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.     

AIDS-related focal brain lesions in the era of highly active antiretroviral therapy

OBJECTIVE: To compare the years since the introduction of highly active antiretroviral therapy (HAART) with the pre-HAART era for trends in the proportions of HIV-related focal brain lesion-causing disorders. METHODS: A prospective, single-center study of all consecutive HIV-infected patients with a neurologic presentation and focal brain lesions observed between January 1991 and December 1998 was undertaken. RESULTS: The major diagnoses in the 281 patients were toxoplasmic encephalitis (36.4%), primary CNS lymphoma (26.7%), progressive multifocal leukoencephalopathy (18.2%), and focal HIV encephalopathy (5.0%). During the HAART period, patients were less likely to be male, contracted HIV more often through heterosexual exposure, had fewer previous AIDS-defining events, received antiToxoplasma prophylaxis less frequently, had a CD4+ lymphocyte count 2.5 times higher, and had diagnosis based more often on PCR assays from CSF, reducing the need for brain biopsy and enhancing the likelihood of in vivo diagnosis. Using all patients hospitalized per year as reference population, the risk of focal brain lesions strongly increased during the pre-HAART period and declined significantly during the HAART years. In the HAART period a relevant decline of primary CNS lymphoma was found (OR for 1998, 0.25; p for trend = 0.03) and the effect of progressive calendar year was confirmed on multivariable analysis (OR, 0.52; 95% CI, 0.28 to 0.97). The frequency of toxoplasmic encephalitis decreased during the pre-HAART era and was stable afterwards. For progressive multifocal leukoencephalopathy, a slight increase was seen over time. Focal white matter lesions without enhancement or mass effect increased between 1991 and 1998. CONCLUSIONS: During the HAART era, AIDS-related primary CNS lymphoma showed a strong decline, toxoplasmic encephalitis remained stable, and progressive multifocal leukoencephalopathy showed a slight increase. Focal white matter lesions without mass effect or contrast enhancement became the most frequently seen focal brain lesion. For differential diagnosis, PCR-based assays from CSF led to a shift from brain biopsy toward a minimally invasive approach with an augmented likelihood of in vivo diagnosis.     

Cerebrovascular disease in HIV-infected individuals in the era of highly active antiretroviral therapy

The widespread use of highly active antiretroviral therapy (HAART) in HIV-infected individuals mostly in developed countries has dramatically improved their prognosis. In such advantaged regions of the world, therefore, many patients are now transitioning from middle into older age, with altered patterns of disease. While previously a rare complication of HIV infection, cerebrovascular disease (particularly that associated with atherosclerosis) is becoming relatively more important in this treated group of individuals. This review summarises the evidence regarding the shifting epidemiology of cerebrovascular diseases affecting HIV-infected individuals. While outlining the association between HIV infection and AIDS and cerebrovascular disease, as well as opportunistic diseases and HIV-associated vasculopathies, the current evidence supporting an increase in atherosclerotic disease in treated HIV-infected individuals is emphasised and a management approach to ischaemic stroke in HIV-infected individuals is presented. Evidence supporting the important role of HAART and HIV infection itself in the pathogenesis of atherosclerotic disease is discussed, together with preventative approaches to this increasingly important disease process as the population ages. Finally, a discussion regarding the significant association between cerebrovascular disease and HIV-associated neurocognitive disorder is presented, together with possible mechanisms behind this relationship.     

Aging exacerbates extrapyramidal motor signs in the era of highly active antiretroviral therapy

