Simplification, cost-reduction strategies and examples from the field

Teri Roberts Diagnostics Advisor MSF Access Campaign

Virological Monitoring Detects Treatment Failure Early On Adapted from Bartlett et al. Lancet Infect Dis 2009

Across programmes: 2% of treated patients are on 2nd-line ART In South Africa (Khayelitsha), where routine virological monitoring is available: 12% on 2nd-line after 5 years

HIV Policy and Progress Indicators Across 16 Countries

Cameroon

OPT

CAR

OPT

DRC

OPT

Ethiopia

NO

Guinea

OPT

India

REQ VL for Tx failure Routine VL Available VL for Tx failure Routine VL Available VL for Tx failure Routine VL OPT LTD

Kenya

OPT REQ YES NO LTD

Lesotho

OPT NO LTD NO LTD NO LTD NO LTD

Malawi Mozambique Myanmar

REQ OPT OPT NO LTD NO YES NO LTD NO LTD REQ NO

South Africa Swaziland Uganda Zambia

REQ OPT OPT OPT OPT LTD OPT LTD NO LTD

Zimbabwe

OPT NO

How to increase access to virological monitoring?

• • • • •

Reduce complexity Reduce price

– Market entry – – – Volume Competition Open and polyvalent platforms – Price transparency Field validate new and current tests (point of care and lab-based) Perform operational research to define best adapted and most feasible tests for different settings Introduce viral load testing in a phased in approach – Define testing frequency – – Replace CD4 monitoring with viral load monitoring Implement evidence-based algorithms to prioritise patients

Sample Sample volume Sample prep

Laboratory-based test

Plasma, DBS 200 – 1000μl

Point-of-care test

Fingerstick, heelstick ≤100μl Consumables Simple, no contamination Minimal, open access Reagents Power Instrument Hands-on time Time to result Range Training / skill Regulation Cost per test No cold storage, stable ≥40°C for ≥18 months AC and battery Open access and polyvalent, 1 room, no contamination ≤1 hour ≤1 day Quantitative, all subtypes, ≥50 copies/ml Medium WHO PQ (opt CE, FDA) ≤$10 Simple, part of POC test Minimal (1 lancet, 1 collection tube, 1 cartridge) Part of cartridge, no cold storage, stable ≥40°C for ≥18 months AC, battery (≥8 hours), solar Closed system, automated, small and lightweight, environmentally robust (heat, humidity, rigorous movement) ≤10 minutes ≤30 minutes Quantitative / semi-quantitative, all subtypes, ≥1000 copies/ml Minimal, basic (≤2 days), no precision pipetting WHO PQ (opt CE, FDA) ≤$8

Simplifying sample transport by using DBS

• • • • • • • • • Quick processing of whole blood Inefficient sample networks Alternative: dried blood spots Long distances, ambient

temperature

Time to result: e-health, m-health Fingerprick DBS NucliSENS EasyQ® HIV-1 v2.0 viral load test (bioMerieux) for DBS MSF validation of fingerprick DBS in Malawi Other tests for use with DBS?

• • • •

NucliSENS EasyQ® HIV-1 v2.0 (bioMérieux)

1. Extraction room Thyolo district hospital, Malawi DBS validated Real time NASBA (isothermal signal amplification), RNA specific Logistical challenges: – laboratory infrastructure – – unreliable power supply unreliable water supply – – provision of RNAse-free water unreliable air-conditioning – non-adherence to cold chain transportation, especially at customs – inability to find local laboratory technicians with molecular biology expertise – lack of in-country trouble-shooting and maintenance services 2. Amplification room

Generic HIV viral load assay (Biocentric)

• • • • Nhlangano health center, Swaziland Open system, low cost Real time RT-PCR (DNA and RNA) Logistical challenges • Use of plasma as a sample type (use of DBS is research use only) • Most of the other challenges as for the NucliSENS test

ExaVir

TM

Load Version 3 (Cavidi)

• • • Yangon, Myanmar (field site is in Shan state) Subtype independent, relatively low cost, minimal lab requirements, not as prone to contamination and not as dependent on precision pipetting as molecular lab tests ELISA of HIV reverse transcriptase activity Challenges include: • Must be performed on plasma • Plasma must be frozen at -20°C • Need for back-up vacuum pump • Relatively low through-put for lab test • Good water quality is essential • Positive and negative controls must be supplied in-house • Sample preparation to isolate the reverse transcriptase enzyme is labour intensive

For more information, please grab a copy of our viral load report (also available on our website: www.msfaccess.org)

SAMBA Performance evaluation of semi-quantitative HIV viral load test for therapy monitoring in resource-poor settings

