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Cheaper HIV Drugs for Poor Nations Bring a New Challenge: Monitoring Treatment

Cheaper HIV Drugs for Poor Nations Bring a New Challenge: Monitoring Treatment As efforts to make anti-HIV drugs more affordable and available in developing countries are beginning to pay off, medical experts say it's time to address a related challenge: Even while more patients are receiving the life-prolonging therapies, the tests and equipment needed to monitor the effects of their treatment are out of reach. Tests that clinicians in wealthier countries consider standard of care, particularly those used for determining when to initiate drug therapy or whether a therapeutic regimen is failing to suppress viral replication, are rarely available—too complex for most laboratories in resource-poor countries to perform, and too expensive for most patients. Now, however, a coalition of researchers, physicians, patient advocacy groups, government agencies, and others is making a concerted effort to develop and deliver cheap, simple, and effective alternative treatment-monitoring technologies to improve the medical management of patients on antiretroviral therapy in developing countries in Africa, Asia, and elsewhere. View LargeDownload Current technologies used in industrialized countries include assays for CD4 T cell numbers to determine the degree of immune impairment and tests to measure levels of HIV in the patient's blood. "But these technologies are expensive, complex, and require lots of training and very fragile materials," noted Veronica Miller, PhD, director of the Forum for Collaborative HIV Research. The Forum, a public-private partnership project based at George Washington University, in Washington, DC, receives funding from the US government, the pharmaceutical industry, and foundations. The costly tests used in North America and Europe "are just not very transportable into an area where it's difficult to maintain expensive and fragile equipment, and where you don't have the personnel trained to do these assays," Miller said. Thus, in its first international initiative, the Forum is focusing on transferring HIV monitoring and diagnostic technology to poor countries by identifying promising alternative technologies and bringing together key players in academia, industry, government, and advocacy groups to move those technologies forward. Diagnosis, monitoring lag Physicians treating HIV-infected patients in Africa say that diagnostic and monitoring tests are so expensive that they often have to treat patients without monitoring their CD4 T cell numbers or viral load. "Patients think that it is ridiculous to have monitoring tests which cost more than their lifesaving treatment," said Peter Mugyenyi, MD, head of the Joint Clinical Research Centre in Kampala, Uganda. Currently, the cost of two standard monitoring tests for CD4 T cell counts and viral load is more than twice the monthly cost of antiretroviral drug therapy in Uganda, he noted. For patients who are struggling to deal with even the "reduced" cost of the drugs, monitoring tests are a luxury they cannot afford. Uganda's experience is by no means unique, said Gregg Gonsalves of the patient advocacy group Gay Men's Health Crisis in New York City. After hearing comments similar to Mugyenyi's from a physician at a clinic in Khayelitsha, a shantytown near Cape Town's airport in South Africa, he and Project Inform activist Ben Cheng, MS, (now Project Manager for the Forum's initiative on transferring HIV monitoring and diagnostic technology to resource-poor settings) contacted other clinics and found "we had touched a nerve," said Gonsalves. An international meeting last November organized by Gonsalves and Cheng brought together HIV researchers, industry representatives, advocacy groups, and others to explore the need for such tests and consider how to get affordable and simpler diagnostic and monitoring technology to developing countries. One consequence of that meeting is the Forum's initiative, which is intended to identify what is needed to validate promising alternative diagnostic and monitoring tests for use in poor countries and to bring together the researchers, government agencies, diagnostic equipment manufacturers, and other parties necessary to carry the work forward. Because of the urgent need to provide anti-HIV drugs to the millions of people infected in the developing world, the guidelines recently released by the World Health Organization (WHO) reflect a pragmatic decision to classify tests such as those for CD4 cell counts as "desirable" and for viral load as "optional." (The WHO guidelines, Scaling Up Antiretroviral Therapy in Resource-Limited Settings, are available online at http://www.who.int/HIV_AIDS/first.html.) Instead, the guidelines advise including a white blood cell count and differential (to allow assessment of neutropenic side effects and the total lymphocyte count) as part of basic recommended testing for patients with HIV. But they also urge the introduction of simple and less costly methods to assess CD4 T cell counts, a priority issue "because CD4 cell counts are the best indicator of immunologic response to treatment." The WHO guidelines also say that while viral load testing should be considered optional in poor countries because of "resource constraints," clinical monitoring (based on patient reports, physical examination, and—depending on the drug combination used, perhaps a limited number of laboratory tests—) is essential for safe and effective antiretroviral therapy. Finding simpler alternatives At a recent workshop sponsored by the Forum for Collaborative HIV Research, researchers, representatives of diagnostic equipment manufacturers, and others reviewed the current status of some alternative assays for CD4 cell counts and viral load and considered what steps would be necessary to validate these procedures and put them to work in developing countries. Currently, monitoring CD4 T cell counts requires a flow cytometer, which typically costs about $100 000. Added to this expense is the cost of reagents and the money needed to train and pay laboratory staff to run the complex tests. Another complication is the difficulty (and cost) of maintaining and repairing the equipment. "There are places [in the developing world] with technologies such as flow cytometers for measuring CD4 cells, but those are few and far between," explained Alan Landay, PhD, of Rush-Presbyterian-St Luke's Medical Center in Chicago. Because of this, researchers are pressing ahead to develop and test alternative technologies that would be feasible in a range of settings, from district hospitals to central laboratories in major cities. Similarly, current tests used to measure viral load are also out of reach in most settings in the developing world. "They're expensive and