HIGHLY ACTIVE ANTIRETROVIRAL THERAPY FOR TREATING HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS
Highly active antiretroviral therapy (HAART, also known as combination antiretroviral therapy cART), has had a major impact on the incidence, prevalence and clinical impact of the most severe forms of HIV-associated neurocognitive disorders (HAND). Its effectiveness in the less severe expressions of HAND remains unclear. For example, several longitudinal observational studies since the introduction of HAART for treating HIV infection reported a dramatically reduced incidence of cases of the most severe form of HAND, HIV-associated dementia (HAD) [1–6]. In the Concerted Action on Seroconversion to AIDS and Death in Europe (CASCADE) study, the incidence of HAD was reduced from 6.5 per 1000 person-years (pre-HAART) to 0.7 per 1000 person-years (post-HAART) [6]. In the multicenter AIDS cohort study (MACS) the incidence of HAD was reduced from 21.8 per 1000 person-years (pre-HAART) to 5.0 per 1000 person-years (post-HAART) [7].
Whilst HAART prevents new cases of HAD, recent work suggests the incidence and prevalence of “milder” cases of HAND (i.e., asymptomatic neurocognitive impairment, ANI and mild neurocognitive disorder, MND) has not changed appreciably with the introduction of HAART. One large cohort study involving six academic medical centres across the United States, the Central Nervous System (CNS) HIV Anti-Retroviral Therapy Effects Research (CHARTER) study, reported the prevalence of HAND at around 44%, which was virtually unchanged from results obtained in the pre-HAART era using similar neurocognitive assessment techniques [4]. As Tan et al. [8] suggested recently ‘There is a therapeutic gap on milder forms of HAND.’
Initiation of HAART produces variable effects on patients with milder HAND. Some patients definitely improve whereas others remain stable or respond only partially [9–12]. These different outcomes may be explained by various factors. These include patient background characteristics, HIV disease-related factors, HIV clade and resistance-related mutations and antiretroviral drug-related factors, as described below. The presence of co-morbid background factors associated with neurological damage [7, 13–15], such as head injury with loss of consciousness, may limit the potential for HAART to improve HAND. In terms of HIV disease-related variables, different hypotheses have been proposed to explain why HAND continues despite HAART. A well-accepted hypothesis is the legacy effect. This theory suggests that the HIV replication that occurs in the CNS may produce non-reversible neuronal damage, especially in individuals who experience marked CD4 cell depletion. This hypothesis is supported by the correlation observed between the CD4 nadir and the severity of HAND [16]. Another major disease-related factor is the possible presence of active replication of HIV in the CNS. Improvement of cognition is observed more frequently in patients with HIV suppression in the cerebrospinal fluid (CSF) compared to patients without CSF HIV suppression, and it is independent of their HIV status in plasma [9]. Other factors include the ability of the antiretrovirals to target CNS cells [17] and to suppress the production of neurotoxic viral proteins (e.g. tat), as well as any neurotoxicity related with the use of HAART itself [18].
The search for the most effective antiretrovirals to treat or prevent neurocognitive impairment is ongoing. Evidence supporting the use of any one specific antiretroviral to protect against or reverse neurocognitive decline is limited, and there is no data supporting different HAART combinations. Direct evidence from a randomized, placebo-controlled trial supports the efficacy of zidovudine [19, 20]. Indirectly, several antiretrovirals such as stavudine, lamivudine [21], indinavir [22], boosted lopinavir [23], saquinavir or nelfinavir [24] have demonstrated benefits on neurocognitive performance, based on their effectiveness in reducing HIV-RNA levels in the CSF. The neurocognitive efficacy of other antiretrovirals, such as abacavir, raltegravir, enfuvirtide or maraviroc, has been tested in HAART intensification studies, where those drugs have been added to conventional HAART. No benefit on neurocognitive performance has been observed in any of these studies [25–27].
