HIV-associated neurocognitive disorders, including neuropsychological impairment, minor cognitive motor disorder, and HIV-associated dementia, may significantly reduce the quality of life of individuals living with HIV infection.

Although it is well known that antiretroviral therapy may reduce the incidence of HIV-associated neurocognitive disorders (probably by decreasing HIV replication in the central nervous system (CNS), the prevalence of these disorders has increased, possibly due to the failure of antiretroviral drugs to completely suppress HIV replication in the brain. Ongoing HIV replication may enable adaptation to neural cells, progressive brain injury, and antiretroviral drug resistance.

Drugs that can effectively penetrate the CNS offer the best chance for improvements in individuals with HIV-associated neurocognitive disorders. Unfortunately, many antiretroviral drug regimens may fail in the CNS because an important component of these regimens, protease inhibitors, can bind extensively to plasma proteins. This effect leaves insufficient unbound drug to penetrate into the brain and cerebrospinal fluid (CSF). However, this negative property is balanced by the potency of these drugs, many of which can inhibit HIV replication at nanomolar concentrations.

Lopinavir/ritonavir (Kaletra) is an excellent example of such a drug, according to the authors of the current study, which appears in the September 19, 2007 online edition of Clinical Infectious Diseases. Although up to 99% of lopinavir is bound to plasma proteins, concentrations of the drug in CSF exceed the population median inhibitory concentration for wild-type HIV by greater than 5-fold.

The pharmacokinetics, potency, and high barrier to resistance of lopinavir/ritonavir enable safe administration without other antiretroviral drugs for limited durations, according to the authors, who administered lopinavir/ritonavir to antiretroviral drug-naive individuals for 3 weeks and then added other anti-HIV drugs to the treatment regimen.

The primary objective of the current study was to determine whether lopinavir/ritonavir independently reduced the HIV RNA level in CSF.

This open-label, 24-week study of sequential antiretroviral therapy enrolled 15 patients who received lopinavir/ritonavir monotherapy. Ten subjects reached the primary study endpoint at week 3, before at least 2 other antiretroviral drugs were added to their treatment regimen.

The investigators obtained CSF and blood samples before treatment and after 3, 12, and 24 weeks on therapy.

Results

Because lopinavir/ritonavir penetrates the CNS in therapeutic concentrations and appears to reduce HIV replication in the CNS, the authors theorized, "The drug may benefit subjects who receive a diagnosis of or are at risk for HIV-associated neurocognitive disorders."

Discussion

"Our study is unique, because it was designed to address a problem that many previous studies have not addressed -- identifying the contribution of a single drug to reduction of the HIV in CSF," the authors declared in the discussion of their findings.

Because prior studies initiated all components of a combination regimen at the same time, the contribution of a single drug could not be determined. "By administering a single drug [lopinavir/ritonavir] with a high viral genetic barrier to resistance, our study was able to demonstrate that the study drug alone, not other drugs in the regimen, reduced HIV RNA levels in the CSF," wrote the authors.

Finally, the authors observed, "Lopinavir/ritonavir therapy alone for 3 weeks reduced HIV RNA levels in the CSF of all subjects; in 80% of them, HIV RNA levels were reduced by > 10-fold."

Departments of Medicine, Psychiatry, and Neurosciences, University of California, San Diego, CA; and Abbott Laboratories, Abbott Park, IL.

10/23/07

Reference
S Letendre, G van den Brande, A Hermes, and others. Lopinavir with Ritonavir Reduces the HIV RNA Level in Cerebrospinal Fluid. Clinical Infectious Diseases. October 19, 2007 [Epub ahead of print; scheduled for print publication in the December 1, 2007 issue].