Angela Hutchinson and colleagues conducted a cost-effectiveness analysis of pooled nucleic acid amplification testing following HIV testing and show that it is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings. Detection of acute HIV infection (AHI) with pooled nucleic acid amplification testing (NAAT) following HIV testing is feasible. However, cost-effectiveness analyses to guide policy around AHI screening are lacking; particularly after more sensitive third-generation antibody screening and rapid testing.We conducted a cost-effectiveness analysis of pooled NAAT screening that assessed the prevention benefits of identification and notification of persons with AHI and cases averted compared with repeat antibody testing at different intervals. Effectiveness data were derived from a Centers for Disease Control and Prevention AHI study conducted in three settings: municipal sexually transmitted disease (STD) clinics, a community clinic serving a population of men who have sex with men, and HIV counseling and testing sites. Our analysis included a micro-costing study of NAAT and a mathematical model of HIV transmission. Cost-effectiveness ratios are reported as costs per quality-adjusted life year (QALY) gained in US dollars from the societal perspective. Sensitivity analyses were conducted on key variables, including AHI positivity rates, antibody testing frequency, symptomatic detection of AHI, and costs. Pooled NAAT for AHI screening following annual antibody testing had cost-effectiveness ratios exceeding US$200,000 per QALY gained for the municipal STD clinics and HIV counseling and testing sites and was cost saving for the community clinic. Cost-effectiveness ratios increased substantially if the antibody testing interval decreased to every 6 months and decreased to cost-saving if the testing interval increased to every 5 years. NAAT was cost saving in the community clinic in all situations. Results were particularly sensitive to AHI screening yield.Pooled NAAT screening for AHI following negative third-generation antibody or rapid tests is not cost-effective at recommended antibody testing intervals for high-risk persons except in very high-incidence settings.Please see later in the article for the Editors' Summary Since 1981, acquired immunodeficiency syndrome (AIDS) has killed about 25 million people and about 30 million people are now infected with the human immunodeficiency virus (HIV), which causes AIDS. HIV, which is most often transmitted through unprotected sex with an infected partner or injection drug use, infects and kills immune system cells, leaving infected individuals susceptible to other infectious diseases. The first, often undiagnosed stage of HIV infection—acute HIV infection (AHI)—lasts a few weeks and sometimes involves a flu-like illness. During AHI, the immune system responds to HIV by beginning to make antibodies that recognize the virus but seroconversion—the appearance of detectable amounts of antibody in the blood—takes 6–12 weeks. During the second, symptom-free stage of HIV infection, which can last many years, the virus gradually destroys the immune system so that by the third stage of infection unusual infections  begin to occur. The final stage of infection (AIDS) is characterized by multiple severe infections and by the development of unusual cancers.Antiretroviral drugs control HIV infections but don't cure them. It is very important, therefore, to prevent HIV transmission by avoiding HIV risk behaviors that increase the risk of HIV infection such as having sex without a condom or with many partners. Individuals with AHI in particular need to avoid high-risk behaviors because these people are extremely infectious. However, routine tests for HIV infection that measure antibodies in the blood often give false-negative results in people with AHI because of the time lag between infection and seroconversion. Nucleic acid amplification testing (NAAT), which detects HIV genetic material in the blood, is a more accurate way to diagnose AHI but is expensive. In this study, the researchers investigate whether pooled NAAT screening (specimens are pooled before testing to reduce costs) for AHI in clinic settings after third-generation antibody testing is a cost-effective HIV prevention strategy. That is, does the gain in quality-adjusted life years  achieved by averting new HIV infections outweigh the costs of pooled NAAT screening?The researchers combined effectiveness data from a US study in which AHI was detected using pooled NAAT in three settings  with a “micro-costing” study of NAAT and a mathematical model of HIV transmission. They then calculated the costs per