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Symptomatic cerebrospinal fluid escape

Mastrangelo, Andreaa; Turrini, Filippob; de Zan, Valentinaa; Caccia, Robertab; Gerevini, Simonettac; Cinque, Paolaa,b

doi: 10.1097/QAD.0000000000002266
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Cerebrospinal fluid (CSF) viral escape is defined by detectable HIV-RNA in CSF despite undetectable or lower-than-CSF level in plasma of patients receiving combination antiretroviral therapy (cART). This condition may occasionally be associated with neurological problems, consisting of new and progressive cognitive decline and/or focal symptoms and signs, defining the ‘symptomatic CSF escape’. Brain MRI usually shows diffuse white matter hyperintensities that recall the presentation of HIV encephalopathy in the precART era. However, patients develop symptomatic CSF escape with relatively high CD4+ cell counts and suppressed or low systemic virus replication. In addition, the frequent CSF pleocytosis and the pathological demonstration of CD8+ T-cell brain infiltrates in some cases of symptomatic escape indicate that inflammation is an important component in the pathogenesis of this condition. Low nadir CD4+ cells are common, likely reflecting the establishment of a HIV reservoir in the central nervous system (CNS). CSF escape seems to result from reactivation of CNS infection when cART potency is lowered, because of low patient's adherence, drug resistance, or use of drug combinations that are poorly effective in the CNS and cART optimization is key to revert escape and neurological disease in the great majority of cases.

aDepartment of Infectious Diseases

bUnit of Neurovirology, Division of Immunology, Transplantation and Infectious Diseases

cDivision of Neuroradiology, IRCCS San Raffaele Scientific Institute, Milan, Italy.

Correspondence to Dr Paola Cinque, MD, PhD, Department of Infectious Diseases, San Raffaele Scientific Institute, Via Stamira d’Ancona, 20, 20127 Milan, Italy. E-mail: cinque.paola@hsr.it

Received 26 July, 2018

Revised 25 March, 2019

Accepted 9 April, 2019

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Introduction

Severe neurological manifestations resulting from HIV infection of the central nervous system (CNS), including HIV-associated dementia, have been a common complication in untreated patients, but are rarely observed after the introduction of combination antiretroviral therapy (cART). In treated patients, a heterogeneous landscape of milder but more frequent neuropsychological modifications has been related to HIV persistence in the CNS (the so-called ‘HIV-associated neurocognitive disorders’, HAND) [1,2], although the causative role of HIV itself rather than other possible concomitant conditions is debated [3,4].

The physiopathological mechanisms for HIV-induced neurological disease in untreated patients rely on the strong CNS tropism of the virus, with a persistent, noncytopathic infection of brain microglia and perivascular macrophages, with consequent immunoactivation and neurodegeneration [5,6]. Even in treated patients, the limited diffusion of some antiretrovirals through the blood–brain barrier may allow HIV to persist and replicate at this level [7]. Thus, the CNS has the potential to harbour an important HIV reservoir, which might impede the achievement of a definitive cure. There is indeed evidence of virus evolution inside the brain, including selection of resistance mutations that might affect cART efficacy locally and theoretically also reseed the periphery [8]. Moreover, uncontrolled intrathecal HIV replication and the subsequent inflammation could be harmful by themselves, leading to neurological disease.

Cerebrospinal fluid (CSF) escape is a phenomenon in which HIV replication in the CNS overcomes the replication in the peripheral compartment [9]. It has been defined as the presence of CSF viral load higher than plasma viral load, or as the presence of detectable CSF viral load in virologically suppressed individuals on stable cART for at least 6 months. However, these definitions have varied between studies, making it difficult to compare findings among different patients’ cohorts.

