Cognitive Health in Persons With Human Immunodeficiency Virus: The Impact of Early Treatment, Comorbidities, and Aging

With the advent of virally suppressive antiretroviral therapy (ART), life expectancy for persons with human immunodeficiency virus (HIV) with access to ART now approaches that of the general population. As persons with HIV age, noninfectious comorbidities occur more frequently compared with persons without HIV. Such comorbidities are likely to affect cognitive health, which may also be affected by lifestyle factors that may differ in persons with HIV. At the National Institutes of Health–supported meeting on Biotypes of Central Nervous System (CNS) Complications in persons with HIV, a session was devoted to early HIV treatment, noninfectious comorbidities, and aging as each pertains to cognitive health. Areas of consideration included acute and early HIV infection (presentation by Phillip Chan), drugs of abuse (Scott Letendre), stroke and cerebrovascular disease (Felicia Chow), mental health (John Joska), and aging (Julian Falutz). These presentations were followed by a discussion session led by Woody Lin, Jose A. Muñoz-Moreno, Paola Cinque, and Jeff Taylor. Alan Winston and Bruce Brew chaired the meeting with Jasmini Alagaratnam and Htein Linn Aung acting as rapporteurs. Here we present the main topics covered in the presentations, and the associated discussions highlighting knowledge gaps and future directions. Cognitive disorders remain prevalent among persons with HIV with viral suppression in the ART era. It is well described that a longer duration of untreated HIV, lower nadir CD4+ T-lymphocyte count, and previous AIDS-defining illnesses are associated with cognitive impairment in persons with HIV [1]. The time of onset of CNS injury following HIV acquisition and its reversibility after early initiation of ART remain unclear. The extent to which early ART protects the CNS remains a major question in the field [2, 3]. Recent studies assessing the CNS impact of acute HIV infection (AHI) [4] or primary HIV infection (PHI, here defined as the first 12 months following HIV infection) have provided insight into some of these questions. The RV254 Thai AHI cohort characterizes the very earliest effects of HIV on the CNS. HIV RNA is detectable in the cerebrospinal fluid (CSF) within days of HIV acquisition, with more than 90% of individuals having detectable CSF HIV RNA by the end of AHI [5]. Although slowed hand movements [6], peripheral neuropathy [6], depressed mood [7, 8], impaired cognition [9] and elevated CSF inflammatory and immune activation markers [10] are common during untreated AHI, the timing of CNS HIV compartmentalization and onset of neuronal damage remain elusive. Recent work suggests that these events may occur as early as the first year of HIV infection. CSF neurofilament light chain protein, a biomarker of axonal injury, is elevated in up to 40% (PHI) and 75% (chronic HIV infection) of individuals, but rarely during AHI [11, 12]. Evidence of compartmentalized HIV replication within the CSF was demonstrated in up to 30% of individuals during PHI [13–15]. Conversely, a recent deep sequencing study revealed that only a limited number of persons with AHI had evidence of compartmentalized HIV in CSF, exclusively among those who acquired multiple transmitted or founder (T/F) viruses [16]. While evidence supporting HIV compartmentalization and neuronal injury during AHI is lacking, initiation of ART during AHI points toward favorable neurological outcomes [10, 11, 17, 18]. The frequency of CSF viral escape was 1% in RV254 participants who commenced ART during AHI [18], compared with up to 5%–10% in individuals who commenced ART during chronic infection. Additionally, the cognitive test performance and mood symptoms of RV254 cohort participants improved with immediate ART and remained stable up to 288 weeks of follow-up [17]. RV254 participants also normalized inflammatory and immune activation biomarkers in CSF but not in plasma after 96 weeks of ART [10]. Biomarker studies focusing on later time points are needed to determine the long-term benefit of early ART in the CNS. To date, the cohorts investigating early HIV infection on the CNS have predominantly enrolled young men and therefore results may not generalize to other populations with differing demographic factors and comorbidities, including age, sex, coinfections, infection with multiple T/F viruses, and substance use, each of which may alter the degree of HIV transmigration between blood and CSF. Furthermore, cohorts assessing the early effects of HIV on the brain have been undertaken in settings with the infrastructure to identify early HIV infection; this may not be achievable in all healthcare settings. There are differences in compartmentalization and degree of neuroinvasion of HIV into the CNS, though the factors that drive such differences are unclear. Similarly, the reasons for higher CD4/CD8 ratios and larger differences between plasma and CSF HIV RNA in people with AHI need further study. Given that macrophage activation markers are strongly associated with cognitive decline, it would be important to investigate whether these markers normalize in the blood compartment over the longer term (>10 years of follow-up) and whether associations with cognitive impairment persist. In people who initiated early ART, cognitive function remains stable, though whether this remains true in the longer term requires longer follow-up. Participants with the poorest cognitive performance at baseline had the greatest improvements over 6 years of follow-up. This is in contrast with what is seen in people with chronic HIV infection, who are at higher risk