Treatment Overview


Earlier highly active antiretroviral therapy (HAART) to prevent severe immunosuppression may help to prevent HIV-associated neurocognitive disorders (HAND),1,2 though data are relatively preliminary.2

  • CD4 depletion may be associated with neurocognitive impairment2 and HAND is less likely in those who achieve undetectable plasma viral load and have no history of severe immunosuppression.1


HAART has a beneficial effect on cognitive impairment in symptomatic individuals,3 and has been shown to reduce the prevalence of neurocognitive impairment.4,5

  • The principal aim of antiretroviral therapy in HAND is to produce complete virological suppression in both plasma and the central nervous system (CNS).6
  • As the severity of HIV-related neurocognitive impairment at HAART initiation has been identified as a predictor of persistent neuropsychological deficits, some data suggest that HAART should be initiated as soon as possible after the diagnosis of HAND.7

The European AIDS Clinical Society (EACS) Guidelines8 recommend that if neurocognitive impairment is detected:

  • patients not already receiving antiretroviral therapy (ART):8
    • start plasma and cerebrospinal fluid (CSF) ART guided by a genotypic drug resistance (GDR) test
    • the inclusion of potentially CNS-active drugs should be considered
  • patients already receiving ART:8
    • the inclusion of potentially CNS-active drugs should be considered for all patients receiving ART
    • in patients whose plasma viral load is >50 copies/mL: optimize ART with plasma GDR test
    • in patients whose CSF viral load is >50 copies/mL, and whose plasma viral load is <50 copies/mL: optimize ART by CSF GDR testing
    • in patients whose CSF viral load is <50 copies/mL, and whose plasma viral load is <50 copies/mL: continue ongoing ART and reconsider other causes of neurocognitive impairment
    • refer to the diagnostic tools section for more information.

It has been suggested that the use of ART drugs with better estimated CNS penetration effectiveness (CPE, table 1) may be associated with better neurocognitive functioning, particularly among patients receiving more than 3 antiretrovirals and/or those with virological suppression.5,10–12

  • However, conflicting data exist, and poorer neurocognitive performance has been associated with the use of antiretrovirals with good CNS penetration.13,14
  • In addition, clinical status at ART initiation may influence antiretroviral selection and CPE score,15 which could be a potential confounding factor in some studies.
  • Therefore a large, controlled trial on the influence of CPE on cognitive impairment is warranted before definitive conclusions can be made.13,14

Table 1. CNS penetration of different antiretrovirals according to proposed CPE score9

Drug class 4 3 2 1
NRTIs zidovudine (ZDV) abacavir (ABC)
emtricitabine  (FTC)
didanosine (ddl)
lamivudine (3TC)
stavudine  (d4T)
tenofovir (TDF)
zalcitabine (ddl)
NNRTIs nevirapine (NVP) delavirdine (DLV)
efavirenz (EFV)
etravirine  (ETR)  
PIs indinavir/r  (IDV/r) darunavir/r (DRV)
fosamprenavir/r  (FPV)
indinavir (IDV)
lopinavir/r  (LPV/r)
atazanavir (ATV)
atazanavir/r (ATV/r)
fosamprenavir (FPV)
nelfinavir (NFV)
ritonavir (RTV)
saquinavir (SQV)
saquinavir/r (SQV/r)
tipranavir/r (TPV/r)
Entry/fusion inhibitors   maraviroc (MRV)   enfuvirtide (ENF)
Integrase inhibitors   raltegravir (RAL)    

Note: Larger numbers reflect estimates of better penetration in the CNS (for example, a ranking of 4 indicates the highest degree of penetration)
PIs = protease inhibitors; NNRTIs = non-nucleoside reverse-transcriptase inhibitors; NRTIs = nucleoside/nucleotide reverse transcriptase inhibitors; /r = ritonavir boosted

The European AIDS Clinical Society (EACS) guidelines list the following 'potentially CNS-active' drugs8

  • Agents with demonstrated clear CSF penetration:
    • NRTIs: ZDV, ABC
    • NNRTIs: EFV, NVP
    • Boosted PIs: IND/r, LPV/r, DRV/r
    • Other classes: MRV
  • Drugs with proven “efficacy”:
    • NRTIs: ZDV, d4T, ABC
    • Boosted PIs: LPV/r

Treatment of HAND with non-antiretroviral agents

The guidelines from the New York State Department of Health AIDS Institute recommend that patients with HIV-associated dementia (HAD) may benefit from psychotropic medications, although they are more likely to develop side effects than non-infected people.16

  • Non-pharmacologic management of HAD involves simplifying tasks and trying to calm confused or agitated patients.
  • Treatment of delirium in people living with HIV should try to correct the underlying conditions that led to delirium. Patients can be treated with low doses of antipsychotics or sedatives.

In addition, the development of agents that control free radicals, neurotoxicity, pro-inflammatory processes and apoptosis may hold promise for the treatment of neurocognitive impairment.12

  • However it has been suggested that treatment with adjunctive agents has had disappointing results.6



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  2. Department of Health and Human Services. Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents. Accessed 3 March 2011.
  3. De Ronchi D, Faranca I, Beradi D, et al. Risk factors for cognitive impairment in HIV-1-infected persons with different risk behaviors. Arch Neurol. 2002;59:812–348.
  4. McCutchan JA, Wu JW, Robertson K, et al. HIV suppression by HAART preserves cognitive function in advanced, immune-reconstituted AIDS patients. AIDS. 2007;21(9):1109–1117.
  5. Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73:342–348.
  6. McArthur J, Steiner J, Sacktor N, Nath A. Human immunodeficiency virus-associated neurocognitive disorders: Mind the gap. Ann Neurol. 2010;67:699–714.
  7. Tozzi V, Balestra P, Bellagamba R, et al. Persistence of neuropsychologic deficits despite long-term highly active antiretroviral therapy in patients with HIV-related neurocognitive impairment. Prevalence and risk factors. J Acquire Immune Defic Syndr. 2007;45:174–182.
  8. European AIDS Clinical Society (EACS). Guidelines. Version 6.0. Accessed 18 October 2011.
  9. Letendre SL, Ellis RJ, Ances B, McCutchan JA. Neurologic complications of HIV disease and their treatment. Top HIV Med. 2010;18(2):45–55. 
  10. Smurzynski M, Wu K, Letendre S, et al. Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS. 2011;25:357–365.
  11. Cysique LA, Vaida F, Letendre S, et al. Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology. 2009;73:342–348.
  12. Clark US, Cohen RA. Brain dysfunction in the era of combination antiretroviral therapy: implications for the treatment of the aging population of HIV-infected individuals. Curr Opin Invest Drugs. 2010;11:884–900.
  13. Marra CM, Zhao Y, Clifford DB, et al. Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS. 2007;23:1359–1366.
  14. Wright E. Neurocognitive impairment and neuroCART. Curr Opin HIV AIDS. 2011. [Epub ahead of print].
  15. Garvey L, Winston A, Walsh J, et al. Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology. 2011;76:693–700.
  16. Office of the Medical Director, New York State Department of Health AIDS Institute in collaboration with the Johns Hopkins University Division of Infectious Diseases. Clinical Guidelines: Cognitive Disorders and HIV/AIDS. Accessed 3 March 2011.