On July 3, 2012, the US Food and Drug Administration (FDA) approved the first at-home rapid HIV testing kit, the OraQuick® In-Home HIV Test. Unlike other tests that require laboratory assistance for specimen collection and/or running the test, this new test detects antibodies to HIV from a patient-collected oral fluid swab and provides results within 20-40 minutes, offering at-risk individuals another option to determine their HIV status.
In an interview with Medscape, Elliot Cowan, PhD, Chief of the Product Review Branch in the Division of Emerging and Transfusion Transmitted Diseases at FDA's Center for Biologics Evaluation and Research, provides some background on the test's approval process and discusses key issues that play an important role in maximizing benefit from this type of testing strategy.
Medscape: Let's start with some background on the role of at-home testing for HIV infection. What considerations went into whether a test like this should be approved? Who is likely to benefit most from its use?
Dr. Cowan: When we are evaluating a new test, we normally look at sensitivity and specificity. But an extra layer that we added onto this was a risk analysis. We wanted to understand what the potential benefit could be -- and what the potential risks could be -- for bringing a test like this forward.
The test showed reduced sensitivity compared to other available tests. It does not meet the expectations for sensitivity that were recommended by the Blood Products Advisory Committee back in 2006, which was 95% at the lower bound of the 95% confidence interval. The overall sensitivity level is 92%, compared to greater than 99% for the professional-use test, and the lower bound of the confidence interval for this test came in at around 84%.
Although this over-the-counter test is exactly the same test device as the professional-use test using oral fluid, there was a drop-off in sensitivity with people who were testing themselves, for reasons that we can get into later on. For specificity, it was just as good as a professional-use test.
Given the reduced sensitivity, we decided that we would conduct a formal risk-benefit assessment to look at the public health implications of a test performing at this particular level of sensitivity.
When we conducted this risk analysis, we found that there is potentially a considerable public health benefit. There are about 1.2 million people infected with HIV in the United States, and it is estimated that about 18% of them don't know it, according to the Centers for Disease Control and Prevention. Using a model that was generated by FDA, we showed that there was a potential with this test to inform an additional 44,000 or so people who don't know that they're infected with HIV that they are, in fact, HIV positive. And this would, in turn, be projected to avert about 4000 new HIV transmissions, all in the first year of use.
This brings us to the question, who would benefit most from a test like this? The short answer is people who are at the highest risk for HIV infection. And the more people who are at higher risk for HIV infection actually use the test, the greater the public health benefit is expected to be.
But there is a corresponding individual risk that goes along with this: the individual risk is of a false-negative result, when someone is told that he or she is not infected, but, in fact, is HIV positive.
When we presented this information to our advisory committee, they weighed all of the evidence and decided that the public health benefits outweigh the individual risks. Recognizing that there is some risk, there still appears to be a greater benefit to those who are not otherwise being tested. We're hoping that this type of test will lead some of these people to be tested and let them know their HIV status.
Medscape: Following on that point, what do we know about why people don't get tested? Why would an over-the-counter test like this likely be more appealing to them? Is it a question of stigma -- that they're uncomfortable going to a physician or clinic, so allowing them to have direct access to the test would make them more likely to be tested?
Dr. Cowan: I suspect that there are a number of issues that are preventing people from getting tested, but based on what we've heard at advisory committee meetings in public sessions, it seems that there is still a major issue with stigma. Many people are very concerned that simply going to a clinic or a doctor's office to be tested for HIV will be known to the community, and the stigma that is associated with that is still a heavy burden to bear.
With an at-home test, you have the ability to purchase it directly over the Internet or in a store and to learn the results immediately, so the entire process can be completely confidential and anonymous. I should also point out that that the Home Access® HIV-1 Test System, also FDA approved, allows you to purchase a kit over the Internet or in a store and to collect a blood specimen in your home anonymously. You then mail the specimen to a professional laboratory for testing and obtain the results in about a week, and positive results have been confirmed by additional testing.
Medscape: Going back to the issue of false negatives and false positives, there is the potential for a false negative, in which someone doesn't realize that he or she is HIV positive, doesn't enter care, and perhaps is not as conscious about the risk for transmission. Then there is the potential for a false positive, in which someone thinks that he or she is infected but isn't. Focusing first on the false-negative possibility, how likely is someone to see a false-negative result? And what should one do about it? How should physicians counsel their patients about the possibility of a false negative?
Dr. Cowan: First, it is important to understand that a negative result when using this test kit does not necessarily mean that the individual being tested is not infected with HIV, especially if he/she had been engaging in behavior that puts him or her at risk for HIV infection. It could be particularly concerning if a couple were to use this test, get negative test results, and then, assuming they're not infected with HIV, engage in, for example, sex without a condom if both had engaged in high-risk behavior prior to that. A test like this should not be used to decide whether to engage in behavior that puts an individual at risk for HIV infection.
That being said, based on the numbers from the clinical trials that were done to support the approval of the test, among people who are infected with HIV, we would expect to see 1 false negative for every 12 true positives.
