The BDI was completed by all enrolled participants on the day of neurocognitive testing (n = 26). The median score was 1 (0–13), reflecting low overall levels of depressive symptoms in the cohort. Of the 26 individuals enrolled, three had a diagnosis of depression well controlled with buproprion (n = 2) or the selective serotonin reuptake inhibitor paroxetine (n = 1). An additional five individuals were receiving treatment for anxiety disorders with either benzodiazepines, or selective serotonin reuptake inhibitors. Four participants used, as needed, the sedative zolpidem for occasional sleep disturbance.
Recreational drug use was not uncommon amongst the study cohort, with 69% (18/26) reporting past or current use of illicit substances. Amongst those substances reported used in the past, cocaine was the most common, with 30.8% (8/26) of the entire cohort reporting its prior use. This was followed in frequency by marijuana and methamphetamine, with 11.5% (3/26) for both. Past use of intranasal heroin and ecstasy were both reported by 7.7% (2/26). Prior use of opium, alkyl nitrites and ketamine were infrequently reported at 3.8% (1/26). At the time of screening, the most commonly used illicit substance was marijuana, with 34.6% of the cohort reporting active recreational use. This was followed by cocaine at 15.3% (4/26), methamphetamine at 15.3% and ecstasy, with 7.7% of the cohort reporting its occasional use. Thirty one per cent of the enrolled cohort (8/26) reported no past or current history of recurrent illicit drug use. The three most common general medical conditions reported by study participants were hypercholesterolemia at 26.9% (7/26), seasonal allergies/allergic rhinitis at 23.1% (6/26) and anxiety disorders at 19.2% (5/26). Details of reported medical conditions are listed in Supplemental Table 1, http://links.lww.com/QAD/A780. Three individuals (11.5%) reported no significant medical history in addition to their diagnosis of HIV.
Wide range achievement test 3 test results
Raw scores for the spelling, vocabulary and arithmetic tests were converted to T-scores with a distribution mean of 100 and a standard deviation of 15 . T-scores and deficit scores of the study group reflected the high education status of the group as a whole (Table 2).
Neurocognitive testing results
Composite raw scores and T-scores for each neurocognitive test as well as a summation of test deficit scores and the number of individuals with any measured deficit are detailed in Table 2. None of the study participants displayed any deficits in either the WAIS-III symbol search, Stroop colour and word interference or Grooved Pegboard (Dominant hand) tests, although individual deficits were occasionally noted within other tests of processing speed, abstraction/executive functioning and motor skills respectively. The HVLT-R Trials 1–3 test had the highest number of individuals with any deficit (9/26 = 34.6%), with deficit scores ranging from 0 to 2. Mean GDS for the study group was 0.19 (0.00–0.60). Figure 2 provides means and standard deviations for each cohort deficit score across the measured cognitive domains (Fig. 2a) as well as the GDS (Fig. 2b). Using a GDS cutpoint as at least 0.50 for impairment, only one individual was found to be impaired with a GDS of 0.60. Statistical comparison of cohort deficit scores using the Kruskal–Wallis test reveals a significant difference in performance across the cognitive domains (P = 0.01). Dunn's multiple comparison post-test shows the cohort performed statistically better on tests of motor skills when compared to tests of learning. No other significant differences between group performances in cognitive domains were found.
Within the study group, there was no statistical association between GDS and duration cART, duration of infection prior to initiation of cART, years of education, CD4+ Nadir or CD4+ at enrolment, CPE score at initiation of cART or CPE score at enrolment, ethnicity or age at screen (P> 0.10, all variables). Multiple linear regression was also used to assess GDS scores in each cognitive domain. Again, no association between domain-specific deficit scores and the variables listed above were found after Bonferroni correction for multiple testing (significance threshold P
Self-perception of cognitive functioning and motor health are largely consistent with objectively measured global deficit score in this cohort
In an effort to classify individuals with ANI or MND in the presence of GDS scores indicative of NCI, participants were asked for indicators that the NCI produces some degree of interference in daily functioning as defined by self-report of the following: reduced mental acuity (such as the ability to think or reason); inefficiency in work; inefficiency in homemaking or social functioning; and motor difficulties (such as the ability to walk or hold objects) . These questions were asked as above during the screening visit and participants were asked to consider the time frame covering the period since their diagnosis of HIV. Of the 26 individuals who proceeded to the study visit, one individual (4%) reported perceived inefficiencies in work, one individual (4%) reported perceived inefficiencies in homemaking. No individuals reported any perceived motor difficulties. Four individuals (15%) reported some perceived (mild) reductions in mental acuity. Of note, the one individual in our cohort with impairment in a minimum of two cognitive domains and objective evidence of NCI reported no perceived reduction in any of the queried domains, and is therefore classified as having ANI.
