Noeline Nakasujja

Antiretroviral therapy improves cognitive impairment in HIV+ individuals in sub-Saharan Africa

Background: Highly active antiretroviral therapy (HAART) can improve cognitive performance in some patients with HIV-associated cognitive impairment in the United States. The effect of HAART on HIV dementia in sub-Saharan Africa is largely unknown. Objective: To evaluate neuropsychological test and functional performance in HIV+ individuals after 3 and 6 months of HAART in Uganda. Methods: Twenty-three HIV+ individuals receiving HAART also received a detailed clinical history, neuropsychological testing, and a functional assessment. Follow-up evaluations were performed at 3 and 6 months after baseline. Longitudinal changes in the HIV dementia stage, the mean Z score for each neuropsychological test, and the Karnofsky Functional Performance Scale were evaluated at 3 and 6 months. Results: The mean (SD) CD4 cell count improved from 71 (15) at baseline to 161 (30) at 3 months (p = 0.005) and 222 (46) at 6 months (p < 0.001). Improvements were found in the Memorial Sloan Kettering HIV dementia stage and in tests of verbal memory, psychomotor speed, and executive functioning after 3 and 6 months of HAART (p < 0.001 at 6 months for each neuropsychological test). There was also improvement in the Karnofsky Functional Performance Scale at both 3 and 6 months after the initiation of HAART (p < 0.001). Conclusion: Highly active antiretroviral therapy (HAART) can be associated with improvement in neurocognitive and functional performance in HIV+ individuals in sub-Saharan Africa. These results suggest that HAART, if available in areas with limited resources in sub-Saharan Africa, should be provided for patients with HIV-associated cognitive impairment.

HIV Subtype D Is Associated with Dementia, Compared with Subtype A, in Immunosuppressed Individuals at Risk of Cognitive Impairment in Kampala, Uganda

BACKGROUND In the United States, clade B is the predominant human immunodeficiency virus (HIV) subtype, whereas in sub-Saharan Africa, clades A, C, and D are the predominant subtypes. HIV subtype may have an impact on HIV disease progression. The effect of HIV subtype on the risk of dementia has, to our knowledge, not been examined. The objective of this study was to examine the relationship between HIV subtype and the severity of HIV-associated cognitive impairment among individuals initiating antiretroviral therapy in Uganda. METHODS Sixty antiretroviral-naive HIV-infected individuals with advanced immunosuppression who were at risk of HIV-associated cognitive impairment underwent neurological, neuropsychological, and functional assessments, and gag and gp41 regions were subtyped. Subtype assignments were generated by sequence analysis using a portion of the gag and gp41 regions. RESULTS Thirty-three HIV-infected individuals were infected with subtype A, 2 with subtype C, 9 with subtype D, and 16 with A/D recombinants. Eight (89%) of 9 HIV-infected individuals with subtype D had dementia, compared with 7 (24%) of 33 HIV-infected individuals with subtype A (P = .004). CONCLUSIONS These results suggest that, in untreated HIV-infected individuals with advanced immunosuppression who are at risk of developing HIV-associated cognitive impairment, HIV dementia may be more common among patients infected with subtype D virus than among those infected with subtype A virus. These findings provide the first evidence, to our knowledge, to demonstrate that HIV subtypes may have a pathogenetic factor with respect to their capacity to cause cognitive impairment. Additional studies are needed to confirm this observation and to define the mechanism by which subtype D leads to an increased risk of neuropathogenesis.

