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[procaare] Clinical research priorities for ARVs in developing countries
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- Date: Tue, 19 Nov 2002 12:38:27 -0500 (EST)
Clinical research priorities for ARVs in developing countries
Lancet article: Antiretroviral treatment in resource-poor settings: clinical research
Miriam Rabkin, Wafaa El-Sadr, David A Katzenstein, Joia Mukherjee, Henry Masur, Peter
Mugyenyi, Paula Munderi, Janet Darbyshire
Department of Medicine, Columbia University, New York, USA (M Rabkin MD); Mailman School
of Public Health and Division of Infectious Diseases, Harlem Hospital, Columbia
University, New York (Prof W El-Sadr MD); Department of Medicine, Stanford University,
Stanford, CA (D A Katzenstein MD); Department of Social Medicine, Harvard Medical School,
Boston, MA (J Mukherjee MD); Critical Care Medicine Department, US National Institutes of
Health, Bethesda, MD (Prof H Masur MD); Joint Clinical Research Center, Kampala, Uganda (P
Mugyenyi MD); Department of Essential Drugs and Medicines, WHO, Geneva, Switzerland (P
Munderi MD); Medical Research Centre, Clinical Trials Unit, London, UK (Prof J Darbyshire
Correspondence to: Dr Miriam Rabkin (e-mail:firstname.lastname@example.org)
When should antiretroviral treatment be started? How should antiretroviral treatment be
monitored? Selection of antiretroviral drugs (panel 3) Adherence to antiretroviral
treatment Recommendations References
The introduction of highly active antiretroviral treatment transformed the AIDS epidemic.
In populations with access to these drugs, death rates have plummeted. Until recently,
routine use of antiretroviral treatment in regions with few resources such as sub-Saharan
Africa was thought to be technically and economically impossible. The world, however, is
changing. Regimens that are easier to implement are also highly effective, the cost of
some antiretroviral regimens has dropped by 85%, 1 and new resources have become
available.2 Although expense, feasibility, and effective delivery remain formidable
barriers, public health and technical agencies have started to re-examine their
assumptions and to discuss use of antiretroviral drugs in poorly resourced environments.3
Data lending support to use of antiretroviral treatment in poorly resourced regions are
few. Even in well resourced countries, clinicians still do not have evidence-based answers
to simple issues such as: when to start antiretrovirals, how to monitor their therapeutic
and toxic effects, and in what sequence to use them. Answers to such issues are greatly
needed to speed up delivery of antiretrovirals to the populations most in need of
treatment. As a working group convened by the Rockefeller Foundation, we outline an urgent
research agenda that attempts to identify gaps in knowledge and to prioritise issues
affecting access to treatment for the tens of millions of adults living with HIV/AIDS in
poorly resourced regions.
Answers to many of these questions will also benefit patients in well resourced regions.
We do not address the equally important issues about use of antiretrovirals in infants and
children and of prevention of mother-to-child transmission.
When should antiretroviral treatment be started?
Use of antiretroviral treatment is straightforward in adults with symptomatic HIV-1
disease or CD4+ counts of 200 or less, 4-6 but whether asymptomatic adults with more than
200 CD4+ cells/mm3 should also begin treatment is unclear.7-9 Guidelines vary, but the
pendulum is swinging away from very early treatment towards a more cautious strategy of
deferred therapy.10, 11 This shift has been fuelled by the desire to strike a balance
between the efficacy of treatment and its toxic and adverse effects, and the need to
preserve future treatment options. The realisation that, at present, eradication of HIV-1
is not possible and that life-long treatment will be necessary has raised additional
concerns about adherence, resistance, cost, safety, and patient convenience.
The issue of when to start treatment is especially relevant in resource-constrained
settings, where the cost of drugs, laboratory and clinical monitoring, and management of
side-effects is very important. If treatment is started too early, essential resources
could be wasted and the risks of unnecessary toxic effects and drug resistance are
increased. Treatment started too late leads to excess morbidity and mortality. Not only is
the time when treatment should be started unclear, so too is which laboratory tests, if
any, should guide such a decision. Many clinicians and most guidelines in resource-rich
settings encourage measurement of viral load and CD4+ count to ascertain when to start
In the absence of data to support this strategy, and in view of the expense of such
testing, the usefulness of this approach in resource-poor settings has been challenged.
