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Should the CD4 threshold for starting ART be raised? Commentary
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Antiretroviral timing for HIV
When to start antiretroviral treatment has been a problem for physicians dealing
with patients with HIV infection. This paper provides the strongest evidence
from large patient cohorts.
Article The Lancet (online April 9)
Summary of Antiretroviral Treatment NaÏve Studies from CROI: Still Looking for a
Consensus on When to Start - written by Susan J. Little, M.D. Associate
Professor of Medicine University of California San Diego, USA -
(02/27/09)
The Lancet, Early Online Publication, 9 April 2009
doi:10.1016/S0140-6736(09)60654-1
Robin Wood a, Stephen D Lawn a b
a Desmond Tutu HIV Centre, Institute for Infectious Disease and Molecular
Medicine, Faculty of Health Sciences, University of Cape Town, Cape Town,
Observatory 7925, South Africa
b Clinical Research Unit, Department of Infectious and Tropical Diseases, London
School of Hygiene and Tropical Medicine, London, UK
Since the development of combination antiretroviral therapy (ART) for HIV in the
mid-1990s, changes in recommendations on when to start treatment in high-income
countries have been likened to a swinging pendulum.1-3 After the dismal
prognosis for patients in the pre-ART era, the initial approach of early
aggressive therapy was based on enthusiasm derived from theoretical
considerations.4 However, subsequent data from observational studies and
short-term clinical trials revealed unexpected long-term metabolic and
cardiovascular toxicities, leading to a shift in expert opinion toward a more
cautious approach.3 Recommendations to date, however, have largely remained
uninformed by data from randomised trials with clinical endpoints.
Current British and American guidelines recommend that, in the absence of an
AIDS-defining illness, ART should be started in patients with blood CD4 cell
counts in the range 200-350 cells per μL.5, 6 With the development of treatment
regimens with lower toxicity and increasing evidence that HIV-associated
morbidity and mortality develop at CD4 cell counts substantially higher than 200
cells per μL,7 it might be time for the pendulum to swing once more towards
earlier treatment.
In The Lancet today, the When To Start Consortium presents an analysis of data
from over 45 000 patients from 18 observational HIV cohorts in Europe and North
America.7 Frequency of death, or combined AIDS and death, in patients receiving
and not receiving ART was used to identify a minimum threshold of 350 cells per
μL for starting ART. The validity of this recommendation is greatly strengthened
by the large numbers of patients, diversity of cohorts, the ability to compare
event frequencies between narrow overlapping strata of CD4 cell counts and,
crucially, the adjustment for lead-time bias.
Observational data can be subject to unrecognised confounders, and the analysis
did not include non-fatal non-AIDS events or data on quality of life or
adherence. At higher CD4 cell counts, differences in non-AIDS morbidity between
strata for CD4 cells might be important, as shown in a small subgroup analysis
from the Strategies for Management of Antiretroviral Therapy (SMART) study.8 In
that study, ART-naive individuals with CD4 cell counts higher than 350 cells per
μL were randomly assigned either to receive immediate ART or to defer ART until
counts were less than 250 cells per μL. Those who deferred treatment had a far
higher rate of major morbidity and all-cause mortality than did those treated
immediately (4·9 vs 1·0 events, both per 100 person-years, respectively). These
data suggest that, when taking into account serious non-AIDS events, the
potential benefit to be derived from earlier initiation of ART might be even
greater than that suggested by the When To Start Consortium.
The data presented by the When To Start Consortium support a shift in
recommendations towards initiation of ART at a minimum CD4 cell-count threshold
of 350 cells per μL.7 However, while acknowledging the strength of this
analysis, these observational data are not definitive. Randomised trials are
needed in which more varied data are collected. At high CD4 cell counts,
differences in absolute risk of AIDS and death between early and deferred ART
are small, and uncertainty about the risk to benefit ratio remains. Even when
benefits outweigh risks, cost-effectiveness is unclear. Data are needed on
serious complications of ART that might negate the benefits, such as
cardiovascular, renal, and hepatic disease. Furthermore, the effect on the
quality of life should be assessed. A large randomised study assessing such
variables, the Strategic Timing of Antiretroviral Treatment (START) study, is
due to begin this year.9
The data in the When To Start Consortium study were from cohorts in
industrialised countries and cannot be assumed to be directly applicable to
patients in all settings. Mortality rates and the range of morbidity differ
between cohorts in industrialised countries and resource-limited settings. Data
from South Africa, for example, indicate that unusually high rates of AIDS and
death occur in patients with CD4 cell counts in the range 200-350 cells per
μL.10 Early mortality in patients receiving ART in sub-Saharan Africa is also
substantially greater than in those treated in high-income countries.11
Moreover, the range of ART drugs available and cost-effectiveness considerations
can be more restrictive in developing countries.
Thus, when considering both high-income and resource-limited settings, the
question of when to start ART might have more than one right answer. WHO
guidelines for resource-limited settings currently recommend initiation of ART
before blood CD4 cell counts fall below 200 cells per μL with an upper threshold
of 350 cells per μL.12 To inform these recommendations, randomised trials should
include patients living in resource-limited settings.
We declare that we have no conflicts of interest.
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