Use of cidofovir in progressive multifocal leukoencephalopathy.

BACKGROUND: Progressive multifocal leukoencephalopathy (PML) is a subacute demyelinating illness caused by the JC virus, a polyomavirus that occurs in 4-5% of HIV-positive patients. Mortality is high, and no useful therapy has been identified. Highly active antiretroviral therapy (HAART) has been reported to be effective in halting progression of the disease in some, but not all, patients. Cidofovir has been shown to be active against polyomaviruses. OBJECTIVE: To review data on the use of cidofovir to treat PML. DATA SOURCES: English-language case reports and clinical studies were located through a literature search (MEDLINE and AIDSLINE, 1995-July 2000). STUDY SELECTION AND DATA EXTRACTION: Relevant case reports and studies describing the use of cidofovir for PML were reviewed. DATA SYNTHESIS: Most case reports describing the use of cidofovir have shown that the drug is effective in the treatment of PML. Some patients were also receiving HAART concurrently; therefore, it is not clear which treatment modality had a greater impact on PML. However, cidofovir may be effective in patients whose disease has progressed despite HAART or who are-unable to tolerate these regimens. A pilot study of cidofovir for treating PML has completed enrollment, but preliminary results showed no benefit. CONCLUSIONS: Cidofovir may be the most reasonable treatment option for PML in HIV-infected individuals who fail to improve with HAART or who are unable to tolerate these regimens. Patients who receive cidofovir should be monitored for renal and ocular toxicity.     

Cidofovir treatment of progressive multifocal leukoencephalopathy in a patient receiving highly active antiretroviral therapy.

Progressive multifocal leukoencephalopathy (PML), a frequently fatal demyelinating disease caused by JC virus, occurs as an opportunistic infection in patients with acquired immunodeficiency syndrome. Curative therapy has been elusive, but recent reports suggest its improvement after institution of highly active antiretroviral therapy (HAART). We describe a case of PML that developed 6 months after the patient, a 55-year-old man, began to receive HAART. The PML progressed despite good virologic and immunologic response to HAART. Substantial symptomatic and radiographic improvement occurred after the addition of cidofovir to the treatment regimen. We reviewed the scientific literature on this rare occurrence of PML after institution of HAART and describe the patient characteristics, potential pathogenesis, and therapeutic options, including the successful use of cidofovir as an adjunctive agent.     

The clinical features of PML

The symptoms associated with progressive multifocal leukoencephalopathy (PML) reflect the location of pathologic brain lesions. These symptoms include visual deficits, cognitive impairment, and motor weakness; in patients with acquired immunodeficiency syndrome (AIDS), presenting signs can also include gait disturbance, dysarthria, dysphasia, and ocular palsy. Recently, PML has been observed in patients treated with biologic agents; natalizumab recipients currently represent the second largest group of patients with PML (behind patients with AIDS). Although brain biopsy is the most accurate and reliable method for diagnosing PML, it is rarely used today. Diagnosis is usually based on detection of JC virus in the cerebrospinal fluid by polymerase chain reaction, the clinical presentation, and demonstration of PML brain lesions on magnetic resonance imaging. With immune reconstitution, the prognosis of PML has improved markedly.     

Human immunodeficiency virus-associated peripheral neuropathies

Peripheral neuropathy has emerged as the most common neurologic complication of human immunodeficiency virus (HIV) infection. It will continue to play an Important role in HIV Infection given the fact that HIV-infected Individuals are living longer, are at risk of long-term metabolic complications, and face an Increasing exposure to potentially neurotoxic antiretroviral drugs. We review the various types of peripheral neuropathy that have been associated with HIV infection, including distal symmetrical polyneuropathy, toxic neuropathy from antiretroviral drugs, diffuse infiltrative lymphocytosis syndrome, inflammatory demyelinating polyneuropathies, multifocal mononeuropathies, and progressive polyradiculopathy.     

Response to HAART and GB virus type C coinfection in a cohort of antiretroviral-naive HIV-infected individuals

