CNS disease with JC virus infection in adults with congenital HIV: a retrospective case series

Abstract

Objective:

To describe the natural history of individuals with congenital HIV who develop JC virus (JCV) infection of the central nervous system (CNS).

Methods:

We retrospectively evaluated individuals with congenital HIV who met criteria for progressive multifocal leukoencephalopathy (PML) or JCV granule cell neuronopathy (JCV GCN) at three major healthcare centers in the northeast USA. Data on adherence to combined antiretroviral therapy (cART), neurologic symptoms, serum markers of immunity and HIV infection, CSF analyses, radiographic features, modified Rankin Scale (mRS) scores, and survival were collected from the electronic medical record up to a censoring date of August 1, 2020.

Results:

Among 10 adults with congenitally acquired HIV, 9 were diagnosed with definitive PML and one was diagnosed with probable JCV GCN. Individuals presented at the time of their PML or JCV GCN diagnosis with a mean mRS of 2.0 (standard deviation 1.0). A premorbid mRS was documented for 6 patients and was zero in all cases. The most common risk factor was confirmed cART nonadherence in nine individuals. Five individuals with PML and one with JCV GCN died, with a latency from symptom onset to death of approximately 3 months for 3 individuals, and approximately 2 years for the remaining 2.

Conclusion:

Youth-adulthood transition is a high-risk point for dropping off from medical care. The study of this timepoint in people living with HIV could help inform effective care in these individuals.

Introduction

JC virus (JCV) is a double-stranded DNA polyomavirus that is common in human populations globally, with estimates of seroprevalence ranging from approximately 40% to 90%.^{1, 2} Primary infection with JCV is self-limited in most exposed individuals, but in the context of profound cellular immunosuppression the virus can cause an opportunistic infection in the brain. JCV infects primarily oligodendrocytes as well as a smaller proportion of neurons and astrocytes.^{3, 4} The lysis of oligodendrocytes results in the heterogeneous syndrome of progressive multifocal leukoencephalopathy (PML), whereas the lysis of granule cell neurons leads to the syndrome of ataxia and cerebellar atrophy known as JCV granule cell neuronopathy (JCV GCN).

While PML was first described in a patient with malignancy, individuals with HIV represent a significant proportion of PML cases.⁵ Previously, PML was estimated to occur in up to 5–10% of individuals with HIV in the pre-combined antiretroviral therapy (cART) era, and there were 1.3–3.3 cases per 1000 person-years at risk after the advent of cART.⁶ Before cART only 10% of individuals survived past one year,⁷ but that number has risen to greater than 50%.^{8, 9} A number of retrospective case series have examined the epidemiology and risk factors of PML, but most have examined horizontal and congenital HIV (cHIV) patients as a single group rather than studying either entity individually.^10–13 The authors have identified sixteen cases of PML associated with cHIV in the literature to date, all of them in pediatric patients.^14–19

As new modalities of treatment for PML arise, future clinical trials will require comparison to historical controls, and characterizing the natural history of PML in specialized populations will assist in tailoring care to individuals. To better understand the clinical characteristics of individuals with congenitally acquired HIV who develop JCV-mediated CNS infection, we retrospectively assessed the demographics, risk factors, clinical features, radiographic characteristics, time to diagnosis, treatment, and outcomes of a multicenter cohort over an extended period following the advent of cART.

Methods

The study protocol was approved by the CUIMC and BWH Institutional Review Boards. Potential study patients were identified retrospectively in the electronic medical record by ICD-9 and ICD-10 codes for PML (046.3, A81.2) in addition to queries for positive results on JCV PCR testing in cerebrospinal fluid (CSF) from January 1, 2007 to August 1, 2020 in the CUIMC cohort and from January 1, 1994 to August 1, 2020 in the BWH cohort. In accordance with BMC policy regarding case series involving three or fewer BMC patients, IRB review was not indicated. The case was reviewed by the BMC Privacy Office to confirm HIPAA compliance.

Patient Selection Criteria

Individuals in the study met American Academy of Neurology criteria for definitive PML, including typical imaging and exclusion of alternative diagnoses in conjunction with either characteristic histopathological features or positive CSF JCV PCR. The individual with JCV GCN was diagnosed through multidisciplinary discussion based on a positive CSF JCV PCR, exclusion of alternative diagnoses, and imaging evidence of cerebellar atrophy.²⁰

Data Collection

Variables of interest were collected in a central de-identified database using Microsoft Excel™. Data extraction from the initial presentation included age at symptom onset, sex, relevant medical history, date of symptom onset, presenting symptoms, JCV PCR copy number in CSF, CD4 count, HIV viral load (VL), use of cART, radiographic features, time to PML diagnosis from symptomatic onset, modified Rankin scale (mRS) score at discharge, and disposition. Follow-up data when available included mRS and time to death from symptomatic onset up to a censoring date of August 1, 2020.

