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ger-stick whole-blood specimens using the OraQuick® · and test (OraSure Technologies, Bethlehem, Pennsylvania). : March 2005, the clinics replaced finger-stick whole-blood sting with oral fluid testing with the OraQuick Advance pid HIV-1/2 Antibody Test.* The clinics use Western blot nfirmatory tests on serum to confirm all whole-blood or al fluid reactive (i.e., preliminary positive) rapid tests. In e 2005, an unexpected increase in the number of falsesitive oral fluid tests occurred, but the increase subsided er several months. In December 2005, while the cluster false-positive oral fluid test results was being investigated, e NYC DOHMH Bureau of STD Control suspended oral id testing in the clinics for 3 weeks and replaced it with ger-stick whole-blood rapid testing, which produced no se-positive test results. On December 21, 2005, NYC OHMH resumed oral fluid rapid testing but also introiced the use of immediate follow-up finger-stick wholeood testing, using a second OraQuick test, after any reactive al fluid test result. In late 2007, another larger increase in e incidence of false-positive oral fluid rapid test results was served. The cause for the episodic increases in false-posive oral fluid tests has not yet been determined. NYC OHMH has again suspended the use of oral fluid testing STD clinics, and finger-stick whole-blood testing is the ly rapid HIV test being used in this setting. These findgs underscore the importance of confirming all reactive IV tests, both from oral fluid and whole-blood specimens. addition, the results suggest that the NYC DOHMH ategy of following up reactive oral fluid test results with immediate finger-stick whole-blood test reduced the numr of apparent false-positive oral fluid test results and might a useful strategy in other settings and locations. The NYC DOHMH Bureau of STD Control routinely fers STD and HIV screening to all patients during the proximately 115,000 annual visits to the 10 STD clinoperated by the city. In 2003, 33,375 conventional (i.e., ɔt rapid) HIV tests were performed. A total of 552 (1.6%) ere positive; 79% of all patients tested received their test sults. In 2004, after on-site finger-stick whole-blood rapid IV testing was initiated with the OraQuick test, HIV sting at the clinics increased 14% to 38,092 tests, and ceipt of results increased to 88% for HIV-positive and 5% for HIV-negative patients. On average, during nuary 2004-February 2005, fewer than one falseositive finger-stick whole-blood rapid test occurred onthly. After oral fluid rapid HIV testing began in March
he OraQuick rapid HIV test can be used to test either blood (finger-stick or enipuncture whole-blood or plasma specimens) or oral fluid.
2005, overall test volume increased an additional 24%, to 47,204 tests in 2005. This upward trend in testing has continued (Figure 1); in 2007, the STD clinics performed 60,281 HIV tests, of which 607 (1.0%) were confirmed positive.
In the first 7 months after oral fluid testing was introduced, 35 (0.16%) of 21,722 tests were false positive by Western blot, consistent with the 99.8% (95% confidence interval [CI] = 99.6% -99.9%) specificity claim by the manufacturer in the product package insert (1). However, in October 2005, staff members at the clinics noticed an increase in the number of false-positive oral fluid test results each month. From an average of five false-positive tests per month, the monthly number of false-positive tests increased to 11 (0.27% of 4,024 tests) in October 2005 and to 36 (0.97% of 3,735 tests) in November 2005 (with a specificity of 99.03%, lower than the lower limit of the manufacturer's CI specifications) (Figure 1). An investigation detected no consistent relation between false-positive results and test-kit handling, storage conditions, or lot numbers or between false-positive results and clinic sites, test operators, or patient characteristics.
Despite the increased number of false-positive results, testing with the noninvasive oral fluid specimens was popular with clinic patients and more convenient for staff members; therefore, the NYC DOHMH continued offering oral fluid rapid HIV testing while attempting to minimize the adverse effects of false-positive test results. In late December 2005, a revised strategy was implemented at the clinics by continuing to offer oral fluid rapid tests but immediately following reactive oral fluid tests with a second. OraQuick test on finger-stick whole-blood specimens. Both test results were documented in the medical record. Counselors continued to explain to patients that any reactive rapid tests required Western blot confirmation but also emphasized that discordant oral fluid and whole-blood test results were likely to be false positive. By February 2006, an oral fluid test specificity of 99.65% was observed, within the CI of the manufacturer's specifications.
