Multistage pooling finds acute and early infection
Multistage pooling finds acute and early infection
Study catches infections that are often missed
Typical HIV screening with enzyme immunoassay (EIA) testing often fails to identify people who have recently become infected, creating missed opportunities to educate and prevent further transmission. North Carolina researchers have studied a cost-effective way to identify the early infections, and they’ve convinced state officials to implement the program on a trial basis.
When investigators assessed the feasibility of universal screening for acute HIV infection among patients who volunteered to be tested, they discovered a significant number of false negatives. Potentially, there could have been a 23% increase in total HIV diagnoses in North Carolina, and it’s possible that 19% of HIV-infected people who show up for routine testing could have acute HIV infection that is undiagnosed.1
The problem traditionally has been that it’s too expensive for communities or states to screen populations for HIV using the RNA polymerase chain reaction test. However, a new program is using a testing model that greatly reduces the cost, and North Carolina will be the first state to launch a demonstration project using the program, says Christopher D. Pilcher, MD, assistant professor of medicine at the University of North Carolina - Chapel Hill. "The state of North Carolina has adopted acute infection screening, using this method as state policy, and is going alone with a year-long demonstration project to show that we can identify people with acute infection," Pilcher says.
"This is something that governments or even the Centers for Disease Control and Prevention thought was feasible, to make large-scale acute infection screening a goal," Pilcher says. "But we think we may have figured out a way to do that and make it feasible."
The EIA antibody test typically doesn’t work when someone is newly infected. P24 antigen tests will identify HIV infection early on, but may only be an effective tool for one to three weeks after the onset of acute infection symptoms, Pilcher explains. The RNA or qualitative nucleic acid tests will identify an HIV-positive specimen a week before the P24 antigen test normally would identify it, and it will continue to be effective until the time an antibody test would show the patient to be positive.
The cost of testing all negative antibody samples with the RNA or P24 antigen tests is high, which is why it’s not routinely done, Pilcher says. One way to circumvent the cost vs. benefit issue is to use a model that pools all of the negative samples and to look cross-sectionally at antibody tests to see how many had RNA in them, Pilcher explains. "About 10% of the total number were HIV-positive and had negative antibody tests, but were positive for RNA," Pilcher says.
This is how it works: Using a pool of 1,000 HIV negative samples, take a tiny amount of serum from each of those samples that was negative and then combine these into pools of 10 specimens. Each of the 10 pools is clearly connected to the original individual samples. Each of these 10 pools is tested using an ultrasensitive RNA test. The pool that shows a positive RNA for HIV infection is then subdivided into smaller pools and, again, each of these is tested with the RNA test. This process is repeated until the samples can be narrowed down to the individual samples that have evidence of acute HIV infection. The number of RNA tests required would be far smaller than if all 1,000 samples were tested.
"If your HIV prevalence in a population was 50%, then this would make no sense, but we suspect it would be relatively low, on an order of one in 1,000," Pilcher says. "The additional effect is that the likelihood of false positives is greatly reduced because we’re only testing the final ten specimens for each one true positive," he adds. "It’s a fact that if you were to test each specimen individually in the thousand, you would expect to get 10 false positives per 1,000 samples," Pilcher explains. "Actually, what we found in the end is an overall specificity of 0.9999, which means there was less than one in 10,000 likelihood of a false positive in our scheme," he adds.
The multistage pooling protocol is a much more efficient and effective way for public health officials to identify people who have recently become infected with HIV, because it doesn’t rely on clinical exams or a patient’s own intuition. Clinicians who are presented with patients who have mono-type symptoms or who suspect they may have recently been exposed to HIV infection can always order an RNA test or a P24 antigen test as a precaution, Pilcher notes.
The benefit of the multistage pooling protocol is that clinicians don’t know exactly whom to weed out for RNA testing, especially if the person isn’t in a high-risk category, doesn’t have acute symptoms, or has symptoms that easily can be attributed to other causes, Pilcher adds.
North Carolina will do the RNA pooling protocol for about a year to try to identify HIV-positive people within two weeks of their HIV test, so they can be notified along with their partners. Then the program will prospectively screen their partners, because people who are in the acute phase of HIV infection are highly infectious, Pilcher says.
Reference
1. Pilcher C, McPherson JT, Leone PA, et al. Real-time, universal screening for acute and early HIV infection in a routine HIV counseling and testing population using multistage pooling and RNA PCR: Cost-effective, specific, and feasible. Presented at the 9th Conference on Retroviruses and Opportunistic Infections. Seattle; Feb. 25-28, 2002. Poster 359-M.
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