The phenotype of human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) in the developed world has changed with the broad institution of highly active antiretroviral therapy (HAART) and with aging of the HIV+ population. Extrapyramidal motor signs were a prominent feature of HAND as defined in the early stages of the epidemic but has not been reevaluated in the era of HAART. Moreover, the contribution of aging to extrapyramidal motor signs in the context of HIV remains undefined. We examined these questions among the 229 HIV+ participants in the Hawaii Aging with HIV Cohort compared to age-, gender-, and ethnicity-matched HIV-negative controls. Extrapyramidal motor signs were quantified using the motor exam of the Unified Parkinson's Disease Rating Scale (UPDRSmotor) and compared to concurrent neuropsychological and clinical cognitive diagnostic categorization. The mean UPDRSmotor score increased with older age (1.68 versus 3.35; P<.001) and with HIV status (1.18 versus 3.56; P<.001). Age group (P=.024), HIV status (P<.001), and the interaction between age and HIV (P=.026) were significantly associated with UPDRSmotor score. Among HIV+ patients, the mean UPDRSmotor score increased with worsening cognitive diagnostic category (P<.001) where it was 2.06 (2.31) in normal cognition (n=110), 3.21 (3.48) in minor cognitive motor disorder (MCMD) (n=84), and 5.72 (5.01) in HIV-associated dementia (HAD) (n=37). We conclude that extrapyramidal motor signs are increased in HIV in the era of HAART and that the impact of HIV on extrapyramidal motor signs is exacerbated by aging. These results highlight the importance of a careful neurological examination in the evaluation of HIV patients.     

Changing pattern of primary cerebral lymphoma in the highly active antiretroviral therapy era

Before the introduction of highly active antiretroviral therapy (HAART), human immunodeficiency virus (HIV)-related primary central nervous system lymphoma (PCNSL) represented one of the most prevalent causes of focal brain lesions in HIV-infected people. The prognosis of PCNSL was very poor, with median survival time not exceeding 2 months. Brain biopsy was the method of choice for the definitive diagnosis, but it was and remains an invasive procedure with morbidity and mortality as well as considerable costs in terms of patients' management and quality of life. The strict association between AIDS-PCNSL and Epstein-Barr virus led to the suggestion that EBV DNA in cerebrospinal spinal fluid (CSF) might serve as a diagnostic marker, reducing the time required for diagnosis and allowing a minimally invasive approach. The clinical usefulness of this methodology has been largely demonstrated through clinical practice. After the introduction of HAART in clinical practice, a survival benefit has been observed for most persons with acquired immunodeficiency syndrome (AIDS)-associated opportunistic infections and cancers. In particular, for patients with non-Hodgkin lymphoma, a higher likelihood of response to chemotherapy as well as a longer survival has been found as a consequence of the use of combined antiretroviral therapy. Although larger studies did not show significant changes in survival of HIV-infected patients with PCNSL in the era of HAART, small case series and anecdotal reports showed the benefit of HAART in the treatment of PCNSL. Nevertheless, these patients' survival still remains very poor and it could be hypothesized that, other than specific cancer prognostic determinants and severe immunodeficiency, viral pathogenesis as well as EBV-specific immunologic dysfunction may be responsible.     

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.     

New features of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy and natalizumab

Over the past three decades, progressive multifocal leukoencephalopathy (PML) evolved from being a clinical rarity to become an important cause of neurological complications in acquired immunodeficiency syndrome (AIDS) patients. Recently this disease unexpectedly occurred in patients receiving the novel immunomodulatory medication natalizumab. These changes in the epidemiology of PML also brought new questions with regard to the pathogenesis of this disease. The authors review the current challenges in the diagnosis and management of patients with PML, based on the recent advances in the understanding of the JC virus biology and discuss potential methods to monitor disease evolution and predict outcome.     

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.     

Central nervous system opportunistic infections in developed countries in the highly active antiretroviral therapy era

A marked decrease in incidence has been observed for most central nervous system (CNS) opportunistic infections (OIs) after the use of highly active antiretroviral therapy (HAART) in developed countries. However, the spectrum of these OIs in acquired immunodeficiency syndrome (AIDS) patients has remained almost unchanged. CNS toxoplasmosis, cryptococcosis, tuberculosis, and progressive multifocal leukoencephalopathy (PML) remain the most frequent ones. Primary CNS lymphoma should be included in the differential diagnosis of all cases with focal lesions. Final diagnosis is currently made by combining neuroimaging techniques (single-photon emission computed tomography [SPECT], positron emission tomography [PET], magnetic resonance imaging [MRI] and/or computed tomography [CT] scan) and molecular studies of cerebrospinal fluid (CSF) and therapeutical response. Stereotactic biopsy should only be performed in the case of atypical lesions or nonresponse to recommended treatments. After treatment of the acute phase, lifelong maintenance therapy is necessary to prevent OI recurrences. Once HAART is initiated, some patients can develop a clinical worsening of some CNS OIs with or without atypical neuroimaging manifestations. This paradoxical worsening is known as the immune reconstitution inflammatory syndrome (IRIS) and it results from reconstitution of the immune system's ability to recognize pathogens/antigens in patients with prior OIs and low CD4+ T-cell counts. In this context, IRIS can be seen in patients with CNS cryptococcosis, tuberculosis, or PML. On the other hand, HAART-induced immune reconstitution can improve the prognosis of some untreatable diseases such as PML, and can allow maintenance therapy of some CNS OI to be safely discontinued in patients with high and sustained CD4+ T-cell response.     