There are a number of factors that contribute to this. One is the window period between when someone is infected and when antibodies are present that can be detected. The window period for this test is approximately 3 months. That is, if one were infected with HIV less than 3 months ago, the test is not going to be as accurate in detecting the infection. And the closer it is used to the time that the individual was first infected within that 3-month period, the less likely the test will be to pick up an infection, simply because the body needs sufficient time to generate antibodies to the virus.
This 3-month period is longer than the window with other types of tests; some laboratory-based tests, for example, can have a much shorter window period, down to just a few weeks.
So, the message that should be given to someone who has a negative result with this test is this: If you are engaging in behavior that puts you at risk for HIV infection within the past 3 months and you've tested negative, you should get retested at a later time.
Medscape: The window period is the same regardless of how many times one takes the test over the course of 3 months; they're not more likely to get a positive result if they retest within that same period. What should clinicians tell their patients about retesting?
Dr. Cowan: Correct; retesting within the same window period would not necessarily eliminate the possibility of a false negative. If an individual did engage in behavior that put him or her at risk for HIV infection within the past 3 months, the clinician can recommend that the individual be retested using a different type of test that has a shorter window period, especially if there are signs and symptoms of infection. For example, if someone has flu-like symptoms and engaged in high-risk behavior, it might be prudent to have that person undergo testing using a test with a much shorter window period, such as a test that detects HIV antigens or HIV RNA.
Note that the window period is not necessarily the only reason that the sensitivity of this test is relatively lower than that of other tests. Of the 8 false negatives that were seen during the clinical trials, only 1 was formally attributed to testing during the window period. We don't know what caused the remaining 7 false negatives, but it appears that it was not due to testing during the window period. Other, unknown factors might have contributed to these false-negative cases; the test might not have been performed properly or the individual might not have interpreted the test properly.
This underlines the importance of following all of the instructions exactly when running the test and interpreting the results. It's also very important to make sure that the test kit is stored properly. The maximum storage temperature is 80° F. People have a tendency to leave things in their cars for extended periods of time, and this can be a problem, especially over the summer. Again, it's very important to follow all of the instructions and to store the test properly to make sure that there won't be errors as a result of something that was done that is contrary to the way that the test was intended to be used.
So, to sum up, even if someone has waited an appropriate amount of time -- and there is therefore antibody present to detect -- there is still the possibility of a false-negative result. For individuals engaging in high-risk behavior, follow-up professional testing would be appropriate.
Medscape: The flip side of this is the possibility of a false-positive test. How accurate are the positive results, and what should one do in the event of a positive result?
Dr. Cowan: The false-positive rate is quite low, based on the clinical trials that were done. As I mentioned earlier, among people who are infected with HIV, 1 in 12 will get a false-negative result. But among people who are not infected with HIV, you would expect 1 false positive out of 5000 true negatives, which is essentially the same as the professional-use test.
Having said that, no test is perfect and there will be false-positive results. This is meant to be a screening test and needs confirmation. If one does get a positive result, it's very important to follow up with additional professional medical testing.
Medscape: Use of this test can change the way patients enter care for HIV, because patients would go to a clinician already knowing their HIV status. What can clinicians do to prepare for this? Should they familiarize themselves with the patient education materials that accompany the test so that they know what the patient is seeing and what to expect if a patient were to come in?
Dr. Cowan: Yes, that would certainly be a good idea. The test comes with a number of printed materials. There is a booklet that is designed to serve as pretest counseling, called "HIV, Testing & Me," which has background information on HIV and testing. Another booklet, called "What Your Results Mean to You," is designed for posttest counseling and includes information on next steps and what to do with the test results. The kit includes a pencil for taking notes and a page on which the individual can write down an example of what the test looks like so that if it's positive -- or negative -- he or she can show it to a clinician for follow-up care.
There is also an insert written in Q&A format that has information on the performance of the tests, including results of the clinical trials, and when the test should and should not be used. There are a number of messages that are prominently displayed regarding the issues of false positives and false negatives, what a negative result means and what a positive result means, and what the window period is.
Most important, there is a consumer support center staffed 24/7 that's available to help people if they have questions about HIV or about using or interpreting the test. They are also equipped to refer people for additional testing as necessary and for entry into care based on where the caller lives. All staff at the call center will be bilingual, so they will be able to handle calls in both Spanish and English.
Medscape: Is there a recommended age under which individuals should not use this test?
Dr. Cowan: Yes. It's meant for people aged 17 and older. When someone purchases the test in the store, for example, the barcode will advise of any age restrictions.
Medscape: What do you see as the greatest challenges with this test moving forward?
Dr. Cowan: There are challenges that lie ahead on many levels. People can now be empowered to test themselves for HIV, but there is a lot of responsibility that they are assuming as well. They need to understand the limitations of the test, how the test should be used, and what the results actually mean. For clinicians, there is the challenge of trying to encourage individuals at higher risk to be tested on a regular basis, and for those who are HIV positive, to enter into care. There is the challenge of postmarket surveillance, to see how well the test is performing in the hands of the people who are using it. Efforts are under way to try to obtain the greatest public health benefit from at-home rapid HIV testing.