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NeuroAids Vol. 4, Issue 2 (February 2001)        

Clinical Trials and Clinical Targets in NeuroAIDS

T.F. Kresina1 and E.S. Stover2, and D.M. Rausch2

1Opportunistic Infections Research Branch, Therapeutics Research Program, Division of AIDS, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892

2Center for Mental Health Research on AIDS, National Institute on Mental Health, National Institutes of Health, Bethesda, MD 20892


Keywords: peripheral neuropathy; clinical trials; HIV-associated dementia; HIV-1

Abstract Introduction: The Neurological Manifestations of HIV Infection Antiretroviral Therapy Adjunct Therapy Conclusions and Future Directions References

Neurological manifestations of HIV infection remain an important clinical issue in the medical management of patients with HIV infection. Neurological manifestations not only lead to pain and disability, but also are an independent risk factor for mortality. This article reviews the rationale for, and progress in, the development of therapies explicitly targeted to neurological manifestations of HIV disease. Further progress depends on the identification of mechanism-based molecular and cellular targets and the identification of surrogate markers to assess progression of neurological disease. Concluding remarks address directions for future clinical research and the global dimensions of HIV neurological disease.

Introduction: The Neurological Manifestations of HIV Infection
Abstract Introduction: The Neurological Manifestations of HIV Infection Antiretroviral Therapy Adjunct Therapy Conclusions and Future Directions References

Neurological manifestations of HIV disease persist as serious and frequent clinical concerns. They can interfere with patients' independence, employment, quality of life, and adherence to complicated treatment regimens (1). Alarmingly, they may also be an independent risk factor for mortality (2).

Neurological manifestations include a broad range of conditions either primary to HIV pathogenesis or secondary to anti-retroviral medications, opportunistic infections or neoplasms. Primary HIV pathogenesis in the CNS includes minor neurological impairments and HIV-1 associated cognitive/motor complex (also known as HIV-1 encephalopathy or AIDS dementia complex). Peripheral neuropathy stems from HIV pathogenesis or is an adverse effect of antiretroviral treatment, but its etiology is poorly understood. Opportunistic infections and neoplasms include cryptococcal meningitis, CNS toxoplasmosis; or activation of the common human polyomavirus JC virus (JCV) infection, causing progressive multifocal leukoencephalopathy (PML); and primary CNS lymphoma.

Rationale for New Drug Development

Findings from treatment, epidemiology, and virology research offer a powerful rationale for the development of new therapies expressly targeted to neurological manifestations. Most neurological manifestations are currently treated with potent antiretroviral therapy (ART ) to control viral replication. While exceedingly beneficial in reducing HIV mortality and morbidity, ART is not without limitations. Some of the agents in ART penetrate poorly into the CNS (3)(4). Further, ART is associated with significant side effects, including peripheral neuropathy, and it is ineffective for 20-50 percent of patients (5). Finally, its full impact on the range of cognitive and motor neurological impairments, while under investigation, is not yet known, nor is its long-term efficacy (1).

Epidemiology findings in the era of ART are both encouraging and worrisome. There appears to be lower incidence of HIV associated dementia, opportunistic infections, and primary CNS lymphoma (6). However, with increasing life expectancy, the prevalence of HIV-associated dementia or milder neurological impairments may increase. According to a review of 30 studies conducted before the era of ART, subtle neurocognitive impairment affects 35 percent of asymptomatic HIV+ people, compared with 12 percent of seronegative controls experiencing head injury or other neurological disorders (7). The incidence of PML has remained relatively constant (8). Nucleoside analogue reverse transcriptase inhibitors (ddC, ddI and d4T) contribute to the six patterns of HIV-associated peripheral neuropathy, which affect 30-40 percent of patients (8). In largely untreated populations, peripheral neuropathy is inversely related to CD4 count and ranges from 10-30% of infected patients (9).

