The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline participant profile

The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline... © 2019 The Authors. DOI: 10.1111/hiv.12795 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association HIV Medicine (2020), 21, 30--42 ORIGINAL RESEARCH The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline participant profile 1,† 2,† 3 1,4 2 5 6 7 8 MM#1;etral, KEA Darling I Locatelli, I Nadin, G Santos, P Brugger, H Kovari, A Cusini, K Gutbrod, 9 10 10 4 11 11 12 13 14 PE Tarr, A Calmy, TD Lecompte, F Assal, A Monsch, U Kunze, M Stoeckle, M Schwind, P Schmid, 15 16 1,‡ 2,‡ § R Pignatti, C Di Benedetto, R Du Pasquier, and M Cavassini for the NAMACO study group Swiss HIV Cohort Study Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland, 2 3 Service of Infectious Diseases, Lausanne University Hospital, Lausanne, Switzerland, Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland, Service of Neurology, University Hospital of Geneva, Geneva, Switzerland, Neuropsychology Unit, Department of Neurology, University Hospital Zurich, Zurich, Switzerland, Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland, Department of Infectious Diseases and Hospital Epidemiology, Bern University Hospital and University of Bern, Bern, 8 9 Switzerland, Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland, University Department of Medicine, Kantonsspital Bruderholz, University of Basel, Bruderholz, Switzerland, HIV Unit, Infectious Diseases Division, Medicine Department, University Hospital of Geneva, Geneva, Switzerland, Memory Clinic, Felix Platter Hospital, University Center for Medicine of Aging, Basel, Switzerland, Infectious Diseases Unit, Basel, Switzerland, 13 14 Neurology Clinic, St Gallen, Switzerland, Infectious Diseases and Hospital Epidemiology Division, Kantonsspital St Gallen, St Gallen, Switzerland, Department of Neurology, Neurocentre of Southern Switzerland, Lugano Regional Hospital, Lugano, Switzerland and Infectious Diseases Unit, Lugano Regional Hospital, Lugano, Switzerland Objectives The aim of the study was to examine baseline neurocognitive impairment (NCI) prevalence and factors associated with NCI among patients enrolled in the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study. Methods The NAMACO study is an ongoing, prospective, longitudinal, multicentre and multilingual (German, French and Italian) study within the Swiss HIV Cohort Study. Between 1 May 2013 and 30 November 2016, 981 patients ≥ 45 years old were enrolled in the study. All underwent standardized neuropsychological (NP) assessment by neuropsychologists. NCI was diagnosed using Frascati criteria and classified as HIV-associated or as related to other factors. Dichotomized analysis (NCI versus no NCI) and continuous analyses (based on NP test z-score means) were performed. Results Most patients (942; 96.2%) had viral loads < 50 HIV-1 RNA copies/mL. NCI was identified in 390 patients (39.8%): 263 patients (26.8%) had HIV-associated NCI [249 patients (25.4%) had asymptomatic neurocognitive impairment (ANI)] and 127 patients (13%) had NCI attributable to other factors, mainly psychiatric disorders. There was good correlation between dichotomized and continuous analyses, with NCI associated with older age, non-Caucasian ethnicity, shorter duration of education, unemployment and longer antiretroviral therapy duration. Correspondence: Dr Katharine Darling, Service of Infectious Diseases, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Tel: +41 21 314 1022; fax: +41 21 314 1008; e-mail: katharine.darling@chuv.ch Equal first author contributions. Equal last author contributions. Members of the NAMACO study group are listed under Acknowledgements. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 30 The NAMACO study baseline profile 31 Conclusions In this large sample of aging people living with HIV with well-controlled infection in Switzerland, baseline HIV-associated NCI prevalence, as diagnosed after formal NP assessment, was 26.8%, with most cases being ANI. The NAMACO study data will enable longitudinal analyses within this population to examine factors affecting NCI development and course. Keywords: aging, HIV-associated neurocognitive disorder, neurocognitive impairment, neuropsychological testing Accepted 11 July 2019 originally to answer different clinical questions [8,11]. Introduction Thirdly, the level of HIV control is not uniform: some The availability of safe and effective antiretroviral ther- cohorts group patients together, regardless of HIV viral apy (ART) for HIV infection has enabled people living load or whether or not they are on ART, while others with HIV (PLWH) to age. As the population of older exclude patients with detectable viraemia. PLWH increases, so does the prevalence of comorbidities. In Switzerland, the Neurocognitive Assessment in the One such comorbidity, neurocognitive impairment (NCI), Metabolic and Aging Cohort (NAMACO) study was set up has been described since the start of the HIV epidemic, as a longitudinal study to examine NCI within a well- but the spectrum post-ART has changed. HIV-associated characterized and well-treated cohort of PLWH, the Swiss dementia (HAD), previously seen in advanced HIV dis- HIV Cohort Study (SHCS) cohort [12]. In the current ease, is now uncommon [1,2], while the prevalence of study, we present the characteristics of NAMACO study milder NCI, which may be asymptomatic, has increased patients and the baseline prevalence of NCI. [3]. Moreover, the presentation of NCI has changed. In the pre-ART era, HAD was subcortical, rapidly progres- sive, and characterized by psychomotor slowing, motor Methods dysfunction and extrapyramidal signs. In the current ART The NAMACO study era, NCI is both cortical and subcortical, relatively stable over time, and characterized by impairments in working The NAMACO study is an ongoing, prospective, longitudi- memory and executive function [4–6]. nal, multicentre and multilingual (German, French and To reflect this shift, the diagnostic nomenclature of Italian) study included within an observational open HIV-associated NCI was revised in 2007 to define stages research cohort study, the SHCS. Since 1988, the SHCS of impairment according to the so-called Frascati criteria has collected data at twice-yearly standardized SHCS clinic [7]. In increasing severity, the stages are: asymptomatic visits on the demography, behaviour, medical history (HIV neurocognitive impairment (ANI), corresponding to mild and non-HIV), HIV infection parameters, treatments and to moderate neurocognitive deficits without repercussions comorbidities of all enrolled patients aged ≥ 18 years [12]. in activities of daily living (ADL); mild neurocognitive The NAMACO study was set up to examine the cogni- disorders (MNDs), corresponding to mild to moderate tive and neurological impact of HIV infection in an aging neurocognitive deficits with repercussions in ADL; and HIV-positive population and has been established in col- HIV-associated dementia (HAD), corresponding to moder- laboration with physicians, neuropsychologists, neurolo- ate to severe neurocognitive deficits with repercussions in gists and study nurses. ADL [7]. Diagnosing NCI as specifically HIV-associated requires the exclusion of confounding factors, such as Standard protocol approvals, registrations and patient psychiatric disorders and organic cerebral pathology [7]. consents Despite these definitions, the NCI literature can be con- The ethics committees of each cantonal hospital centre fusing. Firstly, ANI, MNDs and HAD may be referred to approved the NAMACO study protocol and all patient par- collectively as HIV-associated neurocognitive disorders ticipants signed informed consent prior to being included. (HANDs) if ADL have been assessed [4], or as mild or moderate NCI if the assessment is based on NP testing alone [8]. Secondly, some patient populations make up Patient population and study design cohorts designed from the start to study NCI [3,9], or else The NAMACO study had the following inclusion criteria: subcohorts of long-standing cohorts [10], whereas other HIV-positive status, age ≥ 45 years, enrolment in the populations are pooled from larger studies designed © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 32 MM#1;etral et al. SHCS, engagement in care at one of seven cantonal uni- each NP test was converted to a demographically versity-affiliated hospital centres (Basel, Bern, Geneva, adjusted standard score (z-score). Lausanne, Lugano, St Gallen and Zurich) and sufficient The cognitive domains assessed were based on those oral fluency in the local language to enable neuropsycho- used in the International Network for Strategic Initiatives logical (NP) tests to be performed. SHCS-affiliated infec- in Global HIV Trials (INSIGHT) and Strategic Timing of tious disease physicians received a list of eligible patients Antiretroviral Treatment (START) Study Group [8] and attending their clinics and were responsible for inviting were in accordance with the guidelines published by patients to participate in the NAMACO study between 1 Antinori et al. [7]. The tests are sensitive in detecting May 2013 and 30 November 2016. Enrolment was dis- NCI, rapid and easy to perform, standardized for several continued at 981 patients. Nonenrolment of eligible age and education groups, and available in different lan- patients was related to manpower at each site; as age and guages. The Hopkins Verbal Learning Test-Revised is par- language were the only limiting criteria beyond the need ticularly appropriate for longitudinal studies as it to be seen at a university-affiliated SHCS centre, patients provides six parallel forms to avoid the practice effect at were not, in principle, disproportionately selected on the retest which has been described as a reason for improve- basis of neurocognitive symptoms or previous neurologi- ment in NP function over time [15,16]. In addition to the cal history. tests used in the START study, we chose to include the While all SHCS patients are asked European AIDS Clin- five-point Figural Fluency and the Victoria Stroop test, to ical Society (EACS) screening questions on memory, rea- enrich the assessment of executive function, and the soning and attention difficulties [13] at their twice-yearly Wechsler adult intelligence scale 4th edition (WAIS-IV) cohort visits, NAMACO study patients also undergo a Digit Span Subtest to assess attention and working mem- standardized NP assessment at baseline and again at 2 ory (Table 1). (2016–2018) and 4 years (2018–2020). For all NAMACO study patients, regardless of their EACS screening ques- Self-administered assessments tion responses, NP assessment is performed by either a As functional scales are required to differentiate neuropsychologist or a neurologist trained in behavioural between ANI and MNDs, Lawton’s Instrumental Activi- neurology and working under the supervision of a neu- ties of Daily Living (IADL) were assessed [17,18] to ropsychologist. quantify the impact of NCI, if present, on daily func- As part of the study, patients with NCI are invited to tion. Three supplementary questions were added, undergo further investigations according to EACS guide- inspired by the Patients’ Assessment of Own Function- lines [14], namely, full neurological examination, cere- ing Inventory questionnaire (a subjective measure of brospinal fluid (CSF) collection via lumbar puncture and cognitive function), on professional work quality and cerebral magnetic resonance imaging (Fig. 1), to examine productivity and on relatives’ comments about cogni- the benefit of these interventions as diagnostic tools and tive decline (Appendix 1). Functional impairment was factors associated with NCI. defined as difficulties being reported in at least two The current study was a cross-sectional analysis inves- items out of 11 (Fig. 2). tigating the neurocognitive status of patients at the time Depression severity was graded using the Center for Epi- of enrolment (baseline). demiologic Studies Depression (CES-D) scale by way of a questionnaire rating mood. Although the CES-D scale has commonly been used to assess depression among PLWH, it Neurocognitive evaluation does have limitations in this setting as some items in the ques- Cognitive complaints tionnaire may be related to having HIV infection rather than For each of the three EACS screening questions