**5. HIV-associated neurocognitive disorder**

#### **5.1. Introduction**

Cognitive dysfunction in HIV infection is either due to the virus itself or caused by opportunistic disease resulting from progressive immunosuppression like CNS infections (cryptococcal meningitis, toxoplasma encephalitis, and progressive multifocal leukoencephalopathy) and neoplasia (lymphoma) [8].

Primary HIV-related neurocognitive disease is a result of direct infection by the virus, due to its predilection to invade (neurotropism) and cause disease (neurovirulence) in the CNS [9]. It is now identified worldwide as the commonest preventable and treatable neurocognitive illness in people below the age of 50 years [10].

Clinically, HIV neurocognitive illness comprises a spectrum ranging from mild asymptomatic neurocognitive impairment (ANI) through moderate mild neurocognitive disorder (MND) to severe HIV associated dementia (HAD) cognitive deficits [10]. The cardinal manifestations are a triad of cognitive, behavioral, and motor dysfunction.

#### **5.2. Epidemiology**

due to noninfectious inflammatory diseases like sarcoid, Behçet's disease, uveo-meningeal syndromes usually have a more complicated course and always must be considered because

CT or MRI may help to exclude suspected structural disease like parameningeal infectious foci, but is generally not necessary. A Chest X-ray may be indicated when tuberculosis is

Management is symptomatic (fluids, analgesics, anti-inflammatories, antipyretics, antiemetics) with hospitalization often not required. If bacterial or partially treated bacterial meningitis is suspected, empiric antibiotics should be commenced. Acyclovir is used for HSV-1 or HSV-2, or severe EBV and VZV infections; antiretrovirals can be considered for HIV. Corticosteroids

Hyponatremia as a consequence of infection-induced syndrome of inappropriate antidiuretic

The outcome following aseptic viral meningitis is generally excellent with full recovery in 5–14 days after onset of symptoms. Rarely headaches, lightheadedness, and fatigue may persist for longer in some patients. The natural history of aseptic meningitis is determined by the natural history of the HIV infection and its effects on immunity. It is not clear whether the aseptic meningitis syndrome in HIV is a prelude to dementia, CNS neoplasia, or focal brain

Cognitive dysfunction in HIV infection is either due to the virus itself or caused by opportunistic disease resulting from progressive immunosuppression like CNS infections (cryptococcal meningitis, toxoplasma encephalitis, and progressive multifocal leukoencephalopathy)

Primary HIV-related neurocognitive disease is a result of direct infection by the virus, due to its predilection to invade (neurotropism) and cause disease (neurovirulence) in the CNS [9]. It is now identified worldwide as the commonest preventable and treatable neurocognitive

Clinically, HIV neurocognitive illness comprises a spectrum ranging from mild asymptomatic neurocognitive impairment (ANI) through moderate mild neurocognitive disorder (MND) to

are not recommended because of their inhibitory effect on immune responses [1].

hormone secretion (SIADH) needs to be recognized and managed.

**5. HIV-associated neurocognitive disorder**

illness in people below the age of 50 years [10].

they may respond to specific treatments [2, 3].

suspected as an underlying cause of aseptic meningitis.

*4.1.7. Imaging*

128 Advances in HIV and AIDS Control

*4.1.8. Treatment*

*4.1.9. Prognosis*

lesions [1, 2].

**5.1. Introduction**

and neoplasia (lymphoma) [8].

The HIV epidemic can be described in three phases. The first of these is the illness prior to the introduction of antiretrovirals, followed by the era of monotherapy with zidovudine (AZT), and now more recently, the era of highly active antiretroviral therapy (HAART) or combination antiretroviral therapy (cART).

Before the introduction of antiretrovirals dementia was a common manifestation of late disease occurring in over 50% of AIDS patients prior to death. That phase was characterized by a rapid turnover of prevalent dementia cases due to high incidence rates combined with high mortality rates resulting from AIDS-related complications (opportunistic infections and neoplasms). With the availability of monotherapy like zidovudine dementia rates and overall mortality decreased, but prolonged survival and incomplete recovery of prevalent cases has led to a relative increase of patients with the milder forms of HIV neurocognitive impairment (MCMD and NPI). This phenomenon has been enhanced more recently during the current era of HAART.

