HIV and the Brain
If HIV in the brain causes an "inflammatory cascade" that disrupts normal function, it makes sense to ask whether antiretroviral drugs that cross the blood-brain barrier are particularly beneficial in preventing or improving HIV-related neurocognitive impairment.
Ranking CNS Penetration Antiretroviral drugs differ in their capacity to penetrate the brain, due to variations in several pharmacological properties. This may help explain why HIV can evolve into distinct strains within the CNS, even showing different drug-resistance patterns compared with plasma virus.
Researchers have developed a scoring system, known as the CNS penetration effectiveness (CPE) index, to rank the ability of antiretroviral drugs to enter the brain (see sidebar). CPE scores have been used in several studies looking at the comparative efficacy of agents with good versus poor penetration.
Rankings of CNS penetration are subject to disagreement, however, as drug levels in the brain can be difficult to determine. CSF levels are not necessarily a good indicator of drug levels in brain tissue, and different measuring methods can produce varying results. Efavirenz (Sustiva, also part of the Atripla coformulation), for example, has an intermediate CPE score, but some recent research suggests it actually penetrates the brain quite well.
Some drugs float more or less freely in the blood while others bind to proteins. Compared with nucleoside/ nucleotide reverse transcriptase inhibitors (NRTIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs) bind more readily with proteins, which impairs their ability to cross the blood-brain barrier. But boosting with ritonavir (Norvir) may raise drug concentrations enough to enable significant penetration.
Low molecular weight also favors better brain penetration. As a class, PIs have a higher weight than NNRTIs, which in turn are "heavier" than NRTIs. Drugs that are lipophilic, meaning they dissolve in or combine with lipids, also tend to have better penetration, a property that favors NRTIs over PIs and NNRTIs. Some drugs are subject to the action of molecular "pumps" that expel drug molecules from cells.
Tenofovir (also part of the Truvada and Atripla combination pills) does not cross the blood-brain barrier in significant amounts. According to Letendre, this factor should be considered in the ongoing debate about the relative benefits and risks of tenofovir versus abacavir (Ziagen, also in the Epzicom and Trizivir coformulations), which penetrates the brain relatively well.
There are less data on the most recently approved drug classes. One recent study indicated that boosted darunavir (Prezista), the newest PI, reaches high CSF levels. Letendre holds that integrase inhibitors are unlikely to cross the blood-brain barrier in appreciable amounts, though pharmacokinetic studies suggest they do so to some degree. The CCR5 antagonists maraviroc (Selzentry) and vicriviroc appear to penetrate the CNS, and the M-tropic HIV strains that predominate in the brain should be susceptible to CCR5 blocking.
CNS Penetration Effectiveness
The CNS Penetration Effectiveness (CPE) scale was developed to rank the ability of antiretroviral drugs to cross the blood-brain barrier. (Due to insufficient data, the chart below does not include the most recently approved drugs.)
Penetration and Performance
Does CNS penetration matter with regard to neurocognitive impairment? Constructing regimens that contain at least one drug that penetrates the brain has been emphasized to greater or lesser degrees as ideas about therapy have evolved. Some studies indicate that drugs that enter the brain can improve neurocognitive function, whereas others suggest that regimens that produce full plasma HIV RNA suppression protect the brain equally well.
Good penetration is clearly associated with reduced levels of HIV in the CSF, as demonstrated by Letendre and colleagues' work with the CHARTER cohort. In the January 2008 Archives of Neurology, they reported that ART regimens with a total CPE score less than 2 (determined by adding the individual scores for each drug) were associated with an 88% increase in the odds of detectable CSF virus, leading them to conclude that "Poorer penetration of [antiretroviral] drugs into the CNS appears to allow continued HIV replication in the CNS."
As to whether this correlates with improved performance, a smaller analysis published in 2004 indicated that among 31 patients with baseline cognitive impairment, using a regimen containing more CSF-penetrating drugs led to a significantly greater reduction in CSF viral load, and CSF virological suppression was in turn linked to greater improvement in neuropsychological test performance.
