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Neurocognitive impairment in HIV-1-infected adults in Sub-Saharan Africa: a systematic review and meta-analysis

Open AccessPublished:August 16, 2013DOI:https://doi.org/10.1016/j.ijid.2013.06.011

      Summary

      Objective

      To estimate the burden of HIV neurocognitive impairment (NCI) among adult patients on and off antiretroviral therapy (ART) in Sub-Saharan Africa.

      Methods

      Estimates were derived from a random effects meta-analysis of prospective studies reporting HIV status, utilization of ART, and the presence of NCI determined using the International HIV Dementia Scale.

      Results

      Sixteen studies with quality data from seven countries in Sub-Saharan Africa up to June 2012 were included. Among HIV patients, the frequency of NCI pre-ART was 42.37% (95% confidence interval (CI) 32.18–52.56%), and among those on ART for ≥6 months was 30.39% (95% CI 13.17–47.61%). Respective NCI estimates in studies from Uganda were 46.49% (95% CI 30.62–62.37%) and 28.50% (95% CI −1.31–58.30%). NCI was more common among patients with a concomitant psychiatric ailment. HIV-positive patients compared to HIV-negative controls were predisposed to NCI (odds ratio (OR) 6.49, 95% CI 1.68–25.08); the estimated unadjusted attributable risk of HIV infection leading to NCI was 85%. Meta-regression showed no associations between age, gender, CD4 cell counts, or years of education with NCI. Patients on ART were less likely to have NCI compared to HIV-infected pre-ART patients, with OR 0.36 (95% CI 0.19–0.69). In longitudinal studies with the same patients followed before and at ≥6 months after ART, the OR of NCI after ART compared to pre-ART was 0.23 (95% CI 0.14–0.37). The combined burden of NCI among pre-ART and on-ART patients in Sub-Saharan Africa was estimated at 8 121 910 (95% CI 5 772 140–10 471 680). No publication bias was observed, although residual confounding from differing environmental factors, stages of HIV infection, and viral clades might be a limitation.

      Conclusions

      HIV strongly predisposes to NCI leading to a huge burden in Sub-Saharan Africa, and scale-up of ART can substantially reduce it.

      Keywords

      1. Introduction

      HIV infection is a major cause of neurocognitive impairment (NCI).
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      Successive attempts have been made to harmonize and unify the definition and nosology of NCI, eventually culminating in a definition formulated by the American Academy of Neurology in 2007 (AAN2007) referred to as HIV Associated Neurocognitive Deficits (HAND).
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      previously referred to as ‘AIDS dementia complex’ (ADC). As the neuropathological correlate of NCI is thought to be primarily of sub-cortical origin, assessment methods used in Sub-Saharan Africa for cortical diseases may be insensitive for evaluating it. Thus, there have been attempts to adapt and standardize more sensitive assessment tools and test batteries, mindful of local cultures, ease of administration, interpretation, and comparability between populations. This has led to the use of the extensive multi-domain test batteries largely in industrialized countries (e.g., the full or modified versions of the HIV Neurobehavioral Research Center, University of California San-Diego (HNRC) battery) and the less extensive but more easily administered screening tools such as the International HIV Dementia Scale (IHDS) mostly used in developing countries, especially in Sub-Saharan Africa.
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      The IHDS examines the three main domains of motor speed, psychomotor speed, and memory registration/recall. It consists of three subtests: timed finger tapping, timed alternating sequence test, and registration/recall of four items at 2 min.
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      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      A previous meta-analysis and a systematic review addressed detailed neuropsychological profiles and NCI among HIV-infected patients before and after the highly active antiretroviral therapy (HAART) era.
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      In these reviews, data presented were extracted from studies conducted worldwide with varied tools, and no point-estimates could be derived thereby limiting their epidemiological significance, especially in Sub-Saharan Africa. In this study, a systematic review and meta-analysis of studies that used IHDS was conducted to obtain more precise prevalence estimates of NCI, approximate the burden of NCI, and approximate the potential impact of ART on NCI among HIV-infected adults in Sub-Saharan Africa.

      2. Materials and methods

      This study was conducted and reported in accordance with the following available guidelines: Meta-analysis of Observational Studies in Epidemiology (MOOSE) and Preferred Reporting Items for Systematic Reviews and Meta-analysis (PRISMA) statements.
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      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.
      To build up the meta-analysis and systematic review, we searched for relevant English-language papers in MEDLINE, the Cochrane Database, African Journals On-Line (AJOL) database, Global Health, PsycINFO, existing systematic reviews, specialty journals, other search engines, e.g. Google, and several websites. Medical subject heading (MeSH) terms were used in the search. ‘Africa’, ‘AIDS’, ‘adults’, cognition’, ‘cognitive deficit’, ‘cognitive impairment’, ‘dementia’, ‘depression’, ‘HIV’, ‘impairment’, ‘memory’, ‘mental’, ‘neuro-cognitive impairment’, ‘neuro-psychological impairment’, ‘neuro-psychiatric’, ‘psychological impairment’, ‘Sub-Saharan Africa’, and ‘studies’ were used in various combinations as primary search keywords, with no period restriction until the end of June 2012. The review was restricted to studies that defined NCI using IHDS among adults aged ≥18 years, with HIV-1 (excluding HIV-2) infections, and to Sub-Sahara Africa. We also used our knowledge, experiences, and discussions with colleagues and recognized experts, as well as previous publications on the subject. When required, we contacted authors and also manually searched the reference lists of all identified publications and recent systematic reviews. Books, chapters, and review articles on the subject were also consulted.

      2.1 Selection criteria

      Two reviewers independently assessed each potentially relevant study for eligibility. Disagreements were resolved by consultation with a third reviewer. The full texts of all accessible English-language studies evaluating or reporting on NCI among HIV-infected adults in Sub-Saharan Africa were selected, applying the following inclusion criteria: (1) prospective observational studies that used IHDS for detecting NCI; and (2) when HIV status and ART use was stated or could be discerned. Studies were excluded if they did not fulfill the inclusion criteria (e.g., if they did not use IHDS or defined NCI clinically), or lacked or had insufficient data or desired information.

      2.2 Data extraction

      Data were dredged, ascertained, and obtained on a standardized form used to record relevant items and entered into a database; the following were recorded: study characteristics, authors, year of publication, country, study design, setting, test battery, cut-off scores for defining NCI, age of participants, gender, HIV status and stage of infection, formal education, CD4 cell counts, proportion of participants with NCI, duration of ART, viral clades, potential confounders, sources of bias, quality measures, and comments. Another reviewer checked the extracted data for accuracy.

      2.3 Quality assessment

      The study quality was assessed using a modified version of the Downs and Black checklist,
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      and assessment included other items also known to be associated with study quality.

