Wednesday 29 June, 2016 13.00 EDT
1 November 2012
Is protease inhibitor monotherapy sufficient to keep HIV under control in the brain?
Shortly after HIV enters the body it infects cells of the immune system. As these infected cells are carried by the blood stream, HIV is spread throughout the body, including to the brain and spinal cord—the Central Nervous System (CNS). HIV does not infect brain cells, but it does infect cells of the immune system that travel to or are permanent residents of the brain. These HIV-infected cells release proteins and chemical signals that cause inflammation and impair the functioning of brain cells. If left untreated, HIV infection can eventually result in serious neurological issues—causing the brain to shrink, affecting clear thinking, bringing about difficulty controlling muscles and movement, degrading memory and key reflexes, and inciting changes to personality.
In high-income countries such as Canada, Australia and the United States and in regions such as Western Europe where potent combinations of anti-HIV therapy (commonly called ART or HAART) are widely available, severe HIV-related neurocognitive problems are no longer common compared to in the pre-HAART era. However, some research teams have reported that very mild neurocognitive impairment, detectable only with sophisticated and complex testing, appears to be relatively common among some ART users in the current era. The reasons for this are not clear but might be related to the following:
- aging of HIV-positive people
- possible impact of co-morbidities (such as cardiovascular disease, diabetes, hepatitis C co-infection) on the brain
- low-grade persistent inflammation in the CNS
- potential neurotoxicity of ART
- the inability of some anti-HIV drugs to enter or remain within the CNS
At present, ART generally refers to at least the following combinations of drug classes:
- two nukes + a non-nuke
- two nukes + a ritonavir-boosted protease inhibitor
- two nukes + an integrase inhibitor
When starting therapy for the first time, one of these combinations is usually prescribed. Among treatment-experienced patients, sometimes more complex regimens are used.
One type of simplification
Standard ART is expensive. Some doctors and their patients are also concerned about potential side effects from ART and would like to use fewer therapies. To try to find simpler regimens of anti-HIV drugs, researchers, mainly in Western Europe, have been conducting clinical trials of simplified therapy—particularly based on a protease inhibitor boosted with a small dose of ritonavir (Norvir). This is generally called protease inhibitor monotherapy (PI monotherapy).
The drugs most commonly used for PI monotherapy are as follows:
- darunavir (Prezista) and ritonavir
- lopinavir (in Kaletra; a fixed-dose combination of lopinavir and ritonavir)
In general, most clinical trials of PI monotherapy have found that such combinations are not as effective as standard triple therapy, the cornerstone of ART. However, in such trials when virologic failure occurred among participants given PI monotherapy, adding two nukes to their regimen was able to return HIV viral load to less than 50 copies/ml in 93% of cases.
Small and short
Based on published clinical trials so far, researchers estimate that the risk of PI monotherapy failing after one year is about 10%. However, it is important to bear in mind that most trials of PI monotherapy have had relatively small numbers of participants and did not last for more than one or two years. As a result, the overall long-term safety and effectiveness of PI monotherapy is not known.
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.
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.
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.
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.
Results from Switzerland
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.
A note about assessing neurocognition in MOST
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.
No treatment failure but hints of central nervous system injury
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:
- The CSF from four participants whose regimen (PI-monotherapy) failed had the highest levels of S100B and neopterin.
- The researchers also found that, even in participants on PI-monotherapy who had no evidence of viral failure either in the blood or in the CSF, S100B levels were higher than in the CSF of participants on ART.
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.
Putting it all together
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.
Moving away from monotherapy to dual therapy
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:
- atazanavir + Kivexa
- darunavir + maraviroc
- Kaletra + 3TC (lamivudine)
- Kaletra + raltegravir (Isentress)
- maraviroc + raltegravir
A mind of her own – understanding and dealing with HIV-related neurocognitive issues
We thank Magnus Gisslén, MD, PhD, University of Gothenburg, Sweden, for his research assistance, helpful discussion and expert review. We also thank neurologist, Professor Renaud Du Pasquier MD, University Hospital Lausanne, Switzerland, for his expert review of the Swiss CSF study.
—Sean R. Hosein
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