Colin D. Hall

Failure of Cytarabine in Progressive Multifocal Leukoencephalopathy Associated with Human Immunodeficiency Virus Infection

BACKGROUND Progressive multifocal leukoencephalopathy affects about 4 percent of patients with the acquired immunodeficiency syndrome (AIDS), and survival after the diagnosis of leukoencephalopathy averages only about three months. There have been anecdotal reports of improvement but no controlled trials of therapy with antiretroviral treatment plus intravenous or intrathecal cytarabine. METHODS In this multicenter trial, 57 patients with human immunodeficiency virus (HIV) infection and biopsy-confirmed progressive multifocal leukoencephalopathy were randomly assigned to receive one of three treatments: antiretroviral therapy alone, antiretroviral therapy plus intravenous cytarabine, or antiretroviral therapy plus intrathecal cytarabine. After a lead-in period of 1 to 2 weeks, active treatment was given for 24 weeks. For most patients, antiretroviral therapy consisted of zidovudine plus either didanosine or stavudine. RESULTS At the time of the last analysis, 14 patients in each treatment group had died, and there were no significant differences in survival among the three groups (P=0.85 by the log-rank test). The median survival times (11, 8, and 15 weeks, respectively) were similar to those in previous studies. Only seven patients completed the 24 weeks of treatment. Anemia and thrombocytopenia were more frequent in patients who received antiretroviral therapy in combination with intravenous cytarabine than in the other groups. CONCLUSIONS Cytarabine administered either intravenously or intrathecally does not improve the prognosis of HIV-infected patients with progressive multifocal leukoencephalopathy who are treated with the antiretroviral agents we used, nor does high-dose antiretroviral therapy alone appear to improve survival over that reported in untreated patients.

HIV-infected subjects with the E4 allele for APOE have excess dementia and peripheral neuropathy

HIV produces a chronic viral infection of the central nervous system that elicits chronic glial activation and overexpression of glial cytokines1–5 that are also implicated in Alzheimer disease (AD) pathogenesis6–11. A genetic risk factor for AD is the E4 isoform for apolipoprotein E (APOE)12,13. Here we compare the frequency of neurologic symptoms for subjects with and without the E4 isoform (E4(+)and E4(–), respectively) in an HIV cohort14–17. Compared with E4(–) subjects, twice as many E4(+) subjects were demented (30% compared with 15%) or had peripheral neuropathy (70% compared with 39%) at least once, and they had threefold more symptomatic examinations (13% compared with 3% and 42% compared with 14%, respectively)(P < 0.0001). Thus, neurologic symptoms for HIV-infection and AD are linked through an etiologic risk factor. Long-term survivors of HIV infection with E4 may be at high risk for AD; conversely, gene–viral interactions may speed AD pathogenesis.

Lamotrigine for HIV-associated painful sensory neuropathies: A placebo-controlled trial

Objective: To evaluate the efficacy and tolerability of lamotrigine (LTG) for the treatment of pain in HIV-associated sensory neuropathies. Methods: In a randomized, double-blind study, patients with HIV-associated distal sensory polyneuropathy (DSP) received LTG or placebo during a 7-week dose escalation phase followed by a 4-week maintenance phase. Randomization was stratified according to whether or not patients were currently using neurotoxic antiretroviral therapy (ART). Results: The number of patients randomized was 92 (62 LTG, 30 placebo) in the stratum receiving neurotoxic ART and 135 (88 LTG, 47 placebo) in the stratum not receiving neurotoxic ART. Mean change from baseline in Gracely Pain Scale score for average pain was not different between LTG and placebo at the end of the maintenance phase in either stratum, but the slope of the change in Gracely Pain Scale score for average pain reflected greater improvement with LTG than with placebo in the stratum receiving neurotoxic ART (p = 0.004), as did the mean change from baseline scores on the Visual Analogue Scale for Pain Intensity and the McGill Pain Assessment Scale and patient and clinician ratings of global impression of change in pain (p ≤ 0.02). The incidence of adverse events, including rash, was similar between LTG and placebo. Conclusions: Lamotrigine was well-tolerated and effective for HIV-associated neuropathic pain in patients receiving neurotoxic antiretroviral therapy. Additional research is warranted to understand the differing response among patients receiving neurotoxic antiretroviral therapy compared with those not receiving neurotoxic antiretroviral therapy.

