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New Rapid And Point Of Care Hepatitis C Tests May Be Worldwide Game Changers
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- full published text below following intro article
redorbit.com October 16, 2012
from Jules: I knew rapid HCV point-of-care testing would be available very soon when I designed the concept & model for the Check Hep C NYC screening project. The rapid test was a major key in my plan. Previously a major barrier was that individuals in marginalized & underserved communities in NYC & other urban areas would disappear or simply not return for their results from a standard HCV test, for many reasons. I knew with a 20-minute rapid test we could keep them at the site with a patient navigator. Now in out NY project we keep them for the 20-minutes & if HCV+ test them on the spot with a PCR so 90% who are rapid test HCV+ are doing the PCR. This reflects the success of this model. The concept & model was designed with 6 steps: awareness project;\, rapid testing at 8 sites throughout NYC, 7 well educated patient navigators, 6 community-based care clinics, and weekly internet-based education by an expert hepatologist for the clinic care providers where case studies & education are provided online, this expands the treater pool. The target for this NY demonstration project is highly marginalized underserved communities including those with IDU history. Without mobilizing an entire city, like we are doing in NYC, and creating a large totally encompassing program, identifying & keeping in care the 80% undiagnosed will not happen. Isolated screening projects will not capture & retain individuals with HCV. Our model creates a safe environment for patients to enter & stay. We are identifying the many barriers to care that heretofore many are totally unaware of. Our model creates an 'HCV Urban Plan' or an 'HCV Ryan White Care Act', an infrastructure, because there is no infrastructure in HCV like there is in HIV, so we must create an infrastructure, which this NY project is a model for that can be duplicated anywhere globally. If the Obama Affordable Care Act stays in place it will not provide many of the services the NY model does & can provide, although services that emerge from the Obama Care act can be easily integrated into a broader program of an expanded model like in NY. Yes, the Ny program is a smaller demonstration project, although its doing 5000 rapid tests in 1 year. The NY model can & should be expanded to a totally citywide project that can be expanded to include all affected potential patient communities, with a appropriate supplemental components for all affected people.
"Although rapid diagnostic tests (RDTs) and point-of-care tests (POCTs) provide a time- and cost-saving alternative to conventional laboratory tests, their global uptake partly depends on their performance.........We found POCTs of blood (serum, plasma, or whole blood), RDTs of serum or plasma, and POCTs of oral fluid to be accurate and suitable for screening initiatives. In light of their accuracy and the urgent need to increase hepatitis C screening in marginalized and at-risk populations and in endemic HCV settings, these tests could play a substantial role in expanded global screening initiatives, which would eventually impact the control of HCV infection at the population level."
Image Caption: This is the point of care test for hepatitis C virus (HCV) infection. Credit: Dr. Nitika Pant Pai
RI MUHC study evaluates accuracy and convenience
Timely screening and diagnosis is critical to the success of new treatments and ultimately to the survival of hepatitis C patients. A new study led by the Research Institute of the McGill University Health Centre (RI MUHC) is the first to show that hepatitis C rapid and point of care tests with a quick turnaround time are highly accurate and reliable as conventional first-line laboratory tests. This head-to-head analysis, published in the current issue of the Annals of Internal Medicine, will lead to changes in screening practices and ultimately impact the control of hepatitis C infection worldwide.
"We were able to determine that point-of-care and rapid tests in oral fluids and blood ranged in accuracy from 97 to 99 per cent, which is significant," says senior author, Dr. Nitika Pant Pai, Assistant Professor in the Department of Medicine at McGill University and clinical researcher at the RI MUHC. "With their quick turnaround time and convenience we can now use these tests to screen many patients worldwide."
Although conventional lab testing is in place in developed countries, it is available only to those who visit community clinics and specialized hospitals and have a risk profile, or symptomatology, that warrant screening. Typically, results are available within a week, but may only be communicated to the patient during their next visit, which may be one to three months later. Delays like this may result in reduced patient follow-up and potentially impact transmission of the virus in the community.
