https://www.gastrojournal.org/article/S0016-5085(99)70185-X/pdf

Real-time detection system for quantification of hepatitis C virus genome

Viral kinetics in patients with chronic hepatitis C treated with standard or peginterferon α2a

Background 
Hundreds of studies have evaluated the diagnostic accuracy of nucleic-acid amplification tests (NAATs) for tuberculosis (TB). Commercial tests have been shown to give more consistent results than in-house assays. Previous meta-analyses have found high specificity but low and highly variable estimates of sensitivity. However, reasons for variability in study results have not been adequately explored. We performed a meta-analysis on the accuracy of commercial NAATs to diagnose pulmonary TB and meta-regression to identify factors that are associated with higher accuracy.


Methodology/Principal Findings 
We identified 2948 citations from searching the literature. We found 402 articles that met our eligibility criteria. In the final analysis, 125 separate studies from 105 articles that reported NAAT results from respiratory specimens were included. The pooled sensitivity was 0.85 (range 0.36–1.00) and the pooled specificity was 0.97 (range 0.54–1.00). However, both measures were significantly heterogeneous (p<.001). We performed subgroup and meta-regression analyses to identify sources of heterogeneity. Even after stratifying by type of commercial test, we could not account for the variability. In the meta-regression, the threshold effect was significant (p = .01) and the use of other respiratory specimens besides sputum was associated with higher accuracy.


Conclusions/Significance 
The sensitivity and specificity estimates for commercial NAATs in respiratory specimens were highly variable, with sensitivity lower and more inconsistent than specificity. Thus, summary measures of diagnostic accuracy are not clinically meaningful. The use of different cut-off values and the use of specimens other than sputum could explain some of the observed heterogeneity. Based on these observations, commercial NAATs alone cannot be recommended to replace conventional tests for diagnosing pulmonary TB. Improvements in diagnostic accuracy, particularly sensitivity, need to be made in order for this expensive technology to be worthwhile and beneficial in low-resource countries.

/pdf/commercial-nucleic-acid-amplification-tests-for-diagnosis-of-gvhpq0ce63.pdf

Commercial nucleic-acid amplification tests for diagnosis of pulmonary tuberculosis in respiratory specimens: meta-analysis and meta-regression.

ContextHepatitis C virus (HCV) is a common blood-borne pathogen that relies heavily on nucleic acid testing for confirmation of infection. Nucleic acid tests are invaluable for the diagnosis of HCV infection and provide critical prognostic information for guiding treatment and measuring the response to antiviral therapy.ObjectiveTo review the currently available molecular diagnostic tests for HCV, their clinical applications, and how these tests shed light on the natural history of HCV.Evidence AcquisitionSearch of MEDLINE (1966 to July 2006), article reference lists, and national meeting abstracts for the diagnosis and applications of molecular diagnostic tests for HCV. Studies were selected on the basis of clinical relevance.Evidence SynthesisQualitative nucleic acid tests have low limits of detection (<50 IU HCV RNA/mL) and are used for confirmation of HCV infection and for screening blood donations. Hepatitis C virus genotype test results provide important prognostic information related to therapeutic response and are routinely used for selecting treatment regimens. Quantitative HCV RNA testing provides prognostic information regarding likelihood of treatment response and plays an important role in monitoring the antiviral response to treatment. Sustained virological response is defined as testing negative for HCV RNA 6 months after cessation of therapy. Recent studies suggest that the rate of response to therapy is also important. For example, conversion to an HCV RNA negative test result after 4 weeks of therapy constitutes a rapidvirological response and is a strong predictor of treatment success. Patients who have not had an earlyvirological response, defined as at least a 2-log decline in HCV RNA after 12 weeks of therapy, are unlikely to respond with an additional 36 weeks of therapy, and should stop therapy.ConclusionsA sensitive nucleic acid test should be used to confirm all cases of acute or chronic HCV infection. A genotype test and quantitative HCV RNA test should be performed on all patients prior to therapy to best assess probability of response and to aid in selection of appropriate therapeutic regimen. Monitoring HCV RNA during treatment provides important information on likelihood of sustained virological response. The same type of quantitative HCV RNA test should be used throughout a patient's treatment course.

https://jamanetwork.com/journals/jama/articlepdf/205592/jcr70001_724_732.pdf

Molecular diagnostics of hepatitis C virus infection: a systematic review.

