NeuroAIDS in children

Handbook of Clinical Neurology, Vol. 152 (3rd series) The Neurology of HIV Infection B.J. Brew, Editor https://doi.org/10.1016/B978-0-444-63849-6.00008-6 Copyright © 2018 Elsevier B.V. All rights reserved

Chapter 8

NeuroAIDS in children JO M. WILMSHURST1*, CHARLES K. HAMMOND1, KIRSTY DONALD1, JACQUELINE HOARE2, KAREN COHEN3, AND BRIAN ELEY4 1 Department of Paediatrics, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa 2

Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa

3

Division of Clinical Pharmacology, Department of Medicine, Groote Schuur Hospital, Cape Town, South Africa 4

Department of Infectious Diseases, Red Cross War Memorial Children’s Hospital, Cape Town, South Africa

Abstract The human immunodeficiency virus-1 (HIV-1) enters the central nervous system compartment within the first few weeks of systemic HIV infection and may cause a spectrum of neurologic complications. Without combination antiretroviral therapy (cART), 50–90% of all HIV-infected infants and children develop some form of neuroAIDS. Of the estimated 2.3 million children less than 15 years of age who were living in subSaharan Africa at the end of 2014, only 30% were receiving cART, suggesting that there is a large burden of neuroAIDS among HIV-infected children in sub-Saharan Africa. There is complex interplay between the disease process itself, the child’s immune reaction to the disease, the secondary complications, the side-effects of antiretroviral drugs, and inadequate antiretroviral drug uptake into the central nervous system. In addition there is the layering effect from the multiple socioeconomic challenges for children living in low- and middle-income countries. Adolescents may manifest with a range of neurocognitive sequelae from mild neurocognitive disorder through to severe neurocognitive impairment. Neuroimaging studies on white-matter tracts have identified dysfunction, especially in the frontostriatal networks needed for executive function. Psychiatric symptoms of depression, attention deficit hyperactivity disorder, and behavioral problems are also commonly reported in this age group. Antiretroviral drugs may cause treatment-limiting neurologic and neuropsychiatric adverse reactions. The following chapter addresses the neurologic complications known to be, and suspected of being, associated with HIV infection in children and adolescents.

INTRODUCTION Of the 36.9 million human beings living with human immunodeficiency virus-1 (HIV-1) infection, 2.6 million (or 7.0%) are children less than 15 years of age. More than 90% of infected children acquire HIV-1 through motherto-child transmission during the antenatal, perinatal, or breastfeeding periods, and most infected children live in low- and middle-income countries (LMICs), primarily in sub-Saharan Africa (sSA) (2.3 million or 88.5% of all HIV-infected children) and South-East Asia (0.2 million

or 7.8% of all HIV-infected children), where healthcare is frequently severely limited (UNAIDS, 2015). Without combination antiretroviral therapy (cART), 50–90% of all HIV-infected infants and children will develop neuroAIDS (Abubakar et al., 2008; Kovacs, 2009). cART is critical for preventing or limiting the frequency and severity of neuroAIDS (Chiriboga et al., 2005; Laughton et al., 2012, 2013). However, access to cART that is optimally administered is still unattainable for the vast majority of HIV-infected children living in LMICs.

*Correspondence to: Jo M. Wilmshurst, Department of Paediatrics, 5th Floor ICH, Red Cross War Memorial Children’s Hospital, Klipfontein Road, Rondebosch, Cape Town, South Africa 7700. Tel: +27-21-658-5370, E-mail: [email protected]

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At the end of 2014, only 30% of the 2.3 million HIV-infected children in sSA were receiving cART (UNAIDS, 2015). The spectrum of central nervous system (CNS) and peripheral nervous system effects caused by HIV-1 are collectively referred to as neuroAIDS. NeuroAIDS frequently manifests during the first year of life. For children infected with HIV-1 in utero, neuroAIDS may commence during the intrauterine period. Early studies showed that 13–35% of untreated HIV-infected children will develop progressive HIV encephalopathy (HIVE), a severe manifestation of neuroAIDS. The majority of these children manifest with this condition during the first year of life (Van Rie et al., 2007). Even when considered, there are often significant delays in initiating cART during early childhood, allowing neuroAIDS to manifest. Since mid-2008 the World Health Organization (WHO) has recommended that all HIV-infected children less than 1 year old be commenced on cART without undue delay (WHO, 2008). However, in a recent analysis of more than 30,000 children commenced on cART in four southern African countries, only 16% were started before the age of 1 year (Davies et al., 2013). These observations suggest that suboptimal cART administration is widespread, resulting in a large burden of neuroAIDS among HIV-infected children in LMICs, and often underrecognized because of limited diagnostic capacity. Management of the nervous system manifestations of HIV infection is influenced by the complex interplay between the disease process itself, the child’s immune reaction to the disease, secondary complications, adverse effects of antiretroviral drugs (ARVs), and variable penetration of ARVs into the CNS. In addition, there is the layering effect from the multiple socioeconomic challenges for children living in LMICs.

PATHOGENESIS IN CHILDREN CNS entry by HIV-1 occurs soon after systemic infection, and is mainly facilitated by infected macrophagesmonocytes and or CD4+ T lymphocytes in a “Trojan horse” effect. Viral strains isolated in the brain are predominantly CCR5-trophic, suggesting that viral entry is mediated mainly by monocytes (Arrildt et al., 2015). Elevated lipopolysaccharides induce monocyte activation which promotes virus trafficking into the brain (Brenchley et al., 2006; Ancuta et al., 2008). Once established within the CNS, HIV-1 primarily infects perivascular macrophages and microglia; the entry into the cells by the virus is related to specific macrophagetropic HIV-1 Env variants (Sturdevant et al., 2012; Arrildt et al., 2015). The virus invades neural progenitor cell proliferation, supporting the concept that

HIV-1 is amplified in the maturing/developing brain (Schwartz et al., 2007). Further inflammatory mediators induce neurotoxicity, leading to neuropathology which includes formation of microglial nodules and multinucleated giant cells, reactive astrogliosis, and loss of specific subpopulations of neurons. As such, neuronal injury and death are caused by direct and indirect pathogenic mechanisms, and the consequences are the development of neurologic and neurocognitive manifestations (Kaul and Lipton, 2006).

SPECIFIC NEUROLOGIC COMPLICATIONS The range of neurologic complications in children with HIV-1 infection is diverse and either directly related to HIV-1 brain infection (e.g., HIVE) or to secondary disorders such as CNS opportunistic infections, cerebrovascular diseases, and malignancies (Donald et al., 2014; Wilmshurst et al., 2014a).

HIV encephalopathy HIVE is prevalent in 18% of HIV-infected children (Donald et al., 2014). The Centers for Disease Control and Prevention criteria for the diagnosis of HIVE require the presence of at least one of the following for 2 months (CDC, 1994): ●

●

●

failure to attain or loss of developmental milestones or loss of intellectual ability verified by standard developmental scale or neuropsychologic test impaired brain growth or acquired microcephaly demonstrated by head circumference measurements or brain atrophy on computed tomography (CT) scan or magnetic resonance imaing (MRI) acquired systemic motor deficit manifested by two or more of the following: paresis, pathologic reflexes, ataxia, or gait disturbance.

The most severe form of this disorder typically occurs among young children who develop rapidly progressive disease in association with profound immunosuppression (Mitchell, 2006). Although there has been a marked decline in the incidence of HIVE since the introduction of cART, the decline surpasses the access to cART. Other modalities inclusive of improved global healthcare are suggested (Donald et al., 2014).

CNS opportunistic infections CNS opportunistic infections are reported to affect 8–34% of HIV-infected children (Donald et al., 2014). Table 8.1 outlines the common CNS infections and mass lesions in HIV-infected children.

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Table 8.1 Central nervous system (CNS) infections and lesions in human immunodeficiency virus (HIV)-infected children (Buchanan and Bonthius, 2012; Donald et al., 2014; Wilmshurst et al., 2014a) CNS infection or lesion

Comments

Bacterial meningitis

Commonly due to Streptococcus penumoniae or Haemophilus influenzae type B in unvaccinated children. Unusual pathogens include Salmonella, Treponema pallidum, Bartonella species, Listeria monocytogenes, and Nocardia asteroides complex. Identification requires comprehensive infective workup Mainly caused by Mycobacterium tuberculosis or atypical Mycobacterium. Common in settings with high TB prevalence. Typical neuroimaging findings are less marked. Significant drug interactions may complicate management. Risk of IRIS with ART initiation Causes subacute or chronic encephalitis/ventriculitis, acute ascending radiculomyelitis, or acute or subacute neuropathy Causes acute or subacute encephalitis Causes acute or subacute encephalitis. Increased risk of subsequent cerebrovascular disease Causes progressive multifocal leukoencephalopathy, rare in children Rare in children Less common in children than in adults Infections by Candida species and Aspergillus fumigatus may be complicated by fungal abscesses Caused by Mycobacterium tuberculosis. Mass lesion with surrounding edema on neuroimaging. Treat with combined ART and anti-TB medication Caused by Epstein–Barr virus (EBV). Contrast-enhancing lesion with mass effect on neuroimaging. Confirmed by demonstrating EBV in CSF Onset within 1 year of measles infection of vaccination in immune- compromised children. Presents with altered mental status, medically refractory seizures, and motor deficits. Due to persistence of the infectious measles virus. Neuroimaging normal at presentation but later show atrophy and ventriculomegaly. Diagnosis is by brain biopsy Onset 3–20 years after measles infection in the first 2 years of life. Presents with behavioral deterioration, progressive dementia, and myoclonus. Due to defective measles virus. Measlesspecific antibodies markedly elevated in serum and CSF. Neuroimaging show focal leukodystrophy and diffuse cortical atrophy. EEG is characteristic, showing periodic slow-wave complexes

Tuberculous meningitis

Cytomegalovirus Herpes simplex virus Varicella-zoster virus JC virus Toxoplasma encephalitis Cryptococcal meningitis Other fungal infections Tuberculoma Primary CNS lymphoma Measles inclusion body encephalitis

Subacute sclerosing panencephalitis

ART, antiretroviral therapy; CSF, cerebrospinal fluid; EEG, electroencephalogram; IRIS, immune reconstitution inflammatory syndrome; TB, tuberculosis.

