Reports

This report is based on medical evidence presented at sanctioned medical congress, from peer reviewed literature or opinion provided by a qualified healthcare practitioner. The consumption of the information contained within this report is intended for qualified Canadian healthcare practitioners only.

NEW FRONTIERS in MEDICINE HIV/AIDS - 16th Conference on Retroviruses and Opportunistic Infections (CROI)

Montreal, Quebec / February 8-11, 2009

Neurocognitive loss, one of the few complications of HIV infection that did not diminish dramatically with the introduction of combination antiretroviral therapy (CART), is increasing in prevalence, according to a series of recent studies that are documenting this phenomenon and explaining its cause.

CHARTER Results

One of the largest of these studies, called CHARTER (CNS HIV Anti-Retroviral Effects Research), evaluated 1555 HIV- positive patients with comprehensive neuropsychological evaluations at six centres in the US. Those on CART actually had a higher rate of neurocognitive impairment (43% vs. 31%; P<0.01) than those not on ART, but this was attributed to the higher rate of AIDS in the treatment group prior to therapy. However, 45% of the entire cohort and one-third of those on effective therapy without comorbidities, such as head trauma, epilepsy, drug abuse or previous AIDS, had neurocognitive deficits.

“Biological and clinical indicators of HIV disease severity were related to neurocognitive impairment in patients without significant comorbidities; thus, both HIV and comorbidity contribute to cognitive loss in the CART era,” stated Dr. Robert K. Heaton, HIV Neurobiological Research Center, and Professor of Psychiatry, University of California, San Diego (UCSD). He reported that in CHARTER population substudies, HIV was detectable by standard assays in the cerebrospinal fluid (CSF) of 34% of patients and by ultra-sensitive assays (>2 copies RNA/mL) in 41%. Almost 5% of patients had higher CSF viral loads than peripheral plasma viral loads. Worse viral loads in the CSF were associated with greater cognitive loss.

CSF and Plasma Viral Loads

The disparity between plasma and CSF viral loads is an important finding. It has long been known that ARTs are not equally effective at crossing the blood-brain barrier (BBB), but new evidence indicates that the degree of CSF penetration is correlated with better neuropsychological performance. In a study led and recently published by Dr. Scott Letendre, co-author of the CHARTER study and Assistant Professor of Infectious Diseases, UCSD, CART with a high CNS Penetration Efficacy (CPE) score reduced the likelihood of having a detectable viral load in the CSF by 88% relative to CART with a low CPE score (Letendre et al. Arch Neurol 2008;65:65-70).

“CART that better penetrates the BBB is associated with greater reductions of HIV in the CSF and greater improvements in neuropsychological performance. An actively enrolling, randomized clinical trial of CNS-targeted therapy may provide the evidence necessary to amend international treatment guidelines,” Dr. Letendre told delegates.

CSF Drug Penetrations

The CPE scores in this and subsequent studies were generated by considering each agent in the regimen according to a rating system that not only incorporates variables that effect BBB penetration, such as protein binding, lipophilicity and ionization, but also CSF drug concentrations and clinical evidence of viral suppression in the CSF. Within this three-tier rating system, ARTs are identified as having low, intermediate or high penetration.

Drugs differ markedly within classes. Among nucleoside reverse transcriptase inhibitors (NRTIs), the two agents with the highest penetration are abacavir (ABC) and zidovudine (AZT). The NRTIs with the lowest are tenofovir, didanosine and zalcitabine. Emtricitabine, lamivudine and stavudine are associated with intermediate penetration. Of the commonly used non-NRTIs (NNRTIs), efavirenz has intermediate penetration and nevirapine has high penetration. Of the protease inhibitors (PIs), atazanavir with or without ritonavir (RTV) has intermediate penetration. When boosted with RTV, lopinavir, amprenavir and indinavir all reach high penetration. Most of the remaining PIs have low penetration.

“Treatment of HIV-associated neurocognitive disorders should be focused on optimizing BBB penetration,” Dr. Letendre maintained. Although he, like many experts, emphasized that plasma viral suppression remains the primary goal even in individuals who already have signs of neurocognitive impairment, otherwise effective regimens with a high CPE, such as an NRTI combination of ABC/AZT with a PI that also has good BBB penetration has important implications for long-term outcome. He remarked, “Even mild HIV-associated neurocognitive disorder is associated with worse antiretroviral adherence and shorter survival.”

Corroborative Findings

In a CHARTER substudy of 300 patients who were taking CART, 41% had detectable HIV in the CSF. Again, the risk of detectable HIV in the CSF was more common in patients taking a regimen with a low CPE. Dr. Letendre also reported that 26% of those with detectable HIV in the CSF did not have detectable HIV in the plasma and these patients also had significant cognitive deficits. Moreover, he suggested that the risk of neurocognitive deficits might occur at levels of HIV replication in the CSF that is lower than the 50 copies/mL goal for control of HIV in the plasma.

Investigators noted that the persistence of neurocognitive impairment after the introduction of CART was a surprise. Although initially attributed to irreversible deficits acquired before CART was available, rates of neurocognitive impairments have been increasing. Although comorbidities such as head injuries and drug abuse are likely contributors to the far higher rates of neurocognitive dysfunction in individuals with HIV when compared to age-matched controls, HIV is suspected of both direct neurotoxicity and indirect neurological damage mediated by the inflammation in the CNS. In a newly completed neuroimaging study of more than 200 HIV patients and 28 HIV negative controls, diffuse inflammatory changes were observed even in those HIV patients without detectable neurological impairment.

“HIV patients show patterns of brain injury in chronic and stable disease that mirror those previously described in the pre-HAART era,” stated Dr. Bradford Navia, Associate Professor of Neurology, Tufts University, Boston, Massachusetts. However, in those with neurocognitive deficits, the inflammatory changes were accompanied with distinct neuronal injury primarily in the basal ganglia. These data support the theory that persistent infection and inflammation are involved in the pathophysiology of HIV-associated neurocognitive deficiency with growing risk of this deficiency over an increasing period of uncontrolled infection.

These data are already leading some experts in this field to recommend changes in treatment strategy. One of the fundamental steps, according to Dr. Letendre, is to screen all HIV-infected patients for neurocognitive function. He cautioned that early signs of neurocognitive loss can be subtle and recommends the use of brief but formal screening tools.

“Do not just ask the patient, ‘how is your memory,’” Dr. Letendre told delegates. He noted that there are now several validated questionnaires, many of which are brief and self- administered. While these questionnaires can identify patients who are candidates for more comprehensive evaluation, they also provide a baseline with which to follow neurocognitive function over time.

In patients with neurocognitive loss, altering the regimen to include drugs with a high BBB penetration may be a reasonable step, but several investigators questioned whether it may be important to select a CART with a high CPE early in the course of disease due to the likelihood that at least some neurocognitive loss is irreversible. Dr. Heaton specifically questioned whether CNS damage is an early phenomenon that would be best treated by prophylaxis. He added that studies to address this question would be warranted.

Summary

The persistence of neurocognitive loss in HIV patients in the era of CART is being recognized as a major health threat in an aging HIV-infected population. In Canada, where it is estimated that more than half of all HIV/AIDS patients will be older than age 50 by the year 2015, strategies to prevent neurocognitive loss may constitute an important part of preserving long-term quality of life. Selecting therapies with good penetration of the BBB has been associated with improved HIV control in the CSF and may play a critical role in addressing the rising prevalence of HIV-associated neurocognitive impairments.