An Overview of Neurologic Complications of HIV and Opportunistic Infections

By the end of 2022, the number of people with HIV (PWH) reached 39 million, with approximately 75% taking combination antiretroviral therapy (ART).¹ Since the introduction of ART in 1996, HIV has been transformed from a fatal disease to a chronic illness, with dramatic reductions in acquired immunodeficiency syndrome–related illnesses and deaths.¹

Despite advances in treatment, up to 50% of PWH experience neurologic complications.² HIV can affect both the central nervous system (CNS) and peripheral nervous system (PNS) in acute infection and throughout the course of the illness. These complications may result from direct effects of the virus or indirectly from immune dysfunction that increases susceptibility to CNS opportunistic infections (OIs), heightened immune responses in the setting of ART initiation, and neurotoxic effects of ART. In addition, as PWH on long-standing ART live longer, the incidence of aging-related neurologic conditions, such as cognitive impairment³ and cerebrovascular diseases, has substantially increased.⁴

Despite improvements in HIV-related care worldwide, health care disparities and barriers to obtaining ART in resource-constrained settings, particularly in sub-Saharan Africa and southeast Asia, pose obstacles to the prevention and treatment of HIV infection and its complications. Moreover, no effective therapies exist to reverse the chronic neurologic complications of HIV. Hence, these conditions remain substantial sources of morbidity and mortality among PWH globally. This review focuses on the most common neurologic complications associated with HIV infection, with emphasis on clinical presentation, diagnostic findings, and treatment updates.

Neuropathogenesis of HIV Infection

HIV can enter the CNS as early as 1 to 2 weeks after infection through the trafficking of infected CD4+ T cells across the blood–brain barrier.⁵ HIV viral particles subsequently are transferred to perivascular macrophages and microglia. Once infected, these cells can disrupt normal neuronal function directly, by releasing neurotoxic viral proteins, and indirectly, through the release of inflammatory cytokines, which damage the surrounding neurons through bystander effects.⁶

These infected cells can also act as a CNS viral reservoir, where low-level HIV replication continues to occur, at times resulting in HIV viral particles that are genetically unique from those found in the blood, or CNS compartmentalization.⁷ This can lead to CSF HIV RNA escape (ie, quantifiable HIV RNA is present in the cerebrospinal fluid [CSF] despite plasma viral suppression below measurable clinical limits).⁸

CNS viral reservoir and viral compartmentalization contribute to ongoing neuroinflammation and immune activation in the CNS even after ART initiation and viral suppression in PWH. In addition, because HIV invades the CNS very early in the course of infection, it remains unclear whether early initiation of ART, even during acute HIV infection (AHI), can prevent these phenomena.⁹ As a result, PWH continue to experience a wide range of neurologic complications despite systemic viral suppression. The Figure provides an overview of these HIV-associated neurologic manifestations and their risk factors.

Neurologic Manifestations of AHI

At the time of HIV seroconversion, approximately 10% of individuals may experience neurologic manifestations,¹⁰ which are associated with higher CSF HIV RNA levels compared with those who are neurologically asymptomatic.¹¹ The most common neurologic presentation during AHI is aseptic meningitis, which is characterized by fever, headache, and neck stiffness, and can occur in up to 25% of PWH within the first 2 to 3 weeks of infection.¹¹ Other less common neurologic presentations during AHI include acute inflammatory demyelinating polyneuropathy, isolated cranial nerve VII palsy, transverse myelitis, optic neuropathy, and acute disseminated encephalomyelitis.⁹ During AHI, individuals may test negative for HIV antibodies, which can lead to a missed diagnosis. Therefore, clinicians should include HIV infection in the differential diagnosis for those neurologic conditions, and consider the addition of nucleic acid tests to determine plasma HIV-1 RNA levels. Once HIV infection is confirmed, ART should be initiated promptly, along with disease-specific and symptomatic treatments, discussion of which is beyond the scope of this review.

Chronic Neurologic Complications of HIV

HIV CNS Escape

HIV CNS escape occurs when there is quantifiable HIV RNA in the CSF despite plasma viral suppression below measurable limits⁸ or when there is a higher level of HIV RNA in the CSF than in plasma in those with unsuppressed plasma HIV RNA.¹² Individuals may or may not experience symptoms, and this condition can be secondary in association with a concurrent non–HIV-related OI.^12,13 The prevalence is highly variable among studies, ranging from <10% in asymptomatic individuals¹⁴ to as high as 25% in those who are neurologically symptomatic.¹⁵

