The Need for Novel HIV/AIDS Diagnostics for Use at the

The Need for Novel HIV/AIDS Diagnostics for Use at the Point of Care

Maurine M. Murtagh

Diagnostics MeetingShanghai, China

25 September 2012

Agenda

1. HIV/AIDS Testing Landscape and Access

2. Testing at the Point of Care

3. Target Product Profiles for POC Test Platforms

Diagnostics for HIV/AIDS is a Continuum of Testing

ILLUSTRATIVEN

eed

for

Ser

vice

RapidTesting

and Early InfantDiagnosis

(EID)

CD4Resistance

Testing

Chemistry & Hematology

CD4 and

Viral LoadChemistry & Hematology

Staging and Monitoring

Safety Tests for ART

Initiation

Monitoring 1st Line

Monitoring 2nd LineDiagnosis

Challenges at any one point can become bottlenecks for patients proceeding further through the HIV care and treatment program.

These blockages prevent full realization of potential volumes for anti-retroviral drugs and other tests further downstream, which impacts program costs and also reduces the number of patients proceeding healthily into and through the anti-retroviral therapy (ART) program.

Intended Use and Goal of CD4, Viral Load and EID Tests

CD4, viral load and EID testing have presented the greatest barriers to HIV/AIDS testing in resource‐limited settings. The purpose of these tests is as follows:

CD4: To measure CD4+ T cells in the blood of HIV positive adults and children to inform initiation onto, and evaluation of, ART. Test may be semi‐quantitative or fully quantitative.

Viral Load: To measure HIV‐RNA in the blood of HIV positive patients in order to monitor HIV positive adults and children on ART. Test may be fully quantitative or semi‐quantitative.

EID: To measure the HIV‐DNA in the blood of infants under 18 months of age for purposes of HIV detection. Test is qualitative.

The Tiered Laboratory System in Resource‐Limited Settings

With the exception of rapid testing for HIV detection, most testing (CD4, viral load and EID) is done at levels 3 and 4 of the system, while most patients present at Level 1, where testing capabilities are limited or non‐existent.

• 4 ‐ National Reference Laboratory• Senior health specialists

• 3 ‐ Regional/provincial Laboratories

• Specialists/senior technicians

• 2 ‐ District Hospital• Technicians and assistants

• 1 ‐ Primary care• Health Centers, Health Posts and Outreach

For medium‐ to high‐throughput settings, lab‐based CD4 testing can be cost‐effective.

But, transport of whole blood samples is required; blood collected on dried blood spot (DBS) cards is not an option yet due to variability in results and failure to detect immature lymphocytes.

Return of results is typically slow and patients are lost to follow‐up.

Monitoring HIV Patients in Resource‐Limited Settings – CD4

CD4 testing capabilities, which are primarily lab‐based, are generally well‐established in resource‐limited settings.

However, less than 30% of patients in need of the test are estimated to have access to it.

However, the use of DBS is now an option for some of the commercially‐available platforms.

Access to viral load testing is estimated at less than 10%.

Monitoring the HIV Patient on ART in Resource‐Limited Settings – Viral Load

At the present time, viral load testing is exclusively lab‐based, with most testing done on sophisticated, high‐throughput instruments by highly‐trained technicians.

The existing options are relatively expensive and the assays are deemed to be complex; sample transport is required for patients not near central laboratory facilities.

Detecting HIV Infection ‐ Infants

• Because of the presence of maternal antibodies following birth, detection of HIV infection in infants under 18 months of age is generally performed via virological testing (usually DNA PCR).

• Early Infant Diagnosis (EID) is generally performed in centralized laboratories using DBS cards, which are transported from urban and rural settings.

• Return of test results is often slow and young patients are lost to follow‐up.

• Current access to EID is estimated to be less than 40% of infants in need.

Access to CD4, Viral Load and EID Testing in Resource‐Poor Settings is still LimitedThe need for large and relatively expensive laboratory‐based systems that require well‐trained technicians and good sample transport networks to provide access to testing for those in some urban, and virtually all peri‐urban and rural settings have combined to limit implementation of CD4, viral load and EID testing in resource‐limited settings.

• Patients have to make multiple visits to health facilities to obtain a single test result.

• This results in long travel time, travel costs and lost man‐hours.

• Limited capacity at central labs often leads to long patient backlogs and waiting periods between tests.

• In some rural settings, up to 40% of patients who receive a positive HIV diagnosis do not receive the follow‐up tests they need to help them initiate treatment and monitor disease progression.

And, further . . .