Bacterial meningitis is more prevalent in HIVinfected children than in HIV-infected adults, especially in unvaccinated children. The most common bacteria implicated are Streptococcus pneumoniae and Haemophilus influenzae type B (Commey, 1995; Madhi et al., 2001; Molyneux et al., 2003). Management should include standard comprehensive infective workup and appropriate antibiotic treatment. Immunization and long-term co-trimoxazole prophylaxis are important interventions for preventing opportunistic infections in HIV-infected children (Bwakura-Dangarembizi et al., 2014; Wilmshurst et al., 2014b). Tuberculous meningitis (TBM) is common in HIVinfected children from high tuberculosis (TB)-endemic regions. The HIV-TBM co-infection may present a diagnostic challenge compromising early recognition, as the typical neuroimaging features of TBM (such as basal enhancement and hydrocephalus, as shown

in Fig. 8.1) may be absent or subtle (van der Weert et al., 2006). As such, a low threshold for TBM diagnostic considerations is always necessary in HIV-infected children (Donald et al., 2014). Further, the results of screening tests for TB should be interpreted with caution as the responses may not be as definitive as in immune-competent children (Lancella et al., 2016). There are also challenges in the management of HIVTBM co-infection. The WHO recommends a 12-month anti-TB treatment regimen where children with suspected or confirmed TBM should be treated with a four-drug regimen (isoniazid, rifampicin, pyrazinamide, and ethambutol) for 2 months, followed by a two-drug regimen (isoniazid and rifampicin) for 10 months (WHO, 2010; Bolton et al., 2014). However, some recent studies have recommended shorter treatment duration of 9 months (Lancella et al., 2016).

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Fig. 8.1. Computed tomography of the brain with contrast of a child with tuberculous meningitis, illustrating his edematous brain with hydrocephalus and basal enhancement.

In HIV-infected persons, it is hypothesized that TB granulomas are poorly organized due to impaired cellular recruitment, leading to an increase in susceptibility to both active and disseminated TB disease (Diedrich et al., 2016). This may explain the persistence of M. tuberculosis in some HIV-infected children despite optimal treatment. Significant drug interactions may also complicate the management of TBM. Rifampicin markedly reduces the concentration of lopinavir, a protease inhibitor (PI) used in pediatric practice. When rifampicin-based tuberculosis treatment is administered together with the lopinavir–ritonavir combination in children, additional ritonavir must be administered to prevent subtherapeutic lopinavir concentrations with resultant viral escape and development of resistance (Ren et al., 2008). There is a modest decrease in nevirapine concentrations when administered concomitantly with rifampicin-based tuberculosis treatment, and lead-in dosing at half-dose must be omitted when initiating nevirapine in patients taking rifampicin (Cohen et al., 2008). The effect of rifampicin-containing tuberculosis treatment on efavirenz concentrations is complex, with middosing concentrations of efavirenz usually decreasing marginally when efavirenz is co-administered with rifampicin (Ren et al., 2009). Rifampicin administration may on occasion cause a paradoxic elevation in plasma efavirenz concentration as a result of CYP2B6 loss-of-function polymorphisms (Gengiah et al., 2012; Bertrand et al., 2014; Dooley et al., 2015).

Isoniazid coadministration with efavirenz usually causes mild, insignificant decrease in efavirenz middosing plasma concentration. However, isoniazid may also contribute to elevated efavirenz concentrations by inhibiting CYP2A6, an important pathway for metabolizing efavirenz in individuals who are CYP2B6 slow metabolizers. Furthermore, individuals with slow metabolizer phenotypes for both CYP2B6 and NAT2 genes have been shown to have markedly elevated efavirenz concentrations when co-treated with rifampicin and isoniazid-containing antiTB therapy (Bertrand et al., 2014; Luetkemeyer et al., 2015). Additional treatment consideration includes the timing of cART initiation, as intervention with cART results in reconstitution of antimycobacterial specific immunity with the risk of the TB flaring up in HIV-infected patients as a consequence of the immune reconstitution inflammatory syndrome (IRIS) (Kampmann et al., 2006; Vinnard and Macgregor, 2009). Paradoxic clinical deterioration due to TBM-IRIS should be considered when new neurologic signs develop shortly after initiation of ART in children (Schoeman and van Toorn, 2014). Other opportunistic infections, such as cryptococcal meningitis, progressive multifocal leukoencephalopathy, toxoplasmosis, and cytomegalovirus (CMV), occur less frequently in children than in adults, since reactivation of prior infections is less likely in childhood (Wilmshurst et al., 2014a). CMV infection may cause subacute or chronic encephalitis or ventriculitis, acute ascending radiculomyelitis, or acute or subacute neuropathy Kozlowski et al., 1990). Herpes simplex virus and varicella-zoster virus also cause acute or subacute encephalitis in children with HIV infection (Annunziato and Gershon, 1998; Wilmshurst et al., 2014a). In HIV-infected adults, John Cunningham (JC) virus causes progressive multifocal leukoencephalopathy. This is rarely reported in children. The typical findings on MRI are symmetric white-matter hyperintensities most marked over the posterior regions in the axial fluid-attenuated inversion recovery (FLAIR) sequence (Fig. 8.2) (Nuttall et al., 2004). Also, JC virus DNA can be detected in the cerebrospinal fluid (CSF) in patients with progressive multifocal leukoencephalopathy (Wilmshurst et al., 2014a). Fungal meningitis may be caused by Candida species or Aspergillus fumigatus. These infections may be complicated by fungal abscesses (Kozlowski et al., 1990). Cryptococcal meningitis is less common in children than in adults (Wilmshurst et al., 2014a). Toxoplasma encephalitis is rare in children (Simmonds and Gonzalo, 1998). In HIV-infected patients, unusual pathogens such as atypical mycobacteria, Treponema pallidum, Bartonella

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Fig. 8.2. Axial fluid-attenuated inversion recovery magnetic resonance image demonstrating hyperintensity of the deep left cerebellum extending into the middle cerebellar peduncle in a child with immune reconstitution inflammatory syndrome. (From Nuttall et al. (2004), with permission from Wolters Kluwer Health.)

species, Listeria monocytogenes, and Nocardia asteroides complex may cause CNS infection and should also be considered (Wilmshurst et al., 2014a). Mass lesions in children are most likely to be caused by tuberculoma or lymphoma. In tuberculoma, brain CT scan with contrast may show tuberculous granuloma. On MRI axial T2-weighted image, the tuberculoma may show as a low signal lesion with surrounding edema. Treatment is with a combination of cART and anti-TB medication (Wilmshurst et al., 2014a). Neuro-oncologic complications are an expanding field with their own management challenges in children who are already vulnerable (Wilmshurst et al., 2014a). Primary CNS lymphoma is the most common CNS mass lesion in HIV-infected children and the second most common cause of focal neuropathologyy after stroke (Little, 2006). Tumors tend to be high-grade multifocal B-cell tumors. Affected children present with new focal neuropathology, headache, seizures, and subacute onset of change in cognitive status or behavior. On neuroimaging, lesions enhance with contrast, and are associated with mass effect and edema. Confirmation of the diagnosis may be challenging,

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and empiric treatments for TB and toxoplasmosis are logical interventions. Demonstration of Epstein–Barr virus in CSF can accurately confirm the lymphoma. Outcome is usually poor (Little, 2006). The CNS complications of measles can occur within days or years of acute infection and are often severe. These include primary measles encephalitis, acute postinfectious measles encephalomyelitis, measles inclusion body encephalitis (MIBE), and subacute sclerosing panencephalitis (SSPE) (Buchanan and Bonthius, 2012). MIBE affects immunocompromised children who, within the past year, have either been acutely infected with measles virus or vaccinated for measles (Mustafa et al., 1993). Patients present with altered mental status, intractable focal seizures, focal motor deficits, cortical blindness, language or articulation problems, and dysphagia (Mustafa et al., 1993; Buchanan and Bonthius, 2012) Less frequently, patients present with emotional lability, headache, vomiting, fever, hypertension, or other autonomic signs (Buchanan and Bonthius, 2012). No effective treatment for MIBE exists. ART with prolonged intravenous ribavirin is reported, with limited success (Mustafa et al., 1993; Freeman et al., 2004; Buchanan and Bonthius, 2012). SSPE is due to persistent infection with defective measles virus and is seen in children who contract measles before the age of 5 years, the greatest risk being in infants infected before age 1 year (Buchanan and Bonthius, 2012; Griffin, 2014). The disease manifests 6–15 years after the acute measles infection, but cases manifesting earlier are reported from South Africa following an outbreak of measles between 2009 and 2011 (Kija et al., 2015). In the early stages, patients presented with behavioral problems and decline in intellectual function. This was followed by motor dysfunction (myoclonic jerks, dyskinesias, and cerebellar ataxia). There was progressive neurologic deterioration characterized by rigidity and later ocular manifestations, including necrotizing retinitis, optic neuritis, and cortical blindness. With disease progression, patients lapse into stupor, total mutism, autonomic instability, and eventual death (Buchanan and Bonthius, 2012; Griffin, 2014). SSPE affects both immune-competent and immunecompromised hosts. The risk of CNS infection is increased when infection with the measles virus occurs at a younger age, especially <2 years, when the immune system is immature and residual maternal antibodies may still be present (Griffin, 2014). In settings where there is a high burden of HIV infection, the incidence may be expected to be further increased. Children of HIVinfected mothers are at increased risk of acquiring measles early, even before age 9 months when the first measles vaccine is given. This was the case in the South

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African series, with one patient being HIV-positive and another being HIV-exposed (Kija et al., 2015). Numerous therapeutic agents, including amantadine, interferon-alpha, isoprinosone, and ribavirin, have been used for treatment of SSPE. The most commonly used regimen is a combination of isoprinosone and interferon-alpha, with some suggestion that this combination slows disease progression (Griffin, 2014). Routine measles vaccination, however, remains the best approach for preventing both MIBE and SSPE (Buchanan and Bonthius, 2012; Griffin, 2014). As it is a live attenuated vaccine, its use is contraindicated in severely immunosuppressed HIV-infected children. It is however safe in asymptomatic HIV patients and can be considered in symptomatic HIV patients who are not immunosuppressed (Buchanan and Bonthius, 2012).

