hiv drug resistance in sub-saharan africa experiences with paser prof tobias rinke de wit wednesday,...
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HIV Drug Resistance in sub-Saharan Africa
Experiences with PASERProf 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
Gottfried Hirnschall WHO, IAS Conference July 26, 2012
10 million
ART coverage per region
AR
T c
overa
ge
* 2010 IDU HIV case reporting (18 countries)
Gottfried Hirnschall WHO, IAS Conference July 26, 2012
ART eligibility is increasing
Gottfried Hirnschall WHO, IAS Conference July 26, 2012
* HTPN 052 trial http://www.hptn.org/research_studies/hptn052.asp
*
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
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
HIVDR in Africa
LAASER organizational structure
Linking Asian and African Societies
for an Enhanced Response to HIV/AIDS
2006-2012
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 sitesselected 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 No No
KAR ARV/TB clinic NGO Urban 2004 870 Yes No Yes
CHC ARV clinic in general hospital
FBO Urban 2006 494 Yes No Yes
RSA MMH HIV GP practice Private Urban 2000 No Yes Yes
TLC ARV clinic in general hospital
Public Urban 2004 9500 Yes Yes Yes
ACC ARV clinic NGO Rural 2005 1000 Yes No Yes
Kenya CRH ARV clinic in general hospital
Public Urban 2003 4439 Yes Yes No
MAT ARV clinic in general hospital
FBO Urban 2007 501 Yes No Yes
Uganda JCR ARV clinic Public Urban 1992 7200 Yes Yes Yes
JFP ARV clinic Public Rural 2003 1800 Yes No Yes
MBA ARV clinic Public Rural 2001 1230 Yes No Yes
Zim CON ARV clinic NGO Urban 2004 1000 Yes Yes Yes
Nigeria LUT ARV clinic in teaching hospital
Public Urban 2002 4237 Yes No Yes
* Rural sites underrepresented Situations at date of patient enrolment (2007-2009)
PASER covers all important African 1st line ART regimens
0%
10%
20%
30%
40%
50%
60%
70%
80%
90%
100%
Over
all
Zambia
South Af
rica
Ugan
da
Keny
a
Zimba
bwe
Nige
ria
ZDV*
TDF*
D4T*
ABC*
PI-based
*+ 3TC/FTC
+ EFV/NVP
PASER represents all major HIV-1 subtypes in Africa
pol sequences, REGA and STAR algorithms (n=2436)
Zambia South Africa Uganda
Kenya Zimbabwe Nigeria
Total
A C D G CRF02 Other
Graphs by country
PASER – key scientific results
Hamers et al., Int J Epidemiology Nov 2010
PASER and TASER: the teams
PASER studies in figures
2733 patients initiating 1st line followed up for at least 24 month
250 patients enrolled at second line switch followed up for 24 months
6 countries13 clinical sitesEnrolment Mar 2007 – Sept 2009
PASER M
2 cross sectional cohorts of ART-naive newly infected individuals
• 81 patients in Mombasa
• 77 patients in Kampala
PASER S
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
• Dual-class resistance in Mbale
• NNRTI and NRTI mutations
Pre-therapy HIVDR (NNRTI) is on the rise in East Africa
Gupta RK et al., Lancet 380, 1250-8, 2012
• 26,102 patients from Africa, Asia, Latin America
• 29% annual increase of HIVDR in East Africa (36% for NNRTI) and Southern Africa (23%)
Key message #2
“Baseline HIVDR poorer prognosis”
Patients who already have (some) HIVDR show poorer prognosis after starting 1st
line ART
No PDR (n=2404)
PDR and fully-active
ART (n=52)
PDR and partially-ac-
tive ART (n=123)
0.0
0.5
1.0
1.5
2.0
2.5Virological failure
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<0.0001
P=0.001
Hamers et al. Lancet Inf Dis 2012
Pre-therapy HIVDR doubles first-year risk of virological failure and acquired HIVDR
Odds
rati
o
Slower recovery of CD4 in patients with pre-tharapy HIVDR
Key message #3
HIVDR is transmitted in Africa and has reached moderate levels in several settings
Transmitted HIVDR
Early WHO surveys from Africa reported low levels of TDR (<5%)
Bennett et al. AVT, 2008
TDR in Kampala and Mombasa (PASER-S)
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) Low (1)
Mombasa
4 VCT, ‘09/’10
K70R K103N (5) I85V, N88D, L90M
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)
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
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
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 (n=64)
Clinical + CD4 count + targeted VL (n=186)
10
90%
27%73
% 57%
43%
42%
58%
Cohort 1 (n=100)Virological failure by
routine pVL test, 12 mo ART
3TC FTC AZT d4T ddI TDFABC EFV NVP ETR RPV0
10
20
30
40
50
60
70
80
90
100High-level resistance
Intermediate resistance
Low-level resistance
Potential low-level resistance
Susceptible
Reverse-transcriptase inhibitors
% o
f s
equ
en
ce
s
Lack of VL monitoring more HIVDR
Cohort 2 (n=161)Clinico-immunological
failure, 26 mo ART
Hamers CID12; Sigaloff JID12Stanford hivdb algorithm
Key message #5
“HIVDR in children may be more pronounced in Africa”
pediatric HIVDR
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
ART initiation
or switch
~310 (75%)
first-line
ARV-naive PMTCT
~ 50 (15%)
second-line
• Prospective cohort study of 360 children in Uganda
on ART• Initiated in January 2010• Funded by EDCTP, NACCAP
0
5
10
15
20
25
First-line (n=279) ARV-naive (n=233)
ARV-exp (n=46)
%
Any mutation
NRTI
NNRTI
2-class
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)
HIVDR among children initiating first-line ART
>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 d
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on
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any
on y
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!
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”
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 with WHO
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
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
Acknowledgements
PharmAccess FoundationDept of Global Health AMC-UvAAmsterdam Institute for Global
Healthand Development Elske StraatsmaJohn DekkerAnnedien PlantengaNicole SpiekerRaph HamersKim SigaloffDesiree LathouwersAletta KliphuisPeggy van LeeuwenCorry MantingPascale OndoaJoep LangeMichèle van VugtTobias Rinke de Wit
UMCU Virology, The NetherlandsRob SchuurmanAnnemarie 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