The neurocognitive disorders associated with HIV (HAND) remain among the most common clinical disorders encountered in people infected with HIV, even in an era in which potent antiretroviral therapy is widely deployed. HAND is currently considered to encompass a hierarchy of progressively more severe patterns of central nervous system (CNS) involvement ranging from asymptomatic neurocognitive impairment (ANI), to minor neurocognitive disorder (MND), to the more severe HIV-associated dementia (HAD) . With the improved survival of individuals treated with antiretrovirals, comorbid conditions have become increasingly salient, including particularly coinfection with hepatitis C and the effects of aging. Treatment guidelines for preferred initial antiretroviral regimens and for second or salvage regimens are essentially silent on the approach to HAND. For example, HIV-nephropathy is one indication for initiation of HAART, yet inexplicably HAND is not, unless it is severe enough to manifest as dementia. Brain penetration is crucial to achieve the goal of maximal suppression of HIV replication. Cerebrospinal fluid (CSF) antiretroviral concentrations are generally much lower than plasma concentrations, particularly for the protease inhibitors, and active efflux pumps, such as the P-glycoprotein may eliminate this class of drug . An index of the CNS penetration of antiretrovirals can differentiate HAART regimens by their theoretical CNS penetration  and specific combinations have better brain penetration or greater efficacy in reversing HAND's deficits or suppressing CSF HIV RNA [4–7]. It remains uncertain whether individuals who have had prolonged aviremia can develop HAND. The study by Simioni et al. sheds new light on this question by studying individuals with long-duration aviremia. It also raises concerns about the adequacy of current screening techniques for HAND. In their study, HAND was diagnosed in a high proportion of 200 long-duration (several years) aviremic individuals. The overall prevalence of cognitive complaints was 27%. The prevalence of HAND was 84% among patients with cognitive complaints and 64% in those without. ANI was found in 24%, MND in 52%, and HAD in 8%. HAND was more common in women, those with lower premorbid IQ (as measured by NART scores), or with neuropsychiatric symptoms.
The study highlights the clinical utility of a simple, robust, and predictive screening test for HAND. In the pre-HAART era, instruments such as the HIV Dementia Scale (HDS) were developed and tested  and were subsequently modified for use in international settings . We have less information about the performance characteristics of the HDS or other tests in the HAART era. The study by Simioni et al. suggests that using a cut-off of 14 points or less on the HDS produced a positive predictive value for HAND of 92% in those with complaints and 82% in noncomplainers. In other neurological disorders, such as Alzheimer disease, screening tests such as the MMSE are widely used for early detection and disease tracking. The development of a comparable and reliable test for HAND would be clinically very useful.
Some limitations of the study by Simioni et al. need to be considered. First, the issue of metacognition, namely the insight that an individual may have regarding his or her own cognitive processes. In the elderly, severe depression is frequently associated with cognitive dysfunction. This is termed ‘pseudodementia’ and is not typically associated with mild depression or younger age. In early pre-HAART studies, we did not find evidence for an effect of depression on neurocognitive function . In recent studies, however, depression appears consistently to be associated with incident HAND . In the study by Simioni et al., several instruments were included to assess anxiety and depression and HAND was associated with abnormal scores on the Neuropsychiatric Inventory. A second limitation is the generalizability of these results to other populations with lower levels of education because 73% had at least a high school education. This suggests a relatively high educational level, possibly reflecting a higher level of cerebral reserve. Previous studies have suggested this may be a protective factor against the development of HAND . A third limitation is that other important comorbidities for HAND, namely hepatitis C and substance abuse, were either of low frequency (19% of the cohort were hepatitis C seropositive) or were excluded (active drug use). Hepatitis C antigens have been detected in the brain  and among those with a history of injection drug use, coinfection can be found in up to two thirds. Epidemiological studies suggest that neurocognitive impairment is amplified when both viruses are active (S. Letendre, 2009, personal communication).
