Incidence and prevalence of neurological disorders associated with HIV since the introduction of highly active antiretroviral therapy (HAART)

OBJECTIVE: To determine the change of incidence and prevalence of neurological disorders caused by the human immunodeficiency virus (HIV) and opportunistic infections in HIV positive patients under treatment since the introduction of highly active antiretroviral therapy (HAART). METHODS: The data of all HIV infected patients were retrospectively analysed, who were examined in the HIV outpatients clinic of the neurological department of the University Clinic Essen between 1995 and 1998 (n=563, total number of visits=735). Data from identified patients were divided into two groups according to the time of examination from 1995 to 1996 (334 visits) and from 1997 to 1998 (401 visits). The incidence and prevalence of neurological disorders were statistically compared between both time intervals. RESULTS: Significantly more patients received HAART in 1997-8 (p<0. 001) and mean CD4+ cell count was significantly higher in 1997-8 (p<0.001). The prevalence of HIV associated dementia and HIV associated polyneuropathy were significantly lower in 1997-8 (both: p=0.02) and the incidence of toxoplasma encephalitis decreased from 5.7% in 1995-6 to 2.2% in 1997-8 (p=0.015). Based on the small number of patients significant changes in HIV associated myopathy, progressive multifocal leukoencephalopathy, cryptoccocal meningitis, and cytomegalovirus-encephalitis could not be detected. CONCLUSION: The prevalence of the most frequent HIV associated neurological disorders and incidence of toxoplasma encephalitis decreased since the introduction of HAART. This may be due to the improvement of immunostatus by HAART as demonstrated by the higher CD4+ cell count in the later time interval. Direct antiretroviral effects within the nervous system may be considered causative as well. The prevalence and incidence of HIV associated neurological disorders and opportunistic CNS infections decreased after introduction of HAART.     

Effects of highly active antiretroviral therapy (HAART) on psychomotor performance in children with HIV disease

OBJECTIVE: This study assesses the effects of HAART on psychomotor performance of symptomatic HIV-infected children. It is one of the first studies to look at neurobehavioral functioning in children infected with HIV in resource-limited countries. DESIGN: A longitudinal pilot study of vertically HIV-infected children at the HIV Netherlands Australia Thailand Research Collaboration Center in Bangkok, Thailand. METHODS: A total of 34 children participated in the study of whom 16 had never received antiretroviral (ARV) therapy and were about to start HAART (Newly treated children), 7 did not receive antiretroviral therapy (Untreated children) and 11 had been treated with HAART for more than one year (HAART experienced children). All children were administered 4 psychomotor tasks at baseline and after 4 months. The Newly treated and the Untreated children were also evaluated after 12 months. RESULTS: In general, the children performed similarly on all psychomotor tasks at baseline. After 12 months of HAART, there was a significant increase in CD4% in the Newly treated group. Overall, psychomotor performance did not change at the 4-month evaluation in all groups. At the 12-month evaluation psychomotor performance had deteriorated substantially on all tasks in both the Newly treated and the Untreated children. CONCLUSIONS: There was no significant difference in psychomotor functioning between children newly treated, previously treated and untreated with HAART over the course of one year. Psychomotor performance deteriorated after 12 months of HAART, which provides important indications concerning the lack of benefits of HAART on psychomotor functions in children despite immunologic reconstitution. Further research with larger sample sizes is needed to confirm these findings.     

Neurological manifestations of HIV-infection in the era of highly active antiretroviral therapy (HAART)

After the introduction of highly active antiretroviral therapy (HAART) in 1996 the neurological manifestations of human immunodeficiency virus (HIV-1)-infection did not decline in incidence and prevalence like the other complications of immunodeficiency; in contrast, due to the longer survival times of HAART treated HIV-1-positive individuals, prevalence of virus associated neurological disease increased during the last years, as international studies underline. Therefore, clinicians and HIV-therapists should be able to diagnose HIV-1-associated neurological disease even in early stages. This article describes symptoms and signs, neuro-imaging and cerebrospinal fluid findings as well as therapy options in primary HIV-1-associated neurological disease like encephalo- and myelopathy and polyneuropathy. Furthermore, those opportunistic infections, caused by bacteria, viruses other than HIV and parasites emerging with manifest immunodeficiency and remaining to be relevant in the HAART era are presented from diagnostic, differential-diagnostic and therapeutic points of view. An extra paragraph describes the interaction of HAART with neurological/psychiatric standard therapies.     

