Long-awaited results from a three-year PrEP clinical trial evaluating a new candidate medication for PrEP were revealed at the HIV science conference CROI on March 6, 2019. The PrEP medication tested in the trial was FTC/TAF, sometimes referred to as F/TAF (brand name Descovy). F/TAF is an HIV antiretroviral medication that was approved by the FDA for treatment of HIV in 2016.
Truvada (emtricitabine/tenofovir disoproxil fumarate, or F/TDF) is presently the only medication approved by the Food and Drug Administration (FDA) in the U.S. for use as pre-exposure prophylaxis (PrEP). F/TAF contains a newer formulation of one of the drugs in Truvada: tenofovir alafenamide fumarate (TAF) replaces tenofovir disoproxil fumarate (TDF). Both medications contain FTC or emtricitabine.
In the DISCOVER study, 5,387 cisgender men who have sex with men and trans women who have sex with men were randomized to receive either F/TDF (Truvada) or F/TAF (Descovy) for daily oral PrEP. People enrolled in the study were considered “high risk” for HIV, with two or more instances of condomless anal sex in the previous 12 weeks or rectal gonorrhea, chlamydia or syphilis in the previous 24 weeks.
F/TAF is “non-inferior” to F/TDF
Preliminary results from the trial showed that like F/TDF (Truvada), F/TAF was effective in preventing HIV infections among study participants, according to Brad Hare, MD, an HIV specialist at Kaiser Permanente who presented the results of the study.
The study met rigorous criteria (called “non-inferiority” criteria) for proving that F/TAF is effective in preventing HIV, and that F/TAF is as effective as F/TDF in preventing HIV infection. The rate of new infections in the study was 0.16 (per 100 persons observed for one year) in the F/TAF arm and 0.34 in the F/TDF arm.
Although not statistically superior, F/TAF demonstrates a 53% numerical improvement in protection when compared to F/TDF,” said Hare.
Importantly, HIV transmission rates in both groups were much lower than would be expected if no PrEP had been provided. Cohorts matched for reported sexual behavior and sexually transmitted infections would be expected to have HIV transmission rates over 4.0, or more than 10 times higher.“
A total of 22 individuals in the study became infected with HIV (7 in the F/TAF arm and 15 in the F/TDF arm) over 8,756 person-years of follow-up. No trans women were infected with HIV during the study.
Five infections (one in the F/TAF arm and four in the F/TDF arm) are believed by study physicians to have been present at baseline, before study participants started taking PrEP.
Five people in the F/TAF arm and 10 people in the F/TDF arm had low or undetectable drug levels in dried blood spot analysis. Two people (one person taking F/TAF and one person taking F/TDF) were diagnosed with drug levels felt to be adequate for protection, said Hare.
Less likelihood of bone density and kidney function changes with F/TAF
Descovy was safe and well-tolerated by participants, and people taking F/TAF experienced adverse events at the same very low rate as in previous safety studies. Markers of bone and kidney health were slightly improved with F/TAF compared to F/TDF.
A subset of 383 study participants had changes in bone mineral density of the spine and hip measured with DEXA scans. On average, those on F/TAF showed slight increase in bone density, and those on F/TDF showing an approximate 1% decline in bone density over 48 weeks. This difference was found to be statistically significant.
There were also small but highly statistically significant differences in estimates of kidney function, similar to what has been observed in studies of F/TAF and F/TDF for HIV treatment.
Sexually transmitted infections
A substantial number of participants had sexually transmitted infections (STIs) when they started the study, and continued to experience high rates of gonorrhea, chlamydia and syphilis during the study.
During the study, the incidence rate for gonorrhea (at any anatomical site) was 47.1 among participants taking F/TAF and 45.3 among participants taking F/TDF. The rate of chlamydia incidence was 41.9 (F/TAF) and 41.6 (F/TDF), and the rate of syphilis was 10.3 (F/TAF) and 9.5 (F/TDF).
PrEP programs continue to be an important way to diagnose and treat STIs and thereby break chains of transmission.
Implications for F/TAF as PrEP
Before F/TAF can be widely used and prescribed, the positive results from the DISCOVER study still need to be formally reviewed by the FDA before a formal indication for PrEP is added to the medication’s label. Additional reviews will also be needed from the scientific and medical community and the CDC, which are responsible for issuing recommendations for use to clinicians. The communities of gay and bisexual men and transgender women will also need to consider these findings, and provide guidance regarding how this new option fits in to our work to end HIV transmission.
Some clinicians may rely of the data to begin prescribing F/TAF for particular persons for whom Truvada is not a suitable option, on a case-by-case, or “off-label” basis. Such off-label prescribing is common in U.S. medical practice, and is employed by healthcare providers based on their actual clinical experience and with reasonable knowledge that doing so will be safe and effective.
For instance, those with demonstrated renal (kidney) dysfunction may be able to use F/TAF successfully, because the drug is delivered at lower levels that lead to relatively decreased peripheral blood levels compared to Truvada, and as such renal dysfunction is less likely. Additionally, F/TAF causes less loss of bone mineral density for long-term users of the drug. While the bone changes observed with F/TDF have been small, non-progressive and reversible, there may be persons with known bone disease (called osteoporosis) who will prefer F/TAF to the current standard of F/TDF.
“Options for HIV prevention should be as diverse as our sexuality, said Robert Grant, MD, PrEP research pioneer and one of DISCOVER study’s lead investigators. “We have Truvada-based PrEP, which is safe and effective, and is driving HIV transmission down everywhere it is used. The news from our study this week is so important and we look forward to a thorough review of the evidence by the FDA, scientists, and the community.”
There are important limitations to this study. No cis-gender women were enrolled, so there is no information available about F/TAF efficacy or safety for cis women. F/TDF or Truvada remains a safe and effective PrEP strategy for cis women or trans men who have vaginal or front hole intercourse. Another limitation is that F/TAF was only offered for daily dosing. It remains unclear whether F/TAF can be used for PrEP 2-1-1 or sex event-driven dosing. Further evaluation is underway, and for now, it is not recommended.
Those taking or considering PrEP may wonder if F/TAF might be an option for PrEP before it is approved by the FDA. While it is important to wait for regulatory review of DISCOVER trial results and other available data, based on these preliminary data, F/TAF may have a limited role in helping some people avoid HIV infection—if Truvada is not preferred, not available, or contraindicated due to known renal or bone-loss conditions, among other reasons.
Having additional options for biomedical HIV prevention services gives community members more options for solutions that fit in their lives. New drug candidates for PrEP are made available when they are known to be safe and effective. In addition to F/TAF (Descovy), the integrase inhibitor cabotegravir is now being evaluated in a study in which it is delivered by injection every 8 weeks. This injection is in lieu of a pill that people take orally, and preliminary results are expected in one to two years. San Francisco AIDS Foundation is evaluating PrEP 2-1-1 for those who seek an alternative to daily dosing, and is improving the experience of interim STI/HIV testing for PrEP users.
Hare, C. The Phase 3 DISCOVER Study: Daily F/TAF or F/TDF for HIV Pre-exposure Prophylaxis. CROI 2019, Abstact 104.
San Francisco AIDS Foundation (SFAF) has the largest PrEP program in the San Francisco Bay Area and has pioneered many key innovations, including nurse leadership, same-day PrEP starts, express testing for STIs while on PrEP, and most recently, use of Truvada on an intermittent dosing basis (PrEP 2-1-1) for those having anal sex. With this commitment to innovation and assessing public health impact, SFAF also served as one of the largest study sites for the DISCOVER trial evaluating F/TAF for PrEP.
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