HIV drug resistance in Africa Prof Tobias Rinke
HIV drug resistance in Africa Prof Tobias Rinke de Wit Pharm. Access Foundation & Amsterdam Institute for Global Health and Development
Moving to 20 million
Progress towards the 90– 90 targets Africa, 2017 59% * 81% * 78% = 37% Source: UNAIDS Ending AIDS Progress towards the 90– 90 targets 2017
Viral heterogeneity Resistance High genetic diversity of HIV-1 • Production of 1 -10 billion virus particles per day • Reverse transcription prone to error • No proof-reading mechanism • ~1 (random) mutation per new provirus • Large numbers of mutants quasispecies • subtypes A-K • sub-subtypes A 1 -A 4, F 1 -F 2* • CRF (>52 circulating recombinant forms)* • HIV drug resistance * Tatem, AJ, Hemelaar J, Gray RR and Salemi M, AIDS 26, 2012
Viral Load Resistance: a selection process Time
HIV is a swarm
When you start ART…
The amount of virus is reduced
If you do not take ART correctly… Y Y US OB TO TO O LZ . . there will be in-complete suppression of replication
Resistant virus will occur ‘Selection pressure’ causes the resistant strains to replicate
Pill sharing
Adherence is key Catherine Orrell, personal communication, 2014
Should we fear a dramatic increase of HIVDR? Lancet 2001 The malaria disaster "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
2006 Int J Epidem 2012
HIV drug resistance
PASER cohorts 6 countries 13 clinical sites Enrolment Mar 2007 – Sept 2009 PASER S PASER M 2733 patients initiating 1 st line followed up for at least 24 month 208 Nigeria 250 patients enrolled at second line switch followed up for 24 months 32 Nigeria 2 cross sectional cohorts of ART -naive newly infected individuals • 81 patients in Mombasa • 77 patients in Kampala Int J Epidem 2012
Pre-treatment HIVDR (PDR)
PDR doubles (Y 1) risk of VF and acquired HIVDR 2. 5 P=0. 001 Odds ratio 2. 0 1. 5 P<0. 0001 Virological failure Acquired drug-resistance 1. 0 0. 5 91% 86% 75% % Viral suppression 0. 0 No PDR (n=2404) PDR and fullyactive ART (n=52) PDR and partiallyactive ART (n=123) Hamers et al. Lancet Inf Dis 2012
PDR Slower recovery CD 4
PDR regimen switching Proportion of patients who switched N=88/2372=3. 7% N=18/117=15. 4% N=70/2255=3. 1% Cox PH analysis: switch due to VF+ADR * adjusted for sex and age Boender et al. , CID 2015
Proportion ART re-initiators is increasing WHO HIVRes. Net, courtesy S. Bertagnolio
Prior ARV use increases risk of VF patients with prior ART have 3 x higher risk of VF Characteristic N No of events Unadjusted OR (95%CI) Pvalue **adjusted OR (95%CI) P-value Prior ARV use No 1948 184 1. 0 Yes 83 17 2. 47 (1. 42 -4. 30) <0. 001 2. 72 (1. 42 -5. 21) 0. 002 Type of prior ARV use None 1948 184 1. 0 ART 41 10 3. 09 (1. 49 -6. 41) 0. 002 2. 99 (1. 25 -7. 15) 0. 014 sd. NVP 29 5 2. 00 (0. 75 -5. 30) 0. 165 3. 25 (1. 14 -9. 22) 0. 027 Others 13 2 1. 74 (0. 38 -7. 92) 0. 472 1. 38 (0. 27 -7. 13) 0. 703 models were adjusted for pre-treatment drug resistance, pre-treatment CD 4 counts, type of first ART initiated, sex, age, calendar year of ART treatment initiation and adherence *others; non-sd. NVP mono-therapy or dual therapy Inzaule et al. , submitted 2017