      2.4 Data analysis

      The prevalence of NCI as a percentage with the respective 95% confidence interval (95% CI) was calculated for each study, among HIV-infected adults on or off ART and among HIV-uninfected controls. We also determined the odds of NCI as the number of patients who developed it divided by the number of HIV-infected patients who did not develop it for HIV-infected adults on/off ART and for HIV-negative controls for relevant studies. When no or zero NCI cases were found in the numerator, we added 0.5 to the numerator and denominator of both groups when estimating the odds.
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      We did not assume zero NCI cases when this was not reported among controls, only when it was stated. The odds ratio (OR) and respective 95% CI for NCI in the HIV-positive compared to the HIV-negative control group and for those on ART compared to those off ART were calculated. The log OR and the standard error of log OR were computed for the respective studies. Meta-analyses were then conducted for prevalence estimates and for the OR from comparative studies.
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      Because of the differences expected between studies, we combined results and obtained meta-analysis estimates using a random effects model (REM). We evaluated for statistical heterogeneity by conducting tests of between-study heterogeneity and I2 statistics with I2 > 50% denoting substantial heterogeneity. Sensitivity analyses primarily consisted of investigating the influence of a single study on the overall summary estimate.
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      Assessing the influence of single study in the meta-analysis estimate (sb26).
      Restricted scenario analyses were then performed on data derived from studies with distinct characteristics. Publication bias and small study effect were assessed using adjusted rank correlation tests and the regression asymmetry test, termed Begg's and Egger's tests.
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      Given inconsistency and the insensitivity of the tests,
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      publication bias was considered to exist only if detected in both tests. The crude attributable risk and population attributable risk percent were computed using the REM-derived OR with Levin's formula.
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      Epidemiology.
      We also performed univariate, weighted, least-squares meta-regressions to identify study-level characteristics (mean or median age of participants, years of formal education, CD4 cell counts, and proportion of female participants) associated with the risk of NCI.
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      How should meta-regression analyses be undertaken and interpreted?.
      The estimates derived for the prevalence of NCI among the HIV-infected on and off ART were applied to the total adult HIV-infected populations on and off ART in Sub-Saharan Africa, respectively.

      UNAIDS 2012. Regional Fact Sheet 2012. Available at: http://www.unaids.org/en/regionscountries/regions/ (accessed June 30, 2012).

      The two were then summed to give an estimated burden of NCI in Sub-Saharan Africa. All analyses were carried out using Stata version 11.0 (Stata Corp., College Station, TX, USA).

      3. Results

      A flow diagram of the process of article selection for the meta-analysis and review is shown in Figure 1.
      Figure thumbnail gr1
      Figure 1Flow diagram of the process of article selection for the meta-analysis and review.