The prognostic role of GB virus type C (GBV-C) viraemia in HIV-infected subjects treated with highly active antiretroviral therapy (HAART) is still undefined. The aim of this analysis is to assess the relationship between GBV-C infection and response to antiretroviral therapy among HIV-infected subjects initiating HAART when antiretroviral-naive. A prospective, observational study of 400 HIV-infected patients with measurements of GBV-C RNA, hepatitis C virus (HCV) antibodies and HCV RNA determined from plasma stored prior to HAART initiation. Time to virological (achieving HIV RNA < or =500 copies/ml) and immunological success (a CD4+ count increase of > or =200 cells/microl), and the time to virological relapse (confirmed HIV RNA >500 copies/ml) were assessed by Kaplan-Meier methods and Cox proportional hazard regression model. Of the subjects, 117 (29.3%) were GBV-C positive and, overall, 351 (87.8%) patients achieved virological success. After controlling for a number of confounders including HCV RNA, GBV-C viraemic patients experienced a significantly lower risk of HIV rebound than those who were GBV-C negative [relative hazard (RH)=0.56, 95% CI: 0.34-0.93, P=0.03]. Conversely, the probability of achieving initial virological success or CD4+ count response after HAART did not differ between GBV-C-negative and -positive subjects. These results suggest that GBV-C coinfection may play a role in determining the rate of HIV rebound possibly by competing with HIV replication after HIV load has been successfully suppressed by HAART.     

Increasing survival with HIV: impact on nursing care

The introduction of highly active antiretroviral therapy (HAART) has transformed human immunodeficiency virus (HIV) infection from a rapidly progressive catastrophic illness to a chronic condition. Individuals with HIV are living longer and developing conditions usually associated with aging, as well as complications from pre-existing or subsequently acquired conditions. In addition, toxicities associated with HAART may precipitate or exacerbate comorbid conditions. As opportunistic infections account for fewer admission and lower mortality rates, new patterns of illness are emerging. Complex interactions among multiple, sometimes overlapping conditions require focused yet comprehensive attention in care and management. Nurses will encounter HIV-infected patients in an increasing range of care settings, and an understanding of the range and interaction of potential comorbidities and their treatments with HIV and its treatment will be required to provide safe and effective care.     

Analysis of CCR5, CCR2, SDF1 and RANTES gene polymorphisms in subjects with HIV-related PML and not determined leukoencephalopathy.

Progressive Multifocal Leukoencephalopathy (PML) is a fatal demyelinating disease of the central nervous system (CNS) caused by JC virus (JCV), a human polyomavirus that can lytically infect and destroy the oligodendrocites in immunosuppressed individuals. After the introduction of highly active antiretroviral therapy (HAART) for AIDS treatment, a PML-like leukoencephalopathy, known as non-determined leukoencephalopathy (NDLE), has also been observed. Since a number of host genetic factors have been identified as having an impact on susceptibility to HIV-1 infection and in the progression to AIDS and death, in this work we analysed the pattern of distribution of different chemokine and chemokine receptor polymorphisms that seem to be involved in HIV+ neurological diseases. The CCR5, RANTES, CCR2 and SDF1 genes were molecularly analysed in 84 HIV+ HAART treated subjects: 55 without neurological disorders (HIV+), 12 HIV+ NDLE and 17 HIV+ PML patients. The RANTES -403 G/A polymorphism was significantly associated with NDLE. These data suggest that mutation of the RANTES allele can predispose to the induction of demyelination similarly to what has been observed in Multiple Sclerosis (MS) and may suggest a possible explanation for the development of leukoencephalopathy without detection of JCV.     

Alpha herpesvirus infections in AIDS patients

Alpha-herpesvirus infections by herpes simplex virus and varicella-zoster virus among HIV-infected patients were summarized. These infections were occurred in a high frequency and shown to be extensive lesions, prolonged virus excretion from the lesions, generalized infection, and uncommon diseases as compared these of with immunocompetent patients. Acyclovir-resistant viruses appeared. These evidences supplied the profound understanding of the pathogenesis and new subjects in the field of herpesvirus infection. Recent introduction of HAART against HIV and the appropriate use of anti-herpesvirus drugs, however, reduced the development of severe infection, and provided successful treatment, respectively.     

Immune reconstitution inflammatory syndrome and human immunodeficiency virus-associated myocarditis

Myocarditis is a well-recognized cardiac manifestation of human immunodeficiency virus (HIV) infection, and alterations in the immune system likely play an important role in the pathogenesis of heart muscle disease in HIV-infected patients. Highly active antiretroviral therapy (HAART) has greatly improved survival in HIV patients but not without uncovering new and unique manifestations of disease. Immune reconstitution inflammatory syndrome is a collection of inflammatory disorders in which a pathologic inflammatory response and clinical deterioration occur during recovery of the immune system after HAART. To our knowledge, a correlation between immune reconstitution inflammatory syndrome and HIV-associated myocarditis has not been described previously. We report a case of acute myocarditis presenting with refractory ventricular arrhythmias in a patient with AIDS who experienced rapid immune recovery with the initiation of HAART. The case underscores the importance of recognizing this potential complication of AIDS treatment and calls for renewed vigilance concerning cardiac manifestations of HIV, especially during the immune reconstitution phase.     