Depression symptoms and cognitive function among individuals with advanced HIV infection initiating HAART in Uganda

BackgroundAmong patients with HIV infection, depression is the most frequently observed psychiatric disorder. The presence of depressive symptoms and cognitive dysfunction among HIV patients has not been well studied in Sub-Saharan Africa. Initiation of highly active antiretroviral therapy (HAART) may have an effect on the prevalence and the change over time of depression symptoms and cognitive impairment among HIV-positive individuals.MethodsWe recruited 102 HIV-positive individuals at risk of cognitive impairment who were initiating HAART and 25 HIV-negative individuals matched for age and education. Depression was assessed using the Centre for Epidemiologic Studies Depression Scale (CES-D). Neurocognitive assessment included the International HIV Dementia Scale (IHDS), an 8 test neuropsychological battery and the Memorial Sloan Kettering scale. Assessments were carried out at 0, 3 and 6 months.ResultsThe HIV-positive group had more respondents with CES-D score > 16 than the HIV-negative group at all 3 clinic visits (54%Vs 28%; 36% Vs 13%; and 30% Vs 24% respectively; all p < 0.050 OR 2.86, 95% CI: 1.03, 7.95, p = 0.044). The HIV positive group had higher likelihood for cognitive impairment (OR 8.88, 95% CI 2.64, 29.89, p < 0.001). A significant decrease in the mean scores on the CES-D (p = 0.002) and IHDS (p = 0.001) occurred more in the HIV-positive group when compared to the HIV-negative group. There was no association between clinical Memorial Sloan Kettering score and depression symptoms (p = 0.310) at baseline.ConclusionDepression symptomatology is distinct and common among cognitively impaired HIV patients. Therefore individuals in HIV care should be screened and treated for depression.

FREQUENCY OF AND RISK FACTORS FOR HIV DEMENTIA IN AN HIV CLINIC IN SUB-SAHARAN AFRICA

neurologic disorders. We would like to clarify a few points they raise regarding our estimate in relation to others. First, our review was not a true meta-analysis; we did not pool the original data from the studies we reviewed because of their heterogeneity, instead we simply described the median and range of estimates the studies yielded. While not ideal, the inherent limitations of extrapolating findings from other countries than the United States were reduced by restricting our review to studies in developed countries where advanced health care resources were generally available. The few recently published North American studies yielded some very high estimates of MS occurrence, perhaps related to the mainly northern European origin of the communities studied, a group associated with higher MS risk not representative of the entire US population. Data reported directly from voluntary registries are not a reliable basis for estimating either incidence rates or prevalence in a population. Lack of motivation or knowledge among persons eligible to submit their names may lead to underreporting. Conversely, over-reporting may easily occur without adequate methods to adjust for duplicate reports, eliminate unverifiable or false reports, and account in a timely manner for deaths and out-migration. The possibility of major error—either overestimation or underestimation—is large. Among all studies we reviewed, the median estimated prevalence of MS was 0.93 per 1,000. In comparison, the National Health Interview Survey of 1989 to 1994 yielded anMS prevalence estimate of 0.85/1,000 population4 and a study of two counties in Colorado yielded 0.84/1,000.5 We did not include these two population-based studies in our review because Noonan et al.4 relied on selfreported diagnoses and Nelson et al.5 was published before 1990. Finally, our estimate was limited to definite or probable cases of MS. The earlier NIH estimate of MS prevalence of 1.2 /1,0006 also included possible cases, which may account for much of the modest difference between the two estimates. We strongly support relying on the best possible studies—and not anecdotal evidence or nonpopulation-based data—conducted in the same way over time, to inform us about the true frequency and time trends of diseases with major burden to the US population.

Pattern of neuropsychological performance among HIV positive patients in Uganda

BackgroundFew studies have examined cognitive functioning of HIV positive patients in sub-Saharan Africa. It cannot be assumed that HIV positive patients in Africa exhibit the same declines as patients in high-resource settings, since there are differences that may influence cognitive functioning including nutrition, history of concomitant disease, and varying HIV strains, among other possibilities. Part of the difficulty of specifying abnormalities in neuropsychological functioning among African HIV positive patients is that there are no readily available African normative databases. The purpose of the current study was to evaluate the pattern of neuropsychological performance in a sample of HIV positive patients in comparison to HIV negative control subjects in Uganda.MethodsThe neuropsychological test scores of 110 HIV positive patients (WHO Stage 2, n = 21; WHO Stage 3, n = 69; WHO Stage 4, n = 20) were contrasted with those of 100 control subjects on measures of attention/concentration, mental flexibility, learning/memory, and motor functioning.ResultsAnalysis of covariance (ANCOVA) revealed significant group differences on measures of verbal learning and memory, speed of processing, attention and executive functioning between HIV seropositive and seronegative subjects.ConclusionUgandan patients with HIV demonstrated relative deficits on measures of verbal learning and memory, speed of processing, attention, and executive functioning compared to HIV negative controls. These results from a resource limited region where clades A and D are prevalent are consistent with previous findings in the developed world where clade B predominates.

