Central nervous system antiretroviral efficacy in HIV infection: a qualitative and quantitative review and implications for future research

Abstract

BackgroundThere is conflicting information as to whether antiretroviral drugs with better central nervous system (CNS) penetration (neuroHAART) assist in improving neurocognitive function and suppressing cerebrospinal fluid (CSF) HIV RNA. The current review aims to better synthesise existing literature by using an innovative two-phase review approach (qualitative and quantitative) to overcome methodological differences between studies.MethodsSixteen studies, all observational, were identified using a standard citation search. They fulfilled the following inclusion criteria: conducted in the HAART era; sample size > 10; treatment effect involved more than one antiretroviral and none had a retrospective design. The qualitative phase of review of these studies consisted of (i) a blind assessment rating studies on features such as sample size, statistical methods and definitions of neuroHAART, and (ii) a non-blind assessment of the sensitivity of the neuropsychological methods to HIV-associated neurocognitive disorder (HAND). During quantitative evaluation we assessed the statistical power of studies, which achieved a high rating in the qualitative analysis. The objective of the power analysis was to determine the studies ability to assess their proposed research aims.ResultsAfter studies with at least three limitations were excluded in the qualitative phase, six studies remained. All six found a positive effect of neuroHAART on neurocognitive function or CSF HIV suppression. Of these six studies, only two had statistical power of at least 80%.ConclusionsStudies assessed as using more rigorous methods found that neuroHAART was effective in improving neurocognitive function and decreasing CSF viral load, but only two of those studies were adequately statistically powered. Because all of these studies were observational, they represent a less compelling evidence base than randomised control trials for assessing treatment effect. Therefore, large randomised trials are needed to determine the robustness of any neuroHAART effect. However, such trials must be longitudinal, include the full spectrum of HAND, ideally carefully control for co-morbidities, and be based on optimal neuropsychology methods.

Pharmacokinetics and Pharmacodynamics of Antiretrovirals in the Central Nervous System

“…[180] A very interesting study (randomized and controlled) was conducted by Ellis and coll. but unfortunately it was prematurely interrupted for slow accrual (326 patients screened and 59 enrolled): CNS-targeted HAART was not associated with either virological nor neurocognitive improvements although in patients with baseline suppressed viral load a trend for improved cognitive performances over time was observed.…”

Randomized Trial of Central Nervous System–Targeted Antiretrovirals for HIV-Associated Neurocognitive Disorder

“…Observational studies have yielded mixed results, some suggesting greater benefits with higher CPE, others not [6]. In a recent review [7], more rigorously designed studies with greater power were more likely to demonstrate benefits, a view supported by expert opinion [8]. However, inconsistent reports and competing toxicity considerations lead to clinical equipoise, mandating a randomized trial.…”

Update and New Directions in Therapeutics for Neurological Complications of HIV Infections

“…Since macrophages are the primary cellular targets of HIV in the brain, inadequate control of HIV in these cells may be needed to treat HAND [4]. Because excellent reviews of CNS penetration and macrophage efficacy recently been published [15,32,50], no further consideration of them will be given here.…”