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HIV-Associated Opportunistic Infections of the CNS Review HIV-associated opportunistic infections of the CNS Ik Lin Tan, Bryan R Smith, Gloria von Geldern, Farrah J Mateen, Justin C McArthur Survival in people infected with HIV has improved because of an increasingly powerful array of antiretroviral Lancet Neurol 2012; 11: 605–17 treatments, but neurological symptoms due to comorbid conditions, including infection with hepatitis C virus, HIV Neuroscience Program, malnutrition, and the eff ects of accelerated cardiovascular disease and ageing, are increasingly salient. A therapeutic Johns Hopkins University, gap seems to exist between the salutary eff ects of antiretroviral regimens and the normalisation of neurological Baltimore, MD, USA (I L Tan MBBS, B R Smith MD, function in HIV-associated neurocognitive disorders. Despite the advances in antiretroviral therapy, CNS opportunistic G von Geldern MD, infections remain a serious burden worldwide. Most opportunistic infections can be recognised by a combination of F J Mateen MD, characteristic clinical and radiological features and are treatable, but some important challenges remain in the Prof J C McArthur MBBS) diagnosis and management of HIV-associated opportunistic infections. Correspondence to: Prof Justin C McArthur, Department of Neurology, Johns Introduction lineages. HIV-1 also infects CD4-negative cells, including Hopkins University, Meyer 6113, HIV infection leads to substantial morbidity and astrocytes, but in a restrictive manner. HIV-1 subtypes are 600 North Wolfe Street, mortality worldwide. In 2009, 33·3 million adults and defi ned by chemokine co-receptors: T-tropic viruses use Baltimore, MD 21287, USA children were living with HIV, two-thirds of whom were CXCR4 (receptor for SDF1, also termed CXCL12) to infect [email protected] in sub-Saharan Africa. lymphocytes, and M-tropic viruses use CCR5 (receptor for Overall, the annual incidence of new infections has RANTES, also termed CCL5, and MIP1α or CCL3/4) to declined by 19% since the peak of the worldwide HIV infect macrophages.10,11 epidemic in 1999, in line with the Millennium Development HIV infection is characterised by three stages: acute Goal. Nevertheless, about 2·6 million individuals were primary infection, an asymptomatic (latent) stage, and newly infected in 2009, and the incidence continues to symptomatic chronic illness. Disease progression is increase in some regions.1 7000 new HIV infections occur highly variable: from 6 months after seroconversion to daily, 95% of which are in low-income and middle-income more than 20–30 years, or minimal progression might be countries, where only about a third of patients who require seen in elite suppressors. In the absence of cART, the antiretroviral drugs have access to them.1 mean time to the development of AIDS is 10–11 years,12 In high-income countries, the introduction of and median survival after AIDS develops is 1·3–3·7 years, combination antiretroviral therapy (cART) in 1996 greatly depending on the CD4-cell count.13 changed the incidence of neurological opportunistic After primary infection, acute disseminated viraemia is infections, from 13·1 per 1000 patient-years in 1996–97 to seen.14 The initial massive depletion of gut-associated 1·0 per 1000 in 2006–07 (tables 1, 2).2,7 Many of the memory T cells15 leads to physical and immunological opportunistic infections that aff ect the CNS are AIDS- breaches of the gut mucosa, as well as expansions of some defi ning conditions, including progressive multifocal HIV-specifi c CD8-positive T-cell responses,16 the crucial leukoencephalopathy (PML), CNS cytomegalovirus, CNS tuberculosis, cryptococcal meningitis, and cerebral Incidence per toxoplasmosis, including toxo plasmic encephalitis 1000 person-years 8 (table 2), and all have high associated mortality. Treatment Overall 1·0* of CNS opportunistic infections in conjunction with Progressive multifocal leukoencephalopathy 0·7 cART improves survival, but such infections continue to Toxoplasmic encephalitis 0·4 be important, especially where access to cART is limited. Cryptococcal meningitis 0·2 In this Review we focus on the most common CNS opportunistic infections associated with HIV infection Data are from 2006–07.2 *The sum of the individual opportunistic infections is worldwide, and provide a summary of each in terms of more than 1·0 because some individuals have more than one infection. epidemiology, clinical presentations, diagnosis, and Table 1: Incidence of HIV-associated CNS opportunistic infections treatment. Biology of HIV-1 Common CNS opportunistic infections HIV-1 infection accounts for most of the global HIV Asian and Pacifi c regions3 Cryptococcal meningitis, cerebral toxoplasmosis, tuberculous meningitis, pandemic. Only 1–2 million of the 33 million HIV Japanese