of further deterioration in cognitive function [19, 20]. The prevalence of HIV infection is high in people who inject addictive drugs. A systematic review estimated that the prevalence of HIV among people who inject drugs globally is 17.8% (10.8%–24.8%) [21]. Drug use is also common among people with HIV; for instance, the United States (US) Centers for Disease Control and Prevention reported that about 12% of persons with HIV have ever injected an addictive drug [22] and about 40% have used a noninjection drug in the past 12 months in the US [23]. HIV infection and drug use have synergistic effects on the CNS [24, 25]. For example, both HIV infection and drug use alter dopamine uptake and release by dysregulating the dopamine transporter and subsequently lead to increased extracellular dopamine level in the CNS [26]. This, in turn, could have adverse effects because extracellular dopamine can affect lymphoid, myeloid, and glial cell function [26]. For example, dopamine can increase the migration of CD14+CD16+ monocytes across blood-brain barrier models, which is important as in people with HIV, these cells harbor higher HIV DNA content and have been linked to cognitive impairment [27, 28]. HIV infection and drug use also affect the vascular system, which may manifest as white matter abnormalities in the brain. A recent study reported that both HIV infection and methamphetamine use increased fractional anisotropy in diffuse tensor imaging, which reflects disruption of white matter tracts and is associated with poorer cognitive outcome [29]. The combined effects of HIV infection and drug use on cerebral blood flow and functional blood flow are also evident [30]. Understanding the effects of different patterns of addictive drugs on the brain is important. Drug use pattern can vary based on sites, regions, and countries; the use of standardized data collection across studies will allow assessment of geographical variation of drug use, along with additional information, such as the route, quantity (both current and over the lifetime), and age of first drug use. Syndemic social and structural factors should also be considered when managing drug use and HIV. Poor socioeconomic status and childhood adversity often coexist with drug use and also have an adverse impact on engagement in healthcare [31, 32]. Thus, data on social and structural factors, along with drug use patterns, are important. Genetic and epigenetic factors also play a role in how HIV and addictive drug use affect the CNS. For instance, the effects of methamphetamine on cognition may differ based on genotypic variation in catechol-O-methyltransferase (which is involved in the metabolism of dopamine and other neurotransmitters) [33] and cytochrome P450-2D6 enzyme, which metabolizes methamphetamine [34]. A postmortem study of brain tissues reported the synergistic effects of HIV and drug use on the increase in global DNA methylation, which is associated with neuropsychiatric disorders [35]. Interventions that could address these epigenetic changes may decrease the legacy effects of drug use. The concept of molecular networks, which identifies HIV transmission networks through viral genetics, also require consideration [36]. These transmission networks can be mapped geographically, to examine where transmissions occur, where they are concentrated, how networks interact with each other, and where high-transmission events occur [37]. Using this information, targeted interventions could be provided to “high transmitters” to encourage drug use cessation and use of safer practices [38]. Clinical trials of new drugs to treat drug dependency (eg, naltrexone or bupropion for methamphetamine dependence) have had encouraging results and could be used in these interventions [39]. Other factors to consider include the stressful effects of drug use withdrawal on HIV disease and mental health, and the nonlinear effects of some drugs on the brain. For example, even though heavy use of cannabis is detrimental, mild to moderate use may be beneficial in persons with HIV, possibly related to the anti-inflammatory effects of cannabis counterbalancing the adverse effects of chronic dopaminergic stimulation [40, 41]. Key gaps exist in multiple areas of how drug use affects CNS biotypes. As summarized in NIH RFA-DA-22-040 (https://grants.nih.gov/grants/guide/rfa-files/RFA-DA-22-040.html) and other sources, these can be categorized as those that relate to (1) cognition, psychiatry, and behavior; (2) pathogenesis; (3) prevention and therapeutics; and (4) modeling. With regard to cognition, psychiatry, and behavior, key gaps include (1) identifying the influence of psychiatric comorbidities on drug use/effects in persons with HIV and (2) determining strategies and interventions to reduce stigma and address social and structural issues that affect persons with HIV. With regard to pathogenesis, key gaps include identifying (1) the influence of infectious diseases on prevention and treatment of drug use disorders in persons with HIV and (2) the influence of drug use on the molecular mechanisms of HIV latency in the CNS. Examples of key gaps in prevention and therapeutics include developing and testing (1) methods to deliver HIV and drug use therapeutics to persons with HIV and (2) approaches to achieve sustained ART-free remission among persons who use drugs and who experience ART interruptions and delays, and relapse in drug use. Continuing work in modeling of HIV and drug use includes using spatial genomics and other state-of-the art strategies to address questions at the intersection of HIV and drug use disorders. Both large vessel stroke and cerebral small vessel disease (CSVD) contribute to