Of great concern are recent studies suggesting independent evolution of HIV in the cerebral spinal fluid (CSF) and the CNS: these compartments contain HIV genotypes distinct from those in the blood and in other regions of the CNS (10)(11)(12)(13). The CNS may also contain virus with different drug resistance profiles (14). These findings prompt concerns about possible CNS viral reservoirs that cannot be eradicated with current treatment. New treatment strategies are warranted in the face of this uncertainty, and they critically depend on understanding HIV neuropathogenesis.

HIV Neuropathogenesis

Infection of the human CNS with HIV appears to be an early event in HIV pathogenesis (15)(16)(17), confirmed in the primate model via peripheral inoculation of the related simian immunodeficiency virus (18)(19). HIV infection of the CNS induces distinctive pathological changes, found in 25 percent of patients at autopsy (20). A pathological hallmark is the multi-nucleated giant cell, formed by fusion of infected cells of monocyte lineage (21)(22), as well as perivascular infiltration of immune cells, white matter pallor (reduced uptake of myelin stain), reactive astrocytosis (proliferation of astrocytes), microglial nodules, inflammation of the choroid plexus, and various degrees of neuronal loss and damage to dendrites (22)(23)(24)(25). The pathological changes are typically localized to subcortical structures, including deep white matter and basal ganglia, but may also be found in the cortex. Viral load in the brain at autopsy is broadly distributed, yet is highest in the basal ganglia and hippocampus (26). Unfortunately, there is neither an established viral threshold for neuropathogenesis nor strong correlation between viral load in the brain and neurological manifestations (27). However, recent research has found a correlation between viral load in CSF and the degree of dementia (2)(28)(29)(30), indicating that CSF may provide a valuable index of viral replication and inflammation of the brain, particularly in advanced HIV disease (31).

The principal cells infected by HIV within the CNS are microglia/macrophages (MG/MP) (32). While HIV does not directly infect neurons, neuron dysfunction or apoptosis is an indirect consequence of HIV infection. Upon their infection or activation, MG/MP release a barrage of factors that are toxic to nearby neurons, including cytokines, chemokines, and viral proteins (32)(33). The mechanisms of how they induce neurotoxicity are poorly understood. There is some evidence that viral protein-induced neurotoxicity is mediated by chemokine receptors on neurons (34).

Chemokines and their receptors represent exciting new therapeutic targets because of their multiple roles in HIV disease: (1) as co-receptors (with CD4) to facilitate HIV infection of T-cells and monocytes; (2) as chemoattractants that control recruitment of leukocytes across the blood brain barrier (BBB) and within the CNS; and (3) as possible vehicles for neurotoxicity because of chemokine receptor expression on neurons (35)(36)(37).

Antiretroviral Therapy
Abstract Introduction: The Neurological Manifestations of HIV Infection Antiretroviral Therapy Adjunct Therapy Conclusions and Future Directions References

Antiretroviral Therapy

There are several ongoing clinical trials studying the impact of ART on neurological manifestations of HIV as part of the Adult AIDS Clinical Trails Group (AACTG). These trials are addressing three important medical management questions: (1) Does ART reduce a broad range of neurological manifestations associated with HIV infection? (2) Are there specific antiviral drugs that efficiently penetrate the brain or cerebral spinal fluid? and (3) Are there antiviral regimens that more effectively suppress viral load in the CSF? If so, is treatment associated with improved cognitive performance? Most other AACTG clinical trials of novel antiretroviral regimens exclude individuals with more advanced stages of peripheral neuropathy or other neurological manifestations.

Peripheral neuropathy

Results of recent clinical trials indicate that responders to ART show improvements in perception thresholds for warmth, cold and heat pain, with improvement associated with higher pretreatment CD4+ levels (38). Thus, individuals with less advanced immunodeficiency may have the capacity to improve function of the thermal and nociceptive systems. A recent study has shown an additive neurotoxicity of ddI, d4T and hydroxyurea and the increasing relative risk of neuropathy with these agents (39). These paradoxical sets of findings may reflect peripheral neuropathy's apparent multicausation by HIV and ART.

