CNS Drugs (2014) 28:131–145 DOI 10.1007/s40263-013-0132-4

REVIEW ARTICLE

Neurological and Psychiatric Adverse Effects of Antiretroviral Drugs Michael S. Abers • Wayne X. Shandera Joseph S. Kass

•

Published online: 21 December 2013  Springer International Publishing Switzerland 2013

Abstract Antiretroviral drugs are associated with a variety of adverse effects on the central and peripheral nervous systems. The frequency and severity of neuropsychiatric adverse events is highly variable, with differences between the antiretroviral classes and amongst the individual drugs in each class. In the developing world, where the nucleoside reverse transcriptase inhibitor (NRTI) stavudine remains a commonly prescribed antiretroviral, peripheral neuropathy is an important complication of treatment. Importantly, this clinical entity is often difficult to distinguish from human immunodeficiency virus (HIV)induced peripheral neuropathy. Several clinical trials have addressed the efficacy of various agents in the treatment of NRTI-induced neurotoxicity. NRTI-induced neurotoxicity is caused by inhibition of mitochondrial DNA polymerase. This mechanism is also responsible for the mitochondrial myopathy and lactic acidosis that occur with zidovudine. NRTIs, particularly zidovudine and abacavir, may also cause central nervous system (CNS) manifestations, including mania and psychosis. The non-nucleoside reverse transcriptase inhibitor (NNRTI) efavirenz is perhaps the antiretroviral most commonly associated with CNS toxicity, causing insomnia, irritability and vivid dreams. Recent studies have suggested that the risk of developing these adverse effects is increased in patients with various cytochrome P450 2B6 alleles. Protease inhibitors cause perioral paraesthesias and may indirectly increase the relative risk of stroke by promoting atherogenesis. HIV integrase inhibitors, C–C chemokine receptor type 5 (CCR5)

M. S. Abers (&)  W. X. Shandera  J. S. Kass Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA e-mail: [email protected]

inhibitors and fusion inhibitors rarely cause neuropsychiatric manifestations.

1 Introduction Antiretroviral drugs are associated with a variety of adverse effects on the central and peripheral nervous systems. The frequency and severity of neuropsychiatric adverse events is highly variable, with differences between the antiretroviral classes and amongst the individual drugs in each class. Furthermore, there is considerable variability in the level of evidence supporting an association between each drug and a given adverse event. The clinical importance of adverse effects associated with combined antiretroviral therapy (cART) is especially important given the fact that patients commit to lifelong therapy. While this review focuses on the negative consequences of cART, it is important to emphasize the fact that these medications are responsible for a considerable decline in the morbidity and mortality of human immunodeficiency virus (HIV), including neurological manifestations of HIV [1]. The purpose of this review is to discuss the existing literature on the neurotoxic effects of antiretrovirals. For each neuropsychiatric manifestation, we describe the frequency, clinical presentations, pathogenesis, risk factors and, when applicable, potential therapies to reduce the burden of toxicity. In general, limited data are available to support specific management strategies. In such cases, we recommend adherence to cART guidelines. We performed an extensive search for any articles related to the topic of adverse effects of antiretrovirals on the central or peripheral nervous systems. Articles in

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English were identified by searching PubMed and Google Scholar for any combination of the following terms: ‘HIV’, ‘AIDS’, ‘cART’, ‘HAART’, ‘antiretrovirals’, ‘protease inhibitors’, ‘reverse transcriptase inhibitors’, ‘integrase inhibitors’, ‘fusion inhibitors’, ‘neurologic’, ‘psychiatric’, ‘neuropsychiatric’, adverse events’, ‘adverse effects’, ‘side effects’ or ‘complications’. Each antiretroviral was also included in the search. All abstracts and full articles published prior to August 2013 were reviewed. References cited in these articles were also reviewed. Using Google Scholar, we also searched the articles for any subsequent papers that cited an article of interest. Other materials that were used included package inserts for antiretrovirals.

Zidovudine, however, inhibits skeletal muscle mitochondria, causing myopathy, and is not associated with peripheral neuropathy [91]. Several authors have suggested that NRTI-induced peripheral neuropathy is caused by cumulative toxicity. In support of this theory are data showing that the incidence of peripheral neuropathy in patients taking stavudine increased from 7 % after 1 year to 19 % after 5 years [208]. Other lines of evidence suggest that the cumulative dose is not associated with the risk of developing peripheral neuropathy [12, 205]. In one study, the risk of developing peripheral neuropathy was found to reach a maximum after 90 days of therapy [205]. Risk factors are listed in Table 1.

