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17 March 2019, 09:45
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TAF as PrEP: is efficiency a matter of form?

TAF as PrEP: is efficiency a matter of form? - picture 1

Two studies of experimental schemes for pre-exposure prophylaxis of HIV infection (PrEP) using the drug tenofovir alafenamide (TAF) immediately confirmed the effectiveness of the therapy, but yielded conflicting results. According to experts who presented data at the Conference on Retroviruses and Opportunistic Infections (CROI), such discrepancies may be related to the TAF absorption profile in body tissues.

TAF is a prodrug of tenofovir, which has a higher absorption rate and therefore has significantly lower levels in the blood and body fluids than the previously patented tenofovir disoproxyl fumarate (TDF). This is an absolute plus for people taking tenofovir as part of antiretroviral therapy (ART) for HIV infection, since a similar concentration profile means that it causes less toxicity to the body (in particular, to the kidneys) and loss of minerals by bone tissue.

During the conference last week, it also became known that TAF is not inferior to TDF and like PrEP in combination with emtricitabine, and is actively used by gay and bisexual men.

However, to date, none of the studies of TAF as a means of PrEP among women has not yielded results. That is why it was extremely interesting to know what two studies of the drug used in the primates group as a means for pre-exposure prophylaxis of modified SHIV will show.

The most recent PrEP product was a mini-suppository containing TAF and elvitegravir (EVG). This insert does not differ in size from conventional ARV tablets.

The author of the study, Dr. Charles Dobard of the Centers for Disease Control and Prevention (CDC) of the United States, explained that the composition, made in the form of a suppository, has a number of advantages: it has low systemic absorption and minimal toxicity, it is also easy to transport and is always ready to use.

A similar technology, but containing non-HIV preventive substances, carrageenan and griffithin (to fight the herpes simplex virus 2 and HPV) was presented at the R4P conference last year.

The rationale presented for combining TAF and elvitegravir was that the two drugs act at different stages of the HIV life cycle and therefore can provide good protection both as PrEP and as PEP (postexposure prophylaxis).

Speaking about this, experts also noted that when taking elvitegravir orally, it requires strengthening with a cobicistat or ritonavir, while when used locally, the drug does not need stimulants and demonstrates a higher efficiency profile.

Charles Dobard presented the results of studies to determine the optimal dosage and demonstrated that a suppository containing 20 mg TAF and 16 mg EVG gives the best levels of tissue concentration. This study also showed that during the analysis the composition was practically not determined in the plasma, which means that both substances were absorbed directly in the tissues of the mucous membrane with slight systemic absorption.

Suppositories were administered vaginally to six female rhesus monkeys four hours before infection with the modified monkey immunodeficiency virus (SHIV). Observations were carried out weekly for 13 weeks. Eight monkeys also received a placebo and passed the same weekly tests.

Seven of the eight placebo monkeys were infected (87.5%) in the first four weeks. At the same time, only one of the six treated with TAF / EVG suppository was diagnosed with SHIV infection in the ninth week (16.7%). This amounted to 92% effectiveness in the prevention of the virus.

According to Dobard, it turned out to be comparable to the effectiveness of using 1% tenofovir gel as a microbicide.

Currently, studies are ongoing to determine the effectiveness of the suppository at a different dosage administered to the patient 24 hours before contact or as PEP 4 hours after exposure.

Oral TAF as PrEP

Despite the relatively high rates demonstrated by TAF as a prophylactic in the form of a rectal suppository combination, the results of another study, which evaluated the effectiveness of the drug when taken orally, were much less encouraging.

Dr. Ivana Massoud of the CDC said that TAF, in contrast to the data obtained on primates with vaginal administration, showed mixed results here.

While it has proven itself in combination with emtricitabine as a daily PrEP therapy, in more stringent tests designed to test for the possibility of other dosages, oral TAF has not shown the required effectiveness in any study using a low dose to prevent mother-to-child transmission. nor in a study testing the duration of TAF concentration retention.

The Massoud group, in addition to these tests, also examined the limits of effective 

TAF, periodically introducing it as a single drug PrEP.

For this, nine macaques were administered a dose of the drug orally 24 hours before the exposure of the virus to the vagina, and then another dose, but two hours later. This was repeated once a week until infection, or until 15 weeks. Further, the results obtained were compared with data from six monkeys receiving placebo tablets, as well as with 15 individuals from the control group.

During the experiments, it was found that two of the seven monkeys that were given TAF, it was poorly absorbed. Intracellular levels of tenofovir diphosphate (TFV-DP), a metabolized version of tenofovir, averaged 15 femtomols per million blood lymphocytes, compared with 341 fm / 106 cells in the remaining six. Extreme individuals were excluded from the analysis, however, experts faced the question of the possibly low bioavailability of the drug.

Three of the seven other monkeys given oral TAF were infected: two for 3 weeks, and one for 9. Under the same conditions, the virus was detected in 19 of the 21 control individuals who received a placebo.

This meant that the average efficiency indicator was 73%, that is, it was statistically significant (p = 0.036) in comparison with the two control groups, but did not show the required result (p = 0.194) in real time. This deviation was associated with a low bioavailability of the drug.

A study of drug dosages demonstrated that intracellular TFV-DP levels were almost the same in infected and uninfected primates at 351 and 331 fm / 106 cells, respectively. This indicates that the regimen prescribed by the animals brought the concentration of the drug closer to the acceptable level.

According to experts, one of the possible reasons for changes in the effectiveness of TAF when used as PrEP may be that during sexual intercourse, the fight against HIV in the cells on the surface of the vagina and intestines can be much more important than the traditional intracellular work of ART.

This position is confirmed by the results of a study conducted by a group of microbiologists from the University of Nebraska.

Dr. Courtney Fletcher and her colleagues performed a direct comparison of TAF levels in the tissues of several HIV-positive patients receiving treatment and taking standard doses of TAF or TDF.

Based on the analysis, it was found that among those taking TAF, tenofovir levels were 7.9 times higher in leukocytes (lymphocytes) and 6.2 times higher in lymph node lymphocytes than in patients taking TDF. Levels of the agent in the lymph nodes are especially important because they are the main areas of HIV replication, which at the same time are poorly absorbed by ART.

On the other hand, in lymphocytes covering the mucous membranes of the small and rectum, TDF levels were higher than TAF levels by 37 and 9.4 times, respectively.

This was probably due to a lower level of bioavailability of TDF and meant that there was more drug left in the intestines, and this could be a serious advantage of the drug when used as PrEP.

Author: Ivan Shangin

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