The Medical Outcomes Study HIV (MOS-HIV) Health Survey was applied to a subset of study participants in an effort to standardize results of subjective questions of self-perception. This tool has been used extensively in clinical trials, demonstrating sound psychometric properties in varied populations . Ten dimensions of health were evaluated. The subscales of this 35-question instrument are scored as summated rating scales on a 0-to-100 scale with higher scores indicative of better health. Seventeen of the enrolled individuals completed the survey either at the time of the study visit (n = 11) or at time points ranging from between 2 and 26 months after the study visit (n = 6). Overall self-reported perceptions of general health, functional status and well-being were positive, with mean values for self-reports of cognitive, social, role and physical functioning all above 90. Although self-perceptions of cognitive health were largely consistent with the low rate of NCI in this cohort, no formal statistical correlation exists between GDS and MOS-QOL cognitive function scores (P = 0.56). Health transition scores indicate that the majority of respondents believed their overall physical and emotional health to have been largely unchanged or a slightly better than in the month prior to questioning. Composite MOS-HIV survey health results are shown in Table 3.
As the number of people living with HIV-infection continues to grow, the prevention and mitigation of diseases that are at higher risk in infected individuals has become increasingly important. HAND persists as an important potential complication of HIV-infection , carrying with it the possibility of significant morbidity and mortality . HIV infiltrates the CNS during primary infection, initiating complex inflammatory and viral processes that may result in neuronal damage and neurocognitive decline . A recent paper by Suh et al. suggests that intrathecal inflammation progressively increases during primary HIV . An interruption of the accrual of these inflammatory insults might therefore mitigate or abort the CNS immune activation that is widely implicated in HAND pathogenesis [27,28], resulting in decreased rates of HAND in individuals initiating cART at earlier time points. Combined with the finding that when compared to individuals without NCI, those with a diagnosis of ANI may have up to a six-fold increased risk for earlier development of symptomatic HAND , the need to implement clinically tested strategies to halt the initiation of NCI becomes clear. It is therefore of great clinical value to investigate if the early initiation of cART might successfully modify the risk of HAND.
Here we present data that observed rates of HAND in this cohort of HIV-infected men who initiated cART during acute/early infection are low, with only one individual (4%) in the study group meeting objective criteria for NCI following comprehensive neurocognitive testing. The finding of low rates of NCI amongst this highly educated group of individuals who have been maintained on uninterrupted, suppressive cART for several years was in-line with our clinical expectations and consistent with the largely positive self-perceptions of general and cognitive health reported amongst study participants. In an effort to identify NCI that was largely attributable to HIV-infection, we chose to investigate a cohort in which a number of comorbid illnesses thought to confound HAND diagnoses or negatively impact neurocognitive function were excluded. The observed screen failure rate in this study (35%) was largely attributed to unexpectedly high rates of substance dependence and psychiatric illness within the screening group and highlights the pervasiveness of comorbid illness in those with HIV, and the difficulty in investigating the isolated effects of HIV on cognition. It is important to note however, that a significant percentage of our study population did report the use of illicit drugs on a recreational basis that did not meet criteria for dependence or abuse. In addition, although a small number of individuals reported formal diagnoses of depression, depressive symptoms appeared well-managed pharmacologically. The decision to exclude those with comorbidities was a reasonable approach, as the potential for even a small number of individuals with confounder-attributable NCI to skew the findings within a relatively small cohort existed. However, there are reports suggesting that historic substance abuse  and coinfection with the hepatitis C virus  may not have a significant effect on observed HAND prevalence. It should also be noted that although not exclusionary, none of our enrolled participants had diabetes and although several had hypercholesterolemia, none had been diagnosed with significant cardiovascular disease.