Cases

Patient A

A 21 year-old man with history of cHIV/AIDS complicated by Pneumocystis carinii pneumonia (PCP), fungal esophagitis, and Mycobacterium avium complex (MAC) infection over the preceding five years presented with abdominal pain, nausea, and gait instability. His HIV VL on admission was 940,519 copies/mL, and CD4+ count was 42 cells/uL. He had been nonadherent with cART during adolescence because of “fear of rejection” if his status were discovered. His outpatient medical care was pediatric, but he was admitted under the adult internal medicine service. MRI showed non-enhancing T1 hypointense and T2 hyperintense lesions in the right cerebellum. CSF JCV PCR was 1,800 viral copies/mL. He was started on darunavir, emtricitabine/tenofovir alafenamide, ritonavir, and raltegravir. He was discharged to a nursing home but returned one week later due to worsening dysarthria and dysphagia. MRI showed interval increase in T2/FLAIR signal abnormality within the brainstem and cerebellum, and immune reconstitution inflammatory syndrome (IRIS) was suspected. He did not receive additional treatment for IRIS. His cART was continued and his symptoms continued to progress, eventually precluding oral intake. He died 89 days after presentation.

Patient B

An 18 year-old woman with history of cHIV and no history of AIDS-defining illnesses presented with ataxia, left hemiparesis, and confusion. Her HIV VL on admission was 2,277 copies/mL, and CD4+ count was 293 cells/uL. She had been nonadherent with cART for several years prior to presentation, citing resentment towards her illness and passive suicidal ideation. Her outpatient care had been pediatric, and she was admitted under the inpatient pediatric service. MRI showed T2/FLAIR hyperintensities throughout the frontal, parietal, and temporal lobes. A qualitative assay of CSF JCV was positive. She was started on mirtazapine, emtricitabine/tenofovir, darunavir, ritonavir, and raltegravir. She developed IRIS after restarting cART and received a one-month course of oral steroids. She clinically improved over the following 2–3 months but then experienced a subacute decline. Ten months after her initial diagnosis of PML, she was admitted for new-onset focal seizures, then developed increasing disinhibition with cursing and angry outbursts. She refused all medications, and she was eventually transitioned to comfort-focused care. She died 621 days after initial presentation.

Patient C

A 19 year-old man with history of cHIV/AIDS complicated by autoimmune hemolytic anemia (AIHA) and presumptive PCP over the year prior to presentation presented with fever, chest pain, respiratory distress, a right homonymous hemianopia, and memory deficits. He had been adherent with cART through adolescence, but self-discontinued his regimen upon going to college one year prior to presentation in order to conceal his HIV status from roommates. All outpatient and inpatient care was through pediatric providers. His HIV VL on admission was 1,060,324 copies/mL, and CD4+ count was 30 cells/uL. His hemoglobin was found to be 3.0 g/dL, prompting admission to pediatric ICU for empiric antibiotics and steroids. He was restarted on his previous cART regimen. MRI showed mild to moderate global brain atrophy and T2/FLAIR hyperintensity in the left occipital lobe. CSF JCV PCR was positive at 3,300 viral copies/mL, and he was given an infusion of cidofovir for new PML diagnosis. He was discharged home, but his neurological condition continued to deteriorate over the following months. He was transitioned to comfort-focused care, and died 619 days after initial presentation.

Patient D

A 23 year-old woman with history of sickle cell disease and cHIV complicated by prior oral thrush presented with several months of left leg weakness, left arm shaking, and behavioral changes. Her HIV VL on admission was 40 copies/mL, and CD4+ count was 134 cells/uL. The patient reported general good health and reliable cART adherence throughout her youth. After starting college she expressed a desire to be “carefree,” stopping her cART one year prior to presentation. Her outpatient care was through pediatrics, but she was admitted under the adult neurology service. MRI showed T2/FLAIR enhancement in the frontal, parietal, and occipital lobes. Qualitative assay of JC virus in CSF returned positive. She was restarted on a cART regimen of emtricitabine/rilpivirine/tenofovir, at which point she developed IRIS with new seizures. She was treated with prednisone and multiple anti-epileptic drugs, then discharged with mild cognitive impairment but independent functional status. Her CD4 counts normalized and her HIV VL became undetectable, but over the following year she developed significant left lower extremity weakness. She was admitted 10 months after initial presentation for this, and was ultimately diagnosed with functional neurologic disorder overlaid on her organic disease. She remains alive but still unable to ambulate through censoring date, with mRS of 4.

