World Health Organization Surveys of Transmitted and Acquired HIV Drug Resistance in Resource 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

2 Goal of the WHO HIVDR Surveillance Strategy Standardized survey methods Inform population-based selection of 1 st and 2 nd line ART regimens Support national programs in minimizing the emergence and transmission of HIVDR Gilks et al. Lancet, 2006

3 Elements of the WHO HIVDR Surveillance 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

4 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)

5 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

6 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 up 191 (8.9%) Transfer out 169 (7.9%) Died 26 (1.2%) Unclassifiable 6 (0.3%) Stopped 1 (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 Regimens: AZT/3TC/NNRTI: 22% D4T/3TC/NNRTI: 74% TDF/3TC/NNRTI: 3.2% Other: 0.8%

7 Surveys of Acquired HIVDR: HIVDR in patients before ART initiation (N = 1,503) HIVDR defined as low, intermediate or high per Stanford HIVdb algorithm NNRTINRTI PI Subtype distribution: C: 77.4% CRF02_AG: 9.1% G: 8.8% A: 2.7%

8 Surveys of Acquired HIVDR: Mutation Prevalence before ART initiation (N = 1,503) NNRTINRTI PI 1 TAMs: 1.3% (N = 19; 13 pathway 2) 3 TAMS: 0.3% (N = 4)

9 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 algorithm NRTIs commonly used in 2 nd line regimens NNRTINRTI PI 1 TAMs: 15.6% (N = 20; 18 pathway 2) 3 TAMS: 4.7% (N = 6)

10 Surveys of Acquired HIVDR: HIVDR in patients retained and alive at 12 Months (N = 128) NNRTINRTI

11 Viral Load Suppression by Site at 12 months (per protocol analysis) Viral Load Suppression ART Sites Surveyed VL <1,000 c/ml HIVDR Detected N= ~140 Patients enrolled per clinic Denominator = Patients enrolled – (death + transfer out + unclassifiable)

12 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

13 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

14 Surveys of Transmitted HIVDR <24 yrs & 1 st 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 (N47) to classify prevalence of transmitted HIVDR* –Low prevalence <5% –Moderate prevalence 5-15% –High prevalence >15% *M.Myatt et al. Antiviral Therapy 2008 D.Bennett et al. Antiviral Therapy 2008 Recently infected & ART naïve population

15 Surveys of Transmitted HIVDR Using WHO Method (Feb 2011) 41 surveys conducted in 20 countries 85% between –75% (N=31) in Africa –22% (N=9) Asia –1 Mexico

16 41 surveys of TDR in 20 countries 83% low TDR, 17% moderate TDR Low (<5%) Moderate (5-15%) Ouagadougou, Mexico City, Douala Yaoundé, Lilongwe, Maputo, Ho Chi Min, Ouagadougou

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

18 Surveys of Transmitted HIVDR Conclusions Overall, 41 surveys conducted most between % 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 )

19 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

20 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 Angola Botswana Burkina Faso Burundi Cameroon Chad Cote d'Ivoire Ethiopia India Indonesia Malawi Mexico Mozambique Namibia Nigeria Senegal South Africa Swaziland Tanzania Thailand Uganda Viet Nam