A case report of a man in Toronto who was infected with a multidrug-resistant HIV strain in spite of apparently large adherence, consistent with PrEP, was Conference on Retroviruses and Opportunistic Infection (CROI 2016) in Boston today.
Dr David Knox, a physician at the Toronto Maple Leaf Clinic, said the patient was a gay man of approximately 43 years man who had undergone PrEP two years ago. He had an HIV positive partner who had undetectable viral load
He was a regular listener at the outpatient clinic and tested for HIV on average every three months. It was suggested to him that he start Truvada PrEP on April 2013 and it seemed to have good adherence to it due to frequency of pharmacy refills.
Two years later in April of 2015 he began to have symptoms after a period of exposure to HIV with multiple partners. The symptoms were not classic seroconversion symptoms for HIV but involved an episode of fever with abdominal pain intense enough for him to go to the hospital for a consultation where a reading revealed an inflammation of the colon.
During that time he went into his regular HIV test and showed that he had HIV infection, with a negative HIV antibody test but a positive p24 HIV antigen test, which shows earlier. Their HIV viral load three days later was 28.000 copies / ml - quite low for acute HIV infection and suggestive that their PrEP had "blunted" viral replication without stopping the infection, or that the virus was highly resistant to medications and was replicating weakly.
The patient stated peremptorily that he maintained excellent adherence to PrEP's way to Dr. Knox, to question that he may now be seeing a case of true failure in PrEP, commissioned further tests. A resistance test was performed for all classes of antiretroviral drugs for the virus patient from a specimen collected one week after their HIV diagnosis.
The other needs explanation. The patient was treated as a public health setting center of few financial resources and his former blood samples had not been saved. So there was no direct way to prove that it had drug levels compatible with high adherence around the time of exposure to HIV.
There was an indirect way, though. Dr Knox analyzed a test called the "dry blood" site (DBS) of the 20 patient days after he was diagnosed. The test point of a DBS is that the levels of the drug inside measures red blood cells, rather than within the white blood cells that the HIV infects, or in the blood plasma. The drug levels rise much more slowly within red blood cells, taking 17 days to reach half of their steady state levels and a full eight weeks to reach the steady state saturated drug altogether. Drug levels also rose steadily and are less susceptible, in the short term, to ups and downs. Drug levels in the DBS patient were effectively 47% higher than the mean value, suggesting consistent PrEP adherence during most of the period covering their HIV exposure. If he had been taking the drug since he submitted his diagnosis, drug levels would be only 47% of the mean steady state level or 31% of his actual level in this patient.
This is an indirect way of measuring drug levels. Given that the age of onset of symptoms occurred four weeks prior to the patient's HIV diagnosis and the dry blood test was performed over three weeks thereafter and that the period of risk according to the patient started two weeks earlier of the onset of symptoms, thus leaving nine weeks for the drug to accumulate; this test does not entirely rule out the possibility that he would have failed to join PrEP at the time he took a risk and that he had started PreP again. However, the patient insists that this is not the case.
There was a small blood sample from his diagnostic test, taken three days before the patient found out to be seropositive,
This revealed high levels of tenofovir and emtricitabine levels so high that they were above the limit of quantification of the test. However this was not a long-term test and drug levels and again could not totally rule out the possibility that he had had a lapse in adherence around time he was exposed to HIV.
Resistance testing showed that the HIV patient did not have a significant resistance to the class of antiretroviral drugs known as protease inhibitors. He had a mutation of resistance to the first generation of NNRTI nevirapine drugs, and complete resistance to emtricitabine. He also had extensive resistance to the first generation of NRTIs that drugs such as zidovudine (AZT) and stavudine (d4T), and these mutations also confer some resistance to tenofovir. However it did not present the call to K65R which confers high level of resistance to tenofovir and it was estimated that the pattern of mutation and resistance was only 1,3 times resistance to tenofovir, which means that 30 drug levels% higher than those required for resistant viruses should not have been strong enough to prevent infection - and it had much higher drug levels present in the tests. Resistance, however, is a complex process and some combinations of mutations can catalyze higher levels of resistance than they will produce alone.
Not relevant to the apparent failure of PrEP, but to the spread of drug resistance, was the fact that this patient also had two mutations of resistance to the drug integrase inhibitor and drug resistance elvitegravir.
HIV transmission with integrase inhibitor resistance é very rare, and in particular resistance to all drugs except raltegravir, the first integrase inhibitor. the observed resistance patterns is compatible with the unnamed person who has passed the virus being in a fault scheme of Stribild (two classes of four the combination drug pill of tenofovir, emtricitabine, cobicistat and elvitegravir).
Since four of the five first-line regimens are recommended by the Department of Health and Human Services, they are based on integrase inhibitors, and that this class of drugs is being evaluated for use as PrEP, and would be a concern that more viruses resistant to integrase inhibitors began to circulate.
The patient himself was placed on a class three regimen potent medications like dolutegravir, rilpivirine and darunavir boosted and became the undetectable only three weeks after onset.
In conclusion, this is probably not an absolutely booming point - it would take a level of drugs in samples collected at the time of infection for this. But on the balance of probabilities, with three different measures all accepted the patient self report, this is probably the first documented case of Truvada PrEP, despite high adherence and more than adequate levels of drug although recently Two cases were reported on monotherapy with tenofovir.
It is not unexpected that there would be cases of PrEP failure; but the fact that this is the first case report among the tens of thousands of people held with PrEP shows that it is very rare.
Translated in 02 of March of 2016 by Cláudio Souza from the text in Almost-Certain case of PrEP failure due to drug resistance Reported at CROI 2016 by Gus Cairns Published in: 25 February 2016 for AIDSMAP