Pharmacovigilance and PML in the oncology setting

Methods developed by the Southern Network on Adverse Reactions project, the only state-funded pharmacovigilance program in the nation, are invaluable in identifying rare and serious drug events and in disseminating related safety reports quickly throughout the medical community. An important discovery was identification and reporting of an association of rituximab and progressive multifocal leukoencephalopathy (PML) in patients without human immunodeficiency virus (HIV). A recent investigation identified 57 patients with rituximab-associated PML, including bone marrow samples, brain biopsies, and autopsy materials from patients with lymphoma and PML who tested positive for JC virus. The investigation identified an association of rituximab-chemotherapy administration and PML, although a causal relationship remains an area of active investigation. Additional investigations evaluated the epidemiology of PML in the oncology setting before and after the introduction of rituximab for lymphoma treatment. Focused analyses investigated risk factors for development of this rare complication. Further studies are needed to investigate the pathophysiology, epidemiology, and risk factors for PML developing among HIV-negative cancer patients who receive rituximab and chemotherapy.     

Highly active antiretroviral therapy-associated metabolic syndrome and cardiovascular risk

The introduction of highly active antiretroviral therapy (HAART) has significantly modified the course of human immunodeficiency virus (HIV) disease, with longer survival and improved quality of life of HIV-infected subjects. However, HAART regimens, especially those including protease inhibitors, have been shown to cause in a high proportion of HIV-infected patients a metabolic syndrome (lipodystrophy/lipoatrophy, dyslipidemia, type 2 diabetes mellitus, insulin resistance) that may be associated with an increased risk of cardiovascular disease (coronary artery disease and stroke). A careful stratification of the cardiovascular risk and cardiovascular monitoring of patients under HAART is needed according to the most recent clinical guidelines.     

Research progress in slow virus infections in Japan and the diagnostic points

There have been many progresses of researches on slow virus infections including sub-acute sclerosing panencephalitis (SSPE), progressive multifocal leukoencephalopathy (PML) and prion diseases. In Japan, many researches were conducted in relation with the research group on prion disease and slow virus infection sponsored by the Ministry of Health, Welfare and Labor. Particularly in prion disease, the nation-wide surveillance has shown many important epidemiological and clinical results. However the elucidation of pathomechanisms and development of effective treatments of prion disease, SSPE and PML are far from contentment and we the mankind need further efforts to overcome these diseases.     

Treatment options for progressive multifocal leukoencephalopathy in HIV-infected persons: current status and future directions

Progressive multifocal encephalopathy (PML) caused by JC virus was frequently encountered in AIDS patients before combination antiretroviral therapy (cART). Incidence decreased and the outcome improved with cART. The immune reconstitution with cART is beneficial for HIV-infected patients and is an effective treatment for PML. However, when it is excessive an inflammatory response immune syndrome might occur with deterioration of PML. So far, no specific therapy has proven efficacious in small clinical trials in spite of some optimistic case reports. Combination of drugs targeted at different stages of JC virus life cycle seems to have a better effect. Passive and active immune therapies, immune competence “boosters” appear promising. New future approaches such as gene editing are not far away.     

A rational approach to PML for the clinician

The first step in the management of progressive multifocal leukoencephalopathy (PML) is awareness of the disease. Patients vulnerable to PML are those with immunosuppression, either through their disease or use of immune-modulating therapy. In patients susceptible to PML who exhibit focal neurologic signs and symptoms, brain magnetic resonance imaging can detect the telltale PML brain lesions--subcortical white matter hyperintense areas on T2-weighted images and fluid-attenuated inversion recovery sequences and hypointensity on T1-weighted images, typically without enhancement. Demonstration of JC virus DNA by ultrasensitive polymerase chain reaction in cerebrospinal fluid is diagnostic for PML. Immune restoration whenever possible is the cornerstone of treatment. Highly active antiretroviral therapy has dramatically improved the prognosis for patients infected with human immunodeficiency virus. Alternatively, restoration of immunity is frequently attended by the immune reconstitution inflammatory syndrome which can be clinically devastating or even fatal. In the case of natalizumab-associated PML, withdrawal of therapy and prompt institution of plasmapheresis to desaturate target receptors provides the best chance for long-term survival.     

