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HIV and the Brain

Summer/Fall 2009

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Changing Epidemiology

Prior to the widespread availability of combination ART, it was estimated that about 20% of people with HIV/AIDS developed dementia. About 90% -- including many patients without evident impairment prior to death -- showed some type of pathological brain changes on autopsy.

Today, the incidence (number of new cases) of HAD is dramatically lower -- less than 1% in some studies. In the European CASCADE cohort, for example, the incidence rate of HAD fell from 6.49 per 1,000 person-years (PY) before 1997 to 0.66 per 1,000 PY by 2003.2006. However, HAD prevalence (total cases) may actually be higher because affected individuals are living longer.

"Severe, life-shattering dementia is rare," said HIV neurology expert Scott Letendre from the University of California at San Diego (UCSD) in an overview presented at CROI. However, he added, a large number of people with HIV continue to experience mild or moderate neurological disorders.

Looking at this less severe form of impairment, several recent studies indicate that the overall rate of HIV-related neurocognitive problems is around 50%.about the same as during the pre- ART era. The proportion varies, however, according to demographic characteristics, degree of immune suppression, co-existing conditions, and other factors.


At both CROI and the IAS conference, investigators with the large CHARTER (CNS HIV Antiretroviral Therapy Effects Research) study presented findings on the epidemiology and natural history of HIV-related neurocognitive impairment.

Sponsored by the National Institutes of Health, CHARTER was designed to explore the changing presentation of HIV-related neurological complications in the ART era. The study is following 1,555 HIV positive patients enrolled between 2003 and 2007 at six sites (Baltimore, Galveston, New York City, St. Louis, San Diego, and Seattle). Participants have varying treatment histories and degrees of immune dysfunction and neurocognitive impairment; there were no neurological or psychiatric exclusion criteria.

About three-quarters of study participants are men, half are black, about 40% are white, and the average age at study entry was 43 years; about 25% are coinfected with hepatitis C virus (HCV). Most are taking combination ART and the median CD4 count is relatively high (above 400 cells/mm3), but the average nadir level was below 200 cells/mm3, indicating a history of advanced immune suppression.

The CHARTER team reported in a poster at IAS that 52% of cohort participants overall had some degree of neurocognitive impairment relative to the general HIV negative population. This fell to 40% when considering only those patients with the fewest comorbidities (additional conditions that contribute to impairment), but rose to 85% among those with the most comorbidities. Over four or more study visits, 29% of participants experienced a decline in neurocognitive function, 47% remained stable, and 17% improved.

Looking at extent of impairment, 21% were classified as having mild cognitive impairment, 29% had moderate impairment, and 2% had severe impairment. In more practical terms, presenter Igor Grant said that while about half of all participants had neurocognitive impairment, about 25% had deficits, revealed by testing, that patients and their families had not noticed.

Opportunistic Illnesses in the Brain

Most of the opportunistic pathogens that strike people with impaired immune function can infect the brain. Below is a description of several illnesses that primarily or frequently involve the central nervous system (CNS). Other opportunistic illnesses (OIs) less commonly linked to brain disease include histoplasmosis, coccidioidomycosis, aspergillosis, and human herpesvirus 6 (HHV-6).

In addition, many pathogens that are not traditionally classified as opportunistic and do not normally cause brain disease may do so in the setting of advanced immune suppression, including Staphylococcus, Streptococcus, Salmonella, herpes simplex virus, varicella zoster virus, Treponema pallidum (neurosyphilis), and Plasmodium (malaria).

Cryptococcal meningitis (CM): inflammation of the membranes surrounding the brain (meninges) caused by the yeast-like fungus Cryptococcus neoformans. Symptoms may include headache, fever, nausea, and confusion (stiff neck and sensitivity to light are less common compared with other forms of meningitis); altered mental state may result from increased pressure within the skull and altered glucose levels. CM usually occurs among people with advanced immunosuppression and is seldom seen in those on effective combination ART. Treatment involves potent initial therapy typically including the antifungal drug amphotericin B, followed by maintenance therapy with an antifungal such as fluconazole (Diflucan) until a patient achieves sustained immune recovery on ART (>200 CD4 cells/mm3).