Epilepsy There is a higher prevalence of epilepsy in children with HIV infection than in immune-competent children, with an overall prevalence quoted between 7.6% and 14% (Govender et al., 2011; Samia et al., 2013). Epilepsy in children with HIV-1 infection may be related directly to HIV damage or may be secondary to acquired pathology (Donald et al., 2014). Seizures commonly occur as part of the acute disease course, HIVE, and insults sustained from neuroinfections (Kellinghaus et al., 2008; Siddiqi and Birbeck, 2013). Though generalized seizures certainly exist in HIVinfected children, focal-onset seizures are more likely due to the venerability of the CNS to brain lesions (Siddiqi and Birbeck, 2013). In the acute management of seizures in an HIV-infected child, a thorough clinical assessment and laboratory investigations are important to identify the underlying cause. Laboratory studies should include serum glucose and electrolytes, liver function tests, creatinine, complete blood count, blood and urine cultures, toxicology screen, and a chest X-ray. An initial cranial CT scan to exclude a mass lesion prior to lumbar puncture should be done. CSF examination is recommended in all immune-compromised patients, even if they are afebrile. This should include cells, chemistry, bacterial cultures, and viral studies (Siddiqi and Birbeck, 2013). The long-term management of epilepsy in HIVinfected children is complex. In resource-poor settings, antiepileptic drug (AED) access is often limited to the older generation of AEDs, and management is compounded by drug–drug interactions with cART. Phenytoin, phenobarbital, and carbamazepine induce the cytochrome P450 enzyme complex, such that their concurrent use with ARVs that are metabolized by cytochrome P450

isoenzymes may result in drug–drug interactions. These AEDs can have significant interactions with PIs and nonnucleoside reverse transcriptase inhibitors (DiCenzo et al., 2004; Lim et al., 2004; Ji et al., 2008). Depending on the specific drug combinations, the adverse effects may include breakthrough seizures, virologic failure, or drug toxicity (Birbeck et al., 2012; Siddiqi and Birbeck, 2013). Along with seizure types and comorbid medical conditions, the selection of an AED should be dictated by the patient’s cART regimen. Where available, the favored AEDs for use in HIV-infected persons are valproic acid, lamotrigine, levetiracetam, lacosamide, gabapentin, and pregabalin (Samia et al., 2013; Siddiqi and Birbeck, 2013). The benefits of valproic acid include its broad spectrum of activity and relative affordability as compared with newer AEDs. Also, valproic acid does not have significant interactions with PIs or nucleoside reverse transcriptase inhibitors (NRTIs) that could result in ART failure (Siddiqi and Birbeck, 2013). Valproate is thus a reasonable choice in resource-poor settings where the newer AEDs are not available. Zidovudine concentrations are increased by concomitant valproate, due to inhibition of glucoronidation (Lertora et al., 1994), and patients treated with these drugs concomitantly should be monitored closely for zidovudine adverse effects (primarily anemia and neutropenia). Routine dose adjustment of zidovudine is not recommended. The recommendation by a joint panel of the International League Against Epilepsy and the American Academy of Neurology is to avoid enzyme-inducing AEDs in people on cART regimens that include PIs or nonnucleoside reverse transcriptase inhibitors (Birbeck et al., 2012). In settings with limited AED availability, valproate and lamotrigine are recommended as first-line agents in children. Levetiracetam is an alternative (Birbeck et al., 2012; Siddiqi and Birbeck, 2013).

Cerebrovascular disease Between 1.3% and 2.6% of HIV-infected children develop strokes (Park et al., 1990; Patsalides et al., 2002), although a higher prevalence of 4–36% of cerebral ischemic lesions is reported in autopsy series (Park et al., 1990; Qureshi et al., 1997). Cerebrovascular disease may occur from multiple etiologies, including HIV-associated cerebral vasculopathy, opportunistic vasculitides, cardioembolism, or coagulopathy (Table 8.2) (Hammond et al., 2016a). HIV-associated cerebral vasculopathy affects predominantly medium-sized vessels with radiologic evidence of vessel stenosis, occlusion, or aneurysmal dilatation without any identifiable cause other than the HIV infection (Connor, 2009). It results directly or indirectly from HIV

NEUROAIDS IN CHILDREN Table 8.2 Etiology of cerebrovascular disease in human immunodeficiency virus (HIV)-infected children HIV-associated cerebral vasculopathy ● Due to direct infection of HIV (direct) ● Due to vasculitis/perivasculitis (indirect) Opportunistic vasculitis ● Varicella-zoster virus ● Cytomegalovirus ● Mycobacterium ● Candida albicans ● Crypotococcus ● Treponema Malignancies ● Primary central nervous system lymphoma ● Secondary tumors Coagulopathies ● Protein S deficiency ● Protein C deficiency ● Thrombocytopenia Cardioembolism ● Bacterial endocarditis ● Marantic endocarditis ● HIV-associated cardiac dysfunction Antiretroviral therapy ● Protease inhibitors (e.g., lopinavir/ritonavir, saquinavir, fosamprenavir, indinavir, nelfinavir, tipranavir) Reproduced with permission from Hammond CK, Eley B, Wieselthaler N, et al. (2016a) Cerebrovascular disease in children with HIV-1 infection. Dev Med Child Neurol 58: 452–460.

infection and excludes vasculopathy associated with opportunistic infections (Benjamin et al., 2012). In the direct mechanism, the virus directly infects the arterial smooth muscle of cerebral vessels, resulting in endothelial dysfunction, medial fibrosis and thinning, damage, or loss of the muscularis and internal elastic lamina, and intimal hyperplasia of the vascular wall (Hammond et al., 2016a). These changes may lead to stenosis, occlusion, or dilatation of the vessels and thus increase the risk of thrombosis and ischemic strokes. In the indirect mechanism, the vasculopathy results from an autoimmune or inflammatory response to the systemic HIV infection. Endothelial cell injury follows the inflammatory response and increases the risk of strokes (Hammond et al., 2016a). HIV-associated cerebral vasculopathy is more frequently reported in patients with active infection or poor virologic control (low CD4 counts or high viral loads) (Chow et al., 2014). Strokes in HIV-infected children may also result from opportunistic vasculitides due to varicella-zoster virus, CMV, Mycobacterium, Candida, cryptococcal or treponemal infections. These are commonly seen in settings with limited access to ART (Pinto, 1996). Primary

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CNS lymphomas cause strokes by focal infiltration of the blood vessel walls resulting in direct vascular injury, invasion of the lumen, and focal thrombosis (Kieburtz et al., 1993). Systemic HIV infection is thought to trigger consumptive coagulopathy, leading to acquired protein S and/or protein C deficiencies as well as thrombocytopenia, leading to hypercoagulable states. Strokes due to cardioembolism may result from various causes such as bacterial endocarditis, opportunistic infections (marantic endocarditis), or cardiac infection with the HIV itself (Hammond et al., 2016a). Prolonged use of cART which include PIs may lead to elevated cholesterol and triglyceride levels, and thus increase the risk of stokes (d’Arminio et al., 2004). Also, rapid immune restoration following the initiation of ART has been associated with cerebral vasculopathy in HIV-infected children (Bonkowsky et al., 2002). Both ischemic and hemorrhagic strokes occur in HIVinfected children. In the more common ischemic strokes, infarcts occur frequently in the cerebral cortex, basal ganglia, or internal capsule, usually in the territories of the middle or anterior cerebral arteries (Hammond et al., 2016a). Hemorrhagic strokes are mostly intracerebral but subarachnoid hemorrhages are reported (Hammond et al., 2016a). Whilst most children present with overt motor manifestations, affected children can have silent events with subtle behavioral changes or cognitive difficulties which can be confused with HIVE, making the identification of the cerebrovascular disease challenging, especially in settings with limited access to neuroimaging (Hammond et al., 2016a). Others may present as transient ischemic attacks and may not be investigated. Neuroimaging has identified underlying moyamoya syndrome which was clinically silent or presented with recurrent transient ischemic attacks (Fig. 8.3) (Hsiung and Sotero de Menezes, 1999; Hammond et al., 2016b). The workup of the HIV-infected child presenting with stroke should include basic blood counts, glucose, and electrolytes, as well as CD4 counts and HIV RNA viral load (Table 8.3). Blood and CSF samples should be sent for infectious screens. Basic imaging should include brain CT scan, chest radiographs, and echocardiography. Where capacity permits, MRI/magnetic resonance angiography should be done as well as screening for opportunistic vasculitis, coagulopathy, and cardioembolism. Further investigations, where indicated, may include metabolic screening and nuclear medicine scans (Benjamin et al., 2012; Hammond et al., 2016a). No management guidelines for stroke in HIV-infected children exist but common practices target risk factors

A

B

C Fig. 8.3. Neuroimaging from patients with moyamoya syndrome. (A) T2-weighted axial magnetic resonance imaging (MRI) demonstrating intense “netlike” collateral formation in the circle of Willis and ambient wing cisterns (1) with chronic infarcts in the left temporal lobe with gliosis (2) and a large lacune in the midbrain. Also note attenuation of the right middle cerebral artery (MCA) (3). (B) T2-weighted axial MRI demonstrating less intense collateral formation around the circle of Willis but with severe attenuation of the right MCA (1). (C) The corresponding magnetic resonance angiography of the same patient in image (B) demonstrates complete occlusion of the right MCA (1), both anterior cerebral arteries (2), and narrowing of the distal internal carotid arteries with attenuation of the M2 segment of the left MCA (3). (From Hammond et al. (2016a), with permission from John Wiley and Sons.)