men- depression (items on positive affect and somatic symptoms tioned above, the response options are never, hardly ever, such as restless sleep and poor appetite) [19,20]. In the current or yes, definitely. Patients answering ‘yes, definitely’ to at study, CES-D scores between 16 and 26 were classed as mild least one question were considered to have cognitive depression and scores ≥ 27 were classed as severe depression complaints. in order to apply a more stringent depression definition. NP assessment NCI definitions and associations The NP test battery covered seven cognitive domains Using the Frascati criteria [7], patients were classified into known to be affected in HIV-associated NCI (Table 1). five categories as follows (Fig. 2): normal NP examination The complete battery required no more than 90 min to (no NCI), ANI, MND, HAD and non-HIV-associated NCI perform if the patient had no deficits. The raw score for (‘other’). In patients in the ‘other’ category, NCI was © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 33 981 patients ≥45 years old in the Metabolic and Aging Cohort of the SHCS All patients assessed at baseline, then at 2 years and at 4 years Presence of cognitive complaints screened for by physician using EACS screening questions (memory loss, mental slowing and attention difficulties) - Standardized neuropsychological evaluation (7 cognitive domains, shown in Table 1) - Functional scale (IADL and PAOFI, as described in the text) - Depression questionnaire (CES-D) No neurocognitive impairment Neurocognitive impairment - Full neurological examination -Brain MRI - Lumbar puncture Fig. 1 Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study design. SHCS, Swiss HIV Cohort Study; EACS, European AIDS Clinical Society; IADL, Instrumental Activities of Daily Living; PAOFI, Patients’ Assessment of Own Functioning Inventory; CES-D, Center for Epidemiologic Studies Depression scale; MRI, magnetic resonance imaging. attributed to confounding conditions such as substance use, cognitive complaints and toxin consumption (smoking, psychiatric disorders (including severe depression: CES-D alcohol use, past injecting drug use, current cannabis use scores ≥ 27), ART toxicity, neurodegenerative disorders, and current noninjecting cocaine use). Efavirenz use was opportunistic central nervous system (CNS) infection, stroke analysed individually given the higher rates of neuropsy- history and trauma, rather than to HIV infection (Fig. 2). chiatric adverse events associated with this treatment Patients with CES-D scores of 16–26 (moderate to severe than with other antiretroviral treatments [21]; treatment low mood) were assigned to the ‘other’ category if the with dolutegravir was not assessed at baseline as this examining neuropsychologist considered the NP profile to treatment became available in Switzerland 1 year into the be related to depression rather than to HIV infection alone. NAMACO study. All these variables were obtained from To identify potential factors associated with NCI, we the SHCS database extraction closest in time to each examined: demographic factors (age, sex, ethnicity, edu- patient’s neurocognitive assessment. For the current cation and employment), HIV-related factors (viral load, study, comorbidities and toxin consumption were anal- CD4 T-cell count at baseline and nadir CD4 count, dura- ysed as binary (presence or absence) rather than continu- tion of current ART, CPE score at baseline, ART drug ous data. class, namely, nucleoside reverse transcriptase inhibitor, protease inhibitor, integrase strand transfer inhibitor or Statistical analysis efavirenz, and mode of HIV acquisition), cardiovascular risk factors [diabetes, hypertension, and total and high- Descriptive analyses are presented as mean and standard density lipoprotein (HDL) cholesterol], other comorbidities deviation (SD) for symmetric continuous variables, as (hepatitis B and C, and syphilis), depression score, median and interquartile range (IQR) for asymmetric © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 34 MM#1;etral et al. Table 1 The seven cognitive domains examined and the neuropsy- Data availability statement chological tests performed in the standardized neuropsychological assessment of all patients enrolled in the Neurocognitive Assess- Anonymized data will be shared by request from any ment in the Metabolic and Aging Cohort (NAMACO) study qualified investigator. Standardized neuropsychological assessment Cognitive domain Neuropsychological tests Results Motor skills Finger Tapping (dominant and nondominant NAMACO patients hands) Grooved Pegboard (dominant and Of the 981 patients enrolled, 782 (79.7%) were male, 899 nondominant hands) Speed of information WAIS-IV, Coding (91.7%) were Caucasian and 627 patients (63.9%) were aged processing Colour Trails 1 > 50 years [mean (#1; SD) age 54.5 #1; 7.5 years] (Table 2). Attention and working WAIS-IV Digit Span (forward and backward) At baseline, most patients (96.2%) had viral loads < 50 HIV- memory Executive function Category Fluency 1 RNA copies/mL; the median CD4 count was 634 cells/lL 5-point Figural Fluency (IQR 468, 814 cells/lL) and the median nadir CD4 count was Victoria Stroop (trial 3 and/or 3/1) 180 cells/lL (IQR 74, 270 cells/lL) (Table 2). Colour Trails 2 Verbal episodic memory Hopkins Verbal Learning Test – Revised The percentage of NAMACO patients who were male or Language Category Fluency Caucasian was slightly higher than that of SHCS patients Victoria Stroop (trial 1) eligible for NAMACO but not enrolled or followed up at Sensory and perceptual Grooved Pegboard (dominant and skills nondominant hands) non-NAMACO centres (Table S1). Victoria Stroop (trial 1) *WAIS-IV, Wechsler adult intelligence scale 4th edition. Prevalence of NCI and cognitive domains affected Of all 981 patients, 390 (39.8%) presented with NCI, of continuous variables and as percentages for categorical whom 263 patients (26.8% of 981) had HIV-associated variables. NCI and 127 patients (13.0% of 981) had non-HIV-associ- NCI was analysed as a dichotomized and as a continu- ated NCI. Examining patients with HIV-associated NCI, ous variable. For the dichotomized analysis, NCI was 249 patients (25.4% of 981) had ANI, eight patients dichotomized as follows: no impairment (no NCI) versus (0.8%) had MNDs and six patients (0.6%) had HAD. impairment (ANI, MND, HAD and other). In this setting, a Examining the 127 patients with non-HIV-associated multivariable logistic regression model was applied to NCI, the majority had a psychiatric disorder (mostly identify factors associated with NCI occurrence. For the depression) (79 of 127 patients; 62.2%), a history of sub- continuous analysis, NCI was considered as a continuous stance use (26 patients; 20.5%), a history of trauma, variable based on NP test mean z-scores calculated per stroke or unspecified pathology (32 patients; 25.2%) or domain. The mean of the mean z-scores was calculated previous opportunistic infections (nine patients; 7.1%). for each patient for five of the seven domains; the two Taking the 981 patients together, the seven cognitive domains of language and sensory-perceptual skills were domains examined were impaired as follows: motor skills not included in the overall mean z-score calculation as in 396 patients (41%), speed of information processing in these domains (1) shared NP tests used for other domains 325 patients (33.1%), attention and working memory in and (2) were impaired in relatively few patients. For the 324 patients (33%), executive function in 240 patients continuous analysis, a multivariable linear model was (24.8%), verbal episodic memory in 169 patients (17.2%), applied to identify factors associated with a decreased language in 68 patients (7%) and sensory and perceptual mean z-score (worse NP performance). skills in 56 patients (5.8%) (Fig. 3). These proportions were In our analysis, the primary objective was to examine similar in patients with HIV-associated NCI and in those the prevalence and factors associated with NCI of any with mild to moderate and severe depression (Fig. 3). aetiology, HIV-associated and other. We then conducted a sensitivity analysis, removing patients with other NCI, Individual factors associated with NCI to examine only those with specifically HIV-associated NCI (ANI, MND and HAD). The patient variables associated with NCI were roughly All analyses were conducted using R Core Team version the same whether the outcome was dichotomized (pres- 2014 (R Foundation for Statistical Computing, Vienna, ence versus absence of NCI) or considered as a continu- Austria; www.R-project.org). ous variable (z-scores). The main risk factors for NCI © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 35 Standardized neuropsychological assessment (detailed in Table 2) NCI present? No Yes Potential contributing factors? Substance use Psychiatric disorder (diagnosed or CES-D ≥ 27) Efavirenz No Yes Neurodegenerative disorder CNS opportunistic infection Ischemic stroke Trauma / unspecified NCI: other NCI: HIV-associated ≥1.0 SD below mean ≥1.0 SD below mean in≥2 NP domains in≥2 NP domains ANI ≥1.0 SD below mean No in≥2 NP domains IADL MND ≤9/11 ≥1.0 SD below mean in≥2 NP domains Yes HAD ≥2.0 SD below mean in≥2 NP domains Fig. 2 Neurocognitive assessment algorithm of the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study. Neurocog- nitive impairment was classified according to the Frascati criteria [7] as shown in the boxes with dashed outlines. CNS, central nervous system; CES-D, Center for Epidemiologic Studies Depression scale; NCI, neurocognitive impairment; NCI, HIV-associated neurocognitive disorder; ANI, asymptomatic neurocognitive impairment; MND, mild neurocognitive disorder; HAD, HIV-associated dementia; IADL, Instrumental Activities of Daily Living; SD, standard deviation; NP, neuropsychological. were older age, non-Caucasian ethnicity, shorter duration mode of HIV acquisition was a significant risk factor in of education, unemployment, presence of cognitive com- the dichotomized model, losing significance when exam- plaints, high depression score, longer ART duration and ined as a continuous outcome; syphilis was a significant heterosexual mode of HIV acquisition (Table 3). The ART protective factor in the dichotomized model, just not duration effect had a significant quadratic form in both reaching significance when examined as a continuous dichotomized and continuous models: the chance of NCI outcome. increased significantly when ART duration increased In a sensitivity analysis excluding non-HIV-associated (positive linear term), stabilizing with long ART durations NCI (‘other’) (analysis of 854 patients), we obtained sub- (negative quadratic term); mean z-scores decreased sig- stantially similar results (Table S2). The differences con- nificantly when ART duration increased (negative linear cerned the depression score, presence of cognitive term), stabilizing with long ART durations (positive quad- complaints and mode of HIV acquisition, which did not ratic term). reach significance as risk factors for NCI, while hepatitis Slight differences between the two models were as fol- B virus coinfection was a significant risk factor. lows: a significant protective effect of cannabis was Finally, the percentage of NCI in the seven participat- observed in the continuous model, losing significance ing centres was examined according to language. when examined as a dichotomized outcome; unknown Although NCI prevalence was observed to be higher in © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 36 MM#1;etral et al. Table 2 Demographic, comorbidity and HIV-related data for 981 exclude a patient population effect on NCI. Adjusting for HIV-positive patients enrolled in the Neurocognitive Assessment in further patient variables, or examining only HIV-associ- the Metabolic and Aging Cohort (NAMACO) study ated NCI, did not alter this centre effect. Parameter Discussion Age (years) [mean (SD)] 54.5 (7.5) Sex (male) [n (%)] 782 (79.7) In this study, examining a very large and highly charac- Ethnicity [n (%)] terized cohort of aging HIV-positive individuals with Caucasian 899 (91.7) Black/other 81 (8.3) well-controlled infection, we observe a baseline preva- Education (years) [mean (SD)] 13 (2.8) lence of HIV-associated NCI (HANDs) of 26.8%. For non- Employment [n (%)] HIV-associated NCI, the majority of confounding factors Unemployed (working < 25% of potential work time) 373 (38.0) Employed part-time (25–75%) 81 (8.3) were psychiatric disorders, mainly depression. Older age, Employed full-time (80–100%) 527 (53.7) non-Caucasian ethnicity, shorter duration of education, Cognitive complaints [n (%)] 244 (25.1) being unemployed and longer ART duration were the CES-D [median (IQR)] 10 (4–17) Drug use [n (%)] main factors associated with both HIV- and non-HIV-as- History of injecting drug use 137 (14.0) sociated NCI. These associations were observed using two Current cannabis use 103 (10.5) different statistical models, considering NCI as a dichoto- Current noninjecting cocaine use 16 (1.6) At-risk alcohol consumption 161 (16.5) mized and as a continuous variable. Cardiovascular risk factors The majority of our patients with NCI had ANI, the Cigarette smoking [n (%)] 356 (36.4) clinical relevance of which has been a matter of debate. Diabetes [n (%)] 59 (6.0) Hypertension [n (%)] 398 (40.6) Some researchers argue that NCI prevalence is increasing Cholesterol [mean (SD)] 5.1 (1.1) merely through the overestimation of impairment among HDL cholesterol [mean (SD)] 1.4 (0.45) asymptomatic individuals who, without formal NP test- Coinfections [n (%)] Hepatitis B virus 460 (46.9) ing, would pass as cognitively normal [22,23]. This is Hepatitis C virus 171 (17.4) reflected in the EACS guidelines which recommended Syphilis 249 (25.4) screening PLWH regardless of symptoms until 2014 [14] HIV parameters HIV viral load < 50 copies/mL [n (%)] 942 (96.2) and then, from 2015, recommended assessing only symp- CD4 count (cells/lL) [median (IQR)] 634 (468–814) tomatic patients [24]. The Mind Exchange Program rec- Nadir CD4 count (cells/lL) [median (IQR)] 180 (74–270) ommends screening for cognitive impairment within 6 ART duration (years) [median (IQR)] 12.7 (6.5–18) Current CPE score ≥ 7[n (%)] 756 (78.9) months of diagnosis but with a different tool from the ART drug class [n (%)] three questions recommended by EACS [25]. Other Nucleoside reverse transcriptase inhibitor 940 (98.1) national guidelines vary in recommendations for screen- Protease inhibitor 419 (43.7) Integrase strand transfer inhibitor 259 (27.0) ing and the screening tool used, but all recommend a Efavirenz 203 (21.2) comprehensive assessment with exclusion of confounding Likely mode of HIV acquisition [n (%)] factors before a diagnosis of HIV-associated NCI is made Men who have sex with men 506 (51.6) Heterosexual 325 (33.1) [26]. Injecting drug use 118 (12.0) The clinical relevance of ANI is suggested by virtue of Other/unknown 32 (3.3) NCI being a dynamic state, with patients changing NCI IQR, interquartile range; CES-D, Center for Epidemiologic Studies stage with time. Among 347 patients (121 with ANI and Depression scale; HDL, high-density lipoprotein; ART, antiretroviral ther- 226 neurocognitively normal) enrolled in the CNS HIV apy; CPE, central nervous system penetration effectiveness; SD, standard deviation. Antiretroviral Therapy Effects Research (CHARTER) study, *59 patients (6%) black; 22 (2.2%) other (non-black, non-Caucasian). having ANI was found to convey a two- to six-fold Answering, ‘Yes, definitely’ to at least one of the three questions. ≥ 3 alcoholic drinks per day or ≥ 6 alcoholic drinks in one sitting at increase in the risk of developing symptomatic NCI [27]. least once a week. Again in the CHARTER study, of 436 patients followed up over a mean of 35 months, 60.8% were found to French-speaking compared to German-speaking regions, remain neurocognitively stable while the others either this was related to one French-speaking centre having a declined or improved [28]. Similarly, among 197 patients higher NCI prevalence than all the other centres and to enrolled in the Multicenter AIDS Cohort Study (MACS), one German-speaking centre having a particularly low 77% remained neurocognitively stable, 13% deteriorated NCI prevalence. All NCI rates examined were adjusted for and 10% improved over a 4-year period [5]. We would age, sex, origin, duration of education, mode of HIV argue that, if NCI stage can change over 2 to 4 years, it transmission and presence of cognitive complaints to is worth conducting a cohort study where the baseline © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 37 Motor skills Speed of Attention and Executive Verbal Language Sensory and information working function episodic perceptual processing memory memory skills All HIV-associated NCI CES-D>27 CES-D>16 Fig. 3 Percentage of patients with deficits in each of the seven cognitive domains examined by neuropsychological testing. The category ‘All’ refers to all 981 patient participants; the category ‘HIV-associated NCI’ comprised 263 patients diagnosed with an HIV-associated neurocogni- tive impairment (NCI); the category ‘CES-D > 27’ comprised 90 patients with a Center for Epidemiologic Studies Depression (CES-D) score > 27 and the category ‘CES-D > 16’ comprised 262 patients with a CES-D score > 16. assessment is sensitive enough to identify patients with syphilis is contrary to the findings of previous studies mild or very mild impairment. We would further argue and is difficult to explain when CNS inflammation has that, as older individuals are more likely to have NCI been described in the context of neurosyphilis [35,36]. In than younger individuals, even with controlled viraemia our multivariable models, dichotomized and continuous, [3,29], and as the population of older PLWH is increasing, each element was examined as an independent variable. studies of NCI should include the widest possible spec- It is possible that the protective effect of syphilis is linked trum of impairment to gain understanding of how NCI is to a variable that we did not enter into our model; likely to evolve. That said, although NP testing remains whether the effect is real will become clearer as the 2- the gold standard of NCI diagnosis, it is time-consuming year and 4-year NAMACO study data are analysed. and costly in resource-limited environments [30]. We Depression was a common confounder in our patients therefore agree with current clinical guidelines on NCI with NCI. This is not surprising as the depression prevalence assessment until research on asymptomatic NCI justifies among PLWH is estimated to be two to four times that of change. the general population [37]. In depressed individuals, exec- Our results differ from those of some other studies in utive function, speed of information processing, attention terms of factors associated with NCI; perhaps this is and working memory and verbal episodic memory have related to differences in data collection methods, sample been reported to be impaired [38,39] and this may have size and the population analysed. Unlike an Italian study influenced the profile of cognitive domains impaired of 245 asymptomatic HIV-positive patients [31], we did among NAMACO study patients overall. Nevertheless, dis- not observe an association between NCI and cardiovascu- entangling cognitive disorders as attributable to HIV infec- lar risk factors. However, the Italian patient population tion or to depression is not straightforward, especially was younger (mean age 46 years) with a higher percent- when the profile of NCI observed with both conditions is similar, that is, of a subcortical nature. This underpins the age of smokers (54.3%). Nadir CD4 count has been reported as a predictor of NCI among patients in the value of incorporating the clinical judgement of neuropsy- CHARTER study, the Dutch TREVI Cohort study and the chologists in categorizing patients with NCI as having HIV- AIDS Clinical Trials Group (ACTG) Longitudinal Linked associated or other NCI, particularly those with CES-D Randomized Trials (ALLRT) study [11,32,33]. The fact that scores of 16–26, that is, below the diagnostic cut-off of 27. we did not observe this association is possibly related to The association between depression and neurocognitive the relatively high nadir CD4 count in our population performance is the subject of a separate study within the (median 180 cells/lL); among the French Aquitaine NAMACO study population (G Santos, I Locatelli, I Nadin, R Cohort of 400 patients, nadir CD4 count (median 260 Du Pasquier, KEA Darling, M Cavassini, unpublished data). cells/lL) was also not associated with NCI [34]. Finally, This study has limitations. There is a possible recruit- the negative association we observed between NCI and ment bias among NAMACO study participants compared © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association Percentage of participants 38 MM#1;etral et al. Table 3 Demographic and clinical associations with neurocognitive impairment in multivariate models applied to 981 HIV-positive patients. Impairment is presented as a dichotomous variable (multivariate logistic model, left-hand columns) and as a continuous variable (multivariate linear model, right-hand columns) Dichotomized analysis Continuous analysis Odds ratio* P-value 95% CI Effect P-value 95% CI Age (years) 1 1.03 0.020 0.00 0.06 #3;0.01 0.001 #3;0.01 0.00 Sex (male) 1.24 0.393 #3;0.28 0.72 #3;0.09 0.060 #3;0.19 0.00 Ethnicity (ref: Caucasian) 8 8.80 <0.0001 1.41 3.03 #3;0.64 <0.0001 #3;0.76 #3;0.52 Education 0 0.85 <0.0001 #3;0.23 #3;0.09 0 0.04 <0.0001 0.03 0.06 Employment Part-time (25–75%) (ref: unemployed) 0.57 0.071 #3;1.17 0.04 0 0.17 0.004 0.05 0.29 Full-time (80–100%) (ref: unemployed) 0 0.45 <0.0001 #3;1.18 #3;0.40 0 0.15 <0.0001 0.08 0.23 Cognitive complaints 1.53 0.024 0.05 0.79 #3;0.10 0.005 #3;0.17 #3;0.03 CES-D 1 1.05 <0.0001 0.03 0.06 #3;0.01 <0.0001 #3;0.01 #3;0.01 Drug use History of injecting drug use 1.42 0.468 #3;0.60 1.30 #3;0.02 0.809 #3;0.19 0.15 Current cannabis use 0.67 0.170 #3;0.99 0.17 0 0.12 0.032 0.01 0.22 Current noninjecting cocaine use 1.31 0.709 #3;1.23 1.61 #3;0.01 0.922 #3;0.25 0.23 Alcohol consumption at risk 1.05 0.821 #3;0.39 0.48 0.00 0.993 #3;0.08 0.08 Cardiovascular risk factors Cigarette smoking 1.00 0.999 #3;0.36 0.36 #3;0.04 0.292 #3;0.10 0.03 Diabetes 1.73 0.105 #3;0.11 1.22 #3;0.12 0.064 #3;0.25 0.01 Hypertension 0.82 0.240 #3;0.53 0.13 0.01 0.736 #3;0.05 0.07 Cholesterol 0.98 0.843 #3;0.17 0.14 0.01 0.563 #3;0.02 0.04 HDL cholesterol 1.07 0.745 #3;0.33 0.46 0.03 0.358 #3;0.04 0.11 Coinfections Hepatitis B virus 1.08 0.812 #3;0.53 0.67 #3;0.06 0.327 #3;0.17 0.06 Hepatitis C virus 1.39 0.065 #3;0.02 0.69 #3;0.04 0.189 #3;0.11 0.02 Syphilis 0 0.57 0.007 #3;0.98 #3;0.16 0.07 0.051 0.00 0.15 HIV parameters HIV viral load < 50 copies/mL 0.63 0.285 #3;1.30 0.39 #3;0.02 0.862 #3;0.19 0.16 CD4 count at enrolment 0.97 0.312 #3;0.10 0.03 0.00 0.734 #3;0.01 0.01 Nadir CD4 count 1.01 0.896 #3;0.13 0.14 #3;0.02 0.190 #3;0.04 0.01 ART duration 1 1.13 0.021 0.02 0.23 #3;0.03 0.002 #3;0.05 #3;0.01 ART duration 0.99 0.005 #3;0.01 0.00 0 0.00 0.001 0.00 0.00 Current CPE score ≥ 7 1.20 0.409 #3;0.24 0.61 #3;0.06 0.157 #3;0.14 0.02 ART drug class Nucleoside reverse transcriptase inhibitor 0.99 0.982 #3;1.17 1.23 0.06 0.604 #3;0.17 0.29 Protease inhibitor 1.34 0.126 #3;0.08 0.67 #3;0.04 0.314 #3;0.11 0.03 Integrase strand transfer inhibitor 0.87 0.505 #3;0.53 0.26 #3;0.01 0.827 #3;0.08 0.07 Efavirenz 0.90 0.651 #3;0.55 0.34 #3;0.02 0.671 #3;0.10 0.07 Likely mode of HIV acquisition Heterosexual (ref: MSM) 1 1.97 0.002 0.24 1.12 #3;0.12 0.008 #3;0.20 #3;0.03 Injecting drug use (ref: MSM) 0.62 0.364 #3;1.50 0.54 0.03 0.790 #3;0.16 0.22 Other/unknown (ref: MSM) 3 3.07 0.013 0.24 2.02 #3;0.13 0.149 #3;0.30 0.05 CI, confidence interval; SD, standard deviation; IQR, interquartile range; CES-D, Center for Epidemiologic Studies Depression scale; HDL, high-density lipoprotein; ART, antiretroviral therapy; CPE, central nervous system penetration effectiveness; MSM, men who have sex with men. P-values < 0.05 are shown in bold text. *Odds ratios with P-values from a multivariate logistic model based on a binary outcome of neurocognitive impairment: no impairment (0) versus impairment (> 0). Difference in mean z-score. Answering, ‘Yes, definitely’ to at least one of the three questions. ≥ 3 alcoholic drinks per day or ≥ 6 alcoholic drinks in one sitting at least once a week. to other SHCS patients aged ≥ 45 years. Men who have verbal knowledge. Patient recruitment depended on sex with men (MSM) and Caucasians, in particular, are SHCS-affiliated infectious disease physicians who had a slightly over-represented in the NAMACO study, and this list of eligible patients. Although