INTRODUCTION — Changes in memory, concentration, attention, and motor skills are common in patients with HIV . When not clearly attributable to an alternate cause other than HIV infection, such neurocognitive impairments have been collectively classified as HIV-associated neurocognitive disorders (HAND). The main therapeutic approach to HAND is antiretroviral therapy (ART).
The management of HAND will be discussed here. The epidemiology, clinical manifestations, and diagnosis of HAND are discussed elsewhere. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis".)
An overview of the range of neuropsychiatric conditions associated with HIV infection and more detailed reviews of other specific conditions are discussed separately. (See "Overview of the neuropsychiatric aspects of HIV infection and AIDS" and "Depression, mania, and schizophrenia in HIV-infected patients" and "Substance abuse and addiction in HIV-infected patients".)
TERMINOLOGY — Neurocognitive deficits in certain individuals with HIV, without alternative explanation other than HIV infection, have long been described. However, the terminology used to refer to this phenomenon has undergone substantial evolution since its initial characterization.
This topic uses a widely employed classification scheme that groups such neurocognitive deficits under the umbrella term HIV-associated neurocognitive disorders (HAND). The range of deficits included in this scheme is defined by performance on standardized neuropsychological testing and the impact on activities of daily living.
In general terms, HIV-associated dementia (HAD) refers to severe neurocognitive deficits that lead to substantial functional impairment. Milder deficits are termed mild neurocognitive disorder (MND) if they lead to minor symptoms or impairment and asymptomatic neurocognitive impairment (ANI) if they do not. This is discussed in detail elsewhere. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'Terminology'.)
GENERAL PRINCIPLES — Antiretroviral therapy (ART) is the main treatment modality for HIV-associated neurocognitive disorders (HAND). The available data support a preventive and therapeutic value of ART for the more severe manifestations of HAND (ie, HIV-associated dementia [HAD]). However, other aspects of ART for HAND are not well defined, specifically, the impact of ART on milder forms of cognitive impairment and the optimal regimen for HAND.
Efficacy of ART for HAND
ART for HAD — Antiretroviral therapy (ART) has a clear beneficial effect on the treatment and prevention of HAD.
Early in the history of antiretroviral use, a randomized controlled trial demonstrated that treatment of HIV infection resulted in improved cognitive function in patients with HAD. In that trial, those who were randomly assigned to zidovudine monotherapy had better subsequent performance on neuropsychological testing compared with baseline and compared with patients who received placebo . Other observational studies and case series have noted substantial clinical improvement, albeit with some residual impairment, in neurocognitive performance with ART initiation in patients with HAD . Finally, the widespread use of ART has had a profound effect on the incidence of HAD, which rarely develops in patients on suppressive ART. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'Prevalence in the ART era'.)
The pathology of HAD includes active HIV infection of the brain with microglial nodules typical of viral encephalitis, and occasional multinucleate giant cells that are formed from infected monocytes in the brain. These pathologic findings, often accompanied by elevated cerebrospinal fluid (CSF) HIV RNA viral loads in untreated patients, suggest that the progressive neurologic dysfunction of HAD is driven by HIV in the brain, which is consistent with the observation that HAD responds to ART [4,5].
ART for milder forms of HAND — The impact of antiretroviral therapy (ART) on the milder forms of HAND (ie, minor neurocognitive disorder [MND] and asymptomatic neurocognitive impairment [ANI]) is not as clear as that for HAD. There are no systematic data demonstrating an improvement in milder neurocognitive deficits with ART initiation, and some studies report a substantial prevalence of mild, persistent cognitive dysfunction despite use of suppressive ART [6-8]. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'Prevalence in the ART era'.)
The uncertain impact of ART on milder forms of HAND is consistent with the lack of pathologic evidence of active HIV infection of the central nervous system (CNS) with these conditions . This is in contrast to pathological evidence of CNS HIV infection in the development of HAD (for which ART is effective). Even though there are no clear alternative explanations for mild cognitive dysfunction if confounding conditions have been eliminated, this ambiguity regarding the role of HIV CNS infection in mild impairments lends further uncertainty about the potential effect of ART and of particular drug regimens in this setting.
