monitoring and diagnostic tools for the management of...

Monitoring and Diagnostic Tools forthe Management of Antiretroviral

Therapy in Resource-Poor Settings

a workshop sponsored byGay Men’s Health Crisis

andProject Inform

With support fromNational Institutes of Health (US)

andThe Rockefeller Foundation

Sunday-TuesdayNovember 11-13, 2001

Hyatt Regency Bethesda HotelBethesda, MD

Monitoring and Diagnostic Tools for the Management of Antiretroviral Therapy in Resource-Poor Settings• Mary Bassett/Rockefeller Foundation• Ben Cheng/Project Inform• Gregg Gonsalves/Gay Men’s Health Crisis• Jonathan Kagan and Daniella Livnat/National Institute

of Allergy and Infectious Diseases• David Katzenstein/Stanford University/University of

Zimbabwe• Eve Lackritz and Mark Rayfield/Centers for Disease

Control and Prevention• Peter Mugyenyi/Joint Clinical Research Center• Thomas Quinn and J. Brooks Jackson/Johns Hopkins

University• Basil Vareldzis/World Health Organization

Monitoring and Diagnostic Tools for the Management of Antiretroviral Therapy in Resource-Poor Settings

• Statement of Goals: • identify the role of laboratory monitoring vs. clinical

monitoring in the management of antiretroviral therapy in resource-poor settings;

• identify the role of the current tools in use, in development or currently off-the-market, in the diagnosis of HIV infection and the monitoring of immunologicaland virological status and response to therapy in patients in resource-poor settings;

• to identifying the research needs and priorities in these areas, including the need to develop new, less expensive, less complex technologies, and;

• to address pricing issues around these assays.

Monitoring and Diagnostic Tools for the Management of Antiretroviral Therapy in Resource-Poor Settings

Peter Mugyenyi, Joint Clinical Research Center, Uganda:Either• Make current tests, required equipment and facilities

widely available, affordable and and user friendlyOr • Find alternative way of monitoring the patientsCharles Gilks, WHO:• Lack of access to monitoring and diagnostic tools

should not be used as a reason not to treat patients with HAART

Clinical and Laboratory Markers of Prognosis and Response to Treatment in HIV Disease

• Session Goals: to discuss the data on the capacity of clinical symptoms, basic laboratory markers (e.g. TLC, hemoglobin) and more sophisticated assays (e.g. CD4+ T-cell counts, viral load) to predict disease prognosis and the response to antiretroviraltreatment.


Victor De Gruttola, Harvard, US:• value of disease markers in monitoring patients on

therapy depends on goals of therapy at the individual and population level.

• surrogate endpoints, predictors of disease progression, and triggers for changes in therapy are DISTINCT uses of markers. Different analyses are required for establishing each role of a disease marker.

• markers that indicate rapidly that drugs have lost activity may be the most for reducing risk of development of resistance, but this needs further study.


Charles Gilks, WHO, Geneva:• TLC is poor predictor of CD4 count• CD4 count, TLC and WHO stage predict survival• WHO modified staging also predicts survival

– CD4 modified Stage 4, median survival is 13 months– TLC modified Stage 4, median survival is 11 months– TLC modified Stage 3, median survival is 17 months

• TLC-modified WHO staging is useful predictor of survival and can be used to initiate treatment

• WHO stage correlates poorly with viral load


Robin Wood, University of Cape Town, South Africa:• TLC poor predictor of CD4 unless lymphopenia

(<1250/ul) present• Combination of clinical stage & TLC allows accurate

risk stratification• Prophylaxis & Rx can be initiated at TLC 1250/ul ±

symptomatic disease • On HAART, change in TLC mirror CD4 but not viral

load.


Thomas Benfield, EuroSIDA Coordinating Centre, Denmark• Four independent risk factor predicted clinical progression in

patients on HAART: • Current level of haemoglobin, • Current CD4 cell count• Current viral load, • previous AIDS defining events (severe ever or mild with 12

months)• Risk of clinical progression on treatment may be evaluated using

a scoring system based on hemoglobin and CD4 with or without history of clinical events


• Development and monitoring of ART in Africa (DART)• A collaboration between the Rockefeller

Foundation, Joint Clinical Research Center (Uganda), University of Zimbabwe, and the Medical Research Council (UK)

• Objectives:1. compare the impact of clinical monitoring alone

vs. laboratory monitoring (i.e. CD4 counts, hematology, biochemistry) in the management of ART;

2. compare continuous ART vs. structured treatment interruptions.

Immunological Assays for the Management of HIV Disease and Antiretroviral Therapy in

Resource-Poor Settings

Summary and Recommendations

What are the Critical Factors Influencing the Ability to Deploy CD4 Testing?

• Cost of the technologies– instrument/machinery– reagents

• Laboratory infrastructure– human resources e.g. scarcity of

technicians, level of training– material resources e.g. electricity,

refrigeration

Model for CD4 Testing in Resource-Poor Settings

• reference center >>>• how many?