the study protocol had is probably related to the requirement for NAMACO study clear inclusion criteria, we cannot exclude recruitment participants to speak the local language to enable perfor- bias related to physicians (degree of involvement with mance of the neurocognitive tests that require sufficient study, personal judgement as to which patients would be © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 39 suitable participants or who ‘should’ be assessed) or to Fruh, € Stefanie Clarke and Stefania Rossi, for their work in patients (more/less willing to participate if cognitively NAMACO. Finally, we thank Dr Kevin Robertson for his symptomatic). We presented NCI diagnosis according to advice regarding the selection of cognitive tests and his the Frascati criteria to enable comparison between our encouragement to launch the study. The NAMACO study patient population and other cohorts. However, we group: director: Matthias Cavassini; co-director: Renaud acknowledge that applying other diagnostic criteria might Du Pasquier; neuropsychologists: M#1;elanie M#1;etral, Samanta have classified our patients differently. The low number Simioni, Peter Brugger, Klemens Gutbrod, Andreas U. of patients with MNDs in particular is surprising and may Monsch, Ursi Kunze, Marianne Schneitter, Isaure Nadin, be related to the relatively low sensitivity of functional Severin Fruh, € Marc Schwind, Riccardo Pignatti and Ste- impairment scales which differentiate between MNDs and fanie Clarke; neurologists: Fr#1;ed#1;eric Assal, Tobias Derfuss, ANI. In our future analysis within the NAMACO study, Sebastian von Arx, Gunter € Eisele, Leonardo Sacco, Manuel notably the 2-year follow-up, we will focus on patient z- Bertschi, Thomas Hundsberger and Renaud Du Pasquier; scores rather than on Frascati-based NCI labels. In order infectious disease specialists: Alexandra Calmy, Thanh to dovetail the NAMACO study with a database that Doco Lecompte, Christoph Hauser, Alexia Cusini, Rainer extensively characterizes each patient in terms of ART Weber, Helen Kovari, Barbara Hasse, Philip Tarr, Marcel history and other HIV- and non-HIV-related variables, Stoeckle, Christoph Fux, Enos Bernasconi, Caroline Di Ben- patients needed to be enrolled in the SHCS and followed edetto, Alessandra Bruno, Patrick Schmid, Katharine Dar- up regularly in larger hospital centres. Against these limi- ling and Matthias Cavassini; SHCS data centre: Alexandra tations, the NAMACO study did not focus on enrolling Scherrer; data management unit: Alexandra Scherrer, Yan- only patients with cognitive complaints and has a large nick Vallet and Deolinda Alves; statistician: Isabella Loca- patient cohort designed specifically to study NCI. More- telli; pharmacologist: Laurent Decosterd; neuro-imaging over, this study reflects the cognitive status of PLWH specialists: Cristina Granziera, Gunnar Krueger, Reto Meuli aged ≥ 45 years in the whole of Switzerland, which and Maria Vargas. means that the cognitive battery had to be administered Conflicts of interest: KEAD’s institution has received in three languages: German, French and Italian. Such an research funding unrelated to this publication from achievement required NP test validation in three lan- Gilead and sponsorship for specialist meetings from MSD. guages. To the best of our knowledge, this is the first A. Cusini has received travel grants and meeting expenses neuropsychological study (in any field, not only HIV) to from MSD, BMS, Gilead and Astellas paid to her institu- assess patients in parallel in the three linguistic regions tion. PET’s institution has received research grants and of Switzerland. In addition to the large cohort, the link to advisory fees from ViiV and Gilead. A. Calmy’s institu- the SHCS makes the NAMACO study database a high- tion has received unrestricted education grants from Abb- quality resource with which to examine factors important Vie, Gilead, MSD and ViiV. CDB has received sponsorship in determining NCI prevalence, incidence and course. for specialist meetings from Janssen-Cilag and AbbVie. In conclusion, we observed that over a quarter of RDP is a board member at Gilead. MC’s institution has aging patients (≥ 45 years old) enrolled in the NAMACO received a research grant from ViiV and Gilead and study had HIV-associated NCI, a proportion that may offered expert testimony for AbbVie, MSD, Gilead and increase as our patient cohort ages, despite optimal viral Sandoz. The other authors report no conflicts of interest. suppression. Among patients with non-HIV-associated Financial disclosure: The NAMACO study is supported NCI, psychiatric disorders, particularly depression, were by the Swiss National Science Foundation (grant number prevalent. The longitudinal analysis of NAMACO study 163348) and the Swiss HIV Cohort Study (grant number participants at 2 and 4 years from baseline will shed 148522, project 811). Additional funding has been pro- light on how NCI develops and may be modified in our vided by the Swiss HIV Cohort Foundation and ViiV cohort. Healthcare. Acknowledgements Disclaimer We thank all the patients participating in the NAMACO The opinions expressed in this article are those of the study. We thank all the infectious disease physicians and authors and do not necessarily represent those of ViiV. the study nurses working in the centres for their dedicated ViiV had no role in the study design, data collection and patient work and contribution to the NAMACO study. We analysis, decision to publish, or preparation of the manu- thank the neuropsychologists Samanta Simioni, Severin script. © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 40 MM#1;etral et al. 13 Simioni S, Cavassini M, Annoni JM et al. Cognitive Author contributions dysfunction in HIV patients despite long-standing MC, RDP, PT and A. Calmy designed the study. MM, IL, suppression of viremia. AIDS 2010; 24: 1243–1250. IN and GS finalized the neuropsychologist database. IL 14 European Aids Clinical Society Guidelines Version 7.1. performed the statistical analysis. MC and RDP supervised Available at http://www.eacsociety.org/files/guidelines_e nglish_71_141204.pdf. 2014 (accessed 1 July 2019). the study. MM and KEAD wrote the manuscript. All 15 Heilbronner RL, Sweet JJ, Attix DK, Krull KR, Henry GK, investigators contributed to data collection and interpre- Hart RP. Official position of the American Academy of tation, reviewed drafts of posters and the manuscript, and Clinical Neuropsychology on serial neuropsychological approved the final manuscript. assessments: the utility and challenges of repeat test administrations in clinical and forensic contexts. Clin References Neuropsychol 2010; 24: 1267–1278. 16 Grund B, Wright EJ, Brew BJ et al. Improved neurocognitive 1 McArthur JC, Brew BJ, Nath A. Neurological complications test performance in both arms of the SMART study: impact of HIV infection. Lancet Neurol 2005; 4: 543–555. of practice effect. J Neurovirol 2013; 19: 383–392. 2 Bhaskaran K, Mussini C, Antinori A et al. Changes in the 17 Lawton MP, Brody EM. Assessment of older people: self- incidence and predictors of human immunodeficiency virus- maintaining and instrumental activities of daily living. associated dementia in the era of highly active antiretroviral Gerontologist 1969; 9: 179–186. therapy. 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Daily Living (IADL) scale F1000Research 2017; 6: 312. 31 Fabbiani M, Ciccarelli N, Tana M et al. Cardiovascular risk factors and carotid intima-media thickness are associated PATIENT ID:__________ DATE OF VISIT: ___________ VISIT N: ____ with lower cognitive performance in HIV-infected patients. HIV Med 2013; 14: 136–144. 32 Ellis RJ, Badiee J, Vaida F et al. CD4 nadir is a predictor of A. Ability to use telephone HIV neurocognitive impairment in the era of combination 1. Operates telephone on own initiative; looks up and dials numbers 1 antiretroviral therapy. AIDS 2011; 25: 1747–1751. 2. Dials a few well-known numbers 1 3. Answers telephone but does not dial 1 33 van den Dries LWJ, Wagener MN, Jiskoot LC et al. 4. Does not use telephone at all 0 Neurocognitive impairment in a chronically well-suppressed B. Shopping HIV-infected population: the Dutch TREVI Cohort study. 1. Takes care of all shopping needs independently 1 2. 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Performs light daily tasks but cannot maintain acceptable level of 1 central nervous system inflammation but does not explain cleanliness cognitive impairment in HIV-infected individuals with 4. Needs help with all home maintenance tasks 1 syphilis. Clin Infect Dis 2017; 65: 943–948. 5. Does not participate in any housekeeping tasks 0 E. Laundry 37 Nanni MG, Caruso R, Mitchell AJ, Meggiolaro E, Grassi L. 1. Does personal laundry completely 1 Depression in HIV infected patients: a review. Curr 2. Launders small items, rinses socks, stockings, etc. 1 Psychiatry Rep 2015; 17: 530. 3. All laundry must be done by others 0 F. Models of transportation 38 McDermott LM, Ebmeier KP. A meta-analysis of depression 1. Travels independently on public transportation or drives own car 1 severity and cognitive function. J Affect Disord 2009; 119: 2. Arranges own travel via taxi, but does not otherwise use public 1 1–8. transportation 3. Travels on public transportation when assisted or accompanied by 1 39 Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive another impairment in depression: a systematic review and meta- 4. Travel limited to taxi or automobile with assistance of another 0 analysis. Psychol Med 2014; 44: 2029–2040. 5. Does not travel at all 0 G. Responsibility for own medications 1. Is responsible for taking medication in correct dosages at correct time 1 2. Takes responsibility if medication is prepared in advance in separate 0 Supporting Information dosages 3. Is not capable of dispensing own medication 0 Additional supporting information may be found online H. Ability to handle finances in the Supporting Information section at the end of the 1. Manages financial matters independently (budgets, writes checks, pays 1 article. rent and bills, goes to bank); collects and keeps track of income © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 42 MM#1;etral et al. Scoring (TOTAL): if the patient receives a score of 0 for at least two of 2. Manages day-to-day purchases, but needs help with banking, major 1 the items above (A–L), then s/he is considered to be functionally purchases, etc. impaired. 3. Incapable of handling money 0 https://www.sm.ee/sites/default/files/content-editors/eesmargid_ja_tege vused/Tervis/Ravimid/eacsguidelines_v6.1_nov2012.pdf. Source: see Lawton and Brody [17]. Source: see Lawton and Brody [7]. Supplementary questions on job Supplementary question concerning social performance entourage I. Job performance M. Entourage 1. Unable to perform some aspects of previous job (not due to medical 0 1. Comments made by entourage (close family, friends, colleagues, etc.) 0 symptoms) regarding decline in cognitive function L. Job performance 1. Reduced efficiency or productivity; or more errors or difficulties 0 meeting expectations; or greater effort to perform the same activities © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png HIV Medicine Pubmed Central

The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline participant profile

