* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Download Is the Glass Three-Quarters Full or One-Quarter
Survey
Document related concepts
Herpes simplex virus wikipedia , lookup
West Nile fever wikipedia , lookup
Hepatitis C wikipedia , lookup
Human cytomegalovirus wikipedia , lookup
Marburg virus disease wikipedia , lookup
Hospital-acquired infection wikipedia , lookup
Neonatal infection wikipedia , lookup
Henipavirus wikipedia , lookup
Oesophagostomum wikipedia , lookup
Hepatitis B wikipedia , lookup
Sexually transmitted infection wikipedia , lookup
Antiviral drug wikipedia , lookup
Diagnosis of HIV/AIDS wikipedia , lookup
Epidemiology of HIV/AIDS wikipedia , lookup
Microbicides for sexually transmitted diseases wikipedia , lookup
Transcript
E D I T O R I A L C O M M E N TA R Y Is the Glass Three-Quarters Full or One-Quarter Empty? Justin C. McArthur1 and Scott L. Letendre2 1 Johns Hopkins University, Baltimore, Maryland; 2University of California, San Diego (See the article by Spudich et al., on pages 1686–96.) The neurological manifestations of HIV infection continue to be a major source of morbidity and mortality, despite the advances in highly active antiretroviral therapy (ART) during the past decade. The annual incidence of HIV dementia before ART was ∼7% in patients with AIDS [1] but has decreased by 50% since the introduction of ART [2]. Viral invasion of the central nervous system (CNS) occurs as an extremely early event after HIV infection [3, 4], yet we do not know whether latency is established at this early point; additionally, in general, productive infection is uncommon until after the development of immunosuppression [5]. Once in the CNS [6], HIV establishes a chronic infection that predominantly involves monocytes, perivascular macrophages, microglial cells, and, to some extent, a restricted infection of astrocytes [7, 8]. Since the earliest years of the HIV epidemic, there has been great interest in studying cerebrospinal fluid (CSF) in HIV infection, because this compartment represents a “window” into HIV replication, treatReceived 21 August 2006; accepted 28 August 2006; electronically published 3 November 2006. Potential conflicts of interest: none reported. Financial support: National Institutes of Health (grants NS44807 and MH075673 to J.C.M. and AI27670, MH58076, and MH62512 to S.L.). Reprints or correspondence: Dr. Justin C. McArthur, Johns Hopkins Hospital, Meyer 6-109, 600 N. Wolfe St., Baltimore, MD 21287-7609 ([email protected]). The Journal of Infectious Diseases 2006;194:1628–31 2006 by the Infectious Diseases Society of America. All rights reserved. 0022-1899/2006/19412-0002$15.00 ment response, and damage in brain parenchyma. The study by Spudich et al. [9] in this issue of the Journal of Infectious Diseases provides new information about the virological responses to ART in the CSF. It represents a cross-sectional analysis of 139 HIV-positive subjects categorized as having therapeutic success or failure on the basis of their virological response to ART. The estimated blood-brain barrier penetration of antiretroviral regimens was categorized using 2 methods, including one used in an ongoing National Institutes of Health–funded study of the effects of antiretroviral therapy on CNS HIV infection—the CNS HIV Antiretroviral Effects Research (CHARTER) study. The primary outcome measure was CSF HIV RNA levels below the lower limit of quantification of 2.5 copies/mL, which was achieved in 72% of subjects with successful therapy. Among subjects with failed therapy, CSF HIV RNA levels were much lower than in those who received no antiretrovirals, which is consistent with prior reports [10, 11]. Taken together, the results demonstrate that ART suppresses HIV in CSF of a larger proportion of ART-treated subjects than it does in plasma. The authors note that this “disproportionate” treatment effect on the CNS compartment may be due to reduced T cell activation and trafficking and stands in contrast to previous pessimistic predictions of compartmentalized infection and the limited tissue penetration of antiretrovirals. Further- 1628 • JID 2006:194 (15 December) • EDITORIAL COMMENTARY more, the authors observed a relatively small number of cases of CNS escape (i.e., HIV RNA levels much greater in CSF than in plasma), and this did not appear to have clinical consequences. Along with considerable clinical implications, these findings have important limitations. One potential limitation is the study’s cross-sectional design. The ongoing study will generate important longitudinal observations, but the present analyses do not adjust for 2 key, time-based measures: duration of the current regimen [12] and duration of treatment failure [13]. For example, were HIV RNA levels 12.5 copies/mL associated with shorter