HIV CNS escape may present with subacute onset of nonlateralizing symptoms, such as cognitive decline, confusion, headache, altered sensorium, seizures, and tremors.¹⁶ If HIV CNS escape is suspected, the CSF should be sent for quantification of HIV-1 RNA and genotypic drug resistance testing. Neuroimaging is also helpful to confirm the diagnosis and to rule out other possible underlying etiologies. The most common neuroimaging characteristics include diffuse subcortical white matter hyperintensities on T2-weighted fluid-attenuated inversion recovery and a perivascular pattern of contrast enhancement.¹⁷

The treatment of HIV CNS escape involves optimizing the ART regimen based on the plasma and CSF genotypic drug resistance results.¹⁸ It is also important to identify and address barriers to ART access to improve adherence. In secondary CNS escape, treatment of the underlying OI will lead to a reduction of CSF HIV RNA levels, and no additional HIV-specific treatment is necessary.¹⁹ In addition, corticosteroid use has been associated with reduced mortality rates in individuals with concomitant CD8+ encephalitis,²⁰ although a full description of this entity is beyond the scope of this review.

Cognitive Impairment

HIV-associated neurocognitive disorder is the umbrella term that has historically been used to describe cognitive impairment in PWH, including the categories of asymptomatic neurocognitive impairment, mild neurocognitive disorder, and HIV-associated dementia.²¹ The clinical significance of asymptomatic neurocognitive impairment is unclear, and the widespread use of standardized cognitive tests with universal cutoffs can lead to false-positive rates of cognitive impairment, particularly in individuals with lower education level, lower socioeconomic status, or cultural or language barriers.²² Recent recommendations propose that the term HIV-associated neurocognitive disorder no longer be used and that the classification of cognitive impairment should take into consideration the clinical symptoms, low performance on cognitive tests, and abnormal findings on neurologic investigations.²³

In the pre-ART era, severe cognitive impairment was frequently reported in PWH, specifically in the domains of information processing and motor tasks, mood disturbances, and movement disorders. After the widespread implementation of ART, the prevalence of severe cognitive impairment has decreased, although self-reported cognitive impairment remains common in PWH.²⁴

The development of cognitive impairment in virally suppressed PWH may be because of the involvement of the CNS early in HIV infection. Viral reservoirs within the CNS drive sustained production of proinflammatory cytokines, resulting in chronic neuroinflammation and oxidative stress that contribute to the pathogenesis of cognitive impairment.²⁵ Other risk factors associated with the development of cognitive impairment in PWH include longer duration of infection and low nadir CD4+ T-cell counts before ART. ²⁵ Other factors not related to the direct effects of HIV that contribute to the development of cognitive impairment include advanced age, vascular comorbidities, psychiatric disorders, coinfections, and substance use.²³

Cognitive impairment in PWH should not be diagnosed in the setting of acute illness. Brief screening tests can be administered in the outpatient setting in stable individuals,²⁶ and if the individual screens positive for cognitive impairment, a formal neuropsychologic evaluation should be conducted. Once cognitive impairment is confirmed, a comprehensive neurologic examination, neuroimaging with MRI brain (or CT of the head, if MRI is not available), and CSF examination should be considered to rule out pathologies such as CSF HIV RNA escape or CNS OI or coinfection.²⁷ In addition, other common causes of cognitive impairment (eg, thyroid dysfunction, vitamin B12 deficiency, syphilis) should be evaluated.

There are no specific approved medical treatments for HIV-associated cognitive impairment. A multidisciplinary approach is required for symptomatic management. In PWH, ART is the cornerstone of treatment, to maintain viral suppression and reduce viral replication and neuroinflammation.²⁸ Efavirenz has been associated with adverse cognitive symptoms,²⁹ and PWH reporting cognitive impairment while taking efavirenz should be switched to an alternative ART regimen if possible. Other risk factors for cognitive impairment should also be identified and treated. Routine monitoring of cognitive function with screening tools should be performed every 6 to 12 months, and adjunctive therapies that address physical and mental health, such as exercise, should be encouraged.³⁰

Cerebrovascular Diseases

Aging PWH face an increased risk of age-related diseases, including cardiovascular and cerebrovascular disorders. There is accumulating evidence that PWH have a substantially higher risk of developing major adverse cardiovascular events, including myocardial infarction, heart failure, and stroke, compared with people without HIV.³¹ Although suppressive ART has led to a decline in overall stroke incidence, there is still an increased risk of stroke among PWH.³² Moreover, PWH may experience worse stroke outcomes than sex- and age-matched individuals without HIV.³³ The pathophysiology behind this finding is not fully understood, but is thought to be related to a multitude of factors, including HIV-related premature atherosclerosis and vasculopathy, OIs or coinfections causing vasculitis, higher rates of cardiomyopathy, and increased rates of risk factors such as smoking and hypertension.³⁴ Specific HIV-associated factors that increase the risk of cerebrovascular disease include lower CD4 T-cell count, nonsuppressed viral load,³⁵ and certain ART regimens such as protease inhibitors³⁶ and abacavir.³⁷