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© 2019 The Authors. DOI: 10.1111/hiv.12795 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association HIV Medicine (2020), 21, 30--42 ORIGINAL RESEARCH The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study: baseline participant profile 1,† 2,† 3 1,4 2 5 6 7 8 MM#1;etral, KEA Darling I Locatelli, I Nadin, G Santos, P Brugger, H Kovari, A Cusini, K Gutbrod, 9 10 10 4 11 11 12 13 14 PE Tarr, A Calmy, TD Lecompte, F Assal, A Monsch, U Kunze, M Stoeckle, M Schwind, P Schmid, 15 16 1,‡ 2,‡ § R Pignatti, C Di Benedetto, R Du Pasquier, and M Cavassini for the NAMACO study group Swiss HIV Cohort Study Service of Neurology, Department of Clinical Neurosciences, Lausanne University Hospital, Lausanne, Switzerland, 2 3 Service of Infectious Diseases, Lausanne University Hospital, Lausanne, Switzerland, Department of Ambulatory Care and Community Medicine, University of Lausanne, Lausanne, Switzerland, Service of Neurology, University Hospital of Geneva, Geneva, Switzerland, Neuropsychology Unit, Department of Neurology, University Hospital Zurich, Zurich, Switzerland, Department of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, Zurich, Switzerland, Department of Infectious Diseases and Hospital Epidemiology, Bern University Hospital and University of Bern, Bern, 8 9 Switzerland, Department of Neurology, Bern University Hospital and University of Bern, Bern, Switzerland, University Department of Medicine, Kantonsspital Bruderholz, University of Basel, Bruderholz, Switzerland, HIV Unit, Infectious Diseases Division, Medicine Department, University Hospital of Geneva, Geneva, Switzerland, Memory Clinic, Felix Platter Hospital, University Center for Medicine of Aging, Basel, Switzerland, Infectious Diseases Unit, Basel, Switzerland, 13 14 Neurology Clinic, St Gallen, Switzerland, Infectious Diseases and Hospital Epidemiology Division, Kantonsspital St Gallen, St Gallen, Switzerland, Department of Neurology, Neurocentre of Southern Switzerland, Lugano Regional Hospital, Lugano, Switzerland and Infectious Diseases Unit, Lugano Regional Hospital, Lugano, Switzerland Objectives The aim of the study was to examine baseline neurocognitive impairment (NCI) prevalence and factors associated with NCI among patients enrolled in the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study. Methods The NAMACO study is an ongoing, prospective, longitudinal, multicentre and multilingual (German, French and Italian) study within the Swiss HIV Cohort Study. Between 1 May 2013 and 30 November 2016, 981 patients ≥ 45 years old were enrolled in the study. All underwent standardized neuropsychological (NP) assessment by neuropsychologists. NCI was diagnosed using Frascati criteria and classified as HIV-associated or as related to other factors. Dichotomized analysis (NCI versus no NCI) and continuous analyses (based on NP test z-score means) were performed. Results Most patients (942; 96.2%) had viral loads < 50 HIV-1 RNA copies/mL. NCI was identified in 390 patients (39.8%): 263 patients (26.8%) had HIV-associated NCI [249 patients (25.4%) had asymptomatic neurocognitive impairment (ANI)] and 127 patients (13%) had NCI attributable to other factors, mainly psychiatric disorders. There was good correlation between dichotomized and continuous analyses, with NCI associated with older age, non-Caucasian ethnicity, shorter duration of education, unemployment and longer antiretroviral therapy duration. Correspondence: Dr Katharine Darling, Service of Infectious Diseases, Lausanne University Hospital, Rue du Bugnon 46, 1011 Lausanne, Switzerland. Tel: +41 21 314 1022; fax: +41 21 314 1008; e-mail: katharine.darling@chuv.ch Equal first author contributions. Equal last author contributions. Members of the NAMACO study group are listed under Acknowledgements. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. 30 The NAMACO study baseline profile 31 Conclusions In this large sample of aging people living with HIV with well-controlled infection in Switzerland, baseline HIV-associated NCI prevalence, as diagnosed after formal NP assessment, was 26.8%, with most cases being ANI. The NAMACO study data will enable longitudinal analyses within this population to examine factors affecting NCI development and course. Keywords: aging, HIV-associated neurocognitive disorder, neurocognitive impairment, neuropsychological testing Accepted 11 July 2019 originally to answer different clinical questions [8,11]. Introduction Thirdly, the level of HIV control is not uniform: some The availability of safe and effective antiretroviral ther- cohorts group patients together, regardless of HIV viral apy (ART) for HIV infection has enabled people living load or whether or not they are on ART, while others with HIV (PLWH) to age. As the population of older exclude patients with detectable viraemia. PLWH increases, so does the prevalence of comorbidities. In Switzerland, the Neurocognitive Assessment in the One such comorbidity, neurocognitive impairment (NCI), Metabolic and Aging Cohort (NAMACO) study was set up has been described since the start of the HIV epidemic, as a longitudinal study to examine NCI within a well- but the spectrum post-ART has changed. HIV-associated characterized and well-treated cohort of PLWH, the Swiss dementia (HAD), previously seen in advanced HIV dis- HIV Cohort Study (SHCS) cohort [12]. In the current ease, is now uncommon [1,2], while the prevalence of study, we present the characteristics of NAMACO study milder NCI, which may be asymptomatic, has increased patients and the baseline prevalence of NCI. [3]. Moreover, the presentation of NCI has changed. In the pre-ART era, HAD was subcortical, rapidly progres- sive, and characterized by psychomotor slowing, motor Methods dysfunction and extrapyramidal signs. In the current ART The NAMACO study era, NCI is both cortical and subcortical, relatively stable over time, and characterized by impairments in working The NAMACO study is an ongoing, prospective, longitudi- memory and executive function [4–6]. nal, multicentre and multilingual (German, French and To reflect this shift, the diagnostic nomenclature of Italian) study included within an observational open HIV-associated NCI was revised in 2007 to define stages research cohort study, the SHCS. Since 1988, the SHCS of impairment according to the so-called Frascati criteria has collected data at twice-yearly standardized SHCS clinic [7]. In increasing severity, the stages are: asymptomatic visits on the demography, behaviour, medical history (HIV neurocognitive impairment (ANI), corresponding to mild and non-HIV), HIV infection parameters, treatments and to moderate neurocognitive deficits without repercussions comorbidities of all enrolled patients aged ≥ 18 years [12]. in activities of daily living (ADL); mild neurocognitive The NAMACO study was set up to examine the cogni- disorders (MNDs), corresponding to mild to moderate tive and neurological impact of HIV infection in an aging neurocognitive deficits with repercussions in ADL; and HIV-positive population and has been established in col- HIV-associated dementia (HAD), corresponding to moder- laboration with physicians, neuropsychologists, neurolo- ate to severe neurocognitive deficits with repercussions in gists and study nurses. ADL [7]. Diagnosing NCI as specifically HIV-associated requires the exclusion of confounding factors, such as Standard protocol approvals, registrations and patient psychiatric disorders and organic cerebral pathology [7]. consents Despite these definitions, the NCI literature can be con- The ethics committees of each cantonal hospital centre fusing. Firstly, ANI, MNDs and HAD may be referred to approved the NAMACO study protocol and all patient par- collectively as HIV-associated neurocognitive disorders ticipants signed informed consent prior to being included. (HANDs) if ADL have been assessed [4], or as mild or moderate NCI if the assessment is based on NP testing alone [8]. Secondly, some patient populations make up Patient population and study design cohorts designed from the start to study NCI [3,9], or else The NAMACO study had the following inclusion criteria: subcohorts of long-standing cohorts [10], whereas other HIV-positive status, age ≥ 45 years, enrolment in the populations are pooled from larger studies designed © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 32 MM#1;etral et al. SHCS, engagement in care at one of seven cantonal uni- each NP test was converted to a demographically versity-affiliated hospital centres (Basel, Bern, Geneva, adjusted standard score (z-score). Lausanne, Lugano, St Gallen and Zurich) and sufficient The cognitive domains assessed were based on those oral fluency in the local language to enable neuropsycho- used in the International Network for Strategic Initiatives logical (NP) tests to be performed. SHCS-affiliated infec- in Global HIV Trials (INSIGHT) and Strategic Timing of tious disease physicians received a list of eligible patients Antiretroviral Treatment (START) Study Group [8] and attending their clinics and were responsible for inviting were in accordance with the guidelines published by patients to participate in the NAMACO study between 1 Antinori et al. [7]. The tests are sensitive in detecting May 2013 and 30 November 2016. Enrolment was dis- NCI, rapid and easy to perform, standardized for several continued at 981 patients. Nonenrolment of eligible age and education groups, and available in different lan- patients was related to manpower at each site; as age and guages. The Hopkins Verbal Learning Test-Revised is par- language were the only limiting criteria beyond the need ticularly appropriate for longitudinal studies as it to be seen at a university-affiliated SHCS centre, patients provides six parallel forms to avoid the practice effect at were not, in principle, disproportionately selected on the retest which has been described as a reason for improve- basis of neurocognitive symptoms or previous neurologi- ment in NP function over time [15,16]. In addition to the cal history. tests used in the START study, we chose to include the While all SHCS patients are asked European AIDS Clin- five-point Figural Fluency and the Victoria Stroop test, to ical Society (EACS) screening questions on memory, rea- enrich the assessment of executive function, and the soning and attention difficulties [13] at their twice-yearly Wechsler adult intelligence scale 4th edition (WAIS-IV) cohort visits, NAMACO study patients also undergo a Digit Span Subtest to assess attention and working mem- standardized NP assessment at baseline and again at 2 ory (Table 1). (2016–2018) and 4 years (2018–2020). For all NAMACO study patients, regardless of their EACS screening ques- Self-administered assessments tion responses, NP assessment is performed by either a As functional scales are required to differentiate neuropsychologist or a neurologist trained in behavioural between ANI and MNDs, Lawton’s Instrumental Activi- neurology and working under the supervision of a neu- ties of Daily Living (IADL) were assessed [17,18] to ropsychologist. quantify the impact of NCI, if present, on daily func- As part of the study, patients with NCI are invited to tion. Three supplementary questions were added, undergo further investigations according to EACS guide- inspired by the Patients’ Assessment of Own Function- lines [14], namely, full neurological examination, cere- ing Inventory questionnaire (a subjective measure of brospinal fluid (CSF) collection via lumbar puncture and cognitive function), on professional work quality and cerebral magnetic resonance imaging (Fig. 1), to examine productivity and on relatives’ comments about cogni- the benefit of these interventions as diagnostic tools and tive decline (Appendix 1). Functional impairment was factors associated with NCI. defined as difficulties being reported in at least two The current study was a cross-sectional analysis inves- items out of 11 (Fig. 2). tigating the neurocognitive status of patients at the time Depression severity was graded using the Center for Epi- of enrolment (baseline). demiologic Studies Depression (CES-D) scale by way of a questionnaire rating mood. Although the CES-D scale has commonly been used to assess depression among PLWH, it Neurocognitive evaluation does have limitations in this setting as some items in the ques- Cognitive complaints tionnaire may be related to having HIV infection rather than For each of the three EACS screening questions men- depression (items on positive affect and somatic symptoms tioned above, the response options are never, hardly ever, such as restless sleep and poor appetite) [19,20]. In the current or yes, definitely. Patients answering ‘yes, definitely’ to at study, CES-D scores between 16 and 26 were classed as mild least one question were considered to have cognitive depression and scores ≥ 27 were classed as severe depression complaints. in order to apply a more stringent depression definition. NP assessment NCI definitions and associations The NP test battery covered seven cognitive domains Using the Frascati criteria [7], patients were classified into known to be affected in HIV-associated NCI (Table 1). five categories as follows (Fig. 2): normal NP examination The complete battery required no more than 90 min to (no NCI), ANI, MND, HAD and non-HIV-associated NCI perform if the patient had no deficits. The raw score for (‘other’). In patients in the ‘other’ category, NCI was © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 33 981 patients ≥45 years old in the Metabolic and Aging Cohort of the SHCS All patients assessed at baseline, then at 2 years and at 4 years Presence of cognitive complaints screened for by physician using EACS screening questions (memory loss, mental slowing and attention difficulties) - Standardized neuropsychological evaluation (7 cognitive domains, shown in Table 1) - Functional scale (IADL and PAOFI, as described in the text) - Depression questionnaire (CES-D) No neurocognitive impairment Neurocognitive impairment - Full neurological examination -Brain MRI - Lumbar puncture Fig. 1 Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study design. SHCS, Swiss HIV Cohort Study; EACS, European AIDS Clinical Society; IADL, Instrumental Activities of Daily Living; PAOFI, Patients’ Assessment of Own Functioning Inventory; CES-D, Center for Epidemiologic Studies Depression scale; MRI, magnetic resonance imaging. attributed to confounding conditions such as substance use, cognitive complaints and toxin consumption (smoking, psychiatric disorders (including severe depression: CES-D alcohol use, past injecting drug use, current cannabis use scores ≥ 27), ART toxicity, neurodegenerative disorders, and current noninjecting cocaine use). Efavirenz use was opportunistic central nervous system (CNS) infection, stroke analysed individually given the higher rates of neuropsy- history and trauma, rather than to HIV infection (Fig. 2). chiatric adverse events associated with this treatment Patients with CES-D scores of 16–26 (moderate to severe than with other antiretroviral treatments [21]; treatment low mood) were assigned to the ‘other’ category if the with dolutegravir was not assessed at baseline as this examining neuropsychologist considered the NP profile to treatment became available in Switzerland 1 year into the be related to depression rather than to HIV infection alone. NAMACO study. All these variables were obtained from To identify potential factors associated with NCI, we the SHCS database extraction closest in time to each examined: demographic factors (age, sex, ethnicity, edu- patient’s neurocognitive assessment. For the current cation and employment), HIV-related factors (viral load, study, comorbidities and toxin consumption were anal- CD4 T-cell count at baseline and nadir CD4 count, dura- ysed as binary (presence or absence) rather than continu- tion of current ART, CPE score at baseline, ART drug ous data. class, namely, nucleoside reverse transcriptase inhibitor, protease inhibitor, integrase strand transfer inhibitor or Statistical analysis efavirenz, and mode of HIV acquisition), cardiovascular risk factors [diabetes, hypertension, and total and high- Descriptive analyses are presented as mean and standard density lipoprotein (HDL) cholesterol], other comorbidities deviation (SD) for symmetric continuous variables, as (hepatitis B and C, and syphilis), depression score, median and interquartile range (IQR) for asymmetric © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 34 MM#1;etral et al. Table 1 The seven cognitive domains examined and the neuropsy- Data availability statement chological tests performed in the standardized neuropsychological assessment of all patients enrolled in the Neurocognitive Assess- Anonymized data will be shared by request from any ment in the Metabolic and Aging Cohort (NAMACO) study qualified investigator. Standardized neuropsychological assessment Cognitive domain Neuropsychological tests Results Motor skills Finger Tapping (dominant and nondominant NAMACO patients hands) Grooved Pegboard (dominant and Of the 981 patients enrolled, 782 (79.7%) were male, 899 nondominant hands) Speed of information WAIS-IV, Coding (91.7%) were Caucasian and 627 patients (63.9%) were aged processing Colour Trails 1 > 50 years [mean (#1; SD) age 54.5 #1; 7.5 years] (Table 2). Attention and working WAIS-IV Digit Span (forward and backward) At baseline, most patients (96.2%) had viral loads < 50 HIV- memory Executive function Category Fluency 1 RNA copies/mL; the median CD4 count was 634 cells/lL 5-point Figural Fluency (IQR 468, 814 cells/lL) and the median nadir CD4 count was Victoria Stroop (trial 3 and/or 3/1) 180 cells/lL (IQR 74, 270 cells/lL) (Table 2). Colour Trails 2 Verbal episodic memory Hopkins Verbal Learning Test – Revised The percentage of NAMACO patients who were male or Language Category Fluency Caucasian was slightly higher than that of SHCS patients Victoria Stroop (trial 1) eligible for NAMACO but not enrolled or followed up at Sensory and perceptual Grooved Pegboard (dominant and skills nondominant hands) non-NAMACO centres (Table S1). Victoria Stroop (trial 1) *WAIS-IV, Wechsler adult intelligence scale 4th edition. Prevalence of NCI and cognitive domains affected Of all 981 patients, 390 (39.8%) presented with NCI, of continuous variables and as percentages for categorical whom 263 patients (26.8% of 981) had HIV-associated variables. NCI and 127 patients (13.0% of 981) had non-HIV-associ- NCI was analysed as a dichotomized and as a continu- ated NCI. Examining patients with HIV-associated NCI, ous variable. For the dichotomized analysis, NCI was 249 patients (25.4% of 981) had ANI, eight patients dichotomized as follows: no impairment (no NCI) versus (0.8%) had MNDs and six patients (0.6%) had HAD. impairment (ANI, MND, HAD and other). In this setting, a Examining the 127 patients with non-HIV-associated multivariable logistic regression model was applied to NCI, the majority had a psychiatric disorder (mostly identify factors associated with NCI occurrence. For the depression) (79 of 127 patients; 62.2%), a history of sub- continuous analysis, NCI was considered as a continuous stance use (26 patients; 20.5%), a history of trauma, variable based on NP test mean z-scores calculated per stroke or unspecified pathology (32 patients; 25.2%) or domain. The mean of the mean z-scores was calculated previous opportunistic infections (nine patients; 7.1%). for each patient for five of the seven domains; the two Taking the 981 patients together, the seven cognitive domains of language and sensory-perceptual skills were domains examined were impaired as follows: motor skills not included in the overall mean z-score calculation as in 396 patients (41%), speed of information processing in these domains (1) shared NP tests used for other domains 325 patients (33.1%), attention and working memory in and (2) were impaired in relatively few patients. For the 324 patients (33%), executive function in 240 patients continuous analysis, a multivariable linear model was (24.8%), verbal episodic memory in 169 patients (17.2%), applied to identify factors associated with a decreased language in 68 patients (7%) and sensory and perceptual mean z-score (worse NP performance). skills in 56 patients (5.8%) (Fig. 3). These proportions were In our analysis, the primary objective was to examine similar in patients with HIV-associated NCI and in those the prevalence and factors associated with NCI of any with mild to moderate and severe depression (Fig. 3). aetiology, HIV-associated and other. We then conducted a sensitivity analysis, removing patients with other NCI, Individual factors associated with NCI to examine only those with specifically HIV-associated NCI (ANI, MND and HAD). The patient variables associated with NCI were roughly All analyses were conducted using R Core Team version the same whether the outcome was dichotomized (pres- 2014 (R Foundation for Statistical Computing, Vienna, ence versus absence of NCI) or considered as a continu- Austria; www.R-project.org). ous variable (z-scores). The main risk factors for NCI © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 35 Standardized neuropsychological assessment (detailed in Table 2) NCI present? No Yes Potential contributing factors? Substance use Psychiatric disorder (diagnosed or CES-D ≥ 27) Efavirenz No Yes Neurodegenerative disorder CNS opportunistic infection Ischemic stroke Trauma / unspecified NCI: other NCI: HIV-associated ≥1.0 SD below mean ≥1.0 SD below mean in≥2 NP domains in≥2 NP domains ANI ≥1.0 SD below mean No in≥2 NP domains IADL MND ≤9/11 ≥1.0 SD below mean in≥2 NP domains Yes HAD ≥2.0 SD below mean in≥2 NP domains Fig. 2 Neurocognitive assessment algorithm of the Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study. Neurocog- nitive impairment was classified according to the Frascati criteria [7] as shown in the boxes with dashed outlines. CNS, central nervous system; CES-D, Center for Epidemiologic Studies Depression scale; NCI, neurocognitive impairment; NCI, HIV-associated neurocognitive disorder; ANI, asymptomatic neurocognitive impairment; MND, mild neurocognitive disorder; HAD, HIV-associated dementia; IADL, Instrumental Activities of Daily Living; SD, standard deviation; NP, neuropsychological. were older age, non-Caucasian ethnicity, shorter duration mode of HIV acquisition was a significant risk factor in of education, unemployment, presence of cognitive com- the dichotomized model, losing significance when exam- plaints, high depression score, longer ART duration and ined as a continuous outcome; syphilis was a significant heterosexual mode of HIV acquisition (Table 3). The ART protective factor in the dichotomized model, just not duration effect had a significant quadratic form in both reaching significance when examined as a continuous dichotomized and continuous models: the chance of NCI outcome. increased significantly when ART duration increased In a sensitivity analysis excluding non-HIV-associated (positive linear term), stabilizing with long ART durations NCI (‘other’) (analysis of 854 patients), we obtained sub- (negative quadratic term); mean z-scores decreased sig- stantially similar results (Table S2). The differences con- nificantly when ART duration increased (negative linear cerned the depression score, presence of cognitive term), stabilizing with long ART durations (positive quad- complaints and mode of HIV acquisition, which did not ratic term). reach significance as risk factors for NCI, while hepatitis Slight differences between the two models were as fol- B virus coinfection was a significant risk factor. lows: a significant protective effect of cannabis was Finally, the percentage of NCI in the seven participat- observed in the continuous model, losing significance ing centres was examined according to language. when examined as a dichotomized outcome; unknown Although NCI prevalence was observed to be higher in © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 36 MM#1;etral et al. Table 2 Demographic, comorbidity and HIV-related data for 981 exclude a patient population effect on NCI. Adjusting for HIV-positive patients enrolled in the Neurocognitive Assessment in further patient variables, or examining only HIV-associ- the Metabolic and Aging Cohort (NAMACO) study ated NCI, did not alter this centre effect. Parameter Discussion Age (years) [mean (SD)] 54.5 (7.5) Sex (male) [n (%)] 782 (79.7) In this study, examining a very large and highly charac- Ethnicity [n (%)] terized cohort of aging HIV-positive individuals with Caucasian 899 (91.7) Black/other 81 (8.3) well-controlled infection, we observe a baseline preva- Education (years) [mean (SD)] 13 (2.8) lence of HIV-associated NCI (HANDs) of 26.8%. For non- Employment [n (%)] HIV-associated NCI, the majority of confounding factors Unemployed (working < 25% of potential work time) 373 (38.0) Employed part-time (25–75%) 81 (8.3) were psychiatric disorders, mainly depression. Older age, Employed full-time (80–100%) 527 (53.7) non-Caucasian ethnicity, shorter duration of education, Cognitive complaints [n (%)] 244 (25.1) being unemployed and longer ART duration were the CES-D [median (IQR)] 10 (4–17) Drug use [n (%)] main factors associated with both HIV- and non-HIV-as- History of injecting drug use 137 (14.0) sociated NCI. These associations were observed using two Current cannabis use 103 (10.5) different statistical models, considering NCI as a dichoto- Current noninjecting cocaine use 16 (1.6) At-risk alcohol consumption 161 (16.5) mized and as a continuous variable. Cardiovascular risk factors The majority of our patients with NCI had ANI, the Cigarette smoking [n (%)] 356 (36.4) clinical relevance of which has been a matter of debate. Diabetes [n (%)] 59 (6.0) Hypertension [n (%)] 398 (40.6) Some