The Hand that Rocks the Cradle

Neurocognitive disorders occurring in patients treated for HIV

by Daniel S. Berger, M.D.

We know that the survival rate of HIV-positive individuals has improved through better treatment, and people are living longer. What follows, of course, is a rapid current of normal aging within the population of treatment-experienced patients. Until relatively recently, the health problems in HIV-positive patients that traditionally surfaced during their disease course were often only HIV-related. As our patients get older, we now see a plethora of aging-related medical issues that require attention.

At least some of these complications can be attributed to the natural course of aging, which we also know is true in normal, HIV-negative individuals. However, there’s the big question of whether long-term treatment-experienced individuals, who now show signs of these non-HIV-related medical complications, may in fact be experiencing them prematurely. We know definitely, for example, that bone loss occurring in a 30- or 40-year-old HIV-positive person is untimely.

This article is about the phenomenon of long-treated patients suffering from subtle, or sometimes obvious, cognitive dysfunctions. There is increasing evidence that HAND (HIV-associated neurocognitive disorders), is not uncommon and probably more progressive than expected with normal aging.

Individuals who are being treated with effective anti-HIV medications achieve undetectable viral loads in the blood. However, the mistaken belief is that their cerebrospinal fluid (CSF), the fluid that cushions the brain, should have comparable findings to the blood or have undetectable virus in the brain. Although we cannot perform brain biopsies on patients, by the use of very sensitive assays for viral load from the CSF that surrounds the brain, we do have an indirect way of measuring virus in the central nervous system (CNS). Conventionally used viral load tests detect HIV down to 50 copies/ml, but some tests are more sensitive. These more sensitive assays detect down to 2 copies/ml. This testing is being used for research purposes and studies investigating whether there is detectable virus in the CSF.


During the recent Conference on Retroviruses and Opportunistic Infections, held in Montreal (February 2009), several studies relating to neurocognitive impairment were presented. I believe that clinicians were surprised to hear some of the statistical results. In the CHARTER study, 1555 HIV-positive patients, from six sites around the U.S., participated; their average age was 43 years. The group was mostly male (77%); 49% were African American, 39% non-Hispanic white, and 9 % Hispanic; 58% were from the MSM (men having sex with men) population. Average CD4 counts were about 420 cells and CD4 nadir (lowest level during their disease course, usually before starting treatment) was 174 cells. The vast majority were on antiviral therapy.

Overall, 45% of the patients in this study were shown to have some neurocognitive impairment (NCI), based on the comprehensive testing that was done, which increased when individuals had other illnesses (co-morbidities) present. Also, when there was minimal co-morbidity, patients with AIDS diagnoses and lower CD4 nadirs had higher rates of NCI. Reasonably, this would indicate that starting treatment early, when the nadir of CD4 counts is still high, might have a positive impact on preventing HAND from occurring. Also, agents that have better penetration of the blood brain barrier may be an effective tool for helping avoid HAND down the road.

Of antiviral medications that penetrate the brain, nevirapine (Viramune) has long been understood to be an agent achieving the highest CSF levels. One poster in Montreal showed that efavirenz (Sustiva or EFV) and FTC (Emtriva) penetrate the CSF better than was originally thought, however. Dr. Scott Letendre, a lead researcher in the field, pointed out (in a personal communication) that EFV levels are very low in CSF compared with blood (about 0.5%), but in most samples (about 95%) seem to exceed the IC50 (half maximal inhibitory concentration). [IC50 is a measure of the effectiveness of a medication in inhibiting biological or antiviral activity.] The extent to which the levels exceed the IC50 is similar to the better protease inhibitors, but still not as good as nevirapine (up to 100-fold over the IC50). When you combine the lower-than-nevirapine levels and the CNS side effects of EFV, Dr. Letendre believes that it’s a good idea to avoid EFV in people with HIV and cognitive impairment.

Other interesting presentations delved into the surrounding issues. A subset of patients participating in the CHARTER study had paired samples of blood and CSF collected; 300 subjects taking antiretrovirals with undetectable viral loads (<50 copies) in both blood and CSF were investigated here. Using the assay that detects HIV down to 2 copies/ ml, 41% of these individuals had detectable virus in their CSF. At least 25% of individuals have detectable HIV solely in their CSF, but not in their blood. These patients have much worse cognitive performance. The authors concluded that the cognitive impairments may be the result of incomplete effectiveness of treatment of HIV in the CNS.

In the clinic

From a very clinical standpoint, I find that symptoms of HAND can be identified by asking patients some simple questions.

“Can you remember phone numbers the way you once used to?”

“Do you remember the name of the last movie you saw in the theatre, or the TV program watched the night before?”

“Is forgetting keys, wallet or phone, becoming more noticeable?”

“Have there been increasing difficulties with simple addition or tasks related to numbers?”

These are questions I use in the exam room looking for suspected HAND. Although these kinds of changes are seen often, most physicians, under our current economic conditions and medical system, may not have the time to examine patients this way. From the patient’s perspective, most learn how to adapt to their impairments, continuing in their daily routines and job responsibilities. I often suggest some helpful exercises to patients facing these issues, such as learning how to write things down more often, or practice utilizing and sharpening their short-term memory.

I believe it’s possible for patients that do not show signs of severe HAND to improve their cognitive abilities by exercising the mind, so to speak. Here are a few examples of what I’ve suggested to patients. I think that learning new skills, specifically ones that require the use of memory, such as learning a new language or computer program, are helpful. Also, it may be useful to practice daily reading of articles from a newspaper or magazine and then close the article or newspaper and practice recalling what was just read. Newspapers and magazines contain crossword puzzles as well, another mind game that could also be fun. Admittedly, I’m not able to site references or studies that confirm my suspicions about these suggestions, but some of my patients have improved their cognitive skills this way. After all, we do know that patients with other diseases, such as strokes, have been able to regain neurologic functions with the help of therapy.


Although treatment with HAART has been successful in major ways, an area that needs more attention is HAND. If the treatment pendulum is swinging back to starting therapy at higher CD4 counts, this may result in some patients eventually avoiding some of these neurocognitive issues, now coming to light. If other antiretroviral agents are developed that have superior CNS penetration, they may become handy tools, as these issues are rapidly gaining importance.

Dr. Daniel S. Berger is a leading HIV physician in the U.S. and is Clinical Associate Professor of Medicine at the University of Illinois at Chicago. He is founder and medical director of Northstar Healthcare, the largest private HIV treatment and research center in the Greater Chicago area. Dr. Berger has published extensively in such prestigious journals as The Lancet and The New England Journal of Medicine and serves on the Medical Issues Committee for the Illinois AIDS Drug Assistance Program and the AIDS Foundation of Chicago. Dr. Berger has been honored by Test Positive Aware Network with the Charles E. Clifton Leadership Award.