Guidelines for the Prevention and Treatment of Opportunistic Infections in Adults and Adolescents With HIV

Epidemiology

Progressive multifocal leukoencephalopathy (PML) is an opportunistic infection of the central nervous system (CNS), caused by the human polyoma virus JC virus (JCV) and characterized by focal demyelination.^1,2 JCV has a worldwide distribution, and 20% to 70% of people exhibit serologic evidence of exposure by their late teens or as adults.^3-7 Primary JCV infection usually occurs asymptomatically in childhood resulting in a chronic carrier state in most individuals. Viral DNA is detected in the urine of 20% to 30% of healthy adults.^4,8-12

PML is a rare manifestation of JCV reactivation and characteristically manifests as a complication of HIV-1 infection and other immunocompromising diseases or therapies.^13-16 In recent years, PML has been reported in patients treated with immunomodulatory humanized antibodies, including natalizumab¹⁷ and efalizumab.¹⁸ Concern has been raised about a possible increased risk of PML in persons with HIV (PWH) treated with rituximab for non-Hodgkin lymphoma,^19,20 but PML has not been documented in that setting. PML can occur during chronic immunosuppression after organ transplantation and often has a poor prognosis.²¹

Before the advent of combination antiretroviral therapy (ART), PML developed in 3% to 7% of patients with AIDS^22-24 and was almost invariably fatal; spontaneous remissions were rare.²⁵ With the widespread use of ART, incidence of PML decreased substantially,^26,27 and mortality in PWH who develop the disease has declined.^28-30 Although most CNS opportunistic infections are effectively prevented when CD4 T lymphocyte (CD4) cell counts are maintained above 100 to 200 cells/mm³, PML still occurs occasionally in patients treated with ART.^2,31,32 PML also can develop in the setting of immune reconstitution after ART initiation, which is discussed below.^2,30,33

Clinical Manifestations

PML manifests as focal neurological deficits, usually with insidious onset and steady progression. Because the demyelinating lesions can involve different brain regions, specific deficits vary from patient to patient. Although some regions seem to be more favored, any region of the CNS can be involved, including the occipital lobes (hemianopsia), frontal and parietal lobes (aphasia, hemiparesis, and hemisensory deficits), and cerebellar peduncles and deep white matter (dysmetria and ataxia).¹³ Spinal cord involvement is rare, and the optic nerves are not involved.³⁴ Although lesions can be multiple, one lesion is clinically predominant. Initial symptoms and signs usually begin as partial deficits (e.g., weakness in one leg) that worsen over time and involve a larger territory (e.g., evolution to hemiparesis), as individual lesions expand concentrically or along white matter tracts. Less localized clinical syndromes—such as behavioral changes, dementia, or encephalopathy—result from multiple lesions in the setting of PML and are rarely the presenting clinical phenotype.³⁵

The time course of evolving demyelination, with clinical progression over several weeks, often provides a clue to diagnosis because the other major opportunistic focal brain disorders (cerebral toxoplasmosis and primary CNS lymphoma) characteristically progress in hours to days and cerebral infarcts begin even more abruptly. Nonetheless, PML is sometimes mistaken for an evolving stroke, which, like PML, is bright on diffusion-weighted magnetic resonance imaging (MRI). Focal brain lesion can mimic strokes; however, the progressive course should make this diagnosis less likely, and PML must be considered. Headache and fever are not characteristic of PML, and when present may indicate presence of another opportunistic infection. Seizures occur in nearly 20% of PML cases and are associated with lesions immediately adjacent to the cortex.^36,37

Diagnosis

Initial recognition of PML relies on a combination of clinical and neuroimaging findings: steady progression of focal neurological deficits with MRI almost always demonstrating distinct white matter lesions in areas of the brain corresponding to the clinical deficits. The lesions are hyperintense (white) on T2-weighted and fluid-attenuated inversion recovery sequences and hypointense (dark) on T1-weighted sequences.² The T1 findings can be subtle and may help distinguish lesions due to PML from those of other pathologies, including the white matter lesions of HIV encephalitis. A linear, paramagnetic band or rim in the paralesional U-fibers has been described as a common finding in PML and has been proposed to have diagnostic value independent of underlying predisposing disease. Histopathological studies show this band corresponds to iron accumulation within phagocytic cells, although the pathophysiology leading to this remains unclear.^38,39

Brain imaging with magnetic resonance (MR) or computed tomography is critical to identifying PML and differentiating it from other important treatable diseases that occur in advanced HIV. In contrast to cerebral toxoplasmosis and primary CNS lymphoma, no mass effect or displacement of normal structures is usually evident in PML imaging. Although contrast enhancement is present in 10% to 15% of cases, it is usually sparse with a thin or reticulated appearance adjacent to the edge of the lesions. Exceptions to these characteristic imaging findings can occur when the inflammatory form of PML develops in the setting of immune reconstitution after initiation of ART (see below). Advanced neuroimaging techniques—such as diffusion-weighted imaging (DWI) and MR spectroscopy—may provide additional diagnostic information.^40-42 New PML lesions and the advancing edge of large lesions have a high signal on DWI and a normal-to-low apparent diffusion coefficient, signifying restricted diffusion. These changes relate to regions of active infection and oligodendrocyte swelling. MR spectroscopy can show areas of decreased N‑acetylaspartate and increased choline related to axonal loss and cell membrane and myelin breakdown, respectively, with the greatest changes at the center of lesions.⁴³ Recently, a hyperintense cortical signal seen on MRI scan in non-enhanced T1-weighted cortex images has been associated with seizures complicating inflammatory PML.³⁷

In most cases of PML, the combined clinical and radiographic presentations support a presumptive diagnosis. Because the primary treatment method for PML is restoring the patient’s immune function, confirming the diagnosis is especially important to ensure ART is initiated rapidly.

