The Clinical Edge
Insights and commentary from the HIV/AIDS Division at UCSF/San Francisco General Hospital
Dr. Christopher Pilcher explains how technological advances in HIV testing are allowing for earlier identification of infection.
In San Francisco as in many other cities around the United States, we have seen some remarkable recent trends in HIV prevention and care. Guidelines that recommend universal antiretroviral therapy (ART) have led to more and more HIV-infected individuals being virally suppressed, and hence less likely to transmit HIV. At the same time, men who have sex with men have been testing more frequently, so if they become infected they are more likely to discover their infection and enter care early. In a world where most people with HIV are in care and virologically suppressed, what remains to drive HIV transmission? The answer, unfortunately, is acute HIV infection.
When care can be initiated and ART provided early in infection, both the clinical benefits and the prevention benefits of ART are optimal. Unfortunately, acute infection is the most contagious phase of HIV infection, and is not detected by HIV antibody tests. For this reason, for the past 8 years, San Francisco public testing sites have been looking for acute HIV infections by having all samples that were negative for antibodies to HIV also screened for HIV RNA. We have found that this consistently adds more than 10% to the number of cases detected among men who have sex with men; detection of acute HIV infections and rapid initiation of care have become routine.
San Francisco's experience with acute HIV case finding is about to go mainstream. In June 2014, the CDC issued the first change to its national HIV testing recommendations in over a decade, specifically tackling the challenge of testing for acute HIV testing head-on. There was little fanfare and most clinicians are unaware of the changes in testing policy, but they already have impacted practice in many HIV testing laboratories and programs.
The most dramatic change under the new testing guideline is that the CDC no longer recommends screening for HIV using only an HIV antibody test; rather, it recommends a test capable of detecting acute infections. Specifically, the CDC recommends using a 4th-generation HIV p24 antigen-antibody "combo" assay for nearly all testing situations. These detect viral p24 antigen proteins and/or anti-HIV antibodies, whereas previous generations of HIV screening tests were based on detection of antibodies only. Because p24 antigen appears in the blood before HIV antibodies develop in response to HIV infection, 4th-generation tests can detect HIV infection earlier. Testing laboratories outside the United States have been using these assays for years, but they were late in coming to the United States (owing in part to companies' slow pace in seeking FDA approval). The primary goal of this change is to make acute HIV case-finding possible in all testing programs nationwide.
The new algorithms also mark the disappearance of the Western blot as an acceptable "confirmatory" test. In its place, the CDC recommends using an antibody test that can both confirm HIV infection status and differentiate HIV-1 from HIV-2 infection. This recommendation is intended to reduce the number of unresolved discrepant or problem samples. At present, there are only two FDA-approved assays in the United States that meet this set of criteria (the Multispot and the newly approved Geenius test).
We must become accustomed to using 4th-generation "combo" screening assays and HIV-1/2 discriminatory antibody tests. Interpreting results can be somewhat complex: a positive "confirmatory" antibody test confirms infection, but a negative confirmatory result does not rule out acute HIV infection. In cases where a 4th-generation assay is repeatedly reactive but antibodies are not detected by the confirmatory test, both positive and negative results for HIV are reported. In these cases, another direct test for HIV (an HIV RNA test) is recommended. Practically speaking, this means an upsurge in the frequency of "discordant," "discrepant," or otherwise apparently inconclusive results. It may take some time for clinicians to become entirely comfortable with the new tests. This complexity notwithstanding, the hope behind these changes is that acute HIV cases will be recognized by more testing programs than ever before.
These changes to testing policy are not going to simplify the task of testing, particularly for programs built on getting results immediately. The 4th-generation assays can be done only in a laboratory setting, require specimen processing, and take several hours to perform; and, depending on the results, the complete algorithm can take days to perform. The new recommendations seem to allow rapid testing only if the rapid test (eg, a "CLIA-waived" fingerstick rapid test device) is duplicated by testing of a venous blood sample by a "recommended" algorithm. All-rapid-test algorithms are conspicuously absent--and many rapid testing programs face difficult decisions about how (or how closely) to adhere to new policies.
Some jurisdictions that are now dealing with very high rates of acute HIV cases (such as San Francisco) have yet to adopt 4th-generation combo testing, but have opted to stick with a combination of antibody tests and HIV RNA screening, which in head-to-head studies has proven the most sensitive in identifying acute HIV infection.
Just as we are getting comfortable with these changes, other technological advances in testing are close at hand. The biggest of these is the deployment of rapid HIV RNA tests (several of which are already being used in clinical trials). Interestingly, the new CDC recommendations already provide an "alternative algorithm" for laboratories that use an approved HIV RNA test in combination with an HIV antibody test for screening, rather than a 4th-generation antigen-antibody combo test. So, the CDC recommendations set the scene for next-generation technology--it is now up to the rapid RNA test manufacturers to move their tests to market. When they do, we anticipate the paradigm to shift further toward being able to identify people earlier in acute HIV infection so we can quickly link them to care.