Cytomegalovirus (CMV): a herpesvirus that can infect the brain, but is more often associated with retinitis (inflammation of the retina in the eye) or gastroenteritis (irritation and inflammation of the stomach and intestines). Neurological symptoms may include confusion, lethargy, and fever. A very common pathogen, as many as 80% of U.S. adults are infected with CMV (often as children), but it usually does not cause illness unless immune function is severely compromised (<50 CD4 cells/mm3). Standard therapy is ganciclovir (Cytovene) or valganciclovir (Valcyte); injections of the antiviral drugs cidofovir and foscarnet also may be used. Maintenance therapy can be stopped after sustained immune recovery on ART (>100 cells/mm3). Immune reconstitution inflammatory syndrome (IRIS), a paradoxical worsening of symptoms as immune function improves, is a concern.

Mycobacterium avium complex (MAC) and tuberculosis (TB): disseminated M. avium and M. tuberculosis can spread from elsewhere in the body and infect the brain, causing meningitis or encephalitis (inflammation of the brain). Brain imaging findings are similar for the two diseases. CNS manifestations usually occur in people with advanced immune suppression. MAC prophylaxis with clarithromycin or azithromycin is recommended for patients with less than 50 CD4 cells/mm3. Treatment for both diseases requires prolonged combination antibiotic therapy; one frequently used drug, rifabutin, can interact with protease inhibitors. MAC maintenance therapy can be discontinued after sustained immune recovery on ART (>100 cells/mm3). IRIS is a concern with both diseases. For TB, recent studies show that delaying ART initiation until after TB treatment increases mortality.

Primary CNS lymphoma: lymphoma that originates in the brain, spinal cord, or eyes, rather than spreading from elsewhere in the body. Most HIV-related cases are B-cell non-Hodgkin lymphoma (NHL), though other types may also occur. Symptoms vary according to which parts of the brain are affected, and may include confusion, lethargy, personality changes, motor impairment, partial paralysis, and seizures. Brain imaging usually shows a single lesion; a brain biopsy may be done to distinguish it from other OIs. CNS lymphoma is strongly linked to Epstein-Barr virus (a type of herpesvirus) and usually occurs in people with advanced immunosuppression (<50 cells/mm3). ART is a mainstay of treatment; incidence of CNS lymphoma has fallen and prognosis has improved since the introduction of effective combination therapy, though the disease is still often fatal. Specific treatment involves various regimens of radiation therapy and chemotherapy; surgery is not used.

Progressive multifocal leukoencephalopathy (PML): a life-threatening brain disease caused by the JC polyoma virus. The disease is characterized by demyelination, or loss of the insulation around neuron axons. It typically affects multiple localized (focal) areas, usually in the subcortical white matter. Symptoms vary depending on which parts of the brain are affected, and may include progressive motor impairment, weakness or paralysis, vision loss, and sometimes seizures and personality changes. Due to its localized nature, global neurocognitive impairment and dementia are unusual. JC polyoma virus infection is common, but usually only causes symptoms when immune function is compromised. There is no specific therapy for PML, and ART initiation or optimization is the mainstay of treatment; patients on suppressive therapy often achieve long-term PML remission. IRIS after starting ART is a concern, however. The incidence of PML has not declined as dramatically as that of most other OIs since the advent of combination ART, but most studies show survival has increased.

Toxoplasmosis: parasitic infection of the brain with the protozoa Toxoplasma gondii. Symptoms may include headache, fever, confusion, motor weakness, and seizures. Active disease usually occurs due to reactivation of existing cysts as immune function declines. The disease is rare in people with more than 200 CD4 cells/mm3, while those with less than 50 cells/mm3 are at greatest risk. Initial infection occurs through consuming raw or partially cooked meat that contains Toxoplasma cysts, or through contaminated cat feces. Patients with advanced immune suppression should receive trimethoprim-sulfamethoxazole (TMP-SMX; Bactrim or Septra) as primary prophylaxis. Treatment involves a combination of drugs, usually including pyrimethamine, and perhaps also corticosteroids to manage immediate symptoms. Maintenance therapy is recommended, though evidence suggests it may be safely discontinued after sustained immune recovery on ART (>200 CD4 cells/mm3). Here, too, IRIS is a potential concern.

Other Studies

In the September 12, 2007, issue of AIDS, Kevin Robinson and co-investigators with the ALLRT (AIDS Clinical Trials Group Longitudinal Linked Randomized Trials) study -- made up of 1,160 patients enrolled in several ACTG randomized clinical trials of ART -- reported that 39% of study participants had evidence of at least mild neurocognitive impairment at baseline (26% had mild-to-moderate impairment when stricter criteria were used).

