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Recurrent CSF escape in an HIV-1 infected patient receiving antiretroviral therapy
Authors
Joana Martins, Ernestina Santos, Paula Salgado, Luís Maia, Daniel Dias, Mónica Marta,
Margarida França
Abstract
Cerebrospinal fluid (CSF) HIV-1 viral load higher than plasma viraemia, or CSF escape, is
a severe complication seldom described in HIV infected patients receiving suppressive
combination antiretroviral therapy (ART). Recurrent CSF escape after ART
intensification with complete clinical resolution has not been yet recognized. We
present a 35 year-old man with HIV-1 infection diagnosed in 2007, during primary
infection. He started ART in 2009 with good immune and viral response. In the course
of disease he was admitted twice for encephalitis. Clinical presentation was similar and
characterized by neuropsychiatric symptoms (disorientation, recent memory deficits,
aphasia, seizures and behaviour changes). MRI revealed diffuse T2 and FLAIR
hyperintensities involving white matter and temporal, medial frontal and insular lobes
cortex, without gadolinium enhancement. CSF analysis showed mildly elevated
protein, lymphocytic pleocytosis (>78% CD8 cells), and a viral load higher than plasma
(log difference 2,3). After the first episode (2010) the patient had full recovery without
residual neurological disability after intensifying ARV to improve CNS penetration. In
2014, a more severe presentation with worsening cognitive function and psychotic
symptoms required ART intensification. Persistent cognitive dysfunction was evident
even 18 months later.
We describe a patient with CSF/plasma HIV viral load dissociation, with high CD4 cell
count and undetectable plasma viraemia. Recurrence should prompt a close follow-up
these patients given the possibility of permanent sequelae.
Article:
Neurological manifestations are occasionally observed in HIV infected patients
receiving effective antiretroviral therapy (ART) with suppressed viraemia and stable
immunological state.(1) HIV-1 replication in the central nervous system (CNS)
independently of plasma viral load, or cerebrospinal fluid (CSF) escape, is thought to
underlie such condition.(2) Such patients have undetectable plasma HIV-1 viral load
but have increased viraemia in CSF (0.5 or 1 log greater than plasma).(1)
We present a 35 year-old man with a past illness history of idiopathic generalized
epilepsy (normal brain MRI) diagnosed 10 years before and controlled with
levetiracetam. In 2006, he had also been successfully treated for Syphilis and severe
depression. HIV-1 primary infection was diagnosed in 2007. He started ART
(emtricitabine, tenofovir, atazanavir/ritonavir) in January of 2009, because of low CD4
count, with good immune and viral response. In July of 2010 he was admitted with
subacute encephalitis. He had developed recent memory deficits, fever and seizures
followed by disorientation and sensitive aphasia over a period of 7 days. CSF analysis
revealed 68 leukocytes/μL (66 lymphocytes with 74% CD8 cells), protein 1,04 g/L and
glucose 0,50 g/L. Viral PCR was negative for the following viruses in the CSF: JCV, HSV1, HSV-2, VZV, CMV, HSV-6; EBV was positive but considered to be a latent infection.
HIV-1 viral load in CSF was 9440 copies/mL (log 3,98) unlike plasma HIV, which was 46
copies/ml (log 1,66). Plasma CD4 cell count was 714/mm3. Brain MRI revealed bilateral
T2 and FLAIR hyperintense lesions involving periventricular white matter and temporal,
medial frontal and insular lobes, without gadolinium enhancement, consistent with
HIV encephalopathy (figures 1A, 1B). ART was optimized aiming a better CNS
penetration (zidovudine, abacavir, lopinavir/ritonavir; CPE score=10). Clinical
resolution was reported after 2 weeks. Six months later, brain MRI hyperintense
lesions regressed but cortical and subcortical brain atrophy ensued (figures 1C, 1D).
HIV load lowered to 130 copies/mL (log 2,11) in CSF and undetectable RNA in plasma.
He restarted his job and remained clinically and immunological stable. In July of 2014
he presented with sleepiness and deficits in recent memory. CSF analysis showed 32
leukocytes/μL (80% CD8 cells), protein 90 g/L. HIV-1 load was 4210 copies/ml (log 3,61)
in CSF and 99 copies/ml (log 1,99) in plasma. Plasma CD4 cell count was stable
(570/mm3). Viral PCR in CSF remained negative for other virus. Brain MRI revealed
larger T2 and FLAIR hyperintensities involving the same structures as before, as well as
brainstem, without gadolinium enhancement (figures 1E, 1F). Neuropsychological
evaluation was compatible with moderate/severe dysfunction in multiple domains
(memory, attention, visual construction, abstract reasoning and executive functions).