Cheaper, simpler tests of viral burden and immune function are a high priority. Results of
pilot studies13-15 suggest that total lymphocyte counts correlate with disease progression
and survival in symptomatic patients, and some guidelines endorse use of such a measure to
help make decisions about when to start treatment.16 Tests such as the heat denatured p24,
17 Dynabeads, 18 and Cyto-Sphere19 assays may also be useful, although data for use of
these treatments are imperfect. Simplified flow cytometry protocols have also been
developed.20 Providers in some resource-poor settings have simply restricted use of
antiretroviral treatment to patients with HIV who are symptomatic, an approach that
obviates the need for costly laboratory assays altogether.21 Panel 1 outlines some of the
issues about starting treatment.
Panel 1: Research questions for when treatment should be started Is there a clinical
advantage to starting antiretroviral treatment in asymptomatic patients with a CD4+ count
above 200? Are there cheaper and simpler methods of measuring CD4+ cell count? Are there
cheaper and simpler methods of measuring viral load? Are there laboratory markers other
than CD4+ cells and viral load that can successfully guide decisions about when to start
In the absence of laboratory data, are clinical criteria sufficient to guide decisions
about when to start antiretroviral treatment?
How should antiretroviral treatment be monitored? Antiretroviral treatment has several
characteristics suggesting that regular laboratory monitoring is important. Virological
and immunological responses and failures are usually asymptomatic. Similarly, although
some adverse effects of antiretroviral treatment are associated with clinical symptoms and
signs, other adverse events can only be detected by laboratory assays.
US guidelines endorse use of CD4+ cell counts and viral load measurement every 3-4 months
to assess the continued effectiveness of antiretroviral treatment.12 Use of these tests at
this frequency has not been validated, however, and the assays are prohibitively expensive
and technically more complex than what can presently be provided in most resource-poor
settings. In Uganda, for example, the cost of routine tests of efficacy (CD4+ cell count
and viral load) approaches the cost of a month of antiretroviral treatment (Peter
Mugyenyi, personal communication). Results of studies in which the best combination of
syndromic management, less frequent surveillance, and of cheaper, simpler monitoring tests
is assessed should widen the settings in which antiretroviral treatment can be used.
Monitoring for toxic effects
Although many patients tolerate antiretroviral treatment without difficulty,
antiretrovirals are associated with short-term and long-term toxic effects. Guidelines
from resource-rich countries recommend that asymptomatic patients should be monitored
every 3-4 months with laboratory tests (of haemopoietic, renal, and hepatic function) and
a medical history and physical examination.12 None of these strategies has been studied,
either individually or in combination, and the expense of such monitoring tests may
preclude their use in some environments.
Panel 2 summarises some of the issues that need to be addressed in monitoring of
Panel 2: Research questions for monitoring of antiretroviral treatment Is laboratory
testing for effectiveness and toxic effects necessary every 3-4 months, or is less
frequent laboratory testing appropriate?
What is the minimum laboratory monitoring needed to ensure safety and effectiveness?
Are there less expensive but equally useful methods to measure immune function and viral
burden in monitoring of effectiveness of antiretroviral treatment?
Would an algorithm using only clinical variables (weight gain, quality of life, decreased
frequency and severity of complications) to assess treatment success or failure be
Selection of antiretroviral drugs (panel 3)
Although safety, effectiveness, and acceptability should govern the choice of
antiretroviral treatment, individualised regimens might not be possible in many
environments. Standard low-cost regimens and algorithms to guide their use will accelerate
the widespread deployment of antiretroviral treatment needed in resource-poor settings
where care is provided mainly by nurses and health workers.