At the upper end of the range, Matteo Vassallo and colleagues reported at CROI that among 107 participants with an average CD4 count above 500 cells/mm3 in the French Neuradapt cohort, 69% had HAND (11% with ANI, 10% with MCMD, 4% with HAD, and 44% with neuropsychological deficits that did not fall within these categories).

At the lower end, Fabrice Bonnet and colleagues reported that about 25% of 230 HIV positive participants (median age 46 years) in the French Aquitaine cohort -- another group with well-controlled HIV disease -- had mild neurocognitive disorder. Though low compared with other HIV studies, this rate is considerable higher than the 6% rate for the general French population aged 65 or older.

Global Picture

HIV-related neurocognitive impairment is a concern on a global scale. As more people in low-income countries gain access to ART, researchers have begun to see patterns that more closely resemble those in wealthy countries, with the rate of severe dementia declining and the frequency of mild cognitive impairment rising.

Robertson and colleagues with the International Neurological Study reported that nearly one-third of more than 800 participants in resource-limited countries in Africa, Asia, and South America had some form of HIV-associated neurological disease. The largest proportion, however, had peripheral neuropathy (nerve damage causing pain or tingling in the feet or hands), while just 6% had mild neurocognitive disorder and 1% had dementia.

Several other researchers have reported neurocognitive impairment rates more in line with those seen in the U.S. and Europe (for example, 57% in Nigeria, 47% in India, and 37% in China). Some studies, however, indicate that HAND rates may be lower in certain regions of the world, which some researchers suggest may be due to differences in predominant HIV subtypes.

Aging and Alzheimer's Disease

Some recent research suggests that in addition to changes in overall prevalence of HAND, the pattern of neurocognitive impairment may be shifting as the HIV positive population ages.

A growing number of people with HIV appear to have neurocognitive manifestations more akin to those of Alzheimer's disease than classic HIV dementia. An analysis of 141 participants in two Australian cohorts, for example, found that along with an overall decrease in severity from the pre-ART to the ART era, patients were less likely to have subcortical symptoms such as poor attention, and more likely to experience impairment in complex cognitive functions such as learning.

Other researchers have shown that, compared with the general population, HIV positive individuals are more likely to have pathological changes in the brain similar to those seen in people with Alzheimer's, notably the presence of excessive amyloid protein.

Several factors may put HIV positive people at increased risk for Alzheimer's disease. Studies of the general population indicate that metabolic abnormalities and inflammation increase the likelihood of developing this form of dementia. Many HIV positive people have metabolic risk factors such as elevated blood lipids (fats) or insulin resistance associated with chronic HIV infection or antiretroviral treatment.

Furthermore, a growing body of evidence suggests that chronic inflammation may underlie many of the non-AIDS-defining conditions -- such as cardiovascular, liver, and kidney disease -- that occur despite relatively high CD4 counts, and this likely also applies to neurological disease.

Chronic inflammation due to lowlevel residual virus, as well as immune reconstitution inflammatory syndrome (IRIS), may promote neurodegeneration. Some research suggests that HIV's neurotoxic effects may induce brain changes similar to those associated with Alzheimer's disease. The HIV Tat protein, for example, appears to inhibit amyloid breakdown.

Within the HIV negative population, Alzheimer's dementia usually develops after age 65 (though some people have early-onset disease). A growing proportion of people with HIV are over age 50, and recent research suggests that long-term HIV infection may essentially accelerate the aging process. One study presented at CROI found that some aspects of brain function in HIV positive people resemble those of HIV negative people about 15 years older.

If this is the case, people with HIV may develop Alzheimer's disease -- or perhaps a novel condition with similar clinical symptoms and pathological findings -- earlier than expected, and the processes underlying Alzheimer's and HIV-associated dementia may interact in ways that are not yet understood, possibly resulting in more severe neurocognitive impairment.

Neurocognitive Risk Factors

Many studies have looked at risk factors for neurocognitive impairment in people with HIV, producing a large body of conflicting data. It is clear that multiple factors contribute to neurological problems, but it is unclear how these interact with individual susceptibility, and it is not possible to reliably predict which individuals will or will not develop cognitive problems.

In addition to the factors discussed below, HIV-related neurocognitive impairment has also been linked.with varying degrees of lower education level, psychiatric conditions such as depression, use of recreational drugs (including methamphetamine), and heavy alcohol consumption.

Immune Suppression

Immunosuppression is one of the strongest predictors of HAND, especially its more severe manifestations in untreated individuals. This applies not only to current CD4 cell count, but perhaps even more so to the CD4 nadir level.