One strategy to guide drug selection attempts to capitalize on evidence that the CSF level of each antiretroviral is modulated by its capacity to penetrate across the blood–brain barrier (BBB) and the capacity of BBB efflux transporters to transport the drug outside the CNS. A hypothesis proposed by Letendre et al. [28] suggested that some HAART combinations are not effective in fully suppressing CNS HIV replication owing to insufficient CNS penetration. On the basis of each drug’s molecular properties and pharmacokinetic and pharmacodynamics studies, this group proposed a CNS Penetration and Effectiveness (CPE) score to help clinicians choose the treatment on the basis of the probability of achieving concentrations effective in suppressing HIV replication in the CSF [29, 30]. The CPE ranks each antiretroviral from 1 (least CNS effective) to 4 (most CNS effective); the sum of the score of drugs included in the regimen is proposed as an index of likely efficacy in the CNS. It should be noted that the CPE approach attempts to assign the CPE rank of an antiretroviral (ARV) by considering not only the concentration of the drug in the CSF, and also that the achieved concentration is at a level that permits at least 50% inhibition of HIV replication (IC-50). Examples of these criteria include abacavir, zidovudine, emtricitabine, efavirenz, nevirapine, lopinavir, darunavir, amprenavir, raltegravir and maraviroc [31–34]. In some but not all studies, CPE correlates inversely with the risk of detectable levels of HIV-RNA and HAND [9, 12, 35–40]. A review by Cysique et al. [41, 42] and current European AIDS Clinical Society (EACS) guidelines recommend the use of high CPE antiretrovirals in patients with HAND with ongoing CSF replication. However, the data supporting these recommendations are still not definite and await completion of ongoing trials such as the Cognitive Intervention Trial-2 (CIT-2) [43]. In summary, the approach to drug selection and understanding of CNS efficacy is complex and evolving: CPE rankings, pharmacokinetics and antiviral activity. The use of new HAART strategies, such as nucleoside-sparing regimens, and the introduction of new antiretroviral drugs, as well as the existence of different viral clades or resistance mutations between plasma and CSF need to be taken into account [44, 45].
One issue that is receiving close attention is the potential neurotoxicity of antiretroviral regimens. In 2009, Marra et al. [37] observed worse neurocognitive performance in patients on regimens with higher CPE scores, and in 2010, the ACTG 5170 reported finding slight improvement in neurocognitive performance after cessation of HAART [46]. Liner et al. [47] suggested that there may be critical levels of many ARVs beyond which neurotoxicity becomes more likely. One agent, efavirenz, has been particularly associated with CNS side effects such as vivid dreams, mood disturbance and other neuropsychiatric symptoms [48, 49] including higher rates of neurocognitive impairment [50], although this latter complication may reflect an interaction between this agent and advanced age [51]. As the population of HIV-infected individuals ages, the issue of CNS risks and benefits of antiretroviral treatment may become more prominent.
ADJUVANT PHARMACOTHERAPIES FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDER
Treating HAND with HAART is insufficient to prevent neurocognitive disorder or restore neurocognitive normality in most HIV-infected patients. Several adjuvant treatments have been evaluated in addition with HAART for treating HAND. Most of these drugs are neuroprotective or CNS anti-inflammatory agents. A review of the studies published for the major drugs tested as adjuvants is reported below.
Minocycline
Minocycline, a second-generation tetracycline antibiotic, has become a candidate to treat HAND because of its good penetration across the BBB and its potential protective and anti-inflammatory effect in the CNS [52]. The results of a 24-week multicentre, randomized, double-blind, placebo-controlled trial enrolling 107 HIV patients with neurocognitive impairment showed no differences in the neurocognitive status between minocycline and placebo [53]. Results from the analysis of surrogate markers such as neuroimaging and CSF markers are not yet available.
Memantine
Memantine, an N-methyl-d-aspartate (NMDA) receptor blocker, has been proposed as adjuvant therapy for HAND because of a known protective effect against glycoprotein (gp) 120 toxicity in animal models. In a 20-week multicentre, randomized, double blind placebo-controlled trial including 140 patients with HAND receiving HAART, no improvement in neurocognitive function was observed with the addition of memantine [54]. However, a potential neuroprotective effect, as demonstrated by magnetic resonance spectroscopy (MRS) in the white matter and parietal cortex, was observed. In another clinical trial, including 19 patients in a 12-week blinded phase and 45 more in a 48-week open-label phase, neurocognitive performance improved with the use of memantine after the 12 weeks of the blinded phase, but this benefit was not sustained in the open label phase [55]. The evidence appears to be inconclusive, but further assessment of memantine for the treatment HAND may be warranted.