2 NRTIs

2.3 Clinical Presentation, Diagnosis and Treatment

2.1 Peripheral Neuropathy

NRTI-induced painful peripheral neuropathy presents as a distal and symmetrical, predominantly sensory polyneuropathy, which is dose dependent. The onset of symptoms typically occurs within 3 months of initiation of therapy. The lower extremities are typically involved early, with paraesthesias and dysaesthesias, often with loss of proprioception and possibly hypo- or areflexia. Upper extremity involvement typically occurs later (Table 2). An important diagnostic dilemma is distinguishing between HIV-induced sensory neuropathy (HIV-SN) and NRTI-induced neuropathy. Like NRTI-induced neuropathy, HIV-SN is a symmetrical distal polyneuropathy. Because these conditions have identical clinical features, many investigators have sought an accurate, non-invasive diagnostic test to differentiate the two. In a recent study, a venous lactic acid level above the upper limit of normal (2.2 mmol/L in that study) was found to have sensitivity of

Peripheral neuropathy is a common and dose-limiting side effect of nucleoside reverse transcriptase inhibitors (NRTIs). The frequency varies among specific NRTIs, with the most neurotoxic NRTIs causing peripheral neuropathy in as many as one third of patients [2]. 2.2 Mechanism The mechanism of NRTI neurotoxicity involves inhibition of mitochondrial DNA (mtDNA) polymerase c in axons and Schwann cells, resulting in depletion of mtDNA [3]. Other mitochondrial targets are also involved [4, 5]. Acetyl-L-carnitine (ALCAR), a key player in mitochondrial function, increases the local concentration of nerve growth factor (NGF) [6], which is important for peripheral nerve health. Some investigators have reported reduced ALCAR levels in patients with NRTI-induced peripheral neuropathy [7]—an inconsistent finding [8]. In addition to mitochondrial toxicity, administration of NRTIs results in inflammatory damage to sensory axons and dorsal root ganglia [9]. Small, unmyelinated fibres are particularly vulnerable to the effects of NRTIs [10]. Of the NRTIs, stavudine is slightly more neurotoxic than didanosine [9, 11]. Combining these NRTIs increases the risk of neuropathy. In one population, the relative risks (RRs) of neuropathy were 1.39 in patients taking didanosine alone, 2.35 in those taking stavudine alone and 3.5 in those taking didanosine ? stavudine [11]. In general, zidovudine, lamivudine, tenofovir, abacavir and emtricitabine are not considered neurotoxic. Differences in neurotoxic potential between NRTIs appear to be tissue specific. For example, didanosine and stavudine inhibit Schwann cell and axonal mitochondria, resulting in peripheral neuropathy, and are not associated with myopathy.

Table 1 Selected risk factors for nucleoside reverse transcriptase inhibitor-induced peripheral neuropathy • Lower CD4 count [205, 206] or higher HIV viral load [206] • Body mass index \18 kg/m2 [208] • Height C170 cm [207] • Age C35 years [205, 207] • Haemoglobin \10 g/dL [208] • Decreased creatinine clearance [14] • Genetic risk factors s Mitochondrial haplogroup T: 7028C[T, 10398G[A, 13368G[A [209] s Mitochondrial subhaplogroup L1c [210] s DNA polymerase c mutation [211] s TNFa 1031*2 [212, 213], 308*2 [212] Haplogroup T defined by three polymorphisms noted above;10–15 % of people of European ancestry are in haplogroup T [209] HIV human immunodeficiency virus, TNFa tumour necrosis factor a

Neurological and Psychiatric Adverse Effects of Antiretroviral Drugs Table 2 Selected neuropsychiatric adverse events associated with antiretrovirals Antiretroviral

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improve epidermal nerve fibre density or mtDNA levels [18].

Adverse event

2.4 Other Manifestations of NRTI Neurotoxicity Common ([10 %) Efavirenz

Dizziness, insomnia, vivid dreams, impaired concentration, lightheadedness, headache, aggression, anxiety

Zidovudine

Myopathy

NRTIs

Peripheral neuropathy

Ritonavir

Circumoral paraesthesias

Raltegravir

Myopathy

Occasional (1 to \10 %) Efavirenz

Memory loss, hallucinations, depression

Ritonavir

Peripheral neuropathy, dysgeusia

Enfuvirtide

Peripheral neuropathy

Raltegravir

Headache, dizziness, suicidality, nightmares

Rare (\1 %) Efavirenz

Mania

NRTIs

Mitochondriopathy syndromes

NRTIs nucleoside reverse transcriptase inhibitors

90 % and specificity of 90 % [13] for NRTI-induced neuropathy. Other features that favour NRTI-induced neuropathy over HIV-SN include a more abrupt onset, a latency of onset of a few weeks and resolution of the neuropathy with discontinuation of therapy. Dose reduction has been suggested as a management option for some patients (see Sect. 2.7 below). In cases of severe peripheral neuropathy, altering the cART regimen to avoid neurotoxic NRTIs should be attempted, if possible. After discontinuing NRTI therapy, patients may notice worsening of their symptoms, a phenomenon known as ‘coasting’ [14]. If symptoms persist for longer than 2 months after discontinuation, the diagnosis of NRTIinduced peripheral neuropathy should be reconsidered [14]. The majority of clinical trials on the treatment of neuropathy in HIV patients were not designed to address NRTI-induced neuropathy specifically. Patients with NRTI-induced neuropathy were, however, included in those trials. In a systematic review and meta-analysis of randomized controlled trials of treatment of HIV-SN (as of 2010), the authors found only smoked cannabis, 8 % topical capsaicin and recombinant human NGF (rhNGF) to be more efficacious than placebo in treating HIV-SN [15]. While the efficacy of lamotrigine for HIV-associated neuropathy has not been shown, patients whose neuropathy is NRTI induced appear to benefit significantly from lamotrigine, with a number needed to treat to improve neuropathy of 2.88 [15, 16]. In the same study, ALCAR was not superior to placebo on intention-to-treat analysis, but it did significantly outperform placebo on per-protocol analysis [15, 17]. In an open-label study, ALCAR failed to

