Two cases of failure of PrEP with tenofovir monotherapy

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tenofovirA report initially presented to the 2015 BHIVA presented details at the 2015 year conference where two therapeutic cases in tenofovir mono-therapeutic PrEP failed to unequivocally prevent HIV infection in two homosexual men. In one case, although tenofovir appears to show the suppression of man's HIV viral load in its blood plasma, it has failed to prevent HIV from infecting the cells of its immune system. Tenofovir monotherapy was tested as PrEP in two large studies, Partner PrEP And Bangkok Tenofovir Study, with moderate to good results and has been assumed on the basis of animal studies that tenofovir may be enough to prevent HIV, Although the results were mixed.

In the event of an unequivocal Truvada (tenofovir + emtricitabine) has been reported but the cases raise a number of interesting questions: whether the levels of tenofovir needed to prevent infection need to be greater than those used for treatment; whether co-infection with hepatitis B may have become more likely to be infected with HIV; whether men would have been infected if they had been taking tenofovir + emtricitabine Truvada (); and if not, what exactly represent the contributions for the prevention of two drugs. Editor's note (!!!) (...) 🙂

Men were not taking tenofovir specifically as pre-exposure prophylaxis (PrEP) but instead were taking it as a treatment for chronic hepatitis B. One had persistent hepatitis B infection for six years and had been treated with tenofovir for four years; the others had hepatitis B seven years ago and had taken tenofovir for three years.

In the case of the first patient (patient one), the date of HIV infection can be identified almost exactly as he tested HIV-antibody positive only twelve days after a confirmatory Western blot HIV antibody test found negative serology HIV. Although this is an unusually short time to develop anti-HIV antibodies, it is not unknown. It was estimated that the most likely date for her actual exposure to HIV, based on her report of receptive intercourse anal sex with a casual male partner without a condom, was one day after her negative HIV test result. Six days later, he reported mild flu-like symptoms suggestive of HIV seroconversion disease and was tested again.

The second patient patient (B) did not have a recent HIV-negative test but was hospitalized with a severe flu-like syndrome with fatigue and muscle pain, suggestive of HIV seroconversion. Based on his first positive HIV test where he was HIV-negative antibodies but p24 positive, and also in his unbonded receptive anal sex account it was estimated that his probable time of infection was about two weeks prior to the test.

human checkBoth men appeared to have excellent adherence to tenofovir based on tablet counts. More to the point, tenofovir drug levels were taken on the day they tested HIV positive. One patient had taken tenofovir 24 hours before their drug level test and was therefore in the preventative standard of Truvada or the lower blood level would be expected. Their level of tenofovir was about 75 nanograms per milliliter of blood (ng / ml), meaning that it had a lower standard than levels of about 80% of patients, but still within the therapeutic level to treat both hepatitis B and HIV. (Tenofovir IC95, which is the amount of drug in the blood sufficient to reduce HIV replication in 95% It is from 6,8 to 35 ng / ml.)

Patient B had taken tenofovir seven hours prior to its HIV test result and had a blood level of 230 ng / ml or greater than 75% of the mean number of patients seven hours after a dose. Both results indicate that their tenofovir absorption was normal.

Both patients had CD4 cell counts of 550-600 cells / mm3 - namely lower than typical CD4 counts observed in HIV-negative patients - and while the patient had a relatively normal CD4: CD8 Ratio of 1.16, patient B had "reversed "The ratio typically observed in people with HIV - 0,49. [HIV negative people generally have more CD4 cells than CD8 cells: in people with HIV this ratio is usually reversed immediately after the acute infection and thus remains untreated. However, these numbers show that despite tenofovir, both patients had suffered significant immune damage in the acute phase of HIV infection - as is customary.

The major difference between the two patients was that in one patient tenofovir, while not preventing HIV infection, did not appear to be suppressing its HIV viral load in the blood. Although the HIV-positive test, and that HIV integrated into its cell at no point, it produced a viral load with more than 50 copies / ml. This "blunting" of HIV viral load has been seen before in cases of PrEP failure, particularly in animal studies that have established their efficacy . This means that your HIV can not be tested to see if it had acquired, or already had tenofovir resistance. This patient was changed to Eviplera (rilpivirine / tenofovir / emtricitabine) as soon as he tested HIV positive.

