Thorsten Nolting

Neuropsychiatric side effects of efavirenz therapy

The non-nucleoside analogue inhibitor of the reverse transcriptase, efavirenz (EFV), has become commonly used in highly active antiretroviral combination therapy in the treatment of HIV infection. Although being effective in suppressing plasma viral load, neuropsychiatric side effects have been reported in individuals treated with EFV. There are early complications, such as acute psychosis resembling reactions to LSD intake, as well as nightmares occurring for several days up to 4 weeks after the start of therapy. Although LSD-like psychosis provokes the necessity of therapy discontinuation, the nightmares, as well as irritability and concentration problems in daily life, disappear after several weeks of treatment. Late complications are depressive episodes that must be carefully differentiated from pre-existing psychiatric disease and virus-induced brain damage. This review describes neuropsychiatric symptoms provoked by EFV, differential-diagnostic procedures and treatment options, and provides pros and cons for EFV use in clinical practice with respect to drug safety.

Increased dopaminergic neurotransmission in therapy-naïve asymptomatic HIV patients is not associated with adaptive changes at the dopaminergic synapses.

Central dopaminergic (DA) systems are affected during human immunodeficiency virus (HIV) infection. So far, it is believed that they degenerate with progression of HIV disease because deterioration of DA systems is evident in advanced stages of infection. In this manuscript we found that (a) DA levels are increased and DA turnover is decreased in CSF of therapy-naïve HIV patients in asymptomatic infection, (b) DA increase does not modulate the availability of DA transporters and D2-receptors, (c) DA correlates inversely with CD4+ numbers in blood. These findings show activation of central DA systems without development of adaptive responses at DA synapses in asymptomatic HIV infection. It is probable that DA deterioration in advanced stages of HIV infection may derive from increased DA availability in early infection, resulting in DA neurotoxicity. Our findings provide a clue to the synergism between DA medication or drugs of abuse and HIV infection to exacerbate and accelerate HIV neuropsychiatric disease, a central issue in the neurobiology of HIV.

Cidofovir in combination with HAART and survival in AIDS-associated progressive multifocal leukoencephalopathy

Progressive multifocal leukoencephalopathy is a demyelinating disease with a high mortality caused by the JC virus and occurs in about 5% of HIV-infected patients. Highly active anti-retroviral therapy (HAART) has a proven efficacy in prolonging the survival of patients with AIDS-associated PML, but there are differing opinions about adding cidofovir to the treatment of PML. To investigate the benefit of HAART combined with cidofovir, we retrospectively analysed the survival of 33 patients with AIDS-associated PML proven by PCR in CSF, biopsy or at autopsy. Additionally, we also analysed 37 patients with probable PML. Seventeen (51.5%) of the patients with confirmed PML were treated with HAART and 14 (42.4%) with cidofovir in any combination. Of these patients, 13 (39.4%) were treated with HAART and cidofovir in combination, four (12.1%) patients received only HAART without cidofovir and one (3%) patient received only cidofovir without HAART. Fifteen patients did not receive HAART or cidofovir. The cumulative survival was significantly longer in patients with HAART than in patients without HAART (p = 0.006), independent whether cidofovir was given or not. In comparison with single therapy with HAART, the combination of HAART and cidofovir showed no significant increase in survival (p = 0.435). Therefore, a benefit for cidofovir in addition to HAART in the treatment of PML in HIV-infected patients could not be proven.

Measurement of soluble inflammatory mediators in cerebrospinal fluid of human immunodeficiency virus-positive patients at distinct stages of infection by solid-phase protein array.

The objective of this study was to evaluate immune cytokine expression in cerebrospinal fluid (CSF) of patients with human immunodeficiency virus-1 (HIV-1)-associated dementia (HAD) using a novel cytokine array assay. HIV-1 induces a condition resembling classical subcortical dementia, known as HAD. The immune mechanisms contributing to HAD have not been elucidated. Cytokine expression in CSF was determined by solid-phase protein array in 33 neurologically asymptomatic HIV-positive male patients and were compared to levels in non-HIV controls and patients with HAD. Neurological examinations and lumbar and venous punctures were conducted in all patients and controls. Interleukin (IL)-1, IL-4, and IL-10, were up-regulated in all treated acquired immunodeficiency syndrome (AIDS) patients independent of neurological status compared to controls. In contrast, interferon gamma (IFN-γ), IL-1α, IL-15, and tumor necrosis factor alpha (TNF-α) were highly expressed in patients with HAD compared to undemented HIV-positive patients. These results show that solid-phase protein array can detect immunological changes in patients infected with HIV. Cytokine expression levels differ in different disease stages and in patients on different treatment paradigms. Pending further validation on a larger number of patients, this method may be a useful tool in CSF diagnostics and the longitudinal evaluation of patient with HAD.