Leber’s hereditary optic neuropathy (LHON) is a mitochondriopathy characterized by an irreversible loss of visual acuity, which typically progresses sequentially from unilateral to bilateral involvement. It is associated with incomplete penetrance, thus many individuals with the mtDNA mutation will not go on to develop clinical disease. In several cases reports, non-NRTIs (NNRTIs) have been shown to unmask an individual’s predisposition to LHON [19–23]. Given the irreversibility of the visual loss, it is important to avoid NRTIs, if possible, in patients with a family history of LHON [23]. NRTI-induced deafness has been reported in several cases, typically in patients on multiple NRTIs [24–26]. A prospective observational study, however, was unable to detect hearing loss in patients taking zidovudine and didanosine. Importantly, this study lacked a control group, and the sample size was small, with only 19 patients completing the study [27]. Furthermore, a recent study found subclinical hearing loss (especially at high frequencies) in patients taking lamivudine, stavudine and efavirenz [28]. A possible explanation to reconcile these disparate findings is a model that involves the interaction of a number of environmental factors, including NRTI use, resulting in hearing loss. Supporting this model, it has been shown that mice treated with NNRTIs are more likely to develop noise-induced hearing loss [29]. A case–control study also found that NRTI use and age C35 years were risk factors for hearing loss in HIV patients [30]. Mitochondrial damage may also be responsible for NRTI-induced toxicity in the central nervous system (CNS). One study used magnetic resonance spectroscopy to show a reduction in frontal white matter N-acetylaspartate (NAA) concentrations in patients taking didanosine and stavudine. Using NAA as a surrogate measure of neuronal and mitochondrial stability, the authors concluded that NRTI-induced mitochondrial toxicity occurs not only in the peripheral nervous system but also in the brain [31]. 2.5 Zidovudine Zidovudine was the first agent used to treat HIV and remained the only approved medication until 1991. Zidovudine is significantly less neurotoxic to peripheral nerves than didanosine or stavudine [32]. In contradistinction, zidovudine is more often associated with mitochondrial myopathy. The mechanism of zidovudine-induced myopathy is thought to involve either inhibition of DNA polymerase c

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or thymidine kinase, resulting in depletion of mtDNA [33, 34], which is reversible upon zidovudine discontinuation [35, 36]. Depletion of mtDNA also provides a mechanistic explanation for the lactic acidosis that occurs in some patients treated with zidovudine. Mitochondrial damage inhibits the cell’s capacity for oxidative phosphorylation, resulting in excess conversion of pyruvate to lactate. Because the depletion of mtDNA precedes the onset of hyperlactataemia, some investigators have suggested a possible role for the mtDNA:nuclear DNA ratio in monitoring of patients on NRTIs for mitochondrial toxicity [37]. The relationship between mtDNA levels and hyperlactataemia is unclear, and several lines of evidence suggest that mtDNA is a less than ideal marker for mitochondrial toxicity [38, 39]. Other important pathophysiological features include depletion of mitochondrial L-carnitine [33] and a reduction in various mitochondrial enzymes, such as cytochrome c oxidase [40]. In the pre-cART era, the incidence of myopathy was 17 % in patients taking zidovudine for greater than 9 months [41]. However, the dosage currently used in zidovudine-containing regimens is typically 600 mg/day— half the dose used in the pre-cART era. As a result, the incidence of zidovudine-induced myopathy is now decreased. Myopathy typically appears 6–12 months after initiation of zidovudine, with proximal, fatigable weakness and myalgia, especially prominent in the thighs and calves. Muscular atrophy may also be a prominent feature. Serum CK levels are typically elevated, and electromyography reveals myopathic changes [42]. Such clinical and laboratory findings are indistinguishable from myopathy caused by HIV itself. Biopsy remains the gold standard for diagnosis of mitochondrial myopathy associated with zidovudine. Histopathology often reveals ragged red fibres—a classic finding in mitochondrial myopathies—as well as some inflammatory infiltration [43–45]. A reduction in the serum lactate:pyruvate ratio is another diagnostic finding with high sensitivity, though it is infrequently used in clinical practice [46, 47]. With the large anti-HIV armamentarium now available, the best therapeutic option for zidovudine-induced myopathy is dose reduction or discontinuation. If symptoms persist, patients may experience relief with non-steroidal anti-inflammatory drugs [43, 44]. Zidovudine has also been associated with fetal CNS toxicity in women receiving treatment during pregnancy. European fetuses exposed to zidovudine (±lamivudine) perinatally were shown to experience an increased incidence of CNS mitochondrial disease as compared with the expected incidence of genetic CNS mitochondriopathies (0.3 vs 0.01 %, respectively) [48]. The clinical presentation of infants with significant zidovudine neurotoxicity is quite

