US Pharm. 2012;27(1):HS-2-HS-5.
Nearly 1 million people in the United States are infected with HIV, with 1 in 5 being unaware of the infection. Although the rate of newly diagnosed HIV infections was stable from 2006 to 2009, HIV incidence rose an estimated 21% in individuals aged 13 to 29 years, driven by a 34% increase in men having sex with men (MSM).1 One-third of persons with HIV are aged 40 to 49 years, and the greatest increase in HIV infection rate—3.9%—was observed in those aged 60 to 64 years.2 Although blacks/African Americans constitute just 14% of the U.S. population, they have a high HIV infection rate (48%) compared with whites (33%), Hispanics/Latinos (17%), and American Indians/Alaska Natives, Asians, and Hawaiians/other Pacific Islanders (<1%).2 Adult and adolescent males have an infection rate of 72%, versus 20% in females. The causes of HIV transmission in adult and adolescent males are MSM (64%), injection-drug use (16%), heterosexual contact (12%), and the combination of MSM and injection-drug use (7%). Heterosexual contact accounts for 73% of HIV infections in adult and adolescent females, and injection-drug use accounts for 26%; perinatal transmission causes 88% of infections in children.2
HIV type 1 infects mainly CD4-positive (CD4+) T lymphocytes and causes AIDS. Other infected immune cells include macrophages—the main carriers of the virus into the central nervous system (CNS)—and monocytes.3 The CDC defines HIV positivity as a CD4 cell count of <200 cells/mm3 with late-stage HIV infection or AIDs. AIDS-defining illnesses include:
1) Opportunistic infections with Pneumocystis jiroveci (formerly P carinii) pneumonia, cerebral toxoplasmosis, cytomegalovirus (CMV) infection, and disseminated Mycobacterium avium complex.
2) CNS and peripheral nervous system disorders, including AIDS dementia complex characterized by cognitive and memory impairment, peripheral neuropathy (PN), myopathy, and myelopathy.
3) Kaposi’s sarcoma (KS), a cancer associated with HIV and AIDS that is linked to genetic and environmental factors and infectious agents such as human herpesvirus. KS presents as skin lesions and may affect the lymph glands, gastrointestinal tract, and lungs. Non-Hodgkin’s and other lymphomas and cervical cancer are other malignancies that may develop.
4) AIDS wasting syndrome, which results from malnutrition, infections, and metabolic disturbances.
This article will discuss the neurologic disorders that may accompany HIV and AIDS and examine potential management options.
HIV-ASSOCIATED NEUROLOGIC DISORDERS
Despite the availability of effective antiretroviral therapy (ART), more than 25% of people with HIV infection will develop neurologic disorders.4 These disorders range from minor deterioration in motor and information-processing speed to severely incapacitating symptoms that affect the patient’s functional capacity. The disorder may reduce quality of life and cause ART nonadherence and early death.5 Causes of HIV-associated neurologic disorders include HIV itself, opportunistic infections, and HIV therapy.
HIV as a Cause of Neurologic Disorders
HIV enters the CNS via HIV-infected monocytes penetrating the blood–brain barrier. These monocytes then mature into long-lived, persistently infecting perivascular macrophages, which affect the choroid plexus, capillary endothelial cells, microglia, and astrocytes.6 HIV stimulates a persistent inflammatory response in activated and infected macrophages or microglia in the brain that produces cytokines, neurotoxic substances, inducers of oxidative stress, and injurious viral proteins, promoting the progression of various neurodegenerative disorders. In addition, HIV infection of the CNS constitutes a serious barrier to management and eradication of the virus. The CNS is not very permeable to antiretroviral drugs, which results in subtherapeutic cerebrospinal fluid (CSF) levels. Accordingly, the CNS becomes a protected reservoir, along with the gut and several other organs where HIV can evade the immune system, replicate, mutate, and reinfect the circulation.7
HIV Vacuolar Myelopathy (VM): HIV VM usually affects the spinal cord.8 It presents as leg weakness causing unstable gait and may involve total loss of muscle function, spasticity, dorsal sensory loss, erectile dysfunction, and urinary frequency. Incontinence and restriction to a wheelchair are common in advanced stages. Therapy is limited to agents that manage spasticity, including baclofen, tizanidine, dantrolene, and botulinum toxin, as well as physical and occupational therapy.9
Although the incidence of opportunistic CNS infections has declined with the use of highly active ART (HAART), many patients experience the following infections.
