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Is Protease Inhibitor Monotherapy Sufficient to Keep HIV Under Control in the Brain?

November 1, 2012

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Reports From Western Europe

Researchers in Sweden and Switzerland have been conducting clinical trials of PI monotherapy and HIV-related neurological research. Recently, two teams have separately reported that their data strongly suggest that injury to cells within the brain has occurred in some participants when exposed to PI monotherapy. The Swedish team recommends that PI monotherapy be used cautiously until further clinical trials are completed and more detailed information on the brain health of participants becomes available.


Sweden -- Case 1

Doctors in Gothenburg reported details on two participants from a neurological study. As part of that study, participants had samples of their cerebrospinal fluid (CSF) taken from time to time. The CSF is the fluid that bathes the brain and spinal cord. The first participant was a woman who initiated ART in May 2007 when her CD4+ count was 170 cells and her viral load was 82,400 copies/ml. Her combination was as follows:

  • AZT + 3TC (Combivir; a  fixed-dose combination of these two nukes) and Kaletra

After three months of this combination, her viral load in the blood fell to less than 20 copies/ml.

In April 2009, her combination was changed to the following:

  • abacavir + 3TC (Kivexa; a fixed-dose combination of these two nukes) and darunavir 800 mg and ritonavir 100 mg

In August 2009, her doctors discontinued Kivexa because of suspected abacavir skin rash and her regimen was reduced to the PI-based combination of darunavir-ritonavir.

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Four months later, analysis of her blood found a viral load of 119 copies/ml and in the CSF the viral load was 709 copies/ml. Previously, when her regimen included Kivexa, viral load in the CSF was less than 20 copies/ml. Other abnormalities in her CSF included the following:

  • elevated levels (10-fold) of lymphocytes
  • elevated levels of beta2-microglobulin and neopterin -- these chemicals are produced by the immune system when it becomes activated and inflamed in response to infections or tumours
  • signals of injury to the brain cells

Collectively, all of these changes suggested that an infection was underway in the brain (tumours had been ruled out) and inflammation was occurring. All of this was likely due to resurgent HIV infection.

Doctors quickly added Truvada (a fixed-dose combination of two nukes: tenofovir + FTC) to her regimen. Within one month the viral load in her blood fell back to less than 20 copies/ml. Four months later when they performed another spinal tap, the viral load in her CSF had fallen to 56 copies/ml and inflammation was greatly reduced. Furthermore, there were no signals of injury to cells within the brain. The woman did not report any neurocognitive problems. However, formal assessments of her neurocognitive functioning were not performed.


Sweden -- Case 2

The second patient initiated therapy in 2004 when his CD4+ count was 160 cells and his viral load was about one million copies/ml. His initial therapy also consisted of Combivir and Kaletra, which quickly suppressed his viral load in the blood to less than 50 copies/ml and raised his CD4+ count to 790 cells.

In 2007 he took part in a clinical trial where his therapy was intensified with the addition of two anti-HIV agents -- the fusion inhibitor T-20 (enfuvirtide, Fuzeon) and the CCR5-co-receptor blocker maraviroc (Celsentri, Selzentry) -- both for four weeks. After this he returned to his previous regimen.

In all cases, while he was on triple or greater anti-HIV therapy, the viral load in his CSF was less than 50 copies/ml. However, 12 months after changing his regimen to darunavir-ritonavir, the viral load in his CSF had increased to 478 copies/ml.

As with the first patient, during PI monotherapy elevated levels of lymphocytes, beta2-microglobulin and neopterin were detected in his CSF. Also, signals of injury to brain cells were elevated.

Neurocognitive assessment done before and 12 months after changing to a simpler regimen of PI monotherapy did not find signs of decline. Like the case of the first patient, researchers did not find HIV that was resistant to treatment in his CSF.

When doctors added Kivexa to his regimen, within a month his viral load in the blood fell to less than 20 copies/ml and three months later the viral load in his CSF was also less than 20 copies/ml. Although the level of inflammation in the CSF had fallen, ongoing injury to brain cells was detected. The cause of this ongoing injury was not clear.

For purposes of comparison, the Swedish researchers analysed CSF samples from 21 participants who were receiving darunavir-ritonavir and two nukes. In only one of these 21 participants was there a signal suggestive of injury to brain cells.


Assessing Injury in the Brain -- NFL

One marker, or protein, that is emerging as increasingly useful for assessing brain health is called NFL (neurofilament light protein). In general, NFL levels in the CSF are closely associated with injury to brain cells. Elevated levels of NFL have been found in HIV-negative people with dementia, multiple sclerosis, stroke and Alzheimer's disease. One study in HIV-positive people found that increased levels of NFL in the CSF are associated with a high risk for developing HIV-related dementia.


Assessing Injury in the Brain -- S100B

Astrocytes are cells that help maintain the health of the brain and also assist brain cells to communicate. Researchers have found that astrocytes can release a protein called S100B. At low levels, S100B helps the development of brain cells. However, at high concentrations it can cause brain cells to die. One study in HIV-positive participants linked elevated S100B levels in the CSF to an increased risk of death among people with dementia. In another study, elevated S100B levels were linked to neurocognitive dysfunction in HIV-positive people.

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This article was provided by Canadian AIDS Treatment Information Exchange. It is a part of the publication CATIE News. Visit CATIE's Web site to find out more about their activities, publications and services.
 

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