Selegiline
Selegiline, a monoamine oxidase type B (MAO-B) inhibitor, has been proposed as a treatment option for HAND because of its capacity to reduce reactive oxygen species in the brain. Two clinical trials have been performed using transdermal administration of selegiline, the preferred route of administration over the oral route owing to a potential reduction in toxicities. A pilot clinical trial showed that transdermal selegiline was associated with potential neurocognitive benefit [56]. A subsequent 24-week, double-blind, placebo-controlled, randomized clinical trial followed by a 24-week open-label phase indicated that selegiline was ineffective [57, 58]. A sub-study to evaluate the ability of selegiline to reverse HIV-induced metabolic brain injury and decrease oxidative stress was also evaluated by MRS [59]. No differences were observed between subjects taking 3 or 6 mg of selegiline a day or placebo in terms of efficacy, reversal of brain injury or decrease of oxidative stress. The current data do not support selegiline as a treatment for HAND.
Lithium
Lithium, a mood-stabilizing agent, has been proposed as for protective treatment against HIV gp120 excitotoxicity [60]. An open-label pilot study of lithium treatment administered to HIV subjects initiating HAART who presented with neurocognitive impairment showed neurocognitive improvement in most patients as determined by the NPZ8 score; however, this improvement could also be attributed to HAART initiation [61]. Another 10-week open-label study evaluated the safety, tolerability and efficacy of lithium 300 mg twice daily as adjuvant therapy for HAND in 15 cognitively impaired HIV-infected subjects who had been on a stable antiretroviral regimen or off antiretroviral treatment for at least 8 weeks [62]. In this study, no improvement in neurocognitive performance was observed in lithium-treated subjects. However, using MRS, a decrease in glutamate–glutamine peak in frontal grey matter was observed, suggesting an improvement in metabolites linked to brain injury.
Valproic Acid
In a murine model, valproic acid (VPA) has been associated with protection against neuronal loss and dendritic simplification without affecting HIV replication or immune activation. A randomized, double-blind, placebo-controlled pilot trial was performed in 22 HIV patients (6 without neurocognitive impairment and 16 with neurocognitive impairment) to evaluate the efficacy of VPA 250 mg twice daily during a 10-week period [63]. No differences in neurocognitive performance were observed. Nevertheless, an increase in N-acetyl aspartate/creatine ratio – a marker of neuronal damage – was observed in the white matter of the frontal lobe in those receiving VPA. In contrast, in a cohort study, Cysique [64] found long-term use of VPA to be associated with greater decline in neurocognitive function in 8 HIV-infected individuals receiving VPA for neuropathy or epilepsy. These data do not suggest a role for VPA in the treatment of HAND.
Lexipafant
Platelet-activating factor (PAF) has been associated as an inflammatory marker with neuronal injury. Lexipafant, an inhibitor of PAF, was tested as an adjuvant therapy for HAND in a randomized, double-blind, placebo-controlled clinical trial [65]. Thirty subjects were included and randomized to receive 500 mg of lexipafant a day or placebo. Trends of improvement in a summary score of neuropsychological test performance were observed. Further studies are needed to determine the potential role of lexipafant as an adjuvant therapy for HAND.
CPI-1189
CPI-1189 is an antioxidant with the capacity to block TNF-α and has protective properties in experimental mouse models of HAND. CPI-1189 at 50 or 100 mg was tested in 64 HIV subjects with mild-to-moderate neurocognitive impairment during 10 weeks in a double-blind, placebo-controlled trial [66]. CPI-1189 did not improve neurocognitive performance or everyday function, and this agent has not been advanced to additional trials in HIV.
