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HIV Drug Resistance in sub-Saharan Africa Experiences with PASER Prof Tobias Rinke de Wit

HIV Drug Resistance in sub-Saharan Africa Experiences with PASER Prof Tobias Rinke de Wit. Wednesday, November 20, 2013 Bloemfontein, South Africa. Successful scale up of ART. Standardized population based approaches Inexpensive generic fixed dose combinations. 10 million.

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HIV Drug Resistance in sub-Saharan Africa Experiences with PASER Prof Tobias Rinke de Wit

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  1. HIV Drug Resistance in sub-Saharan Africa Experiences with PASER Prof Tobias Rinke de Wit Wednesday, November 20, 2013 Bloemfontein, South Africa

  2. Successful scale up of ART • Standardized population based approaches • Inexpensive generic fixed dose combinations 10 million Gottfried Hirnschall WHO, IAS Conference July 26, 2012

  3. ART coverage per region ART coverage * 2010 IDU HIV case reporting (18 countries) Gottfried Hirnschall WHO, IAS Conference July 26, 2012

  4. ART eligibility is increasing * * HTPN 052 trial  http://www.hptn.org/research_studies/hptn052.asp Gottfried Hirnschall WHO, IAS Conference July 26, 2012

  5. WHO  Simplified ART guidelines • 20-25 ARV drugs approved by FDA • In Africa: 90% of 1st line patients are on combinations of only 6 drugs: 3TC, d4T, AZT, TDF, EFV, NVP 1st line regimens in RLS 2nd line regimens in RLS WHO Progress Report 2011

  6. What is HIV drug resistance ? Drug resistance refers to a reduction in the ability of a particular drug or combination of drugs to cure a disease or block replication of pathogens Resistance = result of mutation and selection

  7. HIVDR in Africa • Intermittent drug supply  stock-outs Pasquet PlosONE11, Oyugi Aids07 • Patient adherence challenges, weak patient support systems Ajose AIDS12 • HR challenges (task shifting) • Use of sub-optimal regimens (single dose NVP for PMTCT) • Use of less costly ARV’s with higher toxicity (d4T) Hamers et al CID • Drug interactions (NVP-rifampicin) Boulle A, JAMA08 • High viral genetic diversity: subtypes  HIVDR? • Late reporting of patients • Lack of virological monitoring Hosseinipour AIDS09; Sigaloff JAIDS11, Gupta TLID09

  8. LAASER organizational structure 2006-2012 Linking Asian and African Societies for an Enhanced Response to HIV/AIDS

  9. PASER & TASER networks

  10. PASER objectives To build capacity on the monitoring and surveillance of HIV drug resistance in Africa by: • Network development • Clinics, laboratories, research groups • Training and mentoring of medical & lab staff • Observational studies • Prospective cohort of acquired HIVDR [PASER-M] • Cross-sectional surveys of transmitted HIVDR [PASER-S] • International clinical databases + HIV sequence databases • Laboratory Quality Assurance network (TAQAS) • To disseminate information, perform advocacy and realize • policy support

  11. PASER sitesselected from >50 * Rural sites underrepresented Situations at date of patient enrolment (2007-2009)

  12. PASER covers all important African 1st line ART regimens *+ 3TC/FTC + EFV/NVP

  13. PASER represents all major HIV-1 subtypes in Africa pol sequences, REGA and STAR algorithms (n=2436)

  14. PASER – key scientific results

  15. PASER and TASER: the teams Hamers et al., Int J Epidemiology Nov 2010

  16. PASER studies in figures 6 countries 13 clinical sites Enrolment Mar 2007 – Sept 2009 PASER S PASER M 2733 patients initiating 1st line followed up for at least 24 month • 2 cross sectional cohorts of ART-naive newly infected individuals • 81 patients in Mombasa • 77 patients in Kampala 250 patients enrolled at second line switch followed up for 24 months

  17. Key message #1“There is HIV drug resistance in Africa and it is on the rise”Baseline HIVDR analyses of >2,500 African patients on 1st line ART

