Sustained suppression of HIV RNA to clinically undetectable levels (<20 copies/ml) in the plasma compartment with effective antiretroviral therapy is achievable and results in restoration of immune system function in persons living with HIV (PLWH). As a consequence of this immune system function restoration, opportunistic diseases have now become rare in PLWH with access to effective antiretroviral therapy and life expectancy approaches that of the general population [1,2].
Despite suppression of HIV RNA in the plasma compartment, successful control of HIV RNA to less than 20 copies/ml in other body compartments such as the genitourinary system, lymphoid tissue and the central nervous system (CNS), is however not always achievable. An interest in assessment of suppression of HIV RNA in the cerebrospinal fluid (CSF) as a possible surrogate for virus control within the CNS has emerged recently for several reasons.
First, CNS disorders, including cognitive dysfunction, continue to be reported in PLWH despite virologically suppressive antiretroviral therapy. Although rates of such cognitive disorders in PLWH are challenging to ascertain due to differences in the cohorts in which they are described and different definitions utilized, such disorders have been reported globally in PLWH including in cohorts from North America , Europe , Australasia , Africa , South America and Asia . Lack of control of HIV replication in the CNS may result in ongoing neuronal damage and consequently in neuro-inflammation, factors which have been implicated in the development of cognitive disorders in PLWH. Indeed, several reports have described the new onset of neurological symptoms in PLWH with discordantly high HIV RNA burden in the CSF [8–10].
Second, although suppressive antiretroviral therapy itself does not eradicate HIV from reservoirs, research strategies to reactivate latent HIV reservoirs to promote their clearance are rapidly evolving and is a high-priority research area in the HIV treatment agenda. Hence, understanding of the CNS as a viral reservoir and successful control of HIV replication within the CNS are key areas requiring further study to accomplish the goals of reducing or eradicating HIV reservoirs.
The presence of HIV RNA in the CSF at a concentration above that in plasma (see below for definitions), suggesting selectively reduced control of viral replication in this compartment, is generally termed CSF HIV RNA escape. This phenomenon of CSF viral escape has been observed in clinical and research settings across many continents around the world. A report from a global CSF HIV escape consortium meeting summarizes the major cohorts reporting this phenomenon . The cause of this syndrome may be variable and often is unknown. Although multiple cases and studies of CSF HIV RNA escape have been reported, consensus on the definition of CSF HIV RNA escape is currently not available with several different definitions currently in use.
Without consensus definitions, clinical research outcomes, and also the development of clinical management guidelines, becomes limited. The ability to compare findings across different cohorts from different geographical regions is hampered making the design of future studies more challenging. Here we summarize some aspects of CSF HIV RNA escape where consensus definitions are likely to be achievable. Furthermore, we provide a consensus definition based on discourse, which took place at the National Institute of Mental Health-sponsored Second Global HIV CSF Escape Consortium meeting held in Pollenzo, Italy on the 12 October 2017 where the authors of this report, with an open audience of HIV clinicians, virologists and scientists, discussed consensus definitions.
Virological definition of cerebrospinal fluid HIV RNA escape
Several virological definitions of CSF HIV RNA escape have been utilized in recent years with some groups defining CSF HIV RNA escape when concentrations of HIV RNA are anything above that observed in plasma, whereas other research groups have utilized threshold definitions whereby CSF HIV RNA is required to greater than plasma HIV RNA by a predefined amount. Prespecified amounts of HIV RNA in CSF compared with plasma HIV RNA utilized in recent publications ranges from 0.5 log10 copies/ml greater  to 1.5 log10 copies/ml greater .
Often, virological definitions are separated into clinical scenarios where the plasma HIV RNA is either undetectable or detectable.
Defining cerebrospinal fluid HIV RNA escape when plasma HIV RNA is below the limit of quantitation
The European AIDS Clinical Society (EACS)  and the US Department for Health and Human Services (DHHS) (https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0) include recommendations on defining CSF HIV RNA escape with both guidelines recommending that any CSF HIV RNA detected above the used PCR-method's limit of quantification (LOQ) when plasma HIV RNA is less than LOQ should be considered CSF escape.
A potential disadvantage to this definition is HIV RNA assay variability, whereby there is inherent variability in all assays and there will be cases of CSF HIV RNA being quantified due to assay variability rather than due to the true increase of HIV RNA in a sample. Likewise, plasma HIV RNA may also be falsely below the limit of quantitation, which can lead to overestimates of CSF escape. Therefore, by classifying CSF HIV RNA escape as any quantifiable HIV RNA in CSF where plasma HIV RNA is below LOQ, false positive cases may ensue. Logically, assay variability also has the potential to lead to false negative cases.