QALY gained (the cost-effectiveness ratio) as a result of HIV prevention by identification and notification of people with AHI through pooled NAAT screening compared with repeat antibody testing. Pooled NAAT for AHI screening following annual antibody testing , they estimate, would cost US$372,300 and US$484,400 per QALY gained for the counseling/testing sites and STD clinics, respectively, whereas pooled NAAT for AHI screening was cost-saving for the community clinic serving MSM. The cost-effectiveness ratio increased for the counseling/testing sites and STD clinics when the antibody testing interval was decreased to 6 months but remained cost-saving for the community clinic. With an antibody testing interval of 5 years, pooled NAAT was cost-saving in all three settings.Cost-effectiveness ratios of US$100,000–US$200,000 are considered acceptable in the US. These results suggest therefore, that the cost of pooled NAAT screening for AHI following negative third-generation antibody testing is not acceptable at the recommended testing interval for high-risk individuals except in settings where HIV infection is very common such as clinics serving MSM. The researchers reach a similar conclusion in a separate cost-effectiveness analysis of pooled NAAT screening following a negative rapid HIV test. Although the accuracy of these results depends on numerous assumptions made in the cost-effectiveness analyses , sensitivity analyses  show that these findings are not greatly affected by changes in many of these assumptions. Thus, the researchers conclude, NAAT screening should be reserved for settings that serve populations in which there are very high levels of new HIV infection.http://dx.doi.org/10.1371/journal.pmed.1000342.Please access these Web sites via the online version of this summary at HIV infection and AIDS and on HIV testing and diagnosisThe US Centers for Disease Control and Prevention provides information on HIV InSite has information on all aspects of HIV/AIDSAvert, an international AIDS nonprofit organization on many aspects of HIV/AIDS, including HIV testing (in English and Spanish)Information is available from AIDS (in English and Spanish)MedlinePlus has links to further resources on measuring effectiveness and cost-effectivenessThe UK National Institute of Health and Clinical Excellence has a page on  Acute HIV infection (AHI) is the stage of disease immediately after HIV acquisition and before HIV antibodies are detectable, when viral replication and shedding peak To screen for AHI, a nucleic acid amplification test (NAAT) that detects the presence of HIV RNA during the window period before antibodies are detectable is performed on seronegative specimens. Pooled NAAT, in which specimens are pooled before testing, is employed because individual NAAT is prohibitively expensive No study to date has evaluated the cost-effectiveness of conducting pooled NAAT screening for AHI in clinic settings; and cost-effectiveness data are needed to inform policy around AHI screening including an evaluation of the relationship between cost-effectiveness of AHI screening in settings with varying HIV incidences Our analysis was conducted concurrently with the Centers for Disease Control and Prevention (CDC) multisite AHI study that used pooled NAAT screening for AHI detection in different clinical settings We calculated the total number of persons identified with AHI and the number of potential HIV transmissions averted due to NAAT screening in three settings. We did not include benefits of antiretroviral therapy (ART) to persons identified with AHI, given inconclusive evidence for the effectiveness of ART during AHI. We also assumed that most persons diagnosed with AHI would start ART when their CD4 count declined below 350 cells/µl, and this has been estimated to occur 6–8 y after infection Effectiveness data were obtained from the CDC AHI study that conducted pooled NAAT after third-generation EIA  in Florida and both a first-generation assay  and third-generation EIA in Los Angeles Pools of 16 EIA-negative specimens were tested with NAAT . Pools with positive results underwent resolution testing in which all specimens were tested with NAAT individually to identify the positive specimen(s) and, if repeatedly positive, additionally tested with viral load quantification . All persons with EIA-negative/RNA-positive test results were considered presumptive cases of AHI. Experienced disease intervention specialists (DIS) notified presumptive cases of their results and initiated follow-up confirmatory testing with Western blot and partner services to identify potentially infected partners Program costs were calculated