Acute paraparesis in HIV-infected patient after initiation of highly active antiretroviral therapy

Journal of NeuroVirology - Neurological syndromes occur in around 40–70% of HIV-infected people. Direct central nervous system involvement by the virus usually manifests as HIV encephalitis,...     

Influence of highly active antiretroviral therapy on persistence of HIV in the central nervous system

PURPOSE OF REVIEW: The epidemiology of HIV infection is changing rapidly in the era of highly actively antiretroviral therapy, as the use of such therapy is increasing in all countries. This has had a significant impact on the neurological manifestations of HIV infection, posing new challenges in diagnosis and treatment. This review provides a critical analysis of the recent literature on the impact of highly actively antiretroviral therapy on HIV-related neurological complications and changes in treatment strategies. RECENT FINDINGS: It is becoming clear that the brain is an important reservoir for the virus, and neuroinflammatory and neurodegenerative changes may continue despite the adequate use of highly actively antiretroviral therapy. Although this antiretroviral therapy has had a significant impact on the severity of HIV dementia, cognitive impairment persists. With improvement in the immune status following treatment with antiretrovirals, in rare cases the brain can become a target of the immune reconstitution. SUMMARY: Highly actively antiretroviral therapy may need to be optimized in patients with HIV-associated cognitive impairment to achieve maximal central nervous system penetration; however, this therapeutic strategy may not be sufficient for halting the process. In some instances, the antiretroviral drugs themselves may become the problem. New strategies for neuroprotection that also target host genes which control HIV replication are being developed.     

A patient with HIV encephalopathy presenting with parkinsonism during HAART therapy]

We report the case of a 32-year-old man presenting symptoms of parkinsonism. Neurological examination revealed parkinsonism symptoms such as akinesia and postural instability, dementia and frontal lobe signs. He was diagnosed as having human immunodeficiency virus (HIV) encephalopathy. Brain MRI, 99mTc ECD-SPECT and 1H-MR spectroscopy demonstrated symmetrical cerebral white matter lesions, predominantly in the bilateral frontal lobes. Frontal lobe dysfunction could be responsible for his parkinsonism associated with HIV encephalopathy. His neurological symptoms improved transiently after the initiation of HAART but fluctuated when antiretroviral drugs were changed because of their side effects. Although HAART effectively decreased plasma HIV-RNA load and increased peripheral blood CD4 cell count, his parkinsonism and dementia eventually exacerbated. Our results suggest that a combination of antiretroviral drugs affects the therapeutic efficacy against HIV encephalopathy, and that CNS symptoms could be aggravated during HAART, even when plasma HIV-RNA load and CD4 cell count are maintained under favorable conditions.     

Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a patient with HIV infection.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from lytic infection of oligodendrocytes by the papovavirus JC (JCV). PML has also been recognized as an AIDS-defining illness. The incidence of PML has increased since 1987 and it occurs in up to 4% of patients with AIDS. To date, there is no treatment available for PML and it usually results in death within 3-6 months of diagnosis. However, there are some reports of remission of PML after antiretroviral therapy. We report a 12-year-old child with hemophilia B and developing AIDS with the onset of PML. With highly active antiretroviral therapy, PML subsided with an increase of CD4 count from 10 to 300/microl in spite of about 1.0 X 10(4) human immunodeficiency virus (HIV)-1-RNA copies. He has survived more than 1 year without specific therapy against JCV. Highly active antiretroviral therapy appears to have improved his prognosis in HIV-associated PML.     

