CROI 2006; Denver, Colorado; February 5-8, 2006

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The Body PRO Covers: The 13th Conference on Retroviruses and Opportunistic Infections

Studies Large and Small Investigate Predictors of HIV-Related Neurocognitive Problems

February 8, 2006

A bevy of studies presented at the 13th Conference on Retroviruses and Opportunistic Infections (CROI), while not groundbreaking, shed some additional light on the possible predictors for neurocognitive impairment and recovery in HIV-infected patients, including those who are receiving (or are about to commence) antiretroviral therapy.

The brain is susceptible to HIV infection; in up to 50% of patients who have progressed to AIDS, infection of the brain will manifest as HIV dementia. Although the use of highly active antiretroviral therapy (HAART) has been associated with a decline in cases of HIV dementia, cognitive problems continue to affect individuals who are living with HIV infection.

As individuals with HIV infection live longer due to the remarkable successes of antiretroviral therapy, there is concern that continued HIV replication in the brain, coupled with the aging process, will cause more individuals to experience cognitive problems. At the same time, there is the recognition that some patients may have cognitive problems that cannot be reversed despite antiretroviral therapy. Clinicians thus have a growing need to develop a better understanding of how to prevent or reverse the course of HIV dementia.

Unfortunately, preventing or reversing dementia can be challenging, given that the brain is relatively separated from the rest of the body by several protective layers called the meninges. Meninges can prevent access by medications, notably a large proportion of the HIV antiretrovirals that are currently available. P-glycoprotein expression accounts for much of the limited penetration of antiretrovirals into brain tissue and cerebrospinal fluid.

In order to help facilitate the search for interventions, several abstracts presented at CROI explored the predictors of HIV dementia, as well as the factors that may help clinicians predict which patients might show improved cognitive scores after starting HAART.

Predictors of Neurocognitive Impairment

One study, presented by Cristina Mussini et al for the CASCADE cohort, showed a significant reduction in the incidence of HIV encephalopathy over time, and elucidated some of the risk factors for HIV encephalopathy. The study followed 7,948 patients in Europe, Australia and Canada. Of this cohort, 129 patients were diagnosed with HIV encephalopathy before 1996, 14 between 1997 and 1999, and only 9 between 2000 and 2004. Reassuringly, the numbers are low for the development of obvious cognitive problems, and have declined over these time periods, suggesting that increasingly effective antiretroviral therapy has had the effect of reducing the risk of dementia. Current CD4+ cell count, prior AIDS diagnosis and history of injection drug use predicted dementia, whereas age and male sex did not. Nadir CD4+ cell count predicted risk, but not as well as current CD4+ cell count (P < .001).

Kevin Robertson, of the University of North Carolina-Chapel Hill, and colleagues analyzed data from another large patient cohort followed over time (1,498 individuals on HAART). They found that neurocognitive impairments were present in 43% of patients and were persistent among 25%. In addition, among the 750 patients who initially had normal cognitive test results and for whom follow-up data was available, 21% became impaired during the course of the study (median follow-up was 93 weeks). In contrast to the Mussini study, in this study, nadir CD4+ cell count was associated with impairment, but current CD4+ cell count was not.

What is remarkable about this study is the high percentage of patients who manifested impairment on testing, and the relatively high percentage who developed impairment despite a change in HAART. Notably, the Mussini and Robertson presentations differed on whether nadir CD4+ cell count or current CD4+ cell count was a better predictor of impairment; we need more information on how strongly predictive either one is.

Another CROI study examined insulin levels and aging as potential risk factors for HIV dementia. Insulin resistance is known to correlate with cognitive impairment in HIV-uninfected persons with Alzheimer's disease, and previous work by Victor Valcour, of the University of Hawaii in Honolulu, et al demonstrated a correlation between diabetes and neurocognitive impairment in HIV-infected individuals.1 At CROI, Dr. Valcour and colleagues presented data from the Hawaii Aging With HIV Cohort, in which 157 HIV-infected persons over the age of 50 were compared with individuals less than 40 years old. This study found that among older (but not younger) individuals with neurocognitive impairment, elevated insulin levels predicted impairment. This finding lends support to the idea that aging itself increases the risk of neurocognitive impairment among HIV-infected persons.

Impact of HAART on Cognitive Impairment

In a detailed look at the ability of HAART to reverse HIV dementia, Valerio Tozzi and colleagues from Italy's National Institute of Infectious Diseases examined 116 cognitively impaired individuals in Rome, Italy, using a battery of 17 tests. Tozzi et al found that, after nine years on HAART, improvement was only seen in about 30% of the antiretroviral-naive patients in the cohort. Impairment was reassessed at several time points (6, 12, 18, 24, 36 and 48 months) among these antiretroviral-naive patients, with a significant improvement found at each time point; however, after the 48-month mark, no further significant improvement was noted. In addition, neurocognitive improvement was not across the board; recovery differed from test to test. Patients improved in tests of mental flexibility and fine motor skill more than memory, concentration and speed.

Predictors of having persistent deficits on these tests included having fewer years of education (10 vs. 12 years), being female (25% vs. 6%), having worse baseline neuropsychological scores, and showing less improvement between baseline and first follow-up tests. However, in a multivariate analysis, only baseline neuropsychological tests and less improvement between first and follow-up tests were correlated with persistent neurocognitive impairment.

