TreatmentUpdate
214

March/April 2016 

TAF + FTC—virus risk reduced in monkeys, but what about people?

The current formulation of tenofovir (sold as Viread) is often an important part of combination HIV prevention and treatment. Tenofovir is also found in several fixed-dose combinations such as the following:

  • Truvada – tenofovir + FTC
  • Stribild – elvitegravir + cobicistat + tenofovir + FTC
  • Complera – rilpivirine + tenofovir + FTC

Tenofovir-containing medicines can cause side effects, particularly in some HIV-positive people who use it. These tenofovir-related side effects can include the development of thinning bones, a possible increased risk for fractures (as reported earlier in this issue of TreatmentUpdate), and kidney dysfunction. The original formulation of tenofovir is called TDF (tenofovir disoproxil fumarate).

A new formulation of tenofovir has been developed and is called TAF (tenofovir alafenamide). The pharmaceutical company that developed TDF is gradually releasing fixed-dose combinations containing TAF. The first TAF-containing combination that was approved in Canada and other high-income countries was Genvoya, which is similar to Stribild except instead of TDF it contains TAF. In clinical trials, TAF appears to be much safer than TDF.

What about PrEP?

Truvada has been approved in Canada, the U.S. and some other countries for reducing the risk of HIV infection as part of a package of prevention measures. A major question is: Will the new version of Truvada, which will contain TAF + FTC, be as effective in reducing the risk of HIV infection?

Unlike TDF, TAF does not accumulate in the blood but is taken up by cells of the immune system. These cells are targets for HIV, so, in theory, if these cells contain TAF (and FTC) they may be protected from HIV infection.

TDF was first tested in monkeys in the mid-1990s and was found to reduce their risk for becoming infected with SIV (simian immunodeficiency virus), which can cause an AIDS-like disease in susceptible monkeys. Experiments with monkeys were used to successfully guide the development of Truvada as PrEP. Now these same experiments with monkeys are being replicated with TAF + FTC.

The U.S. Centers for Disease Control and Prevention (CDC) has released data from experiments with monkeys exposed to low concentrations of the hybrid immune deficiency virus SHIV in the rectum. In these experiments, the monkeys were given either the combination of TAF + FTC (six animals) or placebo (six animals). These interventions (drugs and placebo) were given orally, 24 hours prior to being exposed to SHIV. Two hours after the monkeys were exposed to this virus, they were given another dose of TAF + FTC or placebo.

This schedule of dosing and virus exposure was done once weekly for a total of 19 weeks. However, after the first five weeks (and five exposures to the virus), the researchers put the trial on hold because they found that the animals that were given placebo were not becoming infected at the rate they expected (only two animals on placebo became infected). So the researchers rested the animals for a further five weeks during which time they did not receive drugs, placebo and virus. After this period the trial resumed and the animals received 14 more exposures to SHIV over 14 weeks.

Throughout the study the animals underwent weekly testing of their blood samples to check for possible infection. These tests included detection of any antibodies to the virus as well as tests that sought to find genetic material from SHIV. In addition, technicians assessed cells of the immune system from the animals for the concentration of TAF and FTC.

Key results

Over the course of the study, all the placebo-treated animals became infected, while none of the animals treated with TAF + FTC became infected.

Caution needed

In presenting this research at the 2016 Conference on Retroviruses and Opportunistic Infections (CROI), the CDC researcher made the following statement:

“…while these data show that [TAF + FTC] protects [monkeys] against rectal SHIV infections, it should not be used in humans as a PrEP agent until clinical studies are complete and it is approved [by regulatory agencies] for PrEP.”

Other experiments with women have found that TAF compared to TDF (both drugs given orally) results in about two to 10-fold lower concentrations of tenofovir in the vaginal and rectal tissues over 48 hours. What this will mean for protection from HIV is not clear. That is why it is important to wait for the results from a proposed clinical trial of TAF + FTC as PrEP.

Gilead Sciences is in discussion with the U.S. drug regulatory agency the Food and Drug Administration (FDA) about the clinical trial design(s) necessary to show that TAF + FTC can provide protection from HIV infection in people.

—Sean R. Hosein

REFERENCES:

  1. Tsai CC, Follis KE, Sabo A, et al. Prevention of SIV infection in macaques by (R)-9-(2-phosphonylmethoxypropyl) adenine. Science. 1995 Nov 17;270(5239):1197-9.
  2. Massud I, Mitchell J, Babusis D, et al. Chemoprophylaxis with oral FTC/TAF protects macaques from rectal SHIV infection. Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, MA. Abstract 107.
  3. Garrett KL, Cottrell ML, Prince HA, et al. Concentrations of TFV and TFVdp in female mucosal tissues after a single dose of TAF. Conference on Retroviruses and Opportunistic Infections, 22-25 February 2016, Boston, MA. Abstract 102 LB.

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