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.     

The epidemiology of human immunodeficiency virus-associated neurological disease in the era of highly active antiretroviral therapy

Highly active antiretroviral therapy (HAART) is effective in suppressing systemic human immunodeficiency virus (HIV) viral load and has decreased mortality rates and the incidence of systemic opportunistic infections in patients with acquired immunodeficiency syndrome (AIDS). Multiple studies now suggest that the incidence rates of HIV-associated neurological disease and central nervous system (CNS) opportunistic infections also are decreasing. Since the introduction of HAART in 1996, the incidence of HIV dementia has decreased by approximately 50%. The mean CD4 cell count for new cases of HIV dementia is increasing, but it remains as a complication of moderate-advanced immunosuppression. The incidence of HIV-associated distal sensory polyneuropathy has decreased, although the incidence of antiretroviral drug-induced toxic neuropathy has increased. However, as patients with AIDS live longer as a result of HAART, the prevalence of peripheral neuropathy in HIV-seropositive patients may be increasing. The incidence rates of CNS opportunistic infections (cryptococcal meningitis, toxoplasmosis, progressive multifocal leukoencephalopathy) and primary CNS lymphoma have decreased since the introduction of HAART. As patients develop increasing resistance mutations to antiretroviral drugs and with subsequent decline in CD4 cell counts, in the near future, the incidence of HIV-associated neurological disease may begin to rise.     

Effects of nadir CD4 count and duration of human immunodeficiency virus infection on brain volumes in the highly active antiretroviral therapy era

Cerebral atrophy is a well-described, but poorly understood complication of human immunodeficiency virus (HIV) infection. Despite reduced prevalence of HIV-associated dementia in the highly active antiretroviral therapy (HAART) era, HIV continues to affect the brains of patients with chronic infection. In this study we examine patterns of brain volume loss in HIV-infected patients on HAART, and demographic and clinical factors contributing to brain volume loss. We hypothesized that nadir CD4+ lymphocyte count, duration of HIV infection, and age would be associated with reduced cortical volumes. Volumes of cortical and subcortical regions in 69 HIV-infected neuroasymptomatic (NA) individuals and 13 with at least mild acquired immunodeficiency syndrome (AIDS) dementia complex (ADC) were measured using voxel-based morphometry. Demographic and clinical factors (age, plasma HIV RNA level, current and nadir CD4 counts, duration of infection, central nervous system [CNS] penetration of antiretroviral regimen) along with their interactions were entered into a regression model selection algorithm to determine the final models that best described regional brain volumes. Relative to NA, individuals with ADC exhibited decreased total gray matter and parietal cortex volumes and increased total ventricular volumes. Final regression models showed overall cerebral volume, including gray and white matter volume and volumes of the parietal, temporal, and frontal lobes and the hippocampus, were most strongly associated with disease history factors (nadir CD4 and duration of infection). In contrast, basal ganglia volumes were related most strongly to current disease factors, most notably plasma HIV RNA. These findings indicate that individuals with a history of chronic HIV infection with previous episodes of severely impaired immune function, as reflected by reduced nadir CD4+ lymphocyte count, may be at greatest risk for cerebral atrophy. The pattern of HIV-associated brain loss may be changing from a subcortical to a cortical disease among patients who are largely asymptomatic on HAART.     

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.