<i>Editorial Commentary</i>: Neurocognitive Performance in Ritonavir-boosted Protease Inhibitor Monotherapy

(See the HIV/AIDS Major Article by Arenas-Pinto et al on pages 257–64.) Since the introduction of combination antiretroviral therapy (cART), the incidence of severe neurocognitive impairment has declined significantly, whereas the prevalence of the milder forms has increased. Up to 50% of people living with human immunodeficiency virus (HIV) experience milder forms of HIV-associated neurocognitive disorder (HAND) [1–3], which can significantly impact quality of life [4] and daily functioning, interfering with work place performance [5], ability to carry out tasks independently, and ability to manage medication [1, 6]. Neurocognitive impairment has been associated with greater mortality risk [7] and worse adherence to cART; the latter is particularly concerning, as it can lead to drug resistance and worse disease outcomes [8]. One possible explanation for persistent cognitive impairment in the cART era is that injury to the nervous system may be accrued during the very early stages of infection, before initiation of antiretroviral treatment [3]. An ongoing question of particular interest is whether cART regimes can improve neuropsychological (NP) performance and improve cognition. These questions have been addressed in several studies [1, 9–11], and some regimes have been shown to be more effective in decreasing viral replication in the central nervous system (CNS) and improving cognition [12]. Shortly after a person is infected with HIV, the virus can enter the CNS [13]. The neurocognitive impairments experienced with HAND are predominately “subcortical,” such as problems with learning efficiency, attention, processing speed, and motor skills [4], although recent data suggest that cortical problems, specifically executive impairments, are increasing [14]. Cognitive symptoms such as difficulty with concentration, word-finding, motor skills, and memory impairment are also common, particularly in persons who are depressed or have symptoms of fatigue [4]. Because several cART drugs distribute poorly into the CNS, one theory for the persistently high prevalence of HAND is that HIV in the CNS is incompletely treated. To compare the efficacy of different antiretroviral regimens in the CNS, a method for estimating cART effectiveness in the CNS, the CNS Penetration-Effectiveness (CPE) method was developed [15]. The studies demonstrated that higher CPE values correlated with undetectable cerebrospinal fluid (CSF) viral loads [15], suggesting that estimating cART effectiveness in the CNS may inform selection of cART regimens to better control HIV in the CNS and reduce HIV-related brain injury. A review on this topic found that the majority of published studies reported an association between regimens with higher CPE and either decreased CSF viral load or improved neurocognitive outcomes [16, 17]. In this issue of Clinical Infectious Diseases, Arenas-Pinto and colleagues describe a study that used data from the PIVOT Trial [18]. PIVOT is a UK-based randomized controlled trial of a strategy of switching to boosted protease inhibitors (PIs) infected patients who have achieved sustained virological suppression on cART. Results from this study found no evidence of accelerated neurocognitive decline in those individuals on PI monotherapy compared to those on cART over 3–5 years of follow-up [19]. The results of the substudy presented by Arenas-Pinto in the current issue looked deeper in the data of NP tests and neuroimaging. Interestingly, this study may add one more layer in this complex aspect of the HIV care already very controversial. The idea to use monotherapy is not new, and some prospective studies demonstrated the positive effect of monotherapy on NP functions [20–22]. However, because these studies are pre-cART era, improvement was transient, possibly due to drug resistance [20, 21], and the positive impact was more prominent in AIDS patients [22]. In 2001, Arendt et al [23] investigated the effect of AZT or didanosine monotherapy vs dual-therapy AZT in combination with either zalcitabine, lamivudine, or stavudine. The study showed improvement in individuals treated with monotherapy, but no additive effect of dual-therapy was found [23]. Several methodological issues can be delineated in the studies described above. Some studies were conducted with small samples, treatment effect was tested at various intervals, and variations in the batteries make cross-study comparisons difficult. Only one study used a validated NP methodology [21]. The methodology used by Arena-Pinto et al has several strengths, starting with the study design; contrary to several historical cross-sectional studies, this is a randomized parallel-group multisite prospective study. Second, the study population consisted of 219 participants with an average of 15 years of formal education and substantial rates of self-reported anxiety/depression, alcohol and recreational drug use. Several studies in this topic have excluded individuals with psychiatric comorbidities, which make the highly selected individuals not generalizable to the population seen in clinical practice. Lastly, it is important to mention the neurocognitive battery used. According to the updated nosology for HAND published in 2007 by Antinori et al [24], individuals are classified with neurocognitive impairment if they have NP decline in at least 2 cognitive domains: verbal/language, working memory, abstract/executive function, memory, speed processing, sensory/perceptual and motor skills. The cognitive impairment should also interfere with everyday functioning (this criteria is not required for asymptomatic neurocognitive disorder). Accordingly, Arenas-Pinto's study complied with the recommendation because they used a testing battery that assessed 6 cognitive domains: attention, psychomotor speed, executive functioning, fine motor skills, verbal and nonverbal learning, and memory. In 2013, the Mind Exchange Working Group sought to identify and develop practical answers to key clinical questions in HAND management and published in this Journal recommendations to provide guidance to daily clinical practice [25]. These recommendations suggested that NP testing should include a battery of at least 5 cognitive domains including verbal/language, attention/working memory, abstraction/executive function, learning/recall, speed of information processing, and motor skills, using standard and validated instruments for detection of HAND. Once again, Arenas-Pinto met this criteria. An important issue to be commented is regarding the association between CPE and NP ability domains. Individuals in the study prior to the randomization were effectively suppressed (viral load <50 copies/mL) on 2 nucleoside reverse transcriptase inhibitors (NRTIs) and one non-NRTI or PI. At the entry of the study, they were assigned either to maintain ongoing therapy or to switch to PI-monotherapy. Drugs used prior to randomization had an average of CPE of 7, and those receiving PI-monotherapy (recommended was either ritonavir-boosted lopinavir or ritonavir-boosted darunavir) would then be receiving drugs with CPE of 3. What could be the impact of this drop in the availability of drugs to reduce the viral replication in CNS? Our group recently published a study in which we found that NP impairment ranged from 68% among individuals with the lowest CPE (CPE = 5) to 39% among in those with the highest CPE score (CPE = 9) [1]. Contrarily to Arenas-Pinto et al, our study had a cross-sectional design and perhaps it explains some of our findings. The present study had an average of 3.8 years of follow-up time and consistently with other long-term follow-up studies where cART is associated with stable NP functions over long-term as long as the plasma viral load remains undetectable and the patient is clinically stable over time [26]. Interestingly, the proportion of participants of Arenas-Pinto et al's study that met the criteria of cognitive impairment at end point was much lower (15.8%) than the study entry (45%). All participants were free of previous episodes of virological failure, which clearly decreases the chances of legacy effect where individuals will maintain a high chance to develop CNS escape. The authors conclude that PI-monotherapy does not carry an increased risk of CNS damage and could give confidence to patients and providers who wish to use it as a therapeutic option for long-term management of HIV infection. This is clearly a valid point when we think about HIV as a chronic disease with life-long commitment and where adherence to medications is key. In sum, understanding CNS injury in HIV infection requires an appreciation of some of the complexities of disease progression and its treatment. Nevertheless, neurocognitive impairment remains quite prevalent and is associated with reduced quality of life. Because HIV has become a chronic, manageable disease, simpler alternatives for treatment are always welcome. Such efforts should be critical direction for future research. Potential conflict of interest. Author certifies no potential conflicts of interest. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

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