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Background:  Combination antiretroviral (ARV) therapy reduces HIV RNA levels in cerebrospinal fluid (CSF) and the incidence of HIV-associated dementia (HAD). Despite this, the prevalence of HAD is rising, possibly because ARV fail to completely suppress HIV in the brain. ARV may fail because an important component of many regimens, protease inhibitors (PI), extensively bind to plasma proteins, leaving little unbound drug to penetrate into the brain and CSF. However, these drugs are so potent that even low concentrations may inhibit HIV replication. The primary objective of this study was to determine whether a PI, kaletra (LPV/r), reduces HIV RNA levels in CSF when used by itself.

Methods:  The study was an open-label, 24-week trial of sequential ARV therapy in which 16 ARV-naive subjects underwent screening, which included measurement of HIV RNA in CSF and plasma (RT-PCR) and HIV resistance in plasma (ViroLogic). Of the 16 subjects, 12 were enrolled and were started on LPV/r alone for 3 weeks. At least 2 other ARV were then added to complete 24 weeks. CSF was obtained again at weeks 3, 12, and 24. Data were analyzed using parametric and non-parametric tests, depending on data characteristics. All HIV RNA levels are in log₁₀ copies/mL.

Results:  At baseline, subjects had median CD4 counts of 188/µL and median HIV RNA levels of 3.5 in CSF and 5.4 in plasma. Phenotype testing indicated the lack of resistance to all study drugs. To date, 9 subjects have completed the week 3 visit, the primary study endpoint; 2 subjects withdrew (1 back pain, 1 non-adherence) and 1 is actively enrolled. At 3 weeks, LPV/r reduced HIV RNA levels in CSF (median 1.0, IQR 0.5 to 1.5, p = 0.008) and in plasma (median 1.6, IQR 1.4 to 2.1, p = 0.008). LPV/r reduced HIV RNA less in CSF than in plasma (paired t-test, p = 0.03) and reductions in CSF and plasma did not significantly correlate (r = 0.61, p = 0.14). In those who completed 12 weeks (n = 6 to date), HIV RNA was suppressed below detection in the CSF of 5 and in the plasma of 4. By week 24 (n = 3 to date), HIV RNA was suppressed below detection in both fluids of all subjects.

Conclusions:  This study is novel because it used sequential introduction of ARV to determine whether a highly protein-bound PI can reduce HIV replication in the central nervous system. LPV/r alone reduced HIV RNA in CSF after just 3 weeks, proving that it contributes to control of HIV replication in the brain when used in combination with other ARV and suggesting that it may benefit patients diagnosed with or at risk for HAD.

Keywords: Lopinavir; Cerebrospinal Fluid; HIV RNA