Toxoplasmosis Encephalitis (TE): Toxoplasma gondii is a ubiquitous intracellular protozoan pathogen of humans and animals. Depending upon the geographic location, 15% to 85% of adult humans are infected with T gondii. Cats are the main hosts, but other mammals are carriers. Infection is acquired placentally or by ingesting contaminated water, meat, soil, or cat feces. Once in the gut, the parasite disseminates to the brain, muscles, and eyes, forming intracellular cysts that are highly inflammatory and necrotic to the invaded cells. AIDS-associated TE results from reactivation when the CD4++ count falls <50 cells/mm3. The most common presenting symptoms are fever, headache, focal neurologic deficit, cognitive dysfunction, seizures, and altered mental status.10 A definitive diagnosis of TE requires brain biopsy; a response to empiric toxoplasmosis treatment is also considered to be diagnostic. The treatment of choice for TE is a loading dose of oral pyrimethamine 200 mg followed by 50 mg daily plus oral sulfadiazine 1 g four times daily and oral leucovorin (folinic acid) 10 mg daily to reduce pyrimethamine-induced toxicity.11 An alternative regimen is an oral loading dose of pyrimethamine 200 mg followed by 50 mg daily plus oral clindamycin 600 mg four times daily plus leucovorin 10 mg daily. Acute therapy should be continued for at least 6 weeks, and longer in cases of extensive disease. Secondary prophylaxis should continue until the lesions resolve, symptoms improve, HAART raises the CD4 cell count to 200 cells/mm3, and viral load is suppressed.12
Cryptococcal Meningitis (CM): Cryptococcus neoformans is encapsulated yeast that is found everywhere. It spreads by inhalation of spores in dust and bird droppings. In most individuals, the immune system clears the organism, but in HIV-positive patients the organism remains latent within granulomas, from whence it disseminates to multiple organs.13 The most common presentation is meningoencephalitis in AIDS patients with CD4 cells/mm3 <100. Immediate treatment is critical because the mortality rate remains 15% even with optimal treatment.14 Standard initial treatment for patients with normal renal function is amphotericin B (AmB) 0.7 mg/kg daily combined with flucytosine 100 mg/kg daily in four divided doses for at least 2 weeks.11 After successful induction therapy (significant clinical improvement and negative repeat CSF culture), AmB and flucytosine may be discontinued and follow-up therapy initiated with fluconazole 400 mg daily for 8 weeks until repeat CSF is sterile and the CD4 cell count increases to >200 cells/mm3. Increased intracranial pressure may require repeated CSF drainage via lumbar puncture; otherwise, permanent neurologic deficits, blindness, and death may result. With treatment, most patients survive CM, albeit sustaining some deficits in verbal and motor functioning.
Progressive Multifocal Leukoencephalopathy (PML): PML is a rare demyelinating CNS disorder caused by John Cunningham virus (JCV), a type of human polyomavirus. It is found worldwide, with 70% to 90% seroprevalence.13 PML complicates about 5% of AIDS cases, with CD4 counts <100 cells/mm3.15 Most patients present with altered mental status accompanied by focal symptoms referable to the location of PML lesions, such as hemiparesis, hemianopsia, ataxia, vertigo, speech disorders, and seizures. Diagnosis is established by biopsy or autopsy. Topotecan, cytarabine, and cidofovir have all been tried, but there is no successful treatment for PML. However, HAART has improved the course of AIDS PML, increasing survival and reducing CSF JCV viral load and mortality. Patients who survive AIDS PML are likely to have serious residual neurocognitive deficits.
