General introduction PASER Collaboration with SATuRN Prof Tobias Rinke de Wit Thursday, November 21, 2013 Bloemfontein, South Africa

PASER & TASER networks

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

PASER sites selected from >50 CountrySiteTypeAdminSettingARV exp Total HAART ARVs free Research exp Patient tracing ZambiaLTHGeneral hospitalPrivateUrban1997No KARARV/TB clinicNGOUrban YesNoYes CHC ARV clinic in general hospital FBOUrban YesNoYes RSAMMHHIV GP practicePrivateUrban2000NoYes TLC ARV clinic in general hospital PublicUrban Yes ACCARV clinicNGORural YesNoYes KenyaCRH ARV clinic in general hospital PublicUrban Yes No MAT ARV clinic in general hospital FBOUrban YesNoYes UgandaJCRARV clinicPublicUrban Yes JFPARV clinicPublicRural YesNoYes MBAARV clinicPublicRural YesNoYes ZimCONARV clinicNGOUrban Yes NigeriaLUT ARV clinic in teaching hospital PublicUrban YesNoYes Situations at date of patient enrolment ( )

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

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

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

Baseline 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 Hamers et al. Lancet Inf Dis 2011

Confirmed by WHO data Gupta RK et al., Lancet 380, , ,102 patients from Africa, Asia, Latin America 32.9% annual increase of HIVDR in East Africa

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< P=0.001 Hamers et al. Lancet Inf Dis 2012 Baseline HIVDR doubles 1 st year risk of VF and acquired HIVDR Odds ratio

Slower recovery of CD4 in patients with baseline (pre-treatment) HIVDR

PASER-S studies indicate moderate TDR in Kampala and Mombasa OverallNRTI NNRTI PI Kampala 2 VCT, 09/10 D67G, L210WG190A, G190S, K101EN88D Prevalence6/70 = 8.6% ( )2.9% (2)4.3% (3)1.4% (1) WHO-TSS*Moderate (4/47)Low (2)Low (1) Mombasa 4 VCT, 09/10 K70RK103N (5)I85V, N88D, L90M Prevalence9/68 = 13.2% ( )1.5% (1)7.4% (5)4.4% (3) WHO-TSS*Moderate (5/47)Low (0)Moderate (3)Low (2) Ndembi et al. AIDS, 2011 Sigaloff et al. Aids Res Hum Retro 2011 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

Adding to WHO data 72 surveys 20 moderate level (5-15%) WHO HIV Drug Resistance Report, S Bertagnolio, IAS Conference July 26, 2012

13 The importance of VL testing: 4x less unnecessary switches Clinical + CD4 count (n=64) Clinical + CD4 count + targeted VL (n=186) Sigaloff et al. JAIDS 2011

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

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

>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. Ned Tijdschr Geneeskd 151, , 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, , 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-Saharan Africa. Antivir. Ther. 13, , Hamers, R.L., Rinke de Wit, T.F., Schellekens, O.P. and van Vugt, M. Aidsbehandeling in Afrika. Ned Tijdschr Geneeskd 152, 654, 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. Antiviral Therapy 14, , 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, , 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-line antiretroviral therapy in Lusaka, Zambia. JAIDS 55, , 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 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 comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequencfes versus full sequences. AIDS Res & Ther 7, 38, 2010: 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, , 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.Immune Defic. Syndr, 58, 23-31, 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: /S (11) , published on line, July 28, 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: /S (11) , August 26, 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 Inf Dis, DOI: /S (11) , published online, October 28, 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 (Epub ahead of print). Can be distributed on request, many on your USB sticks!

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

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

Collaboration 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)

Acknowledgements 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 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