Efficacy of specific regimens — There is no clear evidence that certain ART regimens are more effective than others for HAND. No contemporary ART regimen is associated with subsequent development of HAD, and the risk of milder forms of HAND with various regimens has not been prospectively studied.
Some experts have hypothesized that antiretroviral agents that achieve higher levels in the CNS might more effectively treat the HIV CNS infection that is thought to drive the development of HAD and thus be more effective for HAD. Within this framework, antiretroviral agents are assigned a CNS penetration effectiveness (CPE) score based largely on CSF drug kinetics and observations about the levels of the drugs in the CSF. However, clinical studies have not supported use of the CPE score to inform regimen selection in patients with HAND, and we do not use it. If used, we suggest that it be a last consideration in regimen selection, following virologic potency, resistance, simplicity, and side effects. (See 'Regimen selection' below.)
Randomized, controlled trials have generally focused on patients with mild or no baseline neurocognitive deficits (rather than patients with HAD), and they do not clearly demonstrate that ART regimens with high CPE scores result in better neurocognitive outcomes than other regimens [10,11]. In the most rigorous randomized trial available, 49 patients with HIV and mild neurocognitive impairment who were initiating ART or changing their regimen for any reason were randomly assigned to an ART regimen optimized for CPE score versus a non-optimized regimen . Most patients had a modest improvement in neurocognitive performance at 16 weeks, but there was no significant difference in improvement between the two groups. In addition, fewer patients in the CPE-optimized group achieved virologic suppression at 16 weeks (54 versus 82 percent in the non-optimized group), although this difference was not statistically significant.
Observational studies evaluating the use of CPE to guide regimen selection in patients with HAND have resulted in inconsistent findings but overall do not convincingly support a role for CPE-guided therapy [11-18]. In one study of 185 patients with HIV, initiation of an ART regimen with a high CPE score was associated with greater improvements in tests of concentration, speed of mental processing, and mental flexibility . However, a much larger observational study suggested the opposite. In that retrospective study, which included over 60,000 individuals with HIV, initiation of a high versus a low CPE-ranked regimen was associated with the development of HAD (hazard ratio 1.74, 95% CI 1.15-2.65), although the overall number of events was very low . This study illustrates the limitations in assessing an ART regimen based on CPE rank alone, as some regimens with high CPE-scored regimens had many agents, potentially prescribed in the setting of drug resistance, and issues like this may have impacted outcomes more than CPE score.
It is possible that the reason the CPE score does not correlate well with clinical effectiveness is that it does not adequately reflect intracellular drug distribution, which may be more critical to effectiveness than measured concentrations in CSF.
Agents with special concerns — We generally avoid using efavirenz in patients with neurocognitive impairment. Although efavirenz has relatively good CNS penetration and is a highly effective antiretroviral agent, it can be associated with several adverse neuropsychiatric side effects . These might confound early evaluation of neurocognitive deficits. Furthermore, its low barrier to resistance could be problematic in the setting of poor adherence. It is not a first-line agent for treatment of HIV.
Additionally, efavirenz is generally avoided in patients with psychiatric conditions. This is not only because of the well-confirmed association with CNS toxicity, especially early in treatment, but also because of concerns of increased suicidality with efavirenz use that have not been fully confirmed [20,21]. Given these concerns, other agents without potential neuropsychiatric effects seem better choices in patients with psychiatric conditions.
PATIENTS NOT ON ART — Initiation of antiretroviral therapy (ART) is recommended for all untreated patients with HIV to reduce the risk of disease progression (including the risk of HIV-associated dementia [HAD]) and the risk of non-AIDS defining complications. For most patients with HIV, prompt initiation of ART (even on the same day as diagnosis) is preferred. Prompt initiation of ART is particularly important for patients with HAD given the direct benefits of HIV control, which makes ART the main treatment for HAD. (See 'ART for HAD' above.)