Table 8.3 Investigations in human immunodeficiency virus (HIV)-infected children with cerebrovascular disease Basic investigations (for low- and middle-income countries) Test modality

Standard

Specific to HIV-infected children

Blood

Full blood count and peripheral smear Blood glucose, urea, creatinine, and electrolytes Liver function tests Erythrocyte sedimentation rate Fasting lipid profile Cranial CT scan MRI/MRA of head and neck CSF cell counts and chemistry Bacterial cultures

CD4 count and HIV RNA viral load Infectious screen (bacterial and TB cultures, PCR or antigen test for VZV, Mycoplasma, syphilis (RPR, TPHA or VDRL), Toxoplasma, Cryptococcus, HSV, CMV)

Neuroimaging CSF

Cardiovascular assessment Autoimmune screening

Four-limb blood pressure monitoring Electrocardiogram

Coagulation screening

Platelet count Basic clotting screen (PTT, PT, INR) Fibrinogen level Thrombin time Bleeding time Urine dipstick, microscopy, and culture

Others

Further investigations (where availability of resources permit)

Conventional cerebral angiography Test for acid-fast bacilli PCR testing for VZV, HSV, CMV, JC virus, HHV (types 6 and 7), enteroviruses, and adenovirus CSF TB cultures and PCR CSF should also be tested for Aspergillus, Cryptococcus, Toxoplasma, Treponema, and Borrelia Chest X-rays

Mantoux skin test Sputum (or gastric washing) for AFBs, nucleic acid amplification testing, and tuberculosis cultures

Echocardiogram Abdominal Doppler ultrasound According to accepted guidelines (e.g., antiphospholipid antibodies) and as guided by history and clinical findings Protein S and protein C (perform 3 months postevent) Antithrombin III Factor V Leiden Nuclear medicine (SPECT, PET scans)a Lactate (CSF/blood)b Urinary organic and amino acidsc Brain biopsy (rarely)

Reproduced with permission from Hammond CK, Eley B, Wieselthaler N, et al. (2016a) Cerebrovascular disease in children with HIV-1 infection. Dev Med Child Neurol 58: 452–460. a To support features consistent with systemic lupus erythematosus. b To screen for evidence of mitochondrial pathology, such as mitochondrial encephalopathy with lactic acidosis and stroke-like events. c To exclude homocystinuria. AFBs, acid-fast bacilli; CMV, cytomegalovirus; CSF, cerebrospinal fluid; CT, computed tomography; HHV, human herpesvirus; HSV, herpes simplex virus; INR, international normalized ratio; MRA, magnetic resonance angiography; MRI, magnetic resonance imaging; PCR, polymerase chain reaction; PET, positron emission tomography; PT, prothrombin time; PTT, partial thromboplastin time; RPR, rapid plasma reagent test for syphilis; SPECT, single-photon emission computed tomography; TB, tuberculosis; TPHA, Treponema pallidum hemagglutination assay test for syphilis; VDRL, Venereal Disease Research Laboratory test for syphilis; VZV, varicella-zoster virus.

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for stroke. Management priorities should include optimizing virologic suppression, correction of anemia, control of seizures, and aspirin prophylaxis (Hammond et al., 2016a). Neurosurgical interventions may have a role, with endovascular treatment using flow diversion reported in an adult patient with fusiform cerebral aneurysms (Delgado Almandoz et al., 2013). The use of multiple burr holes combined with dural inversion and periosteal synangiosis, whilst reported for people with moyamoya disease, has not been reported for children with HIV and moyamoya disease, but this procedure could offer a potential therapeutic intervention.

Peripheral nerve disease Peripheral nerve disease in HIV-infected individuals commonly presents as HIV-associated distal symmetric polyneuropathy, but other forms of neuropathies include acute inflammatory demyelinating polyneuropathy (AIDP, or Guillain–Barre syndrome), chronic inflammatory demyelinating polyneuropathy (CIDP), autonomic neuropathy, polyradiculopathy, mononeuropathies, mononeuritis multiplex, cranial neuropathies, and amyotrophic lateral sclerosis-like motor neuronopathy (Kaku and Simpson, 2014). The prevalence of peripheral nerve disease in children has not been fully established. Whilst the use of neurotoxic cART, older patient age, history of diabetes, and taller height have been associated with higher

odds of peripheral nerve disease in adults (Evans et al., 2011), no specific risk factors other than neurotoxic cART use have been reported in children. In a cross-sectional study in rural South Africa, a diagnosis of peripheral neuropathy was established in 24% of 182 HIV-infected children on cART (Peters et al., 2014). Clinical features include paresthesia, pain, and weakness, but some may be asymptomatic (Kaku and Simpson, 2014). Poor nutritional state and global wasting may dominate the clinical picture, masking focal wasting due to underlying peripheral neuropathy (Donald et al., 2014). Thus, unless accompanied by pain, the clinical signs can be subtle in the chronically unwell child and easily missed. Peripheral neuropathy can occur from direct and indirect etiologies (Table 8.4). HIV-associated distal symmetric polyneuropathy is associated with HIV infection itself or with toxic effects of ARVs, namely antiretroviral toxic neuropathy. Commonly implicated ARVs are the so-called “d-drugs” – stavudine (d4T), didanosine (ddI), and zalcitabine (ddC) – which are no longer used in routine clinical practice (Kaku and Simpson, 2014; Sankhyan et al., 2015). The evaluation of HIV-infected children with peripheral nerve disease should include the clinical neurologic exam, blood counts (to exclude other forms of neuropathy, such as B12 deficiency), nerve conduction studies, electromyography, and possibly intraepidermal nerve

Table 8.4 Types of peripheral neuropathy in human immunodeficiency virus (HIV)-infected persons Type of neuropathy

Comments

HIV-associated distal symmetric polyneuropathy

Due to direct effect of HIV infection or toxic effect of ART (mainly stavudine and didanosine). Has been reported in both children and adults. Distal, symmetric symptoms (numbness, tightness, burning pain, paresthesias). Decreased/absent reflexes, loss of vibration perception, decreased pinprick or temperature sensation in a stocking-glove distribution May be asymptomatic Ascending muscle weakness with loss of reflexes Relative sparing of sensory symptoms May present with orthostatic dizziness, pupillomotor and visual symptoms, dry eyes and mouth, diarrhea, constipation, gastroparesis, urinary incontinence, change in body sweating Can be rapidly progressive and presents with weakness and numbness of the lower extremities, frequently with sphincter dysfunction CMV has been implicated Relatively rare Present with motor and sensory symptoms in an asymmetric pattern May be due to tuberculosis, syphilis, varicella-zoster virus, meningeal lymphomatosis Rapidly progressive upper and lower motor neuron disease

Acute/chronic inflammatory demyelinating polyneuropathy Autonomic neuropathy

Polyradiculopathy

Mononeuritis multiplex Cranial neuropathies Amyotrophic lateral sclerosis (ALS)-like motor neuropathy

ART, antiretroviral therapy; CMV, cytomegalovirus.

NEUROAIDS IN CHILDREN fiber density measurement by skin biopsy (Kaku and Simpson, 2014). In HIV-infected children with high CD4 counts who present with AIDP or CIDP, CSF cannot be reliably used to confirm the diagnosis, as the CSF in these patients, in steady states, tends to show elevated protein with a mild lymphocytic pleocytosis masking the typical albuminocytologic dissociation (elevated CSF protein without pleocytosis) expected in AIDP and CIDP. CSF studies should also include polymerase chain reaction assays for CMV and other viruses. Management may require termination of cARTs. With the shift away from routine d4T usage, there has been a decrease in the incidence of peripheral nerve disease in HIV-infected individuals (Machado-Alba, 2013; WHO, 2013). Available treatment options focus on symptomatic pain management. Several agents have been used in clinical trials with limited success, but topical capsaicin and recombinant human nerve growth factor show promise. Other potential agents include gabapentin, pregabalin, lamotrigine, amitriptyline, cannabis, prosaptide, Peptide T, and actyl-L-carnitine (Kaku and Simpson, 2014; Wilmshurst et al., 2014a). AIDP and CIDP are typically treated with intravenous immunoglobulin or plasmapheresis. There is a role for corticosteroids in HIV-negative CIDP patients, although caution should be exercised in HIV-positive patients because of immunosuppression (Kaku and Simpson, 2014). Vacuolar myelopathy is relatively common in cARTnaïve adults, but rare in children. Light and electron microscopy shows vacuoles surrounded by a thin myelin sheath and appears to arise from swelling within myelin sheaths. Signs and symptoms include paraparesis, often accompanied by spasticity or ataxia (or both). Possible causes of the vacuolar changes include opportunistic viral infections, tumors, or metabolic derangement related to selective nutritional deficiency (Petito et al., 1985).