Nimodipine
Nimodipine, a voltage-dependent calcium-channel antagonist, was tested as an adjuvant therapy for HAND in a pilot trial that recruited 41 subjects with mild-to-severe neurocognitive impairment. Subjects were randomized to receive nimodipine 60 mg five times a day, 30 mg three times a day or placebo over 16 weeks. There was no evidence of benefit with nimodipine, in terms of improvement in neurocognitive function or immunomodulation (measured using CSF levels of neopterin as a marker of immune activation) [67]. Although this study, similar to others in this field, was not statistically powered to be conclusive, it does not appear that nimodipine treatment is warranted for HAND.
Statins
In vitro data suggest that statins are associated with reduced HIV replication. In a cohort of 658 subjects, a correlation between the use of statins and decreased HIV viral load in the CSF was observed in a univariate analysis, but this was not confirmed in the multivariate analysis. No correlation was found between the use of statins and cognition [68]. Randomized trials to investigate the possible efficacy of statins in HIV neurocognitive impairment have not been conducted.
Selective Serotonin Reuptake Inhibitors (SSRIs)
Selective serotonin reuptake inhibitor (SSRI) antidepressants have been associated in vitro with inhibition of HIV replication. In a cohort of 658 subjects, Letendre et al. [68] showed that those who took SSRIs were more likely to have an undetectable HIV viral load in CSF and a better global neurocognitive performance than subjects without this treatment. The meaning of this result is unclear, as the use of SSRIs could be a marker of engagement in care, better overall adherence to antiretrovirals, or successful treatment of depression, a condition thought to adversely affect both adherence and performance on neuropsychological testing.
Peptide T
Peptide T (d-ala-peptide T-amide) is an octapeptide that is part of the core HIV envelope sequence required for attachment to the CD4 receptor. It has been reported to block the binding of gp120 to brain tissue and to protect neurons in vitro from the toxic effects of gp120 [69]. Whilst there was no evidence of antiviral activity by peptide T in phase I human trials, cognitive improvement was noted in some HIV-infected patients receiving peptide T [70, 71]. In pilot studies, administration of peptide T to HIV-infected patients with cognitive impairment was associated with improvement in cognition and constitutional symptoms. A phase III double-blind, placebo-controlled trial tested the use of 2 mg of intranasal peptide T three times a day for 6 months in 143 HIV-seropositive persons with evidence of cognitive deficits on a screening test battery. Peptide T showed no differences in neurocognitive performance at the study end point. However, additional analyses indicated that peptide T may be associated with improved performance in the subgroup of patients with more evident cognitive impairment or with relatively preserved immunological status (i.e. CD4 cell count > 0.200 × 109/L) [72]. These potential benefits have not been pursued in follow-up trials.
Other Therapies
Other drugs have demonstrated a neuroprotective effect and are potential adjuvant therapies for treating HAND, but have not come to be used in larger scale clinical trials. Some of those drugs are erythropoietin [73, 74], CEP-1347 [75] or N-acetylated-alpha-linked-acidic dipeptidase inhibitor and 2-(phosphonomethyl) pentanedioic acid (2-PMPA) [76].
In conclusion, most of the drugs tested as adjuvant therapies for treating HAND are safe and well tolerated. Nevertheless, efficacies observed in these trials have been modest. Indeed, a systematic review performed by the Cochrane Library in 2008 [77] for adjunctive therapies studied for treating HAND concluded that ‘there is a lack of evidence that any of the adjunctive therapies improves cognitive performance or quality of life.’ As noted above, more recent studies, not included in that Cochrane systematic review, are consistent with the same conclusion.
Clinical guidelines for management of HIV do not recommended the use of any adjuvant therapy for either HAND prevention or treatment. In selected patients with evidence of ongoing HAND despite optimal HAART and elevated levels of inflammatory markers in blood or CSF, adjuvant therapies that have demonstrated an improvement of markers of neuronal damage or inflammation could be offered as an experimental option. On the basis of the evidence provided and the improvement of neuronal damage markers observed in MRI studies with memantine, in our opinion this could be one of the more promising candidates for further clinical trials as adjuvant therapy for HAND.