Regimen selection — The approach to regimen selection for patients with HAND is largely the same as that for the general population with HIV. Certain antiretroviral regimens are recommended for initial treatment of HIV because of extensive data documenting their virologic potency and safety profiles (table 1). For all patients with HIV, primary considerations in selecting one of these recommended regimens include the level of plasma HIV RNA, the baseline plasma virus genotype, potential for drug interactions, and the presence of certain co-morbidities (eg, renal insufficiency). For patients with HAND, in which cognitive status may interfere with adherence to therapy, regimen simplicity is another consideration, and so a once-daily, single-pill regimen may be particularly desirable. Longer-acting antiretrovirals may also offer a further advantage by reducing the risk of nonadherence. Antiretroviral regimen selection is discussed in detail elsewhere. (See "Selecting antiretroviral regimens for treatment-naïve persons with HIV-1: General approach".)
We do not routinely evaluate for central nervous system (CNS) HIV levels or resistance profiles of the cerebrospinal fluid (CSF) virus in patients with HAD who are initiating ART. Although differences in the resistance profiles between the plasma and CSF virus in untreated patients presenting with HAD have been reported, regimen selection based on the resistance of the plasma virus is usually sufficient.
We do not take expected CNS penetration of the antiretroviral regimen into account when selecting a regimen for patients with HAND who are not on ART. Although potential benefits of using an ART regimen with good CNS penetration are hypothetically relevant for HAD, which is characterized by local replication of HIV within CNS macrophages and related cells, clinical studies have not demonstrated an association between CNS penetration and improved neurocognitive outcomes. (See 'Efficacy of specific regimens' above.)
Treatment response — Following initiation of ART, we assess response to treatment through plasma HIV RNA viral load monitoring, as well as clinical evaluation of neurocognitive and general functional status.
Patients with HAD typically respond favorably to initiation of ART, although the overall degree of improvement can vary from dramatic restoration of neurocognitive functioning to amelioration but persistence of motor deficits and cognitive disability. In our experience, initiation of effective ART soon after development of deficits is more likely to be associated with substantial improvement, whereas those with long-term disability at the time of ART initiation rarely experience excellent recovery of function. Extensive atrophy or white matter changes reflecting substantial brain injury predict worse functional recovery.
The time course of improvement is also variable, but it is usually appreciated within a few weeks of treatment initiation and continues for several months.
PATIENTS WITH VIRAL SUPPRESSION ON ART — The main management decision for patients who are on suppressive antiretroviral therapy (ART) but present with neurocognitive impairment or decline is whether there is any neurocognitive benefit to modifying the ART regimen. There are no adequately powered studies that support altering or augmenting the ART regimen in this situation. In a randomized trial of 191 patients with HAND, there was no cognitive or psychiatric benefit at 48 weeks among patients who underwent ART modification compared with those who did not . Our approach to this issue depends on the severity of the presenting symptoms, as outlined in the sections that follow.
Mild or residual symptoms — For patients who have achieved virologic suppression on ART, we generally do not switch ART regimens because of persistent or mild neurocognitive deficits. There is no evidence that altering ART regimens is of benefit for mild impairments or impairments that are residual but stable, even if there is no other potential cause of the deficits. We follow such patients closely, with at least simple office neurocognitive measures over time, to ensure that the deficits are not progressive. (See 'New or progressive severe symptoms' below.)
Although improvements in cognitive functioning in HIV-associated dementia (HAD) following the initiation of ART can be marked, residual deficits often persist, and there are no data indicating that regimen modification leads to further improvements. Additionally, patients can develop mild neurocognitive deficits while on suppressive ART. No studies have clearly demonstrated that switching to a regimen (including those that include agents with greater central nervous system [CNS] penetration) will delay or prevent mild but clinically significant cognitive deficits, and randomized trials evaluating this strategy did not show clear benefit [10,23]. (See 'Efficacy of specific regimens' above.)
Furthermore, regimen switching poses risks, including possible adverse effects or nonadherence that may lead to virologic failure, which could outweigh any theoretic neurocognitive benefit. Similarly, treatment intensification (ie, adding an additional antiretroviral agent to the regimen) likely has no effect in this setting, although this strategy has only been evaluated in small studies [24-26].