• Provincial or district level>>>

• primary care or rural setting>>>

• flow cytometry• high cost• resource-intensive• high precision

• dynabeads/cytospheres• lower cost• less resource intensive• more labor time• lower precision

• Ship or fix samples• least resource intensive• low tech

What are the Pending Questions?

• How do we validate different methods of quantitating CD4 counts in the setting of antiretroviral therapy?

• What is the level of training that is necessary to perform these tests? Who will provide this training (e.g. WHO, NIH, CDC, other international bodies)

• How do we fund the development, evaluation and deployment of these assays?

• Can we provide antibodies and other reagents at low cost to resource poor settings?

What are the Pending Questions? (cont.)

• Do we need to pursue new technologies for CD4 testing (e.g. smaller, simpler, cheaper flowcytometers, dipstick technologies)

• Do we need to do additional comparative studies of alternative methods of quantitating CD4 cells? Or are current lab-based assessments sufficient to move assays into the field or clinical trials?

• Can total lymphocyte count stand in as a surrogate for CD4 counts? In predicting progression? In predicting treatment effect?

Discussion

• we need to develop technologies to automate simple CD4 assays

• we need guidelines for leukogating (using CD45/CD4; 2 antibodies) in order to endorse this strategy

• we need to design additional studies to look at these alternative assays in therapeutic clinical trials

• we need to explore how to revive some of the “orphan” technologies for CD4 testing. How do you develop and market these assays with little commercial appeal in the US/Europe

• we need to reduce the price of current assays and reagents

Discussion(cont.)

• we need to accelerate implementation of dynabeadstechnology

• we need to establish more laboratory centers of excellence in the developing world

• we need a worldwide exemption from taxes and tariffs for diagnostics and monitoring tools

• we need to evaluate the utility of dynabeads, total lymphocyte count in predicting clinical outcome on therapy and for initiation of therapy

• we need funding from NIH and other agencies to conduct studies of diagnostics and monitoring tools for the developing world

Virological Assays for the Diagnosis andQuantitation of Viral Load for the Management of HIV Disease and Antiretroviral Therapy in

Resource-Poor Settings

Summary and Recommendations

Virological Assays for the Diagnosis and Quantitation of Viral Load for the Management of HIV Disease andAntiretroviral Therapy in Resource-Poor Settings

• Characteristics of an ideal test:– Inexpensive – Simple– Rapid– Convenient– Accurate

• New lab technology can revolutionize clinical practice– e.g. Abbott rapid test


• The current cost of standard testing is prohibitive• The high cost of testing makes it critical to

demonstrate a clear benefit of laboratory monitoring on patient outcome

– is clinical monitoring alone or simpler, less expensive tests “good enough?”

• Need to assure quality and avoid deployment of “second class” monitoring technologies


• Spur the development of new or modification of available assays to be able to detect viral load “bins” (e.g. <10,000; 10,000-50,000; >50,000 copies), rather than exact numbers (i.e. semiquantitative viral load)

• Integrate the heterogeneity of settings in decisions about testing (i.e. reference labs can perform PCR, but district health centers may not be able to perform any of the current assays and newer technologies, --e.g. semiquantitative VL dipsticks--may have to be developed, if VL is to be used in this setting)


• PCR, NASBA in real time; TaqMan?• Instruments currently are expensive, but tests

themselves are fast and effective; price reductions are possible

• Optimized p24 assay• initial studies need to be replicated• need for further evaluation in developing world and for

clinical use, standardization• room for significant simplification & price reduction• could be used for diagnosis of pediatric infection and

monitoring of therapy• under license to Perkin-Elmer


• Dipstick• no current VL assay exists, but potential for development

is real• Dried blood spots

• Appropriate for centralized lab model• Flow-through devices

• no current VL assay exists, but potential for development is real

The Challenge

• Short-term– evaluate clinical monitoring strategies as

substitutes for lab-based management of ART– support clinical studies of existing technologies

(e.g. dynabeads, cytospheres, real time NASBA, optimized p24) for use in management of HIV infection, specifically ART

– evaluate alternative markers (e.g. TLC, hemoglobin) as surrogates for treatment effect

– Support novel technology development (e.g. dipsticks, flow-through devices, cheaper, simpler flow)

The Challenge

• Now!– Support price reductions for current tests

• tiered/differential pricing• development of “generic” technologies

– Creative and flexible use of existing technologies (e.g. leukogating, dried blood spots, public domain antibodies)

Lack of a common agenda and leadership in implementation…the field had no real leadership, no real

funding, no real sense of urgency

…it was a fragmented venture with many competing interests that excelled at spelling out what needed to be done but had a tremendously difficult time building on those insightsJon Cohen, Shots in the Dark: the Wayward Search for an AIDS Vaccine

A look into the future?

“Unfortunately so little progress was made

resolving any of these issues that a nearly identical hearing could have occurred more than a decade later.”

Jon Cohen, Shots in the Dark: the Wayward Search for an AIDS Vaccine

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