NEUROCOGNITIVE AND NEUROPSYCHIATRIC COMPLICATIONS IN ADOLESCENTS Neurocognition The neurocognitive effects of HIV in children are hypothesized to be due to a variable combination of direct virusmediated effects on brain macrophages and microglia, and immune-mediated inflammatory responses which are therefore an indirect mechanism of injury. It is well established that cART has direct benefit on both mortality and morbidity in HIV-1-infected children. Mechanisms for this include the obvious pathways of improved immunologic function and viral suppression in the peripheral blood, but also through less direct mechanisms such as improved nutritional status, reduced hospitalization,

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and improved mother–child bonding due to improved general health (Zink et al., 1999; Willen, 2006; Heaton et al., 2011). Increasingly highlighted, but less defined, is the role that cART has played in reducing more severe neurodisability with the consequent evolution of a milder spectrum of HIV-associated neurocognitive disorders in children, especially as they reach school age and adolescence. The degree to which individual or cART agents penetrate the CNS remains an important potential mechanism for the ongoing effects of HIV in children who are on treatment and who have documented viral suppression. Hypothesized compartmentalization of the virus due in part to low drug concentrations in the CNS may occur. Adult studies of the CNS penetration effectiveness score (CPE) of cART regimens on neurocognitive outcomes have reported conflicting or inconclusive results (Cysique et al., 2009, 2011; Marra et al., 2009; Garvey et al., 2011; Smurzynski et al., 2011; Caniglia et al., 2014; Ellis et al., 2014) and there are very few data available in children. Of the studies reported, one recent large multicenter report suggests that, though early cART initiation improves neurocognitive performance at school age, CPE of the pediatric regimens in their cohort was not associated with improved outcomes. (Crowell et al., 2015a). In many resource-poor environments (especially countries in sSA where prevalence of HIV is highest), treatment policies and access to cART for children of varying ages have evolved rapidly but unevenly over recent years. Consequently, there remain many children and adolescents in this region who have initiated cART only after immune compromise or the established diagnosis of HIVE, resulting in neurocognitive deficits that remain permanent despite cART (Hoare et al., 2016). The literature on the developmental and neurocognitive effects of HIV on the maturing brain has become established over the last decade (Smith and Wilkins, 2015). What is less well understood is the individual variability as well as the contributions of additional genetic, medical, nutritional, immunologic, and psychosocial contextual factors on the neurocognitive profile of children vertically infected with HIV. Children and adolescents are reported with a range of neurocognitive sequelae from mild neurocognitive disorder through to severe global developmental delay or neurocognitive impairment. These impairments may have a significant effect on a child’s ability to function within the real-world demands of school academics as well as more adaptive demands of everyday life (Donald et al., 2015; Smith and Wilkins, 2015). Literature reporting the adult HIV neurocognitive effects has increased over recent years and reflects a better understanding of the spectrum of HIV-associated

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neurocognitive disorders (HAND) manifesting in this group. This includes a less severe but impairing range of functional neurocognitive deficits along with the full-blown HIV-associated dementia. In addition the important consequences these impairments may have, in an affected adult’s ability to function, are explicitly recognized. The criteria have clinical utility, as they allow the development of individual management plans for adults with HIV-related cognitive problems. In children, however, there remain no consistent diagnostic criteria for a spectrum of neurocognitive disorders secondary to HIV infection, though recent reports indicate that the adult HAND criteria can be successfully applied to older children and adolescents (Hoare et al., 2016). Endorsement of these criteria for pediatric practice is urgently needed in pediatric neuroHIV in order to better understand the impact, social, and educational management needed to support the large number of children in sSA with vertically infected HIV. In addition, this may have an impact on policies for cART initiation in older children who have not yet qualified for treatment on other clinical or immunologic grounds. It is therefore critical that clinicians managing HIV-infected children are able to identify and address such impairments. Even HIV-infected children who have been on cART with suppressed viral loads from early life have been described as having poorer performance on a number of specific cognitive domains.

Adolescence With the survival of children into adolescence and adulthood, there is increasing recognition that adequate viral suppression on blood studies does not always reflect the same in the brain. Without measurement of levels in the CSF, false reassurance may be occurring. The brain virus reservoir is known to persist and be resistant to cART. Adolescents are manifesting with a range of neurocognitive sequelae from mild neurocognitive disorder through to adolescents who have severe neurocognitive impairment. HIV-infected children have poorer performance on general intelligence testing as well as a number of specific cognitive domains. Neuroimaging studies on whitematter tracts are identifying dysfunction, especially in the frontostriatal networks needed for executive function (Hoare et al., 2015). During adolescence HIV-infected children also face psychosocial stressors that differ from other chronic childhood illnesses. Psychosocial development and behavior during adolescence are profoundly influenced by HIV, with concerns related to adherence, stigmatization, risk taking, and mental health (Domek, 2009). A review of the mental health of children living with HIV suggested that they experience emotional and

behavioral problems, including psychiatric disorders, at higher than expected rates, often exceeding those other high-risk groups (Mellins and Malee, 2013). Loss is frequently both recurrent and cumulative for HIV-infected children. Not only are they dealing with the possible loss of their own life, but in the case of perinatally acquired infection, they are also dealing with the loss of immediate family members (Battles and Wiener, 2002). Children orphaned by AIDS are more likely to have depression, peer relationship problems, posttraumatic stress, and conduct problems than children orphaned by other causes (Cluver et al., 2007). Data from reviews, although based on very limited studies, suggest that attention deficit hyperactivity disorder, anxiety, and depression are all exceedingly common in HIV-infected children (Scharko, 2006). Adolescence is a time of behavioral experimentation and risk taking and a time to assert independence and of self-discovery. Adolescents who were perinatally infected with HIV did not necessarily expect to be able to do some of these things. When confronted with decisions about relationships, engaging in sexual activity, experimentation with drugs and alcohol, most adolescents face dilemmas about the choices available to them. The complexity of these choices is greater for adolescents with HIV who must also consider issues of disclosure of their status, HIV transmission, adverse reactions with cART, and adherence to cART regimens. Achieving independence may be all the more frightening because it entails serious health concerns (Battles and Wiener, 2002). For children and adolescents, greater disclosure in general is related to increased social support, social self-competence, and decreased problem behavior, whereas public disclosure is associated with lower self-competence (Battles and Wiener, 2002). The mental health of adolescents with HIV could be linked to the illness they suffer from, to adolescence in general, and to psychosocial problems generated by the interaction between the illness, the adolescent, and the immediate environment. Certainly, many health professionals report that managing the complexity and range of health concerns in adolescents is more challenging than for other age groups (Sawyer et al., 2007). Poor mental health may lead to denial of infection, apathy, and hopelessness, resulting in medication refusal. Child stress has also been associated with poor adherence. Psychosocial function has been given relatively limited attention; however, these issues may be just as critical as biomedical and socioeconomic factors for the success of treatment (Haberer and Mellins, 2009). AIDS-related mortality among HIV-positive adolescents has risen by 50% despite the scale-up of cART. Poor cART adherence is likely to play a role in the increase of AIDS-related deaths among adolescents and has been

NEUROAIDS IN CHILDREN shown to be associated with psychosocial and mental health difficulties (Dow et al., 2016). Adolescents report unique adherence challenges when compared to adults, including physical and psychologic factors, disruption of daily routines, the importance of support from family and care givers, and adapting to increased responsibility for medication-taking behaviors (Williams et al., 2006; Reisner et al., 2009; Murphy et al., 2011; Buchanan et al., 2012; Lall et al., 2015). The first generation of perinatally infected children entering adolescence and young adulthood face new challenges, which we are only beginning to understand (Koenig et al., 2011). Adolescent development is characterized by impulsivity, limited behavioral control, and risk taking (Arnett, 1992; Steinberg, 2008), all of which could negatively affect adherence. HIV-infected adolescents are likely to face future physical and psychologic health consequences related to the cognitive and adaptive functioning challenges they face if mental healthcare is not made a priority in the fight against HIV (Domek, 2009). This care may need to take into account that parents/care givers share the infection. The impact of HIVon the family surpasses that of virtually all other chronic conditions. This is compounded by the stigma surrounding HIV (Meyers and Weitzman, 1991). Thus, there is an urgent need for longitudinal research assessing the long-term effect of cART and timing of cART initiation on neurocognitive outcomes of vertically HIV-infected older children and adolescents, particularly in sSA (Laughton et al., 2013).

THE IMPACT OF ART ON CHILDREN WITH NEUROLOGIC DISEASE cART is critical for preventing or limiting the frequency and severity of neuroAIDS. However, access to cART that is optimally administered is still unattainable for the vast majority of HIV-infected children living in LMICs.

CNS penetrance of antiretroviral agents It has been hypothesized that ARVs with good penetration into the CNS would result in better neurocognitive outcomes in patients on cART. The CPE score places ARVs into four categories based on the drugs’ physicochemical properties, concentrations achieved in the CSF, efficacy based on CSF virologic suppression, and neurocognitive improvement (Letendre et al., 2008, 2010). A randomized controlled trial failed to demonstrate neurocognitive benefit of regimens with high CNS penetrance in adults. The trial was stopped early on the recommendation of the data safety monitoring board because of slow accrual and low likelihood that a difference in

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the primary outcome (change in global deficit score at week 16) would be detected (Ellis et al., 2014). A large observational cohort (61,398 adults) found that regimens with high CPE scores were, paradoxically, associated with increased risk of HIV dementia, which may be due to confounding by indication, or toxicity of ARVs with higher CPE scores (Caniglia et al., 2014). An analysis including 396 children from two US cohorts found an association between early viral suppression and improved neurocognitive outcome, but no association between CPE score and neurocognitive outcome (Crowell et al., 2015b). All of these studies, however, had methodologic flaws, leaving the issue still unresolved.