New or progressive severe symptoms — In patients with severe neurocognitive impairments that are new or progressive despite suppressive ART, we first perform careful evaluation to rule out other causes of neurocognitive decline. If HIV infection appears to be the only identified cause of the impairments, we evaluate the cerebrospinal fluid (CSF) for the presence of detectable HIV. If present, this suggests symptomatic viral escape syndrome, and we tailor ART to target the HIV populations in the CSF. If CSF HIV levels are undetectable, there is no clear evidence that altering ART regimens is of benefit, and we generally do not switch regimens in these cases.
Confirming the diagnosis — We perform careful neurologic history, examination, laboratory testing, and neuroimaging to evaluate for potential causes of severe neurocognitive deficits that are new or progressive in patients with well-controlled HIV. In patients on ART, particularly if the viral load is suppressed and CD4 cell counts have been restored, such deficits are more likely to be caused by non-HIV-related diseases than HIV infection. Ruling out treatable conditions, such as neurosyphilis, subacute combined disease (B12 deficiency), or thyroid disease (generally hypothyroidism), is critical. Metabolic derangements should also be excluded. Other conditions, such as cerebrovascular disease, neurodegenerative diseases (particularly as patients get older), or substance use, may also lead to neurologic dysfunction and impairment. A detailed discussion of the evaluation of progressive neurocognitive deficits is found elsewhere. (See "Early-onset dementia in adults", section on 'Initial evaluation'.)
If exhaustive evaluation does not indicate a clear alternative explanation for the symptoms, we evaluate for the presence of HIV replication in the CSF, as outlined below.
Evaluating CSF for HIV — For patients on suppressive ART who have severe neurocognitive deficits that cannot be attributable to other, non-HIV causes, we perform lumbar puncture to test cerebrospinal fluid (CSF) for HIV RNA (and genotyping, if detected). Lumbar puncture is generally a safe procedure in the absence of an asymmetric brain mass or coagulopathy. Further management depends on the presence of detectable CSF HIV RNA. (See 'Patients with detectable CSF HIV' below and 'Patients with undetectable CSF HIV' below and 'When CSF HIV testing is not available' below.)
The objective of testing the CSF for HIV RNA is to identify CSF viral escape (detectable CSF virus despite viral suppression in the plasma). Although uncommon, symptomatic CSF viral escape is a diagnostic consideration in virally suppressed patients with new or progressive severe symptoms. It may often be associated with white matter changes in magnetic resonance imaging (MRI) scans, albeit often with higher CD4 counts. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'CNS viral escape syndrome'.)
Patients with detectable CSF HIV — A detectable CSF HIV level in the setting of plasma viral suppression and new or worsening neurocognitive symptoms is consistent with symptomatic CNS escape. An uncommon syndrome, it is essentially a form of isolated treatment failure in the CNS in which local HIV infection within the CNS compartment is not effectively suppressed by systemically suppressive ART.
In such cases, we perform genotypic resistance testing on the CSF HIV, if available. In some patients with HIV, the virus in the CNS compartment evolves independent of the periphery, resulting in different resistance mutation patterns in the CNS virus compared with virus in the plasma.
●Once genotype results are available, we generally recommend switching to an ART regimen tailored to the drug resistance profile of the CSF virus. The regimen must also maintain expected activity against the plasma virus, based on prior genotypes. While optimizing the typical considerations for regimen selection (eg, virologic potency and tolerability), we try to ensure that two or more agents that have expected efficacy against the CSF virus are included.
●If a genotype of the CSF virus is not available, regimen modification is generally done empirically, taking into consideration the patient's treatment history. Possible empiric options include regimens containing the newer integrase inhibitors (eg, dolutegravir or bictegravir) because of their potency and high barrier to resistance. Adding a CCR5 inhibitor (ie, maraviroc) to the existing regimen is another potential option, although evidence supporting this approach is very limited. In a pilot trial of 14 patients with progressive HIV-associated neurocognitive disorder (HAND) symptoms and plasma viral suppression, the nine patients who were given maraviroc in addition to their ART regimen had better global neurocognitive functioning over the subsequent year than the five patients who remained on their baseline regimen . However, in another trial, addition of maraviroc did not improve cognitive and psychiatric functioning . Data on possible CNS drug penetration effectiveness may be a secondary consideration (see 'Efficacy of specific regimens' above). Regimen selection should be done in consultation with an expert in HAND.