Management of intracerebral lesions in patients with HIV: a retrospective study with discussion of diagnostic problems

A total of 95 patients who presented in 1994 and 1995 with focal brain lesions at a London HIV centre were studied retrospectively. Patients were allocated to "definite" or "presumed" diagnostic categories of toxoplasma encephalitis (TE), primary CNS lymphoma (PCNSL) or progressive multifocal leukoencephalopathy (PML), based on strict criteria. The number in each category was: TE, 20; PCNSL, 9; PML, 7; presumed TE, 12; presumed PCNSL, 8 and presumed PML, 17. There were 20 patients in whom a diagnosis could not be made, and there were three non-HIV diagnoses. Demographic data, features at presentation and routine CSF analysis were not discriminatory in making a diagnosis. Toxoplasma titres were a median of 1:256 in those with TE compared to 1:16 in all other groups (p < 0.001) and those with TE were less likely to be on toxoplasma prophylaxis compared to those with PCNSL (p < 0.002). Survival with TE (median of 446 days) was significantly longer than survival in all other groups. Survival with either confirmed or presumed PML was similar. The problems of diagnosis of focal brain lesions in HIV patients are discussed and a management flow chart for mass lesions is proposed.      

Human glial chimeric mice reveal astrocytic dependence of JC virus infection

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease triggered by infection with the human gliotropic JC virus (JCV). Due to the human-selective nature of the virus, there are no animal models available to investigate JCV pathogenesis. To address this issue, we developed mice with humanized white matter by engrafting human glial progenitor cells (GPCs) into neonatal immunodeficient and myelin-deficient mice. Intracerebral delivery of JCV resulted in infection and subsequent demyelination of these chimeric mice. Human GPCs and astrocytes were infected more readily than oligodendrocytes, and viral replication was noted primarily in human astrocytes and GPCs rather than oligodendrocytes, which instead expressed early viral T antigens and exhibited apoptotic death. Engraftment of human GPCs in normally myelinated and immunodeficient mice resulted in humanized white matter that was chimeric for human astrocytes and GPCs. JCV effectively propagated in these mice, which indicates that astroglial infection is sufficient for JCV spread. Sequencing revealed progressive mutation of the JCV capsid protein VP1 after infection, suggesting that PML may evolve with active infection. These results indicate that the principal CNS targets for JCV infection are astrocytes and GPCs and that infection is associated with progressive mutation, while demyelination is a secondary occurrence, following T antigen–triggered oligodendroglial apoptosis. More broadly, this study provides a model by which to further assess the biology and treatment of human-specific gliotropic viruses.     

Multiple sclerosis, natalizumab, and PML: helping patients decide

The treatment benefits of natalizumab in patients with multiple sclerosis (MS) appear to exceed those of other disease-modifying drugs, but progressive multifocal leukoencephalopathy (PML) has been identified as a risk in patients receiving natalizumab. As of August 2011, a total of 150 cases of natalizumab-associated PML had been reported worldwide. The overall risk is estimated at approximately 1.66 in 1,000 patients. Independent risk factors for natalizumab-associated PML are number of infusions beyond 36 and prior use of immunosuppressive drugs. Classifying JC virus antibody status appears to be useful in treatment decision-making for individual MS patients. Patient tolerance for risk plays an important role in the selection of therapy, and the treating physician's perception and tolerance of risk may differ markedly from the patient's. Physicians can help patients make individual informed decisions regarding the use of natalizumab, given the known risk of PML.     

Treatment interruptions in HIV-infected subjects

Despite a high antiviral efficacy, the use of highly active antiretroviral therapy (HAART) in clinical practice is often impaired by the long-term toxicity of antiretroviral treatment, the increased rate of human immunodeficiency virus-1 (HIV-1) drug resistance in treated patients and the cost of therapies, so that possible interruption of HAART has to be considered as part of the current clinical practice. However, this strategy is usually followed by a rapid viral rebound with a substantial loss of CD4 T lymphocytes because the HIV suppression with HAART does not result in reconstitution of the HIV-specific immune response. Structured treatment interruption (STI) has already been investigated in HIV-infected subjects with well-controlled viral replication (initiating treatment during primary or chronic HIV infection) and in those with multiple treatment failures. A clear benefit of STI in patients with chronic infection remains controversial and these benefits are more often observed in patients starting treatment during primary HIV infection.     

Hyperlipidemia in children with HIV infection: an emerging problem

The introduction of highly active antiretroviral therapy (HAART) for the treatment of HIV infection has transformed HIV/AIDS into a chronic illness and the focus of clinical management has shifted from opportunistic infections to long-term management and toxicities of therapy. Pediatric patients with HIV infection perhaps pose the greatest challenge in this arena as they potentially face many decades of living with HIV/AIDS and its therapies. Although there are numerous emerging medical complications associated with chronic HIV infection and HAART, hyperlipidemia is increasingly recognized among HIV-infected children and adults and will be the focus of this review. The nature and prevalence of lipid abnormalities in children with HIV infection is discussed, as well as possible etiologies for these abnormalities and the future management of this growing challenge for children living with HIV disease.