Advanced immune suppression -- below 200 cells/mm3 -- is a clear risk factor for brain OIs and HIV dementia, as demonstrated by the steep decline in their incidence after effective combination ART came into widespread use. The influence of CD4 count differences among people with relatively well-preserved immune function and the impact on milder neurocognitive impairment are less clear-cut.

In a study described in the October 2008 issue of AIDS Research and Human Retroviruses, ART-treated patients in Spain who had a nadir CD4 count of 200 cells/mm3 or less had more neurocognitive impairment than treated or untreated participants with a higher CD4 nadir (73% vs 53%, respectively), and there was a trend toward greater impairment as CD4 nadir fell. This was a small study, and the overall differences did not reach statistical significance; there were, however, significant differences favoring the higher CD4 nadir group on tests of specific cognitive abilities.

In the CHARTER study, participants who never had a CD4 count below 200 cells/mm3 and who had undetectable plasma HIV RNA had about a 30% likelihood of neurocognitive impairment, compared with about 50% among patients with a CD4 nadir below 200 cells/mm3 and detectable plasma viral load. A neuropathology study presented at CROI demonstrated a link between HIV-related brain pathology and nadir CD4 count.

In the ALLRT cohort, having a nadir CD4 count below 200 cells/mm3 was associated with an increased prevalence of neurocognitive impairment, and patients with a current low CD4 count were more likely to have persistent impairment. But current immune status did not predict incident, or new-onset, neurological problems.

In summary, while immune recovery with effective ART reduces the likelihood of HAND, it is unfortunately not enough to completely cancel out the elevated risk of impairment due to a previous low CD4 count.

Older Age

Not surprisingly, increasing age is correlated with a higher likelihood of neurological impairment. As noted above, HIV-related brain problems and deficits related to Alzheimer's disease and other forms of dementia may interact in older patients (typically defined as age 50 or higher), potentially resulting in worse impairment.

A poster at CROI reported a high prevalence of neurocognitive impairment among HIV positive individuals aged 60 and older in the French Sigma study. Among the 37 participants included in a neurological analysis (Neurosigma), the median age was 67 years and the median CD4 count was about 500 cells/mm3, although the median CD4 nadir was much lower at just over 100 cells/mm3. All but one were on combination ART and had undetectable viral load.

Overall, half of the participants showed evidence of impairment on neuropsychological tests. About one-third (30%) were classified as having severe impairment, including 11% with deficits affecting activities of daily living. The researchers concluded that despite sustained response to ART, neurocognitive disorders -- especially of the subcortical type -- occur more frequently in older HIV positive people compared with the general aging population, and that they tend to be underdiagnosed.

In another CROI presentation, Beau Ances and colleagues described findings from an analysis that used functional magnetic resonance imaging (MRI) to assess cerebral blood flow in 26 HIV positive patients (mean age 39 years, about 60% on ART, median current CD4 count 486 cells/mm3, median CD4 nadir 278 cells/mm3) and 25 HIV negative participants at rest and as they performed cognitive tasks.

Both HIV infection and older age were associated with reduced cerebral blood flow, an indicator of impaired neurological function. ART-treated HIV positive individuals aged 50 or older showed MRI patterns similar to those of HIV negative people 10 years older at rest, and 15-20 years older during mental activity. Untreated people with HIV had even greater functional impairment, but this was not correlated with age. The researchers suggested that these differences might reflect HIV-related systemic changes in inflammation, coagulation, and oxidative stress that persist despite ART.

Metabolic Risk Factors

The recognized link between metabolic abnormalities and Alzheimer's disease and other forms of dementia in the general population suggests that these same factors may contribute to HIVrelated neurocognitive impairment.

In the January 1, 2006, Journal of Acquired Immune Deficiency Syndromes, Victor Valcour and colleagues reported a significant association between insulin resistance and impaired cognitive performance -- both MCMD and HAD -- among 145 participants in the Hawaii Aging with HIV Cohort. "Metabolic dysfunction may contribute to the multifactorial pathogenesis of cognitive impairment in the era of HAART," they concluded.

More recently, Allen McCutchan and colleagues presented findings from a metabolic substudy of CHARTER in a poster at CROI. In a cross-sectional analysis, the investigators looked at the link between laboratory markers and neuropsychological test performance among 145 HIV positive participants (average age 46 years) with available fasting blood samples.