Accurate and reliable point-of-care tests and rapid tests offer an alternative to standard tests. "First generation point-of-care tests are convenient, effective and informative for clinical decision making," explains Dr. Pant Pai. "These tests usually don't require specialized equipment, they can provide results within 30 minutes, or maximally within one patient visit or one working day, and many do not require electricity," adds Sushmita Shivkumar, lead author of the study and a medical student at McGill University.
More than 170 million people are infected with hepatitis C worldwide due to unsafe blood transfusion, injection drug use and unsafe therapeutic injections. Hepatitis C and HIV co-infections contribute substantially to disease burden in North America, but the affect of the disease is highest in Africa and Asia. "With promising oral drugs for Hepatitis C on the horizon, accurate and reliable point-of-care and rapid tests will allow millions of infected individuals worldwide to be diagnosed and treated," explains the study's co-author Dr. Rosanna Peeling, Professor and Chair of Diagnostics Research at the London School of Hygiene & Tropical Medicine.
"These tests have the potential to be game changers on a global scale, particularly where first line conventional laboratory based testing is not financed by under-resourced health systems," concludes Dr. Pant Pai. "It is now time to optimize their potential by integrating them in routine practice settings."
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16 October 2012
Accuracy of Rapid and Point-of-Care Screening Tests for Hepatitis C: A Systematic Review and Meta-analysis
Sushmita Shivkumar, MSc; Rosanna Peeling, PhD; Yalda Jafari, MSc; Lawrence Joseph, PhD; and Nitika Pant Pai, MD, MPH, PhD
Ann Intern Med. 16 October 2012;157(8):558-566
Abstract
Background: 170 million persons worldwide are infected with hepatitis C, many of whom are undiagnosed. Although rapid diagnostic tests (RDTs) and point-of-care tests (POCTs) provide a time- and cost-saving alternative to conventional laboratory tests, their global uptake partly depends on their performance.
Purpose: To meta-analyze the diagnostic accuracy of POCTs and RDTs to screen for hepatitis C.
Data Sources: MEDLINE, EMBASE, BIOSIS, and Web of Science (1992 to 2012) and bibliographies of included articles.
Study Selection: All studies evaluating the diagnostic accuracy of POCTs and RDTs for hepatitis C in adults (aged ³18 years).
Data Extraction: Two independent reviewers extracted data and critiqued study quality.
Data Synthesis: Of 19 studies reviewed, 18 were meta-analyzed and stratified by specimen type (whole blood, serum, plasma, or oral fluid) or test type (POCT or RDT). Sensitivity was similarly high in POCTs of whole blood (98.9% [95% CI, 94.5% to 99.8%]) and serum or plasma (98.9% [CI, 96.8% to 99.6%]), followed by RDTs of serum or plasma (98.4% [CI, 88.9% to 99.8%]) and POCTs of oral fluid (97.1% [CI, 94.7% to 98.4%]). Specificity was also high in POCTs of whole blood (99.5% [CI, 97.5% to 99.9%]) and serum or plasma (99.7% [CI, 99.3% to 99.9%]), followed by RDTs of serum or plasma (98.6% [CI, 94.9% to 99.6%]) and POCTs of oral fluid (98.2% [CI, 92.2% to 99.6%]).
Limitation: Lack of data prevented sensitivity analyses of specific tests.
Conclusion: Data suggest that POCTs of blood (serum, plasma, or whole blood) have the highest accuracy, followed by RDTs of serum or plasma and POCTs of oral fluids. Given their accuracy, convenience, and quick turnaround time, RDTs and POCTs may be useful in expanding first-line screening for hepatitis C.
Primary Funding Source: Canadian Institutes of Health Research.