However, setting a defined threshold above which CSF HIV RNA should reach to meet a definition of viral escape in the presence of suppressed plasma HIV RNA will inevitably lead to false negative cases whereby a small amount of HIV RNA in the CSF is considered falsely present and due to inherent assay variability when viral replication or production is actually occurring.
Of 24 individuals at the Pollenzo meeting voting confidentially via an electronic device in reply to the following question responses were as follows ‘The current United States and European guidelines for CSF escape are plasma undetectable with CSF detectable; Do you agree with this criteria (91.7% agreed, 8.3% disagreed)’.
In summary, here general agreement to this question was evident with the below being a recommended definition, which is in agreement with both European and US guidelines.
When plasma HIV RNA is suppressed, the presence of quantifiable HIV RNA in the CSF at any level should be considered CSF HIV RNA escape.
Defining cerebrospinal fluid HIV RNA escape when plasma HIV RNA is above the limit of quantitation
HIV RNA can be found in the CSF in almost all PLWH who are not on antiretroviral therapy and in general is directly proportional to plasma HIV RNA . In neurologically asymptomatic PLWH not on antiretroviral therapy, CSF HIV RNA is typically reported to be lower than plasma HIV RNA. In neurologically symptomatic individuals not on antiretroviral therapy, case reports have described CSF HIV RNA to be higher than plasma HIV RNA .
The EACS  and the US DHHS both recommend defining CSF escape as a quantification of HIV RNA which is greater than plasma HIV RNA without defining any threshold higher. A rationale here being that one would expect CSF HIV RNA to be lower than plasma HIV RNA, so any measurement which is the same or above plasma HIV RNA should be considered clinically significant.
Of 27 individuals at the Pollenzo meeting voting confidentially via an electronic device in reply to the following question responses were as follows: ‘When plasma HIV RNA is detectable, CSF HIV RNA escape should be defined as anything above plasma HIV RNA (70.4% respondents) or 0.5 logarithm higher than plasma HIV RNA (29.6% respondents).’
Although agreement on the voting here was not as strong as for the scenario of CSF escape when plasma HIV RNA is undetectable, in view of EACS and DHHS recommendation and the majority of individuals agreeing with this statement, we would consider this as a recommendation.
When plasma HIV RNA is detectable, CSF HIV RNA greater then plasma HIV RNA, at any level, should be considered CSF HIV RNA escape.
Defining symptomatology of cerebrospinal fluid escape
Although at first glance this question may not appear complex in nature, clinical scenarios are often more complicated than they first appear. Clinical scenarios in which CSF HIV RNA escape may occur include asymptomatic escape, symptomatic escape and escape secondary to other infections in the CNS . Challenges which are often incurred include multiple symptomatology and symptomatology which may not be directly related to CSF escape.
Regarding the first point above, many individuals may have more than one neurological symptom. For example, an individual may have headaches, concentration difficulties and depression. When a CSF examination is undertaken, identifying which of these symptoms has led the clinician to recommending a CSF examination can be challenging to ascertain and in many instances it may be a myriad of symptoms which lead to clinical investigations.
Regarding the second point, high rates of neurological symptoms are described in cohorts of PLWH such as headaches, depression, sleep disturbances and concentration difficulties. Ascertainment of which, if any, of these symptoms have resulted in the recommendation for a CSF examination can be challenging. More distinctly pathological neurological signs or symptoms may also prompt CSF evaluation, in our experience including myelopathy, optic neuropathy, Parkinsonism, facial palsy, and unilateral tremor. If CSF HIV escape is detected in these scenarios it is not yet certain whether this is directly related to the observed findings.
Furthermore, individuals participating in research studies which include CSF examination may be recruited as asymptomatic individuals, and would not otherwise undergo CSF examination, however on further questioning may have neurological symptoms.
On the converse, there will also be clinical scenarios where symptomatology and indication for the CSF examination are clearly definable, for instance in cases with emergence of new cognitive or other neurological symptomatology.
Of 27 individuals at the Pollenzo meeting voting confidentially via an electronic device in reply to the following question responses were as follows: ‘Should symptomatic CSF HIV RNA escape be based on a list of symptoms or criteria (77.8% agreed) or the indication for lumbar puncture examination (22.2% agreed).’
Defining symptomatic versus asymptomatic CSF HIV RNA escape should be based on patient symptomatology.
