art-a development of an a ffordable r esistance t est for a frica
DESCRIPTION
ART-A Development of an A ffordable R esistance T est for A frica. Tobias Rinke de Wit. [email protected]. Rapid Worldwide Access to ART. Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008. - PowerPoint PPT PresentationTRANSCRIPT
Towards Universal Access – Scaling up priority HIV/AIDS interventions in the health sector. WHO/UNAIDS/UNICEF, June 2008
Rapid Worldwide Access to ART
However: Resistance is Looming
Health systems Africa• Stock outages• Shortage of staff• Insufficient patient
adherence support• Sub-optimal drug
prescribing patterns• Limited access to
virological monitoring
Drug Pressure
TimeTime
wild-type virus(drug sensitive)
mutant virus(drug resistant)
Drug Pressure
TimeTime
wild-type virus(drug sensitive)
mutant virus(drug resistant)
Consequences of limited access to VL monitoring
Week 48 NVP/EFZ major
3TC
M184V
TAM
any
ddI/ABC/TDF
K65R
VL infrequent
83% 81% 28% 4%
VL every 3 months
61% 40% 12% 3%
Gupta RK, Hill A, et al., Lancet Infect. Dis. 2009; 9: 409-17
week 48 genotyping data on 8,376 patients, 10 studies, mostly Western world
5
Resistance Tests: What are the Barriers?
● Technically complex
● Technology and kit-dependent
● Sophisticated equipment required
● Requires skilled staff
● Requires special lab infrastructure (contamination)
● Not all HIVDR mutations known
● Mainly subtype B adapted (Europe, US, Australia)
● Expensive
VL + HIVDR Costs
VL tests 1st line 2nd line total/yr2006 250 250 25 2752007 2160 175 2335 234 25692008 1280 1512 140 2932 293 32252009 896 1210 112 2218 222 24392010 717 968 90 1774 177 1951
10460
HIVDR tests2006 250 250 25 2752007 2160 60 2220 222 24422008 1280 518 20 1819 182 20012009 307 176 9 492 49 5412010 104 75 4 184 18 202
5461
Cost for VL and HIVDR testing PASER-M program
Assumptions• VL = $30 / test
• HIVDR = $300 / test
• 10% on 2nd line per Y
• 3,000 patients target
• baseline, Y1, Y2 visits
• 1st line: 10% fail + 10% death/LFU
• 2nd line: 10% fail + 25% death/LFU
0
100000
200000
300000
400000
500000
600000
700000
800000
900000
2006 2007 2008 2009 2010
year
US
$
viral load
HIVDR
total
$ 1,952,139
~ extra $250 per patient per year
Goal of ART-A Consortium
The ART-A Research consortium is a public private initiative that aims to
develop a new and more affordable set of protocols for HIV resistance testing
in resource-poor settings
7
Considerations for ARTA Protocolhighlights
● Should provide affordable and practical solutions for HIVDR determination in Africa
● Should be HIV subtype independent● Should be web-based and freely available to interested
clinics in Africa● Should ideally cover a (semi-)quantitative HIV viral load
test● Should be compatible with African field conditions (DBS-
based)● Should concentrate on RT inhibitors, but not exclude
protease inhibitors● Should be adapted to different levels of clinics● Should produce close to real-time data● Should have a “financial mirror image” calculating costs
both at clinic and country level
9
Location of Activities
10
ART-A consortium
11
● Public/Private (50%/50%)
● Public: Netherlands Organization for Research/Science for Global Development (NWO/WOTRO) under the Netherlands Africa partnership for Capacity development and Clinical Interventions Against Poverty related diseases (NACCAP)
● Private: VIRCO, CLS
● AMC - Center for Poverty related Communicable Diseases (AMC-CPCD)
● New algorithm for Affordable Resistance Testing, accessible via web, validated by HIVDR phenotyping
● Information dissemination using different tools and for different groups (Health care professionals, Health policy makers, etc.)
● Training & technical assistance
● 2 PhD programs
● Financial models
● IP protection
Financing and Delivery
Financing Delivery
www.arta-africa.org
Program Highlights
Potential Customers
• Individual patients/doctors: semi-quantitative viral load, HIVDR
• Population level: mostly HIVDR monitoring & surveillance
Individual PatientsClinic Applications
Examples
A
B
C
D
E
Tertiary (teaching) hospital providing all specialized medical procedures, such as oncology, all surgeries and ICU. Availability of a full range of medical and Para-medical specialists 24/7. HIMS is used for data capturing and analysis. Laboratory, radiology and pharmacy services available.