The World Health Organization estimates (1) that 170 million persons worldwide are infected with the hepatitis C virus (HCV). Developing countries in Africa and Asia report the highest prevalence of this virus, which is transmitted predominantly by unscreened blood transfusions, injection drug use, and unsafe therapeutic injections (2). Because HCV and HIV infections share similar routes of transmission, about 40% of HIV-infected persons are co-infected with HCV (3). The prevalence of HIV-HCV co-infection varies from 16% to 33% in injection drug users in North America to 50% in Brazil (2,4). Morbidity and mortality are also higher in co-infected populations (5 - 8). Chronic hepatitis C infection is associated with long-term complications, such as liver fibrosis, cirrhosis, and hepatocellular carcinoma (1). Although newer treatments for hepatitis C (such as telaprevir or boceprevir with pegylated interferon and ribavirin) have made viral suppression a possibility, timely screening is critical to the success of these newer treatments (9). In addition to the high burden of co-infection, marginalized at-risk populations face social, structural, and economic barriers, such as limited access to testing (10) and lapses in health insurance (11), which hamper early screening and timely engagement with care. The situation is worse in global low-resource settings, where standardized laboratory tests are expensive and often not covered by public health systemsÑand thus are rarely performed or offered on-site or in time, leading to suboptimal care and screening.
In the United States, the Centers for Disease Control and Prevention (CDC) recommends using an enzyme immunoassay (EIA) and either recombinant immunoblot assay or HCV nucleic acid testing for RNA to diagnose hepatitis C infection (12). Although this algorithm effectively detects active infection, the tests are expensive and have long turnaround times. Convenient, quality-assured, antibody-based rapid diagnostic tests (RDTs) and point-of-care tests (POCTs) could facilitate preliminary screening, although they cannot differentiate between acute and chronic infections. Their rapid turnaround time limits loss to follow-up and facilitates early linkages. Although both diagnostic test types are rapid, RDTs require special equipment, such as centrifuges and refrigerators, whereas POCTs eliminate the need for electricity and are more robust at high temperatures, thus offering additional opportunities to expand screening (13).
Several POCTs are in use, including the OraQuick HCV Rapid Antibody Test (OraSure Technologies, Bethlehem, Pennsylvania), Anti-HCV Ab rapid test (Tema Ricerca, Bologna, Italy), SM-HCV Rapid Test (SERO-Med Labor Spezialitaten, Pollenfeld, Germany), Dual Path Platform test (Chembio Diagnostic Systems, Medford, New York), Multiplo Rapid HIV/HCV Antibody Test (MedMira, Halifax, Nova Scotia, Canada), SD Bioline HCV (Standard Diagnostics, Yongin, Korea), Bioeasy HCV Test (Bioeasy Diagn—stica, Belo Horizonte, Minas Gerais, Brazil), Hexagon HCV (Human Diagnostics Worldwide, Wiesbaden, Germany), and Genedia HCV Rapid LF (Green Cross Medical Science, Yongin, Korea). The RDTs on the market include the Diagnos HCV Bi-Dot (J. Mitra, New Delhi, India), HCV Tri-Dot (J. Mitra), Advanced Quality One Step HCV Test (Bionike, San Francisco, California), SeroCard HCV (Trinity Biotech, Bray, Ireland), and HCV Spot (MP Biomedicals, Santa Ana, California).
In 2010, the U.S. Food and Drug Administration approved the OraQuick HCV Rapid Antibody Test and granted a waiver from the Clinical Laboratory Improvements Amendments of 1988 to allow its use in nontraditional settings. This offered the potential to increase HCV screening into hitherto untapped domains.
Given the high absolute burden of HIV-HCV co-infection in marginalized populations (such as injection drug users) in North America and Europe, the high prevalence of HCV mono-infection in Africa and Asia (2), and the high costs of conventional serologic tests, introducing and integrating HCV RDTs and POCTs into mandated HIV programs may lead to cost savings and expedited first-line screening of at-risk populations. Global public health agencies are interested in knowing the diagnostic performance of these tests but, to our knowledge, this evidence has not been synthesized. To address this knowledge gap, we reviewed evidence on the diagnostic performance of globally available RDTs and POCTs to screen for hepatitis C.