Neurological outcomes in late HIV infection: Adverse impact of neurological impairment on survival and protective effect of antiviral therapy

OBJECTIVE In a large multi-center clinical trial of combination reverse transcriptase inhibitors (RTIs), we assessed the impact of antiretroviral therapy on neurological function, the relationship between neurological and systemic benefit, and the prognostic value of neurological performance in late HIV-1 infection. DESIGN Neurological evaluations incorporated in a randomized, multi-center trial of combination antiretroviral therapy. SETTING Forty-two AIDS Clinical Trials Group sites and seven National Hemophilia Foundation sites. PATIENTS Adult HIV-infected patients (n = 1313) with CD4 counts < 50 x 10(6) cells/l. INTERVENTIONS Four combinations of reverse transcriptase inhibitors consisting of zidovudine (ZDV), alternating monthly with didanosine (ddl), or in combination with zalcitabine (ddC), ddl or ddl and nevirapine. MAIN OUTCOME MEASURES Mean change from baseline of a four-item quantitative neurological performance battery score, the QNPZ-4, administered to 1031 subjects. RESULTS Triple therapy and ZDV/ddl combination preserved or improved neurological performance over time compared with the alternating ZDV/ddl and ZDV/ddC regimens (P < 0.001), paralleling their impact on survival in the same trial as previously reported. QNPZ-4 scores were predictive of survival (P < 0.001), after adjusting for CD4 counts and HIV-1 plasma RNA concentrations. CONCLUSIONS Combination antiretroviral therapy can have a salutary effect on preserving or improving neurological function. Superior systemic treatments may likewise better preserve neurological function. The significant association of poor neurological performance with mortality, independent of CD4 counts and HIV-1 RNA levels indicates that neurological dysfunction is an important cause or a strong marker of poor prognosis in late HIV-1 infection. This study demonstrates the value of adjunctive neurological measures in large therapeutic trials of late HIV-1 infection.

Oxandrolone in AIDS-wasting myopathy.

Objective: To evaluate oxandrolone, an oral anabolic steroid with potent anabolic activity and minimal androgenic effects, for the treatment of AIDS‐associated myopathy and wasting. Methods: In a multicenter, double‐blind study, 63 HIV‐seropositive men with > 10% loss of body weight were randomized to receive either placebo, 5 mg/day oxandrolone, or 15 mg/day oxandrolone for 16 weeks. Body weight, neuromuscular evaluation, and measures of well‐being were repeatedly assessed. Results: Patients who received 15 mg/day oxandrolone showed weight gain throughout the 16‐week treatment period. Overall, the 5 mg/day oxandrolone group maintained their weight gain over the 16‐week period, whereas the placebo group showed continual weight loss. At week 16, significantly more patients in the 15 mg/day dose group reported increases in appetite and activity than those receiving placebo. There were no consistent, dose related, statistically significant differences from baseline in laboratory values or adverse events. Conclusion: Oxandrolone, at a dose of either 5 mg/day or 15 mg/day, in contrast to placebo, had a positive impact on the weight and well‐being of HIV‐seropositive patients suffering from wasting and weakness. Measurable improvement in muscle strength was not noted at the doses employed in this study. Oxandrolone was well tolerated in all the patients who were enrolled in the study Based on the results reported here, additional studies using higher doses of oxandrolone seem warranted.

Highly active antiretroviral therapy improves neurocognitive functioning

Summary:Although the effects of highly active antiretroviral therapy (HAART) have resulted in substantial improvements in the systemic health of patients with HIV infection, concerns remain that these medications, which cross the blood–brain barrier poorly, may have a less beneficial effect on nervous system function. This raises the possibility that there may be a progressive long-term decline in neurologic function in patients with adequate systemic response. In a prospective longitudinal study, subjects were evaluated immediately before instituting HAART. Forty-eight subjects underwent ultrasensitive HIV RNA quantitative evaluation of both plasma and cerebrospinal fluid as well as neurologic and neuropsychological examinations. They were reevaluated 6 months after treatment initiation while receiving stable HAART. Both plasma and cerebrospinal fluid viral levels significantly declined after treatment. There was significant improvement in neurologic and neuropsychological functioning after HAART. These results indicate that despite the poor central nervous system penetration of most of these agents, there is satisfactory short-term improvement in both central nervous system viral burden and nervous system function with HAART. However, because treatment failure is increasingly likely over time, continued longitudinal evaluation of this group of subjects is required.

White matter abnormalities revealed by diffusion tensor imaging in non-demented and demented HIV+ patients.