vascular cognitive impairment. The prevalence of stroke is higher among persons with HIV than the general population [42]. A meta-analysis of prospective observational studies reported that the risk of ischemic stroke and hemorrhagic stroke are 1.3 times and 2.2 times higher among persons with HIV than persons without HIV [43]. Furthermore, in high-HIV-prevalence areas of the world, HIV is a primary risk factor for stroke. In a study conducted in Malawi, HIV infection was the second leading risk factor for stroke after hypertension [44]. Despite the robust evidence of a higher burden of stroke among persons with HIV than persons without HIV, findings from previous studies on the risk for CSVD among persons with HIV are mixed. Several studies have demonstrated a higher risk of CSVD, measured by the burden of white matter hyperintensities (WMH), among persons with HIV. One study found the risk of CSVD was 2.3-fold higher among 456 treated persons with HIV under viral suppression compared with 154 persons without HIV [45]. In another study, 203 treated persons with HIV (viral load <200 copies/mL) had a 3.7-fold greater risk of WMH than 58 persons without HIV [46]. However, not all studies have identified a higher burden of CSVD in persons with HIV [47]. For instance, a study conducted among 119 treated and virally suppressed persons with HIV and 55 persons without HIV reported no difference in WMHs between the groups [48]. Several factors may explain these disparate findings, including differences in the age and sex distribution of participants, the degree of viral suppression of persons with HIV, and the quality of matching of persons with HIV and persons without HIV. While the risk of stroke and possibly of CSVD is higher among persons with HIV, differences in the effect of aging on cerebrovascular pathology among persons with HIV compared with persons without HIV has not been shown. Several studies suggest that the effect of age on brain pathology including WMHs is worse among persons with HIV than persons without HIV [49, 50]. However, the Comorbidity in Relation to AIDS (COBRA) study, which recruited persons without HIV who were well-matched to HIV-infected participants in terms of vascular risk factors, did not find accelerated brain pathology among persons with HIV [51]. Both HIV-specific variables (eg, viral load, immunosuppression, and possibly immune reconstitution, inflammatory markers, and antiretroviral drugs) and non-HIV-related vascular risk factors (eg, older age, smoking, and hypertension) contribute to cerebrovascular pathology among persons with HIV [52–56]. However, in most studies, traditional vascular risk factors appear to be the primary drivers of CSVD in persons with HIV [46]. As in the general population, CSVD and cardiovascular risk factors (eg, diabetes and hypercholesterolemia) are associated with poorer cognition among persons with HIV [57–60]. Few studies have evaluated the association between stroke events and cognitive impairment among persons with HIV. In studies that have identified an association between CSVD and cognition, the effect of CSVD on poorer cognition was and not synergistic with HIV infection may moderate the effect of cerebrovascular disease on studies have found a higher risk of stroke associated with HIV for compared with men A study conducted by among persons with HIV with viral load copies/mL) and persons without HIV identified that the of developing ischemic stroke was higher among compared with In studies have sex differences in the association between cardiovascular risk factors and cognition in persons with HIV, with a association present only among and not men future studies should be for sex and based on sex to identify the drivers of risk differences between and men with HIV. and which are prevalent among persons with HIV, may the association between cerebrovascular disease and and are risk factors for stroke and cognitive among both persons with HIV and the general population. may be a through which to and the risk of stroke and cognitive impairment in persons with HIV knowledge gaps in the field include whether cardiovascular risk factors will decrease the risk of cognitive impairment or cognitive among persons with HIV; whether the impact of stroke and CSVD on cognition is in and as in the settings where most of these studies have been the between cerebrovascular disease on which biomarkers identify those at higher risk of cognitive impairment and those who may to health disorders are common among persons with HIV, and prevalence in the ART is estimated to be from to mental health disorders are at more common among persons with HIV than the general population For instance, is about to times more prevalent and current is times more common among persons with HIV than the general population, with has a association with cognitive impairment. and studies conducted among persons with HIV reported that is associated with cognitive impairment and to cognitive disorders However, the association between and cognitive disorders is not greater among persons with HIV than the general population, that is no effect between HIV infection and on cognition The association between and cognition may on the of the and whether it is or In aging may also the effect of on cognition, and older people may be more to the effect of on cognitive disorders. may be related to peripheral In a study conducted among persons without HIV improved inflammatory biomarkers such as and among those who to the treatment, and 6 in all the participants of to In another study conducted among persons with HIV with viral increased protein, an inflammatory was associated with cognitive but only among those with important