A New York City physician has documented a case in which a male patient taking Truvada (tenofovir/emtricitabine) as pre-exposure prophylaxis contracted a rare, highly drug-resistant strain of HIV while apparently taking PrEP daily as prescribed.

This is the second such case of documented PrEP failure in a man who has sex with men (MSM), following the February report at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI) in Boston of a Toronto MSM on PrEP who contracted HIV under similar circumstances.

Considering how popular PrEP has become in the United States in particular, the fact that there have been only two documented cases of PrEP failure so far underlines the strong likelihood that such cases will remain very rare. As of the end of 2015, perhaps more than 80,000 U.S. residents had filled at least one PrEP prescription. Judging from the rapidly increasing quarterly prescribing rate in the United States, the number of people who have taken PrEP is likely now considerably greater.

In both of the documented cases of PrEP failure, the clinicians caring for these men were proactive and savvy enough to order the tests necessary to find scientific evidence supporting the men’s claims that they were adhering well to the daily Truvada regimen. Both men appeared to contract HIV not because they did not take PrEP as prescribed, but because the strains of HIV they contracted were each resistant to the two antiretroviral (ARV) medications in Truvada.

Given the rarity of the transmission of such multi-drug resistant strains, it is unlikely that there have been many other unreported examples of such PrEP failure.

Howard A. Grossman, MD, who until recently was a physician in New York City specializing in primary care for men who have sex with men (MSM), reported the new case at the HIV Research for Prevention (HIVR4P) in Chicago. Grossman, who had a large number of patients on PrEP in New York and who now practices at the Cleveland Clinic in West Palm Beach, Florida, said that the patient who contracted HIV while on PrEP is a man who has sex with men (MSM) in his twenties who is in a relationship with an HIV-positive man. His partner has maintained a fully suppressed viral load thanks to antiretroviral (ARV) treatment.

Considerable research has led scientists to estimate that HIV-positive individuals who have a fully suppressed virus, also known as having an undetectable viral load, are virtually uninfectious. So it is unlikely that the New York City man’s HIV-positive partner passed the virus along to him. Indeed, genetic analysis of each man’s virus found that they were not genetically linked.

Grossman’s patient tested negative for HIV five times between January 2013 and December 18, 2015. He started taking PrEP on January 1, 2016. On May 3, a routine lab-based 4th generation HIV test came up positive.

Under standard PrEP protocol, individuals are supposed to test for HIV every three months in order to receive a new Truvada prescription. Grossman says the man could not make his quarterly appointment, which should have taken place around April 1, but he gave him a new prescription for Truvada anyway until he could make it in for testing.

The man said that before testing positive he had had condomless sex with his partner multiple times, playing both the insertive (top) and receptive (bottom) role. He also said he had been the insertive partner with two male partners during two separate incidents that took place five and a half and 11 weeks before testing positive for HIV, respectively. He did not wear a condom for either sexual encounter.

The man said he had adhered perfectly to the daily Truvada regimen. Grossman ordered dried blood spot testing as well as analysis of a hair sample from the man. The results of each test were consistent with excellent adherence to PrEP during the previous 30 to 60 days.

Such tests are time sensitive. The dried blood spot test can only measure adherence dating back a month or two. And hair tests are limited by the length of an individual’s hair. So time is of the essence for clinicians to conduct such tests to determine adherence to Truvada after someone receiving PrEP tests positive for HIV.

Drug resistance testing of the man’s virus found that it had multiple resistance mutations, including those that confer resistance to each of the two drugs in Truvada, tenofovir and emtricitabine. The transmission of such multidrug-resistant strains of the virus are rare, regardless of whether someone is taking Truvada, suggesting that such cases of PrEP failure will remain quite uncommon. In other words, there is very good reason to believe that researchers were correct when they estimated that PrEP is more than 99 percent effective at preventing HIV when taken daily.

The apparent fact that the man contracted HIV from sex in which he was the insertive partner adds to the rarity of his case. Men are far less likely to contract the virus from insertive sex than from receptive sex. (Granted, self reports about sex can be unreliable; so the man may have in fact contracted the virus through receptive sex.)

Grossman kept the man on Truvada while conducting the initial round of tests to confirm he was indeed HIV positive. Then, on May 26, he prescribed his patient Tivicay (dolutegravir) in addition to Truvada to construct a complete HIV treatment regimen (three or more ARVs are required to treat the virus; Truvada contains only two). After the drug resistance report came back, Grossman also prescribed the man Prezcobix (darunavir/cobicistat) in order to intensify his regimen.

The man is doing well on HIV treatment and maintains an undetectable viral load.

Grossman stresses to POZ “important points,” including that “PrEP works and is the most successful intervention we have had; failures have been vanishingly rare, and that’s not changing; and tops can get infected.” He added that condoms can further reduce the risk of HIV.