      3.1 Overview of selected studies

      Forty-six studies were initially screened.
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      • Saling M.M.
      • Kaplan-Solms K.
      • Cohn R.
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      Neuropsychological deficit in haemophiliacs with human immunodeficiency virus.
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Perriens J.H.
      • Mussa M.
      • Luabeya M.K.
      • Kayembe K.
      • Luabeya M.K.
      • Kapita B.
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      Neurological complications of HIV-1-seropositive internal medicine inpatients in Kinshasa, Zaire.
      • Maj M.
      • Satz P.
      • Janssen R.
      • Zaudig M.
      • Starace F.
      • D’Elia
      • et al.
      WHO Neuropsychiatric AIDS Study, cross-sectional phase II. Neuropsychological and neurological findings.
      • Sebit M.B.
      • Tombe M.
      • Siziya S.
      • Balus S.
      • Nkomo S.D.
      • Maramba P.
      Prevalence of HIV/AIDS and psychiatric disorders and their related risk factors among adults in Epworth, Zimbabwe.
      • Odiase F.
      • Ogunrin O.
      • Ogunniyi A.
      Effect of progression of disease on cognitive performance in HIV/AIDS.
      • Sacktor N.
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      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Modi G.
      • Hari K.
      • Modi M.
      • Mochan A.
      The frequency and profile of neurology in black South African HIV infected (clade C) patients—a hospital-based prospective audit.
      • Salawu F.K.
      • Bwala S.A.
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      Cognitive function in HIV-seropositive Nigerians without AIDS.
      • Wong M.H.
      • Robertson K.
      • Nakasujja N.
      • Skolasky R.
      • Musisi S.
      • Katabira E.
      • et al.
      Frequency of and risk factors for HIV dementia in an HIV clinic in Sub-Saharan Africa.
      • McGrath N.M.
      • Cooke G.S.
      Frequency of and risk factors for HIV dementia in an HIV clinic in Sub-Saharan Africa.
      • Singh D.
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      • John S.
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      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      • Kvalsund M.P.
      • Haworth A.
      • Murman D.L.
      • Velie E.
      • Birbeck G.L.
      Closing gaps in antiretroviral therapy access: human immunodeficiency virus-associated dementia screening instruments for non-physician healthcare workers.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Ogunrin A.O.
      • Emeka U.E.
      • Francis A.
      Usefulness of the HIV Dementia Scale in Nigerian patients with HIV/AIDS.
      • Sacktor N.
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      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Akena D.H.
      • Musisi S.
      • Kinyanda E.
      A comparison of the clinical features of depression in HIV-positive and HIV-negative patients in Uganda.
      • Joska J.A.
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      Association between apolipoprotein E4 genotype and human immunodeficiency virus-associated dementia in younger adults starting antiretroviral therapy in South Africa.
      • Nakasujja N.
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      • Allebeck P.
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      • Ronald A.
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      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
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      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Birbeck G.L.
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      Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia.
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      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      • Joska J.A.
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      Validity of the International HIV Dementia Scale in South Africa.
      • Joska J.A.
      • Westgarth-Taylor J.
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      Characterization of HIV-associated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa.
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      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
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      A multinational study of neurological performance in antiretroviral therapy-naive HIV-1-infected persons in diverse resource-constrained settings.
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      Low prevalence of neuro-psychiatric clinical manifestations in Central African patients with acquired immune deficiency syndrome.
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      Neurological disorders in AIDS and HIV disease in the northern zone of Tanzania.
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      Pattern and outcome of neurological manifestations of HIV/AIDS. A review of 154 cases in a Nigerian University Teaching Hospital—a preliminary report.
      • Sall L.
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      Psychiatric symptoms and disorders in HIV infected mine workers in South Africa. A retrospective descriptive study of acute first admissions.
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      • et al.
      Neurobehavioral effects in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) in Gaborone, Botswana.
      • Kanmogne G.D.
      • Kuate C.T.
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      • Doh R.
      • et al.
      HIV-associated neurocognitive disorders in Sub-Saharan Africa: a pilot study in Cameroon.
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      • Robbins R.N.
      • Remien R.H.
      • Mellins C.A.
      • Joska J.A.
      • Stein D.J.
      Screening for HIV-associated dementia in South Africa: potentials and pitfalls of task-shifting.
      • Imam I.
      Neurological manifestations of HIV infection in Nigerians.
      • Joska J.A.
      • Fincham D.S.
      • Stein D.J.
      • Paul R.H.
      • Seedat S.
      Clinical correlates of HIV-associated neurocognitive disorders in South Africa.
      • Kinyanda E.
      • Hoskins S.
      • Nakku J.
      • Nawaz S.
      • Patel V.
      Prevalence and risk factors of major depressive disorder in HIV/AIDS as seen in semi-urban Entebbe district, Uganda.
      • Sebit M.B.
      Neuropsychiatric HIV-1 infection study: in Kenya and Zaire cross-sectional phase I and II.
      • Odiase F.E.
      • Ogunrin O.A.
      • Ogunniyi A.A.
      Memory performance in HIV/AIDS—a prospective case control study.
      • Ganasen K.A.
      • Fincham D.
      • Smit J.
      • Seedat S.
      • Stein D.
      Utility of the HIV Dementia Scale (HDS) in identifying HIV dementia in a South African sample.
      • Njamnshi A.K.
      • Djientcheu Vde P.
      • Fonsah J.Y.
      • Yepnjio F.N.
      • Njamnshi D.M.
      • Muna W.E.
      The International HIV Dementia Scale is a useful screening tool for HIV-associated dementia/cognitive impairment in HIV-infected adults in Yaoundé, Cameroon.
      • Oshinaike O.O.
      • Okubadejo N.U.
      • Ojini F.I.
      • Danesi M.A.
      The clinical spectrum of neurological manifestations in HIV/AIDS patients on HAART at the Lagos University Teaching Hospital, Lagos, Nigeria.
      • Clifford D.B.
      • Mitike M.T.
      • Mekonnen Y.
      • Zhang J.
      • Zenebe G.
      • Melaku Z.
      • et al.
      Neurological evaluation of untreated human immunodeficiency virus infected adults in Ethiopia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      Subsequently, studies were dropped if they used diagnostic batteries other than IHDS,
      • Turnbull O.
      • Saling M.M.
      • Kaplan-Solms K.
      • Cohn R.
      • Schoub B.
      Neuropsychological deficit in haemophiliacs with human immunodeficiency virus.
      • Perriens J.H.
      • Mussa M.
      • Luabeya M.K.
      • Kayembe K.
      • Luabeya M.K.
      • Kapita B.
      • et al.
      Neurological complications of HIV-1-seropositive internal medicine inpatients in Kinshasa, Zaire.
      • Maj M.
      • Satz P.
      • Janssen R.
      • Zaudig M.
      • Starace F.
      • D’Elia
      • et al.
      WHO Neuropsychiatric AIDS Study, cross-sectional phase II. Neuropsychological and neurological findings.
      • Sebit M.B.
      • Tombe M.
      • Siziya S.
      • Balus S.
      • Nkomo S.D.
      • Maramba P.
      Prevalence of HIV/AIDS and psychiatric disorders and their related risk factors among adults in Epworth, Zimbabwe.
      • Odiase F.
      • Ogunrin O.
      • Ogunniyi A.
      Effect of progression of disease on cognitive performance in HIV/AIDS.
      • Modi G.
      • Hari K.
      • Modi M.
      • Mochan A.
      The frequency and profile of neurology in black South African HIV infected (clade C) patients—a hospital-based prospective audit.
      • Salawu F.K.
      • Bwala S.A.
      • Wakil M.A.
      • Bani B.
      • Bukbuk D.N.
      • Kida I.
      Cognitive function in HIV-seropositive Nigerians without AIDS.
      • Wong M.H.
      • Robertson K.
      • Nakasujja N.
      • Skolasky R.
      • Musisi S.
      • Katabira E.
      • et al.
      Frequency of and risk factors for HIV dementia in an HIV clinic in Sub-Saharan Africa.
      • McGrath N.M.
      • Cooke G.S.
      Frequency of and risk factors for HIV dementia in an HIV clinic in Sub-Saharan Africa.
      • Kvalsund M.P.
      • Haworth A.
      • Murman D.L.
      • Velie E.
      • Birbeck G.L.
      Closing gaps in antiretroviral therapy access: human immunodeficiency virus-associated dementia screening instruments for non-physician healthcare workers.
      • Ogunrin A.O.
      • Emeka U.E.
      • Francis A.
      Usefulness of the HIV Dementia Scale in Nigerian patients with HIV/AIDS.
      • Akena D.H.
      • Musisi S.
      • Kinyanda E.
      A comparison of the clinical features of depression in HIV-positive and HIV-negative patients in Uganda.
      • Joska J.A.
      • Combrinck M.