This scenario however only applies to the developed regions mainly of North America and Europe, where HAART is the standard of management. These regions are largely dominated by the clade B strain of HIV-1.

Clade C virus is responsible for an estimated 50% of infections globally and associated with the epidemics in Sub-Saharan Africa, and parts of Asia, particularly India and China. How the different clades in different populations may influence the pathological and clinical spectrum of HIV infection is poorly documented [4]. Relatively little data is available on HIVrelated neurocognitive impairment from non-clade B regions. In these developing regions, HIV neurocognitive deficits were either poorly documented or thought to be a minor problem compared to the overwhelming burden of opportunistic infections. The apparently low prevalence of dementia was explained by possible under-diagnosis and underreporting, short life expectancy and short survival of HIV infected patients due to fatal opportunistic infections. Subsequent research has found the frequency to be higher than previously suspected with reported figures of 38% in South Africa (clade C), up to 35% in India (clade C), and 31% in Uganda (clades A and D), indicating that the influence of clade subtype on the spectrum of cognitive dysfunction is probably minimal if at all [4, 11].

#### **5.3. Pathophysiology**

HIV enters the brain during the initial viremia following infection. This occurs through infected macrophage/monocyte lineage cells crossing the blood–brain barrier, the so-called "Trojan horse" mechanism or directly across the blood brain barrier [3].

In the brain parenchyma, mainly monocyte-derived cells (microglia and macrophages), and to a lesser extent astrocytes, can be infected by HIV. Penetration of microglial cells is via the cellular surface CD4 receptor in conjunction with the chemokine receptors CCR5 and CCR3 leading to productive infection ultimately resulting in cell death. The exact mechanism of viral entry into astrocytes is unknown as these cells lack both CD4 and chemokine receptors. Following an initial productive phase of astrocyte infection, the virus enters a latent or restrictive, noncytopathic phase. This phase can persist long term and accounts for the latent virus escaping antiretrovirals currently in use.

**5.7. Motor dysfunction**

tion is lost.

Seropositivity for HIV

Focal neurological signs

Metabolic derangement

is largely based on clinical judgement [11].

Absence of

**5.9. Investigations**

Difficulties with fine finger movements and subtle balance problems are early motor features, manifesting with deterioration handwriting and a tendency to appear clumsy. Subtle gait difficulties may resemble the loss of quick righting reflexes as seen in patients with extrapyramidal disease. During these early stages, the neurological examination is normal except for mild slowing of repetitive movements (e.g., finger tapping), and increased deep tendon reflexes. Spasticity (especially of the lower limbs) with clonus, ataxia, frontal release reflexes, tremor, and sphincter disturbance evolve with progression of the disease. Seizures and myoclonus may appear late in the course. In advanced dementia signs of co-occurring myelopathy and/or peripheral neuropathy may contribute to the abnormal motor findings [8, 11, 12]. The presence of clear focal neurological signs like hemiplegia, hemianopia, hemisensory impairment, and cortical deficits such as apraxia, agnosia, or aphasia is suggestive of other or associated pathologies [11].

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In advanced HIV-associated dementia (HAD), the picture becomes global with mutism, abulia, and incontinence followed by a vegetative state where all intellectual and social interac-

Demonstrated impairment in at least two domains of neuropsychological performance

Asymptomatic neuropsychological impairment (ANI), minor neurocognitive disorder (MND), and HIV associated dementia (HAD) form part of a continuum, where activities of daily living are unaffected in ANI and MND, and are impaired to varying degrees in HAD. Since there are no globally accepted measurements of a patient's degree of impairment in work, social, or other daily activities, determining this degree of impairment caused by cognitive dysfunction

HIV-associated neurocognitive impairment is a clinical diagnosis, made after exclusion of other potential causes. The presence of commonly occurring comorbidities like substance use disorders, major depression, and hepatitis B or C infection does not exclude the diagnosis [10].