As highlighted above, the symptomatology associated with CSF may be one of the most challenging areas to reach a consensus. This recommendation is to base any symptomatology on patient reported symptoms, rather than the actual indication for CSF examination. Often, these will be the same, however in cases where they differ patient symptomatology should be taken into consideration.
Clinical management of cerebrospinal fluid escape
CSF examinations are undertaken in PLWH for a variety of reasons as outlined in the section above describing defining the symptoms leading to lumbar puncture. For participants in research studies undergoing CSF examination, individuals may otherwise have no symptoms and CSF HIV RNA findings may meet the criteria for viral escape defined above.
Management of CSF HIV RNA escape includes modifying antiretroviral therapy, treating confounding conditions and infections, and excluding other contributing causes. Modifications of antiretroviral therapy may be made based on plasma and CSF resistance testing, CNS penetration/efficacy, or efforts to improve poor adherence (e.g. switching individuals to a potent once-daily regimen). A key point here is whether all individuals with documented CSF HIV RNA escape should receive further clinical management if they are otherwise completely asymptomatic and underwent this examination solely for research purposes or as part of a medical work up for other conditions. As highlighted earlier, assay variability can lead to cases where HIV RNA will be detected at low levels in CSF and in individuals without other symptomatology one can question if further management is required.
Of 28 individuals at the Pollenzo meeting voting confidentially via an electronic device to the following question responses were as follows: ‘Do you treat CSF HIV RNA escape?; always (28.6% responses) and only in the context of symptoms (71.4%).’
Based on these results, our recommendation is to always manage or treat CSF HIV RNA escape in individuals with neurological symptoms. At present there is insufficient evidence to determine whether clinical management of CSF escape in PLWH without symptoms is required. However, in instances where CSF escape is detected in otherwise truly asymptomatic individuals, a careful clinical review of the individual would be justified, as would the case be if plasma HIV RNA was detected. Measures such as ensuring adherence to antiretroviral therapy is optimal and ensuring no symptomatology has developed would be prudent to undertake.
CSF HIV escape should be actively managed in symptomatic cases.
Defining CSF HIV RNA escape from a virological point of view, a symptomatology point of view and its management has many challenges. However, reaching some level of consensus on how these aspects are defined is crucial both for the management of PLWH and for the design and conduct of future research in the field of reservoir eradication and HIV remission. Here, we have highlighted some of the controversies surrounding defining CSF HIV RNA escape and have four suggested definitions (Table 1) based on review of the literature and opinions of clinicians and researchers in this field.
There are several important limitations to the definitions we have outlined. Defining additional characteristics of CSF escape would improve an understanding of the clinical and biological implications of this phenomenon, and may help to further divide the syndrome into categories with distinct therapeutic approaches. These include determination of a typical scope or trajectory of neurologic symptoms that directly associate with CSF escape, since unrelated neurologic findings are unlikely to be improved by efforts to address CSF escape and may require other treatments. In addition, persistence of CSF escape over time or association of the virologic finding of CSF escape with signs of inflammation or blood–brain barrier disruption may provide further defined categories of escape that would require intervention, regardless of the presence of symptoms. The definitions outlined here have focused on a single CSF analysis which is limited by the test–retest reliability of HIV RNA measurement and by a lack of consideration into the trajectory of virological findings which are important considerations for future revisions of such definitions.
Research and clinical management of HIV remains a rapidly evolving field. Antiretroviral therapies continue to be developed and enter clinical practice. Research on the HIV field on viral remission and cure is rapidly expanding. Laboratory assays to quantify HIV are become increasingly sensitive. The phenotype of PLWH attending for care is changing with individuals now living into their later years of life and developing age-related comorbidities. As the field of HIV medicine evolves, it is likely that the optimal ways to define CSF escape in PLWH will also evolve. Guideline criteria to define CSF escape and recommendations for definitions, as outlined here, require ongoing and regular analysis and review.
We thank the National Institutes of Health/National Institute of Mental Health and specifically Drs Jeymohan Joseph and Dianne Rausch who organized and sponsored the Second Global HIV Cerebrospinal Fluid Escape Consortium. We also thank Dr Paola Cinque and the Scientific Committee of the NeuroHIV 2017 Seventh International Meeting on HIV Infection of the Central Nervous System. Ongoing studies of CSF escape by P.C., M.G., R.W.P. and S.S. are supported by NIH grant R01NS094067. A.W. is supported by the National Institute for Health Research (NIHR) Imperial Biomedical Research Centre (BRC).
Conflicts of interest
There are no conflicts of interest.
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