Neurologic and Psychiatric Complications of Antiretroviral Agents

Neurologic and Psychiatric Complications of Antiretroviral Agents Charles Raines, CRNP, MSN Olivia Radcliffe, RN, MSN Glenn J. Treisman, MD, PhD

Advances in highly active antiretroviral therapy (HAART) aim to improve the efficacy of HIV drugs as well as the quality of life in HIV-infected patients. Neurologic and psychologic disturbances that occur because of HIV disease and therapy are of great concern, and because they can overlap and are often difficult to distinguish, their pathogenesis is not clearly understood. Furthermore, these complications can lead to decreased adherence, thereby interfering with treatment outcomes. Antiretrovirals, including nonnucleoside reverse transcriptase inhibitors, can penetrate the central nervous system (CNS) and suppress viral replication, but they can also exacerbate CNS side effects and neuropsychiatric symptoms. When deciding which HAART drug combination is most appropriate for a patient, clinicians must consider the individual’s risk of CNS complications together with the efficacy of the specific HAART regimen. Key words: HIV, antiretroviral, HAART, neurologic and psychologic complications

In recent years, there have been impressive advances in the treatment of HIV and AIDS. Between 1995 and 1997, there was a dramatic decrease in HIV mortality, irrespective of risk factors such as age, race, sex, and HIV-related opportunistic infections. No longer is this disease regarded as the rapidly progressive and fatal illness it once was; patients infected with HIV in developed countries can now expect to live for longer periods of time with improved quality of life (QOL) (Palella et al., 1998).

Much of this success can be attributed to the introduction of a wide range of new therapies, including nucleoside reverse transcriptase inhibitors (NRTIs), nonnucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), and fusion inhibitors. Combinations of these drugs form the basis of highly active antiretroviral therapy (HAART), an effective means of suppressing HIV viremia, restoring CD4 cell counts, and improving immune reconstitution (Bartlett & Gallant, 2004). Viral suppression has been correlated with patient survival, indicating that HAART has a profound impact on patient survival (Lucas, Chaisson, & Moore, 2003). Neurologic and psychiatric complications are frequently observed in patients with HIV infection. Neurologic conditions associated with HIV can include HIV dementia, cognitive disorders, central nervous system (CNS) infections, and polyneuropathies including peripheral neuropathy. Accumulating evidence also suggests that HIV infection increases the patient’s risk of various psychiatric conditions such as mood disorders, depression, mania, and psychosis. These conditions may result from HIV infection of the CNS or as a consequence of AIDS-related opportunistic infections or malignancy (Bartlett & Gallant, 2004). Psychiatric and neurologic disorders may be Charles Raines CRNP, MSN is a faculty instructor in the Division of Infectious Disease, Department of Medicine, Johns Hopkins University School of Medicine. Olivia Radcliffe RN, MSN is a nurse specialist at Johns Hopkins University. Glenn J. Treisman, MD, PhD, is Associate Professor at Johns Hopkins University.

JOURNAL OF THE ASSOCIATION OF NURSES IN AIDS CARE, Vol. 16, No. 5, September/October 2005, 35-48 doi:10.1016/j.jana.2005.07.004 Copyright © 2005 Association of Nurses in AIDS Care

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associated not only with the disease itself, but also with antiretroviral agents used in the HAART regimen (Treisman & Kaplin, 2002), thus complicating disease management and compromising patients’ QOL. It is important to identify the underlying causes of these conditions so that appropriate treatments can be implemented. In many cases, the discontinuation of HAART results in prompt viral reappearance or rebound (Lambotte, Deiva, & Tardieu, 2003). Thus, to be optimally effective, it seems that HAART needs to continue uninterrupted over the lifetime of a patient. This may not be feasible, however, because interruptions in treatment are sometimes necessary to manage potentially serious side effects. Even though a number of advances during the past several years have dramatically simplified many of the regimens, regimen complexity and pill burden were the most common reasons for nonadherence when combination therapy was first introduced, and interactions among antiretroviral agents and with other drugs have become more complex (Department of Health and Human Services [DHHS], 2005). Indeed, analyses of antiretroviral drug adherence data have shown that the more complex a regimen, the less likely it is that patients will be adherent, particularly when some degree of cognitive impairment is also present (Hinkin et al., 2002). To effectively help their HIV-positive patients, nurses need to understand the neurologic and psychologic complications of HIV and HAART as well as the direct action of HIV medications and the most important drug-drug interactions. This review will highlight the involvement of the CNS in HIV infection and in HAART regimens. It will focus on currently used drug combinations, their effectiveness in suppressing HIV infection in the blood and CNS, and their potential for causing neurologic, psychologic, and systemic complications.