Patient B had a viral load of just over 100.000 copies / ml - not especially elevated for acute or recent infection. Despite having actively reproducing HIV in the presence of high levels of tenofovir, it did not have drug resistance mutations, illustrating, as other studies have done, that resistance to tenofovir only rarely develops in cases in which people with HIV use PrEP. However to prevent resistance, patient B was placed on an intensification of the three antiretroviral regimen of the class of Truvada (tenofovir / emtricitabine), boosted darunavir and raltegravir, which resulted in the successful suppression of their viral load.

Both patients had significant intracellular concentration of HIV infection, and HIV integrated into the genetic material of their immune cells - 587 copies per million CD4 cells at the age of patient A and 1432 copies at patient B. This strongly indicates that the virus is integrated into a continuous HIV infection, productive in both patients and with effectively transcribed RNA, evidence that cells were actively producing new HIV viral particles, was found both in patients although at one-tenth of the level in patients one such as patient B.

These cases may be the first cases where it can be undoubtedly demonstrated that a daily dose of tenofovir failed to prevent HIV infection. In one of the largest randomizedgreed PrEP, PrEP partners, there were six cases of HIV infection (Donnell) in people who, during the visit were diagnosed with HIV, had tenofovir levels compatible with daily dosing (two of these were also detected with the drug emtricitabine). However in all but one cases, participants could have caught HIV at any time in the last three months since their last visit, so it may not have been taken in PrEP the actual time they were infected. In one case the participant had a tenofovir level consistent with the daily dosage of one month before being diagnosed with HIV and the visit was diagnosed: this is the only previous case where PrEP failed to protect against infection despite what should have had the appearance of levels of protection; the more likely it is that the data interpretation is required.

The researchers comment that their cases show that "tenofovir monotherapy PrEP in men who have sex with men has limited efficacy and acquisition of data that HIV can occur in the presence of tenofovir drug levels within the therapeutic range required to treat HIV." All it has to say that has never really been established if the level of tenofovir (or any other single drug) would be enough to treat HIV is enough to prevent. They also consider that hepatitis B infection could increase susceptibility to HIV, even where it appears largely suppressed and virologically negative. It also cast doubt on the use of tenofovir monotherapy as PrEP in any patient, and should stimulate further investigation into even more protective regimens and PrEP may add to nervousness by recommending some intermittent PrEP schemes.

However, as the researchers note, the overwhelming majority of cases of so-called "failure" PrEP are due to people not really taking PrEP: the fact that these two cases have been reported underlines that HIV infection in situations where it seems that people on PrEP consistently is extremely rare.

Translated from the original by Gus Cairns in: 14 of January of 2016 by Cláudio Souza of the original in English in Two cases of PrEP failure on solo tenofovir significant research questions pose in 13 / 03 / 2016

Editor's Note: I have noticed in this text a great tendency, and I do not know if it is a result of my neurological pathology known as "Cefrebrus desconfiatus", or some pressure on the author, but Gilead may have realized that it has not yet reached the end of rainbows and that, therefore, will not snatch quintiles of dollars with your produ ... excuse me, remedy. What I do know is that the natural order of living or semi-living things is the irrefutable desire to continue existing, and therefore it is natural that there should be the formation of a strain completely resistant to Truvada and the use of monotherapy with truvada after these events, would be a gesture, if at all, irresponsible and, at its maximum, would be genocide ... Of course this is only a modest hypothesis of a blogger who lives 22 years, who saw the labs and their scientists try to amend the Declaration of Helsinki, changing a paragraph that the subject that was used (...) in tests would receive the best existing treatment for the best treatment available. Put simply, if this change had been achieved, people, human beings used as test tubes in Africa, once infected receive the best available treatment and I have certe absolute that they Terim it stocks and more stocks and DDI and AZT stavudine.

This is the ethic that they themselves attribute, not flinching for a second to recreate the uncontrolled pandemic of AIDS by a handful to more than dollars (or euros would be?).

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