CSF escape could be classified into asymptomatic, symptomatic and secondary. Asymptomatic CSF escape is mostly recognized in the context of research studies, with a frequency ranging from 18% in patients with low-level viremia to 1.5% among those with undetectable viremia, and with lower prevalence in later years, likely associated with more potent drug combinations [10–14], and it may reflect the difficulty to suppress HIV activity in the CNS reservoir [15]. Symptomatic CSF escape is defined in the presence of neurological signs and symptoms resulting from selective HIV replication within the CNS [16–18]. Secondary CSF escape is associated with a concomitant CNS infection, and it has been described in conditions, such as neurosyphilis [19], neuroborreliosis [20], and varicella zoster meningitis [21]. The mechanisms associated with secondary escape include local inflammation with lymphocytes and monocyte recruitment and possible infection of these cells by HIV.

In this review, we will focus on symptomatic CSF escape, and will describe epidemiology and risk factors, clinical manifestation, diagnosis, and treatment, according to published reports and personal experience.

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Prevalence and risk factors

The prevalence of symptomatic CSF escape is difficult to define, being described only in anecdotal reports or small case series. Three different cohorts reported a prevalence of 5, 6 and 12% of CSF escape, respectively, in patients undergoing lumbar puncture examination for the investigation of neurological symptoms [12,22,23]. In a French study, 11 patients in over 4 years of clinical activity were retrospectively found to have neurological symptoms due exclusively to isolated HIV replication in the CNS [16] and an incidence of symptomatic CSF escape of 4.4 per 10 000 person-month was observed among Indian patients receiving atazanavir-containing cART [24]. Recently, another study from India reported symptomatic CSF escape in 20 out of 1584 cART suppressed patients, that is, slightly above 1% of the cases [25]. In conclusion, symptomatic CSF escape appears to be an infrequent clinical event.

Several viral, immunological and treatment-related factors have been associated with an increased risk of symptomatic CSF escape. Case series and individual reports have consistently shown that patients with symptomatic escape had low CD4+ cells nadir, that is, less than 200/μl [9,16,17,24,25]. Low-CD4+ nadir reflects a previous status of profound immune deficiency, which could have favoured the establishment of a viral reservoir in the brain, and it could be hypothesized that, in the presence of an important CNS reservoir, cART could fail to suppress viral replication in the CNS, despite optimal systemic response.

On the other hand, persistent low-level viremia has also been associated with an increased likelihood of CSF escape [12] and plasma viral blips have preceded the onset of neurological manifestations in some instances. This suggests that loss of control of systemic replication could possibly lead to an even greater intrathecal failure with consequent neurological disease. Lack of virus suppression may result from low effective treatment, although inadequate immune control of systemic HIV infection might also contribute.

Indeed, discordantly high HIV-RNA levels in CSF – in the presence of plasma virological failure – have been found in association with sub-optimal cART regimens, such as monotherapy with boosted protease inhibitors [26], low patients’ adherence and presence of resistant viral populations [16,17,26]. All of these conditions are associated with a general reduction of cART potency because of systemic low-drug concentrations, which may become suboptimal in the CNS, where anatomical barriers and different metabolism of brain macrophage and microglial cells may further reduce drug penetration and efficacy.

More in general, it seems that in the presence of a large CNS reservoir, ART-related factors, such as low adherence and drug resistance may contribute to viral failure in the CNS. Indeed, low adherence is associated with cognitive and neurological problems, which on one hand may be the consequence, but on the other hand may also contribute to inadequate drug intake [27]. Resistance mutations to antiviral drugs are frequently identified in both CSF and plasma of patients with symptomatic escape, and sometimes mutations are specifically selected in the CSF. For instance, 5 of the 11 patients of the French cohort mentioned above [16] had a CSF virus that was resistant to current cART regimens at the time of CSF escape. The most commonly reported mutations were the M184V/I [28] and the thymidine-associated mutations T215Y, D67N, and M41L, and, of note, the selection of INSTI-resistance-associated mutations has also been observed in more recent reports. (Table 1).