JCV DNA is virtually never detected in normal cerebrospinal fluid (CSF) samples. Thus, the usual first step in confirming the diagnosis is to test CSF by polymerase chain reaction (PCR) for the presence of JCV DNA. The assay is positive in approximately 70% to 90% of patients not taking ART, for whom a positive result can be considered diagnostic in the appropriate clinical context—namely, subacute onset of focal neurological abnormalities and suggestive imaging findings.^10,44 JCV may be detectable in the CSF of as few as 60% of ART-treated patients.⁴⁵ In patients not taking ART, the number of JCV DNA copies can add additional information for prognosis, although the relationship between copy number and prognosis is less clear in patients taking ART.^46,47 CSF analysis can be repeated if JCV PCR is negative yet suspicion of PML remains high and alternative diagnoses have been excluded. Given that in AIDS patients, multiple opportunistic conditions are sometimes encountered, evaluation of CSF is often indicated to rule out Cryptococcus, neurosyphilis, cytomegalovirus encephalitis, varicella-zoster encephalitis, herpes simplex encephalitis, and tuberculosis. Further, CSF PCR analyses for Toxoplasma and consideration of Epstein-Barr virus generally associated with primary CNS lymphoma is often indicated with progressive multifocal brain disease in the setting of AIDS. Because JCV DNA viral load in CSF may be very low even with active PML, highly sensitive PCR performance is desirable. Sensitive assays that detect as few as 50 copies/mL are now available, with some research laboratories exceeding this level of sensitivity; detection of JCV virus in CSF in any amount with the appropriate clinical and imaging findings strongly supports the diagnosis of PML.⁴⁸ Analysis of plasma samples for detection of JCV by PCR when positive are relatively specific for PML (~92% in patients with HIV), while the sensitivity is less than 40% in this setting.⁴⁹

In some instances, brain biopsy is required in order to rule out other diagnoses. PML usually can be identified by the characteristic tissue cytopathology—including oligodendrocytes with intranuclear inclusions, bizarre astrocytes, and lipid-laden macrophages—with identification of JCV or cross-reacting polyoma virus by immunohistochemistry, in situ nucleic acid hybridization, or electron microscopy.^13,50,51

Generally, serologic testing is not useful because of high anti-JCV seroprevalence in the general population. Recently, however, antibody testing has been assessed for stratifying risk of PML with natalizumab treatment.⁶ Significant increases in JCV-specific antibody titers⁵² and detection of intrathecally produced anti-JCV antibodies may prove useful for diagnostic testing⁵³ but require further prospective study. The value of anti-JCV antibodies in stimulating Fc receptor-bearing effector cell activity contributing to outcome of PML requires further studies.⁵⁴

Preventing Exposure

Currently, no known way exists to prevent exposure to the virus because most individuals are infected in childhood.

Preventing Disease

In many individuals, JCV infection is likely latent and intermittently productive, although clinically silent, in the kidney or other anatomic sites. Systemic infection may increase in the presence of immunosuppression. It remains a subject of debate whether JCV infection is also latent in the CNS or whether PML results from hematogenous dissemination of infection to the brain resulting in subsequent PML lesion development within months of entry to the CNS.^55,56 Therefore, the only known way to prevent disease is to prevent progression of HIV-related immunosuppression with ART (AII).

Treating Disease

No specific therapy exists for JCV infection or PML. The main approach to treatment involves ART to reverse the immunosuppression that interferes with the normal host response to this virus.⁵⁷ In patients with PML who are not on therapy, ART should be started immediately (AII). In this setting, more than half of PML patients with HIV experience a remission in which disease progression stops. Although neurological deficits often persist, some patients experience clinical improvement.^28,29,58-63 In one retrospective study of 118 consecutive patients with PML who received ART, 75 patients (63.6%) survived for a median of 114 weeks (2.2 years) after diagnosis of PML.⁶³ Neurological function in the survivors was categorized as cure or improvement in 33, stabilization or worsening in 40, and unknown in 2. Another retrospective case series reported that 42% of PML survivors on ART had moderate or severe disability.⁶⁴ Peripheral blood CD4 count at presentation was the only variable that predicted survival; the odds ratio for death was 2.7 among patients with CD4 counts <100 cells/mm³ compared with patients who had higher CD4 counts. In other case series, worse prognosis also was associated with high plasma HIV RNA levels at the time of presentation, poor virologic responses to ART, and presence of lesions in the brain stem.^{29,32,59,60,62,63,65} Contrast enhancement on imaging may predict better outcomes, as it is indicative of an immune response to the virus.³¹ In multiple sclerosis patients with PML, younger age, more restricted unilobar disease, and lower CSF JCV DNA copy numbers are associated with better outcomes; whether these associations are true for PML in PWH is unknown.⁶⁶

ART should be optimized for HIV virologic suppression in patients with PML who have received ART but remain viremic because of inadequate adherence or ARV resistance (AIII). More problematic are patients who develop PML despite successful HIV virologic suppression while taking ART. A preliminary report of PML with patients treated intensively with four classes of ART (including enfuvirtide) suggested that the strategy might offer higher-than-anticipated survival,⁶⁷ but it has not yet been followed by structured trial. Therefore, no evidence supports ART intensification for PML (BII).

The use of ARV drugs that better penetrate the CNS also has been proposed, with use of the CNS Penetration Effectiveness (CPE) score of drug regimens as a guide. This score is based on the pharmacology of ARV drugs with respect to their chemical characteristics as well as demonstrated entry into the CNS (or, more often, the CSF) and, where available, on their CNS anti-HIV activity.⁶⁸ One report found at the beginning of the combination ART era that a high CPE score was associated with longer survival after a PML diagnosis, whereas in the late, more recent ART period, the effect of the CPE score disappeared as more potent ARV regimens led to more effective plasma viral load control.⁶⁹ Hence, in the current era, the effectiveness of selecting a treatment regimen with a high CPE score is not established. It seems likely that systemic rather than CNS efficacy is the salient aspect of ART in this setting because ART’s most important effect on PML may be restoration of effective anti-JCV immunity that can limit CNS infection.^70,71 ART regimens should be selected based on likelihood of achieving virologic suppression and not CPE score (BII).

Several studies have evaluated targeted treatments for PML. However, many anecdotal reports of efficacy have not been confirmed by controlled studies and are therefore not recommended. Based on case reports and demonstration of in vitro inhibitory activity against JCV, intravenous (IV) and intrathecal cytarabine (cytosine arabinoside) were tested in a clinical trial, but neither demonstrated clinical benefit.⁷² Therefore, treatment with cytarabine is not recommended (AII). Similarly, cidofovir initially was reported to have a salutary clinical effect, but several large studies—including retrospective case-control studies, an open-label clinical trial, and a meta-analysis that included patients from five large studies—demonstrated no benefit.^45,61-63,73 Thus, treatment with cidofovir is also not recommended (AII).

