US FDA approves TAF-based PrEP for many people at risk for HIV

The US Food and Drug Administration (FDA) last week approved tenofovir alafenamide/emtricitabine (brand name Descovy), a combination pill containing an updated version of tenofovir, as a second pre-exposure prophylaxis (PrEP) option for many people. However, the indication does not include those at risk of acquiring HIV through vaginal sex.

The tenofovir alafenamide (TAF) in Descovy produces higher levels of the active drug in HIV-susceptible immune cells than the tenofovir disoproxil fumarate (TDF) in the only previously approved PrEP regimen, TDF/emtricitabine, which is marketed as Truvada and increasingly available as non-branded generics. This means TAF can be given at lower doses, resulting in less drug exposure for the kidneys, bones, and other organs. Both Descovy and Truvada are manufactured by Gilead Sciences.

TAF/emtricitabine was approved for adults and adolescents weighing at least 35kg who are at risk for sexually acquired HIV, with the exception of people at risk from receptive vaginal sex. In effect, this means it is indicated for cisgender (non-trans) men who have insertive anal or vaginal sex, as well as for cisgender or transgender men and women who have receptive anal sex. But the indication does not extend to cisgender women and trans men who have receptive vaginal sex (sometimes called frontal sex).

Glossary

transgender

An umbrella term for people whose gender identity and/or gender expression differs from the sex they were assigned at birth.

Food and Drug Administration (FDA)

Regulatory agency that evaluates and approves medicines and medical devices for safety and efficacy in the United States. The FDA regulates over-the-counter and prescription drugs, including generic drugs. The European Medicines Agency performs a similar role in the European Union.

receptive

Receptive anal intercourse refers to the act of being penetrated during anal intercourse. The receptive partner is the ‘bottom’.

generic

In relation to medicines, a drug manufactured and sold without a brand name, in situations where the original manufacturer’s patent has expired or is not enforced. Generic drugs contain the same active ingredients as branded drugs, and have comparable strength, safety, efficacy and quality.

oral

Refers to the mouth, for example a medicine taken by mouth.

An FDA advisory panel voted at an August hearing to recommend approval of TAF/emtricitabine PrEP for men who have sex with men and for trans women, but not for cisgender women due to a lack of evidence from clinical trials. In the end, the agency based the indication on type of sexual activity rather than sexual orientation or gender identity. TDF/emtricitabine PrEP has no such limitations.

TAF/emtricitabine for HIV prevention should only be prescribed for people who are confirmed to be HIV negative immediately prior to starting PrEP. People who already have HIV must take TAF/emtricitabine as part of a complete antiretroviral treatment regimen, as using it alone could lead to drug resistance.

TAF/emtricitabine is active against hepatitis B virus as well as HIV. For this reason, people who have HIV and hepatitis B co-infection should be monitored closely when they stop taking PrEP, as this could lead to worsening liver disease.

Approval of TAF/emtricitabine PrEP was based on findings from the DISCOVER trial, which enrolled more than 5300 at-risk men who have sex with men and a small number of trans women, but excluded cisgender women and trans men. They were randomly assigned to take TAF/emtricitabine or TDF/emtricitabine once daily for two years.

As reported at this year's Conference on Retroviruses and Opportunistic Infections, both prevention pills proved highly effective. After one to two years of follow-up, there were seven new HIV infections in the TAF/emtricitabine arm and 15 in the TDF/emtricitabine arm, yielding incidence rates of 0.16 and 0.34 per 100 person-years, respectively. Among those who seroconverted, 15 cases were apparently due to low adherence, while five people were thought to already have had undetected HIV acquired shortly before they started the study.

Given the small number of infections in both groups, the difference in the incidence rates was not statistically significant, meaning it could have happened by chance. Thus, the researchers concluded that TAF/emtricitabine is noninferior to TDF/emtricitabine, meaning they considered it equally effective.

As described at the International AIDS Society Conference this summer, some researchers have suggested that the lower seroconversion rate in the TAF/emtricitabine group reflects a real difference in efficacy. This may be attributable to the fact that TAF leads to higher drug levels in cells, which are reached more quickly and persist longer compared with TDF. This added 'forgiveness' could potentially be important for gay and bisexual men who struggle with adherence to daily PrEP and those using on-demand or intermittent PrEP before and after sex. (Neither TAF/emtricitabine nor TDF/emtricitabine has been approved for intermittent dosing, and this regimen is not recommended for cisgender women.)

Given their exclusion from DISCOVER, the effectiveness of TAF/emtricitabine PrEP for people who have vaginal sex has not yet been demonstrated in a clinical trial. Prior research has shown that tenofovir reaches lower levels and does not last as long in vaginal and cervical tissues compared with rectal tissue. Gilead urged the FDA to extrapolate from existing pharmacokinetic data showing that TAF produces adequate drug levels in women, but the agency declined to approve Descovy for this group without more direct evidence.

Some advocates applauded this decision, calling for clinical trials of TAF/emtricitabine in women and trans men, and arguing that approval in the absence of such evidence would set a bad precedent. Others, however, are concerned that women now have fewer oral PrEP options than men. Although most DISCOVER participants were cisgender men who have sex with men, the FDA reviewers nonetheless extended the indication to heterosexual men.

In a 5 October letter to community members, Gilead indicated that the company has agreed with the FDA to conduct a study evaluating Descovy for PrEP in adult and adolescent cisgender women.

Turning to safety, TAF/emtricitabine has less detrimental effects than TDF/emtricitabine on biomarkers of kidney function and bone loss, although it is not clear whether this matters in terms of clinical outcomes like fractures. On the other hand, TAF/emtricitabine has a less favorable effect on blood lipid levels. TAF/emtricitabine could therefore be a preferable option for individuals at risk for kidney or bone problems, while TDF/emtricitabine might be more advisable for those at risk for cardiovascular disease.

However, for the vast majority of people taking PrEP, TAF/emtricitabine and TDF/emtricitabine are likely to be both well tolerated and highly effective. Some advocates contend that for most people, any small improvements in safety or efficacy will not be worth the added cost of Descovy, which is only available as a branded product, compared with generic TDF/emtricitabine.

References

Food and Drug Administration. FDA approves second drug to prevent HIV infection as part of ongoing efforts to end the HIV epidemic. Press release. October 3, 2019.