in each clinic

Total of 2,150 patients surveyed, when data from the 15 surveys are combined

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N=2,150 Patients starting ART

1,448 (67.3%) Patients retained in care and alive at 12 months

128 Patients with viral load 1,000 c/ml (10%);

all genotyped

1,150 Patients with viral load < 1,000 c/ml (90%)

309 (14.4%) Lost to follow up191 (8.9%) Transfer out

169 (7.9%) Died26 (1.2%) Unclassifiable

6 (0.3%) Stopped1 (0.05%) Switched to second line ART

1,503 (70%) Genotyped before

ART initiation

Acquired HIVDR Surveys Combined Analysis

1,278 Patients with viral load (88.2% of pts on ART@m12)

Regimens:AZT/3TC/NNRTI: 22%D4T/3TC/NNRTI: 74%TDF/3TC/NNRTI: 3.2%Other: 0.8%

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Surveys of Acquired HIVDR: HIVDR in patients before ART initiation

(N = 1,503)

HIVDR defined as low, intermediate or high per Stanford HIVdb algorithm

NNRTI NRTI PI

Subtype distribution:C: 77.4%CRF02_AG: 9.1% G: 8.8%A: 2.7%

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Surveys of Acquired HIVDR: Mutation Prevalence before ART

initiation (N = 1,503)

NNRTI NRTI PI

≥1 TAMs: 1.3% (N = 19; 13 pathway 2)≥3 TAMS: 0.3% (N = 4)

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Surveys of Acquired HIVDR: HIVDR in patients retained and alive at 12

Months (N = 128)

HIVDR defined as low, intermediate or high per Stanford HIVdb algorithmNRTIs commonly used in 2nd line regimens

NNRTI NRTI PI ≥1 TAMs: 15.6% (N = 20; 18 pathway 2)≥3 TAMS: 4.7% (N = 6)

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Surveys of Acquired HIVDR: HIVDR in patients retained and alive at 12

Months (N = 128)

NNRTI NRTI

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Viral Load Suppression by Site at 12 months (per protocol analysis)

ART Sites Surveyed

VL <1,000 c/ml

HIVDR Detected

N= ~140 Patients enrolled per clinic

Denominator = Patients enrolled – (death + transfer out + unclassifiable)

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Surveys of Acquired HIVDR Conclusions

~6% of patients initiating ART at the clinics (naïve and ARV exposed) show HIVDR to any drug (5.0% to NNRTI, 2.7% to NRTI, 1.9% to NRTI + NNRTI)

Viral load suppression (<1,000 c/ml) at 12 months 90% of patients retained in care and alive 70% of patients, when lost to follow up and ART stops are

included in the analysis

The VL suppression rates observed in the 15 clinics surveyed are similar to those reported in cohorts in developed countries

At 12 months, in patients failing ART, 67% had HIVDR to any drug, 65% had NNRTI DR. Prevalence of TAMs remains limited (4.7% with>3TAMs), 52% had 184V and 5% had K65R

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Surveys of Transmitted HIVDR

Objectives

Assess the transmission of HIVDR

Inform selection of PMTCT, PreP and future ART first-line regimens

Inform functioning of HIV prevention programs

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Surveys of Transmitted HIVDR

<24 yrs & 1st pregnancy, if women– First HIV risk-defining event within past

3 years– CD4 >500 c/μL

Results not national or clinic-specific but apply to the geographic area surveyed

Truncated sequential sampling technique (N≤47) to classify prevalence of transmitted HIVDR*

– Low prevalence <5%– Moderate prevalence 5-15%– High prevalence >15%

*M.Myatt et al. Antiviral Therapy 2008D.Bennett et al. Antiviral Therapy 2008

Recently infected & ART naïve population

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Surveys of Transmitted HIVDR Using WHO Method (Feb 2011)

41 surveys conducted in 20 countries 85% between 2005-2007

– 75% (N=31) in Africa– 22% (N=9) Asia– 1 Mexico

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41 surveys of TDR in 20 countries83% low TDR, 17% moderate TDR

Low (<5%)Moderate (5-15%)

Ouagadougou, Mexico City, Douala

Yaoundé, Lilongwe, Maputo, Ho Chi Min, Ouagadougou

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Surveys of Transmitted HIVDR in recently infected population: Mutation Prevalence (N=1,920) (2009 WHO SDRM list)

NNRTI NRTI PI Subtype distribution:C: 58%CRF01_AE: 15.3%CRF02_AG: 11.2% A: 4.0%B: 3.6%D: 2.7%CRF06_cpx: 2.0%CRF11_cpx: 1.0%

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Surveys of Transmitted HIVDR Conclusions

Overall, 41 surveys conducted most between 2005-2007

83% of surveys show TDR <5%, suggesting that TDR remains low in the areas and populations assessed at the time the surveys were conducted

17% of the surveys show moderate (5-15%) levels of TDR in specific geographic regions. These reports are important and merit attention. Surveys should be repeated to confirm results. No treatment guidelines changes are warranted before further investigations

Present data are insufficient to identify trends of TDR over time

In the 1,920 recently infected subjects, overall HIVDR prevalence is 3.7% (95% CI 2.86-4.54)

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Recommendations

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

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Acknowledgments

Bill&Melinda Gates Foundation WHO HIVResNet (Mark Wainberg,

chair) Diane Bennett Don Sutherland Neil Parkin, Data First Consulting Scott Hammer Diane Havlir Mark Myatt CDC/PEPFAR HIVDR working group Tufts University School of Medicine Andrea De Luca Alexandra Calmy Andrew Phillips Annemarie Wensing John Mellors VQA/NIH Program ANRS

www.who.int/hiv/drugresistance/

Angola Botswana Burkina Faso Burundi Cameroon Chad Cote d'Ivoire Ethiopia India Indonesia Malawi Mexico Mozambique Namibia

NigeriaSenegalSouth AfricaSwazilandTanzaniaThailandUgandaViet Nam