Neurologic and Psychologic Consequences of HIV Infection Infection of the CNS may occur early in the course of HIV disease. In one study, 28% of seropositive patients without AIDS had virus present in the cerebrospinal fluid (CSF), as compared with only 5% of

seropositive patients with AIDS (p ⬍ .05) (Resnick, Berger, Shapshak, & Tourtellotte, 1988) Mild to moderate cognitive changes also may occur early in the course of infection with HIV and can present as deficits in attention, memory, information processing, and fine-motor function, which may be difficult to detect without a complete neuropsychological evaluation (Fernandez, 2002). In one study of 395 HIV-infected patients naive to HAART and with no prior psychiatric history, the global prevalence of cognitive impairment and/or symptoms of depression was 17.9% (Starace, Bartoli, et al., 2002). Although such impairment may not always progress to HIV dementia, it may nonetheless have a dramatic impact on daily activities, work performance, drug rehabilitation, and QOL. Psychiatric disorders and drug use are common among HIV-infected subjects (Bing et al., 2001; Vitiello, Burnam, Bing, Beckman, & Shapiro, 2003). The development of AIDS may precipitate a range of psychologic and neurologic disorders, most commonly delirium, dementia, depression, mania, and anxiety. The cause of these conditions may be difficult to dissociate from underlying conditions such as opportunistic infections, neoplasms, metabolic disorders, and other toxicities brought on by AIDS or its treatment (Fernandez, 2002). Delirium is one of the most commonly encountered neurologic impairments in HIV, with a prevalence as high as 40% (Fernandez, 2002). Although the condition can be effectively treated with pharmacologic agents, a thorough evaluation is often needed to determine the underlying cause, which may be an opportunistic infection (e.g., toxoplasmosis or viral infection), a metabolic disturbance (e.g., hypoglycemia), neurotoxicity from substance abuse or antiretroviral therapy, or drug toxicity (Fernandez, 2002). HIV-associated dementia, an important manifestation of HIV infection (Nath & Berger, 2004), is likely to have an impact on public health and economic issues (Starace, Dijkgraaf, Houweling, Postma, & Tramarin, 1998). It is characterized by a progressive slowing of motor and mental function, with deficits in language and memory occurring more insidiously (Maxwell, Scheftner, Kessler, & Busch, 1988). Often, more advanced stages of HIV dementia are accompanied by changes in mood and personality disorders (Fernandez, 2002). HIV infection of the CNS

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seems to be an important component of HIV dementia, because this condition was almost uniformly fatal before the introduction of HAART (Resnick et al., 1988). A variety of neuromuscular complications may occur in patients with HIV (Verma, Micsa, Estanislao, & Simpson, 2004), the most common of which is distal symmetrical polyneuropathy (Verma et al., 2004; Williams, Geraci, & Simpson, 2002). The condition, caused by abnormalities in peripheral nerve function, is characterized by pain and by numbness in the lower extremities (Williams et al., 2002) and has been associated with advanced HIV infection, high viral load, and reduced CD4 levels (Childs et al., 1999; Williams et al., 2002). In line with these observations, aggressive antiretroviral treatment has been shown to improve sensory function in HIVinfected patients (Martin, Solders, Sonnerborg, & Hansson, 2000; Williams et al., 2002). Unfortunately, some antiretroviral agents, particularly the dideoxynucleoside analogs (stavudine, didanosine, and zalcitabine) have also been associated with sensory peripheral neuropathy (Williams et al., 2002). Neuropathy may also occur secondary to opportunistic infection just as do cytomegalovirus and hepatitis C coinfections (Williams et al., 2002). There is no curative treatment for distal symmetrical polyneuropathy, and the best approach to managing the condition consists of discontinuation of the causative agent (e.g., in the case of dideoxynucleoside-related toxicity) and symptomatic treatment of the associated pain (Williams et al., 2002). A number of pharmacologic approaches are used to treat sensory peripheral neuropathy, and although there have not been adequate trials in HIV-related neuropathy, the literature for treatment of neuropathic pain is extensive (Clark, 2000). Psychiatric conditions are also frequently observed in the context of HIV infection. Anxiety disorders are present in about 17% to 36% of persons with HIV and AIDS, and adjustment disorder with anxious mood seems to be most prevalent (Fernandez, 2002). Other mood disorders, such as mania and hypomania, may occur either early or late in the course of HIV disease, and mania has been associated with antiretroviral treatment in patients with no previous psychiatric history (Kieburtz, Zettelmaier, Ketonen, Tuite, & Caine, 1991). Psychosis may