No single or combination of laboratory tests or parameters can reliably establish the diagnosis of HIV-associated cognitive impairment. Ancillary blood and CSF investigations and neuroimaging studies are necessary and useful to exclude other potential causes of cognitive

**5.8. Diagnostic criteria for HIV associated cognitive impairment**

History of progressive alterations in cognition and behavior

Intoxication or withdrawal (alcohol or other substance)

CNS opportunistic infection or neoplastic lesions

Once the virus is within the brain parenchyma, it distributes selectively with the highest concentrations being found in the basal ganglia, subcortical frontal white matter and frontal cortex. This regionally preferential distribution within the brain may relate to viral entry through CSF pathways, to patterns of monocyte trafficking within the brain, or to possibly selective vulnerability of particular neuronal populations or anatomical brain regions. The neuropathology of these changes is white matter pallor, microglial nodules, multinucleated giant cells and gliosis; this pathological constellation is termed HIV encephalitis (HIVE). The extent of damage to synaptic and dendritic structures dominates over fairly mild neuronal loss. *Histopathological damage and clinical severity correspond poorly, which implies that biochemical and immunological factors of host-virus interactions are determinants of the clinical dementia picture rather than structural changes.* Neurotoxicity is thought to occur directly from viral proteins (gp 120, gp 41, tat, nef), or indirectly from macrophage factors (quinolinic acid, prostaglandins, leukotrienes), cytokines, and chemokines (TNF alpha, IL-1, IL-6, IL-10, interferons). In addition, disruption of the blood–brain barrier promotes access of neurotoxins from the systemic to the extracellular CNS compartment. Excitotoxicity through activation of NMDA receptors is the putative final common pathway resulting in neuronal dysfunction from disrupted cell energy metabolism and membrane integrity, with calcium influx leading to apoptosis [8, 11, 12].

#### **5.4. Clinical features**

HIV-associated cognitive impairment and dementia manifest over a period of weeks to months with the triad of cognitive decline, behavioral abnormalities, and motor dysfunction indicative of subcortical frontal lobe and basal ganglia involvement.

#### **5.5. Cognitive decline**

The early affected cognitive domains are verbal and visual memory retrieval, complex sequencing, and mental flexibility with the inability to sustain attention as the underlying phenomenon. The clinical effects are poor short-term memory, impaired concentration and executive dysfunction with mental slowing and flawed judgement. Patients present with increasing forgetfulness (appointments, medication schedules, and telephone numbers) and lose track of conversations and plots; the more complex daily tasks become difficult to complete timeously [11].

#### **5.6. Behavioral abnormalities**

These include lack of interest and drive, loss of libido, irritability, blunting of emotional responses, and waning engagement in work and hobbies, ultimately leading to social withdrawal, apathy, and inertia. Early subtle symptoms can easily be diagnosed as depression. Frank psychiatric presentations with delirium, mania, and psychosis can be presenting features in up to 10% of cases [8, 11].

#### **5.7. Motor dysfunction**

leading to productive infection ultimately resulting in cell death. The exact mechanism of viral entry into astrocytes is unknown as these cells lack both CD4 and chemokine receptors. Following an initial productive phase of astrocyte infection, the virus enters a latent or restrictive, noncytopathic phase. This phase can persist long term and accounts for the latent virus

Once the virus is within the brain parenchyma, it distributes selectively with the highest concentrations being found in the basal ganglia, subcortical frontal white matter and frontal cortex. This regionally preferential distribution within the brain may relate to viral entry through CSF pathways, to patterns of monocyte trafficking within the brain, or to possibly selective vulnerability of particular neuronal populations or anatomical brain regions. The neuropathology of these changes is white matter pallor, microglial nodules, multinucleated giant cells and gliosis; this pathological constellation is termed HIV encephalitis (HIVE). The extent of damage to synaptic and dendritic structures dominates over fairly mild neuronal loss. *Histopathological damage and clinical severity correspond poorly, which implies that biochemical and immunological factors of host-virus interactions are determinants of the clinical dementia picture rather than structural changes.* Neurotoxicity is thought to occur directly from viral proteins (gp 120, gp 41, tat, nef), or indirectly from macrophage factors (quinolinic acid, prostaglandins, leukotrienes), cytokines, and chemokines (TNF alpha, IL-1, IL-6, IL-10, interferons). In addition, disruption of the blood–brain barrier promotes access of neurotoxins from the systemic to the extracellular CNS compartment. Excitotoxicity through activation of NMDA receptors is the putative final common pathway resulting in neuronal dysfunction from disrupted cell energy metabolism

and membrane integrity, with calcium influx leading to apoptosis [8, 11, 12].

indicative of subcortical frontal lobe and basal ganglia involvement.