HAND can develop at almost any stage of HIV infection, although it is more common as immunosuppression advances. Injection drug use, female sex, and age appear to be predictive of neurological progression  (N. Gandhi, 2009, personal communication). In the HAART era, HAND can develop in individuals with less advanced immunosuppression . In resource-limited areas, HAND is probably at least as prevalent as in developed countries [17,18].
ANI is the mildest form of HAND and is characterized by asymptomatic or unrecognized neurocognitive impairment. Individuals with ANI are more likely to develop more severe forms of HAND . HAD represents the most severe form of HAND, with significant functional impairments, and is synonymous with HIV encephalopathy and AIDS dementia complex.
Since the introduction of HAART in 1996, many HAART-treated patients have shown durable and complete suppression of HIV replication. The incidence of moderate or severe dementia fell from about 7% in 1989 to only 1% in 2000, and the severity of neurological disease appears to have been attenuated . Despite this remarkable effect on incidence rates, the prevalence of HAND continues at very high rates. For example, in one cohort (CHARTER), 53% of the total sample had neurocognitive impairment, with increasing rates in those with more comorbid illnesses . Prevalence estimates were 33% for ANI, 12% for MND, and 2% for HAD.
One important question is whether neurocognitive performance can be affected even with good control of HIV viremia. For example, one long-standing cohort study, the MACS, studied neurocognitive performance over a 5-year period in individuals without medical symptoms. There was no measurable decline in performance in the asymptomatic groups . Similar findings were observed in an independent cohort . The CHARTER study demonstrated that in HAART-treated participants with incidental comorbidities, there was a lower rate of NP impairment in aviremic individuals with a nadir CD4 cell count 200 cells/μl or more . This rate was about half (29%) of those with less successful virological control. These findings suggest that cognitive function is generally preserved over many years in individuals who have well controlled HIV replication. In contradistinction, other data suggest that neurological injury can continue to accrue in some individuals regardless of the success of antiretroviral therapy. Immunosuppression was associated with more prevalent neurocognitive impairment but not with incident impairment, and the association of previous advanced immunosuppression with prevalent and sustained impairment suggests that there may be a non-reversible component of neurological injury that tracks with systemic disease progression . Furthermore, 21% developed HAND despite effective HAART (although the precise number who were aviremic is unclear) . Similarly, in a cohort of individuals with AIDS, 21% of aviremic individuals (who also had undetectable CSF HIV RNA) progressed to HAD . A third prospective study also identified HAND in 8–34% (depending on the time point of the assessment) of aviremic patients without comorbidities and with a nadir CD4 cell count less than 200 cells/μl .
Identified risk factors for HAND include a high HIV viral set point, lower CD4 cell counts , anemia, low body mass index, increasing age, systemic symptoms [27,28], injection drug use , and female sex . In early cohort studies before HAART, CSF HIV RNA levels were associated with progression to HIV-D, but this relationship is not seen in HAART-treated individuals . High concentrations of plasma tumor necrosis factor α and CSF monocyte chemoattractant protein 1 were predictive of the development of HAND . Circulating HIV DNA concentrations, which may be related to persistence of infection in cells of the monocyte lineage, are high in individuals with HAND . Host genetic factors may underlie susceptibility to HAND. The most interesting include CCL2 (MCP-1) mutations and mutations in its receptor CCR2 (64-I allele), likely by influencing CNS monocyte infiltration [33,34].
So, is HAND indeed an important clinical disorder and does the study by Simioni et al. suggest that we are facing a hidden epidemic among aviremic individuals. Or rather, are these simply nosological manifestations with no clinical implications. We now know that people with HAND have a significantly increased risk of death . In a Canadian cohort, the survival of individuals with MND/HAND was only one-third of those without (C. Power, 2009, personal communication). Worse antiretroviral adherence may be a contributing factor, as suggested by observations that noted that patients who died had higher plasma HIV RNA levels and were more cognitively impaired at baseline, despite no significant differences in the patterns of HAART usage .
