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Transmitted ARV drug resistance: what’s next?

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. Global scale-up of ART. WHO public health model.

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Transmitted ARV drug resistance: what’s next?

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

  3. Should we fear a dramatic increase in HIVDR? Lancet 2001 "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

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

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

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

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

  8. Prevalence of HIVDR in ARV-naïve individuals, by time since ARV rollout East Africa Southern Africa 29%/yr (95%CI 15-45; p=0.0001) 14%/yr (0-29; p=0.05) NNRTI: 36%/yr (21-52; p<0.0001) NNRTI: 23%/yr (7-42; p=0.0049) Latin America+Caribbean West and Central Africa 3%/yr (–0.9-16; p=0.618) p=0.960 NNRTI: 15%/yr (–1-32; p=0.0646) 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

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

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

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

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

  13. WHO HIV Drug Resistance Report 2012

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

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

  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 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 Infectionsaverted Over 10-year period Nichols et al. AIDS2013

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

  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: • Already HIV-infected when starting PrEP • Non-adherent and infected while on PrEP • 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. 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). van de Vijver, AIDS2013

  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, butnot at unexpectedlevels 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 networkTobias Rinke de Wit (PI), Kim Sigaloff, Pascale Ondoa, Joep Lange, Michèle van Vugt, Rob Schuurman, Wendy Stevens, Kim Steegen, Carole Wallis, Margaret Siwale, KishorMandaliya, Prudence Ive, Ian Sanne, Mariette Botes, Maureen Wellington, RuedyLuthy, Akin Osibogun, Cissy Kityo, Peter Mugyenyi, Nicaise Ndembi and manyothers WHO HIVResNet in particular Silvia Bertagnolio, Michael Jordan Othercollaborators Ravi Gupta – UCL David van de Vijver, Brooke Nichols – Erasmus MC

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