| HIV CSF Escape |
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| Written by Roger Thomsen |
| Thursday, 18 November 2010 14:33 |
HIV Escape in Cerebrospinal Fluid Despite Viral Control in PlasmaIt is usually admitted that detectable CSF HIV viral load above 50 c/ml is a rare event during effective HAART. A recent study (1) shows that this situation could be more frequent. Here we discuss the implications of these results, but also raise some questions and comments about the design limitations of this study.
All cases had sustained viremia <50 c/ml but in 7 cases (10%), HIV RNA level was >50 c/ml in the CSF. The median CSF HIV RNA level was 121 c/ml (range: 52-860 c/ml). CSF pleocytosis was not significantly different in patients with detectable virus. The conclusions of this study are:
T he importance of the brain as a sanctuary site in HIV diseases has been established for many years and is difficult to study as direct sampling is not possible. Studies on CSF are important but such a small cross-sectional study raises several questions:
References: 1-HIV-1 Viral Escape in Cerebrospinal Fluid of Subjects on Suppressive Antiretroviral Treatment. Edén A, Fuchs D, Hagberg L, et al. J Infect Dis. 2010 Nov 4. [Epub ahead of print] 2-Viral Escape in Cerebrospinal Fluid-An Achilles Heel of HIV Therapy? Clifford DB. J Infect Dis. 2010 Nov 4. [Epub ahead of print]
You can comment this article below. Related Articles: Key words: CPE rank, CSF, HIV, brain, replication, reservoir |
| Last Updated on Friday, 19 November 2010 17:05 |
Even if several questions remain open, slow disease evolution in the brain is of major concern. Studies like this one tend to prove that the brain is a time bomb during HAART. These results are in agreement with previous reports, but the precise role of the different antiretroviral drugs is not clear in this paper. More studies are urgently needed, including prospective analysis in large cohorts of patients, as they have the potential to influence prescription choices...
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We would like to thank Dr Thomsen for the interest shown in our study on cerebrospinal fluid viral escape. We would like to take the opportunity to address some of the questions raised in this forum.
Although the comparison to data from the CHARTER cohort presented at CROI 2009 is interesting, the studies differ in important ways. The CHARTER report, containing as yet unpublished data, reported 41 % of study subjects having detectable HIV-1 below the clinical cutoff level of 50 c/ml using a qualitative assay. In our study cohort, we detect CSF HIV-1 RNA above the routine clinical detection level in 10 % of subjects despite being undetectable.
As formal neurocognitive testing was not performed in all subjects, we cannot rule out that some patients may have been diagnosed with asymptomatic neurocognitive impairment (ANI) if formally tested, although more severe impairment was excluded in study subjects. Studies examining the relation of detectable CSF virus, intrathecal immuno-activation and less severe neurocognitive impairment are ongoing to further evaluate this issue. In addition, we fully agree that the role of resistance remains an important question. Intrathecal resistance may, as we have discussed, contribute to study results, and as suggested here, additional studies on viral resistance are ongoing.
The CPE ranking system has been proposed as a useful tool for estimating the overall CNS efficacy in a given drug combination. Although subjects included in the current study used contemporary and commonly used ART regimens, the number of subjects was limited, and prevented any conclusions regarding comparative CNS efficacy for individual drugs in our cohort. Additionally, no correlation to either detectable CSF virus or levels of intrathecal immune activation was found using the CPE ranking system. These results are in line with accumulated data on intrathecal immune activation in relation to CPE rank presented elsewhere (ref. 1). However, the current analysis was again limited by the size of the study population and no conclusion regarding the validity of CPE ranking was drawn.
Additionally, the CPE rank has been established in a cohort containing a mix of subjects with successfully controlled viremia as well as subjects failing therapy. In the context of the current study, analyses including only subjects with successfully suppressed viremia in blood may be of importance. The CPE ranking system constitutes a potential future tool for optimizing treatment, although more data on drug efficacy in the CNS is urgently needed. The CPE ranking system will likely evolve further in the coming years, and additional prospective studies in different cohorts will be needed to establish the role of the scoring system in the clinical management of individual patients.
Regarding the importance of viral ‘blips’ in relation to the occurrence of CSF viral escape, this remains an unresolved issue. We agree that ‘blips’ do not immediately indicate poorer adherence in all cases. Frequent ‘blips’ may also be related to higher levels of residual viremia in blood. However, in our study cohort a significant correlation was seen between the number of viral ‘blips’ and CSF viral escape. It should be noted that our current data does not conclusively demonstrate that the detection of CSF virus constitutes a clinically significant CSF viral escape rather than a CSF viral ‘blip’, although this is also a subject of ongoing studies.
1. Hagberg L, Cinque P, Gisslen M, Brew BJ, Spudich S, Bestetti A, et al. Cerebrospinal fluid neopterin: an informative biomarker of central nervous system immune activation in HIV-1 infection. AIDS research and therapy. 2010;7:15.