      • Valcour V.G.
      • Hoare J.
      • Leisegang F.
      • Mahne A.C.
      • et al.
      Association between apolipoprotein E4 genotype and human immunodeficiency virus-associated dementia in younger adults starting antiretroviral therapy in South Africa.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Myer L.
      • Hoare J.
      • Thomas K.G.
      • Combrinck M.
      • et al.
      Characterization of HIV-associated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa.
      • Robertson K.
      • Kumwenda J.
      • Supparatpinyo K.
      • Jiang J.H.
      • Evans S.
      • Campbell T.B.
      • et al.
      A multinational study of neurological performance in antiretroviral therapy-naive HIV-1-infected persons in diverse resource-constrained settings.
      • Belec L.
      • Martin P.M.
      • Vohito M.D.
      • Gresenguet G.
      • Tabo A.
      • Georges A.J.
      Low prevalence of neuro-psychiatric clinical manifestations in Central African patients with acquired immune deficiency syndrome.
      • Howlett W.P.
      • Nkya W.M.
      • Mmuni K.A.
      • Missalek W.R.
      Neurological disorders in AIDS and HIV disease in the northern zone of Tanzania.
      • Ogun A.S.
      • Ojini F.
      • Okubadejo N.
      • Danesi M.
      • Kolapo K.
      • Osalusi B.
      • et al.
      Pattern and outcome of neurological manifestations of HIV/AIDS. A review of 154 cases in a Nigerian University Teaching Hospital—a preliminary report.
      • Sall L.
      • Salamon E.
      • Allgulander C.
      • Owe-Larsson B.
      Psychiatric symptoms and disorders in HIV infected mine workers in South Africa. A retrospective descriptive study of acute first admissions.
      • Lawler K.
      • Jeremiah K.
      • Mosepele M.
      • Ratcliffe S.J.
      • Cherry C.
      • Seloilwe E.
      • et al.
      Neurobehavioral effects in HIV-positive individuals receiving highly active antiretroviral therapy (HAART) in Gaborone, Botswana.
      • Kanmogne G.D.
      • Kuate C.T.
      • Cysique L.A.
      • Fonsah J.Y.
      • Eta S.
      • Doh R.
      • et al.
      HIV-associated neurocognitive disorders in Sub-Saharan Africa: a pilot study in Cameroon.
      • Imam I.
      Neurological manifestations of HIV infection in Nigerians.
      • Joska J.A.
      • Fincham D.S.
      • Stein D.J.
      • Paul R.H.
      • Seedat S.
      Clinical correlates of HIV-associated neurocognitive disorders in South Africa.
      • Kinyanda E.
      • Hoskins S.
      • Nakku J.
      • Nawaz S.
      • Patel V.
      Prevalence and risk factors of major depressive disorder in HIV/AIDS as seen in semi-urban Entebbe district, Uganda.
      • Sebit M.B.
      Neuropsychiatric HIV-1 infection study: in Kenya and Zaire cross-sectional phase I and II.
      • Odiase F.E.
      • Ogunrin O.A.
      • Ogunniyi A.A.
      Memory performance in HIV/AIDS—a prospective case control study.
      • Ganasen K.A.
      • Fincham D.
      • Smit J.
      • Seedat S.
      • Stein D.
      Utility of the HIV Dementia Scale (HDS) in identifying HIV dementia in a South African sample.
      • Njamnshi A.K.
      • Djientcheu Vde P.
      • Fonsah J.Y.
      • Yepnjio F.N.
      • Njamnshi D.M.
      • Muna W.E.
      The International HIV Dementia Scale is a useful screening tool for HIV-associated dementia/cognitive impairment in HIV-infected adults in Yaoundé, Cameroon.
      • Oshinaike O.O.
      • Okubadejo N.U.
      • Ojini F.I.
      • Danesi M.A.
      The clinical spectrum of neurological manifestations in HIV/AIDS patients on HAART at the Lagos University Teaching Hospital, Lagos, Nigeria.
      • Clifford D.B.
      • Mitike M.T.
      • Mekonnen Y.
      • Zhang J.
      • Zenebe G.
      • Melaku Z.
      • et al.
      Neurological evaluation of untreated human immunodeficiency virus infected adults in Ethiopia.
      had mixed data that could not be differentiated into participants on/off ART,
      • Imam I.
      Neurological manifestations of HIV infection in Nigerians.
      • Joska J.A.
      • Fincham D.S.
      • Stein D.J.
      • Paul R.H.
      • Seedat S.
      Clinical correlates of HIV-associated neurocognitive disorders in South Africa.
      • Kinyanda E.
      • Hoskins S.
      • Nakku J.
      • Nawaz S.
      • Patel V.
      Prevalence and risk factors of major depressive disorder in HIV/AIDS as seen in semi-urban Entebbe district, Uganda.
      if they did not otherwise fulfill inclusion criteria, or if the publications were duplicated.
      • Ganasen K.A.
      • Fincham D.
      • Smit J.
      • Seedat S.
      • Stein D.
      Utility of the HIV Dementia Scale (HDS) in identifying HIV dementia in a South African sample.
      • Njamnshi A.K.
      • Djientcheu Vde P.
      • Fonsah J.Y.
      • Yepnjio F.N.
      • Njamnshi D.M.
      • Muna W.E.
      The International HIV Dementia Scale is a useful screening tool for HIV-associated dementia/cognitive impairment in HIV-infected adults in Yaoundé, Cameroon.
      Studies were also dropped if they used the HIV Dementia Scale (HDS),
      • Kvalsund M.P.
      • Haworth A.
      • Murman D.L.
      • Velie E.
      • Birbeck G.L.
      Closing gaps in antiretroviral therapy access: human immunodeficiency virus-associated dementia screening instruments for non-physician healthcare workers.
      • Ogunrin A.O.
      • Emeka U.E.
      • Francis A.
      Usefulness of the HIV Dementia Scale in Nigerian patients with HIV/AIDS.
      • Joska J.A.
      • Fincham D.S.
      • Stein D.J.
      • Paul R.H.
      • Seedat S.
      Clinical correlates of HIV-associated neurocognitive disorders in South Africa.
      • Ganasen K.A.
      • Fincham D.
      • Smit J.
      • Seedat S.
      • Stein D.
      Utility of the HIV Dementia Scale (HDS) in identifying HIV dementia in a South African sample.
      • Oshinaike O.O.
      • Okubadejo N.U.
      • Ojini F.I.
      • Danesi M.A.
      The clinical spectrum of neurological manifestations in HIV/AIDS patients on HAART at the Lagos University Teaching Hospital, Lagos, Nigeria.
      or used the IHDS but did not allow delineation of NCI.
      • Clifford D.B.
      • Mitike M.T.
      • Mekonnen Y.
      • Zhang J.
      • Zenebe G.
      • Melaku Z.
      • et al.
      Neurological evaluation of untreated human immunodeficiency virus infected adults in Ethiopia.
      Sixteen main studies satisfied the inclusion criteria and were of satisfactory quality.
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Birbeck G.L.
      • Kvalsund M.P.
      • Byers P.A.
      • Bradbury R.
      • Mang’ombe C.
      • Organek N.
      • et al.
      Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia.
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      • Robbins R.N.
      • Remien R.H.
      • Mellins C.A.
      • Joska J.A.
      • Stein D.J.
      Screening for HIV-associated dementia in South Africa: potentials and pitfalls of task-shifting.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      Characteristics of the studies and quality indices assessed are presented in Table 1, Table 2. The studies were from seven countries in Sub-Saharan Africa, comprising South Africa (n = 4), Uganda (n = 6), Zambia (n = 2), Botswana (n = 1), Cameroon (n = 1), Malawi (n = 1), and Nigeria (n = 1). These 16 studies had point-prevalence for NCI in HIV-infected adult patients pre-ART (n = 7),
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      • Robertson K.
      • Kumwenda J.
      • Supparatpinyo K.
      • Jiang J.H.
      • Evans S.
      • Campbell T.B.
      • et al.
      A multinational study of neurological performance in antiretroviral therapy-naive HIV-1-infected persons in diverse resource-constrained settings.
      at ≥6 months on ART (n = 4),
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      • Robbins R.N.
      • Remien R.H.
      • Mellins C.A.
      • Joska J.A.
      • Stein D.J.
      Screening for HIV-associated dementia in South Africa: potentials and pitfalls of task-shifting.
      or at both times (n = 5);
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      three of the latter studies were longitudinal and had NCI prevalence computed for the same subjects at both pre-ART and ≥6 months after commencement of ART
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      (Table 1). All five studies showed lower prevalence of NCI after ≥6 months on ART compared to off- or pre-ART (Table 1). All the studies used an IHDS cut-off of ≤10 for the definition of NCI except two studies that used ≤9.5 and <10.5, respectively,
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      although the former used additional cognitive tests.
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      Further to using IHDS with a cut-off of ≤10, four studies used additional tests, and their combined assessments were used to assign a Memorial Sloane Kettering (MSK) dementia stage.
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      Six of the 16 studies had a healthy/HIV-negative control group; NCI was detected among controls in three of the studies, while the remaining three studies only generated normative data and cut-offs for defining NCI among the controls (Table 1). Most of the studies were cross-sectional (n = 12) and the remaining studies were either cohort (n = 1) or longitudinal (n = 3).
      Table 1Characteristics of included studies on neurocognitive impairment in HIV-1-infected adults in Sub-Saharan Africa
      Study No.Author, year, Ref.CountryStudy designSymptom statusCD4 cell countDemographicsPrevalence of NCI between groups (HIV-pos/neg or ART+/−) (n/N)Comments, observations, or sources of bias
      Age, yearsFemales (%)Years of educationHIV-pos, ART−, (NCI/total (%))HIV-neg (NCI/total (%))HIV-pos ART+ (NCI/total (%))
      1.Sacktor et al., 2005
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      UgandaC-SSymp-37.0 (9.4)-8.725/81 (30.86)NR/100-Excluded Karnofsky <50 and other confounders
      2.Sacktor et al., 2006
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      UgandaLongitudinalSymp

