1. Transmitted ARV drug resistance: what’s next? Raph Hamers, MD PhD Academic Medical Center of the University of Amsterdam Amsterdam Institute for Global Health and Development SATuRN-PASER workshop, Bloemfontein 20-22 November 2013

2. WHO/UNAIDS Global scale-up of ART Standard ART regimens Restricted drug options Limited lab monitoring Decentralized service delivery and task shifting WHO public health model

3. Should we fear a dramatic increase in HIVDR? "Widespread, unregulated access to ARV drugs in sub-Saharan Africa could lead to the rapid emergence of resistant viral strains, spelling doom for the individual, curtailing future treatment options, and leading to transmission of resistant virus." "If compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants…" Robert C. Gallo and Luc Montagnier. Prospects for the Future. Science 2002 "If compliance and careful follow-up of patients is not achieved, we will see a dramatic increase in multidrug-resistant HIV mutants…" Robert C. Gallo and Luc Montagnier. Prospects for the Future. Science 2002 Lancet 2001

4. Transmitted HIVDR in MSM and HSX is stabilizing in Europe Wensing, on behalf of SPREAD eacs-conference Oct 2011 0.37 0.44 0.004 (increase in MSM only) 0.001 P= WHO 2009 Surveillance Drug Resistance Mutation list N=4317

5. PASER-M: Pre-ART HIVDR in 6 African countries Pre-ART HIVDR prevalenceYearly increase risk of pre-therapy HIVDR: Overall: 5.6%38% (p=0.001, multivariate analysis) Pretoria: 1.1% Kampala: 12.3% Hamers et al., The Lancet Inf Dis 2011 2436 sequences from 2590 participants

6. Recent data suggest increasing TDR in certain geographics areas (mostly to NNRTIs) ANC Aghokeng et al AIDS 2011 Ndembi et al AIDS 2011

7. 26,102 patients from 191 datasets from 42 countries in Africa, Asia, Latin America

8. Prevalence of HIVDR in ARV-naïve individuals, by time since ARV rollout Every circle is a study and the size of the circle is proportional to the precision of the estimate from the individual study Gupta et al. Lancet 2012 29%/yr (95%CI 15-45; p=0.0001)14%/yr (0-29; p=0.05) 3%/yr (–0.9-16; p=0.618) East AfricaSouthern Africa Latin America+Caribbean West and Central Africa NNRTI: 36%/yr (21-52; p<0.0001)NNRTI: 23%/yr (7-42; p=0.0049) NNRTI: 15%/yr (–1-32; p=0.0646) p=0.960

9. WHO transmitted HIVDR surveys 2004-2010 72 surveys 20 moderate level (5-15%) WHO HIV Drug Resistance Report 2012

10. WHO transmitted HIVDR surveys Mutation Prevalence n=3588, pooled analysis from 82 surveys WHO 2009 Surveillance Drug Resistance Mutation list Overall prevalence: 3.1% K103N or S: 0.8% D67N/G, K101E/P, Y181C and M184V: between 0.3 – 0.4% WHO HIV Drug Resistance Report 2012

11. TDR to NNRTIs is related to ART coverage in LMIC WHO HIV Drug Resistance Report 2012

12. Multivariate analysis adjusted for sex, age, calendar year, WHO clinical stage, BMI, pretherapy HIVRNA and CD4, prior ARV use, type of NRTI and NNRTI. P<0.0001 P=0.001 Hamers et al. Lancet Inf Dis 2012 Pretherapy HIVDR doubles 1 st year risk of VF and acquired HIVDR PASER-M cohort in 6 African countries Odds ratio 91% 86% 75% % Viral suppression

13. WHO HIV Drug Resistance Report 2012

14. Routine VL monitoring helps to reduce new HIV infections with transmitted drug resistance Mathematical model: VL testing every 6 months, switch >500 c/mL. To preserve current 1 st -line for long term, there is an eventual need for (affordable) VL monitoring in low-middle income countries Phillips AIDS2011 TDR

15. New ART strategies: eligibility is increasing Gottfried Hirnschall WHO, IAS Conference July 26, 2012 * Cohen HTPN052 NEJM Newel KZN Science Treatment as Prevention PMTCT Option B+

16. Early ART for HIV prevention at the cost of HIVDR?

17. Early ART initiation: model based on cohort data from Kampala and Mombasa Effect of initiating ART at different CD4 thresholds TDR prevalence Infections averted Over 10-year period Nichols et al. AIDS2013 TDR prevalence will increase: <200 cells/μL: 9.4%-12.3% <350 cells/μL: 11.6%-13.4% <500 cells/μL: 17.8%-18.7% TDR prevalence will increase: <200 cells/μL: 9.4%-12.3% <350 cells/μL: 11.6%-13.4% <500 cells/μL: 17.8%-18.7%

18. Nichols et al. AIDS2013 The preventive effect of early ART outweighs the increase of TDR 18 46 22 32 Number of new HIV infections averted for each incident case of TDR

19. Early ART: TDR increase eliminated if patients with VF are timely switched to 2nd-line ART Nichols et al. AIDS2013

20. PrEP and HIVDR TDF-FTC effective in iPREX, Partners PrEP, TDF2; not effective in FEM-PREP and VOICE (TDF) because of non-adherence Concerns, in regard to HIVDR: 1.Already HIV-infected when starting PrEP 2.Non-adherent and infected while on PrEP 3.TDF-FTC also in first-line treatment: loss of future drug options? 5 cases of HIVDR have been detected in iPrEx, Partners PrEP, TDF2 (total of 118 infections averted)  All had unrecognized (acute) infections

21. van de Vijver, AIDS2013 PrEP: limited impact on TDR prevalence in sub- Saharan Africa Comparison of 3 independent mathematical models in sub- Saharan Africa Proportional contribution of events contributing to HIV-1 drug resistance 20 years after the introduction of preexposure prophylaxis (PrEP).

22. Conclusions – 1 Pre-ART and TDR are on the rise, particularly in southern and East Africa, mostly confined to NNRTI, associated with duration and coverage of national ART programs Currently, measured levels are of concern, but not at unexpected levels and rates, far majority of patients receive effective regimens Lack of routine HIVDR surveillance data  not up-to-date

23. Conclusions – 2 Interventions to reduce TDR include: Strengthening of program functioning, retention and adherence Routine VL monitoring in conjunction with access to 2nd line ART Exciting evidence that early ART prevents new infections However, implementation of novel TasP strategies will need to be closely monitored to assess the consequences for retention- adherence-HIVDR

24. Acknowledgements PASER network Tobias Rinke de Wit (PI), Kim Sigaloff, Pascale Ondoa, Joep Lange, Michèle van Vugt, Rob Schuurman, Wendy Stevens, Kim Steegen, Carole Wallis, Margaret Siwale, Kishor Mandaliya, Prudence Ive, Ian Sanne, Mariette Botes, Maureen Wellington, Ruedy Luthy, Akin Osibogun, Cissy Kityo, Peter Mugyenyi, Nicaise Ndembi and many others WHO HIVResNet in particular Silvia Bertagnolio, Michael Jordan Other collaborators Ravi Gupta – UCL David van de Vijver, Brooke Nichols – Erasmus MC