HIV-associated cognitive impairment and dementia manifest over a period of weeks to months with the triad of cognitive decline, behavioral abnormalities, and motor dysfunction

The early affected cognitive domains are verbal and visual memory retrieval, complex sequencing, and mental flexibility with the inability to sustain attention as the underlying phenomenon. The clinical effects are poor short-term memory, impaired concentration and executive dysfunction with mental slowing and flawed judgement. Patients present with increasing forgetfulness (appointments, medication schedules, and telephone numbers) and lose track of conversations

These include lack of interest and drive, loss of libido, irritability, blunting of emotional responses, and waning engagement in work and hobbies, ultimately leading to social withdrawal, apathy, and inertia. Early subtle symptoms can easily be diagnosed as depression. Frank psychiatric presentations with delirium, mania, and psychosis can be presenting fea-

and plots; the more complex daily tasks become difficult to complete timeously [11].

escaping antiretrovirals currently in use.

130 Advances in HIV and AIDS Control

**5.4. Clinical features**

**5.5. Cognitive decline**

**5.6. Behavioral abnormalities**

tures in up to 10% of cases [8, 11].

Difficulties with fine finger movements and subtle balance problems are early motor features, manifesting with deterioration handwriting and a tendency to appear clumsy. Subtle gait difficulties may resemble the loss of quick righting reflexes as seen in patients with extrapyramidal disease. During these early stages, the neurological examination is normal except for mild slowing of repetitive movements (e.g., finger tapping), and increased deep tendon reflexes. Spasticity (especially of the lower limbs) with clonus, ataxia, frontal release reflexes, tremor, and sphincter disturbance evolve with progression of the disease. Seizures and myoclonus may appear late in the course. In advanced dementia signs of co-occurring myelopathy and/or peripheral neuropathy may contribute to the abnormal motor findings [8, 11, 12]. The presence of clear focal neurological signs like hemiplegia, hemianopia, hemisensory impairment, and cortical deficits such as apraxia, agnosia, or aphasia is suggestive of other or associated pathologies [11].

In advanced HIV-associated dementia (HAD), the picture becomes global with mutism, abulia, and incontinence followed by a vegetative state where all intellectual and social interaction is lost.

#### **5.8. Diagnostic criteria for HIV associated cognitive impairment**

	- Focal neurological signs
	- Intoxication or withdrawal (alcohol or other substance)
	- Metabolic derangement
	- CNS opportunistic infection or neoplastic lesions

Asymptomatic neuropsychological impairment (ANI), minor neurocognitive disorder (MND), and HIV associated dementia (HAD) form part of a continuum, where activities of daily living are unaffected in ANI and MND, and are impaired to varying degrees in HAD. Since there are no globally accepted measurements of a patient's degree of impairment in work, social, or other daily activities, determining this degree of impairment caused by cognitive dysfunction is largely based on clinical judgement [11].

HIV-associated neurocognitive impairment is a clinical diagnosis, made after exclusion of other potential causes. The presence of commonly occurring comorbidities like substance use disorders, major depression, and hepatitis B or C infection does not exclude the diagnosis [10].

#### **5.9. Investigations**

No single or combination of laboratory tests or parameters can reliably establish the diagnosis of HIV-associated cognitive impairment. Ancillary blood and CSF investigations and neuroimaging studies are necessary and useful to exclude other potential causes of cognitive changes in HIV infection. The main differential diagnostic considerations include delirium secondary to drugs and metabolic derangements, encephalopathies due to substance abuse or head injury, CNS opportunistic disease (meningitis and focal brain lesions), and primary psychiatric conditions. Hepatic and renal failure can cause metabolic encephalopathy directly or via impaired drug clearance.

cognitive impairment. Useful neuropsychological tests include those that examine psychomotor speed, verbal and nonverbal learning, and sustained attention [10]. Performance in these tests is interpreted by comparing patients' results to a normative control database and can be influenced by differences in racial, ethnic, cultural, and social background. Appropriate normative standards are not available for large parts of the developing world. The value of

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The use of HAART has led to a decreased frequency of HIV dementia. This is due to the effect of HAART improving cognitive performance in some patients with already established deficits and delaying or even preventing the onset of symptoms in others. HAART is therefore the suggested standard treatment for patients with HIV-associated cognitive impairment. Despite this, there are no specific consensus treatment guidelines. Current evidence and recommendations support the commencement of HAART at diagnosis of seropositivity. HAART should be initiated at the earliest stage of neurocognitive impairment irrespective of the immunological stage as the severity of the impairment at the initiation of HAART is the