      CD4 <200
      71 (15)32.8 (1.3)778.714/23 (60.87)-1/21 (4.76)Excluded Karnofsky <50 and other confounders; practice effect present
      3.Breuer et al., 2011
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      South AfricaC-SAsymp-37 (31–42)64--30/259 (11.58)Alcohol and psychiatric diseases not excluded; screened by nurses and lay counselors
      4.Lawler et al., 2010
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      BotswanaC-SSymp360.4 (181.4)37.5 (23–50)508.9--46/120 (38.33)Done in urban setting; 80% had viral load <400 copies/ml
      5.Robbins et al., 2011
      • Robbins R.N.
      • Remien R.H.
      • Mellins C.A.
      • Joska J.A.
      • Stein D.J.
      Screening for HIV-associated dementia in South Africa: potentials and pitfalls of task-shifting.
      South AfricaC-SSymp296.1 (162.8)38.5 (9.26)65--52/65 (80.00)Ethanol not excluded; assessed psychiatric diseases
      6.Singh et al., 2008
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      South AfricaC-SSymp

      CD4 <200
      35
      Median (interquartile range).
      34.0
      Median (interquartile range).
      6016/20 (80.00)--60% had depression
      7.Birbeck et al., 2011
      • Birbeck G.L.
      • Kvalsund M.P.
      • Byers P.A.
      • Bradbury R.
      • Mang’ombe C.
      • Organek N.
      • et al.
      Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia.
      ZambiaProspective cohortAsymp/Symp-38.1 (9.5)58.77.2185/440 (42.05)Neuropsychiatric patients recruited; assessed adherence and stigma; no CD4 count
      8.Holguin et al., 2011
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      ZambiaC-SAsymp/Symp-34.064.8912/54 (22.22)NR/57-No CD4 count; excluded ethanol and depression; psychiatric disease not excluded
      9.Joska et al., 2011
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      South AfricaC-SSymp218.09 (150.57)29.75 (3.67)79.210.0565/96 (67.71)NR/94-ART-naïve; HCV not screened
      10.Patel et al., 2010
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      MalawiC-SSymp-36.7657/45 (15.56)-18/134 (13.43)CD4 count not reported
      11.Nakasujja et al., 2010
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      UgandaLongitudinalSymp

      CD4 <200
      130 (69.5)34.2 (6.2)72.69.170/102 (68.63)4/25 (16.00)28/93 (30.11)Assessed functional status; depressive patients found; small number of controls
      12.Njamnshi et al., 2009
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      CameroonC-S + controlAsymp/Symp264.5 (194.2)37.6 (8.8)6728/109 (25.69)-13/76 (17.11)Excluded confounders
      13.Sacktor et al., 2009
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      UgandaC-S + controlSymp

      CD4 <200
      355 (136.3)34.63 (2.35)6510.521/60 (35.00)--IHDS ≤10 in all cases; excluded confounders; 8 of 9 subtype D and 7 of 33 subtype A had dementia
      14.Nakimuli-Mpungu et al., 2011
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      UgandaC-SSymp-40
      Median (interquartile range).
      (18–80)
      69.8--314/500 (62.80)46% of subjects had depression
      15.Sacktor et al., 2009
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      UgandaLongitudinal(6 months)Symp129 (79)34.2 (6.4)729.140/102 (39.22)0/25 (0.00)15/95 (15.79)Excluded OIs clinically; IHDS ≤10 in all cases
      16.Royal et al., 2012
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      NigeriaC-S + controlSymp178.9 (206.8)??61.717/60 (28.33)9/56 (16.07)-NCI associated with subtype G virus
      ART, antiretroviral therapy; ART+, on ART for at least 6 months; ART−, not on ART; Asymp, asymptomatic; C-S, cross-sectional; IHDS, International HIV Dementia Scale; NR, not reported; OIs, opportunistic infections; Symp, symptomatic.
      Data are mean (SD) or median (IQR). Cofounders include ethanol, depression, psychiatric diseases, opportunistic infections, low Karnofsky score, and comorbid conditions. Some studies did not exclude all of them.
      a Median (interquartile range).
      Table 2Quality assessment of studies
      Quality measureSacktor et al., 2005
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      Sacktor et al., 2006
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      Robbins et al., 2011
      • Robbins R.N.
      • Remien R.H.
      • Mellins C.A.
      • Joska J.A.
      • Stein D.J.
      Screening for HIV-associated dementia in South Africa: potentials and pitfalls of task-shifting.
      Lawler et al., 2010
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      Breuer et al., 2011
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      Nakimuli-Mpungu et al., 2011
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      Birbeck et al., 2011
      • Birbeck G.L.
      • Kvalsund M.P.
      • Byers P.A.
      • Bradbury R.
      • Mang’ombe C.
      • Organek N.
      • et al.
      Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia.
      Holguin et al., 2011
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      Singh et al., 2008
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      Nakasujja et al., 2010
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      Patel et al., 2010
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      Joska et al., 2011
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      Sacktor et al., 2009
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      Sacktor et al., 2009
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      Njamnshi et al., 2009
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      Royal et al., 2012
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      Accrued from same populationYYYYYYYYYYYYYYYY
      Accrued during same time periodYYYYYYYYYYYYYYYY
      Modest sample sizeYNYYYYYYNYYYYYYY
      Comparator groupYNNNNNNYNNNYNYNY
      Addressed loss to follow-up in longitudinal studiesNAYNANANANANANANAYNANANAYNANA
      Management of missing dataNAYNANAYNAYNANAYNANANAYNAY
      Age, gender, and other characteristics reported by the groupNYYYYYYYYYYYYYYY
      Were confounders reported?YYYYYYYYYYYYYYYY
      Was functional assessment done/reported?YYNYYYNNNYNYYYYY
      Was alcohol/substance use assessed/reported?YYYYYYNNYYYYYYYY
      Were other potential biases reported?YYYYYYYYNYYYYYYY
      Were measures to curtail bias reported?YYNYYYYYNYYYYYYY
      Y, yes; N, no; NA, not applicable.