Table 1

Table 1

Table 1

Table 1

Table 1

Table 1

A recent study of a large cohort of patients who underwent lumbar puncture for either research or clinical purposes showed that the use of protease inhibitors with nucleoside reverse transcriptase inhibitors (NRTI) was related per se to a three-fold higher risk of CSF/plasma HIV-RNA discordance, and that the risk was higher for atazanavir-containing over atazanavir noncontaining regimens [29]. Indeed, atazanavir has been reported to have low penetration into the CSF, where its concentration is below the minimum inhibitory concentrations in the majority of cases [30]. Therefore, inadequate drug concentrations in CNS may also play a role in causing CSF escape. However, protease inhibitors have often been used in patients experiencing virological failure because of drug resistance, which is per se a risk factor of CSF escape. Therefore, it is possible that, in some patients receiving protease inhibitors, CSF escape reflects a previous history of drug failure more than lack of drug efficacy in the CNS.

In summary, risk factors of symptomatic CSF escape seem to include both factors reflecting the presence of a relevant CNS reservoir, such as low-nadir CD4+, and those associated with low-drug potency in the CNS, either because of low general potency, such as low adherence or drug resistance, or to specific low CNS activity.

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Clinical, MRI, laboratory and pathological findings

Symptomatic CSF escape is clinically characterized by acute or subacute onset of new neurological symptoms in treated HIV-positive patients, usually with well controlled levels of plasmatic viremia [16,17]. The typical scenario is that of a long-term treated person who develops new progressing neurological impairment and/or cognitive deterioration. In the cases reported in the literature, neurological findings varied from headache to focal symptoms to severe encephalopathy (Table 1). Overall, the most frequent presentation was of a subacute onset of cognitive problems, with decline of memory and executive functions, often associated with mild focal deficits. Cerebellar impairment with ataxia, dysarthria and loss of balance was also highly prevalent.

The vast majority of patients with symptomatic CSF escape present with white matter abnormalities at MRI. These mainly consist of hyperintense signal alterations in T2 and FLAIR sequences, either patchy or diffuse, often periventricular or involving the anterior and posterior horns of cerebral ventricles (Table 1 and Fig. 1).

Fig. 1

Fig. 1

Both clinical and MRI presentation of symptomatic escape may recall that of HIV encephalitis common in the precART era and nowadays occurring – rarely – in untreated AIDS presenters. However, whereas HIV encephalitis of untreated patients was associated with low CD4+ cell counts and high plasma and CSF viral load, the encephalopathy of symptomatic escape is seen in patients with normal CD4+ cells, low or undetectable plasma and usually also low-CSF viral load.

Such different viroimmunological milieu is likely to account for the different imaging and CSF findings between the two conditions. In patients with symptomatic escape, MRI abnormalities are often associated with a degree of edema and cerebral swelling, which determines sulcal effacement and compression of brain ventricles (Fig. 1) and reflects neuroinflammation. Edema was not a feature of HIV encephalitis observed in untreated patients, which was on the contrary associated with cortical and subcortical atrophy. Similarly, high-protein CSF level and CSF pleocytosis, with a predominance of lymphocytes (mostly CD8+ T cells), are a common finding of symptomatic CSF escape (Table 1), whereas CSF pleocytosis was unusual in untreated patients with HIV encephalitis.

According to a few cases described in the literature, the pathological correlate of neurosymptomatic CSF escape may in fact be that of an inflammatory encephalitis [31–35]. In a case series of 10 patients with acute or subacute onset of neurological symptoms and ‘HIV-associated CD8+ cell encephalitis’ diagnosed at brain biopsy, 2 had neurosymptomatic CSF escape, whereas in the others the encephalitis was associated with a previous upper respiratory tract infection, immune reconstitution inflammatory syndrome (IRIS) or cART interruption [32]. Neuropathological findings in CD8+ cell encephalitis consisted of an abundant infiltrate of CD8+ lymphocytes, associated with a low expression of HIV proteins in the absence of multinucleated giant cells, a typical feature of HIV encephalitis resulting from HIV replication in brain macrophages [33]. This entity seems to be associated with an exaggerated immune response directed against HIV in the CNS and capable to self-sustain itself despite minimal viral replication.

Of note, the cases of CD8+ cell encephalitis with symptomatic escape had typical bilateral T2 and FLAIR high-signal intensity lesions, received steroids in addition to cART optimization and improved neurologically. Overall, the response to steroids in these cases of symptomatic escape, together with the inflammatory findings at MRI and in the CSF seem consistent with an inflammatory nature of this entity, linked to a dysfunctional immune response in the CNS to HIV.

