November 1, 2012
In Switzerland, researchers have been conducting a clinical trial of Kaletra monotherapy versus ART. Prior to entering this study (called MOST), participants had been taking ART for at least four years, their CD4+ counts were between 450 and 500 cells and viral loads were less than 50 copies/ml.
The MOST study was prematurely stopped because six out of 42 participants (14%) who were taking Kaletra monotherapy had viral loads in the blood that rose and remained above 400 copies/ml. Researchers considered those six participants to have virologic failure. This was in contrast to the comparison group in MOST who took ART and in whom no virologic failures occurred.
Since specific neurocognitive testing to assess very subtle changes (such testing follows a protocol called the Frascati criteria) was not performed in MOST study subjects, including those with elevated viral load in their CSF, it is not possible to be certain whether any of them had HIV-associated neurocognitive disorders. Nevertheless, researchers found that none of them showed any obvious signs of major cognitive disorders.
Out of the six participants whose regimen failed, CSF samples from five were available for analysis. In all five cases, virologic failure occurred in CSF. Also found in these five participants' CSF samples were higher-than-normal levels of neopterin (suggestive of immune activation) and S100B, suggestive of injured astrocytes.
Although extensive neurocognitive testing was not done in MOST, doctors found that none of the participants with elevated viral load in their CSF showed any obvious signs of moderate to severe neurocognitive impairment.
Swiss researchers analysed 65 CSF samples (34 on ART and 31 on PI-monotherapy) from 49 HIV-positive patients enrolled in MOST. They found that, in the CSF of PI-monotherapy patients, concentrations of S100B (suggestive of injured astrocytes) and neopterin (suggestive of immune activation) were significantly higher than in patients on ART.
Other key findings from the CSF analyses in MOST were as follows:
Furthermore, six of 17 participants (35%) taking PI-monotherapy whose regimen was not failing, but only one of 32 (3%) participants on ART (who also was not failing) had elevated levels of S100B in their CSF, specifically S100B values higher than 1,000 picograms/ml. Whether this cutoff may serve to identify patients with suboptimal antiretroviral treatment needs to be confirmed in future studies designed specifically for this purpose.
The Swiss analysis of CSF is important as it suggests that "undetectable viral load in the [blood] and the CSF do not necessarily rule out ongoing inflammation in the brain." Moreover the Swiss team notes that their findings suggest that monitoring the health of astrocytes may be important because damage to astrocytes (using markers such as S100B) may be an early signal of inflammation within the brain.
Researchers at Harvard University have also found that despite effective ART, inflammation in the CSF of HIV-positive people could still be detected.
Other researchers have found ongoing inflammation in experiments on monkeys despite the animals being given potent combinations of anti-HIV drugs. Specifically, researchers used monkeys susceptible to SIV (simian immunodeficiency virus), a virus closely related to HIV that causes an AIDS-like disease in these animals. The researchers found that viral load in the blood and CSF can fall to undetectable levels when the animals are treated. Yet, when analyzing the CSF samples of treated animals, researchers found that inflammation was still occurring.
The research with HIV-positive people in Sweden, Switzerland and the U.S., together with experiments on monkeys with SIV, suggests that inflammation in the brain is a problem with these infections and that such inflammation might not fully resolve despite treatment. This suggests that caution should be exercised with PI monotherapy.
It also suggests that further research is needed with ART users so that neuroscientists can explore the cause of ongoing inflammation in the CNS and ways of dealing with this, particularly as HIV-positive people age.
Some clinical trials of simplified therapy have been completed or are underway. Hopefully these other studies will also investigate the possibility of any changes in the brains of participants.
Some examples of internationally run clinical trials of simplified regimens planned, underway or completed include the following combinations:
"A Mind of Her Own" -- understanding and dealing with HIV-related neurocognitive issues.
We thank Magnus Gisslén, M.D., Ph.D., University of Gothenburg, Sweden, for his research assistance, helpful discussion and expert review. We also thank neurologist, Professor Renaud Du Pasquier M.D., University Hospital Lausanne, Switzerland, for his expert review of the Swiss CSF study.
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