Solutions are Needed

Agenda




We would like to:

SIMPLIFY TESTING

IMPROVE ITS EFFICIENCY

REDUCE ITS COST

INCREASE OVERALL ACCESS TODIAGNOSTICS AND REDUCE LOSS TOFOLLOW‐UP

BUT,

NOT DIMINISH THE QUALITY OF PATIENT CARE

This has led to an interest in decentralizing testing

Moving diagnostic testing closer to the point of patient care.

There are several other promising platforms on the horizon. These include the Daktari, mBio and BD platforms as well as disposable tests from Zyomyxand Omega Diagnostics.

There are already several POC CD4 platforms on the market and more are coming

HumaCount CD4 NOW (formerly PointCare NOW), the Partec mini‐CyFlow and the Alere Pima CD4 Test are already on the market.

Pima POC CD4 Analyzer

Mbio Diagnostics CD4 System BD FACSPresto Zyomyx

CD4 Product Pipeline*

2009 2010 2011 2012 2013

HumaCount

Partec Mini

AlerePima CD4

Daktari

Omega Diagnostics

mBio

Zyomyx

Instruments Disposable

*Estimated - timeline and sequence may change

BD FACSPresto

2014

Monitoring HIV Patients – CD4

Company BD Human Alere

Platform Name FACSCount HumaCount CD4 NOW Pima POC CD4

Use Setting Laboratory Health Center and above Health Center and below

Instrument Bench top, 25.9 kg, not portable

Bench top, 12 kg, not portable

Bench top, 5kg, portable

Specimen Type Whole Blood from venipuncture

Whole Blood from venipuncture

Fingerstick blood

Cost/test $3.50 ‐ $10.00 –volume based

~$10.00, including controls $6.00 ‐ $12.00

Number of samples/run 20 per hour (2 – 3 minutes per test), after initial 60 ‐90 minutes incubation; 30 – 80 samples per day

8 minutes; ~40 – 50 samples per day

18 – 20 minutes; maximum of ~20 samples per day

Equipment Cost ($US) $30,000 ~$25,000 $6,500 to $12,000

Some CD4 products currently in the pipeline will be smaller and lower cost (e.g., Daktari) or higher throughput ( Mbio) or disposable (Zyomyx).

The market still needs easy‐to use, portable, hand‐held or disposable CD4 platforms with flexible throughput that are less expensive (<$5,000 for the device) with lower per‐test costs (<$6.00 per test) that can be used at the health center and below.

What is still needed?

Current 1st generation POC CD4 platforms are relatively expensive with moderate to low throughput and relatively high cost.

HumaCare CD4 NOW

Several of these platforms, including Liat and the Alere Q, may be launched in 2013.

Additional platforms will follow over the next few years.

New Options for Viral Load Monitoring and EID are also on the Horizon

A number of new Viral Load/EID POC diagnostics are in development, but none is on the market.

These will have lower instrument and per‐test costs, but will also have lower throughput than lab‐based systems.

Liat Analyzer Alere Q

Technology Pipeline – Viral Load and EID*

2012 2013 2014 2015 2016

Alere Q

NWGHF VL

NWGHF EIDSAMBA EIDSAMBA VL

Liat

WAVE 80 EOSCAPE

Gene XPert

Micronics

Biohelix

ALL

CavidiAMP

Lumora

Monitoring HIV Patients on ART – POC Viral Load

Company Abbott IQuum Alere WAVE80

Platform Name Abbott RealTime HIV‐1 assay

Liat™ Analyzer Alere Q WAVE80 EOSCAPE‐HIV™ System

Type Large extraction and detection instruments required; not portable

Bench top portable; ~8.3 lbs

Bench top portable; <11 lbs

Bench top portable analyzer with separate processing units

Output Quantitative HIV‐1 RNA DNA Qualitative

Quantitative or qualitative VL

Quantitative HIV‐1 RNA

Quantitative HIV‐1 RNA

Specimen Type Plasma: DBS 200 µL plasma or 10 ‐50 µL fingerstickblood

25 µL fingerstick or 25 µL heel stick

100 µL fingerstick blood

Cost/test $23 ‐ $40 per test, volume based

TBD TBD <$20 per test

Number of samples/run

5 ½ hours – 8 ½ hours. Up to 93 patient samples (+3 external controls); 288 samples per day

~8 ‐ 15 samples per day depending on LOD; TAT 30 ‐ 55 minutes, no batching

Max of ~10 samples per day; TAT 30 – 60 minutes

~50 samples per day with 6‐8 processing units and a single analyzer; TAT 50 minutes; random access

Equipment Cost ($US)

m24sp: $90,000, m2000sp: $120,000; or manual (magnetic racks, plate cooler): $500 and m2000rt: $38,000

~$25,000, may be lower in LRS

TBD ~$10,000 for one analyzer with 2 processing units

Simplicity is another concern. There is a need to be able to use unprocessed samples (blood, not plasma) and a need for few steps between sample collection and test result. Cold chain must not be required for transport or storage.