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present in patients with HIV either as a preexisting condition or as a consequence of CNS infection with the virus (Fernandez, 2002). Patients can experience hallucinations, delusions, and gross distortions of reality (Treisman & Kaplin, 2002). The risk of this psychotic condition can increase with substance abuse (Kendler, Gallagher, Abelson, & Kessler, 1996; Sewell et al., 1994), and patients with neuropsychological impairment were reported to have higher rates of mortality than nonpsychotic patients (Sewell et al.). Depression, a prevalent (Fernandez, 2002; Repetto et al., 2003) and underdiagnosed (Asch et al., 2003) condition among HIV-infected patients, has a significant impact on morbidity and mortality in this population (Cruess, Douglas, et al., 2003). It is the most common reason for HIV-positive patients to undergo psychologic evaluation (Valente, 2003). There is evidence for a fairly high incidence of depression in HAART-naive, HIV-infected patients (15%, N ⫽ 395) (Starace, Bartoli, et al., 2002). Also, HIV-seropositive persons (meta-analysis of 10 studies, N ⫽ 2,596) have been shown to have almost twice the risk of developing a major depressive disorder as compared with HIV-negative individuals, independent of sexual orientation or high-risk behaviors (Ciesla & Roberts, 2001; Starace, Ammassari, et al., 2002). A separate study of 1,231 seropositive patients in the Multicenter AIDS Cohort Study reported that anxiety and somatic depression symptoms were associated with shortened survival (Farinpour et al., 2003). Indeed, living with HIV brings with it a wide range of life stressors, such as the diagnosis itself, disease exacerbation, treatment failure, or the death of a loved one from HIV. Depressive symptoms associated with these events can affect QOL (Tostes, Chalub, & Botega, 2004), and stress can further impair cognitive function (Pukay-Martin, Cristiani, Saveanu, & Bornstein, 2003) and may be greatly amplified by drug or alcohol abuse (Valente, 2003). It is important to recognize symptoms of depression, particularly hopelessness, discouragement, stress, depression, or suicidal feelings. Often, nurses and psychologists are the primary health professionals to discover such feelings. Depression and suicidal feelings should not be regarded as acceptable in patients with a life-threatening illness. Instead, clinicians

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need to recognize these symptoms and pursue further evaluation (Valente, 2003).

Influence of Neurologic and Psychiatric Comorbidity on Treatment Adherence In addition to potentially dangerous suicidal ideation, untreated neurologic and psychologic conditions may have a particularly unfavorable effect on HIV treatment in general (Cruess, Petito, et al., 2003) and on adherence in particular. Depression, for example, has been reported to be a risk factor for poor treatment adherence with HAART (Starace, Ammassari et al., 2002). Although the mechanism by which depression negatively contributes to poor adherence is unclear, pessimistic attitude, hopelessness, and withdrawal from social and emotional interactions (e.g., with support groups and loved ones), which characterize depression may play a role (Starace, Ammassari et al., 2002). Depression has also been shown to have a negative influence on QOL in persons with HIV. Depression and then QOL can be improved by psychopharmacologic intervention (Repetto et al., 2003). In one study, clinically significant depression was present in 80% of 45 HIVpositive patients, and depression was significantly correlated with poorer QOL as measured by the Medical Outcomes Study Short Form 36 scale (Tate et al., 2002). Other psychiatric conditions may also affect treatment adherence with HAART. Wagner Kanouse, Koegel, and Sullivan (2003) reported that serious mental illnesses such as schizophrenia, schizoaffective disorder, and major depression with psychotic features can alter adherence to antiretroviral treatment. They reported that serious mental illness had a negative effect on adherence, which was associated with an increase in viral load. Another longitudinal study of 46 HIV-infected patients reported that treatment adherence (defined as taking ⱖ80% medication, approaching our treatment goal of ⬎95% for best durability) was associated with a lack of previous intravenous drug use (p ⫽ .001), less depression (p ⫽ .04), and better adaptive coping skills (p ⫽ .03) (Singh et al., 1996). Lower psychologic disturbance scores were also associated with poor adherence (p ⫽ .02). Patients who have a history of poor adherence

should thus be assessed for possible psychiatric comorbidity. Clinicians, nurses, and psychologists should be on guard for stereotyping patients presenting with the above disturbances. For example, a patient’s previous history of treatment nonadherence, alcohol or intravenous drug use, or previous psychiatric hospitalizations may significantly influence a physician’s decision to implement effective therapies such as HAART (Bogart, Kelly, Catz, & Sosman, 2000), meaning some HIV-infected patients with untreated psychiatric disorders may not receive effective treatments that could prolong survival. Results such as those outlined above highlight the importance of recognizing and treating psychiatric comorbidities, especially depression, so that treatment adherence can be optimized.

Role of HIV Infection in CNS Pathogenesis and Effect of HAART The effect of HIV on the nervous system is unclear. HIV DNA and HIV antigen have been reported in the brains of patients with HIV dementia, but there is no clear evidence that infection of the brain is the direct mechanism for neuropsychological impairment (Simpson, 1999). Several mechanisms have been proposed, including the release of neurotoxic factors and cytokines by various cells within the brain; neurotoxic effects of the glycoprotein (gp) 120 HIV surface antigen, and activation of the N-methylD-aspartate receptor molecules in the brain (Simpson, 1999). There is evidence that patients with advanced HIV (CD4 count ⬍200 cells/m3) and dementia have a significantly greater viral load in the CSF, an indicator of viral burden in the brain, than do persons without dementia (McArthur et al., 1997; Simpson, 1999). Neurologic and psychiatric complications may occur because of CNS pathology directly related to HIV infection or indirectly as a result of opportunistic infection. A recent study concluded that, during the current era of HAART, the incidence of HIV encephalopathy increased significantly (p ⫽ .014), whereas the incidence of opportunistic infections in the brain (e.g., cytomegalovirus, aspergillosis) and lymphoma decreased (Neuenburg et al., 2002). There