Neuropsychiatric adverse effects of efavirenz Efavirenz is recommended as part of the WHO preferred first-line cART regimen for children 3 years old and above (WHO, 2016). Efavirenz may cause a range of neuropsychiatric side-effects, including dizziness, insomnia, nightmares, impaired concentration, and occasionally severe psychiatric symptoms, including psychosis, depression, and suicidal (Kenny et al., 2012). Neuropsychiatric adverse effects occur commonly after efavirenz initiation, and tend to wane with time (Apostolova et al., 2015). In adult patients, CNS adverse effects are reported in a third of patients on efavirenz-containing cART, with severe CNS adverse effects in 6.1% (Ford et al., 2015). In a Ugandan cohort, 14.1% of children on efavirenzcontaining cART experienced CNS-associated adverse effects (Tukei et al., 2012). Assessment is difficult in young children (Tukei et al., 2012). A recent meta-analysis of data from four efavirenz randomized controlled trials found an increased risk of suicidality in adult patients randomized to efavirenz versus controls (Mollan et al., 2014). Prolonged treatment with efavirenz-containing cART may play a role in HAND, with poorer cognitive function seen in adults with long-term efavirenz exposure (Ciccarelli et al., 2011; Underwood et al., 2015). This requires further study in children. Efavirenz is metabolized predominantly by cytochrome P450 isoenzyme 2B6 (CYP2B6); hydroxylation forms 8-hydroxyefavirenz. Single-nucleotide polymorphisms of CYP2B6 result in impaired efavirenz metabolism and higher efavirenz concentrations. These polymorphisms are particularly common in African patients (Klein et al., 2005; Dickinson et al., 2015). Neuropsychiatric adverse effects are frequently associated with higher efavirenz concentrations (Marzolini et al., 2001; Gallego et al., 2004). High efavirenz concentrations have been associated with severe neuropsychiatric toxicity in children, with case reports in 4 African children

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of cerebellar dysfunction, generalized seizures, and absence seizures, which resolved on efavirenz withdrawal (Pinillos et al., 2016). Psychosis has been reported in a 12-year-old with impaired efavirenz metabolism and markedly elevated efavirenz concentrations; symptoms resolved on efavirenz withdrawal (Lowenhaupt et al., 2007). Efavirenz quantification should be included in the workup of a child on efavirenz-based cART with unusual or unexplained neuropsychiatric symptoms.

Neurologic adverse effects of nucleoside reverse transcriptase inhibitors NRTIs as a class are mitochondrially toxic, and inhibit the enzyme DNA polymerase gamma (Birkus et al., 2002). Mitochondrial toxicity results in a range of clinical manifestations, including peripheral neuropathy. The most potently mitochondrially toxic NRTIs, zalcitabine and didanosine, are now rarely prescribed. Stavudine has been phased out in treatment programs because of concerns about toxicity (lipoatrophy and neuropathy). In a prospective cohort study of Pediatric AIDS Clinical Trials Group participants, 13/1154 (1.1%) children treated with stavudine and lamivudine as their NRTI backbone developed peripheral neuropathy (Van Dyke et al., 2008). Children treated with stavudine-containing cART in sSA have a high rate of stavudine substitution due to toxicity – 28.8 per 1000 child years on treatment (95% confidence interval 23.6–35.2) in a cohort of 2222 children in South Africa (Palmer et al., 2013). The bulk of stavudine-related treatment-limiting toxicity in children in sSA is lipodystrophy, with peripheral neuropathy accounting for the minority of treatment switches: only 2 of 96 (2%) in the South African cohort (Palmer et al., 2013). Current WHO ART guidelines recommend that stavudine not be used as a first-line NRTI, and that children on stavudine-containing regimens be switched to alternative NRTIs (WHO, 2016).

SUMMARY AND FUTURE PERSPECTIVES Access to cART in many LMICs remains limited, allowing neuroAIDS to manifest. Furthermore, in HIVinfected children who are treated with cART, delay in commencing therapy adds to the burden of neuroAIDS. Because of improvement in the general healthcare of perinatally infected children, many more are surviving into adolescence and adulthood. Clinicians should be prepared for an evolution in the clinical manifestations of neuroAIDS as these children progress into adolescence and beyond, both in terms of previously recognized adult neurologic complications and especially the presentation of cognitive and psychiatric complications for which health services need to be aware and actively intervene.

This chapter has described many recent developments which have broadened our understanding of the impact of HIV-1 infection on the developing brain during childhood. There is still room for more descriptive research to better understand the evolution of the clinical manifestations over time, especially in those children who commence cART during early infancy. Furthermore, optimizing non-cART interventions for children and adolescents with neuroAIDS in LMICs requires indepth research.

REFERENCES Abubakar A, Van Baar A, Van de Vijver FJ et al. (2008). Paediatric HIV and neurodevelopment in sub-Saharan Africa: a systematic review. Trop Med Int Health 13: 880–887. Ancuta P, Kamat A, Kunstman KJ et al. (2008). Microbial translocation is associated with increased monocyte activation and dementia in AIDS patients. PLoS ONE 3: e2516. Annunziato PW, Gershon AA (1998). Herpesvirus infections inchildren infected with HIV. In: CM Wilfert, PA Pizzo (Eds.), Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents. Williams & Wilkins, Baltimore. Apostolova N, Funes HA, Blas-Garcia A et al. (2015). Efavirenz and the CNS: what we already know and questions that need to be answered. J Antimicrob Chemother 70: 2693–2708. Arnett J (1992). Reckless behavior in adolescence: a developmental perspective. Dev Rev 12: 339–373. Arrildt KT, LaBranche CC, Joseph SB et al. (2015). Phenotypic correlates of HIV-1 macrophage tropism. J Virol 89: 11294–11311. Battles HB, Wiener LS (2002). From adolescence through young adulthood: psychosocial adjustment associated with long-term survival of HIV. J Adolesc Health 30: 161–168. Benjamin LA, Bryer A, Emsley HC et al. (2012). HIV infection and stroke: current perspectives and future directions. Lancet Neurol 11: 878–890. Bertrand J, Verstuyft C, Chou M et al. (2014). Dependence of efavirenz- and rifampicin-isoniazid-based antituberculosis treatment drug-drug interaction on CYP2B6 and NAT2 genetic polymorphisms: ANRS 12154 study in Cambodia. J Infect Dis 209: 399–408. Birbeck GL, French JA, Perucca E et al. (2012). Antiepileptic drug selection for people with HIV/AIDS: evidence-based guidelines from the ILAE and AAN. Epilepsia 53: 207–214. Birkus G, Hitchcock MJ, Cihlar T (2002). Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother 46: 716–723. Bolton S, McDonald D, Curtis E et al. (2014). Autism in a recently arrived immigrant population. Eur J Pediatr 173: 337–343.

NEUROAIDS IN CHILDREN Bonkowsky JL, Christenson JC, Nixon GW et al. (2002). Cerebral aneurysms in a child with acquired immune deficiency syndrome during rapid immune reconstitution. J Child Neurol 17: 457–460. Brenchley JM, Price DA, Schacker TW et al. (2006). Microbial translocation is a cause of systemic immune activation in chronic HIV infection. Nat Med 12: 1365–1371. Buchanan R, Bonthius DJ (2012). Measles virus and associated central nervous system sequelae. Semin Pediatr Neurol 19: 107–114. Buchanan AL, Montepiedra G, Sirois PA et al. (2012). Barriers to medication adherence in HIV-infected children and youth based on self-and caregiver report. Pediatrics 129: e1244–e1251. Bwakura-Dangarembizi M, Kendall L, Bakeera-Kitaka S et al. (2014). A randomized trial of prolonged co-trimoxazole in HIV-infected children in Africa. N Engl J Med 370: 41–53. Caniglia EC, Cain LE, Justice A et al. (2014). Antiretroviral penetration into the CNS and incidence of AIDS-defining neurologic conditions. Neurology 83: 134–141. CDC (1994). Revised classification system for human immunodeficiency virus infection in children less than 13 years of age [online] [accessed June 2016]. https://www.cdc.gov/ mmwr/preview/mmwrhtml/00032890.htm. Chiriboga CA, Fleishman S, Champion S et al. (2005). Incidence and prevalence of HIV encephalopathy in children with HIV infection receiving highly active antiretroviral therapy (HAART). J Pediatr 146: 402–407. Chow FC, Bacchetti P, Kim AS et al. (2014). Effect of CD4 + cell count and viral suppression on risk of ischemic stroke in HIV infection. AIDS 28: 2573–2577. Ciccarelli N, Fabbiani M, Di Giambenedetto S et al. (2011). Efavirenz associated with cognitive disorders in otherwise asymptomatic HIV-infected patients. Neurology 76: 1403–1409. Cluver L, Gardner F, Operario D (2007). Psychological distress amongst AIDS-orphaned children in urban South Africa. J Child Psychol Psychiatry 48: 755–763. Cohen K, van Cutsem G, Boulle A et al. (2008). Effect of rifampicin-based antitubercular therapy on nevirapine plasma concentrations in South African adults with HIV-associated tuberculosis. J Antimicrob Chemother 61: 389–393. Commey JO (1995). Neurodevelopmental problems in Ghanaian children: part I. Convulsive disorder. West Afr J Med 14: 189–193. Connor MD (2009). Treatment of HIV associated cerebral vasculopathy. J Neurol Neurosurg Psychiatry 80: 831. Crowell CS, Huo Y, Tassiopoulos K et al. (2015a). Early viral suppression improves neurocognitive outcomes in HIVinfected children. AIDS 29: 295–304. Crowell CS, Huo Y, Tassiopoulos K et al. (2015b). Early viral suppression improves neurocognitive outcomes in HIVinfected children. AIDS 29: 295–304. Cysique LA, Vaida F, Letendre S et al. (2009). Dynamics of cognitive change in impaired HIV-positive patients initiating antiretroviral therapy. Neurology 73: 342–348. Cysique LA, Waters EK, Brew BJ (2011). Central nervous system antiretroviral efficacy in HIV infection: a qualitative

