Journal of NeuroVirology

, Volume 17, Issue 1, pp 3-16

First online:

Open Access This content is freely available online to anyone, anywhere at any time.

HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors

  • Robert K. HeatonAffiliated withUniversity of California Email author 
  • , Donald R. FranklinAffiliated withUniversity of California
  • , Ronald J. EllisAffiliated withUniversity of California
  • , J. Allen McCutchanAffiliated withUniversity of California
  • , Scott L. LetendreAffiliated withUniversity of California
  • , Shannon LeBlancAffiliated withUniversity of California
  • , Stephanie H. CorkranAffiliated withUniversity of California
  • , Nichole A. DuarteAffiliated withUniversity of California
  • , David B. CliffordAffiliated withWashington University
    • , Steven P. WoodsAffiliated withUniversity of California
    • , Ann C. CollierAffiliated withUniversity of Washington, Seattle
    • , Christina M. MarraAffiliated withUniversity of Washington, Seattle
    • , Susan MorgelloAffiliated withMt. Sinai School of Medicine
    • , Monica Rivera MindtAffiliated withMt. Sinai School of Medicine
    • , Michael J. TaylorAffiliated withUniversity of California
    • , Thomas D. MarcotteAffiliated withUniversity of California
    • , J. Hampton AtkinsonAffiliated withUniversity of California
    • , Tanya WolfsonAffiliated withUniversity of California
    • , Benjamin B. GelmanAffiliated withUniversity of Texas Medical Branch
    • , Justin C. McArthurAffiliated withJohns Hopkins University
    • , David M. SimpsonAffiliated withMt. Sinai School of Medicine
    • , Ian AbramsonAffiliated withUniversity of California
    • , Anthony GamstAffiliated withUniversity of California
    • , Christine Fennema-NotestineAffiliated withUniversity of California
    • , Terry L. JerniganAffiliated withUniversity of California
    • , Joseph WongAffiliated withUniversity of California
    • , Igor GrantAffiliated withUniversity of California
    • , for the CHARTER and HNRC Groups


Combination antiretroviral therapy (CART) has greatly reduced medical morbidity and mortality with HIV infection, but high rates of HIV-associated neurocognitive disorders (HAND) continue to be reported. Because large HIV-infected (HIV+) and uninfected (HIV−) groups have not been studied with similar methods in the pre-CART and CART eras, it is unclear whether CART has changed the prevalence, nature, and clinical correlates of HAND. We used comparable methods of subject screening and assessments to classify neurocognitive impairment (NCI) in large groups of HIV + and HIV − participants from the pre-CART era (1988–1995; N = 857) and CART era (2000–2007; N = 937). Impairment rate increased with successive disease stages (CDC stages A, B, and C) in both eras: 25%, 42%, and 52% in pre-CART era and 36%, 40%, and 45% in CART era. In the medically asymptomatic stage (CDC-A), NCI was significantly more common in the CART era. Low nadir CD4 predicted NCI in both eras, whereas degree of current immunosuppression, estimated duration of infection, and viral suppression in CSF (on treatment) were related to impairment only pre-CART. Pattern of NCI also differed: pre-CART had more impairment in motor skills, cognitive speed, and verbal fluency, whereas CART era involved more memory (learning) and executive function impairment. High rates of mild NCI persist at all stages of HIV infection, despite improved viral suppression and immune reconstitution with CART. The consistent association of NCI with nadir CD4 across eras suggests that earlier treatment to prevent severe immunosuppression may also help prevent HAND. Clinical trials targeting HAND prevention should specifically examine timing of ART initiation.


HIV Combination antiretroviral therapy HIV dementia