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Response to Calcagno Comment on “Higher CNS Penetration-Effectiveness of Long-term Combination Antiretroviral Therapy Is Associated With Better HIV-1 Viral Suppression in Cerebrospinal Fluid”

Cusini, Alexia*,†; Ledergerber, Bruno*; Widmer, Nicolas; Günthard, Huldrych F.*

JAIDS Journal of Acquired Immune Deficiency Syndromes: October 1st, 2013 - Volume 64 - Issue 2 - p e14–e15
doi: 10.1097/QAI.0b013e3182a82281
Letters to the Editor

*Division of Infectious Diseases and Hospital Epidemiology, University Hospital Zurich, University of Zurich, Zurich, Switzerland

Department of Infectious Diseases, University Hospital Bern, Bern, Switzerland

Division of Clinical Pharmacology, University Hospital Centre and University of Lausanne, Lausanne, Switzerland.

Supported in the framework of the Swiss HIV Cohort Study, by the Swiss National Science Foundation Grants 33CS30-134277 and 3247B0-114006.

A. C. has received travel grant and meeting expenses from Abbott, Merck Sharp & Dohme, Bristol Myers Squibb and Gilead. B. L. has been a board member of Janssen Cilag and was paid for consultancy by Gilead. H. F. G. received grants from the Swiss National Science Foundation and has been active as adviser and/or consultant for the following companies: GlaxoSmithKline, ViiV Healthcare, Abbott, Novartis, Boehringer Ingelheim, Roche, Tibotec, and Bristol-Myers Squibb. H. F. G. has received unrestricted research and educational grants from Roche, Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Tibotec, and Merck Sharp & Dohme (all money to H. F. G. went to institution). N. W. has no conflicts of interest to disclose.

To the Editors:

We thank Calcagno et al1 for their thoughtful comments about our article addressing the effectiveness of antiretroviral treatment in suppressing HIV-1 in cerebrospinal fluid (CSF).2 We particularly thank them for pointing out the wrong central nervous system penetration effectiveness (CPE) score of patient 1 in Table 4 that should be 1/7 not 1/6 and that in Table 5, where the median CPE rank 2010 of the treatment regimens with a detectable viral load in CSF should be 6 with a range of 6–7 not with a range of 6–8.

The repeated statistical analysis with the corrected score of 7 in patient 1 yields a new odds ratio of 0.37 per unit higher (95% confidence interval: 0.22 to 0.61) instead of 0.38 (95% confidence interval: 0.17 to 0.87) and a P value of 0.032 instead of 0.022 maintaining significance (last line of Table 5). Therefore, we confirm our statement that in our series analyzing 87 CSF, the patients taking a treatment regimen with a higher CPE rank had a better suppression of HIV-1 in CSF.

In the absence of formal pharmacokinetic (PK) data on drug elimination in CSF, the extrapolation of the trough levels (Cmin) were based on mean terminal t1/2 in plasma which represented the only surrogate available under the assumption of an instantaneous equilibrium between plasma and CSF. The plasma elimination t1/2 considered were all established in population pharmacokinetic models developed on the basis of a systematic review of published literature.3 The reported values are thus to be considered as an order of magnitude, rather than as precise values, and we advocate for further evaluation of the PK behavior of antiretroviral therapy in CSF.

We agree that the increased low-level viral loads may potentially be attributed to viral blips in CSF and not necessarily to virological failure because no detectable viral loads could be confirmed in a second lumbar puncture. We finally fully support the statement of Calcango et al that incomplete control of viral replication in CSF warrants further evaluation in longitudinal studies.

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1. Calcagno A, D'Avolio A, Di Perri G, et al.. Comment on “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:e118–e119.
2. 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.
3. Arab-Alameddine M, Buclin T, Guidi M, et al.. Pragmatic approach for interpreting antiretroviral drug concentrations based on a systematic review of population pharmacokinetic studies. Abstracts of the Annual Meeting of the Population Approach Group in Europe. 2012;21:202.
© 2013 by Lippincott Williams & Wilkins