Impact of Antiretroviral Therapy on HIV-Related Brain Injury

The report of Lescure et al [1] in this issue clearly documents the decrease in severe neurological disease associated with human immunodeficiency virus (HIV) infection in the era of combination antiretroviral therapy (cART). The authors matched each HIV-infected patient in Denmark by age and sex to 14 HIV-uninfected controls with use of the Danish population registry and compared the incidence of severe neurocognitive disorders (SNCDs) over three 4-year epochs. By the third of these epochs (2005–2008), the incidence of SNCDs among HIV-infected patients had decreased to a level similar to that of the control subjects. This confirms the impression of everyday clinical experience, extends previous reports of the salutary effects of cART on the incidence of the AIDS dementia complex (ADC) [2, 3], and places the magnitude of this therapeutic effect in a population-based perspective. The authors thus show that a nationwide program of treatment using international guidelines–based cART regimens had a profound impact on neurological morbidity. Can we now conclude that beyond treating all HIV-infected individuals early enough in their course to prevent progression of immunosuppression, there is little more that needs to be done to assure protection of the brain from HIVrelated injury? Perhaps. However, before we become complacent, we should address a number of additional questions raised by what we know of antiviral drug pharmacokinetics and by several clinical observations. Indeed, these questions have fostered a growing concern in the Neuro-AIDS community that insufficient attention is being directed to the effects of antiretroviral treatment on central nervous system (CNS) HIV infection and its consequences [4]. It is clear that many antiretroviral drugs do not reach inhibitory concentrations in the CNS, or at least in the cerebrospinal fluid (CSF) that provides a convenient surrogate for brain intracellular fluid in pharmacokinetic studies, although not without certain caveats [5]. Many of the currently favored drugs fail to achieve CSF concentrations shown to be effective in suppressing HIV replication in cell culture, and even those drugs that do penetrate the CNS barriers to drug entry characteristically achieve CSF concentrations considerably lower than those in blood [6]. This limited drug access has led to recommendations that more attention be paid to pharmacological CNS drug penetration, not only in treating symptomatic neurological disease, but more broadly in preventing CNS injury and, thus, perhaps in all patients [4]. To help clinicians address this problem, Letendre et al [6] developed a simplified system, the CNS penetrationeffectiveness rank score. This provides a useful initial guide for clinicians but is also relatively crude, because it is based largely on the pharmacological properties rather than the demonstrated efficacy of the drugs in suppressing CNS infection and its consequences. In fact, it has proven to be difficult to evaluate individual CNS drug efficacy for a number of reasons, including the need to treat with multiple drugs making it difficult to single out the role of individual components, the reluctance of industry to incorporate CSF analysis in the early phases of drug testing when single agents might be used for a brief time, and uncertainty regarding the choice and interpretation of different study end points (eg, CSF HIV concentration, other CSF biomarkers, or neuropsychological test performance). Reports on the effects of the CNS penetration-effectiveness scores on CNS outcomes have been mixed [7–10]. Incorporating this into guidelines for therapy would also entail conflicts with drug toxicity and convenience and, thus, adherence. In their study, Lescure et al [1] did not analyze the effect of different treatment regimens on the incidence of Received 16 September 2010; accepted 17 September 2010. Correspondence: Richard W. Price, MD, Neurology Service, Rm 4M62, San Francisco General Hospital (SFGH), 1001 Potrero Ave, San Francisco, CA 94117 (rwprice@sfgh .ucsf.edu). Clinical Infectious Diseases 2011;52(2):244–247 The Author 2011. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. permissions@oup.com. 1058-4838/2011/522-0001$37.00 DOI: 10.1093/cid/ciq052