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is evidence to suggest that severe forms of HIV encephalitis are likely to emerge despite the success of HAART (Kemmler et al., 2003). These results suggest that, although HAART is effective in restoring the immune response, it does not necessarily reduce HIV-related encephalopathy. This study also indicates that HIV-associated CNS pathology increases as patients live with the disease for longer periods. CNS pathology and the potential for neurologic and psychologic adverse events during therapy are therefore important considerations when deciding which drugs should be included in HAART. A greater systemic HIV burden may drive the progression of CNS disease and the development of HIV dementia. In one study of 1,604 HIV-infected men assessed over 10 years, those with baseline plasma HIV levels greater than 30,000 copies/mL had a risk for HIV dementia 8.5 times higher (p ⬍ .001) than those with levels less than 3,000 copies/mL (Childs et al., 1999), and also, patients with more than 10,000 copies/mL were at 2.3-fold greater risk (p ⫽ .008) of sensory neuropathy than those with less than 500 copies/mL. A prospective multicenter observational study of 9,803 patients (between 1994 and 2002) showed that low CD4 counts and high plasma viral load were associated with development of CNS disease (D’Arminio Monforte et al., 2004). HAART may help improve sensory function, such as sensory perception (warmth, cold, and heat pain) in HIV-infected patients who have a virologic response to therapy (McArthur et al., 1997; Simpson, 1999). These improvements were associated with a higher pretreatment CD4 level, indicating that patients with less advanced immunodeficiency may benefit most from therapy (McArthur et al., 1997; Simpson, 1999). Unfortunately, there are no conclusive data to show that any antiretroviral agent, even those most able to penetrate the CNS, can prevent or improve HIV-associated CNS pathology or neuropsychological outcomes. The long-term controlled studies needed to assess endpoints such as HIV dementia are difficult to perform because of ethical and practical constraints (e.g., the need for a control group with no antiretroviral treatment and for an extended follow-up period). Thus, many clinical trials have focused on the ability of antiretrovirals to suppress viral load in the CSF as an indicator of

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overall benefit in preventing HIV-related pathology in the brain (Simpson, 1999).

Role of Antiretroviral Therapy in Preventing HIV CNS Disease: Which Drugs Are Best? A literature review described the efficacy of triple combination therapy involving dual NRTIs plus a PI (PI triple therapy), NNRTI (NNRTI triple therapy), or a third NRTI (nucleoside triple therapy) in therapy-naive adults with HIV (Bartlett, DeMasi, Quinn, Moxham, & Rousseau, 2001). Plasma levels of HIV RNA were used to assess efficacy. Overall, NNRTI triple therapy provided better suppression of viral RNA at 24 and 48 weeks. An important caveat of this finding is that patients with a high viral load, treatment experience, or unclear treatment history may have greater benefit from boosted PI-based therapies. This study also reported a negative correlation between the number of pills taken per day and patient outcomes at 24 and 48 weeks, both in terms of viral suppression and increased CD4 count. For example, a lower number of pills per day was predictive of a better virological response (r ⫽ ⫺.57; p ⫽ .0085). These results support other studies that suggest simpler regimens are important for optimal adherence, especially for patients with cognitive or other neurologic impairment (Hinkin et al., 2002). Slowing of psychomotor speed is strongly predictive of HIV-associated dementia, AIDS, and patient death (Sacktor et al., 1996), and the success of HAART in suppressing the plasma viral load has made the CNS an important site of ongoing viral replication and possible development of CNS drug resistance (Arendt & von Giesen, 2002). The drug combinations necessary for the most efficient inhibition of viral CNS infection and persistence are not known. Specific regimens that can focus on prevention and treatment of HIV infection in the CNS need to be developed. Discerning the best possible combination for an individual patient requires assessing efficacy in suppressing systemic and CNS HIV infection and the potential for causing or exacerbating CNS effects.

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NRTIs—CNS Efficacy and Adverse Effects Drugs in the NRTI class are not bound by plasma proteins and can diffuse readily between blood and CSF (Wynn, Brundage, & Fletcher, 2002). In vitro studies have shown that zidovudine, didanosine, zalcitabine, and stavudine had comparable permeability across a synthetic blood-brain barrier (Glynn & Yazdanian, 1998). This has made NRTIs attractive for treatment of HIV neurologic disease although, as mentioned above, there are no conclusive data to show that any antiretroviral agent, even those most able to penetrate the CNS, can prevent or improve HIV-associated CNS pathology or neuropsychological outcomes. Zidovudine has been well studied because of its long-term and widespread use among patients with HIV. In one study, zidovudine monotherapy significantly reduced levels of HIV RNA in the CSF, whereas didanosine monotherapy did not (Gisslen, Norkrans, Svennerholm, & Hagberg, 1997; Wynn et al., 2002). These results of reduced CSF viral load are consistent with the improvements in neurologic dysfunction that have been observed in adults with HIV dementia treated long-term with zidovudine monotherapy (Wynn et al.; Yarchoan et al., 1987). The role of NRTI will be challenged with the new data regarding thimidine analogue (zidovudine and didanosine) sparing regimens. Stavudine has now been removed from the preferred list for use of NRTIs in antiretroviral therapy (DHHS, 2005). Similarly, in children with HIV encephalopathy, monotherapy with zidovudine has been shown to improve neurodevelopmental abnormalities and cognition (intelligence quotient scores) (Pizzo et al., 1988; Wynn et al., 2002). Some of these improvements occurred in children with no evidence of encephalopathy prior to treatment (Pizzo et al.). Longterm stavudine therapy also has been shown to improve developmental testing scores in children with HIV (Kline et al., 1995; Wynn et al.). Arendt and von Giesen (2002) evaluated finemotor function as a more sensitive measure of neurologic function and improvement in therapy-naive patients treated with zidovudine or didanosine monotherapy. Both therapies significantly improved CNS function as compared with no antiretroviral therapy (change in contraction time scores over 6 months: no