      3.2 Characteristics of participants in studies

      The proportion of female participants reported in 15 studies ranged from 50% to 79.2%. The mean or median ages of participants in 15 studies ranged from 29.75 to 40 years. The mean or median duration of formal education among participants in nine studies ranged from 7.2 to 10.5 years. Mean or median CD4 cell counts were reported in 10 studies and ranged from 35 to 360.4 cells/ml. Participants recruited in the studies comprised asymptomatic HIV patients (n = 1), a mixed group of asymptomatic and symptomatic infections (n = 3), and symptomatic stable patients (n = 12). Four studies recruited participants with CD4 cell counts <200 cells/ml.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      Several studies evaluated the functional activity and performance status of participants using the Karnofsky scale and excluded those with Karnofsky scale <50%. HIV viral load was reported in studies from Botswana and Nigeria.
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      Studies addressed other potential confounders and some excluded participants with psychiatric morbidity, ethanol/substance use, and possible central nervous system (CNS) opportunistic infections (OIs) (Table 1, Table 2).
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.

      3.3 Findings from the meta-analysis

      3.3.1 Prevalence of NCI among those not on ART

      The REM estimates of NCI among HIV-infected adults pre-ART from 12 studies was 42.37% (95% CI 32.18–52.56%) (Figure 2). There was no publication bias (Begg's test, p = 0.945; Egger's test, p = 0.827) (Figure 7a). Sensitivity analysis showed that no study unduly influenced the findings (Figure 3).
      Figure thumbnail gr2
      Figure 2Prevalence (%) of neurocognitive impairment in HIV-infected adults in Sub-Saharan Africa (pre-ART or off ART).
      Figure thumbnail gr3
      Figure 3Sensitivity analyses showing effect of dropping individual studies on pooled REM prevalence (%) estimates of remaining 11 studies (combined estimates from the 12 comparisons are depicted by the 3 vertical lines).
      In the six studies from Uganda,
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      the REM pooled estimates of NCI among infected patients pre-ART was 46.49% (95% CI = 30.62–62.37%). While the corresponding estimates was 28.50% (95% CI = 1.31–58.30%) for patients on ART from 4 studies. The prevalence of NCI among ART-naïve patients reported by two studies each from South Africa and Zambia is given in Table 1.
      In an REM meta-analysis comprising nine studies,
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      where those with active psychiatric disease, use of anti-psychiatric medication, alcohol or substance use were excluded, the prevalence estimate of NCI was 35.66% (95% CI 24.44–46.87%). The pooled estimate from three studies
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Birbeck G.L.
      • Kvalsund M.P.
      • Byers P.A.
      • Bradbury R.
      • Mang’ombe C.
      • Organek N.
      • et al.
      Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia.
      that included participants with psychiatric diseases or substance use was 62.56% (95% CI 39.28–85.84%).
      Meta-regression was conducted only on studies reporting NCI pre-ART or off-ART. In the analysis, study-specific NCI estimates showed no significant associations with four study-level characteristics: mean/median age of patients in years ranging from 29.5 to 38.1 years had a slope coefficient of −4.95 (95% CI −10.07 to 0.16, p = 0.056) in 12 studies; the slope of the line in the relationship with the proportion of women across a wide range from 50% to 79.2% had a coefficient of 1.06 (95% CI −4.49 to 6.60, p = 0.680) in 12 studies; the slope of the line in the relationship with mean/median formal years spent in education across a wide range from 7.2 to 10.5 years had a coefficient of 2.49 (95% CI −14.95 to 19.94; p = 0.739) in eight studies; and the slope of the line in the relationship with mean/median CD4 cell counts across a wide range from 35 to 355 cells per ml had a coefficient of −0.13 (95% CI −0.29 to 0.035; p = 0.103) in eight studies (Figure 4).
      Figure thumbnail gr4
      Figure 4Meta-regression of NCI in HIV infected adults (pre-ART) by study-level parameters.
      When compared to HIV-negative adult controls, the OR for developing NCI in HIV-infected adults was 6.49 (95% CI 1.68–25.08) (Figure 5). There was no publication bias (Begg's test, p = 0.602; Egger's test, p = 0.469.). Sensitivity analysis showed none of the studies unduly weighed on the estimates. The estimated unadjusted attributable risk of HIV infection leading to NCI was 85% and the population attributable risk percent was estimated as 9.89% assuming a conservative 2.0% adult HIV seroprevalence in Sub-Saharan Africa.
      • Gordis L.
      Epidemiology.

      UNAIDS 2012. Regional Fact Sheet 2012. Available at: http://www.unaids.org/en/regionscountries/regions/ (accessed June 30, 2012).

      Figure thumbnail gr5
      Figure 5NCI among HIV infected compared to uninfected adults (Odds Ratio [95% CI]).

      3.3.2 Prevalence of NCI among those on ART

      The REM estimate of NCI among HIV-infected adults on ART for ≥6 months from nine studies
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Lawler K.
      • Mosepele M.
      • Ratcliffe S.
      • Seloilwe E.
      • Steele K.
      • Nthobatsang R.
      • et al.
      Neurocognitive impairment among HIV-positive individuals in Botswana: a pilot study.
      • Breuer E.
      • Stoloff K.
      • Myer L.
      • Seedat S.
      • Stein D.J.
      • Joska J.
      Reliability of the lay adherence counsellor administered Substance Abuse and Mental Illness Symptoms Screener (SAMISS) and the International HIV Dementia Scale (IHDS) in a primary care HIV clinic in Cape Town, South Africa.
      • Nakimuli-Mpungu E.
      • Musisi S.
      • Katabira E.
      • Nachega J.
      • Bass J.
      Prevalence and factors associated with depressive disorders in an HIV-positive rural patient population in southern Uganda.
      • Robbins R.N.
      • Remien R.H.
      • Mellins C.A.
      • Joska J.A.
      • Stein D.J.
      Screening for HIV-associated dementia in South Africa: potentials and pitfalls of task-shifting.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      was 30.39% (95% CI 13.17–47.61%) (Figure 6). There was no publication bias (Begg's test, p = 0.175; Egger's test, p = 0.287). The sensitivity analysis showed that no study unduly influenced the findings.
      Figure thumbnail gr6
      Figure 6Prevalence (%) of Neuro-Cognitive Impairment (NCI) in HIV infected adults on ART in 9 studies in SSA.
      When five studies reporting on NCI among those on ART compared to pre-ART were analyzed, the pooled REM OR was 0.36 (95% CI 0.19–0.69) with no publication bias (Begg's test, p = 0.462; Egger's test, p = 0.914) (Figure 7, Figure 8). Three of the five were longitudinal studies with the same patients followed before and at ≥6 months after ART yielding an OR of NCI after ART compared to pre-ART of 0.23 (95% CI 0.14–0.37).
      Figure thumbnail gr7
      Figure 7Publication bias on studies of NCI: (a) among patients pre- or off- ART by Egger's plot; (b) comparing [Odds Ratio(95% CI)] of those on-ART to those off-ART by Begg's funnel plot.
      Figure thumbnail gr8
      Figure 8Effect of ART on neurocognitive impairment: estimates on ART compared to pre-ART (OR (95% CI)).