HIV-associated dementia

Anti-retroviral treatment of HIV-associated dementia is currently being addressed by several AACTG antiretroviral "parent" therapy trials supported by the National Institute of Allergy and Infectious Diseases. On the basis of disease surveillance, ART appears to be effective in reducing the incidence of HIV-associated dementia (40) . Recent studies have shown that ART improves some neurological impairments in addition to systemic measures of HIV infection (41)(42)(43)(44). These studies showed that patients responding to therapy had increased CD4+ counts, a reduction in the AIDS dementia complex stage, and changes in multiple cerebral metabolite parameters, including choline/creatine ratio, myoinositol/creatine ratio, myoinositol concentration. The changes were noted in the basal ganglia, midfrontal cortex, glial cells and frontal white matter. Other studies have correlated changes in systemic cytokines to improved neuropsychological function as well as a decrease in HIV RNA in the CSF (45).

Thus far, a major obstacle in clinical trials has been the lack of surrogate markers with which to gauge treatment efficacy. Recently, a much-needed surrogate marker for monitoring of changes in HIV-associated dementia has been suggested. Homovanilic acid, the primary metabolite of dopamine, was shown to be significantly lower in the CSF of HIV-infected individuals compared to controls (46). In addition, individual homovanilic acid levels in the CSF correlated with performance levels on specific neuropsychologic tests indicating specific motor and/or cognitive abnormalities associated with HIV dementia may be related to depressed dopamine levels.

Progressive multifocal leukoencephalopathy

PML remains a devastating demyelinating condition caused by JCV. An initial study has shown that treatment of PML with ART increased the median survival time to 545 days compared to 60 days in the untreated historical controls (47). In the ART cohort, PML lesions either stabilized or improved as assessed by cranial computer tomography. In addition, clearance of JCV from the CSF was noted in most of the treated patients. More recent studies have obtained similar findings (48)(49). In these cohorts, ART prolonged median survival to greater than 300 days in one study and reduced JCV levels in the CSF. In multivariate analysis, only an undetectable JCV load in the CSF predicted longer survival, suggesting that JCV level in the CSF may represent a key marker for progression and survival in PML (50).

Drug penetration and viral clearance from the CNS

It is vital to study the extent and mechanism(s) of drug penetration into, and viral clearance from, the CNS. The first hurdle to overcome is the difficulty of biological sampling in the CNS. A recent study found that ultraintensive sampling of the CSF and plasma of HIV patients can be used to determine pharmacokinetics of antiretroviral drugs in the CNS, as well as drug resistant HIV phenotypes in the CSF (51). CSF levels of stavudine were approximately 42% of plasma drug levels. HIV-1 has discordant decay kinetics in the plasma and CSF compartments, with slower decay in the CSF. Nevirapine CSF pharmacokinetics revealed a CSF/plasma ratio of 0.29 with a dose-adjusted CSF concentration of 25% of that in plasma (52). Lamivudine treatment showed a correlation between plasma and CSF HIV-1 RNA levels (53). Numerous studies have investigated the penetration of indinavir in the CSF with widely ranging results. Recent data indicate that the concentration of indinavir in the CSF can be relatively stable and reach therapeutic levels (54)(55). Zidovudine, the best studied drug for HIV-associated dementia, has been found to reach therapeutic levels in the CSF, accompanied by reduced HIV RNA in the CSF and improved neurological function (56). In vitro studies have shown efavirenz to be a potent inhibitor of HIV-1 infection in microglia cells, suggesting CNS efficacy on penetration of the BBB (57). Taking these sampling data into account, new clinical trials are needed to establish the best therapeutic regimen for reducing HIV viral loads in the CNS.