Primary CNS Lymphoma (PCNSL): PCNSL is the second most common CNS lesion in AIDS. The major risk factor is CD4 count <100 cells/mm3. PCNSL is associated with Epstein-Barr virus (EBV), a ubiquitous herpesvirus with 90% seroprevalence.16 Most EBV infections are asymptomatic or present as acute mononucleosis. In AIDS, EBV-infected B cells are no longer kept in check, conferring an increased risk of PCNSL. The tumors are promoted by immunosuppression, chronic antigenic stimulation, and cytokine overproduction. AIDS PCNSL often occurs as immunoblastic-subtype, high-grade, diffuse B-cell lymphomas. Prior to HAART, PCNSL occurred in 5% of AIDS patients with neurologic symptoms, but the use of HAART has lowered the incidence and improved survival. Patients can develop cranial neuropathies and/or ocular involvement, increased intracranial pressure, and herniation, which result in papilledema and coma if left untreated. The tumor is treated with cranial irradiation and by instituting and/or optimizing HAART. Chemotherapy, if used, includes methotrexate and ganciclovir to decrease EBV viral load, but no large, controlled trials have established optimal therapy.17 Unfortunately, PCNSL treatments can cause residual cognitive impairment, particularly when both whole-brain radiation and methotrexate-based chemotherapy are used.18
Cytomegalovirus (CMV): CMV, a member of the Herpesviridae family, can infect the brain, spinal cord, meninges, retina, dorsal root ganglion of peripheral nerves, and many visceral organs.19 About 60% of the population shows evidence of CMV exposure, with a greater prevalence in MSM. CMV establishes a lifelong latent infection without clinical disease in immunocompetent individuals and reactivates under conditions such as HIV.20 Neurologic CMV disease presents as encephalitis, ventriculitis, myelitis, radiculoganglionitis, and peripheral polyneuropathy in individuals with CD4 counts <50 cells/mm3. Symptoms are variable, depending upon the area affected. CMV encephalitis and ventriculitis may present with fever, lethargy, confusion, seizures, cranial-nerve palsies, ataxia, hemiparesis, and even coma. Some patients present with dementia, which may or may not be due to concurrent HIV encephalitis. CMV infection of the spinal cord may cause transverse myelitis or myeloradiculitis characterized by flaccid paraparesis associated with back pain, incontinence, areflexia, paresthesias, sensory loss, and ascending weakness.
CSF polymerase chain reaction is considered the gold standard for identifying and quantifying CNS CMV and for following response to therapy. Unlike HIV, CMV can directly infect astrocytes, neurons, oligodendroglia, and endothelial, ependymal, and meningeal cells and can directly kill neural cells by inducing apoptosis. Randomized, placebo-controlled trial data regarding treatment of CNS CMV are lacking, and recommended therapy is extrapolated from case reports and clinical trials involving other organ systems. Initiation of IV ganciclovir at an induction dosage of 5 mg/kg twice daily is recommended. IV foscarnet 90 mg/kg twice daily may be used instead of ganciclovir, but it has greater renal toxicity. Cidofovir may be used if these regimens fail.21 Chronic suppressive therapy should continue until the CD4 count is >100 cells/mm3, and the patient should receive optimized HAART if not already doing so.9,11
Neurosyphilis: HIV infection promotes the development of neurosyphilis, and syphilis is often a coinfection in HIV/AIDS patients.22 This is due to HIV-associated immune dysfunction that impairs the clearance of Treponema, which causes syphilis through the CSF. HIV neurosyphilis presents as acute meningitis, retinitis, deafness, or stroke.22 The recommended therapy is aqueous crystalline penicillin G (18-24 million U daily administered every 4 hours or by continuous infusion for 14 days), followed by 1 dose of benzathine penicillin G (2.4 million U intramuscularly).22
PN has become the major neurologic complication of HIV infection in the developed world, with a prevalence of 30% to 35%.23 Risk factors include prior neuropathy, diabetes, alcoholism, poor nutrition, use of higher doses of the causative nucleoside, or use of a combination of nucleosides.24 Nucleoside or toxic antiretroviral neuropathy in HIV-positive patients has been associated with the use of the nucleotide reverse transcriptase inhibitors didanosine, zalcitabine, and stavudine. This is likely due to mitochondrial damage, downregulation of gene expression for brain-derived neurotrophic factor in the dorsal root ganglion, and specific host genetic polymorphisms.25 These drugs were used extensively early in the epidemic and are still used as part of HAART and in resource-limited settings. The clinical features of antiretroviral neuropathy are similar to those of HIV-induced distal sensory polyneuropathy, but usually begin within 3 to 6 months of starting the offending drug(s).24 The specific treatment is to remove the offending drug(s); otherwise, the lowest dose should be used. In many patients, it takes up to 3 weeks after drug discontinuation before improvement occurs. Symptom reduction may take 6 weeks to 6 months. Unfortunately, in many cases, neuropathic symptoms and disability remain after these drugs are discontinued.