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similar to known mitochondriopathies with CNS involvement, including Leigh’s disease and Alpers’ disease [48– 50]. Common findings include cognitive delay, behavioural abnormalities and seizures. Cortical blindness and brainstem findings have also been reported. Hyperlactataemia is common, and patients have deficiencies in respiratory chain proteins, such as complexes I and IV. Magnetic resonance imaging reveals hyperintensities in the supratentorial white matter and brainstem. Necrotic lesions and basal ganglia abnormalities are not uncommon. Some children show persistent neurological deficits in early childhood, while others improve significantly [49–51]. While this NRTI-induced mitochondriopathy can have devastating consequences for the patient and his or her family, it is necessary to put this adverse event into perspective. First, there is controversy as to whether these cases of CNS mitochondriopathy were caused by NRTIs. While the aforementioned reports actively sought alternative causes of mitochondrial disease, NRTI-induced mitochondriopathy was a diagnosis of exclusion. Studies on infants without perinatal exposure to zidovudine have revealed a relative depletion of mtDNA in infants born to HIV-infected mothers, compared with infants born to HIVnegative mothers [52]. Thus, while NRTIs are known mitochondrial toxins, maternal HIV status and its relative contribution to mitochondrial damage remain unclear in infants with mitochondrial disease. Furthermore, several studies have failed to detect an increase in mitochondrial disease among children exposed to NRTIs perinatally [53, 54]. Most importantly, NRTIs have dramatically reduced the incidence of vertically transmitted HIV and are generally well tolerated [55]. There have also been reports of patients who developed features of mitochondrial syndromes, such as chronic progressive external ophthalmoplegia [56]. The ototoxic potential of zidovudine remains unclear. While zidovudine-induced hearing loss and tinnitus have been observed [30], prospective studies have failed to show an association between treatment with zidovudine and hearing loss [27]. There have been reports of ototoxicity in patients with a history of hearing loss whose hearing worsened after the initiation of zidovudine [25]. In a prospective cohort study of infants born to HIVinfected mothers, perinatal exposure to NRTIs was found to significantly increase an infant’s risk of experiencing a febrile seizure during the first 18 months of life (an 18-month risk of 1.1 % in those exposed to NRTIs vs 0.4 % in those not exposed to NRTIs, log-rank test p = 0.0198) [57]. Headache is not uncommon in patients taking zidovudine but is typically of minimal severity. More serious neurological events, such as insomnia [58], seizures [59– 63] and coma [64], have been reported, albeit rarely.

Neurological and Psychiatric Adverse Effects of Antiretroviral Drugs

The most serious psychiatric adverse events include mania, hallucinations and psychosis [65–68]. In reported cases of neuropsychiatric dysfunction, the latency of onset has been widely variable, ranging from less than 24 h [66] up to 7 months [67]. In the majority of reported cases of serious neurotoxicity, the zidovudine dose was 1,200 mg/ day, significantly higher than the currently recommended dose of 600 mg/day. In addition, many of the reported patients had a personal history of neuropsychiatric illness. While some patients required long-term lithium to manage mania refractory to zidovudine discontinuation, others returned to baseline after stopping zidovudine, and some even reinitiated zidovudine without recurrence [66]. The pathogenesis of zidovudine toxicity in the CNS is currently unknown. Considering the wide range of reported intervals from zidovudine initiation until symptom onset, combined with the fact that a personal history of neuropsychiatric illness was commonly reported, it appears that a variety of factors may predispose certain patients to the adverse effects of zidovudine [69]. CNS toxicity might also be explained by the mitochondrial damage caused by NRTIs. This mechanism is supported by data showing NRTI-induced mitochondrial toxicity in frontal lobe white matter [31]. 2.6 Didanosine Didanosine is toxic to peripheral nerves but not to muscle [70]. Peripheral neuropathy occurs in 15–25 % of adults and in fewer than 5 % of children treated with didanosine [10, 71, 72]. Pancreatitis is less common, occurring in 10 % of patients taking didanosine [73], but appears to result in discontinuation more often than does didanosine-induced neuropathy. Didanosine has been associated with retinopathy, caused by damage to the retinal pigment epithelium (RPE) [74]. RPE mottling and atrophy occur, which progress to well circumscribed lesions at the periphery of the fundus. The macula is not involved, and so central vision is preserved [75]. Electroretinogram amplitude may be decreased [74]. Some have recommended an eye examination every 6–12 months to monitor for didanosine-induced retinal toxicity [76]. If retinopathy occurs, didanosine should be stopped and replaced by an alternative antiretroviral regimen. Dose reduction is not an effective strategy, as lesions may progress even at low doses [75]. Improvement, as assessed by a normalizing electroretinogram, may occur after didanosine is discontinued [77]. Psychiatric adverse events, including mania and auditory hallucinations, have also been reported, although with exceptional infrequency [78]. 2.7 Stavudine Stavudine is a well-known cause of peripheral neuropathy, with a 1-year incidence of approximately 15–30 % [79,