Adjunct Therapy
Abstract Introduction: The Neurological Manifestations of HIV Infection Antiretroviral Therapy Adjunct Therapy Conclusions and Future Directions References

Therapeutic agents besides ART must be targeted to the pathological sequelae of HIV neurological infection. These sequelae range from pain associated with peripheral neuropathy to neuron dysfunction and death. Adjunct therapies investigated thus far, range from neurotropic peptides to nutritional supplementation with antioxidants.

Peripheral neuropathy

As mechanism(s) and pathways are elucidated, new therapeutic targets will be identified for novel analgesics to reduce the pain commonly found in HIV-associated sensory polyneuropathy. A recent clinical trial tested lamotrigine, an anticonvulsant that blocks sodium channels and blocks release of glutamate and aspartate (58). Although in this trial, an adverse event (severe rash) resulted in a large drop-out rate, the completed treatment group experienced a substantial reduction in pain compared to the placebo group. Additional sodium channel inhibitors, amitriptyline and mexiletine, were tested by ACTG 242 protocol team without any proven efficacy (59). A Clinical Program for Clinical Research on AIDS (CPCRA) trial combined acupuncture and amitriptyline (CPCRA 022) for the relief of pain due to peripheral neuropathy in HIV-infected individuals (60). The outcome showed that neither acupuncture nor amitriptyline was more effective than placebo at reducing pain. The safety and efficacy of recombinant human nerve growth factor was also tested in a placebo controlled trial by ACTG team 291 (61). Although a significant improvement in average and maximal daily pain was observed in the treated group compared to placebo, the adverse event of injection site pain was frequent and noteworthy. In an effort to reduce inflammatory mediators associated with neuronal injury, lexipafant, a platelet-activating factor antagonist, was tested for safety and improved neuropsychological performance. The study by the Neurological AIDS Research Consortium showed lexipafant to be safe and well tolerated with a suggestion of improved cognitive impairment (62). Finally, in an attempt to block gp120-induced calcium channel activation, the putative neuroprotectant, peptide-T, was not efficacious compared with placebo in patients with cognitive defects (63).

HIV-associated dementia

Neuroprotectants, such as memantine (ACTG 301), and nimodipine (ACTG 162), an L-type calcium channel antagonist, show great promise for efficacy in HIV-associated dementia (64)(65). These compounds, which reduce gp120-induced neuropathogenesis (66) or block voltage-dependent calcium channels (67), appear to be safe and effective or, at least, stabilize neuropathogenesis. Oral selegiline, an approved and marketed selective monoamine oxidase inhibitor currently used for treatment of Parkinson's disease, is currently being tested in a phase II placebo-controlled, double blind clinical trial (ACTG 5090) for a neuroprotective effect for HIV-associated cognitive impairment. Data suggest that selegiline can enhance choline acetyltransferase and rescue injured or dying neurons through a reduction of oxidative free-radical induced damage (68). Additional candidates for therapeutics are based on the observed CNS oxidative damage induced by HIV infection (69)(70). Antioxidants, in the form of synthetic compounds (CPI-1189) or nutritional supplementation (e.g., methionine, selenium, N-acetylcysteine), have been suggested to decrease neurotoxicity due to oxidative stress (71)(72). Further clinical trials are needed to substantiate this hypothesis.

HIV-associated vacuolar myelopathy

Vacuolization in the thoracic spinal cord has been reported in more than a third of patients with AIDS (73). Vacuolar myelopathy presents, usually, as slowly progressing spastic paraparesis, with loss of vibratory and position sense, and urinary frequency and urgency. Clinical diagnosis occurs with severe pathology, that is, prominent myelin loss in the lateral and posterior spinal cord columns. AIDS myelopathy has not been associated with elevated HIV viral load in CSF (74). Spinal cord pathogenesis may be related to abnormal transmethylation of proteins induced by HIV infection and /or vitamin B12 deficiency (70). Altered transmethylation is a known abnormality in methionine metabolism (75) and thus, pilot studies have been proposed for treatment of AIDS-associated myelopathy with L-methionine (76), S-adenosylmethionine (SAM) (70) or cyanobalamin for B12 deficiency (77) providing some positive data. As above, further nutritional supplement studies are needed in this area.