CNS penetration of antiretrovirals across the blood–brain barrier has become an important consideration in the planned selection of drugs for CNS-targeted treatment. In this respect, protein binding capacities, lipophilic properties and CSF virological responses are the pharmacological parameters that determine which particular drugs achieve better bioavailability within the CNS compartment. Such putative neuro-active antiretrovirals would theoretically be superior in dementia-targeted treatment. However, clinical trials have failed to consis-

Clinical trials of neuroprotective therapies like the NMDA antagonist memantine, and the antioxidant and selective monoamino-oxidase B inhibitor selegiline, targeting pathophysiological mechanisms beyond viral suppression, have to date not yielded conclusive results. Their use in routine clinical practice is not recommended, but remains a subject of further

Symptomatic treatment of depression, anxiety, psychosis or mania in patients with HIV neu-

HIV-associated myelopathies are less frequent manifestations than encephalopathies. The etiologies of HIV myelopathy include mainly infections and neoplasms. Vacuolar myelopathy (VM) is a manifestation of primary HIV infection as is HIV transverse myelitis. Opportunistic infectious etiologies include CMV, HSV1 and 2, VZV, HTLV1, measles, JC virus, tuberculosis (TB), pseudomonas, syphilis, nocardia, cryptococcus, aspergillus, and *Toxoplasma gondii*. Neoplastic myelopathy in HIV occurs with primary CNS lymphoma (PCNSL), metastatic

rocognitive impairment remains an integral part of their management.

standard neuropsychological testing in these regions is questionable [4].

**5.14. Treatment/management**

tently confirm such a benefit [11].

**6. HIV-associated myelopathies**

research.

**6.1. Introduction**

strongest predictor of persistent cognitive deficits.

#### **5.10. Blood tests**

Full blood count, electrolytes, urea and creatinine, liver and thyroid functions, Vitamin B12 level, syphilis serology, CD4 count and viral load should be evaluated.

#### **5.11. Cerebrospinal fluid**

This can be normal but is usually abnormal. Patients with HIV-associated cognitive impairment have CSF abnormalities, typical of a lymphocytic pleocytosis with mildly elevated protein and detectable viral RNA (aseptic meningitis syndrome). Similar abnormalities however can be found in the CSF of neurologically normal HIV patients and are thus nonspecific and unhelpful in confirming a diagnosis of dementia. CSF analysis helps to exclude other etiologies, in particular cryptococcal and tuberculous meningitis, neurosyphilis, CMV encephalitis, and PML [2, 3, 11].

High CSF viral load titers loosely correlate with worsening cognitive performance in patients with advanced disease (CD4 counts below 200 cells/mm<sup>3</sup> ), but since the introduction of HAART and the resultant viral suppression attained by most patients, CSF viral load is no longer useful as a potential marker of CNS infection. Molecular CSF markers of immunological activation like beta2–microglobulin, neopterin, and quinolinic acid are not useful in routine clinical practice due to lack of sensitivity and specificity [11].

#### **5.12. Neuroimaging**

Structural imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is integral to the diagnostic evaluation of patients with suspected HIV associated cognitive impairment ruling out any opportunistic processes. In HAD, cerebral atrophy with ex vacuo ventriculomegaly is the respective radiological finding. The subcortical tissue loss with resultant increase in ventricular size mirrors progressive clinical deterioration. On T2-weighted or T2 FLAIR MRI sequences this appears as patchy and later confluent high intensity white matter signal change, more prominently involving frontal white matter with a characteristic sparing of the subcortical U fibers [11].

Functional imaging techniques (magnetic resonance spectroscopy, MRS; single photon emission computed tomography, SPECT; and positron emission tomography, PET) remain research tools at this stage.

#### **5.13. Neuropsychological testing**

This type of testing, when available, can be used for screening purposes in high-risk asymptomatic or early symptomatic patients, and for follow-up evaluation in patients with established cognitive impairment. Useful neuropsychological tests include those that examine psychomotor speed, verbal and nonverbal learning, and sustained attention [10]. Performance in these tests is interpreted by comparing patients' results to a normative control database and can be influenced by differences in racial, ethnic, cultural, and social background. Appropriate normative standards are not available for large parts of the developing world. The value of standard neuropsychological testing in these regions is questionable [4].