The market needs easy‐to use, portable (and possibly disposable, semi‐quantitative) and robust viral load platforms that are less expensive (<$10,000 for the device) with lower per‐test costs (<$10.00 per test) that can be used primarily at the health center, but are scalable for use below the health center level in the case of a semi‐quantitative disposable test.

What is still needed?

The current pipeline for POC viral load platforms is encouraging, but concerns remain.

Cost is a very important issue with respect to viral load testing at the POC. Instruments at $25,000 and per test costs of $20 or more will generally not be scalable in resource‐limited settings. Lumora BART Platform

Agenda




In Order to Guide Developers in Product Design and Development for POC Diagnostics, Standards are Needed

The required product standards are a set of desired operational and technical specifications for POC diagnostic platforms to be developed.

These standards can be summarized in a Target Product Profile (TPP) that provides a clear set of minimal and optimal standards for each platform, including the device, if any, and the assay.

The TPPs presented here for CD4, viral load and EID testing were developed to identify the market needs for these tests in order to encourage both funders and developers to aim their resources towards these global health needs.

The TPPs summarize specifications for each test platform and are divided into three main sections: (i) intended use; (ii) performance; and (iii) operational characteristics.

Cepheid GeneXpert

Micronics Platform

NWGHF EID Platform

Target Use Setting for POC Testing

The TPPs set forth the highest priority target use setting for each test platform within the healthcare system in‐country.

For POC CD4, Viral Load and EID, most of which will be device‐based platforms, the highest priority target use setting is the health center. For some disposable tests, the health post may also be a high priority target.

The health center was chosen due to its:• Large patient volume• Linkage to care (availability of clinicians,

pharmacy, medical treatment)• Infrastructure, including trained staff• Focus by Ministries of Health to strengthen

delivery and scale‐up access to health services at this level

Test Performance

It is imperative that new diagnostic platforms/tests demonstrate that they perform favorably against appropriate “gold standard” tests and incumbent tests in the field in their test category.

For example, for a quantitative viral load assay, a valid reference test would include the COBAS® TaqMan® HIV‐1 Test from Roche or the Abbott RealTime HIV‐1 Abbott.

The TPPs set out an appropriate minimal and optimal test performance for each assay. As an example, minimal and optimal specifications for a quantitative viral load assay:

Quantitation Semi‐quantitative (with a series of cut‐offs); quantitative preferred

Quantitative

Lower Limit of Detection 1,000 cp/mL <50 cp/mL

Upper Limit of Detection N/A >20,000 cp/mL

Precision Less than 0.5 log for semi‐quantitative; 0.3 log preferred Less than 0.3 log

Operational Characteristics

In order for new POC diagnostics to be transformational in resource‐limited settings, strong technical performance will not be enough.

Cost‐effectiveness will be critical.

In addition, test platforms must have operational characteristics that help compensate for diagnostic system weaknesses in resource‐limited settings.

Operational Characteristics – Cost Effectiveness

• The cost of instruments and reagents will be a crucial factor in implementation and uptake of new POC diagnostics.

• Globally, funding for HIV/AIDS is flat‐lining.

• In‐country, healthcare systems struggle annually to make ends meet and many health centers rely heavily upon healthcare financing (e.g., charging fees to patients for tests) in their annual budgets, and budget shortfalls can be significant. For example, annual budget shortfalls of more than 40% are common.

• The cost of new diagnostic platforms (both instruments and reagents) will be compared to incumbent platforms with similar capabilities.

• To the extent that the platforms are not cost‐effective, they are unlikely to be taken up in resource‐limited settings.

Service fees charged to patients for laboratory testing (Health Center in Indonesia).

Operational Characteristics – System Weaknesses

The following are the most commonly‐identified weaknesses in the diagnostic system in resource‐limited settings:

• Human Resources: Lack of trained staff, high turnover and insufficient training opportunities

• Supply Chain: Ensuring the efficient and reliable supply of essential diagnostic products throughout the laboratory system is a significant obstacle to diagnostic delivery. Long and difficult transport of test reagents and consumables are the norm often under extreme temperature conditions, including temperature spikes.

• Service/Maintenance: Lack of diagnostic equipment and frequent and prolonged breakdowns of equipment (lasting months and sometimes years)

• Diagnostic Errors: Studies have shown that even for simple tests, quality‐controlled and reproducible testing remains a major challenge in resource‐limited settings; test errors are observed frequently.