require expensive equipment that's hard to maintain," said Susan Fiscus, PhD, of the University of North Carolina, Chapel Hill. The tests can also be invalidated by minute amounts of contamination. Two promising alternative tests for measuring CD4 T cell counts were developed a decade ago: tests using magnetic or latex beads (Dynabeads and Cyto-Spheres). But the bead-based assays have only recently gained attention as simpler, more affordable technologies with the potential for use in developing countries, as access to treatment has improved in such settings. "Ten years ago, when we had the assays to monitor, we didn't have the drugs," said Landay. Therefore, only a few small-scale studies of the bead-based CD4 cell tests were undertaken during the past decade, mostly outside Africa. "Today we have the drugs, but we don't have the assays." The CD4 cell assays using Dynabeads and Cyto-Spheres are relatively simple to perform but are much more labor-intensive than conventional assays, because they require manual counting of cells. The tests involve counting (with the aid of a light microscope) magnetic or latex beads that bind to CD4 T cells in a blood sample. Studies suggest that these methods could be useful for identifying patients at critical threshold levels for care. WHO guidelines recommend initiating antiretroviral therapy when an individual's CD4 cell count is below 200/mm3. In one recent study to be presented this week at the XIV International AIDS Conference in Barcelona, researchers from the Agence Nationale de Recherches sur le SIDA (ANRS), in Paris, and investigators at six laboratories in West Africa assessed the feasibility of using the Dynabead technique. In the study, led by immunologist Serge Diagbouga, MD, PhD, of Centre Muraz in Bobo-Dioulasso, Burkina Faso, the researchers compared Dynabead testing with flow cytometry testing in about 700 pairs of samples from 301 HIV-infected patients. Tests were carried out by technicians who had received 48 hours of training. One sample of each pair was tested using conventional flow cytometry in a centralized laboratory; the other was tested on site using the Dynabead method, explained ANRS director Michel D. Kazatchkine, MD, PhD. "Over 95% of patients were classified in a totally consistent fashion between cytofluorometry and the Dynabead technique, particularly at critical thresholds for care," such as around or below 200 CD4 cells/mm3. Studies of the Cyto-Sphere test also showed that the method generally correlated with flow cytometry. But before either of these assays is ready for wide-range use in the developing world, they should be validated in the context of an antiretroviral trial, said Landay. Impact of other infections It's also essential to better understand whether there are population differences in ranges of CD4 cell levels that should be taken into account when staging HIV disease, noted Landay. Researchers need to establish what constitutes "normal" blood levels of CD4 cells in different populations in developing countries. Coinfection with other endemic diseases such as tuberculosis and malaria and other parasitic diseases could affect immune function and alter CD4 cell numbers. The Dynabead-based test currently costs around $2 to $3 per test vs $25 to $30 for conventional CD4 cell count tests, said Kazatchkine. The cost for reagents using Cyto-Spheres for CD4 cell counts is about $10 per test. However, the per-assay cost could be reduced, if the tests become widely used, through negotiated volume discounts with the manufacturers. Researchers are also investigating alternative technologies for measuring viral load, which clinicians use to evaluate the effectiveness of antiretroviral therapy. Poor suppression of HIV levels can indicate such problems as the development of resistance to one or more drugs in the treatment regimen or poor adherence. Conventional tests to measure viral load—PCR (polymerase chain reaction) or bDNA (branched DNA) assays—require expensive equipment and are too pricey to be used in developing countries, costing as much as $100 or more per test. One approach to measuring HIV viral load that is under study involves a heat-denatured p24 antigen test, which detects a protein (p24) that surrounds the viral RNA. This type of assay, which would cost about $10 per test, has excellent sensitivity and specificity in diagnosing HIV-1 infection with subtype B virus, the form of the virus that predominates in North America and Europe. There are a number of viral load tests in all stages of development and validation, and it's important for researchers to evaluate them because a method that would work well in one setting may not be as useful in another, said Fiscus. For example, the currently available heat-denatured p24 antigen test performs well when used with samples from individuals with HIV-1 subtype B infections, but may be less effective in detecting some of the subtypes found in Africa. Such limitations must be addressed for the tests to be useful monitoring tools in Africa and other parts of the world. "Because of issues of specimen collection and processing, because of the various subtypes [of HIV], as well as country-specific differences in terms of training, what works for South Africa may not work for Malawi, and what works for Malawi may not work in India," Fiscus explained. "Each country and each institute or hospital really has to evaluate a kit with their own populations to make sure that it works." Other methods may well supplant the bead-based CD4 cell tests or the p24 assays as the most-likely-to-succeed technologies for staging and monitoring patients infected with HIV in developing countries. Ultimately, the Holy Grail of HIV monitoring technology would be cheap "dipstick"-style tests that require little training to administer and interpret and that could be run in any setting, said Gonsalves. HIV care in developing countries would also be enhanced by the availability of simple and affordable tests for monitoring antiretroviral drug toxicity and drug resistance. The partnerships that are being forged among researchers, industry, health agencies, and others to shepherd through alternative methods for measuring CD4 cell numbers and viral load will help pave the way for the next generation of technologies to get the job done, Miller said. Important as it is to push for simple and affordable monitoring tests in developing countries, however, such concerns remain secondary to making antiretroviral drugs available to those who need them. The vast majority of HIV-infected people in developing countries still have no access to these life-prolonging medications. The chief constraint, said Mugyenyi, continues to be "the still-high cost of drugs, which remain too exorbitantly priced." http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png JAMA American Medical Association