After regimen change, it is useful to repeat the lumbar puncture to determine if the HIV RNA level in the CSF has improved. Resolution of CSF pleocytosis also suggests that HIV has been effectively treated in the CNS. We typically repeat the lumbar puncture approximately 12 weeks after a regimen change.
Support for this strategy comes from retrospective studies describing patients presenting with symptomatic CNS viral escape in whom drug resistance to the ART regimen in use was frequently detected in the CSF viral population [28,29]. Following modifications in the ART regimen to optimize activity against the CSF viral genotype and CNS drug penetration, most patients experienced improvement in symptoms and reduction in CSF HIV level. While a direct causative effect cannot be proven, the clinical improvement, resolution of CSF pleocytosis, and CSF viral suppression following the directed changes in ART suggest there was a local, compartmentalized infection in the CSF that was not effectively treated despite plasma viral suppression.
Patients with undetectable CSF HIV — In the absence of detectable cerebrospinal fluid (CSF) HIV, there is no evidence that changes in ART regimen are beneficial, and we suggest not switching regimens. In such cases, it is more likely that new or progressive severe neurologic deterioration is caused by other, non-HIV conditions. Furthermore, regimen switching poses risks, including possible adverse effects or nonadherence that may lead to virologic failure, which could outweigh any theoretic neurocognitive benefit.
A rare HIV-related cause of neurologic decline in patients who have had virologic suppression on ART is CD8-driven inflammation in the CNS (an immune reconstitution inflammatory syndrome-like phenomenon related to HIV CNS infection itself). If this diagnosis is suspected based on white matter changes on MRI, a trial of corticosteroids (eg, methylprednisolone 1 g daily for three to five days) may be beneficial [30-32]. (See "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'Immune reconstitution inflammatory syndrome'.)
Some expert groups, including an international expert group on HAND (the Mind Exchange Working Group), suggest switching the ART regimen even if the CSF HIV RNA level is undetectable and using the CNS penetration effectiveness (CPE) score to guide selection in patients who have progressive cognitive defects . The rationale for this is the possibility of persistent very low-level virus in the CSF that cannot be detected by standard testing. However, there is no direct evidence to support this strategy and a randomized trial showed no improvement in cognitive or psychiatric functioning with ART modification . (See 'Efficacy of specific regimens' above.)
When CSF HIV testing is not available — Occasionally, it is not possible to perform a lumbar puncture (eg, because the patient declines or because of coagulopathies that cannot be reversed or are too risky to reverse). Education about the safety and ease of performing lumbar puncture can overcome fears in many but not all patients.
If the clinical laboratory does not perform HIV viral load or genotypic testing on CSF, CSF can be frozen and sent to a research or commercial laboratory that does perform those assays. If this is not feasible, the presence of CSF pleocytosis without other identifiable cause can be a surrogate marker to support the diagnosis of the CSF escape syndrome and justify a change in therapy, although it is preferable to more directly document the condition and the presence of drug resistance. In such cases, we use the same approach as with patients with detectable CSF HIV but no genotype available. This is discussed elsewhere. (See 'Patients with detectable CSF HIV' above.)
PATIENTS VIREMIC ON ART — For patients on antiretroviral therapy (ART) who have virologic failure, the initial evaluation includes assessment for adherence and drug resistance. For those with drug-resistant virus, selection of a new ART regimen is primarily guided by the resistance profile and the likelihood that a given regimen can result in sustained viral suppression. Additionally, we try to use a once-daily regimen in patients who have neurocognitive deficits, if possible, because of the importance of regimen simplicity. Long-acting and parenteral therapy approaches are reasonable alternatives for some patients in this situation. The approach to patients with virologic failure is discussed elsewhere. (See "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
We do not check cerebrospinal fluid (CSF) HIV levels to guide management in such patients. Even if systemic virologic failure is accompanied by increases in the CSF HIV RNA, this does not impact ART management, which is guided by plasma virus susceptibility.