Patient E

A 23 year-old woman with history of cHIV/AIDS complicated by oral, esophageal, and vaginal candidiasis; cryptococcus; and herpes zoster infection presented with two weeks of double vision; headaches; and left-sided weakness. Her HIV VL on admission was 72,000 copies/mL, and CD4+ count was 134 cells/uL. She had been intermittently adherent with cART throughout her life as she felt “guilty and depressed” about her HIV status, and most recent regimen on admission was emtricitabine/tenofovir, atazanavir, and ritonavir. All outpatient and inpatient care was through adult medicine. CSF JCV PCR was negative. MRI showed T2/FLAIR hyperintense lesions in her brainstem and cerebellum. She developed a tremor of her left upper extremity, at which point empiric treatment was started for toxoplasmosis and tuberculosis. Six days after admission cerebellar biopsy was performed demonstrating the histopathologic triad of PML. The patient was restarted on her prior cART regimen. The patient was discharged home but ultimately died 131 days after presentation.

Patient F

A 23 year-old man with history of cHIV complicated by immune thrombocytopenic purpura and anal condyloma was admitted for two months of progressive left-sided weakness. His HIV VL on admission was 11,000 copies/mL, ^21–23and CD4+ count was 56 cells/uL. He had been adherent with cART for 10 years with most recent regimen of lamivudine, stavudine, and nelfinavir; however, he subsequently stopped taking those medications, expressing to providers only that “it’s my choice if I want to stop taking them.” MRI showed T2/FLAIR hyperintense white matter lesions in the right fronto-parietal white matter. CSF was unremarkable, including negative JCV PCR. The patient left against medical advice before initiation of an appropriate cART regimen. Brain biopsy was later pursued with pathology consistent with PML. A cART regimen of emtricitabine/tenofovir, atazanavir, ritonavir, and darunavir was started. Over the following years his left-sided weakness progressively worsened and he developed insomnia, attentional deficits, and depression, until he required full-time nursing home care and lacked capacity by five years after initial presentation. At last follow up six years after presentation, his mRS was 4.

Patient G

A ‎‎‎‎27 year-old man with history of cHIV complicated by partially treated Hodgkin’s lymphoma one year prior was admitted for encephalopathy (disinhibition, hypersexuality), leg weakness, and ataxia. His HIV VL on admission was 106,256 copies/mL, and CD4+ count was 60 cells/uL. He had been off cART for approximately one year at the time of admission for unclear reasons. All outpatient and inpatient care was through adult medicine. MRI brain showed confluent T2 hyperintensities throughout the right frontal lobe, and qualitative assay of CSF JCV was positive. He was started on a new cART regimen of emtricitabine/tenofovir and dolutegravir, at which point his mental status deteriorated to include further behavioral disinhibition as well as intermittent obtundation. He was treated with dexamethasone for IRIS and mirtazapine for PML. He was discharged to rehab, and was lost to follow-up. His last documented visit was three months after initial presentation, at which point he had mRS of 5.

Patient H

A 26 year-old man with history of cHIV complicated by shingles and anal condyloma presented with three weeks of dizziness, nausea, vomiting, and progressively severe wide-based gait one week after restarting a cART regimen of emtricitabine/rilpivirine/tenofovir, dolutegravir, and darunavir/cobicistat. He cited medications “causing gagging” as the reason for previous nonadherence. On exam he was found to have left-sided ataxia with cerebellar testing. All outpatient and inpatient care was through adult medicine. His HIV VL on admission was 595,105 copies/mL, and CD4+ count was 29 cells/uL. His HIV VL had been approximately 1.4 million before starting cART. Qualitative assay of CSF JCV was positive. MRI brain showed mild T2/FLAIR hyperintense cortical abnormalities in the bilateral occipital lobes and cerebellar vermis, as well as atrophy of the cerebellar vermis. Repeat qualitative assay of CSF JCV was negative. After extensive interdisciplinary discussion, the diagnosis of JCV GCN was made. The patient remained alive and adherent with cART, using a wheelchair for mobility, as of censure date with an mRS of 4.