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Diagnostic workup and differential diagnosis

The diagnosis of symptomatic CSF escape relies on the virological criteria reported above obtained by the study of HIV replication in paired CSF and plasma samples in a patient with new onset of neurological symptoms or signs. In addition, patients should have been treated with cART for at least 6–9 months, because CSF HIV-RNA level may decay more slowly than correspondent plasma level, and become undetectable even months after the start of therapy. Finally, a secondary escape – associated with concomitant neurological or nonneurological diseases – needs to be excluded.

In the reported cases, HIV-RNA ranged from few hundreds of copies/ml to over 500 000 (Table 1). In the three largest case series of CSF escape, median CSF HIV-RNA was 880, 3900 and 4250 copies/ml, respectively [16,17,25]. By definition, the plasma viremia was either undetectable or lower than in CSF. However, there are cases that meet the definition criteria of symptomatic escape, but emerge in the specific context of a systemic failure to cART, like those observed in patients receiving boosted lopinavir monotherapy [26].

Sequence analysis of CSF and plasma virus in case of symptomatic CSF escape frequently shows different mutation profiles between the two compartments (Table 1). More recently, deep genome sequencing, which enables the characterization of different viral variants within a sample including minority variants, has shown the presence of additional resistant variants in CSF compared with plasma and a consequent higher degree of discordance between CSF and peripheral virus [36].

The differential diagnosis should be made against other neurological diseases that may occur in HIV-positive treated patients, because of HIV infection or other conditions, including those related to aging. Patients with neurosymptomatic escape usually have a CD4+ cell count of above 200 cells/μl, and this makes it improbable the presence of classic opportunistic CNS infections, although IRIS in the context of other CNS infections may be considered [37]. Among conditions characterized by cognitive impairment and presence of white matter abnormalities, cerebrovascular diseases may in some cases resemble those observed in neurosymptomatic escape [38]. Furthermore, after CSF escape is diagnosed by CSF and plasma analysis, secondary CSF escape needs to be excluded, through clinical and laboratory investigations for possible causes of HIV reactivation in the CNS, including CNS infections and primarily neurosyphilis.

More in general, the MRI and CSF findings described above and consistent with inflammation may raise the suspect of CSF escape in cART-suppressed patients with neurological symptoms or signs, and urge the analysis of CSF for HIV-RNA.

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Treatment

Asymptomatic CSF escape seems to be neither predictive of subsequent development of neurological disease nor of peripheral seeding of resistance CSF variants [10]. Therefore, in the absence of symptoms, no change of current cART regimens is usually required. On the contrary, symptomatic CSF escape is a progressive and harmful CNS disease that demands a rapid and effective treatment, based on cART optimization. Keeping into account the cART-related risk factors of symptomatic CSF escape, optimization of cART regimens relies upon consideration of patient's adherence, resistance profile in CSF and plasma, and evaluation of neuropenetration and efficacy of cART [16,17].

The consequences of low patient's adherence to cART may be more clinically significant in CNS infection than systemically because it might lead to even lower intrathecal drug levels, which may not be able to suppress local replication. Therefore, it is essential to maximize adherence in patients with symptomatic escape, if necessary through directly observed treatment and measuring plasma drug concentrations, and usually together with additional cART changes.

In the presence of resistance, higher drug concentrations are required to suppress viral replication, and these may not be achieved in the CNS. The situation of persistent local replication in presence of suboptimal drug levels may lead to compartmentalized virus replication in the CNS and favour additional local selection of mutations. In these cases, cART needs be optimized according to the presence of resistance mutations in CSF, plasma or both.