durations of therapy? If they were, then the 28% prevalence of detectable HIV RNA in CSF in subjects with successful therapy may simply have been due to sampling. However, if they were not, then this result suggests that a substantial minority of subjects with successful therapy may have ongoing, low-level HIV replication in the CNS—a finding that may have important clinical implications. Another substantial limitation, which is acknowledged by the authors, is the low prevalence of individuals with HIV-associated cognitive impairment or advanced immunosuppression. In fact there were only 3 individuals with AIDS dementia complex among subjects with successful therapy, and they had mild stage 1, static disease. Because the predominant cellular source of HIV probably differs between individuals who have earlier stage HIV disease Table 1. Examples of cerebrospinal fluid (CSF) markers that have either associative or predictive value in HIV-associated cognitive disorders. Marker Role Reference CSF Fractalkine sFas Associative Associative [6] [7] Protein carbonyl Sphingolipid products Associated with mild dementia Associated with mild dementia [8] [10] Associative Predictive [11] [12] Blood 4348-kDa protein in cultured blood monocytes MCP-1 polymorphisms NOTE. Associative marker, correlates cross-sectionally; MCP, macrophage chemoattractant protein; predictive marker, longitudinal prediction [3]; sFas, soluble Fas. and normal cognition (trafficking T lymphocytes) and those who have AIDS or active or progressive dementia (trafficking tissue macrophages and microglia), the effectiveness of ART in the CNS probably differs substantially among these individuals. The findings from the largely dementia-free study population at the University of California, San Francisco (UCSF) primarily generalize to the first group, who are at a low risk for the neurocognitive complications of HIV infection. A third important limitation was the analysis of ART penetration. The authors used 2 different approaches to estimate regimen penetration but related scores to group membership, not to HIV RNA levels in CSF. Penetration scores did not differ between groups but were much higher (mean, ∼2.8) than those in a recent analysis of the CHARTER cohort (mean, 1.2) [14]. Because important differences in the stage of disease, the prevalence of cognitive impairment, and antiretroviral regimens appear to exist between the UCSF and the CHARTER cohorts, the findings should not necessarily be viewed as contradictory. Finally, with respect to the relationship between results of resistance analyses in CSF and plasma, the assay could only be performed for 13 subjects because of the assay requirements of an HIV RNA level of 1500 copies/mL. The findings of the study by Spudich et al. raise several questions. First, does the pathogenesis of HIV-associated neurocognitive impairment differ in untreated and treated populations? In the study, 28% of subjects with successful treatment had measurable HIV RNA in CSF. If the CNS is relatively more susceptible to the pathogenic effects of HIV than are other organ systems, this observation may explain the continuing high prevalence of cognitive impairment in treated populations. Second, do clinically useful surrogate markers for HIV-associated brain injury exist at present? The measurement of HIV RNA levels in CSF was originally a derivative of the use of HIV RNA levels in plasma to monitor the state and progression of HIV disease and responses to antiretroviral therapy [15]. Although the HIV RNA level in plasma is arguably one of the best-validated surrogate markers ever developed, levels in CSF have not had a comparable translation into clinical practice, despite their promise having been demonstrated during the pre-ART era [16]. Two reasons for this are that the predominant source of HIV RNA in CSF shifts as HIV infection evolves and that the diagnostic utility of HIV RNA levels in CSF wanes in treated populations. Early during infection, when there is typically CSF pleocytosis, the source of virus in the CSF may be transitory and supplied by the constant traffic of infected cells from the blood to the CSF. As infection progresses and the early CSF pleocytosis abates, the source of CNS virus becomes autonomous and is sustained from sources within the CNS itself [17–19]. Evidence for this comes from studies of the response to ART; the rate of HIV decrease in the CSF is slower than in plasma in individuals with AIDS- or HIV-associated dementia, which is consistent with a longer-lived source of replication, such as brain macrophages [19, 20]. Because effective, and even ineffective, ART can reduce HIV RNA levels in CSF, this measurement has had limited diagnostic sensitivity or specificity [1, 16] in large contemporary cohort studies that have