A year-long caregiver training program improves cognition in preschool Ugandan children with human immunodeficiency virus.

OBJECTIVE To evaluate mediational intervention for sensitizing caregivers (MISC). MISC biweekly caregiver training significantly enhanced child development compared with biweekly training on health and nutrition (active control) and to evaluate whether MISC training improved the emotional well-being of the caregivers compared with controls. STUDY DESIGN Sixty of 120 rural Ugandan preschool child/caregiver dyads with HIV were assigned by randomized clusters to biweekly MISC training, alternating between home and clinic for 1 year. Control dyads received a health and nutrition curriculum. Children were evaluated at baseline, 6 months, and 1 year with the Mullen Early Learning Scales and the Color-Object Association Test for memory. Caldwell Home Observation for Measurement of the Environment and videotaped child/caregiver MISC interactions also were evaluated. Caregivers were evaluated for depression and anxiety with the Hopkins Symptoms Checklist. RESULTS Between-group repeated-measures ANCOVA comparisons were made with age, sex, CD4 levels, viral load, material socioeconomic status, physical development, and highly active anti-retroviral therapy treatment status as covariates. The children given MISC had significantly greater gains compared with controls on the Mullen Visual Reception scale (visual-spatial memory) and on Color-Object Association Test memory. MISC caregivers significantly improved on Caldwell Home Observation for Measurement of the Environment scale and total frequency of MISC videotaped interactions. MISC caregivers also were less depressed. Mortality was less for children given MISC compared with controls during the training year. CONCLUSIONS MISC was effective in teaching Ugandan caregivers to enhance their childrens cognitive development through practical and sustainable techniques applied during daily interactions in the home.

Benefits and risks of stavudine therapy for HIV-associated neurologic complications in Uganda

Background: The frequency of HIV dementia in a recent study of HIV+ individuals at the Infectious Disease Institute in Kampala, Uganda, was 31%. Coformulated generic drugs, which include stavudine, are the most common regimens to treat HIV infection in Uganda and many other parts of Africa. Objective: To evaluate the benefits and risks of stavudine-based highly active antiretroviral therapy (HAART) for HIV-associated cognitive impairment and distal sensory neuropathy. The study compared neuropsychological performance changes in HIV+ individuals initiating HAART for 6 months and HIV− individuals receiving no treatment for 6 months. The risk of antiretroviral toxic neuropathy as a result of the initiation of stavudine-based HAART was also examined. Methods: At baseline, 102 HIV+ individuals in Uganda received neurologic, neuropsychological, and functional assessments; began HAART; and were followed up for 6 months. Twenty-five HIV− individuals received identical clinical assessments and were followed up for 6 months. Results: In HIV+ individuals, there was improvement in verbal memory, motor and psychomotor speed, executive thinking, and verbal fluency. After adjusting for differences in sex, HIV+ individuals demonstrated significant improvement in the Color Trails 2 test (p = 0.025) compared with HIV− individuals. Symptoms of neuropathy developed in 38% of previously asymptomatic HIV+ patients after initiation of the stavudine-based HAART. Conclusions: After the initiation of highly active antiretroviral therapy (HAART) including stavudine, HIV+ individuals with cognitive impairment improve significantly as demonstrated by improved performance on a test of executive function. However, peripheral neurotoxicity occurred in 30 patients, presumably because of stavudine-based HAART, suggesting the need for less toxic therapy.