Prior ARV use increases risk of PDR patients with prior ART have 7 x higher risk of PDR Characteristic N No of events Prior ARV use No Yes 2534 288 119 39 Unadjusted OR (95%CI) Pvalue **adjusted OR (95%CI) P-value 1. 0 6. 82 (4. 30 -10. 82) <0. 001 7. 17 (4. 39 -11. 69) <0. 001 Type of prior ARV use None 2534 288 1. 0 ART 58 20 8. 30 (4. 50 -15. 30) <0. 001 9. 07 (4. 79 -17. 16) <0. 001 sd. NVP 39 10 4. 43 (1. 91 -10. 24) 0. 008 3. 35 (1. 38 -8. 17) 0. 008 Others* 22 9 8. 09 (3. 08 -21. 25) <0. 001 15. 01 (5. 35 -42. 14) <0. 001 models were adjusted for age, sex, country, year of treatment initiation, pre-treatment viral-load, CD 4 counts and WHO clinical stage *non-sd. NVP mono-therapy or dual therapy Inzaule et al. , submitted 2017
Consequences PDR (literature) Children <12 with PDR are: • 15 x more likely to have VF at 24 m • 3 -4 x more likely for ADR at 24 m (Kityo et al. , JAC 2017) Adults with PDR are: • 4 x More likely to have VF at 12 months (Ávila-Ríos S et al. , The Lancet Inf. Dis. 2016) • 2 x More likely for ADR at 12 months (Hamers et al. The Lancet Inf. Dis. 2011) • 3 x More likely to discontinue ART by 12 m (un-published meta-analysis WHO 2017) • Have slower CD 4 recovery (Hamers et al. The Lancet Inf. Dis. 2011) • 3 -4 x More likely to switch to 2 nd line (Boender et al. , CID 2015)
PDR by region and drug class Pre-ART HIVDR prevalence Overall: 5. 6% Pretoria: 1. 1% Kampala: 12. 3% Yearly increase risk of PDR prevalence: 38% (p=0. 001, multivariate analysis) Mostly NNRTI mutations, except Uganda 2436 sequences from 2590 participants Hamers et al. , TLID 11, 750 -9, 2011
Increasing PDR Estimated Incremental annual increase: 23% in Southern Africa, 17% in west-central Africa, 29% in Eastern Africa WHO HIVDR report, July 2017
Pre-treatment NNRTI resistance 6 out of 11 national surveys: >10% NNRTI resistance Source: WHO HIV Drug Resistance Report 2017
Transmitted HIVDR (TDR)
Early TDR recordings Overall Kampala NRTI NNRTI PI D 67 G, L 210 W G 190 A, G 190 S, K 101 E N 88 D 2 VCT, ‘ 09/’ 10 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) K 70 R K 103 N (5) I 85 V, N 88 D, L 90 M Mombasa 4 VCT, ‘ 09/’ 10 Prevalence 9/68 = 13. 2% (6. 2 -23. 6) 1. 5% (1) 7. 4% (5) 4. 4% (3) WHO-TSS* Moderate (5/47) Low (0) Moderate (3) Low (2) WHO-consecutive sampling approach WHO-recommended proxy criteria for recent infection: • • Newly HIV-1 diagnosed and aged ≥ 18 and <25 years Lab evidence of recent HIV-1 infection Ndembi et al. AIDS, 2011 Sigaloff et al. Aids Res Hum Retro 2011
Confirming and extending WHO data: TDR surveys 72 surveys 20 moderate level (5 -15%) WHO HIV Drug Resistance Report, S Bertagnolio, IAS Conference July 26, 2012
TDR location specific K = 1. 1% M =13. 2% 182 participants; 138 women (76%) Transmitted HIVDR: 2/182 = 1. 1% (95% CI, 0. 1 – 3. 9) TDR data can vary substantially between geographically close locations (55 km) limitations to WHO consecutive sampling approach
Acquired HIVDR (ADR)
Overall PASER ADR mutations in line with WHO studies in 40 countries WHO, pooled data n=269 S Bertagnolio WHO, IAS Conference July 26, 2012 Hamers et al. CID 2012 N = 142
Five year VF and ADR among 1 st line patients Lagos Longer term ADR increase (similar observations in other PASER sites)
ADR among adults on failing ART Source: WHO HIV Drug Resistance Report 2017
ADR among children on failing ART Source: WHO HIV Drug Resistance Report 2017
Beyond 2 nd line: towards untreatable HIV in Africa?