Patient I

A 27 year-old man with cHIV and alcohol use disorder in remission presented with dysarthria, dysmetria and nystagmus. His HIV VL on admission was undetectable, and CD4+ count was 54 cells/uL. He had been nonadherent with cART for unclear reasons until an admission one month previously for PCP pneumonia, after which he reported adherence with a new regimen of dolutegravir, etravirine, raltegravir, emtricitabine, ritonavir, and darunavir. He was admitted to the adult medicine service. MRI brain revealed non-enhancing white matter abnormalities in the cerebellum and medulla. CSF JCV PCR was 30,618 copies/mL. The patient was started on dexamethasone for treatment of presumptive IRIS. He showed no noticeable clinical improvement, and treatment was stopped after one month due to neuropsychiatric adverse effects. Repeat LP one month after admission revealed an increased JCV copy number to 228K, and HIV VL was undetectable. He continued to have worsening dysarthria, ataxia, and weakness, at which point he made a request to “die on pediatrics” where he knew all the providers and nurses. He was transferred per his wishes, and died three months after onset of symptoms.

Patient J

A 25 year-old woman with cHIV, diffuse large B-cell lymphoma (DLBCL) in remission, and prior right middle cerebral artery (MCA) strokes presented with six weeks of altered mental status and worsening of her baseline left-sided weakness progressing to hemiplegia. Her HIV VL on admission was 517,629 copies/mL, and CD4+ count was 13 cells/uL. She had been nonadherent with cART throughout her life; per documentation “she can’t provide a reason other than she just doesn’t always want to, even though she knows she needs to.” MRI brain revealed T2 hyperintensities in the left frontal lobe and external capsule. CSF JCV PCR was 247 copies/mL. She was admitted to the adult neurology service and started on a cART regimen of emtricitabine, tenofovir, and dolutegravir. She declined clinically, with worsening somnolence and new seizure activity. MRI brain revealed enhancement consistent with PML-IRIS and she was started on prednisone. She continued to decline and was transitioned to comfort-focused care. She died three months after onset of symptoms.

(See Table 1 for case summaries)

Table 1:

Clinical, laboratory, and demographic information on individual patients.

Patient	Age at Presentation (years)	Presenting Symptoms	Serum HIV VL (copies/mL)	CD4+ Count (cells/mm3)	CSF JCV PCR (copies/mL)	Time Symptom Onset to Diagnosis (days)	cART Adherence	cART	IRIS (Y/N)	Status	Time Symptom Onset to Death (Days)	Pre-PML mRS	mRS at 1-year	mRS at 5-year
A	22	Abdominal pain, Nausea, Gait instability	940519	42	1800	21	Adherence unclear due to conflicting patient reports	FTC/TDF, DRV, RTV, RAL	Y	Deceased	89	0	6	6
B	27	Ataxia, Encephalopathy	2277	293	Positive*	Unknown	Lifelong nonadherence	FTC/TDF, DRV, RTV, RAL	Y	Deceased	621	0	4	6
C	19	Fever, Visual field cut	1060324	30	3300	3	Off cART for one year prior to presentation	TDF, ABC-3TC, ATV, RTV	N	Deceased	619	0	5	6
D	22	Leg weakness, Arm shaking	40	134	Positive*	31	Off cART for five years prior to presentation	FTC/RPV/TDF	Y	Alive		Unknown	4	Unknown
E	23	Diplopia, Headaches, Hemiparesis	72000	10	UD	24	Lifelong intermittent adherence, unclear recent course before presentation	FTC/TDF, ATV, RTV	N	Deceased	131	Unknown	6	6
F	23	Hemiparesis	11000	56	4,246	148	Off cART for six years prior to presentation	FTC/TDF, ATV, RTV, DRV	N	Alive		Unknown	3	3
G	27	Behavior change, Leg weakness, Ataxia	106256	60	Positive	3	Off cART for approximately one year prior to presentation	FTC/TDF, DTG	Y	Alive		0	Unknown	Unknown
H	26	Dizziness, Nausea, Vomiting, Gait disturbance	595105	29	Positive*	5	Nonadherent; restarted one month prior to admission	FTC/RPV/TDF, DTG, DRV/COBI	Y	Alive		0	3	N/A
I	27	Dysarthria, Dysmetria, Nystagmus	UD	43	30,618	25	Nonadherent; restarted one month prior to admission	DTG, ETR, RAL, FTC, RTV, DRV	Y	Deceased	100	0	6	6
J	25	Encephalopathy, Hemiplegia	517629	13	247	52	Lifelong intermittent adherence	FTC/TDF, DTG	Y	Deceased	98	1	6	6