Another persistent increase in false-positive oral fluid test results began in late 2007. Beginning in November 2007, the number of false-positive oral fluid tests increased from 23 (0.51% of 4,503 tests) to a peak of 54 (1.11% of 4,858 tests) in February 2008 (Figure 1). During November 2007-April 2008, the monthly specificity of the oral fluid test ranged from 98.88% -99.49%. In May 2008, fewer false-positive tests occurred; in that month, five (0.11% of 4,749 oral fluid tests) were found to be false positive (specificity: 99.89%).
FIGURE 1. Total number of oral fluid rapid human immunodeficiency virus (HIV) tests administered and number of actual and expected false-positive results,* by month and year- New York City,† March 2005-May 2008$
*As confirmed by Western blot performed on serum. Expected number of false-positive tests and corresponding 95% confidence intervals calculated based on number of oral fluid tests performed monthly and manufacturer's claim for specificity with oral fluid (Orasure Technologies, Inc., OraQuick Advance Rapid HIV-1/2 Antibody Test customer letter and package insert. Available at http://www.orasure.com/uploaded/398.pdf). Among patients tested in 10 sexually transmitted disease clinics.
Oral fluid rapid HIV tests were introduced in March 2005. They were suspended for 3 weeks in December 2005 and replaced by finger-stick whole-blood testing.
During this second instance of increasing numbers of false-positive oral fluid tests, the clinics continued offering immediate follow-up finger-stick whole-blood rapid tests for all patients with reactive oral fluid tests. The usefulness of the NYC DOHMH policy was affirmed by the strong correlation between results from whole-blood rapid tests and confirmatory Western blot tests. During December 2005-May 2008, 1,720 patients had reactive oral fluid rapid tests, and definitive Western blot results were recorded for 1,664 (Figure 2). Missing Western blot results (24 patients) and inconclusive Western blot results (32 patients) were excluded from additional analysis. Of these 1,664 patients, 1,194 also provided a finger-stick specimen; 850 (71.2%) had a reactive finger-stick test, of whom 840 (98.8%) were positive by Western blot. Only one (0.3%) of 344 patients with a reactive oral fluid and negative finger-stick whole-blood rapid test was positive by Western blot.
Despite the NYC DOHMH policy that STD clinics should retest using whole-blood specimens after reactive oral fluid tests, 550 patients with reactive oral fluid results
did not receive a finger-stick test. For 80 of these patients. the test was ordered but not completed; of these, 77 (96.3% had a positive serum Western blot result. A total of 470 (28.2%) patients with reactive oral fluid tests declined the finger-stick test. Of these, 455 (96.8%) were confirmed positive by serum Western blot, compared with 850 (71.2%) of the 1,194 patients who agreed to a finger-stick test. Additional investigation indicated that 29% of patients with a reactive oral fluid test result who then declined the finger-stick test had been reported previoush as HIV-positive to the local HIV/AIDS Reporting System. compared with 21% of patients who agreed to a follow-up finger-stick test.
* Before patients were examined by a clinician, STD clinic staff members drew w vials of blood from all patients who visited the clinics (one for syphilis testing and on for confirmation of HIV, if needed). Clinic providers offered the HIV test to all patients; if accepted, providers requested the signed consent form required by the state of New York, and, when the oral fluid test was being used, they conducted the oral fluid rapid HIV test. Patients with reactive oral fluid tests were offered the tinger stick whole-blood test. The clinics were able to obtain confirmation of results for patients who refused the finger-stick test because the initially drawn tube of blood s sent routinely for Western blot confirmation of all reactive tests.