Pediatric HIVDR
Pediatric HIV Treatment 2016 First-line treatment <3 years PI + 2 NRTI ≥ 3 years NNRTI + 2 NRTI Second-line treatment <3 years Ral + 2 NRTI ≥ 3 years PI + 2 NRTI
HIV drug resistance data in children is scarce 1 out of 3 African countries reporting PDR in children 1 out of 15 worldwide Rojas Sánchez & Holguín, 2014
MARCH-Uganda study • Prospective cohort study of 360 children (≤ 12 years) • Follow-up > 2 Y, VL testing every 6 months • HIVDR test when VL>1000 ART initiation or switch ~310 (85%) ~ 50 (15%) first-line second-line ARV-naive PMTCT
PDR in Ugandan children 10% Pre-treatment HIVDR in children of average 5 Y (8% in naive children, 22% in PMTCT-experienced children) C. Kityo et al. , ARHR, 2016
Alarming pediatric PDR • Meta-analysis including 2, 617 children in 13 African countries • Pooled PDR prevalence is 12. 7% in PMTCT-unexposed and 42. 7% in PMTCTexposed children • PDR prevalence increased in PMTCT-unexposed children from 0% (2004) to 26. 8% (2013) • PI-based first-line ART should be initiated in children (<3 Y) and possibly also in older children Boerma et al, Journal of Antimicrobial Chemotherapy, 2016
VF at 2 nd line ART in children: adolescents at high risk • 16. 4% VF after 54 months overall • 26. 3% among adolescents • 9. 1% among young children • adjusted hazard ratio ~4 for VF among adolescents Including 12 cohorts, 928 children on second-line protease inhibitor (PI)-based ART in 14 countries in Asia and sub-Saharan Africa Boerma et al, JIAS 2017
Pediatric HIVDR survey Nigeria participating EID labs Sokoto 8 15 Katsina Jigawa 3 Zamfara Yobe Borno Kano Kebbi 14 Kaduna Niger 5 Plateau Kwara FCT 1 Nasaraw a Oyo Ogun Ondo Lagos 7 12 Edo 11 Delta Bayelsa Anambra 10 Osun Gombe 16 9 6 Enugu Ebonyi Cross River Imo Abia Rivers Benu e Adamawa 4 Tarab a Kogi Ekiti 13 Bauchi 1. ALTC, Abuja 2. UUTH, Akwa Ibom 3. AKTH, Kano 4. FMC, Jalingo, Taraba 5. JUTH, Plateau 6. NAUTH, Anambra 7. LUTH, Lagos 8. UMTH, Borno 9. PLASVIREC, Plateau 10. OAUTH, Osun 11. UBTH, Edo 12. FMC-Makurdi, Benue 13. FTC-Gombe 14. ABUTH, Kaduna 15. UDUTH, Sokoto 16. OLA, Jos Plateau Non-Participating sites Akwa Ibom 2 Inzaule et al, AIDS 2017
For 430 children with HIVDR results Analyses ongoing with Beth Chaplin / Phyllis Kanki Inzaule et al, AIDS 2017
WHO HIVRes. Net confirms PDR in ART naive children <18 M, 2012 -2016 National surveys: Mozambique, Swaziland, Uganda, Zimbabwe, South Africa Jordan MR et al. CID in press
Capacity building remains important
Capacity building: workshops & on-site training • 2006, Johannesburg: PASER Network meeting • 2007, Dar es Salaam: Advanced Medical Training • 2008, Kampala: PASER Network meeting • 2008, Nairobi: PASER/ARTA* Network meeting • 2009, Lusaka: PASER/ARTA Network meeting • 2010, Entebbe: PASER/ARTA Network meeting • 2012, Kampala: ARTA/PASER Policy workshop • 2013, Bloemfontein: PASER/SATu. RN Medical Training
Advocacy: keep HIVDR on the map STAR, South Africa March 7, 2011 The Nation, Kenya August 1, 2011 Daily Monitor, Uganda April 25, 2012
New class of ARVs