A Year-Long Caregiver Training Program to Improve Neurocognition in Preschool Ugandan HIV-Exposed Children

Objective: Mediational intervention for sensitizing caregivers (MISC) is a structured program enabling caregivers to enhance their child’s cognitive and emotional development through daily interactions. The principal aim was to evaluate if a year-long MISC caregiver training program produced greater improvement in child cognitive and emotional development compared with a control program. Methods: One hundred and nineteen uninfected HIV-exposed preschool children and their caregivers were randomly assigned to 1 of 2 treatment arms: biweekly MISC training alternating between home and clinic for 1 year or a health and nutrition curriculum. All children were evaluated at baseline, 6 months, and 1 year with the Mullen Early Learning Scales, Color-Object Association Test for memory, and Achenbach Child Behavior Checklist for psychiatric symptoms. Caregivers were evaluated on the same schedule with the Hopkins Symptoms Checklist-25 for depression and anxiety. Results: The treatment arms were compared using repeated-measures analysis of covariance with child age, gender, weight, socioeconomic status, caregiving quality, caregiver anxiety, and caregiver education as covariates. The MISC children had significantly greater gains compared to controls on the Mullen Receptive and Expressive Language development, and on the Mullen composite score of cognitive ability. Color-Object Association Test total memory for MISC children was marginally better than controls. No Achenbach Child Behavior Checklist differences between the groups were noted. Caldwell Home Observation for Measurement of the Environment scores and observed mediational interaction scores from videotapes measuring caregiving quality also improved significantly more for the MISC group. Conclusions: The MISC enhanced cognitive performance, especially in language development. These benefits were possibly mediated by improved caregiving and positive emotional benefit to the caregiver.

Randomized trial of minocycline in the treatment of HIV-associated cognitive impairment.

Objective: To evaluate the efficacy and safety of minocycline in the management of HIV-associated cognitive impairment. Methods: We enrolled HIV-positive participants with a CD4 count of 250 to 500 cells/μL in a randomized, double-blind, placebo-controlled study. They received 100 mg of minocycline or matching placebo orally every 12 hours for 24 weeks. Cognitive function was measured using the Uganda Neuropsychological Test Battery Summary Measure (U NP Sum) and the Memorial Sloan-Kettering (MSK) scale. The primary efficacy measure was the 24-week change in an average of 9 standardized U NP Sum z scores. Results: Seventy-three participants were enrolled. Of these, 90% were female, 49% were between the ages 30 and 39 years, and 74% had 6 or more years of education. One participant had MSK score of stage 1 (i.e., mild HIV dementia), and 72 participants had MSK stage 0.5 (i.e., equivocal or subclinical dementia) at the baseline evaluation. The minocycline effect on the 24-week change of the U NP Sum compared with placebo was 0.03 (95% confidence interval −0.51, 0.46; p = 0.37). Conclusion: Minocycline was safe and well tolerated in HIV-positive individuals. However, it did not improve HIV-associated cognitive impairment. Classification of evidence: This study provides Class II evidence that 100 mg of minocycline given orally every 12 hours for 24 weeks had no significant effect compared with placebo in the improvement of cognitive function in antiretroviral therapy–naive, HIV-positive patients.

HIV-associated cognitive impairment in sub-Saharan Africa -- the potential effect of clade diversity.

In the US, HIV dementia occurs in 10–15% of HIV-positive individuals with advanced infection. The prevalence of HIV dementia in sub-Saharan countries, where the vast majority of individuals with HIV reside, is largely unknown. This Review will summarize our current understanding of HIV-associated cognitive impairment in resource-limited settings, focusing specifically on the countries of sub-Saharan Africa. We will describe the frequency of HIV dementia and HIV-associated cognitive impairment from several case series in the sub-Saharan region. We will then summarize recent studies from Uganda and Ethiopia that included detailed neuropsychological assessments. The potential influence of clade diversity on HIV-associated cognitive impairment will be discussed. Differences between the results of the studies in Uganda and in Ethiopia raise the possibility that HIV subtypes might have different biological properties with respect to their capacity to cause HIV-associated cognitive impairment. Further studies are needed to determine the true prevalence of HIV dementia in sub-Saharan Africa and to establish whether specific clade subtypes might influence the presentation of neurological complications.