Selection of a first-line regimen (or regimens) is a key strategic decision. Objectives
include maximising the duration of clinical and immunological benefits and minimising drug
toxic effects and development of antiretroviral resistance. Most guidelines endorse many
combinations of antiretrovirals as first-line treatment, since there are no definitive
comparisons of potent antiretroviral treatment regimens.
Decisions about whether and when to change treatments are very important to the success of
antiretroviral treatment. Changing too soon leads to the risk that antiretroviral options
will be exhausted, but continuing with a failing regimen risks viral resistance, which can
jeopardise the success of subsequent treatment. Maintenance of viral load below the limit
of detection is theoretically appropriate to prevent emergence of resistance, but clinical
and immunological benefit can be maintained with a sustained but low level of viral
replication.22 Although the guidelines of many developed countries advocate use of viral
load testing, viral resistance testing, CD4+ count, and clinical assessment to guide
decisions about changing antiretroviral treatment, such an approach may not be feasible in
resource-limited settings. Up to now, few investigators have assessed changing treatment
solely on the basis of clinical symptoms or low-cost clinical markers, although several
trials have been started.
Panel 3: Research questions for selection of drugs can antiretroviral treatment be safely
and effectively prescribed by non-physicians using standard regimens and structured
clinical algorithms in resource-poor settings?
What are the most appropriate first-line regimens for resource-limited settings? How
should treatment failure be defined? When should antiretroviral treatment be stopped or
changed? Should this decision be based on virological, immunological, or clinical indices?
Are structured treatment interruptions, pulse therapy, or treat-to-safety strategies safe
Adherence to antiretroviral treatment
Non-adherence is the Achilles' heel of antiretroviral treatment; it is associated with
development of viral resistance, 23 virological failure, 24 progression of disease, 25 and
death.26, 27 Increasing attention is being paid to helping patients adhere to
antiretroviral treatment, and treatment guidelines highlight the topic as essential to
successful use of antiretrovirals. Few studies have been published about adherence to
antiretroviral treatment in poorly resourced countries and the results of those that have
been done show that adherence rates are similar to those seen in resource-rich
As non-adherence becomes better understood, interventions to promote adherence have been
studied with increasing rigor. These interventions fall into four broad
categories--patient education, behaviour modification, streamlined regimens, and
interpersonal support (including directly observed therapy)--although most programmes are
combinations of these approaches. No single best approach has been identified. Panel 4
outlines some of the issues associated with adherence to treatment.
Panel 4: Research questions for adherence to treatment
What are the main determinants/correlates of adherence in resource-poor settings?
If there are predictable barriers to adherence in these settings, are they modifiable?
Is fear of disclosure, stigma, or both a barrier to adherence to antiretroviral treatment?
What effect will traditional healers and the parallel health-care system have on adherence
to antiretroviral treatment?
What are effective adherence interventions? Do they differ from region to region or could
a standard package be developed?
The first 6 years of antiretroviral treatment have led to major health gains in many
countries. Answers to fundamental issues on how best to use these agents, however, remain
elusive. Experts in resource-rich countries continue to debate when to start
antiretrovirals, which drugs to use, how to monitor toxic effects and effectiveness, and
how to improve adherence. Use of antiretroviral treatment in resource-limited environments
adds additional issues and complexity. Answers are desperately needed to effectively and
rapidly extend antiretroviral treatment to millions of people infected with HIV-1
worldwide. Very little antiretroviral research has been done in or addressing the key
issues of concern to poorly resourced countries, a situation which must change. The need
to answer these questions should not delay provision of HIV care to those who urgently
need it.Instead, research can and should be built on to treatment programmes to facilitate
wider use of these life-saving drugs.
All authors participated in a working group convened by the Rockefeller Foundation. M
Rabkin wrote the first draft of the report. All authors contributed to the final text.
Conflict of interest statement
This work was supported by the Rockerfeller Foundation. D Katzenstein is a Doris Duke
Charitable Trust Distinguished Clinical Scientist. David Bangsberg, Mary Bassett, and
William Duncan substantially contributed to this report.
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Lancet 2002; 360: 1503-05
Complete article at http://www.thelancet.com/journal
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