Low integrase inhibitor resistance in SSA • 45. 00 • 40. 00 35. 00 • 30. 00 424 patients with VL>400 after 1 year 1 st line ART Accessory mutations at higher frequencies in Kenya, Uganda, Nigeria (subtypes A, G and A/G). major INSTI mutations <5%: Resistant threshold only as minority variants. <2% 2 -4% % 25. 00 5 -10% 20. 00 10 -20% 15. 00 ≥ 20% 10. 00 5. 00 0. 00 All KE UG NG ZA any. IASmajor. DRM SA All KE UG NG ZA SA any. Accessorymutation Integrase inhibitors (like DTG!) are predicted to be effective in SSA Inzaule et al, submitted 2017
DTG as ‘anti HIVDR drug’ Advantages • Superior in 1 st line to EFV, atazanavir, darunavir • Better in 2 nd line than LPV/r and better in 3 rd line than raltegravir • Affordable in FDC with 3 TC and TDF (TLD at $75/year) • Minimal drug interactions, long half-life • Good safety profile, minimal toxicities • High HIVDR threshold and large fitness cost if HIVDR Disadvantages • Neuropsychiatric side-effects, little experience in Africa • Higher IRIS risk for low CD 4 patients starting on DTG • Interaction with some tuberculosis drugs (rifampetine) • Insufficient data during pregnancy and in young children • Supply issues (only 2 generic companies produce DTG) • Pending DTG registration and accommodation in National ART guidelines • Logistical challenges, training, information provision • If positioned as ‘the solution’ decreased funding for HIVDR monitoring
Monitoring VL at the population level
Background • Viral load (VL) is the most reliable indicator of treatment failure during antiretroviral therapy (ART) • Since 2013, the World Health Organization recommends using VL to monitor patients on ART and support appropriate regimen switches. Start antiretroviral therapy First-line treatment failure Second-line treatment VL result Lack of access to VL testing: <40% of those in need
VL suppression in LMICs in adults Meta-analysis of 165 studies >85% <1, 000 cps/ml Boender et al. CID 2015.
VL suppression in LMICs in children Meta-analysis of 72 studies, Including 51, 347 children After 12 months 65 -73% VL <1, 000 cps/ml Boerma et al. CID, in press
VL monitoring: 4 x less unnecessary switches Clinical + CD 4 count (n=64) Clinical + CD 4 count + targeted VL (n=186) Sigaloff et al. , J. Acquir. Immune Defic. Syndr. 58, 23 -31, 2011
No VL monitoring more HIVDR Cohort 1 (n=100) Virological failure by routine p. VL test, 12 mo ART 10 90 % 73 % 27 % Cohort 2 (n=161) Clinico-immunological failure, 26 mo ART 43 % 57% 42% 58% Hamers CID 12; Sigaloff JAIDS 12
Misclassification of first-line failure Clinical failure Accumulation of mutations Immunologic failure Viral Load Unneccessary switch False-negative Virologic failure False-positive
Monitoring HIVDR at the population level
WHO monitoring and surveillance of HIVDR EWI: monitored annually at all/representative national ART clinics: • On-time pill pick-up • Retention on ART at 12 months • Drug stock-out • Viral load suppression • Viral load testing completion • Appropriate switch to second-line ART Surveillance of pre-treatment HIV drug resistance in adults initiating firstline ART Surveillance of acquired HIV drug resistance in adults and children on treatment Surveillance of HIV drug resistance in infants >18 months of age WHO (2017) Tackling HIV drug resistance: trends, guidelines and global action
