HIV-associated dementia and cognitive dysfunction
Paul Blanchard, HIV i-Base
The introduction of increasingly effective antiretroviral drugs has resulted in increased survival of patients with HIV-infection. Prior to the availability of such drugs the development of HIV-associated dementia (HAD) was a much feared and serious consequence of advancing HIV disease. The precise impact of HAART on HAD and the associated cognitive dysfunctions remains, however, to be fully determined.
In the pre-HAART era the mean CD4 count at the time of diagnosis of HAD was 50–100 cells/mm3. Post 1996 and the introduction of more effective ARVs this has risen to around 160 cells/mm3. The reason for this elevation is unclear but both the nadir CD4 cell count and disease duration are likely confounding variables in the current HAART era.
Changes in the natural history of HAD have also been noted. In the pre-HAART era the mean time from diagnosis to death was six months, this has now been lengthened to 44 months. A consequence of such prolonged survival is that the prevalence of HAD is actually increasing. There is also a suggestion that the actual cognitive deficit in HAD may be changing with the increasing use of HAART – involving more cortical type abnormalities and less basal ganglia. The fact also remains that HIV encephalopathy continues to be present in 25% of patients at autopsy, a rate that has not changed since the widespread use of HAART.
Data presented at the 11th CROI provided some additional clues as to how HAD is now manifesting in those patients receiving more effective antiretrovirals.
Neurocognitive impairment in HAART treated patients and survival
Before the introduction of HAART, HAD was recognised as an independent risk factor for death. Tozzi and collegues from the National Institute for Infectious Diseases, Rome, Italy presented prospective data on mortality among patients referred for neuropsychological examination since 1996. 
On testing, of 432 enrolled subjects, 238 (55.1%) were found to be neurocognitively impaired and 194 (44.9%) unimpaired. All subjects were treated with HAART regimens which were changed accordingly with the availability of new drugs and by individual patient response. Median follow up period was 32.4 months and overall 47 deaths were recorded – 38 among impaired and 9 among unimpaired patients.
At enrolment neurocognitively impaired and unimpaired patients did not differ in terms of gender, plasma viral load, or positive HBV surface antigen. However, impaired subjects were older, less educated, had a lower CD4 cell count, more advanced HIV disease, higher prevalence of intravenous drug use, higher prevalence of HCV and showed a higher rate of virological failure during subsequent HAART regimes.
Differences in survival according to neurocognitive status were assessed by means of the Kaplan-Meier method and by the Cox proportional hazard model. After 84 months of follow-up the estimated survival proportions were 68.5% in the impaired group and 84.9% in the unimpaired group (p<0.01). After adjusting for confounding variable the multivariate analysis revealed that neurocognitively impaired patients still showed an increased risk of death as compared to unimpaired patients (HR=2.4; 95% CI: 1.1 – 5.1).
After stratification for virological response to HAART, the estimated risk of death for impaired patients was still significantly higher among the subgroup with virological failure (HR=2.9), but no longer significant among the subjects with durable virological suppression (HR=1.0).
The authors conclude that “Among HIV-positive patients receiving HAART, patients with HIV-associated neurocognitive impairment had an independent and statistically significant higher risk of death then subjects without neurological impairment. …this highlights the clinical relevance of HIV-related CNS involvement even in the HAART era.”
The association between neurocognitive impairment and virological failure revealed in this study requires further investigation. Might impairment be a predisposing factor for poor adherence?
HIV dementia, aging and HAART
Age is a suggested risk factor for the development of HAD. With increasing survival rates aging is a real possibility for many with access to effective antiretrovirals. Would increasing age also, therefore, lead to increased risk of HAD, even if viral replication is suppressed?
Lorenzini and colleagues, again from Italy, attempted to answer this question using a nested longitudinal study on a national cohort of HIV-positive patients with neurological diseases. 
From 2000 to 2003, 195 patients with HIV encephalopathy were notified (these consisted of 53% HAD, 47% MCMD – Minor cognitive motor disorder). The overall prevalence was 21% with an increasing annual rate. Median age was 42 years and a previous ARV exposure was present in 45%, 28% were receiving HAART at diagnosis.
Stratifying patients according to age and exposure to antiretrovirals, among naïve patients the prevalence of HIV encephalopathy was higher in older subjects: 13.7% (20-39 years), 28.3% (40-49 years), and 37.5% (≥50 years). The same proportions for HIV dementia were 7.2%, 15.3%, and 27.3%. Among ARV-experienced patients no significant increase of HIV encephalopathy or HAD for older age was observed. An increased prevalence of HIV dementia among older naïve patients compared to older experienced patients was detected (p = 0.05).
The investigators concluded “…HAART appears to change the relationship between aging and developing HIV dementia, conferring a neuroprotective effect to older patients and affecting the increased prevalence rate of HIV dementia with increasing age.”
Can HAART improve cognitive function and do drugs need to reach the CNS?
It has been hypothesised by a number of researchers that neuropsychological impairment might progress despite virological and immunological response to ARV’s. Poor CNS penetration of active agents and ongoing viral replication in a CNS “sanctuary” site may be one possible reason for continuing cognitive decline. Data on the natural history of HAD and cognitive function from longitudinal studies of those treated with effective ARV’s is scant.
ACTG 362 started life as a study of prophylaxis intervention for MAC. After the impact of HAART made MAC prophylaxis extremely unusual the study was converted into an observational cohort of advanced AIDS patients (CD4 < 50 before entry).  A series of annual cognitive evaluations using three simple tests assessed speed of information processing, mental flexibility and working memory. At study entry most participants were immune reconstituted (mean CD4=230) and HIV suppressed (65% < 500 with only 14% >20,000 RNA copies/mL).