UD: undetectable; cART: combined antiretroviral therapy; ABC: abacavir; ATV: atazanavir; COBI: cobicistat; DRV: darunavir; DTG: dolutegravir; ETR: etravirine; FTC: emtricitabine; RAL: raltegravir; RPV: rilpivirine; RTV: ritonavir; TDF: tenofovir; 3TC: lamivudine

^*Qualitative assay

Results

Patient Demographics

The study included 10 adults with congenitally acquired HIV and a diagnosis of either definitive PML or probable JCV GCN. Median age at symptom onset was 23 years (IQR 4). Four patients were male, and six were female.

Diagnostic Time and Modality

Neurological symptoms at presentation included: focal weakness (70%), ataxia (40%), behavior change (40%), headache (30%), visual changes (20%), paresthesias (20%), and seizure (20%) (Table 2).

Table 2:

Patient characteristics.

Sex	N	%		Location of imaging abnormalities	N	%
Female	6	60		Frontal lobe	5	50
Male	4	40		Parietal lobe	5	50
Race				Cerebellum	3	30
Black	4*	40		Occipital lobe	3	30
Hispanic	2*	20		Brainstem	2	20
White	2	20		Temporal lobe	2	20
Unknown	3	30		Status as of 8/1/2020
Age at symptom onset (years)				Deceased	5	50
<20	1	10		Alive	5	50
20–30	9	90		Diagnostic modality
Presenting symptoms				CSF JCV PCR	8	80
Focal weakness	7	70		Brain biopsy	2	20
Ataxia	4	40		Time from symptom onset to diagnosis (days)**
Behavioral changes	4	40		0–30	6	60
Headache	3	30		31–90	2	20
Paresthesias	2	20		91+	1	10
Seizure	2	20		Treatments given
Visual changes	2	20		Cidofovir	1	10
Apraxia	1	10		Mefloquine	1	10

^*One patient self-identified as both Black and Hispanic.

^**One patient had insufficient data to determine exact diagnostic latency

White matter abnormalities were found in the frontal lobe (50%), parietal lobe (50%), temporal lobe (20%), occipital lobe (30%), brainstem (20%), and cerebellum (30%).

Three individuals were diagnosed within five days of symptom onset. Five were diagnosed on the order of weeks (21–31 days after symptom onset). One person had insufficient records to determine time from symptoms to diagnosis. One person was diagnosed five months (148 days) after symptom onset.

Patient H, the individual with probable JCV GCN, was diagnosed through CSF JCV PCR and clinical signs as well as MRI showing cerebellar vermis atrophy but no white matter changes (Figure 1). Seven individuals were diagnosed with JCV disease through a combination of JCV-positive CSF by PCR, clinical signs, and radiologic markers of white-matter disease (Figure 2). Two individuals received brain biopsy to demonstrate the typical pathologic triad of PML.^{20, 24}

Figure 1:

T2/FLAIR MRI imaging of Patient H, with a diagnosis of JCV GCN. A,B) Axial T2 FLAIR imaging showing abnormal nonenhancing symmetric signal abnormality (T2 prolongation) in the pons and bilateral middle cerebellar peduncles, as well as in the posterior limbs of the internal capsules, and symmetric subtle patchy signal in the periventricular white matter. C,D) Sagittal and coronal T2 FLAIR imaging showing progressive atrophy of the cerebellar vermis (arrow signs).

Figure 2:

MRI imaging of each patient on admission. Each patient is labeled with the letter corresponding to their clinical vignette in the manuscript. The left image for each patient is axial T2/FLAIR, while the right is sagittal T1.

Immune Markers, Therapies, and Responses

Median serum CD4+ cell count on presentation was 30 cells/uL (interquartile range [IQR] 20.0), median HIV viral load was 311,028 copies/mL (IQR 528,73), and median CSF JCV titer was 72,000 copies/mL (IQR 515,352). Nine of the ten individuals had been off cART for time periods ranging from two months to 10 or more years.

Seven individuals developed suspected IRIS at some point during their hospital course. Of those seven individuals, five (71%) were treated with corticosteroids. No individual in this study received maraviroc for treatment of PML-IRIS.

