Latency Is a Myth: New HIV Paradigm May Focus on Inflammation|
evidence indicates that untreated HIV has detrimental effects even at relatively
high CD4 cell counts, suggesting earlier antiretroviral therapy -- above the current
350 cells/mm3 threshold -- may be beneficial, according to an plenary presentation
at the 5th International AIDS Society Conference on HIV Pathogenesis, Treatment,
and Prevention (IAS 2009) taking place this week in Cape Town, South Africa. |
It is well known that combination antiretroviral
therapy (ART) dramatically reduces the risk of opportunistic
illnesses (OIs) and related mortality due to immune suppression. But a growing
number of studies indicate that chronic HIV infection can set off inflammatory
processes that may contribute to various conditions traditionally charcterized
El-Sadr from Columbia University and Harlem Hospital Center in New York City review
some of these studies and their implications for HIV clinical management.
was principal investigator with the SMART
treatment interruption trial, which found that people who stopped ART when
their CD4 cell count rose above 350 cells/mm3 not only had a higher rate of OIs
and death than people who remained on continuous therapy, but also unexpectedly
had more serious non-AIDS conditions including cardiovascular, liver, and kidney
diversity of these manifestations -- along with neurocognitive impairment and
bone loss -- suggests a possible "unifying framework" for the negative
effects of ongoing HIV replication throughout the body, which El-Sadr proposed
may be related to inflammation and the coagulation (blood clotting) cascade.
hypothesis is supported by SMART and other studies showing that various biomarkers
of inflammation and coagulation -- including C-reactive protein and D-dimer
-- are higher in HIV positive compared with HIV negative people, increase with
greater duration of HIV infection, rise when ART is discontinued, and fall when
treatment is started.
to El-Sadr, it is time for a re-conceptualization of the pathogenesis of HIV disease.
The traditional understanding of the natural history of the disease included a
long period of clinical "latency," but the idea that the virus remains
silent for many years increasingly looks like a misperception.
of people starting therapy before severe immune system decline indicate that rates
of both OIs and non-AIDS conditions occur even in HIV positive people with high
CD4 counts during what was traditionally considered the latency period. Indeed,
non-AIDS deaths predominate over AIDS-related deaths in people with more than
are now data to indicate that "ongoing processes in the body due to HIV itself
may be causing some unseen damage that may have a major effect of survival,"
HIV causes detrimental effects even at high CD4 counts, this raises the question
of whether ART should be started sooner. Several research teams, including NA-ACCORD
and the Study
Group on Death Rates at High CD4 Counts in Antiretroviral-Naive Patients,
have now demonstrated that starting treatment above 350 -- or even 500 -- cells/mm3
reduces the risk of illness, improves survival, and promotes more complete CD4
while earlier therapy has clear benefits, it also may have risks, including known
side effect and perhaps new long-term toxicities that are not yet recognized.
Indeed, a "treat early, treat hard" philosophy held sway at the dawn
of the HAART era, with U.S. guidelines recommending treatment below 500 cells/mm3,
until unexpected metabolic and mitochondrial toxicities led to greater caution.
emphasized the importance of controlled studies looking at the benefits and risks
of early ART, including serious non-AIDS events and biomarkers. The impending
START trial will compare current and earlier treatment thresholds in people with
well-preserved immune function. She also suggested that various adjunct therapies
-- for example statins to control inflammation, to be assessed in the ACTG 5275
pilot study of atorvastatin (Lipitor) -- may play a role in future ant-HIV treatment.
will be large enough to "actually get definitive answers," El-Sadr said,
and its findings will have "implications for the management for millions
and millions of people" -- potentially supporting a "paradigm shift"
in the field.
a press conference following the presentation, however, El-Sadr and other speakers
emphasized that even as researchers, clinicians, and patient advocates in wealthy
countries debate the benefits of stating treatment above 350 cells/mm3, about
two-thirds of people with HIV in developing countries worldwide still do not have
access to urgently needed ART based on the old 200 cells/mm3 threshold.
El-Sadr. Inflammation and HIV: A New Paradigm. 5th International AIDS Society
Conference on HIV Pathogenesis, Treatment, and Prevention. July 19-22, 2009. Cape
Town, South Africa. Abstract MOPL104.