for the addition of pooled NAAT to an existing HIV testing program. To derive labor costs, we conducted time-motion studies in the laboratories that performed NAAT, and the DIS maintained logs of the time, effort, and travel required to notify newly identified AHI cases and conduct partner services. We conducted a detailed valuation of the costs of NAAT, including reagents, equipment, labor, consumables, quality assurance procedures, and shipping costs . Screening costs were calculated as an average cost per specimen tested with NAAT. Costs incurred after presumptive AHI was detected included DIS labor and travel costs and laboratory costs for confirmatory testing, based on the actual number of AHI cases detected in each setting. Outcome data on the number of AHI cases detected after pooled NAAT in each setting, days to result notification, and proportion receiving NAAT results were taken from the CDC AHI study .We created a mathematical model of HIV transmission from persons with AHI to their partners, on the basis of the awareness of HIV status, stage of disease (acute or nonacute), and behavior , which is described in detail in We estimated QALYs gained from transmissions averted for each setting, antibody testing technology, and timeframe to HIV diagnosis in the absence of pooled NAAT. The QALYs gained were expressed as the difference in QALYs for a partner with and without HIV infection. We used published HIV-related utility weights to estimate QALYs, assuming uninfected persons had a QALY of 1.0 We conducted sensitivity analyses around multiple parameter values including: transmission rates by awareness of HIV serostatus, antibody testing frequency, reagent and equipment costs, shipping costs, receipt of NAAT results, and symptomatic identification of AHI. We also conducted a threshold analysis on AHI positivity rate to determine the AHI positivity at which AHI screening with NAAT becomes cost-effective after third-generation EIA and rapid testing. Our sensitivity analysis was centered on the municipal STD clinic setting because STD clinics have been suggested as places to conduct AHI screening Total program costs for NAAT screening after testing using a third-generation EIA during the 22-mo study period were approximately US$458,200 for the counseling and testing sites , US$76,900 for the community clinic , and US$349,900 for the municipal STD clinics  . ProgramThe addition of pooled NAAT after a negative third-generation EIA to detect AHI had a cost-effectiveness ratio of US$372,300 per QALY gained for the counseling and testing sites, US$484,400 per QALY gained for the STD clinics, and was cost-saving for the community clinic, assuming that the HIV infections detected through NAAT screening would otherwise have been detected by repeat antibody testing 1 y later .We found that pooled NAAT screening for AHI after a negative third-generation EIA in clinical settings relevant to public health is not likely to be cost-effective for most settings. Pooled NAAT screening for AHI is cost-effective only when targeted to settings with very high HIV incidence, such as the community clinic, where it remained cost-effective compared with retesting for HIV antibody as often as every 3 mo. At US$370,000–US$1 million per QALY gained in counseling and testing sites and STD clinics, pooled NAAT after a negative third-generation EIA was not within acceptable ranges of cost-effectiveness thresholds of US$100,000–US$200,000 per QALY gained Our findings were most sensitive to AHI positivity rate and assumptions about frequency of antibody testing among infected persons. For the municipal STD clinics to fall within the range of threshold values for cost-effectiveness, the AHI positivity rate would need to nearly double to 0.04% from 0.02%. Our analysis is heavily influenced by the transmission rate ratio of those who are aware versus unaware of their status. However, our findings were not sensitive to a 25% variation in this parameter. When we accounted for symptomatic detection of AHI outside the screening program, AHI screening with pooled NAAT became much less cost-effective for the municipal STD clinics. Thus symptomatic detection of AHI cases can be an important consideration in pooled NAAT for AHI detection in clinical settings. In one AHI screening program, 60% of persons tested were symptomatic and providers suspected AHI in 48% of symptomatic cases In the base case scenario, we assumed testing at yearly intervals because all settings evaluated in our analysis serve high-risk populations for whom testing is recommended at least annually The small number of persons with AHI identified by NAAT and the large