  18. Prevalence of HIVDR in ARV-naive individuals by region and drug class Risk of primary HIVDR rose by 38% for each additional year since local ART roll-out

  19. Uganda: pre-therapy HIVDR • Dual-class resistance in Mbale • NNRTI and NRTI mutations

  20. Pre-therapy HIVDR (NNRTI) is on the rise in East Africa • 26,102 patients from Africa, Asia, Latin America • 29% annual increase of HIVDR in East Africa (36% for NNRTI) and Southern Africa (23%) Gupta RK et al., Lancet 380, 1250-8, 2012

  21. Key message #2“Baseline HIVDR  poorer prognosis”Patients who already have (some) HIVDR show poorer prognosis after starting 1st line ART

  22. Pre-therapy HIVDR doubles first-year risk of virological failure and acquired HIVDR P<0.0001 P=0.001 Odds ratio 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

  23. Slower recovery of CD4 in patients with pre-tharapy HIVDR

  24. Key message #3HIVDR is transmitted in Africa and has reached moderate levels in several settings Transmitted HIVDR

  25. Early WHO surveys from Africa reported low levels of TDR (<5%) Bennett et al. AVT, 2008

  26. TDR in Kampala and Mombasa (PASER-S) • WHO-recommended proxy criteria for recent infection: • Newly HIV-1 diagnosed and aged ≥18 and <25 years, or lab evidence of recent HIV-1 infection Ndembi et al. AIDS, 2011 Sigaloff et al. Aids Res Hum Retro 2011

  27. TDR surveys more recent findings (up to-2010) 72 surveys 20 moderate level (5-15%) WHO HIV Drug Resistance Report, S Bertagnolio, IAS Conference July 26, 2012

  28. Key message #4“Viral load testing is crucial”Lack of viral load testing  accumulation of complex HIVDR and unnecessary switching

  29. Targeted VL testing: 4x less unnecessary switches Clinical + CD4 count + targeted VL (n=186) Clinical + CD4 count (n=64)

  30. Lack of VL monitoring more HIVDR Cohort 1 (n=100) Virological failure by routine pVL test, 12 mo ART Cohort 2 (n=161) Clinico-immunological failure, 26 mo ART Stanford hivdbalgorithm Hamers CID12; Sigaloff JID12

  31. Key message #5“HIVDR in children may be more pronounced in Africa” pediatric HIVDR

  32. Extra risk factors for HIVDR in children • Perinatal exposure to antiretroviral medication • Higher baseline viral loads • Limited pediatric formulations • Adherence issues • Reluctance of doctors to switch in case of failure?

  33. MARCH* - objectives • Measure baseline HIVDR prevalence in children initiating 1st or 2nd line ART • Monitor virological response to treatment • Determine prevalence and patterns of HIVDR in children with detectable viral load • Identify risk factors for virologic failure and HIVDR * Monitoring Antiretroviral Resistance in Children

  34. MARCH-Uganda study • Prospective cohort study of 360 children in Uganda on ART • Initiated in January 2010 • Funded by EDCTP, NACCAP

  35. HIVDR among children initiating first-line ART Frequencies (%) of HIVDR mutations in patients initiating first-line treatment either ARV-naïve or with previous PMTCT (n=14) or unknown exposure status (n=32)