Priority Operational Characteristics of POC Diagnostics –Compensating for System WeaknessesIn addition to strong technical performance and cost effectiveness, in‐country research has demonstrated the following high priority characteristics for POC diagnostics:

• Durability: device with no electronic or mechanical maintenance beyond simple tasks; rugged device that will tolerate high temperature tolerances and will tolerate shock and vibration; cartridges with long shelf life and ability to survive extreme temperature fluctuations and humidity; no cold chain or clean water required; battery back‐up

• Ease of use: simple sample preparation (few operator steps); ability to use unprocessed sample specimens; no operator intervention required during analysis; self‐contained kits; little operator calibration; simple user interface and read‐out

• Training: test simple enough that its use can be explained to a healthcare worker in a day’s training or less; test simple enough to permit informal training among healthcare workers

• Self‐contained Quality Control: if device‐based, device designed to cover a large number of quality issues rather than leaving them to staff: e.g., detecting expired kits (reject); detecting inadequate sample volume (reject); running process control

• Sample Capacity/Turnaround Time and Throughput: In order to accommodate varying throughput needs and to give same‐day results, random access is preferred.

The Target Product Profiles

Draft TPPs for each platform have been developed and were vetted by a number of stakeholders in advance of the meeting.

The TPPs translate concepts like “simplicity” and durability into specific standards for each test platform.

Minimal Optimal INTENDED USE This is a diagnostic test to measure HIV‐RNA in order to monitor HIV+ patients on ART to: (i) identify virological failure; (ii) enable clinicians

to switch failing patients to new drug regimens before the accumulation of drug resistance mutations; and (iii) diagnose HIV infection in infants under 18 months of age

Goal of Test Semi‐quantitative viral load measurement and detection of all major HIV‐1 subtypes including N and O at each stage of infection from early through advanced disease; HIV‐2 optional

Fully quantitative viral load measurement and detection of all major HIV‐1 subtypes including N and O at each stage of infection from early through advanced disease; HIV‐2 and recombinants preferred

Target User(s) HIV‐infected adults and children for HIV treatment monitoring; infants under 18 months of age for HIV detection Target Use Setting Health CenterReference Test Real‐time PCR or isothermal amplification on Roche, Abbott, Siemens or bioMérieux viral load platformsResults HIV‐RNA or viral copies/mL

PERFORMANCE Equipment Small, table‐top device; portable device optional Small, portable or hand‐held device Quantitation Semi‐quantitative (with a series of cut‐offs); quantitative preferred Quantitative Lower Limit of Detection 1,000 cp/mL <50 cp/mL Upper Limit of Detection N/A >20,000 cp/mL Precision Less than 0.5 log for semi‐quantitative; 0.3 log preferred Less than 0.3 logAnalytic Specificity No cross reactivity with other organisms No cross reactivity with other organisms

OPERATIONAL CHARACTERISTICS

Sample Specimen Plasma or whole blood from venipuncture; heel stick for young children

Finger prick blood (maximum 200 µL); heel stick for young children

Sample Preparation Minimal sample processing; no more than 3 – 5 steps (requiring operator intervention)

Integrated

Steps performed by healthcare worker between sample preparation and result

No more than 5 steps (requiring operator intervention), excluding waste disposal

1 step, excluding waste disposal

Additional 3rd party consumables

None, except for sample collection None

Cold Chain None required at any point in supply chain or storage Power Requirements 110‐220V AC current; DC power with rechargeable battery lasting

up to 8 hours of testingNone; DC and AC power optional

Kit All materials required for assay and reagents, including buffers or other consumables to test one patient, included in individually packaged, self‐contained kit

Kit Stability and Storage Conditions

Stable for 18 months at 2°C to 40°C, 70% humidity, including transport stress (48h with fluctuations up to 50°C and down to 0°C)

Stable for 24 months at 0°C to 40°C, 90% humidity, including transport stress (48h with fluctuations up to 50°C)

THANK YOU.

Acknowledgments

The Bill & Melinda Gates Foundation

UNITAID

Dr. Trevor Francis Peter

Advanced Liquid Logic, Alere, BD Biosciences, Biohelix, Burnet/Omega Diagnostics, Cavidi, Cepheid, DaktariDiagnostics, Diagnostics for the Real World, Human/PointCare, Iquum, Lumora, Mbio, Micronics, Northwestern Global Health Foundation, Partec, WAVE80 and Zyomyx

Documents

The Need for Novel HIV/AIDS Diagnostics for Use at the