      3.3.3 Burden of NCI in Sub-Saharan Africa

      The burden of NCI was obtained as sum of product of 42.37% (95% CI 32.18–52.56%) of HIV-infected adults not on ART (assumed 16 300 000; UNAIDS 2009) and the product of 30.39% (95% CI 13.17–47.61) of HIV-infected on ART (assuming 80% of the 5 million patients on ART are adults, i.e., 4 million adults (ONE International)).

      ONE International. HIV/AIDS; 2011. Available at: http://www.one.org/international/issuebrief/1584 (accessed June 28, 2012).

      Thus, the combined burden of NCI among pre-ART and on-ART patients totaled 8 121 910 (95% CI 5 772 140–10 471 680) in Sub-Saharan Africa.

      4. Discussion

      This study confirmed that HIV infection is a major predisposing factor for NCI, leading to a huge burden of over 8.1 million adult patients in Sub-Saharan Africa. It reaffirmed that ART confers substantial benefit against NCI, lowering it by over 60%. Indeed, the burden may be an underestimation, as a higher prevalence of NCI has been reported in some studies,
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      and ANI could not be assessed with the IHDS, although there is controversy surrounding its existence as an entity.
      • Gisslen M.
      • Price R.W.
      • Nilsson S.
      The definition of HIV-associated neurocognitive disorders: are we overestimating the real prevalence?.
      Furthermore, applying the lower prevalence of 30.39% to the HIV-infected patients on ART (∼4 million)

      ONE International. HIV/AIDS; 2011. Available at: http://www.one.org/international/issuebrief/1584 (accessed June 28, 2012).

      and the exclusion of children, adolescents, and HIV-2 infections, yielded lower burden estimates. The overall estimates are similar to the 8 million derived from studies conducted in Uganda.
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
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      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.

      John Hopkins Medical Institutions. HIV dementia alarmingly high in Africa. Science Daily; January 29, 2007. Available at: http://www.sciencedaily.com/releases/2007/01/070129171855.htm (accessed June 23, 2012).