BEHAVIOURAL INTERVENTIONS FOR HIV-ASSOCIATED NEUROCOGNITIVE DISORDERS
The availability of HAART since 1996 has helped successfully control HIV viremia and improve immune function in many treated, HIV-infected (HIV-positive) patients, leading to dramatic improvements in medical morbidity and life expectancy [78]. As discussed above, this era also has shown a clear improvement in neurological outcomes with a significant drop in the rate of frank HIV-associated dementia [3, 79, 80].
Despite advances in HAART, HIV-infected patients continue to present with HAND, with an estimated 30–60% living with HAND, according to Grant et al. [2, 81]. HAND remains amongst one of the most common clinical disorders encountered in people infected with HIV [82]. HAND is primarily associated with mild-to-moderate deficits in executive function (i.e. planning, complex attention) and memory (i.e. acquisition and retrieval), along with impairments in psychomotor speed and working memory [78]. Whilst neurocognitive impairment confers a 2.5 times greater risk of poor medication adherence, [83] neurorehabilitative strategies to minimize HAND for people living with HIV may be useful. Combined with current CNS-penetrating antiretroviral regimens, neurorehabilitation strategies are a logical choice for improving HAND. With this said, relatively few studies have been conducted that utilize these intervention techniques.
The few studies that have been conducted utilizing neurocognitive intervention techniques to improve HAND have shown success. HAND impacts a wide range of cognitive functions, but it might be particularly important to specifically target deficits in episodic memory, given their prevalence and relevance to everyday functioning such as remembering to pay bills or take medications [84]. A recent study showed that self-generation, a process to enhance new learning by elaborating and deepening encoding, can be helpful in improving neurocognitive performance. When used in paired-word verbal memory formats, self-generation requires the individual to generate the second word in a pair with the assistance of cue (e.g. first letter of the word, and that it is semantically related to the first word). Using an approach similar to that described above, self-generation improved performance amongst HIV-positive individuals with memory impairment at a level equivalent to the improved performance observed amongst HIV-positive persons who did not have memory impairments [84]. In another study, investigators were able to show improved performance on a category fluency task when using cueing as opposed to not using cueing amongst HIV-infected persons [85]. These findings suggest that neurorehabilitative techniques such as self-generation and cueing may be effective in improving verbal recall in individuals with HIV infection as well as other aspects of their treatment such as appointment times and treatment goals.
Other neurorehabilitive techniques may be appropriate and potentially effective cognitive rehabilitation tools for HAND. A study performed in a population of HIV-infected children in Uganda has examined the effect of a memory- and attention-based cognitive rehabilitation training programme (i.e. Captain’s Log computerized cognitive rehabilitation training (CCRT)), in which moderate improvements on information processing speed and simple attention were made [86]. To date, this is one of the few if not the only studies created to improve neurocognitive disorder amongst a population of those living with HIV. Other neurorehabilitative techniques developed to improve neurocognitive disorders (e.g. attention, memory and executive function) could be created specifically for HAND. Non-experimental evidence has shown that the utilization of specific techniques can improve performance amongst HIV-infected individuals. For example, Weber et al. and Woods et al. [87, 88] showed that older HIV-infected persons who used higher-level mnemonic strategies on a visual working memory task had improved cognitive and everyday functioning outcomes as compared to those who did not use these strategies; this was also reported by older HIV-positive adults who used these memory strategies in their daily lives outside of the laboratory, and suggesting that improvement in daily functioning exists.
Outside of the HIV population and HAND, the majority of cognitive rehabilitation work has been done in the domains of memory, executive function and attention for populations suffering from traumatic brain injury (TBI), as well as neurological (e.g. stroke, multiple sclerosis) and psychiatric (e.g. schizophrenia) disorders. Basic strategies such as using a day planner to compensate for impaired neurocognition have been shown to be effective across these populations and have resulted in improved quality of life and improved everyday functioning outcomes [89, 90]. Whilst remediating HAND, it may be logical to apply strategies used in the cognitive rehabilitation literature for disorders with similar neurocognitive profiles in order to identify possible candidate therapies for those infected with HIV [91]. Whilst over the past two decades great strides have been made to limit the impact of HAND on everyday functioning, the process of effective cognitive neurorehabilitative development strategies has only just begun. Proper design and validity of such interventions specifically created for those living with HIV infection have become a crucial part of the efforts to improve patients’ health outcomes and quality of life.