included substantial proportions of treated individuals [21]. It may have value in select clinical settings, such as identifying CNS escape [6] or assessing the efficacy of a new antiretroviral regimen in treating established dementia. Elevations in a diverse range of immunological markers within the CSF were identified well before introduction of assays for HIV RNA (table 1), and several have been consistently shown to be higher in patients with HIV-associated dementia and to correlate with its severity. Most of these were documented in individuals not treated with ART, and recent studies during the ART era have suggested that these immune activation markers are attenuated [22]. The markers that have been studied most extensively are b2-microglobulin, neopterin, quinolinic acid, and macrophage chemoattractant protein (MCP)–1 [23, 24], but other “footprints” of immunological or other host responses have been reported [25, 26]. None of these has entered mainstream clinical practice with regard to the diagnosis of HIV-associated dementia. The nonspecificity of elevated EDITORIAL COMMENTARY • JID 2006:194 (15 December) • 1629 immune markers has discouraged clinical application for the individual patient. One marker that has consistently shown promise is the b-chemokine MCP-1. The ratio of plasma:CSF MCP-1 may be a predictive marker of subsequent AIDS dementia complex or simian immunodeficiency virus encephalitis [27, 28]. Third, what is the clinical significance of antiretroviral resistance mutations in CSF? Recent studies from the CHARTER cohort have suggested that there are differences in the patterns of antiretroviral resistance mutations between plasma and CSF. Up to one-third of samples were discordant, with no discernible influence of antiretroviral regimen choice (J. Wong, unpublished data). By contrast, cases of clinically obvious CNS escape [29] have been few. This apparent inconsistency raises the question: will treatment failure due to resistant strains of HIV generated within the CNS appear clinically as only primary CNS escape, or will it be clinically indistinguishable from treatment failure due to resistance generated in other tissues? The evidence to date supports the latter alternative. It then follows that better control of HIV in the brain and other protected compartments may result in more treatment successes. Fourth, do the benefits (CD4+ T cell maintenance, neuroprotection) of continuing a failing ART regimen outweigh the risks (e.g., drug toxicity and an increasing generation of resistant mutants) in individuals with no treatment options? The answer to this complex question will likely depend on highly variable clinical circumstances and should be addressed in subsequent treatment guidelines. Given the continued impact of HIVassociated cognitive dysfunction across the world and the evolving nature of neurological damage [30], we argue that it is ever more important to study the CSF in the context of HIV infection. We need the equivalent of the excellent surrogate marker plasma viral load to apply to the diagnosis, staging, and treatment of HIVassociated dementia. Acknowledgments We thank Ron Ellis, Christina Marra, David Simpson, and our colleagues in the CHARTER study for the helpful comments and suggestions. 12. References 1. McArthur JC, McLernon DR, Cronin MF, et al. Relationship between human immunodeficiency virus-associated dementia and viral load in cerebrospinal fluid and brain. Ann Neurol 1997; 42:689–98. 2. Sacktor N, Tarwater PM, Skolasky RL, et al. CSF antiretroviral drug penetrance and the treatment of HIV-associated psychomotor slowing. Neurology 2001; 57:542–4. 3. Resnick L, Berger JR, Shapshak P, Tourtellotte WW. Early penetration of the blood-brain barrier by HIV. Neurology 1988; 38:9–14. 4. Davis LE, Hjelle BL, Miller VE, et al. Early viral brain invasion in iatrogenic human immunodeficiency virus infection. Neurology 1992; 42:1736–9. 5. Tambussi G, Gori A, Capiluppi B, et al. Neurological symptoms during primary human immunodeficiency virus (HIV) infection correlate with high levels of HIV RNA in cerebrospinal fluid. Clin Infect Dis 2000; 30:962–5. 6. Ho DD, Rota TR, Schooley RT, et al. Isolation of HTLV-III from cerebrospinal fluid and neural tissues of patients with neurologic syndromes related to the acquired immunodeficiency syndrome. N Engl J Med 1985; 313: 1493–7. 7. Takahashi K, Wesselingh SL, Griffin DE, et al. Localization of HIV-1 in human brain using polymerase chain reaction/in situ hybridization and immunocytochemistry. Ann Neurol 1996; 39:705–11. 8. Williams KC, Corey S, Westmoreland SV, et al. Perivascular macrophages are the primary cell type productively infected by simian immunodeficiency virus in the brain of macaques: implications for neuropathogenesis of AIDS. J Exp Med 2001; 193:905–15. 