antiretroviral therapy ⫽ .001; zidovudine ⫽ 1.353, p ⬍ .0001; didanosine ⫽ 1.598, p ⬍ .0062). In a multicenter observational EuroSIDA (síndrome de inmunodeficiencia adquirida) cohort study involving 9,803 patients, use of NRTIs (regardless of PI or NNRTI use) seemed to have a protective effect against the dementia complex (D’Arminio Monforte et al., 2004). Despite the apparent short-term efficacy of NRTIs at improving CNS function in HIV-infected patients, there is the potential for the drugs themselves to cause CNS toxicity, and their use can be one of the predictors of sensory peripheral neuropathy (Lopez, Becker, Dew, & Caldararo, 2004). Sensory peripheral neuropathy has been associated with NRTIs, especially stavudine and didanosine (Dragovic & Jevtovic, 2003). This condition may be painful and debilitating. Dose reduction according to body weight or discontinuation of one or more of the NRTIs may be necessary if analgesic or other therapies are ineffective. CNS effects are also observed in patients treated with zidovudine, most notably, insomnia, myalgia, and severe headaches (Richman et al., 1987). There also have been case reports of mania in patients on zidovudine without a prior history of this disorder (Maxwell et al., 1988; Wright, Sachdev, Perkins, & Rodriguez, 1989). In a small study of 112 patients who were treated with at least one NRTI regimen, patients on stavudine alone had twice as much risk of peripheral neuropathy when compared with patients treated with a stavudine and didanosine combination (Dragovic & Jevtovic, 2003). However, this combination is no longer recommended by any of the HIV treatment guidelines, because fatal lactic acidosis has been reported among pregnant women who received both stavudine and didanosine with other antiretroviral combinations. Stavudine plus didanosine should only be used during pregnancy if the potential benefit clearly outweighs the potential risks (DHHS, 2005). Overall, the NRTIs are a useful class of HAART drugs, and evidence suggests they may be effective in suppressing some CNS effects of HIV. Nonetheless, the risks and benefits of continued NRTI therapy must be weighed if neurologic symptoms develop after the implementation of treatment.

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PIs—CNS Efficacy and Adverse Effects PIs are widely used in combination with other antiretrovirals such as NRTIs and are effective in reducing viral plasma load and increasing immune function. PIs as a class generally have the poorest penetration into the CNS and across the blood-brain barrier (Glynn & Yazdanian, 1998). This has led some clinicians to favor the use of other agents in patients with CNS-related HIV-induced conditions. Some studies of the PI indinavir have reported CNS penetration and improvement in patients with HIV dementia (Wynn et al., 2002). However, compared with other PI-containing regimens used in 2004 and 2005, the use of indinavir has decreased because of warnings from the Department of Health and Human Services (DHHS, 2005). Clinical trials that have attempted to assess CSF penetration and/or the effects of other PIs such as ritonavir or saquinavir on CSF HIV RNA levels have yielded largely inconclusive results because of the low levels of the drugs detected in CSF (Wynn et al., 2002). In addition, because PIs are frequently administered in combination with NRTIs in patients with HIV-related neuropathology, their effects may be difficult to dissociate from other drugs (e.g., stavudine) used in the regimen (Wynn et al., 2002). However, some studies have reported stabilization or improvement in cognitive function and magnetic resonance imaging tests in patients who had indinavir, ritonavir, or saquinavir added to an NRTI-based regimen (Filippi, Sze, Farber, Shahmanesh, & Selwyn, 1998; Wynn et al., 2002). Unfortunately, these specific PIs are not used in firstline or salvage therapies because of long-term toxicities and poor tolerability issues. Neurologic adverse events are generally observed less frequently with PI therapy than with NRTIs or NNRTIs. Ritonavir and ritonavir/saquinavir combinations have been reported to induce more neurologic symptoms than indinavir regimens, and high ritonavir plasma concentrations have been correlated with an increased incidence of neurologic side effects (Bonfanti et al., 2000; Gatti et al., 1999). Some PI-containing regimens also have been associated with decreased QOL because of adverse events, high pill burden, and complex dosing schedules (Barreiro, García-Benayas, Soriano, & Gallant, 2002). Simpli-

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fying dosing, reducing pill burden, and decreasing negative side effects will likely improve patients’ QOL. Boosted PI regimens using only 100 mg of ritonavir in conjunction with other PIs has become more popular than ritonavir/saquinavir 400 mg/400 mg because of a decrease in pill burden. Other popular PI-boosted regimens include: ●