number of specimens that need to be tested to find them appear to drive our results. Furthermore, approximately 25% of persons with AHI did not receive their test results, and those who did were notified well into the acute phase, on average on days 32 and 48 of the 49-d acute infection period with third-generation EIA screening and rapid testing, respectively. While pooled NAAT detected HIV infection in antibody-negative persons, it did not result in persons learning of their infection early enough to reduce the potential for transmission during the infectious AHI period as much as was expected, which limited the public health benefit of NAAT screening. Timely testing and delivery of NAAT results are essential if the public health benefits of AHI screening are to be optimized and are important considerations for implementing NAAT in real-world settings. If receipt of results dropped to 50% or results notification takes 22 d rather then 15 d, the cost-effectiveness greatly exceeds US$500,000 per QALY. Pooled NAAT screening was cost-effective in sensitivity analysis with 100% notification and 7-d receipt of results. However, it is unclear how feasible 7-d notification of NAAT results is; in another AHI screening program, time to results notification following AHI screening was similar or slightly longer than that reported in the CDC AHI study AHI positivity rates in a given population are generally higher with pooled NAAT after rapid testing compared to third-generation EIA screening due to the lower sensitivity of the rapid test during the first few weeks after infection. However, these additional cases might be identified much later in the acute phase because of the longer antibody-negative window period, potentially diminishing some of the reductions in acute phase transmissions, which, in our analysis, made pooled NAAT after rapid testing less cost-effective than pooled NAAT after third-generation EIA screening at similar AHI positivity rates.Although high infectivity during AHI has been a prime reason to advocate for NAAT screening to detect AHI, our sensitivity analysis suggests that even notifying persons with AHI of their test results within 7 d after screening  would still result in cost-effectiveness ratios beyond generally accepted threshold values. Larger pool sizes have been suggested as a way to increase AHI screening efficiency and decrease costs. The CDC AHI study was able to retrospectively detect most cases of AHI when retesting samples using a 128-member, two-stage pooling scheme, compared to the original pool size of 16 suggesting an intermediate pool size between 16 and 128 members While routine HIV screening has been found to be cost-effective Our study clearly illustrates that NAAT screening for AHI should be reserved for settings that serve the highest-incidence populations, or circumstances such as donor screening where cost-effectiveness is not a primary consideration Our study is subject to several limitations. Our analysis is based on a clinical trial of NAAT conducted in three types of settings with different HIV positivity rates. Caution should be used in applying these results to similar settings because of limited information on the correlation between AHI and HIV positivity rates and the relationship of these factors to the prevalence of risk behavior. Although we assessed the costs of false-positive NAAT results, we did not include any quality-of-life adjustments. However, there were only two false positive NAAT tests out of 90,834 specimens screened in this study Pooled NAAT screening for AHI after negative third-generation EIA or rapid tests is not cost-effective when antibody testing frequency is at recommended levels for high-risk populations except in very high-incidence settings. When antibody testing frequency is 5 y or greater, pooled NAAT screening is cost-saving; however, most of the benefits achieved occur long after the acute phase and could have been achieved with antibody testing alone.Text S1Technical appendix.(0.16 MB DOC)Click here for additional data file.