113

and quantitative review and implications for future research. BMC Neurol 11: 148. d’Arminio A, Sabin CA, Phillips AN et al. (2004). Cardio- and cerebrovascular events in HIV-infected persons. AIDS 18: 1811–1817. Davies MA, Phiri S, Wood R et al. (2013). Temporal trends in the characteristics of children at antiretroviral therapy initiation in southern Africa: the IeDEA-SA Collaboration. PLoS One 8: e81037. Delgado Almandoz JE, Crandall BM, Fease JL et al. (2013). Successful endovascular treatment of three fusiform cerebral aneurysms with the pipeline embolization device in a patient with dilating HIV vasculopathy. BMJ Case Reports. https://doi.org/10.1136/bcr-2012-010634. DiCenzo R, Peterson D, Cruttenden K et al. (2004). Effects of valproic acid coadministration on plasma efavirenz and lopinavir concentrations in human immunodeficiency virus-infected adults. Antimicrob Agents Chemother 48: 4328–4331. Dickinson L, Amin J, Else L et al. (2015). Pharmacokinetic and pharmacodynamic comparison of once-daily efavirenz (400 mg vs. 600 mg) in treatment-naive hiv-infected patients: results of the ENCORE1 study. Clin Pharmacol Ther 98: 406–416. Diedrich CR, O’Hern J, Wilkinson RJ (2016). HIV-1 and the Mycobacterium tuberculosis granuloma: a systematic review and meta-analysis. Tuberculosis (Edinb) 98: 62–76. Domek GJ (2009). Facing adolescence and adulthood: the importance of mental health care in the global pediatric AIDS epidemic. J Dev Behav Pediatr 30: 147–150. Donald KA, Hoare J, Eley B et al. (2014). Neurologic complications of pediatric human immunodeficiency virus: implications for clinical practice and management challenges in the African setting. Semin Pediatr Neurol 21: 3–11. Donald KA, Walker KG, Kilborn T et al. (2015). HIV encephalopathy: pediatric case series description and insights from the clinic coalface. AIDS Research and Therapy 12: 2-014-0042-0047. Dooley KE, Denti P, Martinson N et al. (2015). Pharmacokinetics of efavirenz and treatment of HIV-1 among pregnant women with and without tuberculosis coinfection. J Infect Dis 211: 197–205. Dow DE, Turner EL, Shayo AM et al. (2016). Evaluating mental health difficulties and associated outcomes among HIVpositive adolescents in Tanzania. AIDS Care 28: 825–833. Ellis RJ, Letendre S, Vaida F et al. (2014). Randomized trial of central nervous system-targeted antiretrovirals for HIVassociated neurocognitive disorder. Clin Infect Dis 58: 1015–1022. Evans SR, Ellis RJ, Chen H et al. (2011). Peripheral neuropathy in HIV: prevalence and risk factors. AIDS 25: 919–928. Ford N, Shubber Z, Pozniak A et al. (2015). Comparative safety and neuropsychiatric adverse events associated with efavirenz use in first-line antiretroviral therapy: a systematic review and meta-analysis of randomized trials. J Acquir Immune Defic Syndr 69: 422–429. Freeman AF, Jacobsohn DA, Shulman ST et al. (2004). A new complication of stem cell transplantation: measles inclusion body encephalitis. Pediatrics 114: e657–e660.

114

J.M. WILMSHURST ET AL.

Gallego L, Barreiro P, Rio Rd et al. (2004). Analyzing sleep abnormalities in HIV-infected patients treated with efavirenz. Clin Infect Dis 38: 430–432. Garvey L, Surendrakumar V, Winston A (2011). Low rates of neurocognitive impairment are observed in neuroasymptomatic HIV-infected subjects on effective antiretroviral therapy. HIV Clin Trials 12: 333–338. Gengiah TN, Holford NH, Botha JH et al. (2012). The influence of tuberculosis treatment on efavirenz clearance in patients co-infected with HIV and tuberculosis. Eur J Clin Pharmacol 68: 689–695. Govender R, Eley B, Walker K et al. (2011). Neurologic and neurobehavioral sequelae in children with human immunodeficiency virus (HIV-1) infection. J Child Neurol 26: 1355–1364. Griffin DE (2014). Measles virus and the nervous system. Handb Clin Neurol 123: 577–590. Haberer J, Mellins C (2009). Pediatric adherence to HIV antiretroviral therapy. Curr HIV/AIDS Rep 6: 194–200. Hammond CK, Eley B, Wieselthaler N et al. (2016a). Cerebrovascular disease in children with HIV-1 infection. Dev Med Child Neurol 58: 452–460. Hammond CK, Shapson-Coe A, Govender R et al. (2016b). Moyamoya syndrome in South African children with HIV-1 infection. J Child Neurol 31: 1010–1017. Heaton RK, Franklin DR, Ellis RJ et al. (2011). HIVassociated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol 17: 3–16. Hoare J, Fouche JP, Phillips N et al. (2015). White matter micro-structural changes in ART-naive and ART-treated children and adolescents infected with HIV in South Africa. AIDS 29: 1793–1801. Hoare J, Phillips N, Joska JA et al. (2016). Applying the HIVassociated neurocognitive disorder diagnostic criteria to HIV-infected youth. Neurology 87: 86–93. Hsiung GY, Sotero de Menezes M (1999). Moyamoya syndrome in a patient with congenital human immunodeficiency virus infection. J Child Neurol 14: 268–270. Ji P, Damle B, Xie J et al. (2008). Pharmacokinetic interaction between efavirenz and carbamazepine after multiple-dose administration in healthy subjects. J Clin Pharmacol 48: 948–956. Kaku M, Simpson DM (2014). HIV neuropathy. Curr Opin HIV AIDS 9: 521–526. Kampmann B, Tena-Coki GN, Nicol MP et al. (2006). Reconstitution of antimycobacterial immune responses in HIV-infected children receiving HAART. AIDS (London, England) 20: 1011–1018. Kaul M, Lipton SA (2006). Mechanisms of neuronal injury and death in HIV-1 associated dementia. Curr HIV Res 4: 307–318. Kellinghaus C, Engbring C, Kovac S et al. (2008). Frequency of seizures and epilepsy in neurological HIV-infected patients. Seizure 17: 27–33. Kenny J, Musiime V, Judd A et al. (2012). Recent advances in pharmacovigilance of antiretroviral therapy in HIVinfected and exposed children. Curr Opin HIV AIDS 7: 305–316.

Kieburtz KD, Eskin TA, Ketonen L et al. (1993). Opportunistic cerebral vasculopathy and stroke in patients with the acquired immunodeficiency syndrome. Arch Neurol 50: 430–432. Kija E, Ndondo A, Spittal G et al. (2015). Subacute sclerosing panencephalitis in South African children following the measles outbreak between 2009 and 2011. S Afr Med J 105: 713–718. Klein K, Lang T, Saussele T et al. (2005). Genetic variability of CYP2B6 in populations of African and Asian origin: allele frequencies, novel functional variants, and possible implications for anti-HIV therapy with efavirenz. Pharmacogenet Genomics 15: 861–873. Koenig LJ, Nesheim S, Abramowitz S (2011). Adolescents with perinatally acquired HIV: emerging behavioral and health needs for long-term survivors. Curr Opin Obstet Gynecol 23: 321–327. Kovacs A (2009). Early immune activation predicts central nervous system disease in HIV-infected infants: implications for early treatment. Clin Infect Dis 48: 347–349. Kozlowski PB, Sher JH, Dickson D et al. (1990). CNS infections in paediatric HIV infection: a multicentre study. In: PB Kozlowski, DA Snider, PM Vietze et al. (Eds.), Brain in pediatric AIDS. Karger, Basel. Lall P, Lim S, Khairuddin N et al. (2015). An urgent need for research on factors impacting adherence to and retention in care among HIV-positive youth and adolescents from key populations. J Int AIDS Soc 18: 19393. Lancella L, Galli L, Chiappini E et al. (2016). Recommendations concerning the therapeutic approach to immunocompromised children with tuberculosis. Clin Ther 38: 180–190. Laughton B, Cornell M, Grove D et al. (2012). Early antiretroviral therapy improves neurodevelopmental outcomes in infants. AIDS 26: 1685–1690. Laughton B, Cornell M, Boivin M et al. (2013). Neurodevelopment in perinatally HIV-infected children: a concern for adolescence. J Int AIDS Soc 16: 18603. Lertora JJ, Rege AB, Greenspan DL et al. (1994). Pharmacokinetic interaction between zidovudine and valproic acid in patients infected with human immunodeficiency virus. Clin Pharmacol Ther 56: 272–278. Letendre S, Marquie-Beck J, Capparelli E et al. (2008). Validation of the CNS penetration-effectiveness rank for quantifying antiretroviral penetration into the central nervous system. Arch Neurol 65: 65–70. Letendre SL, Ellis RJ, Ances BM et al. (2010). Neurologic complications of HIV disease and their treatment. Top HIV Med 18: 45–55. Lim ML, Min SS, Eron JJ et al. (2004). Coadministration of lopinavir/ritonavir and phenytoin results in two-way drug interaction through cytochrome P-450 induction. J Acquir Immune Defic Syndr 36: 1034–1040. Little R (2006). Neoplastic disease in pediatric HIV infection. In: SL Zeichner, JS Read (Eds.), Handbook of pediatric HIV care. Cambridge University Press, Cambridge. Lowenhaupt EA, Matson K, Qureishi B et al. (2007). Psychosis in a 12-year-old HIV-positive girl with an

