Cerebrospinal Fluid Inhibitory Quotients of Antiretroviral Drugs in HIV ‐ Infected Patients Are Associated With Compartmental

Background. Despite the efficacy of highly active antiretroviral treatment (HAART), a large proportion of human immunodeficiency virus (HIV)‐infected patients may develop moderate neurocognitive impairment. Antiretroviral drug passage into the central nervous system may be relevant for preventing and treating HIV‐associated neurocognitive disorder; nevertheless, clear cerebrospinal fluid (CSF) pharmacodynamic targets are not known. Methods. HAART‐treated adults with wild‐type HIV were prospectively enrolled. CSF concentrations (measured by mass spectrophotometric methods) and inhibitory quotients (CSF concentrations divided by in vitro 50% and 95% inhibitory concentrations) were compared among different drugs and related to CSF HIV RNA levels. CSF escape was defined as CSF HIV RNA >50 copies/mL despite contemporary plasma HIV RNA below that threshold. Results. One hundred twenty‐seven patients (91 male [71.7%], 93 white [73.2%], with a median age of 46 years [interquartile range, 40.5–54.5 years]) provided 174 paired CSF and plasma samples. Twice‐daily darunavir, once‐daily darunavir, and efavirenz had the highest CSF 95% inhibitory quotients (18.5, 8.2, and 6.4, respectively). Higher nadir CD4 cell count (P = .01) and plasma HIV RNA <50 copies/mL (P < .001) were independent predictors of controlled CSF HIV RNA. Optimal drug exposure (CSF detectable drugs and 95% inhibitory quotient >1) was protective for CSF escape (P = .01). Conclusions. Cerebrospinal fluid 95% inhibitory quotients may be used to compare antiretroviral drug compartmental exposure; they deserve longitudinal studies to assess the adequacy of CSF drug concentrations in treated HIV‐infected patients. Human immunodeficiency virus (HIV) replication in the central nervous system (CNS) occurs a few days after patients have been infected: the uncontrolled viral production leads to perivascular macrophages, microglia, and astrocyte infection, thus eventually leading to neuronal damage [1]. The widespread use of highly active antiretroviral treatment has led to a dramatic decrease in HIV‐associated opportunistic diseases including dementia; nevertheless, minor neurocognitive impairments are still highly prevalent [2]. Whereas differential antiretrovirals’ penetration into cerebrospinal fluid (CSF) and CNS has been associated with a reduced probability of compartmental HIV replication, its impact on the course and severity of HIV‐ associated neurocognitive disorder (HAND) is still debated. A large cooperative study by the group has categorized antiretrovirals according to their CNS penetration effectiveness (CPE) score; the higher the score, the lower the risk of detectable HIV RNA in CSF [3, 4]. In any case, comparison of different drugs’ penetration into the CNS is difficult given the high interpatient variability in drug exposure and the lack of standardized target concentrations. In several studies, CSF drug exposure was evaluated by referring to the in vitro 50% inhibitory concentration (IC50); however, the use of IC50 as a reference is still debated due to potential selection of resistant variants (at such concentrations, 50% of virions are still theoretically able to replicate). For this reason, 95% and 99% inhibitory concentrations (IC95 and IC99, respectively) have been suggested as a more appropriate threshold without clinical confirmation. Judging the adequacy of raltegravir CSF exposure, for example, has given conflicting results in 3 different studies; patients' characteristics as well as different target concentrations may explain such discordance [5–7]. Acosta and colleagues recently used a large dataset to validate in vitro inhibitory concentrations of several antiretroviral drugs, thus providing a new and standardized approach to the field [8]. Furthermore, inhibitory quotients have been suggested as an integration of drug exposure and viral susceptibility; they were associated with virological efficacy in protease inhibitor (PI) treatment–naive (plasma concentrations divided by ICs) and treatment‐experienced HIV‐infected patients (plasma concentrations divided by different measures of resistance) [9, 10]. The primary objective of this study was to compare CSF 50% and 95% inhibitory quotients (IQ50 and IQ95, respectively) of several antiretroviral drugs in patients not harboring resistance‐associated mutations. The secondary objective was to investigate relationship between CSF concentrations above the IC50 and IC95 and viral control in the CSF.