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208]; however, higher rates have been reported. As newer cART regimens appear to be just as efficacious with less toxicity, its use has dropped precipitously. In the developing world, stavudine remains a commonly prescribed antiretroviral [208]. In a study of Ugandans, Sacktor et al. found that stavudine was effective in the treatment of HIVassociated neurological complications. In that population, 31–38 % of asymptomatic HIV patients treated with stavudine developed manifestations of neuropathy. Neuropathy was never the reason for discontinuing therapy [80]. In other studies, as many 10–13 % of patients treated with stavudine have discontinued therapy as a result of peripheral neuropathy, compared with a 1–2 % discontinuation rate with didanosine [14, 81]. Dose reduction from 40 to 30 mg/day has been shown to reduce the frequency of peripheral neuropathy and increase adherence, without a reduction in efficacy [82]. Other efforts to reduce neurotoxicity include screening patients for risk factors. There have been a number of reports of patients taking stavudine who, after several months, have developed progressive (over days to weeks) ascending weakness, similar to Guillain–Barre syndrome [85]. This rapidly progressive condition, often referred to in the literature as HIV-associated neuromuscular weakness syndrome (HANWS), typically presents with hyperlactataemia, nausea and vomiting [83]. Like Guillain–Barre syndrome, there appears to be a Miller–Fisher variant that presents with hyperlactaemia and the triad of ophthalmoplegia, ataxia and areflexia [84]. A number of cases have been complicated by respiratory failure and, occasionally, death [88, 89]. Electrophysiological studies have revealed a sensorimotor neuropathy that is typically axonal but may also have a demyelinating component [85–90]. The aetiology of this syndrome is exceptionally difficult to determine, with possibilities including stavudine use, HIV itself, immune reconstitution or any combination of these. It is important to note that the mechanism of stavudine- and HIV-induced ascending weakness is thought to involve mtDNA damage. As with the other NRTI-induced mitochondriopathies, patients may present days or weeks after discontinuing therapy. The delayed presentation is possibly explained by the threshold effect [91], whereby ongoing mtDNA depletion fails to manifest clinically until a critical amount of mtDNA damage accumulates. 2.8 Lamivudine Lamivudine can cause peripheral neuropathy and HANWS, but this occurs significantly less frequently than with didanosine and stavudine [85, 92, 93]. Acute dystonia has been reported in patients taking lamivudine. The latency of onset has ranged from less than 2 days up to 1 year.

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Successful therapies include intramuscular scopolamine 0.3 mg and diazepam 5 mg [94, 95].

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the interaction between tenofovir and efavirenz or the tenofovir itself caused the neuropsychiatric manifestations [108].

2.9 Emtricitabine Several reports of neuropsychiatric adverse events have emerged from a study of patients who switched from lamivudine to emtricitabine [96]. The symptoms appeared within the first 3 days of the switch and included headache, paraesthesias, confusion, irritability and insomnia. Switching back to a lamivudine-containing regimen resulted in symptomatic improvement within 3 days [97]. 2.10 Abacavir Psychiatric complications of abacavir have been reported in six cases [98–102]. Half of the cases were male, and their ages ranged from 11 to 47 years, with all but one case occurring in patients aged 37–47 years. In all cases, the symptoms began within 1 month of initiation of abacavir therapy. Commonly reported symptoms included depression, nightmares, hallucinations, mood changes, mania, anxiety and psychosis. Two patients reported suicidal ideation. Four patients experienced headache, often with migrainous features. Headache and mood changes often preceded the onset of more severe psychiatric disturbances, suggesting the need to monitor for toxicity in patients with these symptoms. In all cases, the patient rapidly returned to baseline after discontinuation of abacavir. In a study by Rasmussen et al. [194], abacavir was found to increase the risk of cerebrovascular events (adjusted RR 1.66). This relationship is supported by studies that have shown an increased risk of myocardial infarction in patients taking abacavir [103]. While the mechanism of abacavir-induced vascular events is unknown, there are data to suggest that an inflammatory response plays a crucial role in the pathogenesis. For example, high-sensitivity C-reactive protein (hs-CRP) and interleukin (IL)-6 are significantly elevated in patients taking abacavir, compared with those taking other NRTIs [104]. The association between abacavir and cerebrovascular events is controversial, and large, well-designed studies have failed to confirm this increased risk [105]. The potential vascular risk associated with abacavir was also challenged by a recent meta-analysis by Ding et al. [106], which showed no association between abacavir use and myocardial infarction. 2.11 Tenofovir Neuropsychiatric adverse events have been reported in nine patients who had recently added tenofovir to a cART regimen that included efavirenz [107]. It is unclear whether

3 NNRTIs 3.1 Nevirapine In a case series of three patients, nevirapine was associated with visual hallucinations, persecutory delusions and mood changes 2 weeks after initiating therapy. In all three cases, the patient’s symptom resolved following nevirapine discontinuation [109]. Additionally, nevirapine-induced nightmares and vivid dreams have been reported [110]. Other possible complications of nevirapine include headache, somnolence, dizziness and depression [111]. 3.2 Efavirenz Efavirenz is an NNRTI and one of the most commonly prescribed cART agents. Many studies have reported CNS toxicity in [50 % of patients taking efavirenz. However, the prevalence of CNS toxicity is difficult to determine, because of the inconsistent definition and detection methods used for ‘CNS toxicity’. CNS toxicity usually begins within 2–4 weeks of initiating therapy. Symptoms appearing early in the course of therapy include dizziness, lightheadedness, sleep disturbance, vivid dreams, nervousness and irritability. These symptoms typically resolve 6–8 weeks later, without dose alteration [112]. After approximately 6 months of therapy, patients may begin to experience headache, decreased concentration and mood changes [113]. In one study, patients taking efavirenz for 3 years were found to have higher than baseline levels of abnormal dreaming and anxiety, although their neuropsychological performance did not decrease from baseline [114]. Conversely, another study of patients taking efavirenz for more than 1 year found that 47 % of patients were cognitively impaired, especially in executive functioning. Higher education was found to be a protective factor [115]. Clifford et al. [116] found that CNS side effects during the first week of therapy were more commonly seen in patients taking efavirenz than in those on a non-efavirenz regimen (p \ 0.001). After the fourth week of therapy, there was no difference between the groups (p = 0.038). The investigators interpreted their findings as evidence supporting the decision to continue therapy in patients who experience CNS toxicity. In other studies, neuropsychiatric adverse effects have persisted for 1 year or longer, but the severity has decreased with time and has not appeared to diminish the patient’s quality of life [113, 117–119]. The