  36. >40 publications: international journals • Hamers, R.L., Schuurman R., van Vugt, M., Derdelinckx, I. and Rinke de Wit, T.F. De ontwikkeling van hiv-1 resistentiesurveillance in Afrika. NedTijdschrGeneeskd 151, 2666-2671, 2007. • Hamers, R., de Beer IH, Kaura, H., van Vugt, M., Caparos, L. and Rinke de Wit, T.F. Diagnostic accuracy of 2 oral fluid-based tests for HIV surveillance in Namibia. JAIDS 48, 116-118, 2008. • Hamers, R.L., Derdelinckx, I., van Vugt, M., Stevens, W., Rinke de Wit, T.F. and Schuurman, R. The status of HIV-1 resistance to antiretroviral drugs in sub-SaharanAfrica. Antivir. Ther. 13, 625-639, 2008. • Hamers, R.L., Rinke de Wit, T.F., Schellekens, O.P. and van Vugt, M. Aidsbehandeling in Afrika. NedTijdschrGeneeskd 152, 654, 2008. • Hamers, R.L., Smit, P., Stevens W., Schuurman, R. and Rinke de Wit, T.F. Dried fluid spots for HIV type-1 viral load and resistance genotyping: a systematic review. AntiviralTherapy 14, 619-629, 2009. • Wallis C., Papathanasopoulos, M., Rinke de Wit, T.F. and Stevens, W. Affordable in-house drug resistance assay with good performance in non-subtype B HIV-1. J Virol Meth 168, 505-508, 2010. • Hamers, R.L., Siwale, M., Wallis, C.L., Labib, M., van Hasselt, R., Stevens, W., Schuurman, R., van Vugt, M. And Rinke de Wit, T.F. Baseline drug-resistant HIV-1 at initiation of first-lineantiretroviraltherapy in Lusaka, Zambia. JAIDS 55, 95-101, 2010. • Hamers, R.L., Oyomopito R., Kityo, C., Phanuphak, P., Siwale, M., Sungkannuparph S., Conradie, F., Kumarasamy, N., Botes, Sirisanthana, T., M.E., Abdallah, S., Li, P.C.K., Ngorima N., Kantipong P., Osibogun, A., Lee, C.K.C., Stevens, Kamarulzaman, A., W.S., Derdelinckx, I., Arthur Chen, Y.-M., Schuurman, R., van Vugt, M. and Rinke de Wit, T.F. Cohort profile: the PharmAccess African (PASER-M) and the TREAT Asia (TASER-M) monitoring studies to evaluate resistance – HIV drug resistance in sub-Saharan Africa and the Asia-Pacific. Int J Epidemiol, Epub, Nov 2010. • Steegen, K., Bronze, M., van Craenenbroeck, E., Winters, B., van der Borght, K., Wallis, C.L., Stevens, W., Rinke de Wit, T.F. and Stuyver, L. A comparativeanalysis of HIV drug resistanceinterpretationbasedon short reversetranscriptasesequencfes versus full sequences. AIDS Res & Ther 7, 38, 2010: http://www.aidsrestherapy.com/content/7/1/38. • Ndembi, N., Hamers, R.L., Sigaloff, K.C.E., Lyagoba, F., Magambo, B., Nanteza, B., Watera, C., Kaleebu, P. and Rinke de Wit, T.F. Transmitted antiretroviral drug resistance among newly HIV-1 diagnosed young individuals in Kampala. AIDS 25, 905-910, 2011. • Sigaloff, K.C.E., Hamers, R.L., Wallis, C.L., Kityo, C., Siwale, M., Ive, P., Botes, M.E., Mandaliya, K., Wellington, M., Osibogun, A., Stevens, W.S., van Vugt, M. and Rinke de Wit, T.F. Unnecessary antiretroviral treatment switches and accumulation of HIV resistance mutations; two arguments for viral load monitoring in Africa. J.Acquir.ImmuneDefic. Syndr, 58, 23-31, 2011. • Hamers, R.L., Wallis, C.L., Kityo, C., Siwale, M.M., Mandaliya, K., Conradie, F., Botes, M.E., Wellington, M., Osibogun, A., Sigaloff, K., Nankya, I., Schuurman, R., Wit, F., Stevens, W., van Vugt, M. and Rinke de Wit, T.F. HIV-1 drug resistance among antiretroviral-naïve individuals in sub-Saharan Africa after rollout of antiretroviral therapy: multicentre observational study. Lancet Inf. Dis., DOI:10.1061/S1473-3099(11)70149-9, published on line, July 28, 2011. • Sigaloff K.C.E., Calis, J.C., Geelen, S.P., van Vugt, M. and Rinke de Wit, T.F. Resistance-associated mutations among children on antiretroviral treatment in resource-poor settings: a systematic review. Lancet Inf. Dis., DOI:10.1016/S1473-3099(11)70141-4, August 26, 2011. • Hamers, R.L., Schuurman, R., Sigaloff, K.C.E., Wallis, C.L., Kityo, C., Siwale, M., Mandaliya, K., Ive, P., Botes, M.E., Wellington, M., Osibogun, A., Wit, F.W., van Vugt, M., Stevens, W. and Rinke de Wit, T.F. Effect of pre-treatment drug-resistance on immunological, virological and drug-resistance outcomes after the first year of antiretroviral therapy for HIV-1: multicentre cohort in six African countries. Lancet InfDis, DOI:10.1016/S1473-3099(11)70255-9, published online, October 28, 2011. • Sigaloff, K.C., Mandaliya, K., Hamers, R.L., Otieno, F., Jao, I.M., Lyagoba, F., Magambo, B., Kapaata, A., Ndembi, N. and Rinke de Wit, T.F. High prevalence of transmitted antiretroviral drug resistance among newly HIV type 1 diagnosed adults in Mombasa, Kenya. AIDS Res. Hum. Retrovir., 2012 (Epubahead of print). Can be distributed on request, many on your USB sticks!