On the basis of a report indicating that the serotonergic 5HT2a receptor can serve as a cellular receptor for JCV in a glial cell culture system,^74,75 drugs that block the 5HT2a receptor, including olanzapine, ziprasidone, mirtazapine, cyproheptadine, and risperidone, have been suggested as treatment for PML,⁷⁶ although the rationale for this practice has been questioned.⁷⁷ Again, anecdotes about favorable outcomes^1,78-81 have not been substantiated by reports of genuine benefit in larger case series, cohort studies, or formal clinical trials. Thus, at this time, treatment with serotonergic 5HT2a receptor blockers is not recommended (BIII).

After a cell-culture study indicated that JCV replication could be inhibited by a topoisomerase inhibitor,⁸² an analogue, topotecan, was studied in a small trial. Results suggested a salutary effect in some patients, although the outcome likely was little different from the natural course in other patients with AIDS, and the main toxicities were hematologic.⁸³ At this time, topotecan is not recommended (BIII).

A Phase I/II clinical trial of the antimalarial drug mefloquine was initiated based on its demonstrated in vitro anti-JCV activity. The trial was later halted by the sponsor because demonstration of efficacy was futile.⁸⁴ Mefloquine use for PML treatment is not recommended (BIII). Immunomodulatory approaches to the treatment of PML in PWH also have been tried, but none has yet been studied in a prospective, controlled clinical trial. Although an initial retrospective analysis suggested that interferon-alpha might improve survival,⁸⁵ a subsequent retrospective analysis did not demonstrate benefit beyond that afforded by ART; therefore, interferon-alpha is not recommended (BIII).⁸⁶ A single report described failure of interferon-beta treatment of HIV-associated PML⁸⁷ and natalizumab-related PML developed in patients given interferon-beta for multiple sclerosis.¹⁷ Case reports have described improvement or recovery in PML-related neurological dysfunction in three patients who were not HIV infected and were treated with IL-2: one with Hodgkin lymphoma treated with autologous bone marrow transplantation, one with low-grade lymphoma and allogeneic stem cell transplantation, and one with myelodysplastic syndrome.^88-90 Like the other reports, these too have not been followed up with more substantial trials; therefore, treatment of PML with IL-2 is not recommended (BIII). Recent interest in recombinant IL-7 for treatment of PML when CD4 lymphopenia is persistent, sometimes in combination with VP-1 vaccination strategy, are under consideration as an alternative adjuvant immune therapy to improve PML outcomes.^91-95 Checkpoint inhibitor therapy has been considered recently as a means of enhancing the immune response to JCV most commonly in settings outside of HIV where immune reconstitution may be futile. The outcome of reports is conflicting, and further research is required.^96,97 Use of checkpoint inhibitors for PML in the setting of HIV is not recommended (BIII).

Adoptive transfer of autologous or allogeneic virus-specific T cells, either against JCV or the closely related BK virus, have been used for the treatment of PML. Across the several small case series published to date, a single patient with HIV-associated PML was treated with benefit.^98-100 Use of disease-specific T cells is actively being explored, but at present cannot be recommended for HIV-associated PML. In summary, immunomodulatory agents are not recommended (BIII).

Special Considerations for ART

ART should be (re)started as soon as possible for all patients, ideally before PML develops. For patients with suspected PML, it is especially imperative to start ART quickly (AII). For patients already on treatment who have demonstrated plasma HIV viremia and are adherent to therapy, ART should be adjusted, if possible, based on plasma virus susceptibility (AII).

Monitoring of Response to Therapy and Adverse Events (Including Immune Reconstitution Inflammatory Syndrome)

Treatment response should be monitored with clinical examination and brain MRI. In patients with detectable JCV DNA in their CSF before initiation of ARV treatment, quantification of CSF JCV DNA may prove useful as an index to follow for assessing treatment response. No clear guidelines exist for the timing of follow-up assessments, but it is reasonable to be guided by clinical progress (BIII). Often disease progression occurs before stabilization and improvement occurs.⁶⁷ In patients who appear stable or improved, neuroimaging can be obtained 6 to 8 weeks after ART initiation to screen for radiographic signs of progression or of immune response and can serve as a further baseline for subsequent scans should the patient begin to deteriorate (BIII). In patients who clinically worsen before or after this 6- to 8-week period, repeat neuroimaging should be obtained as soon as worsening is recognized (BIII).

PML-Immune Reconstitution Inflammatory Syndrome

PML has been reported to occur within the first weeks to months after initiating ART^{2,32,33,101-103} with clinical and radiographic features that differ from classical PML, including lesions with contrast enhancement, edema and mass effect, and a more rapid clinical course.^38,104 As with other presentations of immune reconstitution inflammatory syndrome (IRIS), it is more likely after advanced HIV with low CD4 counts and greater decline in HIV viral load on initiation of ARV. This presentation has been referred to as inflammatory PML or PML-IRIS. Both unmasking of cryptic PML and paradoxical worsening in a patient with an established PML diagnosis have been observed. Histopathology typically demonstrates perivascular mononuclear inflammatory infiltration.^105-108 Unmasked PML-IRIS is presumed to represent the effects of a restored immune response to JCV infection in the context of ART, with resultant local immune and inflammatory responses.

Because ART-induced immune reconstitution may be associated with both onset and paradoxical worsening of PML, corticosteroids have been used empirically in this setting with reported benefit.^2,102,109 Further study of corticosteroids for treatment of PML-IRIS is needed to confirm efficacy and refine dosage and duration. At present, however, use of corticosteroids to treat of PML-IRIS may be justified in some PML where edema or mass effect causes serious clinical deterioration (BIII). The decision to use steroids can be difficult because it is the immune response to JCV that controls the infection and treatments that blunt that response could be deleterious. Nevertheless, the inflammatory response against PML can, at times, be more damaging than the virus itself, and corticosteroids appear to have a role in treatment of these patients.

The dosage and duration of corticosteroids for PML-IRIS have not been established. In the absence of comparative data, adjuvant corticosteroid therapy should be tailored to individual patients. One approach, modeled on treatment of multiple sclerosis flairs, is to begin with a 3- to 5‑day course of IV methylprednisolone dosed at 1 g per day, followed by an oral prednisone taper, dosed according to clinical response. A taper may begin with a dose of 60 mg per day in a single dose, tapered over 1 to 6 weeks. Clinical status should be monitored carefully during this taper in an attempt to minimize systemic and immune effects while avoiding IRIS recrudescence. Contrast-enhanced MRI at 2 to 6 weeks may be helpful in documenting resolution of inflammation and edema and to obtain a new baseline, recognizing that the MRI appearance may worsen despite clinical improvement and that clinical status is likely the best indicator of treatment efficacy. Importantly, ART should be continued (AIII).