Worrying EWI results 59 countries, 12, 000 clinics, 2004 -2014 • Overall 99. 1% of patients are prescribed correct drugs (92. 7% in Americas; 95. 9% in Western Africa) • Overall 20% LTFU after 1 year (exceeding recommended 15%); increasing from 11. 9% in 2004 to 24. 5% in 2012; highest in Africa (20%30%) • 1 year retention in ART program: 73. 5% (falling short of recommended 85%); lowest in West and Central Africa • Overall 85. 5% on time pill pickup (lower than recommended 90%); 69. 9% in Africa versus 91. 4% in South-East Asia • Overall 63. 3% on-time appointment keeping (short of 80%); 40. 7% in Western Africa! • Overall 35. 7% drug stock-outs amongst 1, 703 clinics; highest in Africa WHO EWI report 2016
Incremental impact HIVDR over the coming 3 years Adapted from: Phillips et al; JID 2017
Overall HIVDR concerns • T&T programs provide ART in earlier phase (higher CD 4) healthy people have lower adherence more HIVDR? • Reaching 90 -90 -90 implies 27% not virally suppressed, likely key populations at higher risk (adolescents, HIVDR • Doubling target population for ART (to 37 million) increases risk of insufficient ARVs, stock-outs, drug sharing HIVDR • Patients in Africa switch too late to 2 nd line longer ARV exposure during a failing 1 st line increase HIVDR • Increased VL testing increased detection of viral failure, increased switching increased HIVDR testing costs ($) • ARVs used in Africa are low-barrier drugs (expired patents) higher HIVDR • Overall: more HIVDR more ART failures higher population viral load no incidence reduction
WHO: Global Action Plan on HIVDR WHO (2017) Tackling HIV drug resistance: trends, guidelines and global action
Challenges ahead
PEPFAR: 2004 - 2015 funding (US$ millions) www. pepfar. gov June 2014
Challenges for the years to come • Target population of people qualifying for ART has doubled since WHO recommendation 2015 • Generic drug producers are struggling to keep up with drug consumption, given low margins • Stagnating ART supply can result in pill sharing, etc. increased HIVDR • International funding for HIV treatment is stagnating/declining and alternative funding by LMIC is hardly taking off • HIVDR is present, increasing over time and makes 3% of Africa patients already ‘untreatable’; no access to 3 rd line ART • Children are particularly vulnerable (adolescents even more) • More than ever HIVDR monitoring is needed to protect and sustain ART impact in LMIC 70
“Be creative and think big to tackle the real problems” 71
Acknowledgments Pharm. Access Foundation Amsterdam Institute for Global Health and Development Sonia Boender Seth Inzaule Ragna Boerma Raph Hamers Kim Sigaloff Stefanie Kroeze Ferdinand Wit Pascale Ondoa Joep Lange † Michèle van Vugt Tobias Rinke de Wit (PI) UMCU Virology Rob Schuurman Annemarie Wensing Erasmus MC David van de Vijver Brooke Nichols Study participants and staff PASER MARCH WHO HIVRes. Net Silvia Bertagnolio Michael Jordan Joseph Perriens Neil Parkin Treat. Asia/amf. AR Kevin Frost Jeffery Smith Annette Sohn TASER sites UNSW/Kirby Institute Matthew Law Sally Land Aids. Fonds Ton Coenen Uganda Pontiano Kaleebu Cissy Kityo Peter Mugyenyi Immaculate Nankya South Africa Wendy Stevens Carole Wallis Kim Steegen Ian Sanne Francesca Conradie Prudence Ive Mariette Botes † Zimbabwe Ruedy Luthy Maureen Wellington Zambia Margaret Siwale Moheb Labib Kenya Stanley Luchters Saade Abdallah Kishor Mandaliya Nigeria Akin Osibogun Sulaimon Akanmu Nicaise Ndembi
- Slides: 72