Overall, 37% had some degree of neurocognitive impairment. In a multivariate analysis, impaired participants had a significantly larger waist circumference and were more likely to have type 2 diabetes (but not insulin resistance). Differences in blood cholesterol and triglyceride levels did not reach statistical significance. Based on these findings, the researchers concluded that "Weight reduction and [antiretroviral] drugs that are less likely to induce metabolic syndrome and diabetes might help to protect the brain."

In various studies, rates of both metabolic abnormalities and neurological impairment were high, but this correlation does not necessarily imply that the former causes the latter. In the Sigma cohort, for example, about 70% had various metabolic risk factors, including diabetes (27%), high blood pressure (49%), and abnormal blood lipid levels (43%). But the association between neurocognitive impairment and metabolic problems was not statistically significant after controlling for potential confounding factors.

Further studies are needed to tease out the complex interrelationships among chronic HIV infection, antiretroviral drug toxicities, metabolic abnormalities, systemic inflammation, and serious non-AIDS-defining conditions, including neurocognitive disorders.

HIV Viral Factors

Characteristics of the virus itself also appear to influence the development of HIV-related neurocognitive impairment. Typically, HIV uses one of two coreceptors, CCR5 or CXCR4, along with the CD4 cell surface receptor to enter cells. In the brain, the primary targets of HIV -- monocytes, macrophages, and microglia -- lack the CD4 receptor.

Studies suggest that HIV variants that use the CCR5 coreceptor (so-called macrophage- or M-tropic strains) are more likely to cause neurological problems than those using the CXCR4 coreceptor (T-lymphocytetropic or T-tropic strains). Furthermore, "neurotropic" HIV variants that have evolved the ability to enter cells without CD4 receptors and preferentially target the types of monocytes and macrophages found in the brain appear to pose a particular risk.

As noted above, some researchers have proposed that observed differences in the prevalence of HIV-related neurocognitive impairment in various regions of the world may be due to differences in HIV-1 viral subtype.

Some studies have suggested that people with HIV subtype C (the predominant type in India and sub-Saharan Africa) are less likely to develop HAD. An animal study found that mice infected with HIV subtype B performed worse in a maze test than those infected with subtype C. Other research has implicated subtype D (found mainly in east and central Africa).

These differences may in part be attributable to genetic variations in the V3 loop of the HIV-1 envelope, which plays a key role in cell entry. Another potential contributor is variations in the HIV Tat protein, which triggers neurotoxicity. There is also some evidence that HIV may mutate and evolve faster in the brain than elsewhere in the body, leading to amplified immune activation and associated neurological damage.

Hepatitis Coinfection

Due to overlapping transmission routes, a large proportion of people with HIV are coinfected with hepatitis C virus (HCV) or hepatitis B virus (HBV).

Like HIV, HCV is known to enter the brain, and it has been conclusively linked to neurocognitive impairment. As might be expected, coinfection with both HIV and HCV therefore further increases the risk of neurocognitive complications.

In the Neuradapt cohort, HIV/HCV coinfection was the sole independent risk factor for abnormal neuropsychological performance. This association remained even among patients with current or recent hepatitis C treatment. An Italian study found that concurrent HCV was associated with persistence of neurocognitive impairment during an average five years of follow-up. And in the CHARTER study, HCV coinfection was a significant predictor of worsening impairment over time, along with detectable HIV RNA in the cerebrospinal fluid (CSF).

Researchers studying a small cohort of patients at St. Mary's Hospital in London reported at CROI, and at the British HIV Association conference shortly thereafter, that among ten individuals with established HIV infection, acute (within the prior six months) HCV infection was associated with CNS involvement, including increased immune activation and inflammation revealed by brain imaging and impaired performance on neurocognitive tests. HIV/HCV-coinfected patients were significantly more likely to show impairment than were people infected with HIV alone, even though their average age was about ten years younger.

However, at the previous IAS conference in 2007, ALLRT investigators reported that differences in neurocognitive performance scores between HIV/HCV-coinfected participants and those with HIV alone were not statistically significant.

The link between hepatitis B and neurocognitive disorders is more equivocal, as there is little research indicating that it is an important risk factor, either among HBV-monoinfected individuals or those with HIV/HBV coinfection.

But one study presented at CROI suggested that HIV/HBV coinfection predicts greater likelihood of developing neurological problems. In an analysis of the French Aquitaine cohort, having HBV was one of the factors significantly associated with a higher risk of mild neurocognitive disorder, along with older age and advanced HIV disease.

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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.
See Also
Neurological Complications of AIDS Fact Sheet
More on Neurological and Neurocognitive Complications of HIV/AIDS


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