Discussion
Our meta-analysis suggests that POCTs of blood (serum, plasma, or whole blood) have the highest accuracy, followed by RDTs of serum or plasma and then by POCTs of oral fluids. However, all subgroups showed high positive LRs, low negative LRs, and high DORs; the best LRs and DORs were reported for POCTs of serum and plasma, followed by those of whole blood, RDTs of serum and plasma, and POCTs of oral fluids. When sensitivity and specificity are similar, interpretation of the LR and DOR of the test influences conclusive changes from pretest to posttest probability of hepatitis C infection (17). Given the convenience of POCTs and their rapid turnaround time, these results show great potential for expanded first-line screening for hepatitis C infection and demonstrate the utility of blood-based singleton POCTs and of multiplex POCTs designed to provide integrated HIV and HCV screening of at-risk populations.
The high positive and low negative LRs found in each subgroup, especially those that tested serum, plasma, and whole blood, also imply that RDTs and POCTs can meaningfully inform the posttest probability of infection. The pooled accuracies of these tests have implications for their use in clinical and nonclinical outreach settings. For example, POCTs of oral fluids showed a slightly higher false-negative rate than POCTs of whole blood or finger-stick blood, which could be due to the lower concentration of antibodies or the weaker binding in oral fluid than in blood samples (33). The false-negative rate is of particular concern in high-risk groups, in which a high rate is more likely to lead to an undetected infection. In such scenarios, timely confirmatory testing could resolve a preliminary screening result. However, the convenience and rapid turnaround time of oral fluid-based POCTs, their ease of use, and patient preference for noninvasive sample collection may compensate for their slightly lower sensitivity. In sum, these tests could be safely integrated into expanded screening initiatives as first-line screening tests by using downstream blood-based algorithms to detect infections missed by oral fluid tests.
The POCTs that showed promise in individual studies were the Anti-HCV Ab rapid test, SM-HCV Rapid Test, OraQuick HCV Rapid Antibody Test, and Dual Path Platform test. The RDT HCV Tri-Dot also had high accuracy (Table 1).
Our meta-analysis is subject to the detection, spectrum, and sampling biases of the original studies. Of the 6 included case-control studies, only 3 (7,29,32) explicitly mentioned blinded reading of index test results, suggesting possible detection bias in the remaining studies. This could artificially inflate sensitivity and specificity estimates of the index test. The use of a case-control design also entails an extreme comparison of index tests in healthy and sick persons, suggesting possible spectrum bias.
Our results should be interpreted with some cautions. First, reference standards were found to influence the accuracy of POCTs (19 - 20). When the CDC-recommended ideal reference standard was used, sensitivity and specificity were higher than when an imperfect EIA reference standard was used (20). Only 9 of the included studies (11,19 - 25,32) used the CDC-recommended reference standard to ascertain true disease status. Misclassification by reference standards is known to influence the measured sensitivity and specificity of index tests (34). Accuracy estimates from studies that used imperfect reference standards to ascertain true disease status may have been artificially inflated or lowered because of misclassification by the reference standard. A standardization of reference standards is needed for future diagnostic accuracy studies.
Second, important factors to consider when interpreting the test results are co-infection status (for example, with HIV or hepatitis B), immune response, and their influence on diagnostic accuracy. In a CDC study (19), HIV seropositivity was found to have a statistically significant influence on the rate of false-positive results, with an adjusted odds ratio of 11 (CI, 2.53 to 48.17) reported for the Dual Path Platform test and an adjusted odds ratio of 3.95 (CI, 1.53 to 10.24) reported for the Multiplo Rapid HIV/HCV Antibody Test. This illustrates that both HIV co-infection and initiation of HIV treatment could influence the immune response, thus altering test accuracy. However, only 2 CDC-based implementation studies considered this issue (19 - 20).
