|Dr. Lindsey Baden|
"The goal of HIV vaccines is to elicit an immune response against HIV. The goal of HIV testing is to see if there is the presence of an immune response to HIV," Dr. Baden explained. "VISP occurs when the antibody or the immune response elicited cross-reacts with the diagnostic test; there can be confusion if one is not aware of this possibility."
VISP might have important ramifications, Dr. Baden said. "Participants may be at risk for misdiagnosis, and if that occurs, then many social harms occur . . . related to insurance, military service, blood [and] tissue donation, immigration, and a variety of other issues that may arise."
Dr. Baden and coworkers studied VISP occurring with various vaccines that were studied by the HIV Vaccine Trials Network. VISP was determined using 3 common US Food and Drug Administration–approved enzyme immunoassay (EIA) test kits. They evaluated VISP in healthy HIV-seronegative adults who participated in any of 25 phase 1 or 2 phase 2a vaccine trials conducted between 2000 and 2010 in the United States and internationally.
VISP was defined as a positive reaction on 1 or more of the EIA tests and a Western blot result that was negative, indeterminate, or atypical-positive — meaning a blot profile consistent with the vaccine product — in conjunction with a negative test for HIV-1 by nucleic acid testing.
Of the 2176 trial participants receiving a test vaccine, 908 (41.7%; 95% confidence interval [CI], 39.6% - 43.8%) had VISP. The occurrence of VISP varied greatly according to the kind of vaccine being tested (e.g., 86.7% for an adenovirus 5 product but only 6.3% for a DNA-alone product). Similarly, results varied substantially according to the test kit used (range, 8.8% to 40.9% VISP).
Dr. Baden concluded that VISP is a common but highly variable outcome in people who participate in vaccine trials. "The occurrence of this is dependent on several factors, including the vaccine or delivery system, the insert used in the vaccine, and the diagnostic test," he said.
These results indicate the need to develop novel rapid-detection methods that do not detect candidate vaccine antigens; several candidate diagnostics are now being investigated that use antigens that are unlikely to be used in vaccines, he noted.
But Dr. Baden said the easiest way to minimize the concern about false-positive test results is for healthcare providers to be aware of the issue as more people participate in vaccine studies. "All they need to do is ask their patients, and if their patients say they are in a vaccine study, then that should be an important consideration in how diagnostic testing is performed," he advised. In addition, testing might best be done by the vaccine trial site, which would be familiar with results related to the specific vaccine.
Because trial participants with VISP might subsequently become infected with HIV, appropriate testing is imperative, Dr. Baden emphasized, including testing for HIV RNA. Trial sites should also test for VISP at the end of the trial and tell participants their VISP status so that they can inform their healthcare providers.
Jason Haukoos, MD, MSc, assistant professor of surgery at the University of Colorado and an emergency physician in the Department of Emergency Medicine at the Denver Health Medical Center, told Medscape Medical News that relatively few patients have been in HIV vaccine trials, so concerns about VISP are small and Dr. Baden's work should go a long way toward solving the problem of false-positive results caused by VISP.
"And there are also a lot of diagnostics coming out now . . . [that will] not only look for antibodies but also antigens," he said. "If you have a combination antibody–antigen assay, then the VISP issue, I think, goes away on some level." He added that, unfortunately, we are still a long way from having an approved vaccine that will be used widely, so the problem of VISP for the near term is minimal.
Melanie Thompson, MD, from the AIDS Research Consortium of Atlanta, Georgia, and chair of the International AIDS Society–USA Antiretroviral Therapy Guidelines Panel, who was not involved in the study, agreed that false-positive HIV test results from VISP are not yet a problem given the small number of trial participants.
"As vaccine studies are expanding, it is going to become a more general issue," she told Medscape Medical News. Patients in vaccine trials will need to be aware of the issue "because they are going to educate the doctors in the community about VISP," she said. "Any HIV testers in the community need to be aware that persons who have been in vaccine trials may have a false-positive HIV test on the antibody testing."
Even in countries with limited healthcare resources, where many of the vaccine trials occur, she said the problem of VISP should be small if the test sites encourage their trial subjects to come back to them for HIV testing, where the proper test methodologies exist, if they have a positive test result elsewhere.
The work was funded by the National Institute of Allergy and Infectious Diseases and by a University of Washington Center for AIDS Research grant. Dr. Baden has disclosed no relevant financial relationships. Dr. Haukoos reports receiving unrestricted research support from Abbott Laboratories and being supported in part by the Centers for Disease Control and Prevention and the Agency for Healthcare Research and Quality. Dr. Thompson reports receiving research grants awarded to the AIDS Research Consortium of Atlanta from Abbott Laboratories, Avexa, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, GlaxoSmithKline, Gilead Sciences, GeoVax, Katketsuken, Koronis Pharmaceuticals, Merck Research Laboratories, Myriad, Ora-Sure, Panacos Pharmaceuticals (now Myriad), Pfizer, Progenics Pharmaceuticals, Roche Laboratories, Roche Molecular Systems, Serono, Theratechnologies Tibotec Therapeutics, Tobira Therapeutics, Trimeris, and VaxGen; serving on the scientific advisory boards or as a clinical trial design consultant for Chimerix, GeoVax, GlaxoSmithKline, Panacos Pharmaceuticals, Progenics Pharmaceuticals, and Tibotec Therapeutics; receiving honoraria for scientific lectures from GlaxoSmithKline and Serono; and serving on data and safety monitoring boards for Tibotec Therapeutics.
JAMA. 2010;304:275-283. Abstract
AIDS 2010: XVIII International AIDS Conference. Presented July 18, 2010.