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Comment on “Higher CNS Penetration-Effectiveness of Long-Term Combination Antiretroviral Therapy is Associated With Better HIV-1 Viral Suppression in Cerebrospinal Fluid”

Calcagno, Andrea; D'Avolio, Antonio; Di Perri, Giovanni; Bonora, Stefano

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 1st, 2013 - Volume 62 - Issue 4 - p e118–e119
doi: 10.1097/QAI.0b013e3182809d9f
Letters to the Editor

Unit of Infectious Diseases, Department of Medical Sciences, University of Torino, Torino, Italy

The authors have no funding or conflicts of interest to disclose.

To the Editors:

We read with great interest the article by Cusini et al1 addressing the factors associated with cerebrospinal fluid (CSF) viral escape in HIV-positive patients. Although the results are interesting, some points worth further discussion.

First, some issues concerning CSF penetration effectiveness (CPE) differences should be highlighted. Patient 1 has a CPE score (according to the 2 scoring system) of 1.5 and 7 and not 1 and 6 as erroneously reported in table 3 of the article. This will increase the median CPE in the CSF-escapers group to 1.25 and 6.5, respectively, requiring new assessment of statistical significance. Additionally, in table 4 of the article, the 95% confidence interval for CPE in the CSF-detectable group should be 6–7. Furthermore, in figure 1, it seems that 25% of patients with controlled CSF viral replication have a CPE score less than 7; patients with 2010 CPE score ranging from 6 to 7 (such as recommended first-line regimens) cannot be consequently considered at increased risk of less control in the central nervous compartment.

Regarding the drug concentrations measured in the CSF, extrapolation of trough levels by relying on plasma pharmacokinetic (PK) parameters does not seem to be correct. Even if such an approach could be applied to plasma exposure, the time–concentration profile of each drug over the dosing interval in the cerebrospinal compartment is not known, not being necessarily parallel to the one in plasma. The available data on drug penetration into the CSF suggest that multiple transporters could be involved in such a process2; furthermore, the 24-hour profile could be different from the one obtained in the plasma compartment with somehow more stable concentrations over time.3 Just as an example of dramatically different patterns of drug exposure throughout the dosing interval in a compartment as compared with plasma, we previously reported the case of raltegravir in the seminal plasma.4 Data on CSF concentrations are mainly based on limited sample sizes, and PK estimates are not derived from population PK models (with the exception of abacavir).5 Therefore, it is not clear how trough CSF levels have been extrapolated in this article.

Finally, we would like to highlight that all patients in this study had a single detectable CSF viral load with no confirmation in a subsequent lumbar puncture (performed in 50% of subjects). This finding could be potentially attributed to a CSF viral blip and not necessarily to a virological failure associated with neurological symptoms worsening. In a recent longitudinal study, in fact, CSF viral loads above 50 copies/mL were frequent (25% of neurologically stable patients on effective antiretroviral therapy) but they were not associated to neurocognitive complaints nor subsequent treatment failures.6

The clinical meaning of incomplete control of viral replication in CSF and the evaluation of its determinants warrant further investigation in longitudinal clinical studies.

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1. Cusini A, Vernazza P, Yerly S, et al.. Higher CNS Penetration-Effectiveness of long-term combination antiretroviral therapy is associated with better HIV-1 viral suppression in cerebrospinal fluid. J Acquir Immune Defic Syndr. 2013;62:28–35.
2. Calcagno A, Yilmaz A, Cusato J, et al.. Determinants of darunavir cerebrospinal fluid concentrations: impact of once-daily dosing and pharmacogenetics. AIDS. 2012;26:1529–1533.
3. Yilmaz A, Price RW, Gisslén M. Antiretroviral drug treatment of CNS HIV-1 infection. J Antimicrob Chemother. 2012;67:299–311.
4. Calcagno A, Bonora S, D'Avolio A, et al.. Raltegravir penetration in seminal plasma of healthy volunteers. Antimicrob Agents Chemother. 2010;54:2744–2745.
5. Capparelli EV, Letendre SL, Ellis RJ, et al.. Population pharmacokinetics of abacavir in plasma and cerebrospinal fluid. Antimicrob Agents Chemother. 2005;49:2504–2506.
6. Edén A, Hagberg L, Svennerholm B, et al.. Longitudinal follow up of detectable HIV 1 RNA in cerebrospinal fluid in subjects on suppressive antiretroviral therapy. Paper presented at: 19th Conference on Retroviruses and Opportunistic Infections [P488]; March 5-8, 2012; Seattle, Washington.
© 2013 Lippincott Williams & Wilkins, Inc.