HIV-associated distal sensory polyneuropathy in the era of highly active antiretroviral therapy: the Manhattan HIV Brain Bank

OBJECTIVES: To examine distal sensory polyneuropathy (DSP) in a highly active antiretroviral therapy era, human immunodeficiency virus (HIV)-infected cohort, to determine whether clinical manifestations are affected by demographic or other clinical variables. PATIENTS: One hundred eighty-seven patients with HIV infection enrolled in the Manhattan HIV Brain Bank underwent baseline neurologic evaluations between January 29, 1999, and June 17, 2002. Distal sensory polyneuropathy was diagnosed if patients displayed abnormalities in 2 or more of the following: ankle reflexes or vibratory or pinprick perception. Patients were classified as symptomatic if they described pain, paresthesia, or numbness. Nonneurologic information was obtained by interview, laboratory testing, and medical chart review. Psychiatric and substance use disorders were elucidated by semistructured interview. In 36 patients, morphometric analysis was performed on autopsy-derived sural nerves. RESULTS: Of 187 patients, 99 (53%) had DSP. Patients with neuropathy were older than those without (mean +/- SD age, 45.3 +/- 0.7 vs 41.2 +/- 0.8 years, P <.001), and DSP was significantly more common in men (58% [83/99]) than in women (37% [16/99]) (P =.02). The presence of neuropathy was not correlated with plasma viral load, decreased CD4 cell counts, or neurotoxic antiretroviral therapy. Twenty-six of 99 patients with DSP were asymptomatic. Asymptomatic neuropathy was correlated with histories of opiate and sedative abuse and dependence. Symptomatic DSP correlated with ethanol and hallucinogen syndromes, but not neurotoxic therapy. Sural nerve morphometric findings did not distinguish between patients with substance use syndromes and those without. CONCLUSIONS: In contrast to populations before the era of highly active antiretroviral therapy, DSP in the Manhattan HIV Brain Bank cohort is not associated with increased viral load or decreased CD4 cell counts in this cross-sectional analysis. Symptoms in DSP are associated with substance use disorders, but no difference in morphologic structure is seen in nerves of patients with HIV infection with and without substance use histories. Previously reported virologic and immunologic underpinnings of DSP may be affected by highly active antiretroviral therapy. Furthermore, symptoms of DSP in substance users may be altered by central mechanisms of increased or decreased tolerance to sensory disturbance.     

Cytarabine and highly active antiretroviral therapy in HIV-related progressive multifocal leukoencephalopathy

We assessed survival in AIDS-related progressive multifocal leukoencephalopathy (PML) and the effect of cytarabine and antiretroviral therapy in a retrospective analysis of a series of consecutive 35 patients with AIDS-related PML in an academic AIDS referral center over 15 years. Treatment regimens consisted of highly active antiretroviral treatment (HAART), intravenous cytarabine, or both. Median survival after diagnosis in the overall series was 88 days. Patients with low CD4 cell count tended to have shorter survival. Seven patients (20%) had prolonged survival (> 1 year). Cytarabine did not affect survival. Seven patients were treated with HAART, which did not significantly improve survival. We conclude that the prognosis of AIDS-related PML is still poor, with a median survival of 3 months.     

Persistently elevated levels of von Willebrand factor antigen in HIV infection. Downregulation during highly active antiretroviral therapy

Levels of circulating von Willebrand factor (vWf) antigen are thought to reflect endothelial involvement in various disorders. In the present study we found markedly elevated plasma levels of vWf in HIV-infected patients demonstrated on both cross-sectional and longitudinal testing. Notably, we found that a persistent rise in vWf antigen was associated with progression of HIV-related disease. This elevation of vWf antigen represented functionally normal vWf as evaluated by plasma FVIII, ristocetin cofactor assay and vWf multimer analyses. While HIV-infected patients showed enhanced platelet activation, platelets did not contribute substantially to the increased vWf levels. The high vWf levels were significantly correlated with high viral load, and during HAART, the pronounced decline in HIV RNA levels was accompanied by a corresponding decrease in vWf. The persistent elevation of functionally normal vWf during HIV infection, most probably reflecting a persistent endothelial cell activation, may have an important role in the pathogenesis of HIV infection.     