  37. PASER – capacity building & advocacy

  38. Capacity building:Regional Workshops & on-site training * ARTA = Affordable Resistance Testing for Africa

  39. Advocacy: keep HIVDR on the map  STAR, South Africa March 7, 2011 The Nation, Kenya August 1, 2011   Daily Monitor, Uganda April 25,2012

  40. PASER – policy

  41. April 2012: Uganda Policy Workshop “A consensus list of 14 recommendations was approved by 50 specialists and a policy document was offered to key East African health policy makers”

  42. Networking with WHO • PASER clinicalprotocolsare fullycoordinatedwithWHO HIV ResNet • PASER is represented in WHO HIV ResNet Board, technical working groups and policy meetings • WHO is (often) represented in PASER/ARTA meetings • PASER resultscontributed 25% to the data ofthefirstWHO HIVDR Global Report, June 2012 • PASER evaluated the WHO early warning indicators (EWI) • PASER reference labs are in WHO accreditation scheme • PASER consultancy services to WHO • WHO-funded research to inform HIVDR policy (long-term ADR, VF review, etc.) • >10 co-publications with key WHO policy makers

  43. Networking PASER – SATuRN • Expansion of clinical and laboratory databases on African HIV drug resistance, incl. new HIV subtypes (non-C) and incl. retrospective data >2007 • Strengthened joint training programs for African HIV clinicians • Strengthened joint advocacy of HIVDR through presentations at conferences, papers in journals, grey literature, mass media, websites, twitter, etc. • Improved advice to African HIV clinicians r.e. treatment of patients who are failing ART • Coordinated development, validation and marketing of more affordable HIVDR tests • Improved joint research options with increased data available; coordinated grant proposal writing (NIH, UNITAID, EDCTP) • Capacity building of SATuRN as an African network by Africans for Africans

  44. Linkages between PASER, SATuRN and the ASLM (African Society for Laboratory Medicine) to promote development and use of affordable HIVDR tests in future • Collaborations with Kenya: KEMRI-CDC with respect to DBS-based affordable HIVDR test productizing • Establishment of a South African working group on private sector patient HIVDR (medical aids, private labs) to coordinate with the SA National HIVDR Working Group • Co-analyses and co-publications with TASER Asian HIVDR on aggregate data Other (regional) networking

  45. Acknowledgements Clinical sites PIs and study teams Study participants University of the Witwatersrand, South Africa Wendy Stevens Carole Wallis Kim Steegen JCRC, Uganda Cissy Kityo Peter Mugyenyi MRC/UVRI, Uganda Nicaise Ndembi Pontiano Kaleebu PharmAccess Foundation Dept of Global Health AMC-UvA Amsterdam Institute for Global Health and Development Elske Straatsma John Dekker Annedien Plantenga Nicole Spieker Raph Hamers Kim Sigaloff Desiree Lathouwers Aletta Kliphuis Peggy van Leeuwen Corry Manting Pascale Ondoa Joep Lange Michèle van Vugt Tobias Rinke de Wit UMCU Virology, The Netherlands Rob Schuurman Annemarie Wensing

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