A Disintegrin And Metalloproteinases (ADAMs) and ADAMs with Thrombospondin motifs (ADAMTS) are proteinases closely related to Matrix Metalloproteinases (MMPs). These multifaceted molecules bear metalloproteinase and disintegrin domains endowing them with features of both proteinases and adhesion molecules. Proteinases of the ADAM family are associated to various physiological and pathological processes and display a wide spectrum of biological effects encompassing cell fusion, cell adhesion, "shedding process", cleavage of various substrates from the extracellular matrix, growth factors or cytokines... This review will focus on the putative roles of ADAM/ADAMTS proteinases in airway diseases such as asthma and COPD.Lungs are exposed to the outside environment and therefore to toxic and infectious agents or allergens. This may lead to permanent activation of innate immune response elements.  Chronic Obstructive Pulmonary Disease) appear to be growing public health concerns worldwide and the number of listed asthmatic and COPD patients still increases over time.The lung is continuously exposed to the outside environment and various potential aggressions such as noxious and infectious agents or allergens. The innate immune responses are permanently activated in this particular organ. Moreover, secretory materials such as surfactant and mucous also contribute to host defense against inflammation. Among airway diseases, asthma and COPD  and airway obstruction. Hallmarks of asthma are mainly airway hyperresponsiveness caused by a wide variety of stimuli and airway inflammation involving eosinophils and mast cells. Moreover, an asthma-associated remodeling of the airways including extensive changes in the extracellular matrix has been characterized. The main changes reported are a subepithelial fibrosis, a smooth muscle hypertrophy, a glandular metaplasia in the bronchial epithelium, and the deposition of extracellular matrix components throughout the airway wall. These features are very often associated with altered behaviour of airway structural cells including epithelial cells or fibroblasts ,2.COPD is characterized by a progressive airway obstruction mainly linked to tobacco consumption and/or toxic fumes and other environmental factors. COPD patients also display profound modifications of the extracellular matrix leading to an airway remodeling including collagen fibers deposition in the bronchial and bronchiolar walls, mucous hyperplasia, and smooth muscle cell hypertrophy -5.A Disintegrin And Metalloproteinase) [As the key role of extracellular matrix and soluble mediators has been unveiled, there is accumulating evidences demonstrating the crucial role played by matrix metalloproteinases (MMPs) in lung diseases ,7. Theseteinase) -14. ADAMteinase) . This shteinase) . Besidesteinase) . Some ceteinase) ,19. The In the present review, after a brief general description of ADAM proteins, we discuss the implications of these proteinases in various physiological and pathological processes. The potential contribution of ADAM/ADAMTS proteins to asthma pathology will be described as well as ADAMs/ADAMTS' involvement in COPD.http://people.virginia.edu/~jw7g/Table_of_the_ADAMs.html and http://degradome.uniovi.es/). Twenty-five ADAMs are expressed in Homo sapiens while thirty-five members are expressed in Mus musculus. Together with ADAMTS (ADAMs with Thrombospondin motifs type I) and SVMPs , ADAM proteinases constitute the subfamily of adamalysins [(1) a catalytic site containing a consensus sequence (HEXXHXXGXXH) in which three histidine residues coordinate a zinc ion and (2) by a conserved methionine residue forming a "Met-turn" beneath the active zinc site. This "Met-turn" provides a hydrophobic environment for the zinc ion and the three ligating histidine residues at the catalytic centre of the enzyme [To date, about 40 members of the ADAM family have been described in different species  at their C-terminal end and the absence of transmembrane and cytoplasmic domains ,27  which are small proteins with molecular weights ranging from 21 to 28 kDa. These inhibitors display six disulfide bonds in their structure forming a rigid conformation which is mandatory for their biological activity. TIMPs are able to inhibit proteinase activity of several members of the ADAM family [The metalloproteinase system is controlled by endogenous physiological inhibitors  were recognized as fertilin-alpha and -beta in 1987  since thectively ,18,39. Aaggrecan ,41, ADAMaggrecan .Dysregulation of ADAMs expression has been reported in different types of pathologies such as cancer, osteoarthritis, neurodegenerative inflammation or asthma. In most studies, an overexpression of these proteinases has been described and is linked to a dysregulation of tissue homeostasis sometimes leading to a specific pathological phenotype. ADAMs might therefore be considered as potential candidates to target in a therapeutic setting. For instance, ADAM-17 expression is increased in breast cancer tissues and its expression is higher in advanced-grade than low-grade tumors. Patients displaying a huge expression of this proteinase have a shorter overall survival than those with a low expression of ADAM-17  suggestiThe complex structure of ADAMs also