GURE 2. Number and percentage of positive and false-positive oral fluid and finger-stick whole-blood rapid human immunodeficiency us (HIV) tests, as confirmed by serum Western blot results - New York City,* December 2005-May 2008
Although 442 (0.27%) of all 166,058 oral fluid rapid IV tests performed during March 2005-May 2008 were se positive and demand for rapid HIV testing in NYC OHMH STD clinics remains high, test operators and unselors have expressed a lack of confidence in oral fluid pid HIV testing since the abrupt and sustained increase false-positive test results during November 2007-April 008. During this period, nearly half of reactive oral fluid sts in the STD clinics were false positive. Of 31,122 tients tested during those 6 months, 213 (0.69%) reacve oral fluid tests were false positive (specificity: 99.31%, low the lower limit of the CI of the manufacturer's ecifications) compared with 231 (0.70%) reactive oral uid tests confirmed positive by Western blot. Conseiently, in late May, because results from rapid tests perrmed on whole-blood specimens were consistently more curate than those from oral fluid tests and because rapid sting of whole-blood specimens required fewer additional sts for confirmation of HIV infection, NYC DOHMH ain discontinued use of oral fluid specimen testing in ID clinics. Finger-stick whole-blood specimen testing was instituted as the initial rapid HIV testing method. Oral Paid HIV testing data for May 2008, which became availle only after discontinuation of oral fluid testing in the ID clinics, indicated that the recent increase in false
positive oral fluid tests did not continue in May and the test's specificity with oral fluid specimens (99.89%) was within the CI of the manufacturer's specifications; however, rapid HIV testing of oral fluid specimens has not resumed.
Reported by: J Cummiskey, MPH, M Mavinkurve, MPH, R PanethPollak, MPH, J Borrelli, MPH, A Kowalski, MPH, Bur of Sexually Transmitted Disease Control, New York City Dept of Health and Mental Hygiene. S Blank, MD, B Branson, MD, National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention, CDC.
Editorial Note: Both the number of patients tested for HIV and the percentage who receive their test results have increased since rapid HIV testing was introduced in the New York City STD clinics in 2004. Nationally, public health laboratories report that rapid tests overall and oral fluid tests specifically account for an increasing proportion of all HIV tests (2), and patients are substantially more likely to receive rapid test results than conventional test results (3). The New York City data in this report underscore the importance of routinely comparing reactive rapid test results with confirmatory Western blot test results as an essential component of quality assurance in HIV testing (4). Several other jurisdictions have noted clusters of falsepositive oral fluid rapid HIV tests since an initial report from Minnesota in 2004 (5-8). Although the causes of these clusters of false-positive tests remain unexplained (6),
investigations are under way to determine which specific factors (e.g., test device, site, operator, or oral fluid characteristics of specific patients) might be associated with increased numbers of false-positive test results. Several programs have adopted strategies similar to the one used in New York City and are immediately repeating the rapid test on whole-blood specimens from patients who have reactive oral fluid tests. Other strategies under investigation include repeat testing with a second rapid test from a different manufacturer (9).
The specificity of OraQuick rapid tests performed on oral fluid specimens is lower than that of OraQuick rapid tests performed on whole-blood specimens (5). The test manufacturer's 99.8% specificity estimate with oral fluid is based on a clinical trial of 3,682 participants. In New York City STD clinics, performing approximately 5,000 oral fluid tests per month for 3 years, overall specificity has been 99.73%, but the month-to-month specificity has ranged from 98.88% to 99.98%. Although specificity was lower than the manufacturer's claim during certain months, the test's performance in the New York City clinics was not below the Food and Drug Administration (FDA) minimum threshold of 98% for rapid HIV tests.§
Because the prevalence of positive HIV tests has decreased among STD clinic patients concomitant with the increasing number of tests, a slight increase in the percentage of reactive rapid tests that are determined to be false positive (decreased positive predictive value) was expected. However, this change does not account for recurrent clusters of false-positive tests.
The advantages of rapid HIV tests, particularly with oral fluid specimens, include increased availability and acceptability of testing among populations at high risk for HIV infection and increased receipt of test results among those tested (3). The strategy used in New York City, with immediate follow-up using a retest on whole-blood specimens, allowed the STD clinics to continue oral fluid rapid testing while mitigating, somewhat, the adverse effects of false-positive results on both patients and clinic personnel. The strategy also allowed health department staff members to detect the increase in false-positive tests promptly, avert the majority of instances in which patients might have left the clinic with an oral fluid test result only (e.g., with
$US Department of Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research. Development of rapid HIV tests. In: Blood Products Advisory Committee Sixty-Sixth Meeting (vol I); June 15, 2000; Silver Spring, Maryland. Available at http://www.fda.gov/ohrms/dockets/ ac/00/transcripts/3620t1.pdf.
a false-positive result), and avoid the logistical difficult. inherent with training and maintaining inventory, prof ciency, quality assurance, and external controls for rapi HIV tests from more than one manufacturer.