#### **5.14. Treatment/management**

changes in HIV infection. The main differential diagnostic considerations include delirium secondary to drugs and metabolic derangements, encephalopathies due to substance abuse or head injury, CNS opportunistic disease (meningitis and focal brain lesions), and primary psychiatric conditions. Hepatic and renal failure can cause metabolic encephalopathy directly

Full blood count, electrolytes, urea and creatinine, liver and thyroid functions, Vitamin B12

This can be normal but is usually abnormal. Patients with HIV-associated cognitive impairment have CSF abnormalities, typical of a lymphocytic pleocytosis with mildly elevated protein and detectable viral RNA (aseptic meningitis syndrome). Similar abnormalities however can be found in the CSF of neurologically normal HIV patients and are thus nonspecific and unhelpful in confirming a diagnosis of dementia. CSF analysis helps to exclude other etiologies, in particular cryptococcal and tuberculous meningitis, neurosyphilis, CMV encephalitis,

High CSF viral load titers loosely correlate with worsening cognitive performance in patients

HAART and the resultant viral suppression attained by most patients, CSF viral load is no longer useful as a potential marker of CNS infection. Molecular CSF markers of immunological activation like beta2–microglobulin, neopterin, and quinolinic acid are not useful in

Structural imaging with computed tomography (CT) or magnetic resonance imaging (MRI) is integral to the diagnostic evaluation of patients with suspected HIV associated cognitive impairment ruling out any opportunistic processes. In HAD, cerebral atrophy with ex vacuo ventriculomegaly is the respective radiological finding. The subcortical tissue loss with resultant increase in ventricular size mirrors progressive clinical deterioration. On T2-weighted or T2 FLAIR MRI sequences this appears as patchy and later confluent high intensity white matter signal change, more prominently involving frontal white matter with a characteristic

Functional imaging techniques (magnetic resonance spectroscopy, MRS; single photon emission computed tomography, SPECT; and positron emission tomography, PET) remain research

This type of testing, when available, can be used for screening purposes in high-risk asymptomatic or early symptomatic patients, and for follow-up evaluation in patients with established

), but since the introduction of

level, syphilis serology, CD4 count and viral load should be evaluated.

with advanced disease (CD4 counts below 200 cells/mm<sup>3</sup>

routine clinical practice due to lack of sensitivity and specificity [11].

or via impaired drug clearance.

**5.11. Cerebrospinal fluid**

and PML [2, 3, 11].

**5.12. Neuroimaging**

tools at this stage.

sparing of the subcortical U fibers [11].

**5.13. Neuropsychological testing**

**5.10. Blood tests**

132 Advances in HIV and AIDS Control

The use of HAART has led to a decreased frequency of HIV dementia. This is due to the effect of HAART improving cognitive performance in some patients with already established deficits and delaying or even preventing the onset of symptoms in others. HAART is therefore the suggested standard treatment for patients with HIV-associated cognitive impairment. Despite this, there are no specific consensus treatment guidelines. Current evidence and recommendations support the commencement of HAART at diagnosis of seropositivity. HAART should be initiated at the earliest stage of neurocognitive impairment irrespective of the immunological stage as the severity of the impairment at the initiation of HAART is the strongest predictor of persistent cognitive deficits.

CNS penetration of antiretrovirals across the blood–brain barrier has become an important consideration in the planned selection of drugs for CNS-targeted treatment. In this respect, protein binding capacities, lipophilic properties and CSF virological responses are the pharmacological parameters that determine which particular drugs achieve better bioavailability within the CNS compartment. Such putative neuro-active antiretrovirals would theoretically be superior in dementia-targeted treatment. However, clinical trials have failed to consistently confirm such a benefit [11].

Clinical trials of neuroprotective therapies like the NMDA antagonist memantine, and the antioxidant and selective monoamino-oxidase B inhibitor selegiline, targeting pathophysiological mechanisms beyond viral suppression, have to date not yielded conclusive results. Their use in routine clinical practice is not recommended, but remains a subject of further research.

Symptomatic treatment of depression, anxiety, psychosis or mania in patients with HIV neurocognitive impairment remains an integral part of their management.