In new acute stroke, HIV screening should be performed, particularly in individuals without traditional vascular risk factors, as strokes can represent the initial presentation of HIV infection.³⁸ Arterial ischemic stroke is the most common type of stroke in PWH,³⁹ presenting with sudden onset of focal neurologic deficits, such as unilateral weakness or numbness, slurred speech, or visual loss. However, PWH with stroke tend to be younger than people without HIV with stroke,⁴⁰ and may display atypical symptoms, including altered consciousness, acute confusional state, and fever.³⁹

For the acute management of ischemic stroke, studies show that tissue plasminogen activator is effective and safe in PWH, with no difference in mortality or new-onset intraparenchymal hemorrhage rates compared with the general population.⁴¹ Subsequent treatment of ischemic stroke in PWH should be based on the suspected stroke mechanism and is beyond the scope of this review. However, in addition to antiplatelet or anticoagulation and vascular risk factor control, ART should be initiated or adherence encouraged.⁴²

Primary prevention of stroke in PWH should focus on early initiation of ART, ART adherence and viral suppression, control of traditional vascular risk factors, and lifestyle modification. The recent REPRIEVE (NCT02344290) clinical trial showed that pitavastatin 4 mg daily substantially reduced the incidence of major adverse cardiovascular events compared with placebo among PWH with a low to moderate risk of cardiovascular disease.⁴³ Furthermore, smoking cessation, regular physical activity, and a healthy diet are crucial for stroke prevention, particularly considering the aging population of PWH.⁴²

OIs of the CNS

OIs in PWH occur in the setting of uncontrolled viremia, low CD4+ T-cell count (typically <200 cells/µL), and profound T-cell–mediated immunosuppression.⁴⁴ In PWH with advanced HIV or in high-risk individuals with unknown HIV status, OI affecting the CNS should be considered as a possible cause of new-onset neurologic or psychiatric symptoms. CNS OIs may be identified as a primary new infection in a person with HIV or may be unmasked secondarily through the onset of paradoxical immune reconstitution inflammatory syndrome (IRIS) after ART initiation.⁴⁴ Up to 15% of CNS OIs involve multiple concurrent pathogens.⁴⁴

CNS OIs are diagnosed on the basis of clinical presentation, temporal profile, CSF findings, and neuroimaging characteristics. PWH presenting with altered consciousness, headache, meningismus, or behavioral changes should be assessed immediately for potential OIs. Aside from a thorough history and physical and neurologic examination, the following information should be obtained: most recent HIV viral load and CD4 T-cell count, existing (and previous) ART regimen, and any history of OIs. Lumbar puncture for CSF analysis and neuroimaging (CT or MRI with gadolinium contrast) should be performed to establish the diagnosis and determine the appropriate antimicrobial regimen. The Table summarizes the clinical presentation, diagnostic (CSF and neuroimaging) findings, and management of the most common CNS OIs.

Effective ART to maintain viral suppression and CD4+ T-cell count >200 cells/mm3 is the best strategy to prevent CNS OIs in PWH.⁴⁵ However, among individuals newly diagnosed with HIV presenting with concurrent CNS OIs, the optimal timing of ART initiation remains controversial, given the risk of IRIS.⁴⁶

Immune Reconstitution Inflammatory Syndrome

IRIS describes an inflammatory disorder characterized by clinical deterioration or paradoxical worsening of preexisting infectious processes after ART initiation.⁴⁶ IRIS can be paradoxical, which involves the recurrence of symptoms of a previously treated OI; or unmasking, which presents with the inflammatory symptoms of a newly diagnosed OI.⁴⁷

Low CD4+ T-cell count, high viral load at treatment initiation, and a recent diagnosis or a history of an OI are the most substantial risk factors for developing IRIS. CNS IRIS is most commonly associated with OIs caused by JC polyomavirus (progressive multifocal leukoencephalopathy), Cryptococcus, or Mycobacterium tuberculosis.⁴⁷ IRIS can lead to inflammation of brain parenchyma,⁴⁸ typically localized around the site of the underlying OI, and in severe cases, can progress to brain edema, increased intracranial pressure, and herniation.⁴⁹ The mortality rate for CNS IRIS varies between 13% and 75%, depending on the underlying pathogen, as well as other HIV-related and non–HIV-related risk factors.⁴⁷

The diagnosis of CNS IRIS should take into consideration the clinical presentation, temporal profile of symptoms, changes in CD4+ T-cell count and HIV RNA viral load, and exclusion of other potential etiologies that can cause clinical deterioration in PWH. CSF examination with testing of the most common OIs and neuroimaging with MRI brain with contrast should be performed. The CSF profile shows distinct findings of the underlying OI (Table). Brain MRI can demonstrate peripherally restricted diffusion in diffusion-weighted imaging, areas of enhancement in T1-weighted images, and increased signal abnormalities in T2-weighted fluid-attenuated inversion recovery with or without mass effect.⁵⁰

