Single HIV RNA Test Delivered False Positives With Long-Acting Cabotegravir PrEP

A single positive HIV viral load test often falsely identified HIV infection in people who were using long-acting cabotegravir (Apretude) for preexposure prophylaxis (PrEP), according to results from the HPTN 083 open-label extension trial.

In people who received an injection of long-acting cabotegravir within the previous 6 months, an isolated positive HIV RNA test had a positive predictive value of 9.1{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} (95{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} CI 1.6-30.6), reported Raphael Landovitz, MD, of the University of California Los Angeles, during the International AIDS Conference in Munich.

When the last cabotegravir injection had been more than 6 months ago, the positive predictive value of a single HIV RNA test rose to 60{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} (95{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} CI 17-92.7). Overall, the positive predictive value of a single test was 18.5{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} (95{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} CI 7-38).

“We conclude from this preliminary analysis that a single isolated positive HIV RNA test done at study sites performed poorly for detecting HIV infection in the setting of long-acting cabotegravir PrEP,” Landovitz told attendees.

However, repeat RNA testing alone or in combination with antigen-antibody testing could confirm with 100{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} certainty whether an isolated RNA positive test was a false-positive or whether it represented a true infection, he explained.

Among 26,528 HIV RNA tests conducted during the open-label extension, researchers identified 22 isolated false-positive HIV RNA tests, for an overall false-positive rate of 0.08{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497}. The low rate reflected “the large number of testing events and the rarity of both true HIV acquisition events and false-positive RNA results,” Landovitz pointed out.

“Although both true and false-positive test results were infrequent, most isolated positive RNA test results were false positives,” he said. “Guidelines for HIV testing in the context of long-acting cabotegravir PrEP should consider these performance characteristics.”

Primary results from the HPTN 083 trial showed long-acting cabotegravir was superior to daily oral PrEP with tenofovir disoproxil fumarate-emtricitabine (Truvada) among 4,566 men who have sex with men and transgender women.

In December 2021, cabotegravir was the first long-acting injectable for HIV prevention to be approved by the FDA.

In a press release, Jeanne Marrazzo, MD, MPH, director of the National Institute of Allergy and Infectious Diseases, noted that “we are still learning how to optimize the package of services that accompany long-acting PrEP, including HIV testing. The viral load testing findings observed in this study illuminate performance gaps in the current U.S. HIV testing algorithm for injectable cabotegravir PrEP.”

There were significant clinical consequences for false-positive HIV RNA test results, Landovitz emphasized. Trial participants with false-positive test results experienced delays in subsequent long-acting cabotegravir administration and discontinuations. “Happily, none of these participants … have shown evidence of HIV acquisition to date,” he added.

Interestingly, the false-positive tests were disproportionately concentrated among nine of 43 sites in the HPTN 083 study. In fact, half of the 22 false-positive testing events were from one single site. Exhaustive quality assurance and control evaluations of laboratory processes and performance at the sites did not identify a source of these false-positive results, he said.

During a Q&A session, Cheryl Johnson, PhD, of the World Health Organization in Geneva, Switzerland, pointed out that the “results seem to suggest that [nucleic acid testing] for monitoring of cabotegravir implementation performed poorly, may not necessarily be needed, and may also have consequences to patients due to the delays that you reported in the real world.”

“What are the programmatic implications of your findings and how do policymakers take these forward?” she asked.

“It’s a very important question,” Landovitz replied. “You’ll notice I was very careful to stop short of enunciating my opinion on how these results should impact policy and program.”

“My interpretation of these results is that RNA testing likely does more harm than good, except when used prior to initiation of long-acting cabotegravir, and perhaps also when there has been a 6-month or longer hiatus since last injection,” he added.

During this open-label extension trial, 95{e60f258f32f4d0090826105a8a8e4487cca35cebb3251bd7e4de0ff6f7e40497} of participants chose to initiate or continue long-acting cabotegravir for PrEP. The median number of follow-up visits with an RNA screening test was 12 per participant. Of the 26,528 visits with screening tests, most were visits with long-acting cabotegravir use in the past 6 months.

The researchers identified 73 positive HIV RNA or non-RNA tests. Of these, 22 isolated HIV RNA tests were false positives, while five of the isolated HIV RNA tests were determined to be true positives.

Landovitz noted that the results of the analysis are generalizable only to the population studied in the HPTN 083 trial, according to his personal interpretation of the findings.