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 Gottfried Hirnschall WHO, IAS Conference July 26, 2012

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

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

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

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

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

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

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 Country Site Type Admin Setting ARV exp Total HAART ARVs free Research exp Patient tracing Zambia LTH General hospital Private Urban 1997 No KAR ARV/TB clinic NGO 2004 870 Yes CHC ARV clinic in general hospital FBO 2006 494 RSA MMH HIV GP practice 2000 TLC Public 9500 ACC ARV clinic Rural 2005 1000 Kenya CRH 2003 4439 MAT 2007 501 Uganda JCR 1992 7200 JFP 1800 MBA 2001 1230 Zim CON Nigeria LUT ARV clinic in teaching hospital 2002 4237 * Rural sites underrepresented Situations at date of patient enrolment (2007-2009)

PASER covers all important African 1st 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 – key scientific results

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

PASER studies in figures 6 countries 13 clinical sites Enrolment Mar 2007 – Sept 2009 PASER M PASER S 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

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

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

Uganda: pre-therapy HIVDR Titel: duidelijk aangeven dat dit pretherapy HIVDR in ARV-naives betreft Dual-class resistance in Mbale NNRTI and NRTI mutations

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

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

Pre-therapy HIVDR doubles first-year risk of virological failure and acquired HIVDR 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

Slower recovery of CD4 in patients with pre-tharapy HIVDR

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

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

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 Overall NRTI NNRTI PI Kampala 2 VCT, ‘09/’10 D67G, L210W G190A, G190S, K101E N88D Prevalence 6/70 = 8.6% (3.2-17.7) 2.9% (2) 4.3% (3) 1.4% (1) WHO-TSS* Moderate (4/47) Low (2) Low (1) Mombasa 4 VCT, ‘09/’10 K70R K103N (5) I85V, N88D, L90M 9/68 = 13.2% (6.2-23.6) 1.5% (1) 7.4% (5) 4.4% (3) Moderate (5/47) Low (0) Moderate (3) Ndembi et al. AIDS, 2011 Sigaloff et al. Aids Res Hum Retro 2011

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

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

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

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 hivdb algorithm Hamers CID12; Sigaloff JID12

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

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?

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

MARCH-Uganda study Prospective cohort study of 360 children in Uganda on ART Initiated in January 2010 Funded by EDCTP, NACCAP ART initiation or switch ~310 (75%) first-line ARV-naive PMTCT ~ 50 (15%) second-line

HIVDR among children initiating first-line ART Among the children initiating first-line ART, 28 (10.0%) harbored at least one HIVDR mutation. HIVDR per drug class was 5.7% for NRTI and 7.5% for NNRTI; 3.2% had dual-class resistance. PI mutations were not observed. Separate analysis of ARV-naïve and ARV-experienced children revealed at least one HIVDR mutations in 7.7% and 21.7% of samples, respectively. 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)

>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, 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-Saharan Africa. Antivir. Ther. 13, 625-639, 2008. Hamers, R.L., Rinke de Wit, T.F., Schellekens, O.P. and van Vugt, M. Aidsbehandeling in Afrika. Ned Tijdschr Geneeskd 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. Antiviral Therapy 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-line antiretroviral therapy 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 comparative analysis of HIV drug resistance interpretation based on short reverse transcriptase sequencfes 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.Immune Defic. 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 Inf Dis, 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 (Epub ahead of print). Can be distributed on request, many on your USB sticks!

PASER – capacity building & advocacy

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

PASER – policy

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”

Networking with WHO PASER clinical protocols are fully coordinated with WHO 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 results contributed 25% to the data of the first WHO 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

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

Other (regional) networking 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

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