Because of the limited data on this issue, future implementation research studies stratified by co-infection (such as with HIV, hepatitis B, or syphilis) are needed to resolve the issue of accuracy in the presence of co-infection. The influence of co-infection (naive or treated) on diagnostic accuracy will be especially relevant as multiplex POCT assays that integrate tests for HIV, hepatitis B, and HCV are or will be marketed for point-of-care use and as integrated HIV-sexually transmitted illness screening becomes the global standard of care in the near future.
Third, the effect of HCV genotype (genotypes 1 to 6) on diagnostic accuracy is worth further consideration. Genotype explorations were mentioned in a few studies as a potential influence on diagnostic accuracy, but their effect is unknown.
Fourth, at least 4 studies (11,21,30,32) reported receiving industry funding. When comparisons were possible, these studies reported more optimistic estimates of accuracy than did independently funded studies. Although the enforcement of stricter quality standards and the use of particular study designs (such as case-control), select study populations, and the best reference standards may have played a role, these findings need to be independently replicated by non-industry-funded studies.
Fifth, the index tests included in this meta-analysis detected antibodies to HCV and therefore could not detect infection within about 3 months or differentiate between acute and chronic infections (1). If clinical suspicion of a positive POCT or RDT result is high, further testing would be required. In the case of a possible false-negative result, further screening with another RDT or conventional laboratory-based tests could be considered, depending on available resources. For cases with a preliminary positive result, polymerase chain reaction testing is necessary to identify active infection, as is assessment of liver enzyme levels (35). More research is needed to determine how to effectively link screening with further linkages and follow-up, especially in hard-to-reach populations and low-resource settings.
Finally, evidence on POCTs will be of greater use to policymakers and guideline developers if outcomes beyond accuracy are documented. These include patient-centered outcomes and operational research outcomes, such as acceptability, preference, feasibility, impact, uptake, time to initiation of confirmatory testing, referrals, and treatment linkages. Accuracy was the sole focus in these studies, so pertinent downstream issues remain unexplored. Similarly, future research on the cost-effectiveness of RDTs or POCTs in different settings, populations, and contexts is warranted to make informed decisions on these tests and on testing strategies.
To our knowledge, this is the first systematic review to synthesize global evidence on POCTs and RDTs that screen for hepatitis C. We used QUADAS-2 and STARD to assess quality and followed PRISMA guidelines in reporting results. Despite our wide search strategy, we could have missed studies in this rapidly growing field and our review may also be subject to publication bias. Although sensitivity analyses that focused on the accuracy of individual tests would have been useful, they could not be done because of a lack of adequate data by test types and the presence of zero cells that precluded pooling of data. The scarcity of studies and data on some tests may also imply that they are not in use anymore.
Both RDTs and POCTs offer many advantages: a fast turnaround time (27,34), low psychological stress, declaration of results at the point of care with the potential for affecting clinical management, early detection of undiagnosed cases of hepatitis C (21), relatively easier identification of infection by paramedics or other health professionals (27,30,32), and high intra- and interobserver agreement or concordance (19). These advantages could be optimized by integrating them into usual care pathways in outpatient clinics, emergency departments, and public health clinics, as has been done with point-of-care HIV screening assays. Given the lack of global evidence, this review comes closer to independently assessing the role of RDTs and POCTs for widespread use in the field by synthesizing all available data on their accuracy and provides further evidence of the benefit of RDTs and POCTs for other developed countries, such as Canada and the United Kingdom, where their use is not yet approved.
We found POCTs of blood (serum, plasma, or whole blood), RDTs of serum or plasma, and POCTs of oral fluid to be accurate and suitable for screening initiatives. In light of their accuracy and the urgent need to increase hepatitis C screening in marginalized and at-risk populations and in endemic HCV settings, these tests could play a substantial role in expanded global screening initiatives, which would eventually impact the control of HCV infection at the population level.
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