ART-ADevelopment of an Affordable

Resistance Test for Africa

Tobias Rinke de Wit

t.rinkedewit@pharmaccess.org

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)