HIV CSF Escape PDF Print E-mail
Written by Roger Thomsen   
Thursday, 18 November 2010 14:33

HIV Escape in Cerebrospinal Fluid Despite Viral Control in Plasma

It 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.

T
his cross-sectional analysis used archived CSF and plasma specimens from 2 centers (56 patients from Europe, 13 from the US). They were obtained from asymptomatic subjects treated with antiretroviral therapy for >6 months (with no change in the regimen for >3 months). These patients were treated with the 'commonly used first ART regimens', including TDF, ABC, 3TC, FTC, ZDV, ATZ, LPV, EFV.

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:

  1. Autonomous viral replication in the brain is possible during effective ART;
  2. This is a 'frequent' event;
  3. It is related to the duration of treatment: the 7 subjects with detectable CSF HIV RNA had significantly longer treatment duration: median = 77 months, than patients with undetectable CSF virus: 33 months (p=.002).
  4. It is related to the number of previous blips and the history of 1 or more treatment interruptions (71% vs 15% of patients)
  5. It does not correlate with the CPE (Coefficient Penetration Effectiveness) score.

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:

  1. Is that really new? Letendre and colleagues have shown for at least 3 years that HIV RNA remains detectable in the CSF of 42% of patients below the 50 c/ml cutoff (2009 CROI) which is the one used in this study; in the editorial from David Clifford (2), it is stated that 10% is 'a surprisingly high proportion of patients with detectable CSF virus', but in the initial presentation of their study at CROI (Click here) the authors mentioned that this is an 'uncommon finding'...
  2. Were these patients really asymptomatic in terms of neurocognitive impairment? It is known that sub-clinical defects are frequent, but no formal neurocognitive testing was performed in this series;
  3. What was the role of resistance? This issue is discussed by authors but they state that 'CSF viral load....was too low to allow resistance analysis'. Although this is generally true -as levels are <1,000 c/ml- it is now possible to sequence low levels viremia (in particular in the patient with CSF levels at 860 c/ml)...
  4. What is the strength of the conclusion on the CPE rank? The number of patients with detectable CSF HIV levels was quite low, with diverse combinations. On the contrary, the CPE rank was established in a series of several hundreds of patients...
  5. Is the number of blips a real measure of adherence? Currently, with sensitive techniques like the Cobas Taqman, 'blips' frequently observed even in patients with strong adherence... Would the conclusions still have been valid if the authors had performed HIV RNA quantification at the 2 copies/ml level, both in plasma and CSF?

time-bombEven 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...



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.
Key words: CPE rank, CSF, HIV, brain, replication, reservoir
Last Updated on Friday, 19 November 2010 17:05
 

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14.12.2010 (09:53:57)  
Comment on behalf of the authors pt.1 Yes No  

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.

 
   
       
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14.12.2010 (09:56:52)  
Author comments pt. 2 Yes No  

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.

 
   
       
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14.12.2010 (09:57:50)  
author comments pt. 3 Yes No  

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.

 
   
       
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Arvid Edén 14.12.2010 (09:58:54)  
author comments pt. 4 Yes No  

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.

 
   
       
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Arvid Edén 14.12.2010 (10:00:19)  
author comments pt. 5 Yes No  

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.

 
   
       

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