NEUROAIDS IN CHILDREN increased serum concentration of efavirenz. Clin Infect Dis 45: e128–e130. Luetkemeyer AF, Rosenkranz SL, Lu D et al. (2015). Combined effect of CYP2B6 and NAT2 genotype on plasma efavirenz exposure during rifampin-based antituberculosis therapy in the STRIDE study. Clin Infect Dis 60: 1860–1863. Machado-Alba JE (2013). Pharmacosurveillance regarding Colombian patients being treated with stavudine. Rev Salud Publica (Bogota) 15: 446–454. Madhi SA, Madhi A, Petersen K et al. (2001). Impact of human immunodeficiency virus type 1 infection on the epidemiology and outcome of bacterial meningitis in South African children. International Journal of Infectious Diseases 5: 119–125. Marra CM, Zhao Y, Clifford DB et al. (2009). Impact of combination antiretroviral therapy on cerebrospinal fluid HIV RNA and neurocognitive performance. AIDS 23: 1359–1366. Marzolini C, Telenti A, Decosterd LA et al. (2001). Efavirenz plasma levels can predict treatment failure and central nervous system side effects in HIV-1-infected patients. AIDS 15: 71–75. Mellins CA, Malee KM (2013). Understanding the mental health of youth living with perinatal HIV infection: lessons learned and current challenges. J Int AIDS Soc 16: 18593. Meyers A, Weitzman M (1991). Pediatric HIV disease. The newest chronic illness of childhood. Pediatr Clin North Am 38: 169–194. Mitchell CD (2006). HIV-1 encephalopathy among perinatally infected children: Neuropathogenesis and response to highly active antiretroviral therapy. Mental Retardation and Developmental Disabilities Research Reviews 12: 216–222. Mollan KR, Smurzynski M, Eron JJ et al. (2014). Association between efavirenz as initial therapy for HIV-1 infection and increased risk for suicidal ideation or attempted or completed suicide: an analysis of trial data. Ann Intern Med 161: 1–10. Molyneux EM, Tembo M, Kayira K et al. (2003). The effect of HIV infection on paediatric bacterial meningitis in Blantyre, Malawi. Archives of Disease in Childhood 88: 1112–1118. Murphy DA, Armistead L, Marelich WD et al. (2011). Pilot trial of a disclosure intervention for HIV + mothers: the TRACK program. J Consult Clin Psychol 79: 203–214. Mustafa MM, Weitman SD, Winick NJ et al. (1993). Subacute measles encephalitis in the young immunocompromised host: report of two cases diagnosed by polymerase chain reaction and treated with ribavirin and review of the literature. Clin Infect Dis 16: 654–660. Nuttall JJ, Wilmshurst JM, Ndondo AP et al. (2004). Progressive multifocal leukoencephalopathy after initiation of highly active antiretroviral therapy in a child with advanced human immunodeficiency virus infection: a case

115

of immune reconstitution inflammatory syndrome. The Pediatric Infectious Disease Journal 23: 683–685. Palmer M, Chersich M, Moultrie H et al. (2013). Frequency of stavudine substitution due to toxicity in children receiving antiretroviral treatment in sub-Saharan Africa. AIDS 27: 781–785. Park YD, Belman AL, Kim TS et al. (1990). Stroke in pediatric acquired immunodeficiency syndrome. Annals of Neurology 28: 303–311. Patsalides AD, Wood LV, Atac GK et al. (2002). Cerebrovascular disease in HIV-infected pediatric patients: neuroimaging findings. American Journal of Roentgenology 179: 999–1003. Peters RP, Van Ramshorst MS, Struthers HE et al. (2014). Clinical assessment of peripheral neuropathy in HIVinfected children on antiretroviral therapy in rural South Africa. Eur J Pediatr 173: 1245–1248. Petito CK, Navia BA, Cho ES et al. (1985). Vacuolar myelopathy pathologically resembling subacute combined degeneration in patients with the acquired immunodeficiency syndrome. The New England Journal of Medicine 312: 874–879. Pinillos F, Dandara C, Swart M et al. (2016). Case report: severe central nervous system manifestations associated with aberrant efavirenz metabolism in children: the role of CYP2B6 genetic variation. BMC Infect Dis 16: 56. Pinto AN (1996). AIDS and cerebrovascular disease. Stroke 27: 538–543. Qureshi AI, Janssen RS, Karon JM et al. (1997). Human immunodeficiency virus infection and stroke in young patients. Archives of Neurology 54: 1150–1153. Reisner MSL, Mimiaga MJ, Skeer MM et al. (2009). A review of HIV antiretroviral adherence and intervention studies among HIV-infected youth. Topics in HIV Medicine 17: 14. Ren Y, Nuttall JJ, Egbers C et al. (2008). Effect of rifampicin on lopinavir pharmacokinetics in HIV-infected children with tuberculosis. Journal of Acquired Immune Deficiency Syndromes 47: 566–569. Ren Y, Nuttall JJ, Eley BS et al. (2009). Effect of rifampicin on efavirenz pharmacokinetics in HIV-infected children with tuberculosis. J Acquir Immune Defic Syndr 50: 439–443. Samia P, Petersen R, Walker KG et al. (2013). Prevalence of seizures in children infected with human immunodeficiency virus. Journal of Child Neurology 28: 297–302. Sankhyan N, Lodha R, Sharma S et al. (2015). Peripheral neuropathy in children on stauvudine therapy. Indian J Pediatr 82: 136–139. Sawyer SM, Drew S, Yeo MS et al. (2007). Adolescents with a chronic condition: challenges living, challenges treating. Lancet 369: 1481–1489. Scharko AM (2006). DSM psychiatric disorders in the context of pediatric HIV/AIDS. AIDS Care 18: 441–445. Schoeman J, van Toorn R (2014). Tuberculosis. In: P Singh, D Griffin, C Newton (Eds.), Central nervous system infections in childhood. MacKeith Press, London.

116

J.M. WILMSHURST ET AL.

Schwartz L, Civitello L, Dunn-Pirio A et al. (2007). Evidence of human immunodeficiency virus type 1 infection of nestin-positive neural progenitors in archival pediatric brain tissue. Journal of Neurovirology 13: 274–283. Siddiqi O, Birbeck GL (2013). Safe treatment of seizures in the setting of HIV/AIDS. Curr Treat Options Neurol 15: 529–543. Simmonds RJ, Gonzalo O (1998). Pneumocystis carinii pneumonia and toxoplasmosis. In: CM Wilfert, PA Pizzo (Eds.), Pediatric AIDS: the challenge of HIV infection in infants, children and adolescents. Williams & Wilkins, Baltimore. Smith R, Wilkins M (2015). Perinatally acquired HIV infection: long-term neuropsychological consequences and challenges ahead. Child Neuropsychol 21: 234–268. Smurzynski M, Wu K, Letendre S et al. (2011). Effects of central nervous system antiretroviral penetration on cognitive functioning in the ALLRT cohort. AIDS 25: 357–365. Steinberg L (2008). A social neuroscience perspective on adolescent risk-taking. Developmental Review 28: 78–106. Sturdevant CB, Dow A, Jabara CB et al. (2012). Central nervous system compartmentalization of HIV-1 subtype C variants early and late in infection in young children. PLoS Pathogens 8: e1003094. Tukei VJ, Asiimwe A, Maganda A et al. (2012). Safety and tolerability of antiretroviral therapy among HIV-infected children and adolescents in Uganda. J Acquir Immune Defic Syndr 59: 274–280. UNAIDS (2015). How AIDS changed everything – MDG6: 15 years, 15 lessons of hope from the AIDS response [online]. http://www.unaids.org/en/resources/documents/ 2015/MDG6_15years-15lessonsfromtheAIDSresponse [accessed 15/04/2016]. Underwood J, Robertson KR, Winston A (2015). Could antiretroviral neurotoxicity play a role in the pathogenesis of cognitive impairment in treated HIV disease? AIDS 29: 253–261. van der Weert EM, Hartgers NM, Schaaf HS et al. (2006). Comparison of diagnostic criteria of tuberculous meningitis in human immunodeficiency virus-infected and uninfected children. The Pediatric Infectious Disease Journal 25: 65–69.

Van Dyke RB, Wang L, Williams PL et al. (2008). Toxicities associated with dual nucleoside reverse-transcriptase inhibitor regimens in HIV-infected children. J Infect Dis 198: 1599–1608. Van Rie A, Harrington PR, Dow A et al. (2007). Neurologic and neurodevelopmental manifestations of pediatric HIV/AIDS: a global perspective. European Journal of Paediatric Neurology 11: 1–9. Vinnard C, Macgregor RR (2009). Tuberculous meningitis in HIV-infected individuals. Curr HIV/AIDS Rep 6: 139–145. WHO (2008). Report of the WHO Technical Reference Group, Paediatric HIV/ART care guideline group meeting. [online]. Geneva: World Health Organization. http://www.who.int/ hiv/pub/paediatric/WHO_Paediatric_ART_guideline_rev_ mreport_2008.pdf. [accessed July 2008]. WHO (2010). Treatment of tuberculosis in children: whqlibdoc.who.int/publications/2010/9789241500449_ eng.pdf [online]. [accessed June 2016]. WHO (2013). Phasing out stavudine: progress and challenges. Supplementary section to the WHO consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Chapter 9 [online]. http://www.who.int/hiv/ pub/guidelines/arv2013/arv2013supplement_to_chapter09. pdf. [accessed June 2016]. WHO (2016). Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: recommendations for a public health approach, World Health Organization, Geneva. Willen EJ (2006). Neurocognitive outcomes in pediatric HIV. Ment Retard Dev Disabil Res Rev 12: 223–228. Williams PL, Storm D, Montepiedra G et al. (2006). Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics 118: e1745–e1757. Wilmshurst J, Eley B, Brew B (2014a). HIV infections. In: P Singhi, D Griffin, C Newton (Eds.), Central nervous system infections in children. MacKeith Press, London. Wilmshurst JM, Donald KA, Eley B (2014b). Update on the key developments of the neurologic complications in children infected with HIV. Current Opinion in HIV and AIDS 9: 533–538. Zink WE, Zheng J, Persidsky Y et al. (1999). The neuropathogenesis of HIV-1 infection. FEMS Immunol Med Microbiol 26: 233–241.