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rate of discontinuation attributed to CNS toxicity is 2–8 % [113, 116, 120]. A history of psychiatric illness generally or depressive symptoms generally has been shown to increase the risk of efavirenz-induced neuropsychiatric adverse events [121]. Whether the increased rate of CNS toxicity translates into a risk of early discontinuation of therapy is debatable [120, 122]. Substance abuse does not appear to increase the risk of CNS toxicity [120]. Furthermore, among all patients who experience CNS toxicity, those with a history of substance abuse (except for methadone users) are equally likely to remain adherent to therapy [120]. Efavirenz and methadone interact via cytochrome P450, causing an increased rate of methadone clearance. The resultant 45 % decrease in methadone levels predisposes to symptoms of withdrawal, typically within 1 week of co-administration. Some authors have recommended a 5–10 mg/day increase in methadone dosing to compensate for this interaction [123]. Although depression is a common side effect in those receiving interferon (IFN)-a for hepatitis C, simultaneous administration of efavirenz in HIV/hepatitis C co-infection does not appear to significantly increase the frequency of depression [124, 125]. The mechanism of efavirenz-induced neurotoxicity is unknown, but several animal studies have suggested possible mechanisms. Efavirenz can cause stress and depression-like symptoms in rats. These symptoms correlate with an elevation in the pro-inflammatory cytokines IL-1b and tumour necrosis factor (TNF)-a. Paroxetine has been shown to limit the increase in pro-inflammatory cytokines and to improve neuropsychiatric symptoms [126]. Coadministration of efavirenz and nevirapine to mice inhibits creatine kinase [127] and cytochrome c oxidase [128], altering brain metabolism. Damage to individual neurons might be mediated by injury to the dendritic spine [129]. Efavirenz is [99.5 % protein bound, and CSF concentrations are 0.5 % of those in the serum, implying free diffusion between serum and CSF of the unbound form, without P-glycoprotein-induced efflux [130]. The target mid-dose serum concentration is 1–4 mg/L. This range is based on findings of treatment failure at a concentration \1 mg/L and CNS toxicity at concentrations [4 mg/L [131, 132]. Most studies of efavirenz concentrations and CNS toxicity have measured serum concentrations about 12 h after the last dose. The relationship between serum efavirenz levels and CNS toxicity was studied in 130 patients taking efavirenz for approximately 8 months. Patients with mid-dose serum levels [4 mg/L were three times as likely to experience CNS toxicity as patients with levels \4 mg/L [133]. In another study, a mid-dose concentration [2.74 mg/L showed better discriminatory power to determine the risk

of CNS toxicity, with sensitivity and specificity to predict toxicity of 90.9 and 72 %, respectively. In the same study, the authors noted that ‘‘patients having plasma efavirenz concentrations [2.74 mg/L at any point during the study were 5.68 times more likely to present with CNS toxicity (95 % CI 1.97–16.37, p \ 0.001)’’ [134]. In one case report of efavirenz-induced suicidal ideation, the patient’s serum efavirenz concentration was 59.4 mg/L, 15 times the level associated with risk in this study [135]. These data notwithstanding, the relationship between serum efavirenz concentrations and the risk of neuropsychiatric complications remains controversial. Several studies have failed to detect an association between serum efavirenz concentrations and CNS toxicity [119, 136–138]. Efavirenz pharmacokinetics are highly variable among patients and are dependent on a number of factors. With 90 % of an efavirenz dose being cleared by the cytochrome P450 (CYP) 2B6 isoform, the CYP2B6 genotype is among the most important predictors of efavirenz pharmacokinetics [139]. Many single nucleotide polymorphisms (SNPs) are known to affect efavirenz levels, but the greatest attention has been directed towards 516G[T, a marker of CYP2B6 alleles *6, *7 and *9. An individual’s CYP2B6 genotype can greatly influence efavirenz clearance. For example, in one study, the plasma half-life in 516 GG homozygotes was approximately 1 day, which was significantly shorter than the 2-day half-life in 516 TT homozygotes [140]. The frequency of the 515T SNP is higher in Africans (42–46 %), in African-Americans (33–40 %) and in Hispanics (27 %) than in Caucasians (21–23 %) or in Asians (17 %, but 43 % in some Chinese populations) [141–148]. Several studies have shown the clinical utility of determining the CYP2B6 genotype. There is preliminary evidence that a dose reduction from the usual 600 mg/day to between 200 and 400 mg/day (the actual dosage depends on the serum level) in CYP2B6*6 homozygotes and CYP2B6*6/*26 heterozygotes reduces CNS toxicity without altering efficacy [149]. Various genetic markers, such as CYP polymorphisms, are predictive of neuropsychiatric adverse events, and such markers can be used to decide who should receive efavirenz [150]. Prospective trials are needed. A randomized controlled trial was conducted by Gutierrez et al. [151] to test the hypothesis that a stepwise increase in the efavirenz dose would minimize CNS toxicity without compromising efficacy. The stepwise dose increase consisted of 200 mg/day for the first week, 400 mg/day for the second week and 600 mg/day thereafter. Patients randomized to the stepped-dose group experienced a significant reduction in CNS toxicity, compared with those who received the standard 600 mg/day dose from day 1. The sample size was not sufficiently large