Several case reports suggest that maraviroc might be beneficial for PML-IRIS,¹¹⁰ presumably related to the immunomodulatory rather than ARV properties of the CCR5 inhibitor. However, no comparative studies in HIV-associated PML have confirmed benefit of inclusion of maraviroc in HIV therapy in this setting.^110,111 A retrospective cohort study of 27 patients with PML in whom maraviroc was used failed to show utility in preventing PML-IRIS.¹¹² Maraviroc is not recommended as a component of treatment of PML (BIII).

Managing Treatment Failure

PML remission can take several weeks, and no strict criteria exist to define treatment failure. However, a working definition of treatment failure may be continued clinical worsening after 3 months of ART initiation. Changes in plasma HIV RNA levels and blood CD4 count responses provide ancillary predictive information. Failing ART regimens should be changed based on standard guidelines for the use of ART (see Virologic Failure in the Adult and Adolescent Antiretroviral Guidelines). When PML continues to worsen despite fully suppressive ART, one of the unproven therapies described above could be considered after consultation with an expert (CIII), although the possibility of toxicity must be balanced against the unproven benefits of these treatments. The search for other potentially treatable comorbid conditions, like hepatitis C virus and associated cirrhosis, also should be considered in this setting.¹¹³

Preventing Recurrence

Patients who experience remission of PML after ART rarely suffer subsequent recrudescence unless ART is interrupted.^61,114 The main preventive measure, based on its role in reversing the disease, is treatment with an effective ART regimen that suppresses viremia and maintains CD4 counts (AII).

Special Considerations During Pregnancy

Diagnostic evaluation of PML should be the same in pregnant or nonpregnant individuals. Therapy during pregnancy should consist of initiating or optimizing the ARV regimen.