Many other factors were examined, including age, stage of HIV infection, risk category, baseline CD4+ cell count, baseline viral load, virologic response to HAART, changes in CD4+ cell count and viral load with therapy, and the use of antiretrovirals that can penetrate the blood-brain barrier. None of these factors predicted who would improve and who persistently had neurocognitive difficulties.

As Tozzi et al assert, these findings indicate that, although HAART initiation can improve neurocognitive impairment in some cases, it cannot do so much of the time -- and if any improvements do occur, they will likely happen within two years after starting treatment. Thus, it may be important to initiate HAART shortly after neurocognitive impairment is discovered, so that any potential damage can be quickly reversed before it risks becoming irreversible.

In another investigation of the positive impact of antiretroviral use on dementia, Christina Marra and a team of U.S. researchers examined cerebrospinal fluid among 100 participants in the ACTG 736 study. As expected, they found that individuals who took antiretrovirals known to penetrate the blood-brain barrier (such as abacavir [ABC, Ziagen], efavirenz [EFV, Sustiva, Stocrin], indinavir [IDV, Crixivan], nevirapine [NVP, Viramune] and zidovudine [AZT, Retrovir]) were more likely to show lower cerebrospinal fluid HIV viral loads. However, lower cerebrospinal fluid HIV viral loads did not correlate with changes in neuropsychological test results.

Despite these intriguing findings, more detailed analyses of these data are needed before one can draw definitive conclusions about the importance of taking antiretrovirals that cross the blood-brain barrier. When treating an HIV-infected patient who is newly diagnosed with dementia, most clinicians will still justifiably choose a regimen likely to cross the blood-brain barrier.

The Bottom Line

HIV-infected individuals have a high degree of abnormal neurocognitive testing, even early in the course of HIV disease. HAART can improve and normalize these test results to a great degree, and HAART use has resulted in fewer cases of HIV dementia. However, whether these affected individuals, or those around them, actually notice this milder degree of neurocognitive impairment is a question that merits further study and clarification.

Data presented at this conference demonstrate that it is still difficult to predict risks for neurocognitive impairment, but that more advanced HIV disease and baseline neurocognitive dysfunction seem to be most important. In sum, there was not a lot of new data, but there was enough to leave us with continued concern about the long-term, milder effects of HIV infection on brain function.


  1. Valcour VG, Shikuma CM, Shiramizu BT, et al. Diabetes, insulin resistance, and dementia among HIV-1-infected patients. J Acquir Immune Defic Syndr. January 1, 2005;38(1):31-36.

Abstract: Insulin resistance: a novel marker of cognitive function in older HIV-positive adults, the Hawaii aging with HIV cohort (Poster 349)
Authored by: V Valcour, A Williams, M Watters, N Sacktor, O Selnes, B Shiramizu, R Paul, C Shikuma

Affiliations: Univ of Hawaii, Honolulu, US; Johns Hopkins Univ Sch of Med, Baltimore, MD, US; Brown Univ, Providence, RI, US

Abstract: The predictors of HIV encephalopathy and outcome in HIV-positive patients in the era of effective therapy (Poster 351)
Authored by: C Mussini, K Bhaskaran, S Walker, M Dorrucci, C Sabin, A Phillips, K Porter, CASCADE Collaboration
Affiliations: Clin of Infectious and Tropical Diseases, Modena, Italy; Med Res Council Clin Trials Unit, London, UK; Inst Superiore di Sanità, Rome, Italy; Royal Free and Univ Coll Med Sch, London, UK

Abstract: Factors associated with persistent neurocognitive impairment despite long-term HAART in patients with HIV dementia (Poster 354)
Authored by: V Tozzi, P Balestra, M Salvatori, C Vlassi, A Corpolongo, R Bellagamba, S Galgani, P Lorenzini, A Antinori, P Narciso
Affiliations: Natl Inst of Infectious Diseases, L Spallanzani, Rome, Italy
View poster: Download PowerPoint

Abstract: ACTG 736: CSF HIV-1 and cognitive function in individuals receiving potent ART (Poster 361)
Authored by: C Marra, S Sinha, S Evans, S Letendre, R Coombs, F Aweeka, D Clifford, S Shriver, X Li, K Robertson, ACTG 736 Team
Affiliations: Univ of Washington, Seattle, US; Statistical and Data Analysis Ctr, Harvard Sch of Publ Hlth, Boston, MA, US; Univ of California, San Diego, US; Univ of California, San Francisco, US; Washington Univ, St Louis, MO, US; ACTG, Washington, DC, US; Univ of California, Davis, Sacramento, US; Univ of North Carolina at Chapel Hill, US
View poster: Download PDF

Abstract: Neurocognitive impairment in HIV-infected subjects on HAART: prevalence and associations (Poster 362)
Authored by: K Robertson, K Wu, T Parsons, R Ellis, M Smurzynski, R Bosch, J Wu, J McArthur, A Collier, S Evans, ACTG 5001 Protocol Team and the ACTG
Affiliations: Univ of North Carolina at Chapel Hill, US; Harvard, Boston, MA, US; Univ of California, San Diego, US; Johns Hopkins Univ, Baltimore, MD, US; Univ of Washington, Seattle, US
View poster: Download PowerPoint

It is a part of the publication The 13th Conference on Retroviruses and Opportunistic Infections.

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