INTERVENTIONS FOR PSYCHIATRIC DISORDERS IN HIV-INFECTED PEOPLE
Psychopharmacological Treatment
Psychopharmacological treatment in patients with HIV infection is often effective but is frequently complicated by concurrent HAART regimens. This means that clinicians will need to be alert to the possibility of adverse drug–drug interactions and to closely monitor patients to assist them in adhering to complex HAART and psychopharmacologic drug regimens. In addition, HIV patients can be more sensitive to medication side effects, may metabolize drugs more slowly, may have less lean body mass and compromised BBB functioning. General guidelines addressing these issues are summarized in Box 4.1.
- start slow and go slow
- avoid complex regimens
- remove medicines whenever possible
- anticipate drug interactions
- avoid toxic medicines with narrow therapeutic windows.
The present section reviews the literature on the effectiveness of the psychotropic medications most frequently prescribed to HIV patients for major mental disorders. Following this is a separate section dedicated to interaction between psychotropic medications and antiretrovirals.
Antidepressants
Antidepressants are effective for major depressive disorders in HIV, but given that no particular antidepressant medication has been shown to be superior for treatment of depressed HIV-infected patients in controlled clinical trials, therapy should be chosen such as to minimize risks of adverse effects and limit the potential for drug–drug interactions.
Tricyclic antidepressant (TCA) medications were the standard of care when HIV infection was first recognized. Several early studies demonstrated that imipramine is an effective drug for treating depression in HIV patients [92, 93], and it was found to be especially effective when combined with interpersonal therapy and supportive therapy in comparison to psychotherapy alone [94]. Similarly, desipramine and amitriptyline have been shown to be effective for major depression in patients with AIDS [95, 96]. Since most of the studies utilizing TCAs were conducted before the advent of HAART, and therefore enrolled individuals are likely to be more physically ill than the current HIV cohort, some authors have speculated that these earlier studies may have underestimated response rates which might be achieved with patients on well controlled modern antiretroviral regimens [93].
As is true with HIV-uninfected patients, the use of TCAs in clinical practice declined because of high rates of anticholinergic, antihistaminic, antiadrenergic and antimuscarinic side effects (e.g. constipation, dry mouth, drowsiness, headache, cognitive problems, weight gain, dizziness and sexual dysfunction), adverse effects on cardiac conduction and the need to closely monitor therapy in order to guard against their lethality in overdose. On the other hand, when suicide risk is low and cardiac co-morbidities are absent, some of the side effects of TCAs may help patients with insomnia, pain, diarrhoea and poor appetite, but these potential benefits must be weighed against the possible negative impact of its anticholinergic effects on cognition in a vulnerable population.
