0. 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

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

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

3. ART eligibility is increasing*
* HTPN 052 trial 
Gottfried Hirnschall WHO, IAS Conference July 26, 2012

4. 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

5. 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

6. 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

7. LAASER organizational structure
Linking Asian and African Societies
for an Enhanced Response to HIV/AIDS

8. PASER & TASER networks

9. 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

10. 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 ( )

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

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

13. PASER – key scientific results

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

15. 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

16. 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

17. 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

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

19. 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, , 2012

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

21. 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

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

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

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

25. 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% ( )
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% ( )
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

26. 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

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

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

29. 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

30. 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”

31. 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?

32. 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

33. 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

34. 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)

35. >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, , 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, , 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, , 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, , 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, , 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, , 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:
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, , 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: /S (11) , 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: /S (11) , 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: /S (11) , 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!

36. PASER – capacity building & advocacy

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

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

39. PASER – policy

40. 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”

41. 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

42. 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

43. 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

44. 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