Symptomatic CSF escape represents the only condition where specific drug requirements of neuropenetration and/or neuroefficacy may be critical. Current cART regimens are almost universally able to control HIV replication in the CNS through control of systemic replication. However, the brain may be a hard-to-reach site for several currently prescribed antiretrovirals [7], and therefore, cART therapy may need to be revised according to neuropenetration. To help physicians choose a pharmacological combination able to cross the brain barriers, a CNS penetration effectiveness (CPE) score has been proposed in the past (originally in 2008, revised in 2010), which inversely correlated with CSF viral load in a large cohort of patients [39]. However, no sufficient evidence supporting the use of such scoring system for practical purposes has emerged and, specifically, several observations found no differences in CPE scores between individuals with or without CSF escape [16,17,29].

Nevertheless, there are differences between antiretroviral drugs as for their CSF levels in relation to inhibitory HIV concentrations, and use of those with higher ‘neuropenetration’ may be an option in certain cases of symptomatic CSF escape. These include, among currently prescribed drugs, dolutegravir, ritonavir boosted darunavir, efavirenz, maraviroc and most NRTIs [40–42]. NRTIs seem to be highly effective in suppressing HIV replication in brain macrophages [43] and, remarkably, several cases of symptomatic escape have apparently resolved with the use of zidovudine (Table 1 and personal observations). Zidovudine monotherapy was shown to reduce dramatically both incidence of HIV-associated dementia and frequency of HIV-encephalitis at postmortem examination [44,45], and the review of cases in Table 1 shows that zidovudine was included in a successful optimized regimen in about 25% of patients, which may support a role of this drug in neurosymptomatic escape.

cART optimization leads to resolution or improvement of clinical symptoms in most cases of neurosymptomatic escape, together with resolution or reduction of MRI abnormalities, both in lesion size and signal intensity, HIV clearance from the CSF and normalization of pleocytosis [16,17]. The observation that optimized cART improves or resolves the neuroinflammatory signs at MRI and pleocytosis implicates a role of HIV as a trigger of inflammation within the brain. Occasionally, neurosymptomatic escape may relapse, supporting the hypothesis that HIV establishes a reservoir within the CNS at least in certain persons. Relapse cases have been observed following cART simplification after months to years of effective treatment [46], thus underlying the need of complex treatments in some cases to maintain an adequate control of CSF viral replication.

To this regard, dual cART regimens, although promising for control of systemic infection in both ART-experienced and naïve patients, may not offer the maximal efficacy required to suppress HIV replication in the brain in symptomatic escape cases. On the other hand, complex treatments that may require more than three drugs, more frequent administration, that is, twice rather than once daily, and an increased pill burden, may result in low adherence. Therefore, the expected virological efficacy of complex combinations needs be balanced against actual tolerability and patient compliance. In this view, agents that combine high systemic efficacy and CNS penetration with good tolerability and low genetic barrier could represent an option for long-term control of CNS replication in patients at high risk of symptomatic CSF escape.

Finally, corticosteroids have successfully been used in association with cART optimization in several cases of symptomatic CSF escape, such as in patients with histological evidence of CD8+ encephalitis [32]. Steroids may be useful in cases characterized by acute onset and severe or severely progressive manifestations, where high-degree inflammation may cause intracranial hypertension and death. However, anti-inflammatory drugs alone are unlikely to resolve symptomatic CSF escape, as shown in patients treated with steroids and/or intravenous immunoglobulins that improved stably only after cART optimization [30,45] (and our personal observations).

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Conclusion

Symptomatic CSF escape is an infrequent, but well characterized clinical entity that reflects selective HIV replication in the CNS in cART-treated patients. Further challenges for the study of CSF escape include the definition of criteria to be used for diagnostic purposes and to facilitate multicenter studies aiming to identify the pathological drivers of this condition. Symptomatic CSF escape seems to represent a proof of the existence of a brain reservoir that is able to produce replication competent virus despite apparently successful systemic therapy, which would point to the CNS as a target tissue in HIV-cure studies.

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Acknowledgements

This work has partly been supported by National Institute of Health (NIH) – National Institute of Allergy and Infectious Diseases (NIAID) and National Institute of Mental Health (NIMH).

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Conflicts of interest

There are no conflicts of interest.

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        Keywords:

        antiretroviral therapy; cerebrospinal fluid; cerebrospinal fluid escape; HIV; neurological; reservoir; viral load

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