HIV associated dementia (HAD) is the most advanced stage of central nervous system disease caused by HIV infection. Previous studies have demonstrated that patients with HAD exhibit greater cerebral and basal ganglia atrophy than non-demented HIV+ (HND) patients. However, the extent to which white matter is affected in HAD patients compared to HND patients remains elusive. This study is designed to address the potential white matter abnormalities through the utilization of diffusion tensor imaging (DTI) in both HND and HAD patients. DTI and T1-weighted images were acquired from 18 healthy controls, 21 HND and 8 HAD patients. T1 image-based registration was performed to 1) parcellate the whole brain white matter into major white matter regions, including frontal, parietal, temporal and occipital white matter, corpus callosum and internal capsule for statistical comparisons of the mean DTI values, and 2) warp all DTI parametric images towards the common template space for voxel-based analysis. The statistical comparisons were performed with four DTI parameters including fractional anisotropy (FA), mean (MD), axial (AD), and radial (RD) diffusivities. With Whitney U tests on the mean DTI values, both HND and HAD demonstrated significant differences from the healthy control in multiple white matter regions. In addition, HAD patients exhibited significantly elevated MD and RD in the parietal white matter when compared to HND patients. In the voxel-based analysis, widespread abnormal regions were identified for both HND and HAD patients, although a much larger abnormal volume was observed in HAD patients for all four DTI parameters. Furthermore, both region of interest (ROI) based and voxel-based analyses revealed that RD was affected to a much greater extent than AD by HIV infection, which may suggest that demyelination is the prominent disease progression in white matter.

Increased Human Immunodeficiency Virus Type 1 (HIV-1) env Compartmentalization in the Presence of HIV-1-Associated Dementia

ABSTRACT The human immunodeficiency virus type 1 (HIV-1) surface Env protein has been implicated in the development of HIV-1-associated dementia (HAD). HIV-1 env diversity was analyzed by heteroduplex tracking assay in 27 infected subjects with various neurological statuses. env compartmentalization between the blood and cerebral spinal fluid (CSF) was apparent with all neurological categories. However, in subjects with HAD, significantly more CSF virus was represented by CNS-unique env variants. Variants specialized for replication in the CNS may play a larger role in the development of HAD. Alternatively, HAD may be associated with a more pronounced state of immunosuppression that permits more extensive replication and independent evolution within the CNS compartment.

Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy.

The detection and semiquantitation of JC virus (JCV) DNA in cerebrospinal fluid (CSF) is prognostic of survival and is a marker of the course of progressive multifocal leukoencephalopathy (PML). CSF samples from 15 acquired immunodeficiency syndrome (AIDS) patients with biopsy‐proven PML were analyzed by semiquantitative polymerase chain reaction (PCR). A low JCV burden was predictive of longer survival compared with a high JCV burden (median survival from entry, 24 [2–63] vs 7.6 [4–17] weeks). Further analyses indicated a possible threshold of 50 to 100 copies/μl separating high‐ and moderate‐risk cases. Patients with a JCV load below this level survived longer than those with a JCV load above it. Ann Neurol 1999;45:816–820

Cross-sectional characterization of HIV-1 env compartmentalization in cerebrospinal fluid over the full disease course.

Objectives:To characterize HIV-1 env compartmentalization between cerebrospinal fluid (CSF) and peripheral blood plasma over all stages of the HIV-1 disease course, and to determine the relationship between the extent of CSF HIV-1 env compartmentalization and clinical neurologic disease status. Design:Paired blood plasma and CSF specimens were collected from 66 HIV-infected patients cross-sectionally representing all major clinical stages relating to HIV-associated neurologic disease, including primary infection, asymptomatic chronic infection, chronic infection with minor global impairment, and immune deficiency with HIV-associated dementia. Methods:Heteroduplex tracking assays and bulk sequence analysis targeting the V1/V2, C2-V3, and V4/V5 regions of env were performed to characterize the genetic makeup of complex HIV-1 populations in the cross-sectional blood plasma and CSF specimens. The levels of blood plasma/CSF env compartmentalization were quantified and compared across the different clinical stages of HIV-1 neurologic disease. Results:Blood plasma/CSF env compartmentalization levels varied considerably by disease stage and were generally consistent across all three regions of env characterized. Little or no compartmentalization was observed in non-impaired individuals with primary HIV-1 infection. Compartmentalization levels were elevated in chronically infected patients, but were not significantly different between mildly impaired and non-impaired patients. Patients with HIV-associated dementia showed significantly greater blood plasma/CSF env compartmentalization relative to other groups. Conclusion:Increased CSF compartmentalization of the HIV-1 env gene, which may reflect independent HIV-1 replication and evolution within the central nervous system, is specifically associated with HIV-associated dementia and not the less severe forms of HIV-1 neurologic disease.