Módulo 3 – Curso pós-graduado – VIH e Envelhecimento

Neurocognitive Disorders in HIV Infected Patients

Clinical management of HIV-related neurological disorders

Autor: Prof. Doutor Richard W. Price, MD PhD (San Francisco General Hospital, University of California, San Francisco, USA)

CNS/CSF escape in treated patients

For untreated patients, the CSF HIV RNA is usually a lot lower (about tenfold lower) than plasma, although there is considerable variation. With successful treatment, for example to HIV RNA less than 50 copies/mL, the CSF HIV RNA is similarly lower than plasma or down to the level of detection. Even in cases of virological failure, CSF HIV RNA is still usually relatively lower than plasma.

ART is effective, not only in the periphery (at systemic level), but also within the CNS and most treated patients will not exhibit detectable CNS infection. However, there are exceptions in which HIV RNA can be detected in CSF; these have been collectively referred to as CSF viral escape. This escape is defined as ART-treated patients with plasma HIV RNA suppression but with detectable CSF virus (above that of plasma). Escape can be classified in three types (Table 1):2

  • Asymptomatic or incidental escape, uncommon (about 5% of samples).
  • Neurosymptomatic, clinically important but rare.
  • Secondary, when the presence of another CNS infection (e.g. varicella zoster virus) and associated inflammation may result in temporary detectable CSF virus; not clinically important.

Asymptomatic escape is probably equivalent to plasma blips, small episodes of CSF detectable virus with suppressed HIV in plasma, which may come and go. It may be present in stable individuals, with no discernible CNS symptoms and signs related to HIV. The CSF HIV RNA shows, frequently, a small elevation between 40-50 (the detection threshold) and 100, and usually there is no clinical abnormality.

Table 1. Classification of CNS HIV escape.

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Some studies have reported this incident finding.3,4 Éden et al. conducted a retrospective analysis in their Gothenburg cohort, where they perform LPs on almost every patient. In a review of 69 individuals on ART who were plasma suppressed, 7 had CSF HIV higher than 50 copies/mL, with median copies of 121 copies/mL, ranging between 54 and 213 copies/mL. There was a mild elevation of CSF neopterin (an inflammatory biomarker) but normal CSF white blood cell (WBC) count (usually normal). There was no to the ART CPE score.3

More recently, they followed up this study with 75 patients with 418 LPs over time.4 Many of these patients were treated with older drugs (mostly protease inhibitors and non-nucleoside reverse transcriptase inhibitors based regimens), and responded well to therapy. Two thresholds were used for measuring escape. At 50 copies/mL threshold, the proportion of subjects who had any episode of CSF escape was about 23%, increasing to 36% when using the 20 copies/mL threshold. Considering all 418 samples, 5% and 9% had CSF HIV RNA higher than the threshold of 50 and 20 copies/mL, respectively.

In summary, asymptomatic CSF escape is common and appears similar to plasma blip, with an undefined virological character and origin. It is not yet clear whether these CSF elevations originate from a CNS HIV reservoir, or from trafficking blood TCD4+ cells. There is also no evidence that these escape episodes are associated with CNS injury or progressive chronic neurocognitive decline.

Neurosymptomatic escape is a rare but clinically important type of treatment failure, an inflammatory condition usually with a higher CSF viral load that is isolated to or disproportionately high within the nervous system.5,6 It is characterized by subacute onset or progressive neurological disease, in treated HIV-infected patients who present with high CSF: plasma HIV RNA ratio, either CSF VL >50 copies when plasma VL is <50 copies/mL or, if plasma VL 50-1000 copies, then CSF is >2 times higher. MRI usually shows diffuse or multifocal encephalitis. Characteristically there is CSF pleocytosis with >10 cells/µL in CSF. Finally, these cases have no alternative CNS diagnosis (e.g., coincident neurodegenerative disease or opportunistic infection). Many of these patients show resistance to at least one drug in their regimen in the CSF.

Pathologically these patients exhibit TCD8+ encephalitis with inflammatory white matter lesions.7, 8 Something akin to immune reconstitution probably plays a role in neuropathogenesis in these cases. This type of escape indicates sustained productive CNS HIV infection. Important factors include ineffective CNS HIV treatment, drug resistance and limited local drug exposure related to the blood-brain barrier. It is uncertain whether this infection results from reactivation of the CNS reservoir from past seeding.

This is a situation in which penetration of the antiretroviral drugs into the nervous system is critical so that some of these patients are on drugs that penetrate the CNS poorly while others show CNS HIV resistance – often there is a combination of both of these factors.

The reason for the highly inflammatory character of the neurosymptomatic escape may be the relative preservation of systemic immune-inflammatory responses related to ‘successful’ systemic viral suppression and immune reconstitution, besides the eventual TCD8+ pathology or immune reconstitution inflammatory syndrome like features.

Among possible predisposing factors to this form of escape may be a low TCD4+ nadir. Long-term treatment with multidrug exposure and resistance also likely are important factors. Treatment of CNS escape requires switch to drugs without resistance, along with the need to take into account the CNS drug.

Generally, two or more drugs in the regimen should achieve therapeutic concentrations in the CNS without evidence of resistance. In addition, patient adherence is important as with systemic treatment failure. There may be some situations where corticosteroids may be helpful, at least in the short term, as an additional measure, along with the change in antiretroviral drugs.

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