●

●

●

●

●

Kaletra (lopinavir 400 mg coformulated with ritonavir 100 mg; Abbott Laboratories, Abbott Park, IL), three pills twice a day, durably suppresses HIV RNA in CSF (⬍1.7 log10 c/mL), benefiting individuals at risk for or diagnosed with HIV-associated neurocognitive impairment (van den Brande et al., 2005). Atazanavir 300 mg boosted with 100 mg of ritonavir, three pills daily, is comparable to Kaletra (Badaro et al., 2003). Fosamprenavir 700 mg boosted with ritonavir 100 mg, two pills twice a day, caused only one CNSrelated adverse event (headache) in the SOLO study, but results were not statistically significant compared with the comparator unboosted PI (Gathe et al., 2004). Saquinavir mesylate 1,000 mg boosted with ritonavir 100 mg, three pills twice a day, has a better pharmacokinetic profile than Fortovase (saquinavir; Roche Laboratories Inc., Nutley, NJ) boosted with ritonavir (CNS-related adverse events, 4% vs. 21%, respectively), probably because of the drug’s slow dissolution (Kurowski, Sternfeld, Hill, Sawyer, & Moecklinghoff, 2002). Nelfinavir 1,250 mg, not boosted, two new 625-mg pills twice a day, essentially has no penetration into the brain and spinal fluid (Aweeka et al., 1999; Solas et al., 2003). The full dual PI combination regimen now generally used is Kaletra, four pills twice daily with fosamprenavir, two pills twice daily. The next most common regimen is Kaletra, three pills twice a day with saquinavir, two pills twice a day.

NNRTIs—CNS Efficacy and Adverse Effects There are currently three drugs of the NNRTI class— delavirdine, nevirapine, and efavirenz—that differ in their relative CNS permeability and adverse

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effects. Both delavirdine and efavirenz are highly protein-bound in plasma and as a result have low penetration into the CNS (Wynn et al., 2002). Thus, experimental studies have shown a very low permeability of delavirdine across a synthetic blood-brain barrier (Glynn & Yazdanian, 1998). In addition, there are few clinical data available on delavirdine and entry into the CSF, mainly because of the lack of use of delavirdine because of considerable concerns with potency and efficacy. In contrast, many studies on NNRTIs and CNS-related morbidity have focused on efavirenz (Wynn et al., 2002) and nevirapine, even though with the new labeling data on nevirapine, its use has been limited in women with a CD4 count greater than or equal to 250 cells/mm3 and men with a CD4 count around 300 to 400 cells/mm3. Among all of the NNRTIs, nevirapine, following the new labeling, has the greatest penetration into the CNS, with a CSF/plasma ratio as high as 40% (Arendt & von Giesen, 2002). A multinational study established both virologic and immunologic benefit in drug-naive patients treated with nevirapine in combination with zidovudine and didanosine (triple therapy), as compared with patients receiving zidovudine plus nevirapine or zidovudine plus didanosine (double therapy) (Conway, 2000). (It should be noted that the latter two regimens have been taken off of the preferred list for antiretroviral therapy by the DHHS and International AIDS Society.) In this randomized study, 45% of patients had sustained virologic suppression through week 52. Death or disease progression occurred in 12% of the patients in the triple therapy arm, compared with 24% of patients in the latter two groups combined (n ⫽ 100). These results demonstrate the efficacy of nevirapine as a component of triple therapy in drugnaive patients. Nevirapine also has been proven effective in patients previously treated with PIs. At one center, after the replacement of PI-based therapy with either nevirapine or a continuation of the PI therapy alone, the proportion of patients with an undetectable viral load at 48 weeks was 81% versus 63%, respectively (p ⬍ .001) (Barreiro et al., 2000). Poor adherence was reported in 27% of PI failures, as compared with only 9% of failures in the nevirapine arm (p ⬍ .05). Improvement in QOL measures were also superior in the nevirapine group and were attributed to simplic-