Cheaper HIV Drugs for Poor Nations Bring a New Challenge: Monitoring Treatment

JAMA , Volume 288 (2) – Jul 10, 2002

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Publisher
American Medical Association
Copyright
Copyright © 2002 American Medical Association. All Rights Reserved.
ISSN
0098-7484
eISSN
1538-3598
DOI
10.1001/jama.288.2.151
Publisher site
See Article on Publisher Site

Abstract

As efforts to make anti-HIV drugs more affordable and available in developing countries are beginning to pay off, medical experts say it's time to address a related challenge: Even while more patients are receiving the life-prolonging therapies, the tests and equipment needed to monitor the effects of their treatment are out of reach. Tests that clinicians in wealthier countries consider standard of care, particularly those used for determining when to initiate drug therapy or whether a therapeutic regimen is failing to suppress viral replication, are rarely available—too complex for most laboratories in resource-poor countries to perform, and too expensive for most patients. Now, however, a coalition of researchers, physicians, patient advocacy groups, government agencies, and others is making a concerted effort to develop and deliver cheap, simple, and effective alternative treatment-monitoring technologies to improve the medical management of patients on antiretroviral therapy in developing countries in Africa, Asia, and elsewhere. View LargeDownload Current technologies used in industrialized countries include assays for CD4 T cell numbers to determine the degree of immune impairment and tests to measure levels of HIV in the patient's blood. "But these technologies are expensive, complex, and require lots of training and very fragile materials," noted Veronica Miller, PhD, director of the Forum for Collaborative HIV Research. The Forum, a public-private partnership project based at George Washington University, in Washington, DC, receives funding from the US government, the pharmaceutical industry, and foundations. The costly tests used in North America and Europe "are just not very transportable into an area where it's difficult to maintain expensive and fragile equipment, and where you don't have the personnel trained to do these assays," Miller said. Thus, in its first international initiative, the Forum is focusing on transferring HIV monitoring and diagnostic technology to poor countries by identifying promising alternative technologies and bringing together key players in academia, industry, government, and advocacy groups to move those technologies forward. Diagnosis, monitoring lag Physicians treating HIV-infected patients in Africa say that diagnostic and monitoring tests are so expensive that they often have to treat patients without monitoring their CD4 T cell numbers or viral load. "Patients think that it is ridiculous to have monitoring tests which cost more than their lifesaving treatment," said Peter Mugyenyi, MD, head of the Joint Clinical Research Centre in Kampala, Uganda. Currently, the cost of two standard monitoring tests for CD4 T cell counts and viral load is more than twice the monthly cost of antiretroviral drug therapy in Uganda, he noted. For patients who are struggling to deal with even the "reduced" cost of the drugs, monitoring tests are a luxury they cannot afford. Uganda's experience is by no means unique, said Gregg Gonsalves of the patient advocacy group Gay Men's Health Crisis in New York City. After hearing comments similar to Mugyenyi's from a physician at a clinic in Khayelitsha, a shantytown near Cape Town's airport in South Africa, he and Project Inform activist Ben Cheng, MS, (now Project Manager for the Forum's initiative on transferring HIV monitoring and diagnostic technology to resource-poor settings) contacted other clinics and found "we had touched a nerve," said Gonsalves. An international meeting last November organized by Gonsalves and Cheng brought together HIV researchers, industry representatives, advocacy groups, and others to explore the need for such tests and consider how to get affordable and simpler diagnostic and monitoring technology to developing countries. One consequence of that meeting is the Forum's initiative, which is intended to identify what is needed to validate promising alternative diagnostic and monitoring tests for use in poor countries and to bring together the researchers, government agencies, diagnostic equipment manufacturers, and other parties necessary to carry the work forward. Because of the urgent need to provide anti-HIV drugs to the millions of people infected in the developing world, the guidelines recently released by the World