References

1. Koralnik IJ. Progressive multifocal leukoencephalopathy revisited: has the disease outgrown its name? Ann Neurol. 2006;60(2):162-173. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16862584.
2. Cinque P, Koralnik IJ, Gerevini S, Miro JM, Price RW. Progressive multifocal leukoencephalopathy in HIV-1 infection. Lancet Infect Dis. 2009;9(10):625-636. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19778765.
3. Kean JM, Rao S, Wang M, Garcea RL. Seroepidemiology of human polyomaviruses. PLoS Pathog. 2009;5(3):e1000363. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19325891.
4. Egli A, Infanti L, Dumoulin A, et al. Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors. J Infect Dis. 2009;199(6):837-846. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19434930.
5. Antonsson A, Green AC, Mallitt KA, et al. Prevalence and stability of antibodies to the BK and JC polyomaviruses: a long-term longitudinal study of Australians. J Gen Virol. 2010;91(Pt 7):1849-1853. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20219899.
6. Gorelik L, Lerner M, Bixler S, et al. Anti-JC virus antibodies: implications for PML risk stratification. Ann Neurol. 2010;68(3):295-303. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20737510.
7. Knowles WA. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv Exp Med Biol. 2006;577:19-45. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16626025.
8. Kitamura T, Aso Y, Kuniyoshi N, Hara K, Yogo Y. High incidence of urinary JC virus excretion in nonimmunosuppressed older patients. J Infect Dis. 1990;161(6):1128-1133. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2161040.
9. Sundsfjord A, Flaegstad T, Flo R, et al. BK and JC viruses in human immunodeficiency virus type 1-infected persons: prevalence, excretion, viremia, and viral regulatory regions. J Infect Dis. 1994;169(3):485-490. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8158020.
10. Koralnik IJ, Boden D, Mai VX, Lord CI, Letvin NL. JC virus DNA load in patients with and without progressive multifocal leukoencephalopathy. Neurology. 1999;52(2):253-260. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9932940.
11. Lednicky JA, Vilchez RA, Keitel WA, et al. Polyomavirus JCV excretion and genotype analysis in HIV-infected patients receiving highly active antiretroviral therapy. AIDS. 2003;17(6):801-807. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12660526.
12. Kato A, Kitamura T, Takasaka T, et al. Detection of the archetypal regulatory region of JC virus from the tonsil tissue of patients with tonsillitis and tonsilar hypertrophy. J Neurovirol. 2004;10(4):244-249. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15371154.
13. Richardson EP, Jr., Webster HD. Progressive multifocal leukoencephalopathy: its pathological features. Prog Clin Biol Res. 1983;105:191-203. Available at: https://www.ncbi.nlm.nih.gov/pubmed/6304757.
14. Garcia-Suarez J, de Miguel D, Krsnik I, Banas H, Arribas I, Burgaleta C. Changes in the natural history of progressive multifocal leukoencephalopathy in HIV-negative lymphoproliferative disorders: impact of novel therapies. Am J Hematol. 2005;80(4):271-281. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16315252.
15. Amend KL, Turnbull B, Foskett N, Napalkov P, Kurth T, Seeger J. Incidence of progressive multifocal leukoencephalopathy in patients without HIV. Neurology. 2010;75(15):1326-1332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20938025.
16. Anand P, Hotan GC, Vogel A, Venna N, Mateen FJ. Progressive multifocal leukoencephalopathy: a 25-year retrospective cohort study. Neurol Neuroimmunol Neuroinflamm. 2019;6(6). Available at: https://www.ncbi.nlm.nih.gov/pubmed/31554669.
17. Clifford DB, De Luca A, Simpson DM, Arendt G, Giovannoni G, Nath A. Natalizumab-associated progressive multifocal leukoencephalopathy in patients with multiple sclerosis: lessons from 28 cases. Lancet Neurol. 2010;9(4):438-446. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20298967.
18. Molloy ES, Calabrese LH. Therapy: targeted but not trouble-free: efalizumab and PML. Nat Rev Rheumatol. 2009;5(8):418-419. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19648939.
19. Boue F, Gabarre J, Gisselbrecht C, et al. Phase II trial of CHOP plus rituximab in patients with HIV-associated non-Hodgkin's lymphoma. J Clin Oncol. 2006;24(25):4123-4128. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16896005.
20. Mounier N, Spina M, Gisselbrecht C. Modern management of non-Hodgkin lymphoma in HIV-infected patients. Br J Haematol. 2007;136(5):685-698. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17229246.
21. Mateen FJ, Muralidharan R, Carone M, et al. Progressive multifocal leukoencephalopathy in transplant recipients. Ann Neurol. 2011;70(2):305-322. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21823157.
22. Petito CK, Cho ES, Lemann W, Navia BA, Price RW. Neuropathology of acquired immunodeficiency syndrome (AIDS): an autopsy review. J Neuropathol Exp Neurol. 1986;45(6):635-646. Available at: https://www.ncbi.nlm.nih.gov/pubmed/3021914.
23. Anders KH, Guerra WF, Tomiyasu U, Verity MA, Vinters HV. The neuropathology of AIDS. UCLA experience and review. Am J Pathol. 1986;124(3):537-558. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2876640.
24. Lang W, Miklossy J, Deruaz JP, et al. Neuropathology of the acquired immune deficiency syndrome (AIDS): a report of 135 consecutive autopsy cases from Switzerland. Acta Neuropathol. 1989;77(4):379-390. Available at: https://www.ncbi.nlm.nih.gov/pubmed/2540610.
25. Berger JR, Mucke L. Prolonged survival and partial recovery in AIDS-associated progressive multifocal leukoencephalopathy. Neurology. 1988;38(7):1060-1065. Available at: https://www.ncbi.nlm.nih.gov/pubmed/3386823.
26. d'Arminio Monforte A, Cinque P, Mocroft A, et al. Changing incidence of central nervous system diseases in the EuroSIDA cohort. Ann Neurol. 2004;55(3):320-328. Available at: https://www.ncbi.nlm.nih.gov/pubmed/14991809.
27. Casado JL, Corral I, Garcia J, et al. Continued declining incidence and improved survival of progressive multifocal leukoencephalopathy in HIV/AIDS patients in the current era. Eur J Clin Microbiol Infect Dis. 2014;33(2):179-187. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23948752.
28. Clifford DB, Yiannoutsos C, Glicksman M, et al. HAART improves prognosis in HIV-associated progressive multifocal leukoencephalopathy. Neurology. 1999;52(3):623-625. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10025799.
29. Antinori A, Cingolani A, Lorenzini P, et al. Clinical epidemiology and survival of progressive multifocal leukoencephalopathy in the era of highly active antiretroviral therapy: data from the Italian Registry Investigative Neuro AIDS (IRINA). J Neurovirol. 2003;9 Suppl 1:47-53. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12709872.
30. Melliez H, Mary-Krause M, Bocket L, et al. Risk of progressive multifocal leukoencephalopathy in the combination antiretroviral therapy era in the French Hospital Database on Human Immunodeficiency Virus (ANRS-C4). Clin Infect Dis. 2018;67(2):275-282. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29635465.
31. Berger JR, Levy RM, Flomenhoft D, Dobbs M. Predictive factors for prolonged survival in acquired immunodeficiency syndrome-associated progressive multifocal leukoencephalopathy. Ann Neurol. 1998;44(3):341-349. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9749600.