Management of IRIS-related complications includes symptomatic relief in mild cases, treatment of the underlying OI if present, and treatment with corticosteroids in more severe cases.⁴⁹ In steroid-refractory cases, agents targeting the inflammatory cascade, such as tumor necrosis factor–α antagonists and tumor necrosis factor–α monoclonal antibodies, are emerging as promising options for the treatment of CNS IRIS in PWH, although larger clinical trials are required to establish their safety and efficacy.⁵¹

Coinfections

Because of shared risk factors and modes of transmission, PWH are also at increased risk for acquiring concomitant infections that can lead to a range of neurologic symptoms, such as hepatitis C virus (HCV) and syphilis. The neurologic complications of syphilis are discussed in a separate article in this issue.

Hepatitis C Virus. There is evidence indicating that similar to HIV, HCV can cross the blood–brain barrier, leading to neuroinflammation⁵² and neuropsychiatric symptoms, such as impaired cognitive function, mood disturbances, and peripheral neuropathies.⁵² In addition, PWH with HCV coinfection may be at a higher risk of stroke.⁵³

The advent of interferon-free, direct-acting antivirals (DAAs) has resulted in high rates of sustained virologic response and HCV eradication without major adverse effects. Studies have shown that DAA therapy with sustained virologic response is associated with improvements in cognitive function, anxiety, and depression in individuals with HCV monoinfection and HIV/HCV coinfection.⁵⁴ The reversibility of neuropsychiatric outcomes highlights the importance of routine screening, early diagnosis, and prompt initiation of DAA therapy in PWH with HCV coinfection.

PNS Complications

Peripheral nerve disorders are also encountered in all stages of HIV infection. The most common HIV-associated peripheral nerve disorder is sensory polyneuropathy.⁵⁵ This disorder is characterized by distal, symmetric sensory loss accompanied by neuropathic pain and minimal motor weakness. The neuropathy may be caused by inflammation related to the virus itself, neurotoxicity of older-generation ARTs (eg, didanosine, zalcitabine, stavudine), or a combination of both.⁵⁶ Factors not related to HIV infection, including age, alcohol abuse, vitamin deficiencies, and comorbidities (eg, diabetes, thyroid disorders, HCV infection), can also contribute to neuropathy.⁵⁶

The diagnosis of HIV sensory neuropathy is primarily clinical. Neurologic examination reveals impaired pain, temperature, and vibratory sensation, predominantly in the distal lower extremities, and decreased or absent ankle reflexes. Although not routinely necessary, nerve conduction studies may be useful to rule out other pathologies.

There is no specific approved treatment for HIV-associated neuropathies. Medications such as analgesics, anticonvulsants, and antidepressants have been used off-label for symptomatic control of neuropathic pain.⁵⁷ Discontinuation or switching to less neurotoxic ARTs has also been shown to improve symptoms.⁵⁸ In addition, other factors that may exacerbate the symptoms must be controlled, including blood glucose levels and electrolyte or vitamin deficiencies. Although complete resolution is rarely achieved, the primary goal in treating these conditions is to reduce symptoms and improve quality of life.

Aside from sensory polyneuropathy, other PNS complications of HIV infection include polyradiculopathies, mononeuropathies, autonomic neuropathy, mononeuritis multiplex, and motor neuron diseases.⁵⁹ Diagnosing these conditions can be challenging because of diverse, overlapping, and frequently atypical presentations. The temporal progression of symptoms, coexistence of other infections, neurologic examination findings, and ancillary diagnostics such as CSF examination, neuroimaging, and electrodiagnostic studies help distinguish these conditions. Treatment is disease-specific and usually involves a combination of ART and immunomodulating therapies.

Conclusion

Despite substantial progress in HIV treatment, neurologic conditions associated with HIV infection continue to cause disability and death globally. The early involvement of the CNS during AHI and the presence of viral reservoirs in the CNS that drive viral replication and persistent immune activation likely contribute to the pathogenesis of diverse neurologic conditions observed in all stages of HIV infection. With increased life expectancy because of ART, there has been a substantial increase in aging-related neurologic sequelae, such as cognitive impairment and cerebrovascular disorders, in people with long-standing HIV infection. Meanwhile, PWH in resource-limited settings continue to present with CNS OIs and other acquired immunodeficiency syndrome–defining conditions because of barriers to ART access. Research is needed to address the burden of HIV-associated neurologic complications and to explore drug targets in the CNS for the treatment of HIV-associated neurologic complications and strategies for HIV cure.