ity of the dosing schedule, fewer adverse events, and improved well-being (Barreiro et al., 2002). Arendt and von Giesen (2002) examined CNS outcomes in a cohort of HIV-infected patients with psychomotor slowing who were treated with nevirapine (n ⫽ 39) or efavirenz (n ⫽ 65) in combination with two NRTIs. These two groups were compared with patients taking two NRTIs alone, zidovudine monotherapy, or no antiretroviral treatment using sensitive tests to quantify psychomotor slowing. Both nevirapine and efavirenz improved CNS function independent of the NRTIs used, as did NRTI double therapy and zidovudine monotherapy. The greatest changes were observed in the nevirapine group, whereas changes in the efavirenz group did not reach significance (change in contraction time scores over 6 months: efavirenz plus two NRTIs ⫽ .809; nevirapine plus two NRTIs ⫽ 2.342, p ⫽ .0011). The beneficial effects of these two NNRTIs also have been observed in patients pretreated with PIs. Von Giesen, Koller, de Nocker, Haslinger, and Arendt (2003) examined the long-term safety and efficacy of NNRTIs in the context of CNS issues. A comparison of 414 patients on efavirenz and 320 patients on nevirapine showed that as a class, NNRTI treatment was not associated with a higher incidence of neuropsychiatric side effects. The efficacy of these NNRTIs at improving CNS function suggests a potential therapeutic rationale for HIV-infected patients who exhibit signs of motor function abnormalities (Arendt & von Giesen, 2002). Several studies have examined efavirenz-containing regimens for neurological and psychological effects. The principal adverse events associated with the use of efavirenz are CNS related and include severe depression and suicidal ideation (Medical Economics, 2005; Puzantian, 2002). One such study, which compared the sleep patterns of 18 HIV-infected persons on an efavirenz-based regimen with those of 13 HIV drug-naive controls, reported that all patients on efavirenz experienced significant sleep disturbances, especially longer sleep latency and insomnia (Gallego, et al., 2004). A correlation between higher efavirenz plasma levels and abnormal sleep pattern and insomnia (Nunez et al., 2001) may indicate the need for monitoring therapy. Fumaz et al. (2002) compared emotional status, QOL, and adherence in HIV-infected patients receiv-

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ing therapy with efavirenz or PIs in combination with two NRTIs. Patients on efavirenz and two NRTIs had improved QOL as compared with the PI groups at both 24 (p ⬍ .001) and 48 (p ⬍ .001) weeks of treatment, much of which was attributed to the simpler dosing of efavirenz (Fumaz et al., 2002). The two regimens were comparable with respect to medication adherence, CD4 cell counts, and the number of patients with viral loads greater than 200 copies/mL at 48 weeks of treatment. In the efavirenz group, most CNS adverse events had resolved by week 24; however, irritability, abnormal dreaming, and nervousness persisted through week 48 in 13%, 10%, and 8% of the patients, respectively. In an open-label observational study, 1,033 patients who started an efavirenz-containing regimen were assessed for safety and tolerability (Pérez-Molina, 2002). CNS effects were common (24.1%) and caused treatment interruptions in 24.9% of these patients. The most frequently reported complaints (n ⫽ 280) were dizziness (45.7%), sleep disorder (42.5%), and mood disorder (9.7%). In a subgroup of 126 patients (12.2%), CNS symptoms persisted over a 3-month period but did not result in the discontinuation of efavirenz. There was no association between the rate of CNS events and a history of psychiatric disorder or the use of psychoactive drugs (p ⫽ .20); however, patients taking methadone had more CNS adverse events (35.3% vs. 23.3%, p ⫽ .025) and a higher rate of treatment discontinuation (19.1 vs. 7.9%, p ⫽ .003) than did the remainder of the study population. As a consequence of methadone’s opiate-induced effects on gastric emptying and metabolism by cytochrome P450, pharmacologic effects and interaction with antiretrovirals in general may commonly occur (DHHS, 2005). These may diminish the effectiveness of either or both therapies by causing opiate withdrawal or overdose and/or increased toxicity or decreased efficacy of the antiretrovirals. Methadone is known to increase zidovudine levels by 40%, with a possible increase in zidovudine-related side effects. On the other hand, levels of stavudine and didanosine are decreased by methadone by 18% and 63%, respectively. Both efavirenz and nevirapine decrease methadone levels by 43% and 46% respectively, with corresponding clinical opiate withdrawal. The clinical effect is usually seen after 7 days of coadminis-

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tration and is treated with an increase of the methadone dosage, usually at 5 to 10 mg daily until the patient is comfortable. Limited information indicates that PI levels are generally not affected by methadone, except for amprenavir, which seems to be reduced by 30%. However, a number of PIs have significant effects on methadone metabolism. Amprenavir, nelfinavir, and lopinavir administration results in a significant decrease in methadone levels. Lopinavir boosted with ritonavir significantly reduces methadone levels, mainly because of the lopinavir component. (DHHS, 2005). In a large, randomized, double-blind, three-arm controlled trial (a substudy of AIDS Clinical Trials Group [ACTG] 5097), neuropsychological parameters in HIV patients on zidovudine/lamivudine/abacavir, zidovudine/lamivudine/efavirenz (control arm), and zidovudine/lamivudine/abacavir/efavirenz were compared (Clifford et al., 2004). It might be important to note that ethanol increases abacavir levels by approximately 3%, which could be important in patients with hepatitis C. There is now a cautionary note in the labeling of abacavir regarding hepatitis C. Early neurological symptoms different from anxiety and depression, described as vestibular disorder, were greater in patients receiving efavirenz and were restored by week 4 on continuing therapy. Improvement in symptoms was similar between efavirenz and nonefavirenz-treated subjects. This neurological study excluded HIV-infected patients with a history of mental disorder. CNS-related effects do not seem to be a classeffect for NNRTIs. In the 2 non-nucleotides (2NN) study, an open-label, large, randomized trial that compared nevirapine and efavirenz directly for efficacy, tolerability, and safety, the incidence of grade 3 and 4 CNS-related adverse events was seen only in the efavirenz group, except for a patient with depression in the nevirapine twice a day arm (van Leth et al., 2004). Patients with a prior history of depression may be at greater risk of efavirenz-related CNS disturbances. In one study of patients on efavirenz (N ⫽ 104), 92.4% of patients with a history of depression developed at least one depressive symptom of grade 2 or higher, as compared with 39.2% of patients with no history of depression (p ⫽ .014) (L. Boly, personal communication, July 31, 2003). This observation