      In Sub-Saharan Africa, patients generally present with a more advanced symptomatic infection, often with anemia, poor performance status, wasting and severe immunosuppression with low CD4 cell counts, conditions known to predispose to NCI.
      • McArthur J.C.
      • Haughey N.
      • Gartner S.
      • Conant K.
      • Pardo C.
      • Nath A.
      • et al.
      Human immunodeficiency virus-associated dementia: an evolving disease.
      • Wong M.H.
      • Robertson K.
      • Nakasujja N.
      • Skolasky R.
      • Musisi S.
      • Katabira E.
      • et al.
      Frequency of and risk factors for HIV dementia in an HIV clinic in Sub-Saharan Africa.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      Perhaps this accounts for the higher NCI prevalence recorded compared to the cumulative lifetime risk of developing NCI from well-conducted cohort studies in developed countries, as in the USA where 15–20% was observed in the Multicenter AIDS Cohort Study in the pre-HAART era.
      • McArthur J.C.
      • Hoover D.R.
      • Bacellar H.
      • Miller E.N.
      • Cohen B.A.
      • Becker J.T.
      • et al.
      Dementia in AIDS patients: incidence and risk factors. Multicenter AIDS Cohort Study.
      A previous meta-analysis reported on the indices traditionally used in psychological studies, such as quantification of the effect size and assigning of impairment ratings from comparisons with normative data among controls.
      • Cysique L.A.
      • Maruff P.
      • Brew B.J.
      The neuropsychological profile of symptomatic AIDS and ADC patients in the pre-HAART era: a meta-analysis.
      This was not adopted in this review. The strengths of our approach include an ability to derive an accurate point prevalence and therefore burden of NCI. This would not have been feasible with the former approach. Several studies and previous systematic reviews have suggested that ART has beneficial effects on NCI, but to our knowledge no previous report has quantified the extent of the benefit.
      • Joska J.A.
      • Gouse H.
      • Paul R.H.
      • Stein D.J.
      • Flisher A.J.
      Does highly active antiretroviral therapy improve neurocognitive function? A systematic review.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      • Obiabo Y.O.
      • Ogunrin O.A.
      • Ogun A.S.
      Effects of highly active antiretroviral therapy on cognitive functions in severely immune-compromised HIV-seropositive patients.
      Our analysis suggests that ART improves NCI by 63% when compared to similar subjects not on ART and by 77% when the same patients are tested before and at least 6 months after commencement of ART. Such longitudinal studies have the advantage of allowing for within-subject assessments. However, it is likely the actual benefit could be slightly less, as serially conducted testing in the same patient population introduces a practice effect and apparent improvements in performance. Furthermore, as HIV-infected persons age, residual long-term effects can still be seen in the brain structure which likely stem from damage done prior to ART. As antiretroviral (ARV) drugs have different CNS penetrating effectiveness (CPE), it is likely the effect of ART regimens may also be variable. However, our results strongly advocate for scale-up of HAART as an intervention for reducing the massive burden of NCI in the region.
      To improve population homogeneity, analysis was conducted on adults only and NCI was defined with the same test, the IHDS. However, there are several sources of heterogeneity including differences resulting from differing circulating HIV-1 viral clades, and differing study designs and data quality. However attempts were made at deriving estimates from more homogeneous populations, e.g. from individual countries (Uganda), thereby reducing differences from viral clades and cultural/environmental effects. Secondly, the prevalence of NCI for those with and without psychiatric diseases and alcohol/substance use was obtained separately to reduce their confounding effects. NCI was higher in studies with participants with psychiatric diseases or substance use.
      • Singh D.
      • Sunpath H.
      • John S.
      • Eastham L.
      • Gouden R.
      The utility of a rapid screening tool for depression and HIV dementia amongst patients with low CD4 counts—a preliminary report.
      • Nakasujja N.
      • Skolasky R.L.
      • Musisi S.
      • Allebeck P.
      • Robertson K.
      • Ronald A.
      • et al.
      Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda.
      • Birbeck G.L.
      • Kvalsund M.P.
      • Byers P.A.
      • Bradbury R.
      • Mang’ombe C.
      • Organek N.
      • et al.
      Neuropsychiatric and socioeconomic status impact antiretroviral adherence and mortality in rural Zambia.
      It has been suggested that sole psychiatric presentation may be the early phase of NCI. Indeed initial symptoms may be subtle and are therefore easily overlooked and can be misdiagnosed as depression or mental retardation.
      • Nath A.
      • Schiess N.
      • Venkatesan A.
      • Rumbaugh J.
      • Sacktor N.
      • McArthur J.
      Evolution of HIV dementia with HIV infection.
      Meta-regression of study-specific NCI prevalence conducted to explore associations with study-level parameters failed to confirm significant relationships. However, there was a non-significant decreasing trend in NCI with increasing age and CD4 cell counts. Education increases the so-called cognitive ‘cerebral reserve’,
      • Ngandu T.
      • von Strauss E.
      • Helkala E.L.
      • Winblad B.
      • Nissinen A.
      • Tuomilehto J.
      • et al.
      Education and dementia: what lies behind the association?.
      but duration of education had no relationship to NCI. Similarly, no association between gender and NCI was shown, although studies have found it to be higher among females
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      or males.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Myer L.
      • Hoare J.
      • Thomas K.G.
      • Combrinck M.
      • et al.
      Characterization of HIV-associated neurocognitive disorders among individuals starting antiretroviral therapy in South Africa.
      Consistent with previous reports, estimates derived from studies in Uganda with more homogeneous viral populations and a predominance of clades D/A yielded a higher prevalence of NCI. It has been suggested that clade D viruses have more neurotropic activity and generally have a more aggressive natural history.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Sacktor N.
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      • Robertson K.
      • Clifford D.B.
      HIV-associated cognitive impairment in Sub-Saharan Africa—the potential effect of clade diversity.
      Using IHDS and a cut-off score of 10 for defining NCI, studies in Nigeria
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      and Uganda
      • Sacktor N.
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      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      with circulating recombinant form (CRF) 02AG (CRF_02AG) and clade A respectively yielded estimates of 29% and 21%, compared to 89% reported in clade D-infected patients in Uganda. Indeed, the preliminary analysis from Nigeria, involving sequencing of partial pol amplicons from viral isolates, revealed that two of three patients with NCI were infected with subtype G virus and one with the CRF02_AG, while all four individuals without NCI were infected with CRF_02AG.
      The findings should be interpreted in the light of several caveats. Firstly, IHDS is a screening test for NCI. Indeed, in Guinea-Bissau it has been suggested that IHDS may be a less effective screening tool for HAND/NCI, especially in settings of lower educational attainment.
      • Choi Y.
      • Townend J.
      • Vincent T.
      • Zaidi I.
      • Sarge-Njie R.
      • Jaye A.
      • et al.
      Neurologic manifestations of human immunodeficiency virus-2: dementia, myelopathy, and neuropathy in West Africa.
      Furthermore it does not assess depression and other important domains like executive functions and may underestimate the burden of NCI. Investigators in Cameroon using an extensive battery of 19 tests detected significantly lower performance on executive functions as evaluated using three tests (Category Test, Color Trails II, and Wisconsin Card Sorting Test-64), and South African patients with HAD, who screened negative on the IHDS, also performed poorly on some tests of executive functions.
      • Joska J.A.
      • Westgarth-Taylor J.
      • Hoare J.
      • Thomas K.G.
      • Paul R.
      • Myer L.
      • et al.
      Validity of the International HIV Dementia Scale in South Africa.
      • Kanmogne G.D.
      • Kuate C.T.
      • Cysique L.A.
      • Fonsah J.Y.
      • Eta S.
      • Doh R.
      • et al.
      HIV-associated neurocognitive disorders in Sub-Saharan Africa: a pilot study in Cameroon.
      However, we found most investigators of NCI in Sub-Saharan Africa assessed for psychiatric diseases including depression,
      • Sacktor N.C.
      • Wong M.
      • Nakasujja N.
      • Skolasky R.L.
      • Selnes O.A.
      • Musis S.
      • et al.
      The International HIV Dementia Scale: a new rapid screening test for HIV dementia.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.
      • Robertson K.
      • Wong M.
      • Musisi S.
      • et al.
      Antiretroviral therapy improves cognitive impairment in HIV-positive individuals in Sub-Saharan Africa.
      • Njamnshi A.K.
      • Bissek A.C.
      • Ongolo-Zogo P.
      • Tabah E.N.
      • Lekoubou A.Z.
      • Yepnjio F.N.
      • et al.
      Risk factors for HIV-associated neurocognitive disorders (HAND) in Sub-Saharan Africa: the case of Yaoundé, Cameroon.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Rezapour M.
      • Robertson K.
      • Musisi S.
      • et al.
      HIV subtype D is associated with dementia, compared with subtype A, in immunosuppressed individuals at risk of cognitive impairment in Kampala, Uganda.
      • Patel V.N.
      • Mungwira R.G.
      • Tarumbiswa T.F.
      • Heikinheimo T.
      • van Oosterhout J.J.
      High prevalence of suspected HIV-associated dementia in adult Malawian HIV patients.
      • Holguin A.
      • Banda M.
      • Willen E.J.
      • Malama C.
      • Chiyenu K.O.
      • Mudenda V.C.
      • et al.
      HIV-1 effects on neuropsychological performance in a resource-limited country, Zambia.
      • Royal 3rd, W.
      • Cherner M.
      • Carr J.
      • Habib A.G.
      • Akomolafe A.
      • Abimku A.
      • et al.
      Clinical features and preliminary studies of virological correlates of neurocognitive impairment among HIV-infected individuals in Nigeria.
      • Sacktor N.
      • Nakasujja N.
      • Skolasky R.L.
      • Robertson K.
      • Musis S.
      • Ronald A.
      • et al.
      Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda.
      but the addition of assessments missing in IHDS (e.g., executive functions) in combination will definitely improve its accuracy. Combinations of assessments and tests that will yield accurate results while retaining the balance of brevity and simplicity should be explored. Secondly, only about half of the studies included in the review excluded (or declared) participants with active OIs or substance use. Few of the studies excluded those with neurological comorbidities and none utilized neuroimaging for excluding alternative diagnoses to NCI. This could have overestimated NCI, but provides some advantages from the point of view of generalizability of findings to diverse routine patient populations such as exist in HIV clinics in Sub-Saharan Africa.
      • Dickersin K.
      • Berlin J.A.
      Meta-analysis: state-of-the-science.
      Publication bias did not affect the results as our analyses using two concurrent approaches excluded it. Bias from non-inclusion of literature in other languages is unclear but likely to be minimal.
      In conclusion, HIV strongly predisposes to NCI, leading to a huge burden in Sub-Saharan Africa. Early commencement of ART can improve NCI substantially, and its scale-up as an intervention for reducing the huge burden in the region is strongly advocated.
      Conflict of interest: We declare that we have no conflicts of interest.
      Ethical approval: Not required.
      Funding: None.

      Appendix A. Supplementary data

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