Neuropsychiatric symptoms — Neuropsychiatric symptoms are common in dementia, including HIV-associated dementia (HAD). In people with HIV (PWH), depressed mood has been associated with persistent inflammatory markers. In a longitudinal study, PWH with greater systemic inflammation and more depression experienced greater cognitive decline over 12 years of follow-up . Evaluation and treatment of sources of inflammation and antidepressant therapy might help prevent cognitive progression. Patients with depressive symptoms should undergo a complete psychiatric evaluation to determine the need for antidepressant medications. If antidepressants are initiated, the patient should be carefully monitored for the emergence of mania. The management of depression and other neuropsychiatric symptoms in HIV infection or dementia is discussed elsewhere. (See "Depression, mania, and schizophrenia in HIV-infected patients" and "Management of neuropsychiatric symptoms of dementia".)
Methylphenidate (Ritalin) or other stimulants can be effective treatments for apathy in some patients. However, they can precipitate agitation and other side effects; hence, this type of treatment should be undertaken cautiously and monitored carefully.
Optimizing cardiovascular health and other comorbidities — Among patients with HIV on antiretroviral therapy (ART), neurocognitive impairments are more closely associated with comorbidities including diabetes, hypertension, chronic pulmonary disease, frailty, neuropathic pain, depression, and lifetime cannabis use, rather than HIV-specific measures . Increased attention to these common comorbidities in PWH should particularly be addressed to optimize outcomes. Reducing cardiovascular risk through blood pressure control, smoking cessation, managing diabetes mellitus, maintaining a healthy weight, and treating hyperlipidemia can be considered adjunctive therapy of neurocognitive deficits in patients with HIV. Although these interventions have not been formally demonstrated to improve cognition, they are appropriate interventions for general health and may have protective effects on the brain. Management of cardiovascular risk in patients with HIV is discussed in detail elsewhere. (See "Management of cardiovascular risk (including dyslipidemia) in patients with HIV", section on 'Minimizing the risk of cardiovascular disease'.)
Exercise and physiotherapy — Activity and exercise seem likely to have some cognitive benefits in the setting of HIV-associated neurocognitive disorders (HAND) [36-39]. Higher oxygen utilization is associated with better brain white matter imaging markers, suggesting an association of active lifestyle with better brain health in HIV . Randomized studies evaluating this are underway.
Safety assessments — As with all cases of dementia, safety assessments should be used and patients in need of supervision should be referred to appropriate facilities. Poor adherence may be a particular problem for those with HAD, compounding the risk of treatment failure. (See "Management of the patient with dementia".)
INEFFECTIVE THERAPIES — Several agents that are used for other dementia syndromes not associated with HIV infection have been evaluated as adjuvant treatment in clinical trials of HAND with disappointing results. These include memantine , selegiline , lithium , and minocycline [44,45].
PROGNOSIS — Whether milder neurocognitive deficits predispose to or are an early manifestation of HIV-associated dementia (HAD) is debated ; some patients continue to have only minor problems, while others progress to more severe disease. As an example, in a cohort study of nearly 450 patients with HIV who were followed for approximately three years with intermittent neurocognitive assessments, 61 percent remained stable, 16 percent improved, and 23 percent had some deterioration . In an extension of this study in the CHARTER study over 12 years of follow-up, using Glasgow Coma Scale measures of cognition, 70 percent of people with HIV (PWH) remained stable over 12 years, while 6 percent improved and 27 percent showed decline . The mean decline was modest over 12 years. As noted, decline was not associated to HIV disease status, but rather appeared related to comorbid conditions.
There is concern that asymptomatic deficits might be a predictor of further functional impairment. In one study of almost 350 patients with HIV (mean age 44 years) who underwent serial neurocognitive and functional assessments, those who had baseline asymptomatic neurocognitive impairment were more likely to complain of functional impairment than those without baseline cognitive impairment (50 versus 22 percent), suggesting wider fluctuation of functional impairment in those with asymptomatic cognitive impairment .
Additionally, even in the era of effective antiretroviral therapy (ART), neurocognitive disorders represent a marker for an increased risk of death among patients with HIV. In a cohort of 1651 patients, the presence of HIV-associated neurocognitive disorders (HAND) was associated with increased mortality (hazard ratio 3.1, 95% CI 1.8-5.3) .