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also seems to extend to the discontinuation of efavirenz because of depressive side effects, with 22.6% versus 2.0% of the patients with and without a history of depression discontinuing, respectively (p ⫽ .011) (L. Boly, personal communication, July 31, 2003). Similarly, in a retrospective study of 222 patients on efavirenz (23% with a history of mental health disorder), Guest, DeSilva, Flaherty, Le Flore, and Rimland (2002) reported 91% early CNS effects. Patients with mental illness were more likely to experience late CNS effects (p ⫽ .006), have lingering CNS effects, and discontinue efavirenz. The mechanisms for these CNS changes are not clearly understood and could be related to drug levels. In one study of 130 patients receiving efavirenz in combination with other antiretrovirals, CNS toxicity was observed in 24% (⬎ 4,000 ␮g/L), 9% (1,000-4,000 ␮g/L), and 0% (⬍ 1,000 ␮g/L) of the high-, intermediate-, and low-range patients, respectively, whereas virological failure was observed in 50% of the patients in the low-range group (Marzolini et al., 2001). Persistent CNS side effects, including “feeling faint, dizzy, out of control, or restless” were also reported by 10% of the patients in this study. These results suggest an association between efavirenz drug levels, efficacy, and side effects. Therapeutic drug monitoring may be necessary to ensure optimal benefit with minimal toxicity. In view of the potential influence of prior depression history on efavirenz-related CNS effects, therapeutic drug monitoring of efavirenz may be especially important in this subgroup of patients.

Conclusions Despite substantial improvements in the management of HIV infection with HAART, which has significantly increased long-term survival, several limitations of HAART remain, including CNS side effects and neuropsychiatric-associated symptoms. In addition, it would seem that eradication of the virus from reservoirs in the body, most notably the CNS, is not possible with currently available pharmacologic strategies. Thus, long-term treatment with effective antiretroviral drugs remains the mainstay of therapy. Unfortunately, such treatment is complicated by CNS adverse events, complex dosing sched-

ules, and impairment of QOL. CNS complications, including those associated with HIV dementia, are commonly observed in patients with HIV and AIDS. This further complicates long-term treatment in that psychiatric comorbidities such as depression, schizophrenia, and psychosis can lead to nonadherence. Even mild cognitive impairment associated with early-stage HIV brain disease can lead to suboptimal treatment adherence when drug regimens are complex. It is important for nurses interacting with HIV patients to remain vigilant for these potential hurdles to their patients’ long-term treatment success and QOL. Systems to monitor patients with HIV for psychiatric and neurologic disorders need to be implemented to assist in nursing assessment so that appropriate treatments can be initiated. These conditions may be caused by preexisting disease, HIV infection, or antiretroviral drug treatment. Whenever possible, therapy should be initiated to correct the underlying disorder. This may be as simple as recommending counseling, which may have a dramatic impact on the patient’s chances for long-term adherence to treatment and successful viral suppression. In other instances (e.g., neuropathy or sleep disturbance judged to be caused by a specific drug), dose reduction/discontinuation or a change in therapy may be indicated. Pharmacologic treatment of patients with HIV should take into account psychiatric comorbidity, and whenever possible, drugs that are effective in suppressing CNS viral load and symptoms without causing additional drug-related psychiatric comorbidity should be used. Clinicians should also try to limit exposure to antiretroviral drugs so as to maximize future therapeutic options in the event of treatment failure. The overall message from a review of the literature on treatment outcome is that there is no single best approach to treatment. Although data for particular regimens may show better efficacy in overall treatment, individual patient differences make drug selection a complex and critical matter. Pill burden, degree of cognitive impairment, treatment history, psychiatric conditions, and suicidal behavior all strongly influence treatment choice. Although no antiviral drug has been shown to be superior in the treatment of CNS-related consequences of HIV, PIs, have lower CNS penetration than NNRTIs but are

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less likely to produce depression than efavirenz. Some NRTIs, especially zidovudine, are effective in suppressing CNS viral load and symptoms, but their use may be complicated by psychiatric and neurologic adverse events that limit their efficacy or may exacerbate preexisting CNS conditions (Rachilis & Fanning, 1993). In the NNRTI class, nevirapine seems to have the highest degree of CNS penetration, which may explain its clinical efficacy in suppressing CNS symptoms. Efavirenz has been associated with a number of significant CNS effects, including dizziness, sleep disturbances, and mood alterations. Many of these effects resolve after the first few weeks of therapy; however, symptoms may persist (Treisman & Kaplin, 2002). The long-term impact of these effects on treatment adherence and efficacy is not known. Further study will be needed to assess which combination of antiretroviral drugs is most effective and tolerable for patients with HIV and CNS disease.

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