CDC continues to encourage the use of rapid HIV test because they increase the number of persons who are tested and who receive their test results. Six rapid HIV tests have been approved by FDA since 2002 (10). The New York City data indicate that repeating a rapid test on fingerstick whole blood after receiving a reactive oral fluid test result allows clinic counselors to provide more accurate testresult information to patients while minimizing the num ber of finger-stick tests that must be performed. Regardless. confirmatory testing is required to confirm both oral fluid and whole-blood reactive rapid HIV tests. Before testing, all patients should be informed that reactive rapid HIV test results are preliminary and require confirmation. In general, testing with blood or serum specimens is more accurate than testing with oral fluid and is preferred when feasible, especially in settings where blood specimers already are obtained routinely.
Overall, oral fluid rapid tests have performed well and make HIV testing possible in many venues where performing phlebotomy or finger sticks is impractical for screen.ing. However, users should be aware of the unexplained variability in the rate of false-positive test results. CDC will continue to work with FDA and the manufacturer to investigate the causes and extent of increases in falsepositive oral fluid tests, monitor the performance of oral fluid and other rapid tests to ensure that they continue to perform as expected in testing programs, and investigate other combination test strategies to minimize falsepositive test results.
The findings in this report are based, in part, on contributions b S Wright, S Wang, Bur of Sexually Transmitted Disease Control D Hanna, C Ramaswamy, Bur of HIV/AIDS Prevention and Contro New York City Dept of Health and Mental Hygiene; the staff and patients of the New York City Dept of Health and Mental Hygiene STD clinics; and J Schillinger and S Rubin, National Center for HIV AIDS, Viral Hepatitis, STD, and TB Prevention, CDC.
1. OraSure Technologies, Inc., OraQuick® Advance Rapid HIV-12 Antibody Test customer letter and package insert. Available at http www.orasure.com/uploaded/398.pdf.
2. Association of Public Health Laboratories. Public health laboraton issues in brief: 2006 HIV diagnostics survey. Silver Spring, MD Association of Public Health Laboratories; 2007. Available at http: www.aphl.org/aphlprograms/infectious/documents/hiv_issue_brie_
Hutchinson AB, Branson BM, Kim A, Farnham PG. A meta-analysis of the effectiveness of alternative HIV counseling and testing methods to increase knowledge of HIV status. AIDS 2006;20:1597–604. CDC. Quality assurance guidelines for testing using rapid HIV antibody tests waived under the Clinical Laboratory Improvement Amendments of 1988. Atlanta, GA: US Department of Health and Human Services, CDC; 2007. Available at http://www.cdc.gov/hiv/topics/ testing/resources/guidelines/pdf/qa_guidlines.pdf.
Delaney KP, Branson BM, Uniyal A, et al. Performance of an oral fluid rapid HIV-1/2 test: experience from four CDC studies. AIDS 2006;20:1655-60.
Jafa K, Patel P, MacKellar DA, et al. Investigation of false positive results with an oral fluid rapid HIV-1/2 antibody test. PLoS One 2007;1:1-6.
Walensky R, Arbelaez C, Reichmann W, et al. Revisiting expectations from rapid HIV tests and confirmation algorithms in the emergency department [Poster]. Presented at 15th Conference on Retroviruses and Opportunistic Infections, February 3–6, 2008, Boston, Massachusetts. Available at http://www.retroconference.org/2008/pdfs/ 534.pdf.
8. CDC. Supplemental testing for confirmation of reactive oral fluid rapid HIV antibody tests. MMWR 2005;54:1287-8.
9. Knoble T, Delaney K, Menendez O, Dowling T, Facente S. Implementing RTA to identify false positives and immediately refer to care. San Francisco, CA 2007. Presented at the HIV Diagnostics Conference, Atlanta, GA; December 5–7, 2007. Available at http://hivtesting conference.org/powerpoint/4_knoble.pps.
10. CDC. FDA-approved rapid HIV antibody screening tests. Atlanta, GA: US Department of Health and Human Services, CDC; 2008. Available at http://www.cdc.gov/hiv/topics/testing/rapid/rtcomparison.htm.