Discussion

We report 10 cases of CNS disease with either histopathologic or laboratory evidence for the presence of JCV infection in adults with cHIV/AIDS, many of whom experienced decline in health in their late teens to early twenties after self-discontinuing cART. While many of those individuals had comorbid illness accompanying their JCV-mediated CNS infection, their clinical course, CSF and serum evaluation, and imaging findings were suggestive of PML or JCV GCN as the main cause of their presentations. While JCV GCN often presents with pan-cerebellar atrophy, specific atrophy of vermis as seen in Patient H has been documented elsewhere, often earlier in the disease course, and was used as one of the criteria for his ultimate diagnosis.²⁵

Medical follow-up has been a well-documented challenge in the care of cHIV patients.^{26, 27} Specifically, there is evidence that 21 years represents a critical age at which follow-up is lost.²⁸ That is consistent with previous findings across multiple long-term conditions with pediatric onset including type 1 diabetes mellitus²⁹ and mental health disorders.^{30,31, 32} Congenital HIV patients in particular have a high documented rate of psychiatric illness and illicit drug use that have been linked to decreased ability to follow the complex treatment regimens necessary for their disease.³³ These are likely related to both neuropsychiatric sequelae of the disease and environmental and psychosocial factors.³⁴

Of the five individuals among the study cohort who died, two (patients B and C) self-discontinued their cART before their symptoms worsened and ultimately died as a consequence. Patient B had symptomatically stabilized after her PML presentation, but cART discontinuation led to the re-emergence of symptoms and subsequent death. Patient C self-discontinued cART before PML presentation, which was followed by a subacute period of decline characterized by multiple opportunistic illnesses and then death. Adherence for each of these individuals was shaped largely by social factors and psychiatric disease burden. Notably, of the 16 cHIV-PML patients reported previously in the literature, seven died as a result of PML and at least five others have significant long-term morbidity as an outcome.¹⁸ In comparison, while individuals who die from HIV-related PML generally survive significantly longer after diagnosis than those with non-HIV-related PML (1,992 versus 101 days, p = 0.024), the mean survival time of the cohort featured in the present study was on the order of months.¹⁰ However, presenting symptoms between HIV and non-HIV groups have not been shown to substantially differ, which could be consistent with a hypothesis that PML more than neurological effects of underlying disease is the main mediator of symptoms.

The individuals studied here presented with CSF JCV titer at a lower end of the spectrum generally seen in patients with PML. Past studies have reported a broad range of JCV VL in CSF on the order of 10³ to 10⁷, and a correlation has been shown between higher quantitative CSF JCV titer on presentation and increased morbidity and mortality along with speed of symptom progression.^{35, 36} In the study cohort, no patient had CSF JCV titers above the order of 10⁴. Other studies of cHIV-PML in the literature have not reported quantitative CSF JCV titers for further comparison. While our sample size is small and our findings may not be generalizable, CSF JCV titers should be documented in future large studies of cHIV-PML.

Several of the individuals in this case series were shifted from pediatric to adult care during and after their hospitalization. Patient A was 22 years old at presentation but was still seen exclusively by pediatric providers prior to his inpatient admission. He was admitted under the adult internal medicine service with neither a formal transition of care nor pediatric consults. No data is available on transition of outpatient care after his PML presentation, and he unfortunately died soon after this. Patient D was seen by a pediatrician before her PML admission, when she was admitted under the adult medicine service with pediatrics consult. Her subsequent outpatient care was entirely through adult medicine. Those inpatient admissions, rather than planned outpatient signout between providers, served as the care transition points for these individuals. By contrast, Patients B and C were 18 and 19 respectively at presentation with pediatric outpatient follow-up and continued to be seen by pediatrics after admission for PML. Transition of care is a complex navigation of individual patient-provider relationships and medical logistics, and in the cases above, it appears to have occurred incidentally after acute hospitalizations rather than following intentional discussion. Further research on best practice in these situations is needed to understand breaks in care for at-risk individuals.

Conclusion

JCV-mediated CNS disease remains a significant concern for immunocompromised individuals, and even in the post-cART era individuals with HIV are at high risk. The transition from pediatric to adult care that occurs around age 21 for individuals with cHIV represents a time of even further increased risk. As more therapies for PML are developed, characterizing the natural history of disease in vulnerable groups will be helpful in determining effective and individualized treatment plans, both during the transition from pediatric to adult care specifically and throughout the course of the disease.