32. Cinque P, Bossolasco S, Brambilla AM, et al. The effect of highly active antiretroviral therapy-induced immune reconstitution on development and outcome of progressive multifocal leukoencephalopathy: study of 43 cases with review of the literature. J Neurovirol. 2003;9 Suppl 1:73-80. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12709876.
33. Du Pasquier RA, Koralnik IJ. Inflammatory reaction in progressive multifocal leukoencephalopathy: harmful or beneficial? J Neurovirol. 2003;9 Suppl 1:25-31. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12709868.
34. Bernal-Cano F, Joseph JT, Koralnik IJ. Spinal cord lesions of progressive multifocal leukoencephalopathy in an acquired immunodeficiency syndrome patient. J Neurovirol. 2007;13(5):474-476. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17994433.
35. Zunt JR, Tu RK, Anderson DM, Copass MC, Marra CM. Progressive multifocal leukoencephalopathy presenting as human immunodeficiency virus type 1 (HIV)-associated dementia. Neurology. 1997;49(1):263-265. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9222204.
36. Lima MA, Drislane FW, Koralnik IJ. Seizures and their outcome in progressive multifocal leukoencephalopathy. Neurology. 2006;66(2):262-264. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16434670.
37. Khoury MN, Alsop DC, Agnihotri SP, et al. Hyperintense cortical signal on magnetic resonance imaging reflects focal leukocortical encephalitis and seizure risk in progressive multifocal leukoencephalopathy. Ann Neurol. 2014;75(5):659-669. Available at: https://www.ncbi.nlm.nih.gov/pubmed/24752885.
38. Post MJ, Thurnher MM, Clifford DB, et al. CNS-immune reconstitution inflammatory syndrome in the setting of HIV infection, part 2: discussion of neuro-immune reconstitution inflammatory syndrome with and without other pathogens. AJNR Am J Neuroradiol. 2013;34(7):1308-1318. Available at: https://www.ncbi.nlm.nih.gov/pubmed/22790252.
39. Mahajan KR, Amin M, Poturalski M, et al. Juxtacortical susceptibility changes in progressive multifocal leukoencephalopathy at the gray-white matter junction correlates with iron-enriched macrophages. Mult Scler. 2021;27(14):2159-2169. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33749379.
40. Chang L, Ernst T, Tornatore C, et al. Metabolite abnormalities in progressive multifocal leukoencephalopathy by proton magnetic resonance spectroscopy. Neurology. 1997;48(4):836-845. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9109865.
41. Mader I, Herrlinger U, Klose U, Schmidt F, Kuker W. Progressive multifocal leukoencephalopathy: analysis of lesion development with diffusion-weighted MRI. Neuroradiology. 2003;45(10):717-721. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12942223.
42. da Pozzo S, Manara R, Tonello S, Carollo C. Conventional and diffusion-weighted MRI in progressive multifocal leukoencephalopathy: new elements for identification and follow-up. Radiol Med. 2006;111(7):971-977. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17021685.
43. Shah R, Bag AK, Chapman PR, Cure JK. Imaging manifestations of progressive multifocal leukoencephalopathy. Clin Radiol. 2010;65(6):431-439. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20451009.
44. Cinque P, Scarpellini P, Vago L, Linde A, Lazzarin A. Diagnosis of central nervous system complications in HIV-infected patients: cerebrospinal fluid analysis by the polymerase chain reaction. AIDS. 1997;11(1):1-17. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9110070.
45. De Luca A, Ammassari A, Pezzotti P, et al. Cidofovir in addition to antiretroviral treatment is not effective for AIDS-associated progressive multifocal leukoencephalopathy: a multicohort analysis. AIDS. 2008;22(14):1759-1767. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18753934.
46. Yiannoutsos CT, Major EO, Curfman B, et al. Relation of JC virus DNA in the cerebrospinal fluid to survival in acquired immunodeficiency syndrome patients with biopsy-proven progressive multifocal leukoencephalopathy. Ann Neurol. 1999;45(6):816-821. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10360779.
47. Bossolasco S, Calori G, Moretti F, et al. Prognostic significance of JC virus DNA levels in cerebrospinal fluid of patients with HIV-associated progressive multifocal leukoencephalopathy. Clin Infect Dis. 2005;40(5):738-744. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15714422.
48. Berger JR, Aksamit AJ, Clifford DB, et al. PML diagnostic criteria: consensus statement from the AAN Neuroinfectious Disease Section. Neurology. 2013;80(15):1430-1438. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23568998.
49. Ferretti F, Bestetti A, Yiannoutsos CT, et al. Diagnostic and prognostic value of JC virus DNA in plasma in progressive multifocal leukoencephalopathy. Clin Infect Dis. 2018;67(1):65-72. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29346632.
50. Silver SA, Arthur RR, Erozan YS, Sherman ME, McArthur JC, Uematsu S. Diagnosis of progressive multifocal leukoencephalopathy by stereotactic brain biopsy utilizing immunohistochemistry and the polymerase chain reaction. Acta Cytol. 1995;39(1):35-44. Available at: https://www.ncbi.nlm.nih.gov/pubmed/7847007.
51. Jochum W, Weber T, Frye S, Hunsmann G, Luke W, Aguzzi A. Detection of JC virus by anti-VP1 immunohistochemistry in brains with progressive multifocal leukoencephalopathy. Acta Neuropathol. 1997;94(3):226-231. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9292691.
52. Viscidi RP, Khanna N, Tan CS, et al. JC virus antibody and viremia as predictors of progressive multifocal leukoencephalopathy in human immunodeficiency virus-1-infected individuals. Clin Infect Dis. 2011;53(7):711-715. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21852452.
53. Knowles WA, Luxton RW, Hand JF, Gardner SD, Brown DW. The JC virus antibody response in serum and cerebrospinal fluid in progressive multifocal leucoencephalopathy. Clin Diagn Virol. 1995;4(2):183-194. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15566839.
54. Tan CS, Ghofrani J, Geiger E, Koralnik IJ, Jost S. Brief report: decreased JC virus-specific antibody-dependent cellular cytotoxicity in HIV-seropositive PML survivors. J Acquir Immune Defic Syndr. 2019;82(2):220-224. Available at: https://www.ncbi.nlm.nih.gov/pubmed/31513076.
55. Perez-Liz G, Del Valle L, Gentilella A, Croul S, Khalili K. Detection of JC virus DNA fragments but not proteins in normal brain tissue. Ann Neurol. 2008;64(4):379-387. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18688812.
56. Tan CS, Ellis LC, Wuthrich C, et al. JC virus latency in the brain and extraneural organs of patients with and without progressive multifocal leukoencephalopathy. J Virol. 2010;84(18):9200-9209. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20610709.
57. Dunham SR, Schmidt R, Clifford DB. Treatment of progressive multifocal leukoencephalopathy using immune restoration. Neurotherapeutics. 2020;17(3):955-965. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32166631.
58. Dworkin MS, Wan PC, Hanson DL, Jones JL. Progressive multifocal leukoencephalopathy: improved survival of human immunodeficiency virus-infected patients in the protease inhibitor era. J Infect Dis. 1999;180(3):621-625. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10438348.