Health Organization (WHO) reflect a pragmatic decision to classify tests such as those for CD4 cell counts as "desirable" and for viral load as "optional." (The WHO guidelines, Scaling Up Antiretroviral Therapy in Resource-Limited Settings, are available online at http://www.who.int/HIV_AIDS/first.html.) Instead, the guidelines advise including a white blood cell count and differential (to allow assessment of neutropenic side effects and the total lymphocyte count) as part of basic recommended testing for patients with HIV. But they also urge the introduction of simple and less costly methods to assess CD4 T cell counts, a priority issue "because CD4 cell counts are the best indicator of immunologic response to treatment." The WHO guidelines also say that while viral load testing should be considered optional in poor countries because of "resource constraints," clinical monitoring (based on patient reports, physical examination, and—depending on the drug combination used, perhaps a limited number of laboratory tests—) is essential for safe and effective antiretroviral therapy. Finding simpler alternatives At a recent workshop sponsored by the Forum for Collaborative HIV Research, researchers, representatives of diagnostic equipment manufacturers, and others reviewed the current status of some alternative assays for CD4 cell counts and viral load and considered what steps would be necessary to validate these procedures and put them to work in developing countries. Currently, monitoring CD4 T cell counts requires a flow cytometer, which typically costs about $100 000. Added to this expense is the cost of reagents and the money needed to train and pay laboratory staff to run the complex tests. Another complication is the difficulty (and cost) of maintaining and repairing the equipment. "There are places [in the developing world] with technologies such as flow cytometers for measuring CD4 cells, but those are few and far between," explained Alan Landay, PhD, of Rush-Presbyterian-St Luke's Medical Center in Chicago. Because of this, researchers are pressing ahead to develop and test alternative technologies that would be feasible in a range of settings, from district hospitals to central laboratories in major cities. Similarly, current tests used to measure viral load are also out of reach in most settings in the developing world. "They're expensive and require expensive equipment that's hard to maintain," said Susan Fiscus, PhD, of the University of North Carolina, Chapel Hill. The tests can also be invalidated by minute amounts of contamination. Two promising alternative tests for measuring CD4 T cell counts were developed a decade ago: tests using magnetic or latex beads (Dynabeads and Cyto-Spheres). But the bead-based assays have only recently gained attention as simpler, more affordable technologies with the potential for use in developing countries, as access to treatment has improved in such settings. "Ten years ago, when we had the assays to monitor, we didn't have the drugs," said Landay. Therefore, only a few small-scale studies of the bead-based CD4 cell tests were undertaken during the past decade, mostly outside Africa. "Today we have the drugs, but we don't have the assays." The CD4 cell assays using Dynabeads and Cyto-Spheres are relatively simple to perform but are much more labor-intensive than conventional assays, because they require manual counting of cells. The tests involve counting (with the aid of a light microscope) magnetic or latex beads that bind to CD4 T cells in a blood sample. Studies suggest that these methods could be useful for identifying patients at critical threshold levels for care. WHO guidelines recommend initiating antiretroviral therapy when an individual's CD4 cell count is below 200/mm3. In one recent study to be presented this week at the XIV International AIDS Conference in Barcelona, researchers from the Agence Nationale de Recherches sur le SIDA (ANRS), in Paris, and investigators at six laboratories in West Africa assessed the feasibility of using the Dynabead technique. In the study, led by immunologist Serge Diagbouga, MD, PhD, of Centre Muraz in Bobo-Dioulasso, Burkina Faso, the researchers compared Dynabead testing with flow cytometry testing in about 700 pairs of samples from 301 HIV-infected patients. Tests were carried out by technicians who had received 48 hours of training. One sample of each pair was tested using conventional flow cytometry in a centralized laboratory; the other was tested on site using the Dynabead method, explained ANRS director Michel D. Kazatchkine, MD, PhD. "Over 95% of patients were classified in a totally consistent fashion between