9. Spudich S, Lollo N, Liegler T, Deeks SG, Price RW. Treatment benefit on cerebrospinal fluid HIV levels in the setting of systemic virological suppression and failure. J Infect Dis 2006; 194: 1686–96 (in this issue). 10. Letendre SL, Ellis RJ McCutchan, HNRC group. Frequent dissociation of plasma and CSF HIV RNA responses during antiretroviral therapy [abstract 305]. In: Program and abstracts of the 7th Conference on Retroviruses and Opportunistic Infections (San Francisco). Alexandria, VA: Foundation for Retrovirology and Human Health, 2000. 11. McCutchan JA, Letendre SL. Pharmacology of antiretroviral drugs in the central nervous system: pharmacokinetics, antiretroviral resistance, and pharmacodynamics. In: Gendelman E, Grant I, Everall IP, Lipton SA, Swindells S, eds. The neurology of AIDS. 2nd 1630 • JID 2006:194 (15 December) • EDITORIAL COMMENTARY 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. ed. New York: Oxford University Press, 2005: 729–34. Letendre SL, Buzzell M, Marquie J, Cherner M, Ances B, Ellis R, HNRC group. The effects of antiretroviral use on cerebrospinal fluid biomarkers and neuropsychological performance [abstract 346]. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections (Denver). Alexandria, VA: Foundation for Retrovirology and Human Health, 2006. Haas DW, Johnson BW, Spearman P, et al. Two phases of HIV RNA decay in CSF during initial days of multidrug therapy. Neurology 2003; 61:1391–6. Letendre SL, Capparelli E, Best B, et al. Better antiretroviral penetration into the central nervous system is associated with lower CSF viral load [abstract 74]. In: Program and abstracts of the 13th Conference on Retroviruses and Opportunistic Infections (Denver). Alexandria, VA: Foundation for Retrovirology and Human Health, 2006. Mellors IW, Rinaldo CR, Gupta P, White RM, Todd JA, Kingsley LA. Prognosis in HIV-1 infection predicted by the quantity of virus in plasma. Science 1996; 272:1167–70. Ellis RJ, Moore DJ, Childers ME, et al. Progression to neuropsychological impairment in human immunodeficiency virus infection predicted by elevated cerebrospinal fluid levels of human immunodeficiency virus RNA. Arch Neurol 2002; 59:923–8. Ellis R, Hsia K, Spector SA, et al. Cerebrospinal fluid human immunodeficiency virus 1 RNA levels are elevated in neurocognitively impaired individuals with acquired immunodeficiency syndrome. Ann Neurol 1997; 42: 689–98. Staprans S, Marlowe N, Glidden D, et al. Time course of cerebrospinal fluid responses to antiretroviral therapy: evidence for variable compartmentalization of infection. AIDS 1999; 13: 1051–61. Ellis RJ, Gamst AC, Capparelli SA, et al. Cerebrospinal fluid HIV RNA originates from both local and systemic sources. Neurology 2000; 54:927–36. Van den Brande G, Marquie-Beck J, Capparelli E, Ellis R, McCutchen A. Kaletra independently reduces HIV replication in cerebrospinal fluid [abstract 403]. In: Program and abstracts of the 12th Conference on Retroviruses and Opportunistic Infections (Boston). Alexandria, VA: Foundation for Retrovirology and Human Health, 2005. Wiley CA, Baldwin M, Achim CL. Expression of HIV regulatory and structural mRNA in the central nervous system. AIDS 1996; 10: 843–7. McArthur JC, McDermott MP, McClernon D, et al. Attenuated central nervous system infection in advanced HIV/AIDS with combination antiretroviral therapy. Arch Neurol 2004; 61:1687–96. Perelson AS, Essunger P, Cao Y, et al. Decay characteristics of HIV-1 infected compart- ments during combination therapy. Nature 1997; 387:188–91. 24. Martin C, Albert J, Hansson P, Pehrsson P, Link H, Sonnerborg A. Cerebrospinal fluid mononuclear cell counts influence CSF HIV1 RNA levels. J Acquir Immune Defic Syndr Hum Retrovirol 1998; 17:214–9. 25. Price RW, Staprans S. Measuring the “viral load” in cerebrospinal fluid in HIV infection: window into brain infection. Ann Neurol 1997; 42:675–8. 26. Price RW, Paxinos EE, Grant RM, et al. Cerebrospinal fluid response to structured treatment interruption after virological failure. AIDS 2001; 15:1251–9. 27. Mankowski JL, Queen SE, Clements JE, Zink MC. Cerebrospinal fluid markers that predict SIV CNS disease. J Neuroimmunol 2004; 157: 66–70. 28. Kelder W, McArthur JC, Nance-Sproson T, McClernon D, Griffin DE. Chemokines MCP1 and RANTES are selectively increased in cer- ebrospinal fluid of patients with human immunodeficiency virus-associated dementia. Ann Neurol 1998; 44:831–5. 29. Wendel KA, McArthur JC. Acute meningoencephalitis in chronic human immunodeficiency virus (HIV) infection: putative central nervous system escape of HIV replication. Clin Infect Dis 2003; 37:1107–11. 30. McArthur JC, Brew BJ, Nath A. Neurological complications of HIV infection. Lancet Neurol 2005; 4:543–55. EDITORIAL COMMENTARY • JID 2006:194 (15 December) • 1631