PREVENTION — The incidence of HIV-associated dementia (HAD) has dramatically decreased with the widespread use of antiretroviral therapy (ART), reflecting a clear preventive benefit with regards to this severe manifestation of HIV-associated neurocognitive disorders (HAND) (see 'ART for HAD' above). However, milder forms of neurocognitive deficits remain prevalent despite successful ART. For patients who have normal neurocognitive performance, there is no strong evidence that particular ART regimens are less likely to lead to subsequent neurocognitive decline. (See 'Efficacy of specific regimens' above.)
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Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: HIV-associated neurocognitive disorders (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Terminology – Changes in memory, concentration, attention, and motor skills are common in patients with HIV. When these occur without an evident cause other than HIV infection, such impairments have been collectively classified as HIV-associated neurocognitive disorders (HAND). Depending on the severity and impact on daily functioning, cognitive deficits can be classified into three conditions: asymptomatic neurocognitive impairment (ANI), HIV-associated mild neurocognitive disorder (MND), and HIV-associated dementia (HAD). (See 'Introduction' above and "HIV-associated neurocognitive disorders: Epidemiology, clinical manifestations, and diagnosis", section on 'Terminology'.)
●Efficacy of ART for HAND – Antiretroviral therapy (ART) is the main treatment modality for HAND. ART has a clear beneficial effect on the treatment and prevention of HAD, specifically, and all contemporary ART regimens appear effective. The impact of ART on the milder forms of HAND (ie, MND and ANI) is not as clear. (See 'Efficacy of ART for HAND' above.)
●General principles of treatment – Recommendations on ART management in patients with HAND are largely based on expert opinion and are controversial because of the overall paucity of high-quality data comparing particular drug regimens. (See 'General principles' above.)
●Approach to untreated patients – For initial ART of untreated patients with HAND, the approach to regimen selection for patients with HAND is largely the same as that for the general population with HIV (table 1). Because cognitive impairments may interfere with adherence, we suggest a once-daily, single-pill regimen for patients with HAND (Grade 2C).
●Approach to patients on suppressive ART – The predominant management issue for patients who are on suppressive ART but present with neurocognitive impairment is whether there is any neurocognitive benefit to modifying their ART regimen. Our approach to this issue depends on the severity of the presenting symptoms:
•For patients who have mild symptoms or whose impairments are residual but stable from before ART initiation, we do not switch ART regimens, even if there is no other potential cause of the impairments. We follow these patients closely to ensure the deficits are not progressive. (See 'Mild or residual symptoms' above.)
•For patients with severe symptoms that are new or progressive, we first perform careful evaluation to rule out other causes. We then evaluate the cerebrospinal fluid (CSF) for detectable HIV. Its presence suggests symptomatic viral escape syndrome. In such settings, we suggest tailoring the ART regimen to the genotypes of the viral populations in the CSF as well as in the plasma (Grade 2C). For patients who have undetectable CSF HIV levels, we do not switch the ART regimen. (See 'New or progressive severe symptoms' above.)
●Approach to viremic patients on ART – For patients with HAND who are viremic despite ART, the initial evaluation includes assessment for adherence and drug resistance. For those with drug-resistant virus, selection of a new ART regimen is primarily guided by the resistance profile of the virus and the treatment history. (See 'Patients viremic on ART' above and "Selecting an antiretroviral regimen for treatment-experienced patients with HIV who are failing therapy".)
●Adjunctive interventions – Adjunctive interventions include management of neuropsychiatric symptoms (eg, depression), optimizing cardiovascular health, and ensuring personal safety. Exercise may also be beneficial. (See 'Adjunctive measures' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Richard Price, MD, Alexander Thompson, MD, MBA, MPH, Andrew Pieper, MD, PhD, and Glenn Treisman, MD, PhD, who contributed to an earlier version of this topic review.
UpToDate gratefully acknowledges John G Bartlett, MD (deceased), who contributed as Section Editor on earlier versions of this topic and was a founding Editor-in-Chief for UpToDate in Infectious Diseases.
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