Secondary (district) hospital providing a broad spectrum of medical procedures except specialized treatment such as listed in A.
Primary health center consisting of at least one MD plus registered nurse and lab technician offering minor surgery and chronic disease management.
Basic health center staffed by clinical officer offering general health and maternal health care
Health shop/nurse driven clinic giving advice on basic health care issues
Definition Clinic Levels
A
B
C
D
E
Customized Protocols for Different Levels
A: real time VL, genotying, (phenotyping), epidemiology
B: (semi-quantitative) VL, genotype interpretation
C: semi-quantitative VL
D: DBS, VL interpretation
E: DBS, VL interpretation
CPCD
Optimizing sample collection device (DFS)
and extraction protocol
PharmAccess
Optimizing HIV-1 subtype independent primers, amplification and detection protocol
Developing genotyping protocol, supported by
phenotyping quality control (QC) and interpretation
Technology transfer to Africa
Dissemination of information to various
audiences
P1Wits
P2UMCU/CRP
P3VIRCO
P4CLS
P5PAF
Step 1 Step 2 Step 3 Step 4 Step 5 Step 6 Step 7 Knowledge
Overview ART-A Program Activities
•19
Affordable Resistance Testing for Africa:Proposed protocols
DBS collection
RNA Extraction
VL screen
Base-calling software
Genotyping using single-round PCR
VircoTYPEor other algorithms
Low to Medium Viral Load
High Viral Load
Genotyping using nested PCR
Undetectable Viral Load
•Information dissemination•Training•Capacity building
•Financial mirror image
Population LevelEpidemiological Applications
Examples PASER/LAASER
LAASER program
www.laaserhivaids.org
UgandaUGANDA VIRUS RESEARCH INSTITUTE
PASER network
South Africa• Wits-MMH (Joburg)
South Africa• Muelmed Hospital (Pretoria)• RTC Themba Lethu (Joburg)• RTC Acts Clinic (White River)
Uganda• JCRC (Kampala)• UVRI (Entebbe)
Uganda• JCRC-TREAT sites (Mbale,
Kampala, Fort Portal)
Kenya• CPGH (Mombasa)• Mater (Nairobi)
Zimbabwe• Newlands Clinic (Harare)
Reference laboratories
Clinical sites
Nigeria• LUTH (Lagos)
Zambia• Lusaka Trust (Lusaka)• KARA Clinic (Lusaka)• Coptic Hospital (Lusaka)
South Africa• Wits-MMH (Joburg)• Wits-CHRU (Joburg)
The Netherlands• UMCU (Utrecht)• AMC-CPCD (Amsterdam)
Research centers
Uganda• JCRC (Kampala)• UVRI/MRC (Entebbe)
Kenya• ICRH (Mombasa)
PASER: two study protocols
• PASER-M
• HIV treatment centers
• Prospective cohort study
• Patients on HAART (n=240)
• Acquired HIVDR
• PASER-S
• VCT/ANC/STD sites
• Repetitive cross-sectional surveys
• Newly infected/ARV naïve (n=85)
• Transmitted HIVDR
Monitoring Surveillance
Harmonized with WHO HIVResNet protocols
Baseline HIVDR mutations at 8 sitesARV naïve
0123456789
10
Overa
ll (n=
845)
ZA/LTH
(n=80
)
ZA/KAR (n
=186)
ZA/CHC (n
=219)
SA/MM
H (n=13
2)
SA/TLC
(n=8
0)
SA/ACC (n
=98)
UG/JC
R (n=1
11)
KE/CRH (n
=50)
Any
NRTI
NNRTI
PI
Multiclass
Progress made thus far
● DBS based protocols developed that are suitable for resistance testing
● Narrow down HIVDR testing strategy by excluding― PMA tests― Nested PCR
● Focus on single round PCR strategies
● New software developed for automatic sequence analysis
● Phenotying for validating genotypes: high correlation clade B and clade C phenotyping
● Transfer of technology for resistance
● Financial mirror image on the ARTA algorithm in progress
•26
Affordable Resistance Testing for Africa:Proposed protocols
DBS collection
RNA Extraction
VL screen
Base-calling software
Genotyping using single-round PCR
VircoTYPEor other algorithms
Low to Medium Viral Load
High Viral Load
Genotyping using nested PCR
Undetectable Viral Load
C. Wallis
L. Stuyver
This work is supported by a
grant of the Netherlands
Organisation for Scientific
Research / Science for Global
Development (NWO/WOTRO),
under the Netherlands
African Partnership for
Capacity Development and
clinical Interventions
against Poverty related Diseases
(NACCAP)