Taken together, the data suggest that we cannot be complacent and assume that systemic virological and immunological control will uniformly control CNS disease. If indeed there is a ‘hidden epidemic’ of neurological disease in aviremic individuals, then we must develop and promulgate screening techniques to detect and track HAND and screening should be included in routine care. Furthermore, integration of these data into treatment guidelines is important and the assuming that systemic treatment ‘will take care of the brain’ is dangerous. Finally, the population of HIV-infected individuals is aging and further study is needed to assess the concatenation of age-related and HIV-related cognitive deterioration. We cannot ignore the very unique characteristics of the brain as a potential sanctuary for persistent infection and ongoing inflammatory damage.
J.C.M. was supported by grants NS44807 and NS49465 and is currently supported by 1P30MH075673 and NO1MH22005 (CHARTER; Igor Grant, PI).
1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al
. Updated research nosology for HIV-associated neurocognitive disorders. Neurology 2007; 69:1789–1799.
2. Kim RB, Fromm MF, Wandel C, Leake B, Wood AJ, Roden DM, Wilkinson GR. The drug transporter P-glycoprotein limits oral absorption and brain entry of HIV-1 protease inhibitors. J Clin Invest 1998; 101:289–294.
3. Letendre S, Marquie-Beck J, Capparelli E, Best B, Clifford D, Collier AC, et al
. Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 2008; 65:65–70.
4. Clifford DB. Human immunodeficiency virus-associated dementia. Arch Neurol 2000; 57:321–324.
5. Sacktor N, Tarwater PM, Skolasky RL, McArthur JC, Selnes OA, Becker J, et al
. CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 2001; 57:542–544.
6. Cysique LA, Maruff P, Brew BJ. Antiretroviral therapy in HIV infection: are neurologically active drugs important? Arch Neurol 2004; 61:1699–1704.
7. Marra CM, Zhao Y, Clifford DB, Letendre S, Evans S, Henry K, et al
. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 2009; 23:1359–1366.
8. Simioni S, Cavassini M, Annoni JM, Rimbault Abraham A, Bourquin I, Schiffer V, et al.Cognitive dysfunction in HIV patients despite long-standing suppression of viremia
9. Power C, Selnes OA, Grim JA, McArthur JC. The HIV Dementia Scale: a rapid screening test. J Acquir Immune Defic Syndr 1995; 8:273–278.
10. Sacktor NC, Wong M, Nakasujja N, Skolasky RL, Selnes OA, Musisi S, et al
. The International HIV Dementia Scale: a new rapid screening test for HIV dementia. AIDS 2005; 19:1367–1374.
11. McArthur JC, Cohen BA, Selnes OA, Kumar AJ, Cooper K, McArthur JH, et al
. Low prevalence of neurological and neuropsychological abnormalities in otherwise healthy HIV-1-infected individuals: results from the Multicenter AIDS Cohort Study. Ann Neurol 1989; 26:601–611.
12. Sevigny JJ, Albert SM, McDermott MP, McArthur JC, Sacktor N, Conant K, et al
. Evaluation of HIV RNA and markers of immune activation as predictors of HIV-associated dementia. Neurology 2004; 63:2084–2090.
13. Satz P, Morgenstern H, Miller EN, Selnes OA, McArthur JC, Cohen BA, et al
. Low education as a possible risk factor for cognitive abnormalities in HIV-1: findings from the multicenter AIDS Cohort Study (MACS). J Acquir Immune Defic Syndr 1993; 6:503–511.
14. Letendre S, Paulino AD, Rockenstein E, Adame A, Crews L, Cherner M, et al
. Pathogenesis of hepatitis C virus coinfection in the brains of patients infected with HIV. J Infect Dis 2007; 196:361–370.
15. Bouwman FH, Skolasky RL, Hes D, Selnes OA, Glass JD, Nance-Sproson TE, et al
. Variable progression of HIV-associated dementia. Neurology 1998; 50:1814–1820.
16. Dore GJ, McDonald A, Li Y, Kaldor JM, Brew BJ. Marked improvement in survival following AIDS dementia complex in the era of highly active antiretroviral therapy. AIDS 2003; 17:1539–1545.
17. Wong MH, Robertson K, Nakasujja N, Skolasky R, Musisi S, Katabira E, et al
. Frequency of and risk factors for HIV dementia in an HIV clinic in sub-Saharan Africa. Neurology 2007; 68:350–355.