We hypothesized that rates of HAND in the ADARC early infection cohort might be significantly lower than the approximately 40–50% reported in the CHARTER and ALLRT [4,7] studies (n = 1316 and 1160, respectively), in which many individuals initiated cART during chronic HIV-infection or were not on cART at the time of neurocognitive testing. Although this is true (P < 0.0001 by Fisher's exact test), our reported rates of NCI are also lower than that reported in the recent literature for more similar populations. Cross-sectional studies suggest that populations initiating early cART, or maintaining systemic viral suppression on cART may demonstrate decreased HAND prevalence. Crum-Cianflone et al. estimated a 19% prevalence of NCI in a cohort of HIV+ patients diagnosed early in infection. In this cohort, the majority were seroconverters with a median window of 1.2 years and 64% were on cART at the time of study . In a separate study, Cysique et al. found a similar prevalence of NCI (18%) in a chronically infected cohort of HIV+ individuals with plasma HIV RNA levels less than 50 copies/ml . In both cases, this prevalence was similar to what was found in the HIV negative control population for these studies. Although we report a 4% rate of NCI in this observational pilot study, as a result of the small size of our cohort our reported rate is not statistically different from results obtained in these two studies (P > 0.05 by Fisher's exact test). Although challenging, interrogation of a larger cohort would be required to determine if rates of NCI are significantly reduced below 18–19% in non–confounded individuals initiating uninterrupted cART at the earlier time points in our study.
Study limitations include the investigation of a small, exclusively male cohort of participants and the absence of neurocognitive data from a control group. The ability to identify individuals initiating cART during primary infection is challenging and our scientific interest in investigating rates of NCI in individuals maintained on uninterrupted cART as primary infection limited the cohort available for study. However, our use of a comprehensive neurocognitive battery, with detailed medical, psychiatric and drug histories makes these data compelling. Another limitation is the cross-sectional nature of the study, which does not allow for objective longitudinal measurements of HAND. This is particularly important given the overall high educational status of the cohort. Highly educated individuals may have a higher cognitive reserve for normal neurocognitive functioning, effectively making NCI more difficult to uncover until a large amount of reserves are lost . Finally, it should be noted that the median 2010 CPE score at cART initiation was 12, reflecting the fact that four participants had initiated treatment during enrolment in an ADARC study of intensified, five-drug cART  and an additional 12 initiated treatment with Trizivir (abacavir/lamivudine/zidovudine) containing regimens. The median 2010 CPE score of 7 at the time of entry into this pilot study reflects the fact that many had returned to standard three-drug cART by the time of enrolment. As a result, these findings may be difficult to extrapolate to individuals initiating early therapy with standard three-drug regimens. However, the extent to which the initiation of cART regimens with high median CPE scores influenced our rates of NCI is unclear. Although a recent study suggests that higher CPE regimens result in better viral suppression in the CSF , a randomized trial attempting to determine if treatment with CNS targeted cART regimens resulted in improved neurocognitive outcomes was inconclusive . Data on CSF viral loads of enrolled participants, as well as the presence or absence of viral compartmentalization  or genetic signatures potentially associated with neuroadaptation  would be informative. Additionally, given the potential confounding interactions between HIV disease and advancing age on cognitive decline , it would be of interest to investigate cohorts older than the one in our study. Finally, as a result of investigating individuals with both low comorbidities and early treatment, we cannot determine the relative contribution of these two factors to the low rates of HAND observed in this cohort.
Despite the important limitations of this study, the unique nature of a comprehensive neurocognitive assessment of non-confounded men identified during primary infection with HIV makes this work relevant to greater study of HAND. Our findings, although not conclusive, are consistent with the possibility of neuroprotective benefit of initiating suppressive cART during primary infection; a benefit we hypothesize may be the result of an early decrease in CNS immune activation and/or viral replication. They also highlight the pervasiveness of comorbid illness in those with HIV, suggest an important contribution of comorbidities to observed HAND prevalence, and support the development of larger clinical trials comparing neurocognitive outcomes in individuals treated with cART during acute/primary infection as opposed to later time points.
Funding: This study has been supported by the Rockefeller University Center for Clinical and Translational Science (CCTS) grant # 8 UL1 TR000043 from the National Center for Advancing Translational Sciences (NCATS), National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) programme. T.H.E. is the recipient of a National Institute of Mental Health (NIMH) Career Development Award NIH K08MH090900.
