- Category: Pre-exposure Prophylaxis (PrEP)
- Published on Wednesday, 20 January 2016 00:00
- Written by Gus Cairns
A report originally presented to the 2015 British HIV Association conference last year details 2 cases where therapeutic levels of tenofovir used alone for hepatitis B treatment unequivocally failed to prevent HIV infection in gay men. In one case, despite the tenofovir apparently suppressing the man’s HIV viral load in his blood plasma, it failed to prevent HIV infecting the cells of his immune system.
The cases raise a number of questions: whether the levels of tenofovir required to prevent HIV infection need to be higher than those used for HIV treatment; whether hepatitis B virus (HBV) coinfection may have made HIV infection more likely; whether the men would have been infected if they had been taking tenofovir plus emtricitabine (the drugs in Truvada); and if not, what are the exact contributions to prevention of the 2 drugs.
The men were not taking tenofovir specifically as HIV pre-exposure prophylaxis (PrEP) but instead were taking it as treatment for chronic hepatitis B. One had had persistent HBV infection for 6 years and had been on tenofovir for 4 years; the other had had hepatitis B for 7 years and had taken tenofovir for 3 years. Both tenofovir/emtricitabine and tenofovir monotherapy have been studied as PrEP, but only the dual combination is approved by the U.S. Food and Drug Administration and recommended by the CDC.
In the case of the first individual (Patient A), the date of HIV infection can be pinpointed almost exactly, as he tested HIV antibody-positive only 12 days after a confirmatory western blot antibody test found him HIV-negative. Although this is an unusually short time in which to develop HIV antibodies, it is not unknown. It was estimated that the most likely date for his actual exposure to HIV, based on his report of condomless receptive anal sex with a casual male partner, was 1 day after his HIV-negative test result. Then 6 days later he reported mild flu-like symptoms suggestive of HIV seroconversion illness and was tested again.
The second individual (Patient B) had not had a recent negative HIV test but was hospitalized with a severe flu-like illness with fatigue and muscle pain, suggestive of HIV seroconversion. Based on his first positive HIV test, where he was HIV antibody-negative but p24-positive, and also on his account of condomless receptive anal sex, it was estimated that his likely time of infection was about 2 weeks prior to the test.
Both men appeared to have excellent adherence to tenofovir based on pill counts. More to the point, tenofovir drug levels were taken on the day they tested HIV-positive. Patient A had last taken tenofovir 24 hours before his drug level test and was therefore at the "trough" or lowest blood level one would expect. His level of tenofovir was about 75 ng/mL, meaning that he had lower trough levels than about 80% of patients, but still well within the therapeutic level to treat both hepatitis B and HIV. Patient B had taken tenofovir 7 hours before his HIV test result and had a blood level of 230 ng/mL, or higher than 75% of average patients, 7 hours after a dose. Both results indicate that their absorption of tenofovir was normal.
Both men had CD4 cell counts of 550-600 cells/mm3 -- notably lower than typical CD4 counts seen in HIV-negative people. While Patient A had a relatively normal CD4:CD8 ratio of 1.16, Patient B had the "inverted" ratio typically seen in people with HIV -- 0.49. (HIV-negative people typically have more CD4 than CD8 cells; in people with HIV this ratio is usually inverted immediately after acute infection and stays that way without treatment.) Either way, these figures show that despite taking tenofovir, both patients had suffered significant immune damage during acute HIV infection -- as usually happens.
The biggest difference between the 2 patients was that in Patient A the tenofovir, despite not preventing HIV infection, did seem to be suppressing HIV viral load in his blood. Although he tested HIV-positive and had HIV integrated into his cells (see below) at no point did he have a viral load over 50 copies/mL. This "blunting" of HIV viral load has been seen before in cases of PrEP failure, notably in the animal studies that established its efficacy. This means his HIV was too low to be tested to see if it had acquired, or already had, drug resistance to tenofovir. This patient was switched to Complera (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 high for someone with acute or recent infection. Despite having HIV actively reproducing in the presence of high tenofovir levels, he had no drug resistance mutations, illustrating -- as other studies have done -- that resistance to tenofovir only rarely develops in cases where people with HIV take PrEP. However to forestall resistance, he was put on an intensified 3-class antiretroviral regimen of tenofovir/emtricitabine, boosted darunavir (Prezista), and raltegravir (Isentress), which resulted in successful suppression of his viral load.
Both patients had significant intracellular HIV infection, and HIV integrated into the genetic material of their immune cells -- 587 copies per million CD4 cells in the age of Patient A and 1432 copies in Patient B. This indicates quite enough integrated HIV for ongoing, productive infection in both individuals, and indeed transcribed RNA -- evidence that cells were actively producing new HIV viral particles -- was found in both men, though at one-tenth the level in Patient A as in Patient B.
These cases may be the first ones where it can be shown without doubt that a daily dose of tenofovir has failed to prevent HIV infection. In one of the largest randomized studies of PrEP -- Partners PrEP -- there were 6 cases of HIV infection in people who, at the visit they were diagnosed with HIV, had tenofovir levels consistent with daily dosing (2 of these were also taking emtricitabine).
However in all cases but one, the participants could have caught HIV at any time in the previous 3 months since their last visit, so may not have been taking PrEP at the actual time they were infected. In that one case, however, the participant had a level of tenofovir consistent with daily dosing 1 month before being diagnosed with HIV and at the visit she was diagnosed; this is the only previous case where the failure of PrEP to protect against infection despite what should have been protective levels looks like the most likely interpretation of the data.
The researchers comment that their cases show that "tenofovir monotherapy PrEP in men who have sex with men has limited efficacy data and that HIV acquisition can occur in the presence of tenofovir drug levels within the therapeutic range required to treat HIV." They point out that it has never really been established whether the level of tenofovir (or any other single drug) sufficient to treat HIV is sufficient to prevent it. They also hypothesize that hepatitis B virus infection could potentially increase susceptibility to HIV, even where it appears largely Virologically suppressed.
This report may cast further doubt on the use of solo tenofovir for PrEP, and should spur further research into even more protective PrEP regimens and may add to nervousness about recommending some intermittent PrEP regimens.
Nonetheless, as the researchers note, the overwhelming majority of cases of so-called "PrEP failure" have been due to people not actually taking PrEP. The fact that these 2 cases have been reported underlines that HIV infection in situations where it looks like people have been taking PrEP consistently is extremely rare.
J Fox, M Brady, H Alexander, et al. Tenofovir Disoproxil Fumarate Fails to Prevent HIV Acquisition or the Establishment of a Viral Reservoir: Two Case Reports. Journal of Infectious Disease and Therapy. January 9, 2016 (early online publication).
Fox J, H Alexander, M Brady, et al. Pre-exposure prophylaxis fails to prevent HIV-1 infection or the establishment of a significant viral reservoir. 21st Annual Conference of the British HIV Association. Brighton, April 21-24, 2015. Abstract P10.
D Donnell, JM Baeten, NN Bumpus, et al. HIV Protective Efficacy and Correlates of Tenofovir Blood Concentrations in a Clinical Trial of PrEP for HIV Prevention. JAIDS 66(3):340-348. July 1, 2014.