At CROI, CHARTER investigators reported that among 300 cohort participants with both plasma and CSF viral load below 50 copies/mL, 41% of patients with "undetectable" CSF viral load were found to have low-level CSF HIV RNA (between 2.5 and 50 copies/mL) using an ultrasensitive test. Individuals who had detectable HIV RNA in CSF but not in plasma had significantly worse neurocognitive performance than those who had undetectable HIV in both blood and CSF, and also compared with those who had detectable virus in both compartments.
The CHARTER analysis also showed that regimens containing NNRTIs -- which have intermediate-to good CNS penetration -- were associated with improved neurocognitive performance, as was being treatmentnaive when starting the study. And, as the NeuroAIDS Tissue Consortium team reported at the 2008 CROI, an autopsy study of brains from 374 patients revealed that HIV-related brain pathology was about half as likely among people who had taken NNRTIs compared with PIs or no ART.
In the September 1, 2009, Journal of Acquired Immune Deficiency Syndromes, Valerio Tozzi and colleagues reported that higher CPE scores were associated with improved neurocognitive performance in various domains. However, an alternative method that involved simply counting the number of drugs in a regimen thought to have good CNS penetration did not predict improvement.
Two studies published this past summer came to opposite conclusions regarding the association between brain-penetrating ART and neurocognitive function.
Cysique and the UCSD team evaluated cognitive changes in 37 individuals with baseline mild-to-moderate neurocognitive impairment after they started combination ART. As reported in the August 4, 2009, issue of Neurology, cognitive improvement began soon after starting treatment, with 14% demonstrating better neuropsychological test performance by week 12. More patients improved with longer time on ART, reaching 32% at week 24, and 41% at week 36; by week 48, however, the improvement rate had slipped to 33%. Over the same period, only one person experienced worsening test performance.
Neurocognitive improvement was associated with use of drugs with higher CNS penetration scores (CPE >2) and more severe impairment at baseline. Unlike prior research, however, this study did not show a link between improvement and lower CSF viral load or being treatment-naive. "[T]o minimize impact of HAND on productivity and life quality, drug regimens with the estimated CNS penetration ... should be selected when possible based on treatment and toxicity histories and drug resistance testing," the researchers concluded.
In contrast, as reported in the July 17, 2009, issue of AIDS, Christina Marra and coinvestigators with study ACTG 736 actually found a negative correlation between use of CNS-penetrating therapy and neurocognitive performance.
In this longitudinal analysis of 79 patients with advanced HIV disease who were either starting first-line ART or switching therapy, using a regimen with a higher CPE score (.2) did not improve overall performance on a battery of neuropsychological tests, even though it increased the likelihood of CSF viral load suppression. In some functional domains, in fact, test performance actually declined. Searching for an explanation for these unexpected results, the investigators suggested that drugs with good CSF penetration might cause more toxicities in the brain.
Whether or not they are required to improve neurocognitive function, drugs that cross the blood-brain barrier may still be needed to reach latent "reservoir" virus in the brain if HIV eradication is ever to be achieved. More immediately, HIV hiding in the CNS can escape and "reseed" the blood if ART is interrupted.
Given these conflicting results, some researchers have suggested that suppressing HIV in the plasma may be adequate for people with relatively well-preserved immune function and mild cognitive impairment, while brain-penetrating drugs may be necessary for those with more advanced HIV disease and more severe neurocognitive disorders.
"As a general rule, NNRTIs are well penetrating into the CNS, most PIs are poor penetrators, and NRTIs are somewhere in between," Grant summarized at a CROI 2009 press briefing. "There is a modest association between patients on better-penetrating drugs being less likely to have detectable CSF viral load and cognitive impairment. The effects are there, but they're not gigantic."
Letendre noted that although observational studies support treating HAND with better-penetrating ART, data from controlled trials are lacking. Such studies are in the works, however, including neurological substudies in the large treatment strategy trials conducted by INSIGHT (International Network for Strategic Initiatives in Global HIV Trials) and NEAT (Network on European AIDS Treatment).