We gratefully acknowledge the patients of the Aaron Diamond AIDS Research Center Primary HIV-1 Infection Cohort for their commitment to this study and the efforts of the Nursing Staff at the Rockefeller University Hospital, Dr Mayte Suarez-Farinas of the Rockefeller University Center for Clinical and Translational Science for assistance with statistical study design and Dr Judith G. Rabkin for providing assistance in study protocol design.
T.H.E. led the study, supervised the acquisition of data, analysed the data and wrote the manuscript. A.A. performed and scored all comprehensive neurocognitive assessments and edited the manuscript. M.L.M. assisted in patient recruitment and study coordination and edited the manuscript. D.G. assisted in patient recruitment and study coordination and edited the manuscript. D.D. provided input into study design, data analysis and edited the manuscript. M.M. conceived the project, created and maintained the ADARC Primary HIV-1 Infection cohort, critically reviewed the data and edited the manuscript.
Conflicts of interest
M.M. is a paid consultant for Merck and Gilead. He receives grant support from Gilead and GlaxoSmithKline and is on the Speakers Bureau for Gilead and Bristol-Myers Squibb. The remaining authors have declared that no competing interests exist.
These findings were presented in part in abstract form in February 2015 at the 22nd Conference on Retroviruses and Opportunistic Infections, Seattle, Washington.
1. Antinori A, Arendt G, Becker JT, Brew BJ, Byrd DA, Cherner M, et al. Updated research nosology for HIV-associated neurocognitive disorders
2. Richman DD. HIV chemotherapy
3. McArthur JC. HIV dementia: an evolving disease
. J Neuroimmunol
2004; 157 (1–2):3–10.
4. Heaton RK, Clifford DB, Franklin DR Jr, Woods SP, Ake C, Vaida F, et al. HIV-associated neurocognitive disorders persist in the era of potent antiretroviral therapy: CHARTER Study
2010; 75 23:2087–2096.
5. Schouten J, Cinque P, Gisslen M, Reiss P, Portegies P. HIV-1 infection and cognitive impairment in the cART era: a review
6. Ellis RJ, Deutsch R, Heaton RK, Marcotte TD, McCutchan JA, Nelson JA, et al. Neurocognitive impairment is an independent risk factor for death in HIV infection. San Diego HIV Neurobehavioral Research Center Group
. Arch Neurol
7. 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
8. Rippeth JD, Heaton RK, Carey CL, Marcotte TD, Moore DJ, Gonzalez R, et al. Methamphetamine dependence increases risk of neuropsychological impairment in HIV infected persons
. J Int Neuropsychol Soc
9. Fellows RP, Byrd DA, Morgello S, Manhattan HIVBB. Major depressive disorder, cognitive symptoms, and neuropsychological performance among ethnically diverse HIV+ men and women
. J Int Neuropsychol Soc
10. Clifford DB, Evans SR, Yang Y, Gulick RM. The neuropsychological and neurological impact of hepatitis C virus co-infection in HIV-infected subjects
2005; 19 (Suppl 3):S64–S71.
11. Richardson JL, Nowicki M, Danley K, Martin EM, Cohen MH, Gonzalez R, et al. Neuropsychological functioning in a cohort of HIV- and hepatitis C virus-infected women
12. Ryan EL, Morgello S, Isaacs K, Naseer M, Gerits P, Manhattan HIVBB. Neuropsychiatric impact of hepatitis C on advanced HIV
13. American Psychiatric Association. Diagnostic and statistical manual of mental disorders. 4th ed, Text Revision
. Washington, DC: American Psychiatric Association; 2000.
14. Kroenke K, Spitzer RL, Williams JB. The PHQ-9: validity of a brief depression severity measure
. J Gen Intern Med
16. Wilkinson G. The wide range achievement test: manual
. 3rd ed.Wilmington, DE: Wide Range; 1993.
17. Carey CL, Woods SP, Gonzalez R, Conover E, Marcotte TD, Grant I, et al. Predictive validity of global deficit scores in detecting neuropsychological impairment in HIV infection
. J Clin Exp Neuropsychol
18. Heaton RK, Grant I, Butters N, White DA, Kirson D, Atkinson JH, et al. The HNRC 500--neuropsychology of HIV infection at different disease stages. HIV Neurobehavioral Research Center
. J Int Neuropsychol Soc
19. Wu AW, Revicki DA, Jacobson D, Malitz FE. Evidence for reliability, validity and usefulness of the Medical Outcomes Study HIV Health Survey (MOS-HIV)
. Qual Life Res
20. Beck AT, Ward CH, Mendelson M, Mock J, Erbaugh J. An inventory for measuring depression
. Arch Gen Psychiatry
21. GraphPad Prism. http://www.graphpad.com
. San Diego, California, USA: GraphPad Software. [Accessed 10 June 2015].