encephalitis B infections are caused by HIV-2. HIV-1 belongs to the Sub-Saharan Africa4 Tuberculous meningitis, cryptococcal meningitis, cytomegalovirus, malaria family Retroviridae and genus Lentivirus.9 It is a single- Europe and North America2 PML, toxoplasmic encephalitis, cryptococcal meningitis stranded, positive-sense RNA virus that contains a reverse South America5 Cerebral toxoplasmosis, tuberculous meningitis, cryptococcal meningitis; 6 transcriptase, which transcribes viral RNA into DNA that is Chagas disease is reported in southern US states and South America integrated into the host’s genome as a provirus. HIV-1 PML=progressive multifocal leukoencephalopathy. primarily targets CD4 receptors and infects CD4-positive Table 2: Incidence of HIV-associated CNS opportunistic infections by geographical region T lymphocytes and cells of the monocyte or macrophage www.thelancet.com/neurology Vol 11 July 2012 605 Review host immune response against HIV. This robust immune processes (panel 1) and, therefore, unexpected response leads to virus being trapped within dendritic worsening after treatment for an opportunistic infection cells in lymphoid tissue and a marked reduction of is started should prompt consideration of a second viraemia.17 The virus, however, is not completely process. Individuals who have had immunological eliminated from the body and chronic, persistent viral recovery from cART might still be at risk of developing replication leads to systemic immune activation. CNS opportunistic infections. Additionally, quiescent CD4-positive memory T cells and Some infections, such as toxoplasmic encephalitis and macrophages serve as long-term reservoirs for latent HIV cryptococcal meningitis, evolve over hours, whereas infection.18 Persistent viral replication, chronic immune others, such as PML and CNS lymphoma, typically have activation, and progressive deterioration of immune a more indolent course, with development often taking function result in symptomatic disease with severe weeks to months. Many exceptions to these patterns may, immune defi ciency in advanced HIV infection.19 Typically, however, be seen. Although many CNS opportunistic CNS opportunistic infections occur during this stage of infections are associated with non-specifi c symptoms, the HIV infection; waning immunity and high HIV load, such as fever and lethargy, the combination of symptoms both systemically and in the CNS, create a favourable such as a new pattern of headache or headache lasting milieu. Apart from immune defi ciency, other features of longer than 3 days, new-onset seizures, or altered mental HIV-1 might directly facilitate CNS opportunistic function strongly suggest an acute focal brain lesion.20 infections, for example in PML. Most CNS opportunistic The incidence, temporal pattern, and typical CD4-cell infections result from reactivation of latent pathogens, count for common CNS opportunistic infections are including PML, toxoplasmic encephalitis, and primary presented in table 3. CSF and radiographic patterns are CNS lymphoma. HIV infection produces substantial presented in tables 4 and 5, respectively. The neuro- depletion of the CD4-cell count and preferentially destroys imaging features provide a guide, but diagnosis should the cellular immune system, which is crucial for defence never be made on neuroimaging fi ndings alone. against viral, fungal, and parasitic infections. A diagnostic and management algorithm for the assess ment and management of intracranial mass Clinical features of CNS opportunistic infections lesions in patients with AIDS was issued by the Quality CNS opportunistic infections should be suspected in all Standard Subcommittee of the American Academy of people with advanced HIV infection. Individuals who Neurology in 1998.38 We present an algorithm for the are unaware of their HIV status can fi rst present with management of patients presenting with headaches and CNS opportunistic infections. Additionally, in patients symptoms suggestive of CNS infections (fi gure 1). in whom cART is started, immune reconstitution in- Although many advances have been made in the fl ammatory syndrome (IRIS) might unmask previously diagnosis and treatment of CNS opportunistic infections, un suspected CNS opportunistic infections. The main the algorithm approach remains applicable, especially in diagnostic features of CNS opportunistic infections are resource-poor settings—for example, in patients with clinical presentation, temporal evolution, and CSF and multiple CNS lesions, empirical treatment with radiographic features. These infections typically develop antitoxoplasmosis therapy might be appropriate. Patients when the CD4-cell count is lower than 200 cells per μL. with severe immune suppression (CD4-cell count lower One important principle
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