Progressive multifocal leukoencephalopathy

An observational study of a-interferon found a delay in disease progression, symptom relief, and prolonged survival in HIV-associated PML (78). The positive results suggest the need for a controlled clinical trial. An additional study was conducted with cidofovir, a nucleotide analogue that has antiviral activity against a broad range of DNA viruses. Cidofovir, added to ART, was associated with better control of JC virus and improved neurological outcome in individuals with PML compared to ART alone (79). These data need to be interpreted cautiously since a recent report (80) of the results of ACTG363 revealed that cidofovir did not prolong survival beyond that reported without treatment and another study has shown that cidofover therapy was ineffective in a seronegative patient with PML not given HAART (81). Other drugs with observed anti-viral activity against JC virus, topoisomerase inhibitors and camptothecin, are poorly tolerated (82).

Conclusions and Future Directions
Abstract Introduction: The Neurological Manifestations of HIV Infection Antiretroviral Therapy Adjunct Therapy Conclusions and Future Directions References

New clinical trials are needed to address a host of vitally important research areas. These include antiretroviral drug-induced distal sensory peripheral neuropathy; HIV associated dementia and treatment; CNS HIV reservoirs and antiretroviral drug treatment; pathogenesis and treatment of PML and HIV vacuolar myelopathy of the spinal cord. Future research directions are likely to vary according to the nature and frequency of HIV's neurological manifestations in developed versus developing countries.

Developed Countries

Important to the full understanding of neuropathogenesis is the development of animal models of neurodegenerative disease associated with HIV infection (83). Understanding the pathogenic process of HIV-associated neurological disease can provide new insight into targeted interventions for the CNS and bring new therapeutic agents into clinical trials (for example, ACTG 291- recombinant human nerve growth factor). In addition to the issues presented above, important new questions can be addressed in a clinical trial setting, such as: Is methionine deficiency associated with neural damage resulting in vacuolar myelopathy? Is there a role for nutritional supplementation? Do salvage treatment protocols show efficacy for HIV-associated neurological disease (ACTG Protocol 193)? As an extension of these studies, the identification and diagnosis of neurological disease using non-invasive technology is of critical importance for early detection and use in ACTG clinical trials (84)(85)(86). Technological developments in noninvasive imaging, such as magnetic resonance spectroscopy are needed. Other experimental treatment venues may be considered as the field of neuronal stem cells advance (87)(88). Studies in mice have shown that neuronal stem cell transplantation can differentiate into both neuronal and glial cells in neurodegenerative disorders with the use of neurotrophic growth factors. Thus, neuronal regeneration in HIV infected individuals eventually may be possible.

In the nearer term, there is interest in atypical antipsychotic drugs, such as risperidone or olanzapine, for psychotic symptoms of older HIV patients with dementia (ACTG 301) (89)(90). Pain mechanisms must be elucidated in order to promote novel treatments of neuropathic pain associated with HIV infection (91).

Developing Countries

In the context of the global burden of HIV infection, neurological manifestations occur early in HIV infection and are more frequent than in developed countries. For example, a referral hospital in Mexico City found the AIDS defining event in 50% of the patients was neurological illness (92). Common opportunistic infections associated with neurological manifestations include toxoplasmosis and meningeal cryptococcosis found in 32% and 22% of AIDS patients, respectively. HIV-associated dementia complex co-occurred with tuberculosis at a frequency of 9% and ischemic cerebrovascular disease and neoplasm at 5% or less of AIDS patients. This population had a high fatality rate even though a large proportion of associated neurological manifestations were treatable. In Subsaharan Africa, neuromuscular disease confined to the motor roots or anterior horn cells have been reported and a high percentage (77%) of neurological admissions to internal medicine wards were presenting with paraparesis or paraplegia (93)(94). This contrasts with the myalgia, muscle weakness and myopathy reported from the domestic ACTG 175/801 study team (95). Tuberculosis and HIV-1 infection were the predominant etiological agents noted for the spinal cord disease in Africa. Neurology wards in South Africa are noting that HIV patients are presenting with chronic infections, such as tuberculosis meningitis and cryptococcal meningitis (96).

