Clinical Trials and Clinical Targets in NeuroAIDS

T.F. Kresina¹ and E.S. Stover², and D.M. Rausch<sup>2

1</sup>Opportunistic 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

E-mail: tk13v@nih.gov

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

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).

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).

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.

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