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 HIV and Coverage of the
th IAS Conference on HIV Pathogenesis, Treatment and Prevention (IAS 2009)
 July 19 - 22, 2009, Cape Town, South Africa
 The material posted on HIV and about IAS 2009 is not approved by nor is it a part of IAS 2009.
HIV Latency Is a Myth: New HIV Paradigm May Focus on Inflammation

Accumulating 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.

By Liz Highleyman

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 as non-AIDS-related.

Wafaa 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.

El-Sadr 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 disease.
Wafaa El-Sadr

The 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.

This 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.

According 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.

Studies 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 200 cells/mm3.

There 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," El-Sadr said.

If 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 cell recovery.

But 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.

El-Sadr 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.

START 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.

At 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.


W 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.















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