Richard L. Skolasky

HIV-1, hepatitis B virus, and risk of liver-related mortality in the Multicenter Cohort Study (MACS)

BACKGROUND Although coinfection with HIV-1 and hepatitis B virus (HBV) is common, few long-term studies on liver-disease mortality in coinfected people have been undertaken. Our aim was to examine liver-related mortality among people at risk for HIV-1 and HBV infections. METHODS We used data from a multicentre, prospective cohort study to classify 5293 men who had sex with men, according to their HIV-1 antibody status, ascertained semiannually, and their hepatitis-B surface antigen status (HBsAg), which we ascertained at baseline. Mortality rates were estimated in terms of person-years and Poisson regression methods were used to test for significance of relative risks. FINDINGS 326 (6%) men were HBsAg positive, of whom 213 (65%) were HIV-1 positive. Of the 4967 HBsAg negative men, 2346 (47%) were infected with HIV-1. The liver-related mortality rate was 1.1/1000 person years, and was higher in men with HIV-1 and HBsAg (14.2/1000) than in those with only HIV-1 infection (1.7/1000, p<0.001) or only HBsAg (0.8/1000, p<0.001). In coinfected individuals, the liver-related mortality rate was highest with lower nadir CD4+ cell counts and was twice as high after 1996, when highly active antiretroviral therapy (HAART) was introduced. INTERPRETATION Individuals coinfected with HIV-1 and HBV, especially those with low CD4+ nadir counts, are at increased risk for liver-related mortality, underscoring the importance of prevention, identification, and comprehensive management of hepatitis B in people infected with HIV-1.

HIV-associated neurologic disease incidence changes: Multicenter AIDS Cohort Study, 1990–1998

This study examined the temporal trends in the incidence rates of HIV dementia, cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy, and CNS lymphoma from January 1990 to December 1998 in the Multicenter AIDS Cohort Study. The incidence rates for HIV dementia, cryptococcal meningitis, and lymphoma decreased following the introduction of highly active antiretroviral therapy (HAART). The proportion of new cases of HIV dementia with a CD4 count in a higher range (i.e., 201 to 350) since 1996 may be increasing.

Combination antiretroviral therapy improves psychomotor speed performance in HIV-seropositive homosexual men

Background: Combination antiretroviral therapy including protease inhibitors (combo+PI) is effective in suppressing systemic viral load in HIV infection, but its impact on HIV-associated cognitive impairment is unclear. Objective: To determine whether psychomotor speed, a sensitive measure of impairment in HIV dementia, improves with combo+PI compared with other antiretroviral treatments. Methods: A total of 411 HIV-seropositive (HIV+) homosexual men (with longitudinal neuropsychological testing) in the Multicenter AIDS Cohort Study and, in a separate analysis, 282 HIV+ homosexual men with psychomotor slowing at baseline were classified by treatment into four groups: antiretroviral naïve (no antiretroviral medication treatment), monotherapy, combination antiretroviral therapy without protease inhibitors (combo-noPI), and combo+PI. We compared longitudinal performance on three tests of psychomotor speed: the Grooved Pegboard (GP) (nondominant and dominant hands), Trail Making Test B, and the Symbol Digit Modalities Test (SDMT). Results: Relative to antiretroviral-naïve and monotherapy participants, on the GP nondominant hand test, combo+PI participants with abnormal baseline neuropsychological testing showed improved performance (difference = +0.63 standard deviation [SD], p = 0.02). For the SDMT, both combo+PI participants (difference = +0.26 SD, p = 0.03) and combo-noPI participants (difference = +0.29 SD, p = 0.01) with abnormal baseline neuropsychological testing improved compared with antiretroviral-naïve and monotherapy groups. Conclusion: Combo+PI and combo-noPI are associated with improved psychomotor speed performance in HIV+ homosexual men with abnormal neuropsychological testing.

Variable progression of HIV‐associated dementia

A consecutive series of 71 patients diagnosed with HIV-associated dementia (HAD) (1984–1994) were studied to characterize the clinical course of HAD, and to identify predictive markers of rapid neurologic progression. Neurologic progression rate was determined from the change in the Memorial Sloan Kettering (MSK) dementia severity score from diagnosis to death. Those with the most rapid progression in neurologic disability were compared with those with slow or no progression. Autopsy material was immunostained for macrophage activation markers and gp41 in 30 individuals. Median survival was 3.3 months and 6.1 months for rapid-progression and no-progression patients, respectively. Rapid progression was associated with injection drug use but not with race, gender, or age. CD4+ cell counts were lower at diagnosis among rapid-progression than no-progression patients but no differences in AIDS-defining illnesses or patterns of antiretroviral therapy were found. At presentation, rapid-progression patients had more prominent symptoms of mental slowing than those with no progression; however, no other clinical features, CSF, or imaging features distinguished the groups. Less abundant macrophage activation in both basal ganglia and midfrontal gyrus regions, as judged by HAM56 immunostaining, was noted in 9 no-progression patients, compared with 12 rapid-progression patients. Neurologic progression and survival with HAD is highly variable. A significant proportion of individuals with dementia have prolonged survival of more than 12 months and remain cognitively stable. A history of injection drug use and presentation with prominent psychomotor slowing is associated with more rapid neurologic progression, and these patients tend to show more abundant macrophage activation within the CNS.