Thus, neurological manifestations of HIV represent a global burden for which a new generation of clinical trials is contemplated. Trials need to build upon advances in understanding HIV neuropathogenesis and require tailoring to the differing nature, frequency and presentation of neurological manifestations observed in developing and developed nations.


Abstract Introduction: The Neurological Manifestations of HIV Infection Antiretroviral Therapy Adjunct Therapy Conclusions and Future Directions References


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(53) Chien JW, Valdez H, McComsey G, McClernon D, St Clair M, Ledemann MM. (1999) Presence of mutations conferring resistance to lamivudine in plasma and cerebrospinal fluid of HIV-1-infected patients. J Acquir Immune Defic Syndr 1;24(4):277-80. Medline

(54) Martin C, Sonnerborg A, Svensson JO, Stahle L. (1999) Indinavir-based treatment of HIV-1 infected patients: efficacy in the central nervous system. AIDS 13: 1227-32. Medline

(55) Haas DW, Stone J, Clough LA, Johnson B, Spearman P, Harris VL, Nicotera J, Johnson RH, Raffanti S, Zhong L, Bergqwist P, Chamberlin S, Hoagland V, Ju WD. (2000) Steady-state pharmacokinetics of indinavir in cerebrospinal fluid and plasma among adults with human immunodeficiency virus type 1 infection. Clin Pharmacol Ther 68:367-74. Medline

(56) Simpson DM. (1999) Human immunodeficiency virus-associated dementia: review of pathogenesis, prophylaxis, and treatment studies of zidovudine therapy. Clin Infect Dis 29: 19-34. Medline

(57) Albright AV, Erickson-Viitanen S, O'Connor M, Frank I, Ravner MM, Gonzalez-Scarano F. (2000) Efavirenz is a potent nonnucleoside reverse transcriptase inhibitor of HIV type 1 replication in microglia in vitro. AIDS Res Hum Retroviruses 16: 1527-37. Medline

(58) Simpson DM, Olney R, McArthur JC, Khan A, Godbold J, Ebel-Frommer K. (2000) A placebo-controlled trial of lamotrigine for painful HIV-associated neuropathy. Neurology 54: 2115-9. Medline

(59) Kieburtz K, Simpson D, Yiannoutsos C, Max MB, Hall CD, Ellis RJ, Marra CM, McKendall R, Singer E, Dal Pan GJ, Clifford DB, Tucker T, Cohen B. (1998) A randomized trial of amitriptyline and mexiletine for painful neuropathy in HIV infection. Neurology 51: 1682-8. Medline

(60) Shlay JC, Chaloner K, Max MB, Flaws B, Reichelderfer P, Wentworth D, Hilliman S, Brizz B, Cohn DL. (1998) Acupuncture and amitriptyline for pain due to HIV-related peripheral neuropathy: a randomized controlled trial. JAMA 280: 1590-5. Medline

(61) McArthur JC, Yiannoutsos C, Simpson DM, Adornato BT, Singer EJ, Hollander H, Marra C, Rubin M, Cohen BA, Tucker T, Navia BA, Schifitto G, Katzenstein D, Rask C, Zaborski L, Smith ME, Shriver S, Millar l, Clifford DB. (2000) A phase II trail of nerve growth factor for sensory neuropathy associated with HIV infection. Neurology 54: 1080-8. Medline