Depressive symptoms in HIV-infected patients treated with highly active antiretroviral therapy

IntroductionThe prevalence of depressive disorders in HIV-infected patients ranges from 12% to 66% and is undiagnosed in 50% to 60% of these patients. Depression in HIV-infected individuals may be associated with poor antiretroviral treatment (ART) outcomes, since it may direct influence compliance.ObjectiveTo assess the presence of symptoms and risk factors for depression in patients on ART.MethodsCross-sectional study. Certified interviewers administered questionnaires and the Beck Depression Inventory (BDI), and participants' self-reported compliance to ART. Clinical and laboratory variables were obtained from clinical records. Patients with BDI ≥ 12 were defined as depressed.ResultsOut of the 250 patients invited to participate, 246 (98%) consented. Mean age was 41 ± 9.9 years; most were male (63%). Income ranged from 0–14 Brazilian minimum wages. AIDS (CDC stage C) had been diagnosed in 97%, and 81% were in stable immune status. One hundred ninety-one (78%) reported compliance, and 161 (68%) had undetectable viral loads. The prevalence of depressive symptoms was 32% (95% CI 26–40). In multivariate analysis, depressive symptoms were significantly associated with income (prevalence ratio [PR] = 0.85; 95% CI 0.74–0.97; p = 0.02).ConclusionsDepressive symptoms are frequent in patients on ART, and are associated with low income.     

Endothelial markers and HIV infection in the era of highly active antiretroviral treatment

Many circumstances can induce activation and/or injury of the endothelium that plays a role in the development of vascular complications. Raised plasma levels of endothelial markers such as von Willebrand factor (vWF), soluble thrombomodulin (sTM) and soluble vascular cell adhesion molecule-1 (sVCAM-1) have a prognostic and/or diagnostic value. Human immunodeficiency virus-infected patients (HIV+) have a clustering of conditions that activate or injure the endothelium. Highly active antiretroviral treatment produces adverse effects such as dyslipemia, insulin resistance (IR) and body fat changes (named lipodystrophy syndrome) which may contribute to aggravate their endothelial perturbation. The aim of this study was to measure lipid profile, insulin resistance status, and endothelial markers in 38 HIV+ naive of antiretroviral treatment and 63 HIV+ under highly active antiretroviral treatment (33 with lipodystrophy syndrome and 30 without it). Body fat distribution was also evaluated by dual-energy X-ray absorptiometry (DEXA) analysis. Thirty-one HIV negative subjects were used as controls. We looked for association between variables. Insulin resistance status was a common finding in the four groups. Lipodystrophic patients presented an atherothrombotic lipid profile [elevated levels of triglycerides (TG), low-density lipoprotein cholesterol (LDL-chol) and apolipoprotein-B (APO-B)] and a strong loss of fat in legs and arms (lipoatrophy). All endothelial markers evaluated in our naive patients were higher as compared to control group. sVCAM-1 in HIV+ under therapy without lipodystrophy syndrome showed significantly decreased levels as compared to naive group (487 vs. 666 ng/ml) and vWF and sTM tended to diminish although they did not show a significant difference (130% vs. 170%, 41 vs. 45 ng/ml, respectively). Lipodystrophic patients showed a tendency to increased levels of endothelial activation markers (sVCAM-1: 500 ng/ml and vWF: 154%) together with significantly increased levels of an endothelial injury marker (sTM: 50 ng/ml) with respect to HIV+ under therapy without lipodystrophy syndrome. Plasma levels of sTM, as an endothelial injury marker, correlated with peripheral lipoatrophy (rho = -0.357) in lipodystrophic patients. In conclusion, despite the beneficial immunology effect of highly active antiretroviral treatment and the apparent decrease in the endothelial perturbation, the patients who develop lipodystrophy present altered endothelial markers and other risk factors, such as IR and dyslipemia, which turn them into a high atherothrombotic risk group.