An almost certain case of PrEP failure due to drug resistance has just been reported in the year of 2016

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, SeropositivoOrgA case report of a man in Toronto who was infected with a multidrug-resistant HIV strain and despite apparently large adherence, consistent with PrEP, was presented during the Conference on Retroviruses and Opportunistic Infection (CROI 2016) in Boston today.

Dr David Knox, a doctor at the Toronto Maple Leaf Medical Clinic, said the patient was a gay man of approximately 43 years old who had undergone PrEP two years ago. He had an HIV positive partner who had an undetectable viral load

He was a regular listener at the clinic and tested for HIV on average every three months. It was suggested to him that he start Truvada PrEP in April 2013 and he seemed to have good adherence to it due to the frequency of pharmacy refills.

Two years later in April 2015 he started having symptoms after a period of exposure to the HIV virus with multiple partners. The symptoms were not classic HIV seroconversion symptoms, but involved an episode of fever with abdominal pain severe 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 in for his HIV test and regular showed that he had HIV infection, with help a negative test for HIV antibodies, but a positive test for HIV p24 antigen, which shows earlier. His HIV viral load three days later was 28.000 copies / ml - quite low for acute HIV infection and suggestive that his PrEP had "blunted" viral replication without stopping the infection, or that the virus was highly resistant to drugs and was replicating weakly.

The patient firmly stated that he maintained excellent adherence to PrEP in a Dr Knox way, calling into question that he may now be seeing a case of true PrEP failure, commissioned further tests. A resistance test was performed for all classes of antiretroviral drugs for your virus patient from a sample taken one week after your HIV diagnosis.

The other needs explanation. The patient was treated at a public health definition center with little financial resources and his old blood samples had not been kept. So there was no direct way to prove that he had drug levels compatible with high adherence around the time of exposure to HIV.

There was an indirect way, however. Dr Knox analyzed a test called the patient's local “dried blood” (DBS) 20 days after he was diagnosed. The test point of a DBS is that the levels of the drug inside measure red blood cells, rather than inside the white blood cells that HIV infects, or in 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 completely saturated steady state drug. Drug levels have also risen regularly 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 over most of the period covering his exposure to HIV. If he had been taking the drug since he made his diagnosis, the drug's levels would be just 47% of the average steady state level or 31% of his actual level in this patient.

, SeropositivoOrgThis is an indirect way of measuring drug levels. Since the age of onset of symptoms occurred four weeks before the patient's diagnosis of HIV infection and the dry blood test was carried out over three weeks later and the risk period according to the patient started two weeks before the onset of symptoms, thus leaving nine weeks for the drug to accumulate; this test does not entirely exclude the possibility that he would have failed to adhere to PrEP by the time he took a risk and that he would have 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 himself HIV-positive,

This revealed high levels of tenofovir and levels of emtricitabine 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 they could not totally exclude the possibility that he had had a lapse in adherence around the time he was exposed to HIV.

Resistance tests showed that the HIV patient who did not have significant resistance to the class of antiretrovirals known as protease inhibitors. He had a resistance mutation to the first generation of NRTI drugs nevirapine, and complete resistance to emtricitabine. He also had widespread resistance to the first generation of NRTI than drugs such as zidovudine (AZT) and stavudine (d4T), and these mutations also provide some resistance to tenofovir. However, they do not have the so-called K65R that gives tenofovir a high level of resistance and it was estimated that the mutation and resistance pattern was only 1,3 times resistance to tenofovir, which means that drug levels are 30% higher than those needed for resistant viruses should not have been strong enough to prevent infection - and he 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 on their own.

Not relevant to the apparent failure of PrEP, but for the spread of drug resistance, it was the fact that this patient also had two mutations of resistance to the drug integrase inhibitor and resistance to the drug elvitegravir.

HIV transmission with resistance to integrase inhibitor it is very rare, and especially resistance to all drugs except raltegravir, the first integrase inhibitor. the observed resistance patterns is compatible with the unnamed person who passed the virus being on a Stribild (two classes of four the tenofovir pill drug combination, emtricitabine, cobicistat and elvitegravir).

Since four of the five first-line therapeutic regimens are recommended by the Department of Health and Human Services, they are based on integrase inhibitors, and this class of drugs is being evaluated for use as PrEP, and it would be a concern that more viruses resistant to integrase inhibitors began to circulate.

The patient himself was placed on a class three potent medication regimen such as dolutegravir, rilpivirine and boosted darunavir and became undetectable just three weeks after onset.

In conclusion, this is probably not an absolutely loud point - a level of drugs in samples taken at the time of infection would be required for this. But on the balance of probabilities, with three different measures everyone accepted the patient's self report, this is probably the first documented case of Truvada PrEP, despite high adherence and more than adequate drug levels although recently Two cases were reported on monotherapy with tenofovir.

It is not unexpected that there would be possible cases of PrEP failure; but the fact that this is the first case report among the tens of thousands of people on PrEP shows that it is very rare.

Translated on March 02, 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

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