(62) Schifitto G, Sacktor N, Marder K, McDermott MP, McArthur JC, Kieburtz K, Small Epstein LG. (1999) Randomized trial of the platelet-activating factor antagonist lexipafant in HIV-associated cognitive impairment. Neurology 53: 391-6. Medline

(63) Heseltine PN, Goodkin K, Atkinson JH, Vitiello B, Rochon J, Heaton RK, Eaton EM, Wilkie FL, Sobel E, Brown SJ, Feaster D, Schneider L, Goldschmidts WL, Stover ES. (1998) Randomized double-blind placebo-controlled trial of peptide T for HIV-associated cognitive impairment. Arch Neurol 55:41-51. Medline

(64) Jain KK. (2000) Evaluation of memantine for neuroprotection in dementia. Expert Opin Investig Drugs 9:1397-406. Medline

(65) Navia BA, Dafni U, Simpson D, Tucker T, Singer E, McArthur JC, Yiannoutsos C, Zaborski L, Lipton SA. (1998) A phase I/II trial of nimodipine for HIV-related neurologic complications. Neurology 51: 221-8. Medline

(66) Jones MV, Bell JE, Nath A. (2000) Immunolocalization of HIV envelope gp 120 in HIV encephalitis with dementia. AIDS 14:2709-13. Medline

(67)Hegg CC, Hu S, Peterson PK, Thayer SA. (2000) Beta-chemokines and human immunodeficiency virus type -1 proteins evoke intracellular calcium increases in human microglia. Neuroscience 98: 191-9. Medline

(68) Koutsilieri E, Scheller C, Sopper S, Gotz ME, Gerlach M, Meulen V, Riederer P. (2001) Selegiline completely restores choline acetyltransferase activity deficits in simian immunodeficiency infection. Eur J Pharmacol 411:R1-R2. Medline

(69) Goggins M, Scott JM, Weir DG. (1999) Methylation of cortical brain proteins from patients with HIV infection. Acta Neurol Scand 100: 326-31. Medline

(70) Tan SV, Guiloff RJ. (1998) Hypothesis on the pathogenesis of vacuolar myelopathy, dementia and peripheral neuropathy in AIDS. J Neurol Neurosurg Psychiatry 65: 23-8. Medline

(71) Patrick L. (1999) Nutrients and HIV: part one-beta carotene and selenium. Altern Med Rev. 4:403-13. Medline

(72) Patrick L. (2000) Nutrients and HIV: part three- N-acetycysteine, alpha-lipoic acid, L-glutamine, and L carnitine. Altern Med Rev 5: 290-305. Medline

(73) Di Rocco A. (1999) Diseases of the spinal cord in human immunodeficiency virus infection Semin Neurol 19: 151-5. Medline

(74) Geraci A, Di Rocco A, Liu M, Werner P, Tagliati M, Godbold J, Simpson D, Morgello S. (2000) AIDS myelopathy is not associated with elevated HIV viral load in cerebrospinal fluid. Neurol 55: 440-2. Medline

(75) Lu SC. (2000) Regulation of glutathione synthesis. Curr Top Cell Regul. 36 : 95-116. Medline

(76) Di Rocco A, Tagliati M, Danisi F, Dorfman D, Moise J, Simpson DM. (1998) A pilot study of L-methionine for the treatment of AIDS-associated myelopathy. Neurol 51:266-8. Medline

(77) Kieburtz KD, Giang DW, Schiffer RB, Vakil N. ( 1991) Abnormal vitamin B12 metabolism in human immunodeficiency virus infection. Association with neurological dysfunction. Arch Neurol 48:312-4. Medline

(78) Huang SS, Skolasky RL, Dal Pan GJ, Royal W, McArthur JC.(1998) Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol 4: 324-32. Medline

(79) De Luca A, Giancola ML, Ammassari A, Grisetti S, Cingolani A, Paglia MG, Govoni A, Murri R, Testa L, Monforte AD, Antinori A. (2000) Cidofovir added to HAART improves virological and clinical outcome in AIDS-associated progressive multifocal leukoencephalopathy. AIDS 14:F117-21. Medline

(80) Marra CM, Rajicic N, Barker DE, Cohen B, Clifford D and the ACTG363 Team. (2001) Prospective pilot study of cidofovir for HIV-associated progressive multifocal leukoencephalopathy. 8th Conference on retroviruses and opportunistic Infections, chicago. Abstract 596.