"If a patient has neurological symptoms, it's reasonable to switch to more neuro-penetrating drugs," Letendre concluded. "Should all patients be put on neuro-penetrating drugs at the outset? No, that is just one of many factors to consider in individual cases."
In summary, while effective antiretroviral treatment and subsequent immune recovery dramatically reduce the occurrence of brain OIs and severe HIV-related dementia, mild-tomoderate neurocognitive and motor impairment remains a concern in the ART era.
Many people with HIV show signs of impairment on neuropsychological tests that are not apparent even to the affected individual. The clinical relevance of asymptomatic HAND is unclear, as it is not known whether impairment will remain stable as long as a person stays on effective ART, or will inexorably progress as the person ages, perhaps combining with Alzheimer's disease or other age-related disorders.
ART generally improves neurocognitive performance, and it is important for people with memory difficulties or other cognitive problems to receive the support and assistance they need to achieve good adherence to therapy.
But ART is not enough to completely cancel out existing neurological damage, and the risk of impairment remains significant among people with previous advanced immune suppression (i.e., low nadir CD4 count).
"It is possible that low nadir CD4 represents a 'legacy' event whose neurologic consequences persist once triggered," according to the CHARTER investigators. Likewise, the ALLRT researchers concluded that "The association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there is a non-reversible component of neural injury that tracks with a history of disease progression."
In contrast, according to Letendre, CHARTER participants on effective ART with undetectable plasma viral load whose CD4 counts had never dropped below 200 cells/mm3 demonstrated significantly better cognitive performance than those who started ART with more advanced HIV disease.
Tozzi and colleagues found that severity of neurocognitive impairment at the time of ART initiation appeared to be the strongest predictor of persistent neuropsychological deficits despite long-term therapy. "HAART improves neurocognitive functioning but, in our experience, the greater is the impairment, the lower is the probability of its full reversal," Tozzi said.
Furthermore, since HIV-related brain injury is due not to direct infection of neurons, but rather to the toxic effects of viral proteins and the inflammatory cascade and oxidative stress triggered by the virus, even a small amount of residual HIV may be enough to maintain a neurotoxic environment.
Nevertheless, as Ronald Cohen and Assawin Gongvatana pointed out in an editorial accompanying Cysique's Neurology article, the results of that study "indicate that HIV-associated cognitive impairment is treatable and may not reflect permanent structural damage to the brain, such as is presumed to occur in brain disorders like Alzheimer disease."
Taken together, recent research on neurocognitive disorders in people with HIV underline the potential hazards of treatment interruption and add to the growing body of evidence supporting earlier initiation of ART, before significant immune dysfunction occurs.
Since HIV enters the brain within days after infection, however -- well before most people are even aware they have the virus -- it may be practically impossible to start treatment early enough to prevent all neurological damage.
As such, there is a great need to develop other types of neuroprotective therapies, including agents that block the neurotoxic effects of HIV proteins, drugs that inhibit proinflammatory cytokines that trigger neuron injury, antioxidants that neutralize free radicals causing oxidative stress, and growth factors and stem cells to help repair or replace damaged brain tissue (see sidebar). Therapies to manage co-existing risk factors such as metabolic abnormalities and hepatitis C coinfection may also play a role.
Given the multiple factors and processes that play a role in HIV-related neurocognitive disorders, it is likely that a combination of different types of therapies may be needed to fully reverse established impairment.
Liz Highleyman (firstname.lastname@example.org) is a freelance medical writer based in San Francisco.
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Want to read more articles in the Summer/Fall 2009 issue of Bulletin of Experimental Treatments for AIDS? Click here.
This article was provided by San Francisco AIDS Foundation. It is a part of the publication Bulletin of Experimental Treatments for AIDS. Visit San Francisco AIDS Foundation's Web site to find out more about their activities, publications and services.
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