Background: Even though commercial nucleic acid amplification tests (NAATs) have become the most frequently used molecular tests for laboratory diagnosis of pulmonary tuberculosis (TB), published studies report variable estimates of their diagnostic accuracy. We analysed the accuracy of commercial NAATs for the diagnosis of pulmonary TB in smear positive and smear negative respiratory samples using culture as a reference standard. Methods: English language studies reporting data sufficient for calculating sensitivity and specificity of commercial NAATs on smear positive and/or smear negative respiratory samples were included. Meta-regression was used to analyse associations with reference test quality, the prevalence of TB, sample and test type. Predictive values for different levels of pre-test probability were quantified using Bayes' approach. Results: Sixty three journal articles published between 1995 and 2004 met the inclusion criteria. Pooled sensitivity and specificity were 0.96 and 0.85 among smear positive samples and 0.66 and 0.98 among smear negative samples. The number of culture media used as reference test, the inclusion of bronchial samples, and the TB prevalence were found to influence the reported accuracy. The test type had no effect on the diagnostic odds ratio but seemed to be correlated with sensitivity or specificity, probably via a threshold effect. Conclusions: Commercial NAATs can be confidently used to exclude TB in patients with smear positive samples in which environmental mycobacteria infection is suspected and to confirm TB in a proportion of smear negative cases. The methodological characteristics of primary studies have a considerable effect on the reported diagnostic accuracy.

https://thorax.bmj.com/content/thoraxjnl/61/9/783.full.pdf

Current evidence on diagnostic accuracy of commercially based nucleic acid amplification tests for the diagnosis of pulmonary tuberculosis

The benefits shown by the recent introduction of PCR for the in vitro diagnosis of hepatitis C virus (HCV) infection has prompted the development of standardized, ready-to-use assays that can be implemented in routine clinical laboratories. We have evaluated the clinical performance of COBAS AMPLICOR HCV (COBAS), the first instrument system that allows the automation of HCV RNA amplification and detection, to determine its performance in the routine laboratory setting. More than 2,000 specimens collected at five centers were analyzed in parallel by the COBAS and the manual AMPLICOR HCV (AMPLICOR) tests, and the results were compared with the results for biochemical and serological markers of HCV. In this study the two PCR systems showed the same accuracy, with a concordance rate of 99.8%. As expected, the correlation between serology and PCR was not absolute because the presence of anti-HCV antibodies may be associated with a latent or past infection. On the other hand, if the presence of confirmed anti-HCV antibodies and elevated alanine aminotransferase levels are taken as the “gold standard,” indicating an active, ongoing infection, the COBAS and AMPLICOR tests show high and comparable sensitivities (100%) and specificities (98%), with positive and negative predictive values of 100 and 97%, respectively. During the study no false-positive reactions were detected. The use of an internal control allowed the identification of inhibitory substances that prevented amplification for 0.3 and 0.4% of samples tested by the COBAS and AMPLICOR tests, respectively. Compared to the manual system, the COBAS system allowed a significant reduction of hands-on time and could improve the overall laboratory work flow. In conclusion, these results support the use of the COBAS and AMPLICOR tests for the molecular diagnosis of active HCV infections.

Multicenter Evaluation of the COBAS AMPLICOR HCV Assay, an Integrated PCR System for Rapid Detection of Hepatitis C Virus RNA in the Diagnostic Laboratory

A cooperative study was conducted among six laboratories to compare the performance of the Cobas Amplicor (CA) polymerase chain reaction (PCR) system (Roche Molecular Systems, USA) for the detection of Mycobacterium tuberculosis with that of microscopy and culture in routine clinical laboratory diagnosis. A total of 5,221 decontaminated respiratory specimens were tested. The use of an internal control allowed detection of PCR inhibition in 144 (2.8%) specimens. Only two culture-positive samples were CA PCR inhibitory and therefore could not be detected by PCR testing. Of the 333 culture-positive specimens, 278 (83.5%) were positive by the CA PCR. Of the 4,744 culture-negative specimens, 52 (1.1%) were positive by the CA PCR. After analysis of discrepancies, 40 of the 52 culture-negative, CA PCR-positive specimens were classified as true positive. Thus, the overall sensitivities of culture, CA PCR and microscopy were 89.3%, 85.2% and 55.5%, respectively. The overall specificity of the CA PCR was 99.7%. Five of the six centers found similar performances for the CA PCR, with sensitivities ranging from 85.7 to 90.9%. The CA PCR was more sensitive for smear-positive samples, exhibiting overall sensitivities of 96.1% and 71.7% for smear-positive and smear-negative specimens, respectively. These results indicate that the Cobas Amplicor system enables microbiology laboratories with reasonable previous experience in molecular biology testing to perform PCR and to detect Mycobacterium tuberculosis in more than 70% of specimens obtained from infected patients.

Multicenter study of a commercial, automated polymerase chain reaction system for the rapid detection of Mycobacterium tuberculosis in respiratory specimens in routine clinical practice.

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Multicenter Evaluation of the COBAS AMPLICOR HCV Assay, an Integrated PCR System for Rapid Detection of Hepatitis C Virus RNA in the Diagnostic Laboratory

Multicenter study of a commercial, automated polymerase chain reaction system for the rapid detection of Mycobacterium tuberculosis in respiratory specimens in routine clinical practice.