(81) Houston S, Roberts N, Mashinter L. (2001) Failure of cidofovir therapy in progressive multifocal leukoencephalopathy unrelated to human immunodeficiency virus. Clin Infect Dis 32:150-52. Medline

(82) Berger JR. (2000) Progressive multifocal leukencephalopathy. Curr Treat Options Neurol 2:361-68. Medline

(83) Luabeya M, Dallasta LM, Achim CL, Pauza CD, Hamilton Rl.. (2000) Blood-brain barrier disruption in simian immunodeficiency virus encephalitis. Neuropathol appl Neurobiol 26: 454-62. Medline

(84) Chong J, Di Rocco A, Tagliati M, Danisi F, Simpson DM, Atlas SW. (1999) MR findings in AIDS-associated myelopathy. AJNR Am J Neuroradiol 20:1412-6. Medline

(85) Post MJ, Yiannoutsos C, Simpson D, Booss J, Clifford DB, Cohen B, McArthur JC, Hall CD. (1999) Progressive multifocal leukoencephalopathy in AIDS: are there any MR findings useful to patient management and predictive of patient survival? AJNR AM J Neuroradiol 20: 1896-906. Medline

(86) Polich J, Ilan A, Poceta JS, Mitler MM, Darko DF. (2000) Neuroelectric assessment of HIV: EEG, ERP, and viral load. Int J Psychophysiol 38: 97-108. Medline

(87) Gage FH. (2000) Mammalian neural stem cells. Science 287: 1433-8. Medline

(88) Vescovi AL, Snyder EY. (1999) Establishment and properties of neural stem cell clones: plasticity in vitro and in vivo. Brain Pathol 9:569-98. Medline

(89) DeDeyn PP. (2000) Evidence of novel therapeutics in the control of aggression and psychotic symptoms in dementia patients. Int J. Neurosychopharmacol 3 (suppl 1) S59.

(90)De Deyn PP, Rabheru K, Rasmussen A, Bocksberger JP, Dautzenberg PL, Eriksson S, Lawlor BA. (2000) A randomized trial of risperidone, placebo, and haloperidol for behavioral symptoms of dementia. Neurology 53: 946-55. Medline

(91) Martin C, Pehrsson P, Osterberg A, Sonnerborg A, Hansson P. (1999) Pain in ambulatory HIV-infected patients with and without intravenous drug use. Eur J Pain 3:157-64. Medline

(92) Gongora-Rivera F, Santos-Zambrano J, Moreno-Andrade T, Calzada-Lopez P, Soto-Hernandez JL. (2000) The clinical spectrum of neurological manifestations in AIDS patients in Mexico. Arch Med Res 31:393-8. Medline

(93) Zenebe G. (1995) Myelopathies in Ethiopia. East Afr Med J. 72:42-5. Medline

(94) Benatar MG, Eastman RW. (2000) Human immunodeficiency virus-associated pure motor lumbosacral polyradiculopathy. Arch Neurol 57:1034-9. Medline

(95) Simpson DM, Katzenstein DA, Hughes MD, Hammer SM, Williamson DL, Jiang Q, Pi JT. (1998) Neuromuscular function in HIV infection: analysis of a placebo-controlled combination antiretroviral trial. AIDS Clinical Group 175/801 Study Team. AIDS 12:2425-32. Medline

(96) Schutte CM, Van der Meyden CH, Magazi DS. The impact of HIV on meningitis as seen at a South African academic hospital (1994-1998). Infection 28: 2-7. Medline

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