When is a pre-exposure prophylaxis (PrEP) failure actually a provider failure? And how do we tell the difference?
This was a question that came up at CROI 2018 after a poster presentation titled "Seroconversion on PrEP: A Protocol for Untangling Adherence versus Resistance Failure" sparked conversations and debates about how you distinguish an example of tenofovir/emtricitabine (Truvada) failing to protect an individual from acquiring HIV, versus a provider whose negligence and failure to follow Centers for Disease Control and Prevention (CDC) protocol may have put his or her patient at grave risk.
The case presented in the poster begins in December 2015, when a 34-year-old gay white man in the U.S. received an HIV-negative result from an antigen/antibody test, which has an average window of 21-28 days. Two months (or 62 days) after receiving these results, the man's doctor gave him a 30-day prescription for tenofovir/emtricitabine, with 11 refills. No further confirmatory testing was conducted to ensure that the man had not acquired HIV during the unknown three-month window (November 2015-February 2016) or after initiating PrEP.
The man reported discontinuing use in May 2016 "due to perceived lack of risk," then restarted on his own two months (61 days) later. At no point in this process was he ever tested for HIV, nor did he receive any monitoring from his provider. His HIV status and adherence patterns are undocumented during this entire seven-month period.
Related: HIV Infection Despite PrEP: 6 Things You Need to Know
He presented with flu-like symptoms (fevers, chills, muscle pains) at an urgent care center in March 2017. Yet, he still was not offered an HIV test at this point of service. He later went to an HIV clinic where he was tested for HIV for the first time in 16 months, and the results were positive. His virus showed resistance to both tenofovir and emtricitabine, as well as to K103N -- a rare strain that would make him resistant to HIV treatment drugs such as efavirenz (Sustiva, Stocrin) and rilpivirine (Edurant). Hair sampling was able to measure adherence for the previous 90 days, and it demonstrated that he had adherence commensurate with seven doses per week between Jan. 15, 2017 and April 15, 2017.
So, does this case represent a failure of PrEP to protect or a provider failure? It is unlikely we will ever have a complete answer to this case's quandary. But, we do have plenty of science and medical practices to explain what most likely occurred.
The CDC PrEP guidelines strongly emphasize the need for consumers to receive a confirmatory HIV-negative test prior to beginning PrEP and/or another test one month after starting the regimen. The reason for this is that tenofovir/emtricitabine "is inadequate therapy for established HIV infection, and its use may engender resistance either or both drugs." The iPrEx trial (the most influential trial to show PrEP's high efficacy for prevention) also noted that drug resistance "was limited to those who initiated drug after established infection," meaning they started using tenofovir/emtricitabine while already HIV positive. The case shared at CROI indicated that there had been no confirmation that the man was HIV negative prior to beginning PrEP in February 2016; he was not tested for HIV when he restarted after stopping in July 2016; and no HIV testing was offered again until 14 months later in April 2017. This is the most likely explanation for his resistance to both tenofovir and emtricitabine once he finally tested positive.
But what about the K103N drug resistance? This would suggest a resistance to medications that are not found in tenofovir/emtricitabine, meaning he had to have acquired them from a partner who was living with HIV, had a detectable viral level, and had a rare strain resistant to these medications. Does the presence of this mutation suggest that PrEP failed in this case?
"I don't know," responds Mehri McKellar, M.D., one of the study authors who presented the poster at CROI. "I think this is complicated by inappropriate prescribing and follow up practices, such as the two-month gap between initial HIV testing and PrEP initiation, the provision of 11 months of Truvada refills at the initial visit without verifying return visits, and the lack or ineffective counseling on restarting PrEP without a repeat HIV test. As a result, we can't really tell if he was infected with a multi-drug resistant (MDR) virus (making this a PrEP failure) or whether resistance emerged on ongoing two-drug PrEP after HIV infection had already occurred."
David Glidden, Ph.D., co-author of the original iPrex trial results, shares a clearer perspective. "His virus showed multiple mutations," he said. "He could have been infected by a resistant virus (very rare) or he could have been taking PrEP for months after infection (which leads to resistance commonly). Basically, they can't align the time of infection with PrEP use. It's almost certainly not a breakthrough."
Unfortunately, some media outlets have already inaccurately cited this as a "likely" breakthrough, resulting in the public receiving the false impression that there is a scientific conclusion about what happened here. There is not.
What is clear is that PrEP continues to work exceptionally well when medical protocols are followed and when consumers take it as prescribed. The World Health Organization recently reported that at least 300,000 people across the globe are using PrEP. Only two cases have been identified as PrEP failures with verified adherence: one in Toronto and one in Amsterdam. An additional reported case did not contain verified adherence that the drug was used at the time of HIV acquisition. We are also aware that over 12,000 individuals have used tenofovir/emtricitabine in efficacy trials and demonstration projects. Not one HIV acquisition took place when tenofovir/emtricitabine was taken as prescribed.
When consumers and providers are exploring PrEP as a viable option to prevent HIV, it will be important to look at reported breakthrough cases with a closer lens. Did the provider prescribe in compliance with established guidelines? Was the patient adherent? Even under the rare and unfortunate circumstances that a transmission occurs, it is still vital for people to make their sexual health decisions based on access to accurate statistics, evidence-based science, and realistic possibilities.