researchers argue that NCI prevalence is increasing Cholesterol [mean (SD)] 5.1 (1.1) merely through the overestimation of impairment among HDL cholesterol [mean (SD)] 1.4 (0.45) asymptomatic individuals who, without formal NP test- Coinfections [n (%)] Hepatitis B virus 460 (46.9) ing, would pass as cognitively normal [22,23]. This is Hepatitis C virus 171 (17.4) reflected in the EACS guidelines which recommended Syphilis 249 (25.4) screening PLWH regardless of symptoms until 2014 [14] HIV parameters HIV viral load < 50 copies/mL [n (%)] 942 (96.2) and then, from 2015, recommended assessing only symp- CD4 count (cells/lL) [median (IQR)] 634 (468–814) tomatic patients [24]. The Mind Exchange Program rec- Nadir CD4 count (cells/lL) [median (IQR)] 180 (74–270) ommends screening for cognitive impairment within 6 ART duration (years) [median (IQR)] 12.7 (6.5–18) Current CPE score ≥ 7[n (%)] 756 (78.9) months of diagnosis but with a different tool from the ART drug class [n (%)] three questions recommended by EACS [25]. Other Nucleoside reverse transcriptase inhibitor 940 (98.1) national guidelines vary in recommendations for screen- Protease inhibitor 419 (43.7) Integrase strand transfer inhibitor 259 (27.0) ing and the screening tool used, but all recommend a Efavirenz 203 (21.2) comprehensive assessment with exclusion of confounding Likely mode of HIV acquisition [n (%)] factors before a diagnosis of HIV-associated NCI is made Men who have sex with men 506 (51.6) Heterosexual 325 (33.1) [26]. Injecting drug use 118 (12.0) The clinical relevance of ANI is suggested by virtue of Other/unknown 32 (3.3) NCI being a dynamic state, with patients changing NCI IQR, interquartile range; CES-D, Center for Epidemiologic Studies stage with time. Among 347 patients (121 with ANI and Depression scale; HDL, high-density lipoprotein; ART, antiretroviral ther- 226 neurocognitively normal) enrolled in the CNS HIV apy; CPE, central nervous system penetration effectiveness; SD, standard deviation. Antiretroviral Therapy Effects Research (CHARTER) study, *59 patients (6%) black; 22 (2.2%) other (non-black, non-Caucasian). having ANI was found to convey a two- to six-fold Answering, ‘Yes, definitely’ to at least one of the three questions. ≥ 3 alcoholic drinks per day or ≥ 6 alcoholic drinks in one sitting at increase in the risk of developing symptomatic NCI [27]. least once a week. Again in the CHARTER study, of 436 patients followed up over a mean of 35 months, 60.8% were found to French-speaking compared to German-speaking regions, remain neurocognitively stable while the others either this was related to one French-speaking centre having a declined or improved [28]. Similarly, among 197 patients higher NCI prevalence than all the other centres and to enrolled in the Multicenter AIDS Cohort Study (MACS), one German-speaking centre having a particularly low 77% remained neurocognitively stable, 13% deteriorated NCI prevalence. All NCI rates examined were adjusted for and 10% improved over a 4-year period [5]. We would age, sex, origin, duration of education, mode of HIV argue that, if NCI stage can change over 2 to 4 years, it transmission and presence of cognitive complaints to is worth conducting a cohort study where the baseline © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 37 Motor skills Speed of Attention and Executive Verbal Language Sensory and information working function episodic perceptual processing memory memory skills All HIV-associated NCI CES-D>27 CES-D>16 Fig. 3 Percentage of patients with deficits in each of the seven cognitive domains examined by neuropsychological testing. The category ‘All’ refers to all 981 patient participants; the category ‘HIV-associated NCI’ comprised 263 patients diagnosed with an HIV-associated neurocogni- tive impairment (NCI); the category ‘CES-D > 27’ comprised 90 patients with a Center for Epidemiologic Studies Depression (CES-D) score > 27 and the category ‘CES-D > 16’ comprised 262 patients with a CES-D score > 16. assessment is sensitive enough to identify patients with syphilis is contrary to the findings of previous studies mild or very mild impairment. We would further argue and is difficult to explain when CNS inflammation has that, as older individuals are more likely to have NCI been described in the context of neurosyphilis [35,36]. In than younger individuals, even with controlled viraemia our multivariable models, dichotomized and continuous, [3,29], and as the population of older PLWH is increasing, each element was examined as an independent variable. studies of NCI should include the widest possible spec- It is possible that the protective effect of syphilis is linked trum of impairment to gain understanding of how NCI is to a variable that we did not enter into our model; likely to evolve. That said, although NP testing remains whether the effect is real will become clearer as the 2- the gold standard of NCI diagnosis, it is time-consuming year and 4-year NAMACO study data are analysed. and costly in resource-limited environments [30]. We Depression was a common confounder in our patients therefore agree with current clinical guidelines on NCI with NCI. This is not surprising as the depression prevalence assessment until research on asymptomatic NCI justifies among PLWH is estimated to be two to four times that of change. the general population [37]. In depressed individuals, exec- Our results differ from those of some other studies in utive function, speed of information processing, attention terms of factors associated with NCI; perhaps this is and working memory and verbal episodic memory have related to differences in data collection methods, sample been reported to be impaired [38,39] and this may have size and the population analysed. Unlike an Italian study influenced the profile of cognitive domains impaired of 245 asymptomatic HIV-positive patients [31], we did among NAMACO study patients overall. Nevertheless, dis- not observe an association between NCI and cardiovascu- entangling cognitive disorders as attributable to HIV infec- lar risk factors. However, the Italian patient population tion or to depression is not straightforward, especially was younger (mean age 46 years) with a higher percent- when the profile of NCI observed with both conditions is similar, that is, of a subcortical nature. This underpins the age of smokers (54.3%). Nadir CD4 count has been reported as a predictor of NCI among patients in the value of incorporating the clinical judgement of neuropsy- CHARTER study, the Dutch TREVI Cohort study and the chologists in categorizing patients with NCI as having HIV- AIDS Clinical Trials Group (ACTG) Longitudinal Linked associated or other NCI, particularly those with CES-D Randomized Trials (ALLRT) study [11,32,33]. The fact that scores of 16–26, that is, below the diagnostic cut-off of 27. we did not observe this association is possibly related to The association between depression and neurocognitive the relatively high nadir CD4 count in our population performance is the subject of a separate study within the (median 180 cells/lL); among the French Aquitaine NAMACO study population (G Santos, I Locatelli, I Nadin, R Cohort of 400 patients, nadir CD4 count (median 260 Du Pasquier, KEA Darling, M Cavassini, unpublished data). cells/lL) was also not associated with NCI [34]. Finally, This study has limitations. There is a possible recruit- the negative association we observed between NCI and ment bias among NAMACO study participants compared © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association Percentage of participants 38 MM#1;etral et al. Table 3 Demographic and clinical associations with neurocognitive impairment in multivariate models applied to 981 HIV-positive patients. Impairment is presented as a dichotomous variable (multivariate logistic model, left-hand columns) and as a continuous variable (multivariate linear model, right-hand columns) Dichotomized analysis Continuous analysis Odds ratio* P-value 95% CI Effect P-value 95% CI Age (years) 1 1.03 0.020 0.00 0.06 #3;0.01 0.001 #3;0.01 0.00 Sex (male) 1.24 0.393 #3;0.28 0.72 #3;0.09 0.060 #3;0.19 0.00 Ethnicity (ref: Caucasian) 8 8.80 <0.0001 1.41 3.03 #3;0.64 <0.0001 #3;0.76 #3;0.52 Education 0 0.85 <0.0001 #3;0.23 #3;0.09 0 0.04 <0.0001 0.03 0.06 Employment Part-time (25–75%) (ref: unemployed) 0.57 0.071 #3;1.17 0.04 0 0.17 0.004 0.05 0.29 Full-time (80–100%) (ref: unemployed) 0 0.45 <0.0001 #3;1.18 #3;0.40 0 0.15 <0.0001 0.08 0.23 Cognitive complaints 1.53 0.024 0.05 0.79 #3;0.10 0.005 #3;0.17 #3;0.03 CES-D 1 1.05 <0.0001 0.03 0.06 #3;0.01 <0.0001 #3;0.01 #3;0.01 Drug use History of injecting drug use 1.42 0.468 #3;0.60 1.30 #3;0.02 0.809 #3;0.19 0.15 Current cannabis use 0.67 0.170 #3;0.99 0.17 0 0.12 0.032 0.01 0.22 Current noninjecting cocaine use 1.31 0.709 #3;1.23 1.61 #3;0.01 0.922 #3;0.25 0.23 Alcohol consumption at risk 1.05 0.821 #3;0.39 0.48 0.00 0.993 #3;0.08 0.08 Cardiovascular risk factors Cigarette smoking 1.00 0.999 #3;0.36 0.36 #3;0.04 0.292 #3;0.10 0.03 Diabetes 1.73 0.105 #3;0.11 1.22 #3;0.12 0.064 #3;0.25 0.01 Hypertension 0.82 0.240 #3;0.53 0.13 0.01 0.736 #3;0.05 0.07 Cholesterol 0.98 0.843 #3;0.17 0.14 0.01 0.563 #3;0.02 0.04 HDL cholesterol 1.07 0.745 #3;0.33 0.46 0.03 0.358 #3;0.04 0.11 Coinfections Hepatitis B virus 1.08 0.812 #3;0.53 0.67 #3;0.06 0.327 #3;0.17 0.06 Hepatitis C virus 1.39 0.065 #3;0.02 0.69 #3;0.04 0.189 #3;0.11 0.02 Syphilis 0 0.57 0.007 #3;0.98 #3;0.16 0.07 0.051 0.00 0.15 HIV parameters HIV viral load < 50 copies/mL 0.63 0.285 #3;1.30 0.39 #3;0.02 0.862 #3;0.19 0.16 CD4 count at enrolment 0.97 0.312 #3;0.10 0.03 0.00 0.734 #3;0.01 0.01 Nadir CD4 count 1.01 0.896 #3;0.13 0.14 #3;0.02 0.190 #3;0.04 0.01 ART duration 1 1.13 0.021 0.02 0.23 #3;0.03 0.002 #3;0.05 #3;0.01 ART duration 0.99 0.005 #3;0.01 0.00 0 0.00 0.001 0.00 0.00 Current CPE score ≥ 7 1.20 0.409 #3;0.24 0.61 #3;0.06 0.157 #3;0.14 0.02 ART drug class Nucleoside reverse transcriptase inhibitor 0.99 0.982 #3;1.17 1.23 0.06 0.604 #3;0.17 0.29 Protease inhibitor 1.34 0.126 #3;0.08 0.67 #3;0.04 0.314 #3;0.11 0.03 Integrase strand transfer inhibitor 0.87 0.505 #3;0.53 0.26 #3;0.01 0.827 #3;0.08 0.07 Efavirenz 0.90 0.651 #3;0.55 0.34 #3;0.02 0.671 #3;0.10 0.07 Likely mode of HIV acquisition Heterosexual (ref: MSM) 1 1.97 0.002 0.24 1.12 #3;0.12 0.008 #3;0.20 #3;0.03 Injecting drug use (ref: MSM) 0.62 0.364 #3;1.50 0.54 0.03 0.790 #3;0.16 0.22 Other/unknown (ref: MSM) 3 3.07 0.013 0.24 2.02 #3;0.13 0.149 #3;0.30 0.05 CI, confidence interval; SD, standard deviation; IQR, interquartile range; CES-D, Center for Epidemiologic Studies Depression scale; HDL, high-density lipoprotein; ART, antiretroviral therapy; CPE, central nervous system penetration effectiveness; MSM, men who have sex with men. P-values < 0.05 are shown in bold text. *Odds ratios with P-values from a multivariate logistic model based on a binary outcome of neurocognitive impairment: no impairment (0) versus impairment (> 0). Difference in mean z-score. Answering, ‘Yes, definitely’ to at least one of the three questions. ≥ 3 alcoholic drinks per day or ≥ 6 alcoholic drinks in one sitting at least once a week. to other SHCS patients aged ≥ 45 years. Men who have verbal knowledge. Patient recruitment depended on sex with men (MSM) and Caucasians, in particular, are SHCS-affiliated infectious disease physicians who had a slightly over-represented in the NAMACO study, and this list of eligible patients. Although the study protocol had is probably related to the requirement for NAMACO study clear inclusion criteria, we cannot exclude recruitment participants to speak the local language to enable perfor- bias related to physicians (degree of involvement with mance of the neurocognitive tests that require sufficient study, personal judgement as to which patients would be © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association The NAMACO study baseline profile 39 suitable participants or who ‘should’ be assessed) or to Fruh, € Stefanie Clarke and Stefania Rossi, for their work in patients (more/less willing to participate if cognitively NAMACO. Finally, we thank Dr Kevin Robertson for his symptomatic). We presented NCI diagnosis according to advice regarding the selection of cognitive tests and his the Frascati criteria to enable comparison between our encouragement to launch the study. The NAMACO study patient population and other cohorts. However, we group: director: Matthias Cavassini; co-director: Renaud acknowledge that applying other diagnostic criteria might Du Pasquier; neuropsychologists: M#1;elanie M#1;etral, Samanta have classified our patients differently. The low number Simioni, Peter Brugger, Klemens Gutbrod, Andreas U. of patients with MNDs in particular is surprising and may Monsch, Ursi Kunze, Marianne Schneitter, Isaure Nadin, be related to the relatively low sensitivity of functional Severin Fruh, € Marc Schwind, Riccardo Pignatti and Ste- impairment scales which differentiate between MNDs and fanie Clarke; neurologists: Fr#1;ed#1;eric Assal, Tobias Derfuss, ANI. In our future analysis within the NAMACO study, Sebastian von Arx, Gunter € Eisele, Leonardo Sacco, Manuel notably the 2-year follow-up, we will focus on patient z- Bertschi, Thomas Hundsberger and Renaud Du Pasquier; scores rather than on Frascati-based NCI labels. In order infectious disease specialists: Alexandra Calmy, Thanh to dovetail the NAMACO study with a database that Doco Lecompte, Christoph Hauser, Alexia Cusini, Rainer extensively characterizes each patient in terms of ART Weber, Helen Kovari, Barbara Hasse, Philip Tarr, Marcel history and other HIV- and non-HIV-related variables, Stoeckle, Christoph Fux, Enos Bernasconi, Caroline Di Ben- patients needed to be enrolled in the SHCS and followed edetto, Alessandra Bruno, Patrick Schmid, Katharine Dar- up regularly in larger hospital centres. Against these limi- ling and Matthias Cavassini; SHCS data centre: Alexandra tations, the NAMACO study did not focus on enrolling Scherrer; data management unit: Alexandra Scherrer, Yan- only patients with cognitive complaints and has a large nick Vallet and Deolinda Alves; statistician: Isabella Loca- patient cohort designed specifically to study NCI. More- telli; pharmacologist: Laurent Decosterd; neuro-imaging over, this study reflects the cognitive status of PLWH specialists: Cristina Granziera, Gunnar Krueger, Reto Meuli aged ≥ 45 years in the whole of Switzerland, which and Maria Vargas. means that the cognitive battery had to be administered Conflicts of interest: KEAD’s institution has received in three languages: German, French and Italian. Such an research funding unrelated to this publication from achievement required NP test validation in three lan- Gilead and sponsorship for specialist meetings from MSD. guages. To the best of our knowledge, this is the first A. Cusini has received travel grants and meeting expenses neuropsychological study (in any field, not only HIV) to from MSD, BMS, Gilead and Astellas paid to her institu- assess patients in parallel in the three linguistic regions tion. PET’s institution has received research grants and of Switzerland. In addition to the large cohort, the link to advisory fees from ViiV and Gilead. A. Calmy’s institu- the SHCS makes the NAMACO study database a high- tion has received unrestricted education grants from Abb- quality resource with which to examine factors important Vie, Gilead, MSD and ViiV. CDB has received sponsorship in determining NCI prevalence, incidence and course. for specialist meetings from Janssen-Cilag and AbbVie. In conclusion, we observed that over a quarter of RDP is a board member at Gilead. MC’s institution has aging patients (≥ 45 years old) enrolled in the NAMACO received a research grant from ViiV and Gilead and study had HIV-associated NCI, a proportion that may offered expert testimony for AbbVie, MSD, Gilead and increase as our patient cohort ages, despite optimal viral Sandoz. The other authors report no conflicts of interest. suppression. Among patients with non-HIV-associated Financial disclosure: The NAMACO study is supported NCI, psychiatric disorders, particularly depression, were by the Swiss National Science Foundation (grant number prevalent. The longitudinal analysis of NAMACO study 163348) and the Swiss HIV Cohort Study (grant number participants at 2 and 4 years from baseline will shed 148522, project 811). Additional funding has been pro- light on how NCI develops and may be modified in our vided by the Swiss HIV Cohort Foundation and ViiV cohort. Healthcare. Acknowledgements Disclaimer We thank all the patients participating in the NAMACO The opinions expressed in this article are those of the study. We thank all the infectious disease physicians and authors and do not necessarily represent those of ViiV. the study nurses working in the centres for their dedicated ViiV had no role in the study design, data collection and patient work and contribution to the NAMACO study. We analysis, decision to publish, or preparation of the manu- thank the neuropsychologists Samanta Simioni, Severin script. © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 40 MM#1;etral et al. 13 Simioni S, Cavassini M, Annoni JM et al. Cognitive Author contributions dysfunction in HIV patients despite long-standing MC, RDP, PT and A. Calmy designed the study. MM, IL, suppression of viremia. AIDS 2010; 24: 1243–1250. IN and GS finalized the neuropsychologist database. IL 14 European Aids Clinical Society Guidelines Version 7.1. performed the statistical analysis. MC and RDP supervised Available at http://www.eacsociety.org/files/guidelines_e nglish_71_141204.pdf. 2014 (accessed 1 July 2019). the study. MM and KEAD wrote the manuscript. All 15 Heilbronner RL, Sweet JJ, Attix DK, Krull KR, Henry GK, investigators contributed to data collection and interpre- Hart RP. Official position of the American Academy of tation, reviewed drafts of posters and the manuscript, and Clinical Neuropsychology on serial neuropsychological approved the final manuscript. assessments: the utility and challenges of repeat test administrations in clinical and forensic contexts. Clin References Neuropsychol 2010; 24: 1267–1278. 16 Grund B, Wright EJ, Brew BJ et al. Improved neurocognitive 1 McArthur JC, Brew BJ, Nath A. Neurological complications test performance in both arms of the SMART study: impact of HIV infection. Lancet Neurol 2005; 4: 543–555. of practice effect. J Neurovirol 2013; 19: 383–392. 2 Bhaskaran K, Mussini C, Antinori A et al. Changes in the 17 Lawton MP, Brody EM. Assessment of older people: self- incidence and predictors of human immunodeficiency virus- maintaining and instrumental activities of daily living. associated dementia in the era of highly active antiretroviral Gerontologist 1969; 9: 179–186. therapy. 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Neurology 2014; 82: 2055–2062. Study (SHCS) who were recruited to the Neurocognitive 28 Heaton RK, Franklin DR Jr, Deutsch R et al. Neurocognitive Assessment in the Metabolic and Aging Cohort change in the era of HIV combination antiretroviral therapy: (NAMACO) study compared to patients who were eligible the longitudinal CHARTER study. Clin Infect Dis 2015; 60: but not recruited and patients followed up at non- 473–480. NAMACO centres. 29 Coban H, Robertson K, Smurzynski M et al. Impact of aging Table S2. Demographic and clinical associations with on neurocognitive performance in previously antiretroviral- neurocognitive impairment in multivariate models naive HIV-infected individuals on their first suppressive applied to 854 HIV-positive patients (excluding the cate- regimen. AIDS 2017; 31: 1565–1571. gory ‘other’). 30 Carroll A, Brew B. HIV-associated neurocognitive disorders: Appendix 1 : Instrumental Activities of recent advances in pathogenesis, biomarkers, and treatment. Daily Living (IADL) scale F1000Research 2017; 6: 312. 31 Fabbiani M, Ciccarelli N, Tana M et al. Cardiovascular risk factors and carotid intima-media thickness are associated PATIENT ID:__________ DATE OF VISIT: ___________ VISIT N: ____ with lower cognitive performance in HIV-infected patients. HIV Med 2013; 14: 136–144. 32 Ellis RJ, Badiee J, Vaida F et al. CD4 nadir is a predictor of A. Ability to use telephone HIV neurocognitive impairment in the era of combination 1. Operates telephone on own initiative; looks up and dials numbers 1 antiretroviral therapy. AIDS 2011; 25: 1747–1751. 2. Dials a few well-known numbers 1 3. Answers telephone but does not dial 1 33 van den Dries LWJ, Wagener MN, Jiskoot LC et al. 4. Does not use telephone at all 0 Neurocognitive impairment in a chronically well-suppressed B. Shopping HIV-infected population: the Dutch TREVI Cohort study. 1. Takes care of all shopping needs independently 1 2. Shops independently for small purchases 0 AIDS Patient Care STDS 2017; 31: 329–334. 3. Needs to be accompanied on any shopping trip 0 34 Bonnet F, Amieva H, Marquant F et al. Cognitive disorders 4. Completely unable to shop 0 in HIV-infected patients: are they HIV-related? AIDS 2013; C. Food preparation 1. Plans, prepares, and serves adequate meals independently 1 27: 391–400. 2. Prepares adequate meals if supplied with ingredients 0 35 Marra CM, Deutsch R, Collier AC et al. Neurocognitive 3. Heats and serves prepared meals or prepares meals but does not 0 impairment in HIV-infected individuals with previous maintain adequate diet 4. Needs to have meals prepared and served 0 syphilis. Int J STD AIDS 2013; 24: 351–355. D. Housekeeping 36 Ho EL, Maxwell CL, Dunaway SB et al. Neurosyphilis 1. Maintains house alone with occasional assistance (heavy work) 1 increases human immunodeficiency virus (HIV)-associated 2. Performs light daily tasks such as dishwashing, bed making 1 3. Performs light daily tasks but cannot maintain acceptable level of 1 central nervous system inflammation but does not explain cleanliness cognitive impairment in HIV-infected individuals with 4. Needs help with all home maintenance tasks 1 syphilis. Clin Infect Dis 2017; 65: 943–948. 5. Does not participate in any housekeeping tasks 0 E. Laundry 37 Nanni MG, Caruso R, Mitchell AJ, Meggiolaro E, Grassi L. 1. Does personal laundry completely 1 Depression in HIV infected patients: a review. Curr 2. Launders small items, rinses socks, stockings, etc. 1 Psychiatry Rep 2015; 17: 530. 3. All laundry must be done by others 0 F. Models of transportation 38 McDermott LM, Ebmeier KP. A meta-analysis of depression 1. Travels independently on public transportation or drives own car 1 severity and cognitive function. J Affect Disord 2009; 119: 2. Arranges own travel via taxi, but does not otherwise use public 1 1–8. transportation 3. Travels on public transportation when assisted or accompanied by 1 39 Rock PL, Roiser JP, Riedel WJ, Blackwell AD. Cognitive another impairment in depression: a systematic review and meta- 4. Travel limited to taxi or automobile with assistance of another 0 analysis. Psychol Med 2014; 44: 2029–2040. 5. Does not travel at all 0 G. Responsibility for own medications 1. Is responsible for taking medication in correct dosages at correct time 1 2. Takes responsibility if medication is prepared in advance in separate 0 Supporting Information dosages 3. Is not capable of dispensing own medication 0 Additional supporting information may be found online H. Ability to handle finances in the Supporting Information section at the end of the 1. Manages financial matters independently (budgets, writes checks, pays 1 article. rent and bills, goes to bank); collects and keeps track of income © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association 42 MM#1;etral et al. Scoring (TOTAL): if the patient receives a score of 0 for at least two of 2. Manages day-to-day purchases, but needs help with banking, major 1 the items above (A–L), then s/he is considered to be functionally purchases, etc. impaired. 3. Incapable of handling money 0 https://www.sm.ee/sites/default/files/content-editors/eesmargid_ja_tege vused/Tervis/Ravimid/eacsguidelines_v6.1_nov2012.pdf. Source: see Lawton and Brody [17]. Source: see Lawton and Brody [7]. Supplementary questions on job Supplementary question concerning social performance entourage I. Job performance M. Entourage 1. Unable to perform some aspects of previous job (not due to medical 0 1. Comments made by entourage (close family, friends, colleagues, etc.) 0 symptoms) regarding decline in cognitive function L. Job performance 1. Reduced efficiency or productivity; or more errors or difficulties 0 meeting expectations; or greater effort to perform the same activities © 2019 The Authors. HIV Medicine (2020), 21, 30--42 HIV Medicine published by John Wiley & Sons Ltd on behalf of British HIV Association

Journal

HIV MedicinePubmed Central

Published: Oct 7, 2019

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