There was a provisional diagnosis of autoimmune encephalitis and he was treated with
intravenous dexamethasone (10 mg, tid for 18 days) and immunoglobulin therapy
(intravenous 1g, for 5 days), but cognitive deficits worsened and psychotic symptoms
emerged. CSF analysis was consistent with HIV-1 CSF/plasma dissociation, which in the
absence of any other aetiology and the lack of response to immune therapies, led to
the diagnosis of recurrent CSF escape. For that reason, ART was intensified with
raltegravir and maraviroc (CPE score=16). Progressive recovery of deficits was
observed along four weeks. Follow-up CSF was available at 1 and 3 months with HIV-1
RNA load of 1270 and 313 copies/ml, respectively; undetectable plasma viraemia and
800 CD4 cells/mm3. Follow-up imaging revealed resolution of most hyperintense
lesions, persisting diffuse leukoencephalopathy and global atrophy, more prominent
on temporal lobes (figures 1G, 1H). Neuropsychological revaluation confirmed
cognitive improvement, although persisting significant deficits on multiple domains,
apathy and depression.
We report, to the best of our knowledge, the first case of recurrent encephalitis due to
CSF HIV-1 escape in a patient receiving ART. The evidence of CSF/plasma dissociation
and the significant improvement after the regimen intensification supported this
diagnosis. The clinical course and MRI findings are in line with previous
reports.(1)(3)(4) Preserved immune status and suppression of plasma viraemia suggest
that viral resistance and low drug CNS penetration may be involved in the
pathogenesis of CSF escape.(1)(2)(5) After intensification of ART, clinical improvement
and lower viral replication in CNS were documented in both episodes, reflecting the
efficacy of an antiretroviral regimen with optimized CNS penetration on the treatment
of this encephalitis.(5) Analysing the variation of CSF and plasma HIV loads and the
evolution of brain lesions over the course of the disease, we question whether both
parameters may be considered biomarkers of disease and response to treatment. This
case should alert neurologists and infectious disease specialists to the importance of
regular follow-up of CSF HIV viraemia and new treatment combinations in order to
achieve a better CNS penetration and prevent neurological sequelae.
References:
1. Peluso MJ, Ferretti F, Peterson J, Lee E, Fuchs D, Boschini A, et al. Cerebrospinal
fluid HIV escape associated with progressive neurologic dysfunction in patients on
antiretroviral therapy with well controlled plasma viral load. AIDS Lond Engl. 2012
Sep 10;26(14):1765–74.
2. Edén A, Fuchs D, Hagberg L, Nilsson S, Spudich S, Svennerholm B, et al. HIV-1 viral
escape in cerebrospinal fluid of subjects on suppressive antiretroviral treatment. J
Infect Dis. 2010 Dec 15;202(12):1819–25.
3. Canestri A, Lescure F-X, Jaureguiberry S, Moulignier A, Amiel C, Marcelin A, et al.
Discordance Between Cerebral Spinal Fluid and Plasma HIV Replication in Patients
with Neurological Symptoms Who Are Receiving Suppressive Antiretroviral
Therapy. Clin Infect Dis. 2010 Mar 1;50(5):773–8.
4. Khoury MN, Tan CS, Peaslee M, Koralnik IJ. CSF Viral Escape in a patient with HIVAssociated Neurocognitive Disorder. J Neurovirol. 2013 Aug;19(4):402–5.
5. Smurzynski M, Wu K, Letendre S, Robertson K, Bosch RJ, Clifford DB, et al. Effects
of central nervous system antiretroviral penetration on cognitive functioning in the
ALLRT cohort. AIDS Lond Engl. 2011 Jan 28;25(3):357–65.
Table 1: CSF and plasma parameters in both acute phase and follow-up time after ART
intensification.
Laboratory parameters
2010
Acute
6 mo after
2014
Acute
1 mo after
3 mo after
phase
ART+*
phase
ART+*
ART+*
68 (66)
-
32
-
-
Proteins (g/L)
1,04
-
90
-
-
Glucose (g/L)
0,50
-
0,48
-
-
HIV-1 load (cp/ml)
9440
130
4210
1270
313
Log HIV-1
3,98
2,11
3,61
3,1
1,57
CD4+ cells/mm3
714
-
570
-
800
HIV-load (cp/ml)
46
42
99
51
20
Log HIV-1
1,66
1,62
1,99
1,71
1,3
Log CSF/plasma
2,32
0,49
1,62
1,39
0,27
CSF
Cells/mm3 (lymphocytes)
Plasma
* mo, months; ART+, ART intensification; cp, copies.