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19 март 2019, 12:49

Descovy is not inferior to Truvada as a daily PrEP

Descovy is not inferior to Truvada as a daily PrEP - slika 1

Descovy's daily supplement, which contains a newer version of tenofovir combined with emtricitabine, has a comparable protective effect with the traditional regimen of pre-exposure prophylaxis of HIV infection, including tenofovir and emtricitabine (Truvada), said Dr. Brad Hare from Kaiser Permanente Medical Center (San Francisco, USA) at the Seattle Retrovirus and Opportunistic Infections Conference (CROI 2019). As expected, the new composition showed better results in terms of bone and kidney safety.

The only drug currently registered for Truvada’s Daily HIV Prevention (PrEP), which is a combination of tenofovir disoproxyl fumarate (TDF) and emtricitabine, may soon be faced with a “competitor”. Tenofovir alafenamide (TAF) is highly effective and generally well tolerated. An exception are people with impaired renal and bone function.

The drug reaches high concentrations in the tissues, but not in the blood: here it is 90% less than TDF, and this can seriously reduce the risk of problems with bones and kidneys. TAF has already been registered as a component in several combination ARTs, including dual therapy with TAF + emtricitabine (Descovy).

Gilead Sciences TDF / emtricitabine has been available for a long time both in the markets of highly developed countries and in countries with middle and low income levels. But despite the fact that Descovy is a relatively new product that is patented in the US and the EU, for many countries TAF has been licensed for the Patent Pool of Medicines, so inexpensive generic products will be available there.

In the treatment of HIV infection, TAF-based regimens have comparatively high rates of viral suppression and show a higher level of safety for the kidneys and bone tissue compared with TDF-based combinations. However, the efficacy and safety of TAF-based PrEP has not yet been studied.

Dr. Har presented the results of a DISCOVER Phase 3 randomized controlled trial to evaluate the efficacy and safety of TAF / emtricitabine as PrEP among men who have sex with men (MSM) and transgender women at risk of HIV infection.

All participants were randomly divided into groups (1: 1) according to the principle of daily intake of the TAF / emtricitabine or TDF / emtricitabine regimen.

During the study, every 12 weeks, all participants received counseling on adherence and risk reduction, were tested for HIV and screened for STIs.

For 9 months from September 2016 to May 2017, 5387 people from 11 countries of North America (67%) and Europe (34%) took part in the work. Most of them were white (84%), the average age was 34 years. 74 participants were transgender. At the time of registration, 16% of volunteers were already taking TDF / emtricitabine as PrEP.

12 weeks before the start of the study, the average number of acts of anal sex without a condom was 3.5. During the trial, the trend did not change, and 57% of participants had STIs.

The primary endpoint of the study was the incidence of HIV, the first assessment of the indicator was carried out after 48 weeks of the study. In January 2019, the total observation time was 8,756 person-years.

During this time, 22 cases of HIV infection were recorded. Fifteen of them were apparently associated with low or minimal commitment. Five were caused by an infection that was transmitted to participants just before the start of the study. Two more people became infected, despite the “established” regimen of drugs.

Resistance testing revealed four cases in relation to emtricitabine, but all of them were associated with infections that were detected immediately before the study. Those who became infected with HIV during follow-up were younger than the participants, and more often had rectal STIs.

Seven infections occurred in the TAF group and 15 in the TDF group. According to experts, the incidence was 0.16% per year in the TAF group and 0.34% per year in the TDF group.

Adverse events associated with the study drugs were reported in 20 and 23% in the TAF and TDF groups. Serious adverse events associated with the studied drugs were reported in only 0.1% and 0.2%, respectively. These differences were not statistically significant.

At the same time, from the point of view of kidney safety, by week 48, the average change in glomerular filtration rate showed an increase of 1.8 ml / min in the TAF group and a decrease of 2.3 ml / min in the TDF group. These changes were small but statistically significant. Markers of proximal renal tubule damage also favored the TAF group. Eight participants discontinued due to kidney problems (two in the TAF group and six in the TDF group, there is no statistically significant difference).

The bone mineral density was evaluated as part of an additional and 

investigations with 383 participants. At week 48, those in the TAF group had an average increase of 0.5% in the spine and 0.18% in the hip. For those taking TDF, the average decrease was 1.12% on the spine and 0.99% on the hip.

These small changes in renal and bone biomarkers may not be clinically significant. At a press conference, Dr. Hare said that in order for the study to show the difference in clinical events (such as kidney disease or fractures), it must be several times larger than this and last much longer.

Given all of the above, the incidence rate of TAF / emtricitabine compared with TDF / emtricitabine was 0.47 (95% confidence interval 0.19-1.15), which indicates that there were fewer infections with TAF than with TDF, but the difference between them was not statistically significant - this could happen by chance, and to some extent this was due to a higher number of initial infections in people taking TDF. This means that TAF has demonstrated that it is not inferior to TDF in HIV prevention, but not superior to it.

Since the DISCOVER study did not have a control group that received only placebo, these figures are difficult to compare with what would happen if no preventive interventions were proposed. As an example of a control group, experts suggested taking into account surveillance data in those areas covered by the DISCOVER study.

In these areas, in 2016, the incidence of HIV among MSM not taking PrEP was 4.02%, in contrast to 0.08% in the TAF study group for this region and 0.45% in the TDF study group.

However, during the discussion that concluded with the speaker, Dr. Kevin de Kock of the United States Centers for Disease Control and Prevention noted that background incidence rates were not adjusted for the racial profile of DISCOVER participants (which was predominantly white). If this were the case, the background incidence would be lower.

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