In general, TCAs have been replaced in clinical practice by selective serotonin reuptake inhibitors (SSRIs) because of their more benign side effect profile and evidence that the efficacy of TCAs and SSRIs is similar in the treatment of mood disorder [95, 97]. SSRIs are now the most widely used antidepressant treatment for major depression amongst HIV-infected persons [98]. A recent survey of HIV specialty psychiatrists showed that citalopram/escitalopram were the first-line antidepressants for patients with HIV, usually preferred to other antidepressants because of its low likelihood of adverse effects and interactions with HAART, especially in older adults with co-morbid anxiety [98]. A potential benefit of citalopram is that it has been shown to be safe amongst HIV/hepatitis C virus HCV co-infected persons undergoing interferon alpha treatment [99]. Its adverse effects include those typical of other SSRIs (e.g. mild sedation, nausea, diarrhoea or constipation, sweating, anorgasmia). Nevertheless, a recent advisory cautioned against prescribing doses of citalopram above 40 mg daily (and above 20 mg daily in individuals over age 60) because of risks of cardiac conduction delays (i.e. dose-dependent QT interval prolongation). Patients with congenital prolonged QT syndrome, bradycardia, hypomagnesemia, hypokalemia, recent myocardial infarction or uncompensated heart failure are not candidates for citalopram (US Food and Drug Administration (FDA) Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide). http://www.fda.gov/Drugs/DrugSafety/ucm269086.htm
Other SSRIs are also widely used amongst HIV-infected patients. Fluoxetine was the first licensed SSRI, and randomized trials (e.g. References [92, 100]) and open-label studies support its safety and efficacy in treating major depression amongst patients with HIV [95, 101–103]. Adverse effects of anxiety and agitation may occur during the initial phase of treatment, and may necessitate treatment discontinuation. Randomized trials also support the efficacy of paroxetine, and its sedating effects may be helpful for patients suffering from insomnia [97, 104]. Given its mild anticholinergic/antimuscarinic properties, it may be less problematic for HIV patients with cognitive impairment [105]. Sertraline is also safe for HIV patients and has a benign side effect profile [93]. Moreover, sertraline is also a mild gastrointestinal stimulant that could be useful in patients with gastrointestinal slowing [106, 107]. Because of its many interactions with antiretrovirals and because it is not well tolerated by patients with HIV, there are few studies of fluvoxamine in patients affected by HIV and, as such, its use is not recommended [108].
On the basis of their demonstrated efficacy in treating major depression in other populations, additional antidepressants that can be useful in the management of depressive disorder in patients with HIV belong to the Serotonin–norepinephrine reuptake inhibitors (SNRIs) class, which includes venlafaxine, desvenlafaxine and duloxetine. This category of drugs was found to be effective for co-occurring somatic symptoms and neuropathic pain, and its use in patients with HIV is increasing [109–112]. There are potential safety concerns. Venlafaxine and its active metabolite desvelafaxine are usually well tolerated, but they have a dose-dependent tendency to increase blood pressure [113], so close monitoring may be required as doses advance above 225 mg of venlafaxine daily. Venlafaxine is thought to be more lethal in overdose than the SSRIs (but less so than the TCAs). Duloxetine can cause increase in blood pressure and elevation of liver enzymes, so caution is required, particularly when prescribing this drug to HIV/HCV co-infected patients or those with impaired liver function [93, 114]. Another antidepressant, a noradrenergic and specific serotonergic antidepressant, mirtazapine, was found to be effective and well tolerated in 12 HIV-infected patients in an open-label 4-week study [115]. Mirtazapine is sedating and can cause pronounced weight gain, so it can be useful for HIV patients suffering respectively from insomnia and weight loss.
Other open-label studies suggest that a third class of antidepressants, the norepinephrine dopamine reuptake inhibitors, may be therapeutic. In this regard, bupropion appears to be beneficial and well tolerated by HIV-infected patients [116, 117] and may be particularly useful for persons presenting with depressive symptomatology characterized by apathy, since it has an activating effect. However, it is also known to increase the risk of seizure; therefore, before prescribing bupropion, intracranial pathology (toxoplasmosis, CNS lymphoma, cytomegalovirus CMV), alcohol and benzodiazepine withdrawal or other conditions that lower seizure threshold must be excluded [105].
Finally, a serotonin receptor 2A antagonist and reuptake inhibitor, nefazodone, may have efficacy in treating depression in HIV [118], and also a sedating effect that can be a useful strategy in avoiding benzodiazapine, but it was withdrawn from sale in North America and other countries because of an adverse effect of rare but severe hepatoxicity.
Guidelines for Non-response to Treatment
In HIV, consistent with the use of antidepressants in other populations, current guidelines suggest several strategies when an initial antidepressant trial is unsuccessful: these include increasing the dosage of the index antidepressant if tolerable and safe; substitution of another agent from the same class; or addition of a second antidepressant with a slightly different mechanism of action when a single antidepressant is ineffective [119]. Caution is required however, since antidepressant combinations may increase risk of serotonin syndrome. This syndrome is characterized by pyrexia, sweating, diarrhoea, hyper-reflexia, myoclonus, lost of consciousness and seizures [120]. Treatment failure should also be a signal to pause and consider other causes of non-response: this would include reviewing the differential diagnosis of the mood disorder, addressing issues of adherence to therapy and assessing for the possibility that a co-morbid substance use disorder has undermined therapy.
