A report originally presented to the 2015 BHIVA conference
last year details two cases where therapeutic levels of solo tenofovir 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. Solo tenofovir has been tested as PrEP in two
major studies , Partners PrEP and the Bangkok Tenofovir Study, with moderate to good results, and it has been assumed on the basis of solo animal studies that tenofovir might be enough the prevent HIV, though results have been mixed.
No unequivocal case of the failure of Truvada (tenofovir + emtricitabine) has yet been reported, but the cases raise a number of interesting questions: whether the levels
of tenofovir required to prevent infection need to be higher than those used for
treatment; whether hepatitis B co-infection may have made HIV infection more
likely; whether the men would have been infected if they had been taking
tenofovir + emtricitabine (Truvada);
and if not, what are the exact contributions to prevention of the two drugs.
The men were not taking tenofovir specifically as
pre-exposure prophylaxis (PrEP) but instead were taking it as treatment for
chronic hepatitis B infection. One had had persistent hepatitis B infection for
six years and had been on tenofovir for four years; the other had had hepatitis
B for seven years and had taken tenofovir for three years.
In the case of the first patient (patient A), the date of
HIV infection can be pinpointed almost exactly as he tested HIV-antibody positive
only twelve days after a confirmatory HIV 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 one day after his HIV-negative test result.
Six days later, he reported mild flu-like symptoms suggestive of HIV seroconversion
illness and was tested again.
The second patient (patient B) had not had a recent negative
HIV test but was hospitalised 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 two weeks previous 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 nanograms per
millilitre of blood (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. (The IC95 of tenofovir, which is the amount of drug in the blood sufficient to reduce HIV replication by 95%, is 6.8 to 35 ng/ml.)
Patient B had taken tenofovir seven hours before his HIV test result
and had a blood level of 230 ng/ml, or higher than 75% of the average patients,
seven hours after a dose. Both results indicate that their absorption of
tenofovir was normal.
Both patients had CD4 cells counts of 550-600 cells/mm3
– notably lower than typical CD4 counts seen in HIV-negative people – and 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 the tenofovir, both patients had suffered
significant immune damage during acute HIV infection – as usually happens.
The biggest difference between the two patients was that in
patient A the tenofovir, despite not preventing HIV infection, did seem to be
suppressing his HIV viral load in the blood. Although testing HIV-positive
and having HIV integrated into his cell (see below) at no point did he have
a viral load over 50 copies/ml. This ‘blunting’ of the 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
could not be tested to see if it had acquired, or already had, drug resistance
to tenofovir. This patient was switched 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 high for 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, patient B was put on to an intensified three-class antiretroviral regimen
of Truvada (tenofovir/emtricitabine),
boosted darunavir and raltegravir, 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 an ongoing, productive infection in
both patients and indeed transcribed RNA, evidence that cells were actively
producing new HIV viral particles, was found in both patients, though at
one-tenth the level in patients A as 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 randomised studies of PrEP, Partners PrEP,
there were six cases of HIV infection (Donnell) in people who, at the visit
they were diagnosed with HIV, had tenofovir levels consistent with daily dosing
(two of these were also taking emtricitabine). However in all cases but one,
the participants could have caught HIV at any time in the previous three months
since their last visit, so may not have been taking PrEP at the actual time
they were infected. In one case, the participant had a level of tenofovir consistent
with daily dosing one 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 hypothesise that
hepatitis B infection could increase susceptibility to HIV, even where it
appears largely suppressed virologically. It may also cast further doubt over
the use of solo tenofovir as PrEP in any patient, 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’ are due to people not actually
taking PrEP: the fact that these two cases have been reported underlines that
HIV infection in situations where it looks like people have been taking PrEP
consistently is extremely rare.