Dr. Suna Balkan MSF Aids Working Group

Scaling-up in the MSF project Chiradzulu district, Malawi

7000 6000 5000 4000 3000 2000 1000 0 2001

Decentralisation

2002 2003

Inclusions/month Task shifting Need for a POC VL

2004 2005

Cumulated patients under ART

SAMBA system characteristics

• • •

MSF requirements All HIV1 subtypes & recombinants

•

Threshold 1,000 copies/ml Heat stability at 50°C

• • •

Robust & simple instrument

• • • • •

No or minimum electricity Minimum handling No risk of contamination Turn around time allowing same day result Affordable cost

• • • •

SAMBA Can detect Groups M, N, O & recombinants Cut-off at 1,000 copies/ml Heat stable reagents; no cold chain transport or storage Isothermal amplification with simple visual detection Low power requirement 350W Preloaded reagents in a closed cartridge Test time = 90 minutes with throughput of 24/day at 6.5 hr working day

Visual readout of SAMBA semi-quant VL test

<1,000 cp/ml ≥1,000 cp/m l

SAMBA system

SAMBA-prep (sample extraction) 1 to 4 samples per run SAMBA-amp (amplification)

Evaluation of SAMBA London St Thomas & Royal London Hospitals in 134 clinical samples SAMBA >1,000 SAMBA < 1,000 Total (%) Roche Taqman v2 (copies/ml) < 500 (<2.7 log) 2 500 – 2000 (2.7- 3.3 log) * 2 >2,000 (>3.3 log) 34 93 95 (71%) 2 4 (3%) 1 35 (26%) Total 38 96 134 * Roche TaqMan accuracy: +/- 0.3 Log per package inse rt Concordance between SAMBA & Roche = 97.8 % (131/134)

MSF Chiradzulu project background

• • Malawi – 13.2 million population mainly rural – 1 million HIV-infected MSF project based in a rural district – 1 hospital (laboratory),10 health centres – HIV care in 2000,decentralisation in 2003 – 25 000 patients followed under ART – 80% followed in the 10 decentralised health centres – Integrated project with MOH

MSF Arua project background

• Northwestern Uganda • Arua + catchment population : 1,5 M • HIV prevalence 3% • ART project since 2002 • Arua District Hospital • 7000 patients followed under ART • Integrated project with the MOH

SAMBA field trials in Malawi and Uganda

200 HIV+ patients in Malawi 154 HIV+ patients in Uganda recruited from HIV clinic during routine visit 200 µl fresh plasma SAMBA tested on-site by MSF technician Frozen plasma shipped directly Roche TaqMan v2 at Royal London Hospital Results to MSF Discordant SAMBA/Roche Abbott RealTime PCR at Addenbrooke All testing blinded to each other

Malawi results – SAMBA vs Roche TaqMan v2

Viral Load (cp/ml) SAMBA >1,000 SAMBA < 1,000 Total (%) Roche TaqMan version 2 < 500 (<2.7 log) 4 500 – 2,000 (2.7- 3.3 log) * 4 >2,000 (>3.3 log) 46 142 4 0 146 (73%) 8 (4%) 46 (23%) Total 54 146 200 * Roche TaqMan accuracy is +/- 0.3 Log per package insert Overall concordance with Roche v2 = 98% (196/200)

Uganda results – SAMBA vs Roche TaqMan v2

Viral Load (cp/ml) SAMBA >1,000 SAMBA < 1,000 Total (%) Roche TaqMan v2 < 500 (<1.7 Log) 500 – 2,000 * (2.7-3.3 Log) >2,000 >(3.3 Log) 2 0* 56 90 92 (60%) 2* 2 (1%) 4 60 (39%) * Roche TaqMan is 0.3 Log accuracy (package insert) Total 58 96 154 Overall concordance with Roche v2 = 96.1% (148/154)

Conclusion

• • • • • •

SAMBA platform is much simpler than currently available molecular technologies which require highly-trained personnel and sophisticated infrastructure only available in centralised laboratories SAMBA device is much easier to handle and being a closed system, prevents contamination by amplicons Staff training requirement for SAMBA is minimal SAMBA can be implemented in lower healthcare levels such as district hospitals or health centres with a basic laboratory but supplied with electricity Routine use of Samba will be now implemented in Arua and Chiradzulu with on going evaluation Will improve HIV care in a decentralization & task shifting strategy

Virological efficacy of ART over time at MSF sites in Arua and Chiradzulu 100% 80% 60% 40% 20% n = 284 0% <0.5

0.5-1 1-2 2-3 3-4 Years on ART 4-5 5-6 >6 > 65 % of patients on ART have VL < 40 cp/ml after 6 months > 80 % of patients on ART have VL < 1,000 cp/ml after 6 months <40 <1000

Distribution of viral loads in treated and untreated individuals in Malawi & Uganda 50% 40% 1,000 cp/ml 30% 20% 10% 0% > 1x10 6 1x10 5 1x10 4 1x10 3 1x10 2 <100 Roche TaqMan v2 viral load (cp/mL) <40