Alternative Pharmacotherapy
Psychostimulants may be efficacious in treating depressive symptoms in patients with advanced HIV, especially when depressed mood, fatigue and cognitive impairment are prevalent. Specifically, both methylphenidate and dextroamphetamine have been shown to be more effective than placebo in reducing those symptoms with relatively few side effects [121, 122]. Fatigue is a frequent symptom in HIV patients and may or may not be accompanied by major depression: randomized trials indicate that modafinil and armodafinil are effective for HIV-related fatigue [123, 124] and may be helpful in HCV/HIV co-infected patients [125].
Hypogonadism is less prevalent in the era of HAART, but it still remains the most common endocrine disorder of HIV-infected men [126]. The symptoms of testosterone deficiency, depressed mood, fatigue, diminished libido, decreased appetite and loss of lean body mass can be effectively treated with testosterone replacement therapy (esterified testosterone depot, skin patches, gel) [127, 128]. Dehydroepiandrosterone (DHEA), a precursor to testosterone, was found to be effective in the treatment of subsyndromal major depressive disorder when compared to placebo [129].
Anxiolytics
Anxiety is prevalent in HIV disease and it is important to employ a hierarchical approach to its treatment, in order to maximize efficacy and minimize risks. This approach should consider both diagnosis and likely duration of therapy. Benzodiazepines can be effective for acute anxiety, or emotional crises, but are probably over-prescribed for chronic anxiety. SSRIs should be considered the first-line pharmacotherapy for chronic anxiety disorders, including generalized anxiety disorders, panic, disorders, social phobia, obsessive compulsive disorder and post-traumatic stress disorder in HIV, even though empirical evidence for their efficacy almost completely depends on data generated in general (non-HIV) psychiatric samples. When a benzodiazepine is required, the dose should be low, and the medication generally used only for short periods of time to minimize respectively the risk of abuse and adverse effects (confusion, sedation, cognitive impairment, disinhibition). Patients with HAND may be especially vulnerable to these latter effects. If a benzodiazapine is chosen, lorazepam or clonazepam are the most frequently used [130]. When hepatic impairment is present, lorazepam, oxazepam and temazepam are the safest benzodiazapines because of their oxidative metabolism [131]. An alternative to benzodiazapines could be buspirone, which has been shown to be effective in treating anxiety symptoms in HIV-infected opiate users [132]; it has also shown a positive immune modulation in patients with HIV-1 infection [133]. One randomized trial indicates that trazodone, a serotonin receptor 2A blocker and serotonin reuptake inhibitor, could be a good choice for HIV patients with anxiety and insomnia and may be a valuable alternative to benzodiazepines for the treatment of HIV-related adjustment disorders [134].
Mood Stabilizers
Practice guidelines in general psychiatric (non-HIV) treatment recommend lithium, VPA or carbamazepine (CBZ) as standard agents for treatment and prevention of acute manic and depressive episodes in bipolar disorder [135]. This approach warrants modification in HIV-infected patients.
Despite its low metabolic risks and freedom from significant drug–drug interactions, the use of lithium in HIV-infected patients may be complicated for several reasons. Individuals with HIV-related neurocognitive impairment may be vulnerable to the adverse effects of lithium on cognition at the standard serum concentrations employed in non-HIV populations. HIV patients are at risk for HIV-related nephropathy, which can impair lithium clearance [61]. Moreover, patients with HIV are at risk for toxicity because of both rapid idiosyncratic fluctuations in lithium plasma levels and because of effects of diarrhoea, dehydration and poor fluid intake [136].
Related posts:
1.1 Epidemiology of Psychopathology in HIV: Neurocognitive Disorders
2.4 Traumatic Stressors and the Psychoneuroimmunology of HIV/AIDS
3.2 Differential Diagnosis in HIV-Associated Neurocognitive Disorders
4.2 Psychopharmacology and Psychiatric Co-morbidity
Pathogenesis of Mental Health Disorders in HIV
Inex
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