is that may In a study by had a effect on among conducted by the among persons with HIV on stable ART that improved performance in some cognitive after weeks In terms of assessment that are used and to be have when used they were in settings and not in and these not consider of they current symptoms than health need to be in a life events including childhood lower and need to be considered in the These increase the risk for and and drug use which are related to cognitive disorders is a which traditional mental disorders based on genetics, and While is to identify the on neurological in persons with HIV, of into and could be questions to be are whether current or can be into or is needed traditional and whether can time and to all the of There are in the such as small of study of studies with participants, and in used and the following points should be considered for future which are to be used for mental health or a of it is to a large cohort and both and which is whether these data can be across different cohorts for and how trials can be conducted in settings. The impact of on cognitive function in treated persons with HIV is a current that with and impairment. data suggest that persons with HIV on suppressive ART to be at increased risk of common compared to persons without HIV However, the impact of these differences is unclear. is a of increased to and which to increased risk of comorbidities, and is related to the to in multiple and is in to is associated with and an association is between and chronic which may also contribute to other common The of include the of new comorbidities, increased risk of of cognitive and increased A concept is that of cognitive which is a that is by the of both cognitive without and In this the cognitive impairment may be related to the and has the for However, include the the from mild cognitive its with cognitive and whether it is a for is reported to be associated with poorer cognitive performance in multiple both in the general population and in persons with HIV may impaired with the of cognitive With regard to impairment and cognition, and impairment in the general population are associated with increased risk of While these associations have not been in persons with HIV, they are at increased risk of as well as both and which can lead to data suggest that in the general population, impairment may be an early of disease data from studies suggest that persons with HIV who are at high risk for mild cognitive impairment have poorer to in compared with people considered to be at risk In the general population, the of multiple impairment the risk of developing compared with with HIV with may have at a increased risk of but this remains to be In these data in persons with HIV remain and and important knowledge gaps exist with regard to the between and the impact on The of multiple may increase the risk of cognitive impairment in the general population, with evidence to suggest that this is also the in persons with HIV. Cognitive is a and with that need and investigating it can be as a true and into and In persons with HIV, this also remains an but important to be may be and Thus, a major of future will be on interventions to or cognitive disorders associated with and to the health of persons with HIV. The between and remain under as the of to functional status with for studies of the impact of on cognition are Cognitive is an with that need and it can be into and for the into insight into this we have the of the initiation of ART within the first year of HIV acquisition, drug cerebrovascular health, mental health, and aging to cognitive health in persons with HIV. The of these factors, and some other factors not in this are summarized in While current and data to an than synergistic role for the effect of comorbidities on cognitive health in persons with HIV, the the of comorbidities has on cognitive health remains unclear. questions remain increased to some comorbidities in the of traditional risk and whether is increased or of such comorbidities (eg, to be more important in persons with of early treatment, comorbidities, and aging on cognition among persons with human immunodeficiency ART, antiretroviral HIV, human immunodeficiency Several important have been data suggest that the very early initiation of ART may or even the CNS effects of HIV infection, the legacy effects of untreated HIV. However, these findings need to be in other have a longer duration of and include other to CNS health. consideration be to the initiation of ART in individuals with acquired HIV infection. healthcare settings are to HIV testing and that HIV is to those with acquired HIV. To early and treatment are needed across all healthcare settings. the impact of comorbidities, drug and mental health on cognitive health in persons with HIV are likely as in the of this However, the true impact each of these factors has on cognitive health in persons with HIV is to studies are with a duration to the effects of such for studies of duration is but of this should be to and the of other cohorts such as the impact of these and factors across different healthcare settings and different settings is on the is that such have to be and measured across and healthcare settings. A. and A. of the the and and the they A. and the and provided A. and of the provided and to the The National Institutes of the Biotypes of Central Nervous System Complications in With HIV meeting where the topics in this were This as of the of the of Central Nervous System Complications in With by the National Institutes of National of have the for of of that the consider to the content of the have been

Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.