22. 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
23. Letendre SL, Ellis RJ, Ances BM, McCutchan JA. Neurologic complications of HIV disease and their treatment
. Top HIV Med
24. Goodkin K, Wilkie FL, Concha M, Hinkin CH, Symes S, Baldewicz TT, et al. Aging and neuro-AIDS conditions and the changing spectrum of HIV-1-associated morbidity and mortality
. J Clin Epidemiol
2001; 54 (Suppl 1):S35–43.
25. Price RW, Spudich SS, Peterson J, Joseph S, Fuchs D, Zetterberg H, et al. Evolving character of chronic central nervous system HIV infection
. Semin Neurol
26. Suh J, Sinclair E, Peterson J, Lee E, Kyriakides TC, Li FY, et al. Progressive increase in central nervous system immune activation in untreated primary HIV-1 infection
. J Neuroinflamm
27. Hagberg L, Fuchs D, Rosengren L, Gisslen M. Intrathecal immune activation is associated with cerebrospinal fluid markers of neuronal destruction in AIDS patients
. J Neuroimmunol
28. Kaul M, Garden GA, Lipton SA. Pathways to neuronal injury and apoptosis in HIV-associated dementia
29. Grant I, Franklin DR Jr, Deutsch R, Woods SP, Vaida F, Ellis RJ, et al. Asymptomatic HIV-associated neurocognitive impairment increases risk for symptomatic decline
30. Byrd DA, Fellows RP, Morgello S, Franklin D, Heaton RK, Deutsch R, et al. Neurocognitive impact of substance use in HIV infection
. J Acquir Immune Defic Syndr
31. Clifford DB, Vaida F, Kao YT, Franklin DR, Letendre SL, Collier AC, et al. Absence of neurocognitive effect of hepatitis C infection in HIV-coinfected people
32. Crum-Cianflone NF, Moore DJ, Letendre S, Poehlman Roediger M, Eberly L, Weintrob A, et al. Low prevalence of neurocognitive impairment in early diagnosed and managed HIV-infected persons
33. Cysique LA, Brew BJ. Prevalence of nonconfounded HIV-associated neurocognitive impairment in the context of plasma HIV RNA suppression
. J Neurovirol
34. Stern RA, Silva SG, Chaisson N, Evans DL. Influence of cognitive reserve on neuropsychological functioning in asymptomatic human immunodeficiency virus-1 infection
. Arch Neurol
35. Markowitz M, Evering TH, Garmon D, Caskey M, La Mar M, Rodriguez K, et al. A randomized open-label study of 3- versus 5-drug combination antiretroviral therapy in newly HIV-1-infected individuals
. J Acquir Immune Defic Syndr
36. Cusini A, Vernazza PL, Yerly S, Decosterd LA, Ledergerber B, Fux CA, et al. Higher CNS penetration-effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid
. J Acquir Immune Defic Syndr
37. Ellis RJ, Letendre S, Vaida F, Haubrich R, Heaton RK, Sacktor N, et al. Randomized trial of central nervous system-targeted antiretrovirals for HIV-associated neurocognitive disorder
. Clin Infect Dis
38. Power C, McArthur JC, Johnson RT, Griffin DE, Glass JD, Perryman, et al. Demented and nondemented patients with AIDS differ in brain-derived human immunodeficiency virus type 1 envelope sequences
. J Virol
39. Evering TH, Kamau E, St Bernard L, Farmer CB, Kong XP, Markowitz M. Single genome analysis reveals genetic characteristics of Neuroadaptation across HIV-1 envelope
40. Cohen RA, Seider TR, Navia B. HIV effects on age-associated neurocognitive dysfunction: premature cognitive aging or neurodegenerative disease?
. Alzheimers Res Ther
central nervous system; combination antiretroviral therapy; HIV-associated neurocognitive disorder; human immunodeficiency virus (HIV-1); primary HIV infection
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