59. Gasnault J, Taoufik Y, Goujard C, et al. Prolonged survival without neurological improvement in patients with AIDS-related progressive multifocal leukoencephalopathy on potent combined antiretroviral therapy. J Neurovirol. 1999;5(4):421-429. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10463864.
60. Tassie JM, Gasnault J, Bentata M, et al. Survival improvement of AIDS-related progressive multifocal leukoencephalopathy in the era of protease inhibitors. Clinical Epidemiology Group. French Hospital Database on HIV. AIDS. 1999;13(14):1881-1887. Available at: https://www.ncbi.nlm.nih.gov/pubmed/10513646.
61. Cinque P, Pierotti C, Vigano MG, et al. The good and evil of HAART in HIV-related progressive multifocal leukoencephalopathy. J Neurovirol. 2001;7(4):358-363. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11517417.
62. Marra CM, Rajicic N, Barker DE, et al. A pilot study of cidofovir for progressive multifocal leukoencephalopathy in AIDS. AIDS. 2002;16(13):1791-1797. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12218391.
63. Berenguer J, Miralles P, Arrizabalaga J, et al. Clinical course and prognostic factors of progressive multifocal leukoencephalopathy in patients treated with highly active antiretroviral therapy. Clin Infect Dis. 2003;36(8):1047-1052. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12684918.
64. Lima MA, Bernal-Cano F, Clifford DB, Gandhi RT, Koralnik IJ. Clinical outcome of long-term survivors of progressive multifocal leukoencephalopathy. J Neurol Neurosurg Psychiatry. 2010;81(11):1288-1291. Available at: https://www.ncbi.nlm.nih.gov/pubmed/20710013.
65. Pazzi AL, Galli M, et al. The relationship between outcome of progressive multifocal leukoencephalopathy and type and response to ART in previously HAART-untreated patients. Presented at: 14th Conference on Retroviruses and Opportunistic Infections; 2007. Los Angeles, CA.
66. Dong-Si T, Gheuens S, Gangadharan A, et al. Predictors of survival and functional outcomes in natalizumab-associated progressive multifocal leukoencephalopathy. J Neurovirol. 2015;21(6):637-644. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25771865.
67. Gasnault J, Costagliola D, Hendel-Chavez H, et al. Improved survival of HIV-1-infected patients with progressive multifocal leukoencephalopathy receiving early 5-drug combination antiretroviral therapy. PLoS One. 2011;6(6):e20967. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21738597.
68. Letendre S, Marquie-Beck J, Capparelli E, et al. Validation of the CNS Penetration-Effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol. 2008;65(1):65-70. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18195140.
69. Lanoy E, Guiguet M, Bentata M, et al. Survival after neuroAIDS: association with antiretroviral CNS Penetration-Effectiveness score. Neurology. 2011;76(7):644-651. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21248274.
70. Garvey L, Winston A, Walsh J, et al. Antiretroviral therapy CNS penetration and HIV-1-associated CNS disease. Neurology. 2011;76(8):693-700. Available at: https://www.ncbi.nlm.nih.gov/pubmed/21339496.
71. Fanjul F, Riveiro-Barciela M, Gonzalez J, et al. Evaluation of progressive multifocal leukoencephalopathy treatments in a Spanish cohort of HIV-infected patients: do protease inhibitors improve survival regardless of central nervous system penetration-effectiveness (CPE) score? HIV Med. 2013;14(5):321-325. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23217049.
72. Hall CD, Dafni U, Simpson D, et al. Failure of cytarabine in progressive multifocal leukoencephalopathy associated with human immunodeficiency virus infection. AIDS Clinical Trials Group 243 Team. N Engl J Med. 1998;338(19):1345-1351. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9571254.
73. Gasnault J, Kousignian P, Kahraman M, et al. Cidofovir in AIDS-associated progressive multifocal leukoencephalopathy: a monocenter observational study with clinical and JC virus load monitoring. J Neurovirol. 2001;7(4):375-381. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11517420.
74. Elphick GF, Querbes W, Jordan JA, et al. The human polyomavirus, JCV, uses serotonin receptors to infect cells. Science. 2004;306(5700):1380-1383. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15550673.
75. O'Hara BA, Atwood WJ. Interferon beta1-a and selective anti-5HT(2a) receptor antagonists inhibit infection of human glial cells by JC virus. Virus Res. 2008;132(1-2):97-103. Available at: https://www.ncbi.nlm.nih.gov/pubmed/18093678.
76. Altschuler EL, Kast RE. The atypical antipsychotic agents ziprasidone [correction of zisprasidone], risperdone and olanzapine as treatment for and prophylaxis against progressive multifocal leukoencephalopathy. Med Hypotheses. 2005;65(3):585-586. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16004936.
77. Santagata S, Kinney HC. Mechanism of JCV entry into oligodendrocytes. Science. 2005;309(5733):381-382. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16020715.
78. Focosi D, Fazzi R, Montanaro D, Emdin M, Petrini M. Progressive multifocal leukoencephalopathy in a haploidentical stem cell transplant recipient: a clinical, neuroradiological and virological response after treatment with risperidone. Antiviral Res. 2007;74(2):156-158. Available at: https://www.ncbi.nlm.nih.gov/pubmed/17140673.
79. Vulliemoz S, Lurati-Ruiz F, Borruat FX, et al. Favourable outcome of progressive multifocal leucoencephalopathy in two patients with dermatomyositis. J Neurol Neurosurg Psychiatry. 2006;77(9):1079-1082. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16914758.
80. Lanzafame M, Ferrari S, Lattuada E, et al. Mirtazapine in an HIV-1 infected patient with progressive multifocal leukoencephalopathy. Infez Med. 2009;17(1):35-37. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19359824.
81. Cettomai D, McArthur JC. Mirtazapine use in human immunodeficiency virus-infected patients with progressive multifocal leukoencephalopathy. Arch Neurol. 2009;66(2):255-258. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19204164.
82. Kerr DA, Chang CF, Gordon J, Bjornsti MA, Khalili K. Inhibition of human neurotropic virus (JCV) DNA replication in glial cells by camptothecin. Virology. 1993;196(2):612-618. Available at: https://www.ncbi.nlm.nih.gov/pubmed/8396804.
83. Royal W, 3rd, Dupont B, McGuire D, et al. Topotecan in the treatment of acquired immunodeficiency syndrome-related progressive multifocal leukoencephalopathy. J Neurovirol. 2003;9(3):411-419. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12775425.
84. Clifford DB, Nath A, Cinque P, et al. A study of mefloquine treatment for progressive multifocal leukoencephalopathy: results and exploration of predictors of PML outcomes. J Neurovirol. 2013;19(4):351-358. Available at: https://www.ncbi.nlm.nih.gov/pubmed/23733308.
85. Huang SS, Skolasky RL, Dal Pan GJ, Royal W, 3rd, McArthur JC. Survival prolongation in HIV-associated progressive multifocal leukoencephalopathy treated with alpha-interferon: an observational study. J Neurovirol. 1998;4(3):324-332. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9639075.
86. Geschwind MD, Skolasky RI, Royal WS, McArthur JC. The relative contributions of HAART and alpha-interferon for therapy of progressive multifocal leukoencephalopathy in AIDS. J Neurovirol. 2001;7(4):353-357. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11517416.