Dysphagia after anterior cervical decompression and fusion: prevalence and risk factors from a longitudinal cohort study.

Study Design. Retrospective analysis of the incidence and prevalence of dysphagia after anterior cervical decompression and fusion (ACDF). Objectives. To examine the incidence and prevalence of dysphagia after ACDF, determine possible associated patient and procedural characteristics, and examine dysphagia’s impact on long-term health status and function. Summary of Background Data. Dysphagia is a common early complaint after ACDF, but the risk factors associated with its development are not understood. Methods. Telephone surveys (Cervical Spine Outcomes Questionnaire) and clinical assessments (Oswestry Neck Disability Scale and SF-36) were used to evaluate 454 patients who had undergone ACDF at one of 23 nationwide sites for individual and procedure characteristics that might contribute to dysphagia. Results. Of the 454 patients, 30% reported dysphagia at the 3-month assessment (incident cases). The incidence of new complaints of dysphagia at each follow-up point was 29.8%, 6.9%, and 6.6% at 3, 6, and 24 months, respectively. Dysphagia persisted at 6 and 24 months in 21.5% and 21.3% of patients, respectively. The risk of dysphagia increased with number of surgical vertebral levels at 3 months: 1 level, 42 of 212 (19.8%); 2 levels, 50 of 150 (33.3%); 3+ levels, 36 of 92 (39.1%). Patients reporting dysphagia at 3 months had a significantly higher self-reported disability and lower physical health status at subsequent assessments. Conclusion. Duration of preexisting pain and the number of vertebral levels involved in the surgical procedure appear to influence the likelihood of dysphagia after ACDF.

The pathology of Rasmussen syndrome: Stages of cortical involvement and neuropathological studies in 45 hemispherectomies

Summary:  Purpose: Rasmussen syndrome (RS) is a rare form of epilepsy characterized by progressive destruction of a single hemisphere. To characterize the profile of cortical involvement in RS, we studied the pathological changes in the cerebral cortex of 45 hemispherectomies performed at Johns Hopkins Hospital between 1985 and 2002.

Psychosocial risk factors of HIV morbidity and mortality: Findings from the Multicenter AIDS Cohort Study (MACS)

Despite the use of laboratory markers in estimating HIV prognosis, significant variation in the natural history of HIV-1 infection remains unexplained. Recent studies suggest psychosocial risk factors have important prognostic significance in HIV disease. The objective of the present study was to examine the prognostic influence of age, general intellectual functioning, and emotional distress across the spectrum of HIV disease progression. The study sample was drawn from the Multicenter AIDS Cohort Study (MACS), a 13-year, prospective study of HIV-seropositive men recruited from four study centers across the country. The participants were 1,231 HIV-seropositive MACS participants, followed from baseline (median 8/15/87) to the end of the observation period (12/15/98). HIV disease progression was evaluated with respect to three outcome measures: (1) number of years from baseline testing to the first AIDS defining illness (progression to AIDS), (2) years from baseline to HIV-dementia (progression to dementia), and (3) years from baseline to death (survival). The influence of psychosocial risk factors on outcome measures was evaluated using survival analyses. General intellectual functioning, age, and somatic symptoms of depression, were found to be significant predictors of HIV disease progression and survival. Older age at baseline was associated with a more rapid progression to dementia and death. Lower Shipley IQ estimates were associated with a more rapid disease progression (AIDS and dementia) and shortened survival. Somatic symptoms of depression were associated with shortened survival. In addition, age, IQ, and somatic symptoms of depression, had an additive effect with an increase in the number of risk factors associated with accelerated disease progression and shortened time to death. These findings remained consistent, despite controlling for baseline CD4 and HIV medication use. Psychosocial cofactors are important in understanding HIV disease progression. Methods for estimating HIV prognosis may become more reliable if psychosocial factors are considered. Future research will clarify if psychosocial risk factors reflect central nervous system integrity, brain reserve capacity or mediate morbidity and mortality through social economic status, access to health care and other social correlates.

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.

Clinical comparison of muscle‐specific tyrosine kinase (MuSK) antibody‐positive and ‐negative myasthenic patients

We assayed cryopreserved sera from 38 acetylcholine receptor (AChR) antibody‐negative patients with myasthenia gravis (MG) who were followed clinically for muscle‐specific tyrosine kinase (MuSK) antibodies and analyzed and compared their clinical characteristics. None of 13 sera from patients with purely ocular MG were positive. Sera from 10 of 25 patients (40%) with generalized MG were positive for MuSK antibodies. The age at onset of myasthenic symptoms was significantly earlier in MuSK antibody‐positive patients (P = 0.02). MuSK antibodies were present in AChR antibody‐negative patients of either gender, with virtually identical prevalence in women (41.2%) and men (37.5%). The distribution of weakness more commonly involved neck muscles in MuSK antibody‐positive patients, and limb muscles in MuSK antibody‐negative patients. Patients responded to immunosuppressive treatment regardless of whether MuSK antibody was present. We conclude that MuSK antibodies are present and diagnostically useful in a subset of myasthenic patients without AChR antibodies. Although the distribution of weakness differs somewhat depending on whether MuSK antibodies are present, responses to anticholinesterase and immunosuppressive treatments are similar.

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.