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to determine minor differences in efficacy [151]. In addition to stepwise dose escalation, other methods to minimize CNS toxicity, such as dose reduction using therapeutic drug monitoring [152–154] and genotype-based dose reduction [149], have shown success. Further studies will be necessary before genetic testing or TDM can be recommended on a routine basis. Another strategy to minimize efavirenz-induced CNS toxicity involves switching efavirenz to an alternative NNRTI, such as etravirine. This approach has been shown to reduce symptoms of CNS toxicity, especially insomnia and abnormal dreaming [155]. Another topic related to efavirenz neurotoxicity is the association between efavirenz use during the first trimester of pregnancy and neural tube defects (NTDs) and Dandy– Walker malformation. As a result of several reports of NTDs in neonates exposed to efavirenz perinatally or even periconceptionally, efavirenz is classified as category D [156–161]. Gallego et al. found that patients taking efavirenz showed a shortened duration of both deep sleep and rapid eye movement (REM) sleep. The authors suggested that this reduction in sleep efficiency might explain other efavirenz-induced neuropsychiatric adverse events. The study also found higher plasma efavirenz concentrations in patients with insomnia or reduced sleep efficiency [162]. It is important to recognize that an efavirenz metabolite, 8-hydroxy-efavirenz, can potentially cause a false positive urine drug screen for benzodiazepines and tetrahydrocannabinol (THC) [163]. Thus, a positive urine drug screen should be interpreted with caution when a patient’s symptoms may be attributable to use of efavirenz, benzodiazepines or THC. There have been two reports of post-traumatic stress disorder recurrence after initiation of efavirenz [164, 165]. In one case, the patient was able to continue efavirenz during the episodes, and the symptoms resolved within 4 weeks [165]. Other reported CNS adverse events include ataxia, paraesthesias, vertigo and tremor [166]. 3.3 Other NNRTIs Etravirine may cause dizziness and sleep disorders, but the incidence of side effects is significantly lower than for efavirenz [167]. A single case of myopathy has been reported. The patient presented 3 months after initiating etravirine, with upper extremity weakness and elevated serum creatine kinase (CK). Complete resolution was noted 2 months after etravirine discontinuation. Rilpivirine appears to have the same side-effect profile as efavirenz, but each neuropsychiatric adverse event has occurred much less frequently [168].

M. S. Abers et al.

4 Protease Inhibitors Protease inhibitors (PIs) are extensively metabolized by cytochrome P450 and have been shown to interact with a great number of commonly used drugs. In fact, the PI ritonavir is used specifically for its ability to inhibit CYP3A4, thereby inhibiting metabolism of co-administered PIs [169]. Given the tendency of PIs to influence drug metabolism, one must consider co-administered drugs, as well as PIs, as a potential cause of CNS toxicity. The discussion that follows, however, focuses on the direct neurotoxicity of PIs. Despite the fact that PIs have poor blood–brain barrier penetration, there is evidence to suggest that PIs are inherently neurotoxic and potentiate NRTI-induced peripheral neuropathy [170–173]. Pettersen et al. found that PIs were a risk factor for developing a sensory neuropathy in HIV patients. The study also provided in vitro evidence suggesting that indinavir is cytotoxic to dorsal root ganglion (DRG) macrophages. The authors suggested a possible role for macrophage release of neurotrophic growth factors [170]. Thus, indinavir-induced macrophage cytotoxicity would deplete growth factors available to DRG neurons, resulting in sensory neuropathy. Ritonavir consistently shows greater neurotoxic potential than the other PIs [174]. Neurological adverse events typically appear within the first month of treatment and include circumoral paraesthesias (25 %), peripheral paraesthesias (7 %) and taste alterations (12 %) [175, 176]. These side effects have occurred at doses of ritonavir used to inhibit the HIV life cycle. Importantly, ritonavir is currently used for PI boosting at lower doses, at which side effects are likely to be less common. If the adverse events become severe, however, discontinuation of ritonavir results in complete resolution of the symptoms [176]. A higher serum ritonavir concentration is associated with an increased risk of developing neurological side effects [177]. There has been CNS toxicity of PIs in mice fed lopinavir–ritonavir. Worsening cognitive function was thought to have occurred secondarily to metabolic abnormalities [178]. The relevance of this study to humans is currently unknown. There is a tenuous relationship between tipranavir and intracranial haemorrhage, which led the US Food and Drug Administration (FDA) to issue a black-box warning about this risk. One study found that the number needed to harm was administration to between 455 and 5,000 persons per year [179]. An interesting and often ignored manifestation of PI toxicity is altered perception of taste [180]. Importantly, this adverse event has been cited as a reason for poor adherence to PI-containing regimens [181]. Additionally,