Prevalence of neuropsychological impairment (NPI) was estimated at 40% in advanced AIDS patients after prolonged immunological reconstitution on HAART. In addition, better performance was associated with continued or recently improved suppression of plasma HIV RNA levels, and was unrelated to CD4 count. In a univariate model of change, NPZ3 score (Z-scores of Digit Symbol Substitution and Trailmaking A and B) improvement was associated positively with plasma HIV RNA suppression (<500) at time of testing or suppression of HIV (>500 to <500) over the prior 16 weeks. Interestingly lowest lifetime CD4 count (nadir) did not correlate with changes in NPZ3 score.
It was concluded from these data that “…plasma HIV suppression appears to be critical to improvement of cognitive function” and that “…most advanced AIDS patients responding to HAART for prolonged periods do not experience detectable cognitive decline.”
Two separate studies presented in poster form addressed the question of whether there is any additional benefit for cognitive function from drug regimens containing ARV’s thought to have better CNS penetration. Caution must be observed in interpretation as one study was cross sectional  and the other had small numbers of subjects who were not antiretroviral naïve . The cross sectional study revealed that 50.3% of subjects had abnormal neuropsychological performance.
The number of CSF penetrating drugs within each regimen was not correlated with neuropsychological performance. Indeed, the only HIV-related factor independently associated with neuropsychological disorder was plasma HIV-1 replication. The separate, prospective study compared neurological functioning between patients failing HAART placed on regimens containing at least one CNS penetrating agent to those with non-penetrating regimens.
Overall there was a significant improvement in neurological functioning at follow-up. However, no significant differences were found between 10 subjects with CNS penetrating regimens compared to 19 subjects on non-penetrating regimens. Both studies, therefore, found that effective virological suppression (measured by plasma HIV RNA) appeared to be more important than whether or not the regimen contained a CNS penetrating antiretroviral.
AIDS dementia complex, Alzheimer’s disease and ongoing brain injury despite HAART
In perhaps the most disturbing presentation on CNS effects of HIV, Michael Weiner presented the results of his groups work on structural brain changes at the late breaker session . This controlled, longitudinal study used structural MRI, MR spectroscopy, neuropsychological testing and EEG evoked response with measurement taking place with a two year interval. Both HIV-positive and HIV-negative subjects were studied with these groups being divided into heavy or light drinkers to control for the known effects of alcohol intake. A total of 128 participants took part.
The structural MRI results showed that over two years the HIV-positive subjects (all of whom were receiving ART) had greater rates of ongoing white matter loss than the controls (p=0.0013). The annual loss of white matter between HIV-positive and HIV-negative patients who were light drinkers was 1.2% and -0.6%, respectively (p=0.003). White matter atrophy was also found to be greater in those HIV-positive patients with higher viral loads when compared to HIV-negative patients. Subjects with viraemia had significantly greater annual loss of white matter compared to those with good suppression of HIV replication (1.3% vs. 0.6%, respectively; p=0.06). However, no significant differences were found between patients with suppressed infection and HIV-negative controls. No differences were found between the groups with regard to cognition or EEG-evoked response.
The study authors concluded that the rates of ongoing white matter atrophy, although significantly different from controls, were small and not accompanied by progressive cognitive impairment. They did caution, however, that the results suggest that even HAART treated individuals do have ongoing brain damage. Additionally, these effects over a number of years would be expected to produce cognitive impairment similar to that observed in Alzheimer’s disease.
The development of Alzheimer’s disease itself is also becoming an increasing concern for researchers and clinicians caring for those with HIV-infection. Increased age, high lipids, axonal injury and the effects of tat and quinolinic acid on the brain all point to a theoretically increased risk of Alzheimer’s disease in HIV-infection .
Further data on the relationship between Alzheimer’s disease and HAD was presented by Bruce Brew at this meeting .
As a marker for the increased risk of Alzheimer’s cerebrospinal fluid (CSF) was examined for the presence of reduced amyloid beta 1-42 or increased amyloid beta tau (both of which are related to excess amyloid beta production). All subjects were HIV-positive patients with AIDS Dementia Complex. In total 25 patients CSF was analysed and the results revealed that amyloid beta 1-42 levels were significantly lowered and in the same range as those found in Alzheimer’s Disease.
The researchers conclude that “…AIDS Dementia Complex may be complicated by an illness that at least at the biochemical level is similar to Alzheimer’s Disease. Moreover, it raises the possibility that HIV patients in general may be at increased risk of Alzheimer’s.”
Unless stated otherwise, all abstract references are to the Program and Abstracts of the 11th Conference on Retroviruses and Opportunistic Infections (11th CROI). February 8-11, 2004. San Francisco, CA.
- Tozzi, V et al. Neurocognitive impairment and survival in HIV-positive patients treated with HAART: results from an urban observational cohort. Abstract 507.
- Lorenzini, P et al. HAART Modified risk of HIV dementia associated to increasing age. Abstract 489.
- McCutchan, A et al. Improved cognitive function in immune reconstituted advanced AIDS patients is associated with maintenance of HIV suppression. Abstract 498.
- Antinori, A et al. Antiretroviral drugs penetrating CSF do not influence neurocognitive performance in HIV-1-infected patients responding to HAART. Abstract 508.
- Robertson, K et al. Neurological functioning and CNS penetrating antiretroviral regimens. Abstract 501.
- Weiner, MW et al. Progressive white matter loss suggests ongoing brain injury in ART-treated HIV+ patients. Abstract 33 LB.
- Brew BJ. Evidence for a change in AIDS dementia complex in the era of highly active antiretroviral therapy and the possibility of new forms of AIDS dementia complex. Aids 2004,18 Suppl 1:S75-78.
- Brew, B et al. Relationship between Alzheimer’s disease and AIDS dementia complex. Abstract 472.