Intrathecal viral replication and cerebral deficits in different stages of human immunodeficiency virus disease

The objectives of this study is to clarify whether there are phases critical for the infection of the central nervous system (CNS) as defined by active viral replication in the cerebrospinal fluid (CSF) in human immunodeficiency virus (HIV) infection. One hundred and nine HIV-1-positive homo- and bisexual patients in early and late disease stages with or without highly active antiretroviral therapy (HAART) were included in the cross-sectional, diagnostic (phase I) multicenter study. No patients had any overt neurological deficits; all underwent venous and lumbar puncture as well as neuropsychological testing. In untreated early-stage patients, cerebrospinal fluid (CSF) viral load correlated with inflammatory parameters, but not significantly with neuropsychological abnormalities. CSF viral load and inflammatory reactions were suppressed in HAART-treated early-stage patients. In HAART-treated late-stage patients, there was a weak correlation between CSF viral load and CSF cell count as well as a moderate correlation with immune activation markers and with distinct cerebral deficits independent of CSF viral load. Seventeen of the 109 patients had higher CSF than plasma viral loads and marked inflammatory reactions and immune activation. In patients with greater plasma than CSF viral loads, the factors contributing to cerebral deficits still need to be identified. The results suggest not only that there is an early “set point” for CSF/central nervous system (CNS) infection, but also that there is a subgroup of patients in whom intrathecal viral replication correlates with cerebral deficits. Lumbar puncture should be performed in all positive patients to identify members of this subgroup and to ascertain what characteristic factors they have in common in order to improve therapy.

Viral load determines the B-cell response in the cerebrospinal fluid during human immunodeficiency virus infection.

Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) is frequently associated with intrathecal immunoglobulin synthesis and cerebrospinal fluid (CSF) pleocytosis, but little is known about the B‐cell response in the CSF of these patients. In this study, we investigated the relation between virus load and the frequency and phenotype of B cells in the CSF of HIV‐infected patients.

CD8 T-cell subsets and viral load in the cerebrospinal fluid of therapy-naive HIV-infected individuals.

We analysed the potential influence of hepatitis C virus (HCV) co-infection over IL-7 levels and thymic function in naive HIV-infected patients and after effective HAART. HIV–HCV-co-infected patients had lower plasmatic IL-7 levels compared with HIV-monoinfected patients. This effect may not be associated either with HCV monoinfection or with the rate of liver injury. These lower levels may explain, at least partly, the lower CD4 cell repopulation of HIV–HCV-co-infected patients after HAART.

Cytokine levels in CSF and neuropsychological performance in HIV patients

HIV-associated dementia and its precursors are frequently observed complications of HIV infection, even in the presence of combination antiretroviral treatment (cART). The development, surveillance and treatment of this condition are still not completely understood. Cytokines, as immunological transmitters, may be one key to gaining a deeper understanding of the disease. A total of 33 HIV-positive male patients were evaluated by neuropsychological testing, lumbar and venous puncture, neuroimaging and neurological examination. The cytokine content in the CSF (cerebrospinal fluid) was examined by a solid-phase protein array. The Digit–Symbol Test, contraction time analysis, Rey–Osterrieth Figure and Grooved-Pegboard Test showed inferior results in the presence of an inflammatory CSF environment, whereas neuroprotective or anti-inflammatory conditions were correlated to better results in contraction time analysis. Higher CSF levels of cytokines were independently correlated with the duration of HIV infection. The study showed a correlation of cytokine levels in the CSF of HIV patients with test results of their neuropsychological functioning. The effect was pronounced with regard to the more complex executive tasks. Determining CSF cytokine levels may be a useful supplement to the assessment of HIV patients and contribute helpful information to predict neurocognitive performance. Therapeutic strategies to ameliorate a negative impact of an altered cytokine milieu may aid in slowing the evolution of neurocognitive dysfunction.

Cytokine findings in the CSF of HIV-positive patients

Cytokines are important mediators of the immune system, which is attacked and permanently disturbed after infection with HIV-1. Since specific immune reactions against HIV are present in the blood as well as in the CNS, both are involved in infection. Immune dysfunction in the CNS may be largely responsible for the development of neuropsychological symptoms in the course of HIV infection and in end-stage HIV-associated dementia (HAD). As potent and easily accessible indicators of immune function, cytokines were identified early in HIV-research as potential surveillance markers. Despite long-term research on cytokines and their diagnostic value in HAD and its precursors, results are, to date, contradictory. Future studies have to be focused on cytokine networks, infection stage, treatment status, autoimmunity, genetic and environmental factors, and they should also use recent genome- and proteome-research techniques.