18. Wright EJ, Nunn M, Joseph J, Robertson K, Lal L, Brew BJ. NeuroAIDS in the Asia Pacific Region. J Neurovirol 2008; 52:1–9.
19. Ellis R, Langford D, Masliah E. HIV and antiretroviral therapy in the brain: neuronal injury and repair. Nat Rev Neurosci 2007; 8:33–44.
20. Sacktor N. The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy. J Neurovirol 2002; 8(Suppl 2):115–121.
21. Heaton R, Clifford D, Franklin D, Woods S, Ake C, Vaida F, et al.HIV-associated neurocognitive disorders (HAND) persist in the era of potent antiretroviral therapy: The CHARTER Study.Neurology
22. Cole MA, Margolick JB, Cox C, Li X, Selnes OA, Martin EM, et al
. Longitudinally preserved psychomotor performance in long-term asymptomatic HIV-infected individuals. Neurology 2007; 69:2213–2220.
23. Lopardo GD, Bissio E, Iannella Mdel C, Crespo AD, Garone DB, Cassetti LI. Good neurocognitive performance measured by the international HIV dementia scale in early HIV-1 infection. J Acquir Immune Defic Syndr 2009; 52:488–492.
24. Robertson KR, Smurzynski M, Parsons TD, Wu K, Bosch RJ, Wu J, et al
. The prevalence and incidence of neurocognitive impairment in the HAART era. AIDS 2007; 21:1915–1921.
25. Sevigny JJ, Albert SM, McDermott MP, Schifitto G, McArthur JC, Sacktor N, et al
. An evaluation of neurocognitive status and markers of immune activation as predictors of time to death in advanced HIV infection. Arch Neurol 2007; 64:97–102.
26. Cysique LA, Maruff P, Brew BJ. Variable benefit in neuropsychological function in HIV-infected HAART-treated patients. Neurology 2006; 66:1447–1450.
27. Childs EA, Lyles RH, Selnes OA, Chen B, Miller EN, Cohen BA, et al
. Plasma viral load and CD4 lymphocytes predict HIV-associated dementia and sensory neuropathy. Neurology 1999; 52:607–613.
28. McArthur JC, Hoover DR, Bacellar H, Miller EN, Cohen BA, Becker JT, et al
. Dementia in AIDS patients: incidence and risk factors. Neurology 1993; 43:2245–2252.
29. Janssen RS, Nwanyanwu OC, Selik RM, Stehr-Green JK. Epidemiology of human immunodeficiency virus encephalopathy in the United States. Neurology 1992; 42:1472–1476.
30. Chiesi A, Seeber AC, Dally LG, Floridia M, Rezza G, Vella S. AIDS dementia complex in the Italian National AIDS Registry: temporal trends (1987–1993) and differential incidence according to mode of transmission of HIV-1 infection. J Neurol Sci 1996; 144:107–113.
31. Brew BJ, Letendre SL. Biomarkers of HIV related central nervous system disease. Int Rev Psychiatry 2008; 20:73–88.
32. Shiramizu B, Gartner S, Williams A, Shikuma C, Ratto-Kim S, Watters M, et al
. Circulating proviral HIV DNA and HIV-associated dementia. AIDS 2005; 19:45–52.
33. Singh KK, Ellis RJ, Marquie-Beck J, Letendre S, Heaton RK, Grant I, Spector SA. CCR2 polymorphisms affect neuropsychological impairment in HIV-1-infected adults. J Neuroimmunol 2004; 157:185–192.
34. Gonzalez E, Rovin BH, Sen L, Cooke G, Dhanda R, Mummidi S, et al
. HIV-1 infection and AIDS dementia are influenced by a mutant MCP-1 allele linked to increased monocyte infiltration of tissues and MCP-1 levels. Proc Natl Acad Sci U S A 2002; 99:13795–13800.
35. Mayeux R, Small SA. Finding the beginning or predicting the future? Arch Neurol 2000; 57:783–784.