Long-term HAART is associated with various neurologic problems in HIV patients. This is due in part to the significantly higher rate of white-matter (WM) atrophy in the frontal lobe, cerebellum, brainstem, thalamus, and caudate correlated with low CD4 counts and to detectable peripheral virus occurring in most brain regions of HAART patients.26 The rate of WM-volume loss in HIV-positive patients receiving HAART is accelerated relative to normal aging, and the rate of subcortical and cortical gray-matter (GM) loss is accelerated in patients with the worst immune status.26 Research suggests that protease inhibitors—especially the older ones, including indinavir and saquinavir—are associated with sensory neuropathy.27 Before HAART was introduced, accelerated global WM losses and concomitant CSF-volume increases were observed in HIV-positive patients. Thus, the introduction of HAART may have lessened the severity and rapidity of ongoing WM and GM atrophy, but it has not completely halted the neurologic consequences.
Improving control of HIV replication, especially in the CSF, will deter the development of HIV-associated neurologic disorders. This may be accomplished by selecting the most effective HAART for the HIV strain and optimizing HAART distribution into the CNS through use of designed formulations (i.e., liposomes and nanoparticles) to improve CSF penetration and target HIV-infected monocytes and macrophages. HAART distribution in the CNS influences its effectiveness in the body as a whole, since the CSF serves as a reservoir for HIV and provides an environment for replication, mutation, and reinfection of the circulation.
Initiation of HAART when the CD4 count drops <300 cells/mcL may increase the risk of HIV-associated neurocognitive impairment. Long-term HAART is associated with antiretroviral neuroimpairment such that interruption of ART in patients with high CD4 counts may pose increased risk of rebound in HIV replication, loss of CD4 count, and neurocognitive decline.
Other agents that are approved for different indications and are being used in HIV patients have secondary benefits for CNS disorders. Lithium may protect neurons by modulating glycogen synthase kinase 3 enzymes.28 Selective serotonin reuptake inhibitors (SSRIs) can reduce HIV replication in the CNS by undetermined mechanisms. The most effective SSRIs are citalopram, sertraline, and trazodone.29 Hydroxymethyl glutaryl coenzyme A reductase inhibitors (statins) can reduce HIV RNA in CSF by reducing chemokine receptor membrane lipid rafts, preventing adhesion molecules’ expression, and downregulating Rho guanosine triphosphate activity.30 Statins showed the strongest efficacy versus SSRIs. Human erythropoietin has been shown to block neuropathy and is currently in human trials of HIV-associated distal sensory polyneuropathy.31
Most patients with HIV/AIDS will experience neurologic problems during the course of the disease. These neurologic disorders will impact the patient’s quality of life and adherence to ART. Awareness of these neurologic problems will allow the pharmacist to identify at-risk HIV/AIDS patients and work with the health care team to prevent, contain, and/or manage these conditions.
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