Neurological and Psychiatric Adverse Effects of Antiretroviral Drugs

the metallic taste of many PIs (especially ritonavir) influences adherence, especially in children [180, 182]. Cases of RPE damage with macular telangiectasias and intraretinal crystalline have been reported in patients taking ritonavir for greater than 1 year [183]. Other ophthalmological complications of PIs have included photophobia in a patient taking indinavir [184] and a possible case of indinavir-induced uveitis [185]. However, the latter case was questionable given the fact that the patient was also taking cidofovir, a well-described cause of uveitis [186]. Ototoxicity manifesting as bilateral sensorineural hearing loss was reported in a patient 4 weeks after initiation of lopinavir–ritonavir. Hearing was restored following discontinuation of lopinavir–ritonavir [187]. A single 750 mg dose of amprenavir was reported to induce hallucination, tinnitus and vertigo. This episode resolved following discontinuation of amprenavir [188]. Reports on the use of darunavir have suggested no increased risk of neurological toxicity [189]. An emerging topic in the antiretroviral literature is the potential association between the use of some antiretrovirals and an increased risk of stroke. In a recent study, Ovbiagele et al. [190] found that the incidence of stroke was increased with cART administration. It is possible that the atherogenic side-effect profile of current cART regimens (especially PIs and NNRTIs) increases the risk of cerebrovascular disease [191, 192]. In support of this theory, studies have shown that cART is a strong predictor of carotid atherosclerosis, even when metabolic risk factors are controlled for [193]. Other investigators, however, failed to replicate these data [194]. In light of conflicting data and the known benefits of cART, including the risk of stroke in untreated HIV, the use of cART strongly outweighs the possible association of cART and stroke.

5 Fusion Inhibitors Enfuvirtide is a fusion inhibitor, seldom used in treatmentexperienced HIV patients. Several studies have shown an increased risk of peripheral neuropathy in patients taking enfuvirtide [195, 196]. In phase III clinical trials, the risk ratio of developing peripheral neuropathy, compared with placebo, was 1.20 (95 % CI 0.75–1.99) [197].

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upon initiation of raltegravir. One patient was hospitalized for suicidal ideation and psychosis. All four patients continued raltegravir and experienced symptomatic improvement with alterations to their psychiatric pharmacotherapy [198]. In another case series, three patients developed insomnia associated with serum raltegravir concentrations above the upper limit of normal (29–118 ng/mL) [199]. In a meta-analysis of raltegravir 400 mg twice daily, side effects attributed to raltegravir included vertigo (1–2 %), dizziness (3 %), headache (3.4 %), abnormal dreams and nightmares (2.5 %) [200]. In phase III clinical trials, raltegravir was found to cause depression or suicidality in up to 2.5 % [200]. Perhaps the most common neurological adverse effect of raltegravir is an idiosyncratic myalgia and myopathy. The interval from the initiation of raltegravir until the onset of muscular toxicity is highly variable, and serum CK levels may be normal. The myalgias are generally mild and rarely warrant discontinuation of raltegravir [201]. In the phase II study, eight of 48 patients (17 %) treated with elvitegravir for 48 weeks developed psychiatric adverse events. This rate was significantly lower than that observed in the efavirenz comparison group (43 %). The specific psychiatric manifestations were not reported in either group [202]. Cobicistat is a CYP3A4 inhibitor that reduces elvitegravir metabolism. Neuropsychiatric adverse events have not been reported to date.

7 CCR5 Inhibitors Maraviroc is a C-C chemokine receptor type 5 (CCR5) inhibitor, which inhibits entry of HIV-1 into CCR5-containing host cells. Aside from dizziness, maraviroc is not associated with neuropsychiatric adverse events [203]. A specific deletion in the CCR5 gene (CCR5D32), which is especially prevalent amongst Northern Europeans, reduces the risk of HIV-1 infection. The CCR5D32 allele appears to be associated with an increased risk of developing clinical manifestations of West Nile Virus (WNV) [204]. While CCR5 is potentially involved in the host immune response to WNV, the implications of this interaction for patients taking a CCR5 inhibitor are unknown. There have been no documented reports of WNV in patients taking maraviroc.

6 Integrase Inhibitors 8 Conclusion The FDA approved raltegravir in 2007, making it the first HIV integrase inhibitor available for clinical use. Shortly after its approval, reports of possible CNS toxicity began to emerge. In one case series, four patients with depression or bipolar disorder experienced an exacerbation of depression

While cART has led to tremendous reductions in neurological morbidity and mortality associated with HIV, antiretrovirals are associated with a variety of neurological and psychiatric adverse events. This article provides a

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comprehensive discussion of the frequency, clinical presentations, pathogenesis, risk factors and, when applicable, potential therapies for cART neurotoxicity. Future studies should focus on known genetic risk factors to reduce the burden of cART-induced neurological toxicities. Acknowledgments No sources of funding were used in the process of writing this manuscript. The authors have no conflicts of interest to disclose.

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