cytofluorometry and the Dynabead technique, particularly at critical thresholds for care," such as around or below 200 CD4 cells/mm3. Studies of the Cyto-Sphere test also showed that the method generally correlated with flow cytometry. But before either of these assays is ready for wide-range use in the developing world, they should be validated in the context of an antiretroviral trial, said Landay. Impact of other infections It's also essential to better understand whether there are population differences in ranges of CD4 cell levels that should be taken into account when staging HIV disease, noted Landay. Researchers need to establish what constitutes "normal" blood levels of CD4 cells in different populations in developing countries. Coinfection with other endemic diseases such as tuberculosis and malaria and other parasitic diseases could affect immune function and alter CD4 cell numbers. The Dynabead-based test currently costs around $2 to $3 per test vs $25 to $30 for conventional CD4 cell count tests, said Kazatchkine. The cost for reagents using Cyto-Spheres for CD4 cell counts is about $10 per test. However, the per-assay cost could be reduced, if the tests become widely used, through negotiated volume discounts with the manufacturers. Researchers are also investigating alternative technologies for measuring viral load, which clinicians use to evaluate the effectiveness of antiretroviral therapy. Poor suppression of HIV levels can indicate such problems as the development of resistance to one or more drugs in the treatment regimen or poor adherence. Conventional tests to measure viral load—PCR (polymerase chain reaction) or bDNA (branched DNA) assays—require expensive equipment and are too pricey to be used in developing countries, costing as much as $100 or more per test. One approach to measuring HIV viral load that is under study involves a heat-denatured p24 antigen test, which detects a protein (p24) that surrounds the viral RNA. This type of assay, which would cost about $10 per test, has excellent sensitivity and specificity in diagnosing HIV-1 infection with subtype B virus, the form of the virus that predominates in North America and Europe. There are a number of viral load tests in all stages of development and validation, and it's important for researchers to evaluate them because a method that would work well in one setting may not be as useful in another, said Fiscus. For example, the currently available heat-denatured p24 antigen test performs well when used with samples from individuals with HIV-1 subtype B infections, but may be less effective in detecting some of the subtypes found in Africa. Such limitations must be addressed for the tests to be useful monitoring tools in Africa and other parts of the world. "Because of issues of specimen collection and processing, because of the various subtypes [of HIV], as well as country-specific differences in terms of training, what works for South Africa may not work for Malawi, and what works for Malawi may not work in India," Fiscus explained. "Each country and each institute or hospital really has to evaluate a kit with their own populations to make sure that it works." Other methods may well supplant the bead-based CD4 cell tests or the p24 assays as the most-likely-to-succeed technologies for staging and monitoring patients infected with HIV in developing countries. Ultimately, the Holy Grail of HIV monitoring technology would be cheap "dipstick"-style tests that require little training to administer and interpret and that could be run in any setting, said Gonsalves. HIV care in developing countries would also be enhanced by the availability of simple and affordable tests for monitoring antiretroviral drug toxicity and drug resistance. The partnerships that are being forged among researchers, industry, health agencies, and others to shepherd through alternative methods for measuring CD4 cell numbers and viral load will help pave the way for the next generation of technologies to get the job done, Miller said. Important as it is to push for simple and affordable monitoring tests in developing countries, however, such concerns remain secondary to making antiretroviral drugs available to those who need them. The vast majority of HIV-infected people in developing countries still have no access to these life-prolonging medications. The chief constraint, said Mugyenyi, continues to be "the still-high cost of drugs, which remain too exorbitantly priced."

Journal

JAMAAmerican Medical Association

Published: Jul 10, 2002

Keywords: hiv,anti-hiv agents,developing countries,anti-retroviral agents,viral load result

There are no references for this article.