suggests that these enzymes may be functionally relevant to different steps linked to asthma pathogenesis. Indeed, the active metalloproteinase domain of some ADAMs might be important to shed growth factors and cytokines, contributing in this way to the control of inflammation which is a hallmark of asthma pathology. Disintegrin domain might also act in concert with cystein-rich region to interfere with pro-inflammatory cytokines .These data illustrate how much ADAMs are multifunctional proteins and suggest that these proteinases may serve as mediators during the progression of asthmatic pathology but also COPD table .In the lung, different cell types can express different classes of proteinases. Some structural cells from bronchial tree are able to produce enzymes belonging to the metzincin superfamily that are important in regulation processes and in the cascade leading to inflammation. However, some data - especially those concerning the expression of ADAMs in lung tissues - are more recent and rather incomplete  table 22. In lun+ T cells, basophils and neutrophils. Moreover, T helper cells amplify the inflammatory response via the release of Th2 cytokines. Following repetitive exposure to allergens, a chronic inflammation develops with associated tissue alterations such as mucus hypersecretion, vascular leakage, smooth muscle contraction, and bronchial hyperresponsiveness [In some individuals, an inflammatory reaction occurs in the lungs after exposure to specific allergens. Following a single allergen exposure, an early-phase reaction is produced in pulmonary tissues followed by a late-phase reaction. The early-phase reaction is characterized by the activation of mast cells and macrophages and the release of various mediators including histamine and eicosanoids while the late-phase reaction consists of recruitment of eosinophils, CD4siveness . Asthma siveness .2 cytokines (IL-4 and IL-13) [Over the last years, the attention has risen about the roles of ADAM proteinases in processes leading to the asthmatic phenotype described above (see figure d IL-13) . In humad IL-13) . This ovd IL-13) . Neverthd IL-13) .2 cytokines [Paulissen et al, submitted). It is also worth noting that these ADAM-8 depleted animals do not display developmental abnormalities as described by Kelly et al [ADAM-8 is another member of the ADAM family potentially associated to asthma. The first report to suggest an ADAM-8 implication in asthma was published in 2004 . This miytokines . Other aytokines . Recentlly et al . Taken tBesides ADAM-8 overexpression, a modulation of RNA levels of ADAM-9, ADAM-12, ADAMTS-1 and ADAMTS-15 has been demonstrated in induced sputum from asthmatic patients . RecentlAll these data highlight the implication of ADAM proteinases in asthma pathogenesis and suggest that new therapeutic strategies based on the inhibition of certain members of this proteinases family could be investigated.Chronic obstructive pulmonary disease (COPD) is characterized by a destruction of the lung parenchyma leading to alveolar wall destruction (emphysema) and important structural alterations in bronchial walls such as epithelial metaplasia or airway wall fibrosis [fibrosis . The majsingle nucleotide polymorphisms (SNPs) observed in this gene are associated with a higher risk for developing COPD [ADAM-33 has also been identified as a susceptibility gene for COPD since ing COPD . ADAM-33ing COPD .TACE for TNF-alpha converting enzyme) production in lung tissues from rats exposed to tobacco in a COPD model as compared to control animals support the implication of ADAM proteinases in this obstructive lung pathology [Data describing higher ADAM-17  enzymes activity in obstructive airways diseases.target proteinases that appear to play a direct role in pathogenesis as well as potential anti-target ADAMs whose inhibition could cause damages because they have a direct or indirect beneficial effect on lung physiology.This review, aiming at summarizing some lung-related biological actions of ADAMs/ADAMTS, demonstrates to which extent these factors are important in both physiological and pathological processes in lung tissues. Many basic researches have still to be performed to clearly identify The authors declare that they have no competing interests.GP drafted the manuscript. NR supervised the analysis of data and revised the manuscript. MMG, CC, FQC, SB, JH and MEH approved the final version of the manuscript. J-MF initiated the project. AN revised the manuscript critically. DDC initiated the project, was responsible to find grants, and approved the final version of the manuscript. All authors read and approved the final manuscript.