87. Nath A, Venkataramana A, Reich DS, Cortese I, Major EO. Progression of progressive multifocal leukoencephalopathy despite treatment with beta-interferon. Neurology. 2006;66(1):149-150. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16401874.
88. Przepiorka D, Jaeckle KA, Birdwell RR, et al. Successful treatment of progressive multifocal leukoencephalopathy with low-dose interleukin-2. Bone Marrow Transplant. 1997;20(11):983-987. Available at: https://www.ncbi.nlm.nih.gov/pubmed/9422479.
89. Buckanovich RJ, Liu G, Stricker C, et al. Nonmyeloablative allogeneic stem cell transplantation for refractory Hodgkin's lymphoma complicated by interleukin-2 responsive progressive multifocal leukoencephalopathy. Ann Hematol. 2002;81(7):410-413. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12185517.
90. Kunschner L, Scott TF. Sustained recovery of progressive multifocal leukoencephalopathy after treatment with IL-2. Neurology. 2005;65(9):1510. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16275856.
91. Sospedra M, Schippling S, Yousef S, et al. Treating progressive multifocal leukoencephalopathy with interleukin 7 and vaccination with JC virus capsid protein VP1. Clin Infect Dis. 2014;59(11):1588-1592. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25214510.
92. Pavlovic D, Patera AC, Nyberg F, Gerber M, Liu M, Progressive Multifocal Leukeoncephalopathy Consortium. Progressive multifocal leukoencephalopathy: current treatment options and future perspectives. Ther Adv Neurol Disord. 2015;8(6):255-273. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26600871.
93. Soleimani-Meigooni DN, Schwetye KE, Angeles MR, et al. JC virus granule cell neuronopathy in the setting of chronic lymphopenia treated with recombinant interleukin-7. J Neurovirol. 2017;23(1):141-146. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27421731.
94. Miskin DP, Chalkias SG, Dang X, Bord E, Batson S, Koralnik IJ. Interleukin-7 treatment of PML in a patient with idiopathic lymphocytopenia. Neurol Neuroimmunol Neuroinflamm. 2016;3(2):e213. Available at: https://www.ncbi.nlm.nih.gov/pubmed/27144212.
95. Ray U, Cinque P, Gerevini S, et al. JC polyomavirus mutants escape antibody-mediated neutralization. Sci Transl Med. 2015;7(306):306ra151. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26400912.
96. Cortese I, Muranski P, Enose-Akahata Y, et al. Pembrolizumab treatment for progressive multifocal leukoencephalopathy. N Engl J Med. 2019;380(17):1597-1605. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30969503.
97. Clifford DB. Checkpoint therapy for progressive multifocal leukoencephalopathy: pointless? Eur J Neurol. 2020;27(11):2114-2116. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32644212.
98. Berzero G, Basso S, Stoppini L, et al. Adoptive transfer of JC virus-specific T lymphocytes for the treatment of progressive multifocal leukoencephalopathy. Ann Neurol. 2021;89(4):769-779. Available at: https://www.ncbi.nlm.nih.gov/pubmed/33459417.
99. Muftuoglu M, Olson A, Marin D, et al. Allogeneic BK virus-specific T cells for progressive multifocal leukoencephalopathy. N Engl J Med. 2018;379(15):1443-1451. Available at: https://www.ncbi.nlm.nih.gov/pubmed/30304652.
100. Cortese I, Beck ES, Al-Louzi O, et al. BK virus-specific T cells for immunotherapy of progressive multifocal leukoencephalopathy: an open-label, single-cohort pilot study. Lancet Neurol. 2021;20(8):639-652. Available at: https://www.ncbi.nlm.nih.gov/pubmed/34302788.
101. Vendrely A, Bienvenu B, Gasnault J, Thiebault JB, Salmon D, Gray F. Fulminant inflammatory leukoencephalopathy associated with HAART-induced immune restoration in AIDS-related progressive multifocal leukoencephalopathy. Acta Neuropathol. 2005;109(4):449-455. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15739098.
102. Tan K, Roda R, Ostrow L, McArthur J, Nath A. PML-IRIS in patients with HIV infection: clinical manifestations and treatment with steroids. Neurology. 2009;72(17):1458-1464. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19129505.
103. Sainz-de-la-Maza S, Casado JL, Perez-Elias MJ, et al. Incidence and prognosis of immune reconstitution inflammatory syndrome in HIV-associated progressive multifocal leucoencephalopathy. Eur J Neurol. 2016;23(5):919-925. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26914970.
104. Clifford DB. Neurological immune reconstitution inflammatory response: riding the tide of immune recovery. Curr Opin Neurol. 2015;28(3):295-301. Available at: https://www.ncbi.nlm.nih.gov/pubmed/25887769.
105. Miralles P, Berenguer J, Lacruz C, et al. Inflammatory reactions in progressive multifocal leukoencephalopathy after highly active antiretroviral therapy. AIDS. 2001;15(14):1900-1902. Available at: https://www.ncbi.nlm.nih.gov/pubmed/11579261.
106. Safdar A, Rubocki RJ, Horvath JA, Narayan KK, Waldron RL. Fatal immune restoration disease in human immunodeficiency virus type 1-infected patients with progressive multifocal leukoencephalopathy: impact of antiretroviral therapy-associated immune reconstitution. Clin Infect Dis. 2002;35(10):1250-1257. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12410486.
107. Hoffmann C, Horst HA, Albrecht H, Schlote W. Progressive multifocal leucoencephalopathy with unusual inflammatory response during antiretroviral treatment. J Neurol Neurosurg Psychiatry. 2003;74(8):1142-1144. Available at: https://www.ncbi.nlm.nih.gov/pubmed/12876257.
108. Di Giambenedetto S, Vago G, Pompucci A, et al. Fatal inflammatory AIDS-associated PML with high CD4 counts on HAART: a new clinical entity? Neurology. 2004;63(12):2452-2453. Available at: https://www.ncbi.nlm.nih.gov/pubmed/15623736.
109. Fournier A, Martin-Blondel G, Lechapt-Zalcman E, et al. Immune reconstitution inflammatory syndrome unmasking or worsening AIDS-related progressive multifocal leukoencephalopathy: a literature review. Front Immunol. 2017;8:577. Available at: https://www.ncbi.nlm.nih.gov/pubmed/28588577.
110. Martin-Blondel G, Cuzin L, Delobel P, et al. Is maraviroc beneficial in paradoxical progressive multifocal leukoencephalopathy-immune reconstitution inflammatory syndrome management? AIDS. 2009;23(18):2545-2546. Available at: https://www.ncbi.nlm.nih.gov/pubmed/19907215.
111. Januel E, Martin-Blondel G, Lamirel C, et al. Do CCR5 antagonists improve the overall survival of patients with AIDS-related progressive multifocal leucoencephalopathy? J Neurol Neurosurg Psychiatry. 2018;89(10):1125-1126. Available at: https://www.ncbi.nlm.nih.gov/pubmed/29305436.
112. Bernard-Valnet R, Moisset X, Maubeuge N, et al. CCR5 blockade in inflammatory PML and PML-IRIS associated with chronic inflammatory diseases' treatments. Neurol Neuroimmunol Neuroinflamm. 2022;9(1). Available at: https://www.ncbi.nlm.nih.gov/pubmed/34728496.
113. Hentzien M, Guihot A, de Maindreville D, et al. Progressive multifocal leukoencephalopathy despite immune recovery in a HIV/HCV co-infected patient. J Neurovirol. 2020;26(4):607-610. Available at: https://www.ncbi.nlm.nih.gov/pubmed/32458280.
114. Crossley KM, Agnihotri S, Chaganti J, et al. Recurrence of progressive multifocal leukoencephalopathy despite immune recovery in two HIV seropositive individuals. J Neurovirol. 2016;22(4):541-545. Available at: https://www.ncbi.nlm.nih.gov/pubmed/26727910.