An updated formulation of tenofovir that is easier on the kidneys and bones may soon offer a new option for pre-exposure prophylaxis (PrEP) for men who have sex with men, according to findings from the DISCOVER study presented this week at the 2019 Conference on Retroviruses and Opportunistic Infections (CROI) in Seattle.

The Descovy combination pill, containing tenofovir alafenamide (TAF) and emtricitabine, was shown to work as well as the widely used Truvada pill containing tenofovir disiproxil fumarate (TDF) and emtricitabine for HIV prevention in a study of mostly gay ad bisexual men. People who used daily Descovy had smaller changes in kidney biomarkers and slightly less bone loss. But many experts emphasize that Truvada is safe and effective for most people taking PrEP.

“The very low incidence of HIV in both treatment arms, combined with Descovy’s improved renal and bone safety as compared with Truvada, demonstrate that Descovy for PrEP may help build on the progress made by Truvada, a proven public health tool in the fight against HIV,” lead researcher Bradley Hare, MD, of Kaiser Permanente San Francisco said in a press release from Gilead Sciences, which makes both pills.

Truvada dramatically reduces the risk of acquiring HIV through sex if used consistently. The TDF in Truvada is generally considered safe and well tolerated, but it can cause kidney problems and bone loss in susceptible individuals who take it as part of combination antiretroviral therapy for HIV treatment. To date, studies have not seen notable kidney or bone problems in people taking Truvada for PrEP.

TAF is a pro-drug formulation that produces high levels of the active drug, known as tenofovir diphosphate, in HIV-prone cells. This means it can be given in smaller doses, leading to lower drug levels in the blood and less exposure for the kidneys, bones and other organs.

The Phase III DISCOVER trial evaluated whether Descovy would work as well as Truvada for HIV prevention but with fewer side effects.

This large study enrolled more than 5,300 mostly gay and bi men in the United States (about two thirds), Canada, Australia and Europe. The study also enrolled a small number of transgender women (less than 2 percent). The median age of the participants was 34, ranging from 18 to 79.

More than 80 percent of participants were white, about 25 percent were Latino, 9 percent were Black and about 5 percent were Asian. This does not reflect the distribution of HIV incidence in the United States: African Americans make up about 12 percent of the population but account for 43 percent of new HIV infections, according to the Centers for Disease Control and Prevention (CDC).

Eligible participants were at high risk for HIV, having had condomless anal sex two or more times in the past three months or been diagnosed with a sexually transmitted infection (STI) during the past six months. They also had to have normal kidney function and could not have hepatitis B virus (tenofovir is active against HBV as well as HIV). About 70 percent reported recreational drug use, and nearly 17 percent were already on Truvada for PrEP at the start of the study.

Half of the participants were randomly assigned to take Descovy, and the rest took Truvada—both one pill daily—for 96 weeks. Every three months they received HIV and STI testing, monitoring for kidney and bone health, a questionnaire about risk behavior, adherence and risk reduction counseling and other prevention services.

Participants were enrolled between September 2016 and May 2017. Hare presented results from the primary analysis, done after all the participants had reached the 48-week mark and half had reached 96 weeks. At that point, over 80 percent in both groups were still taking Descovy or Truvada.

During follow-up, there were seven new infections in the Descovy group and 15 in the Truvada group, giving incidence rates of 0.16 and 0.34 per 100 person years. This means that if 100 people were followed for a year, less than one new infection would be expected using either PrEP pill. Given the small number of infections, the study does not have the statistical power to show whether Descovy works better than Truvada—but it can show that it is noninferior, or at least as good.

Among the people who became HIV positive, five were suspected of having already had undetected infection at study entry and 15 were found to have low tenofovir levels in dried blood spots, a method used to gauge adherence. None were resistant to tenofovir, but four showed resistance to emtricitabine.

STIs, including gonorrhea, chlamydia and syphilis, were common in both groups (about 46 percent, 41 percent and 10 percent, respectively).

Descovy and Truvada were generally safe and well tolerated. About 20 percent in both groups reported drug-related side effects, but these were usually mild or moderate; less than 1 percent had drug-related serious adverse events. Just 1 percent of Descovy recipients and 2 percent of Truvada recipients stopped treatment because of adverse events.

Looking more closely at kidney safety, estimated glomerular filtration rate (eGFR) and other markers were more favorable in the Descovy arm compared with the Truvada arm. Similarly, bone mineral density at the spine and hip rose slightly in the Descovy arm while declining a bit in the Truvada arm.

While these differences were statistically significant—meaning they probably aren’t attributable to chance alone—it’s not clear whether they predict clinical outcomes such as kidney failure or bone fractures. There was one case of Fanconi syndrome (a type of kidney impairment) in the Truvada arm and none in the Descovy arm. Two people taking Descovy and six taking Truvada stopped PrEP because of kidney problems.

Based on these findings, the researchers concluded that Descovy “is an effective and safer option for PrEP” for gay and bi men and trans women.

Hare said Descovy may be a better PrEP alternative for people at risk for kidney problems, which increase with age. “Some of those folks are either taking Truvada and keeping their fingers crossed or have not been on PrEP,” he told POZ. “I think for people that have moderately impaired renal function, TAF is probably a slam dunk.”

This was the first study to compare a new HIV prevention method against an existing effective method instead of a placebo or nothing, and it had the lowest number of new infections ever seen in a major prevention trial, Sharon Hiller, PhD, of the University of Pittsburgh School of Medicine, noted at a CROI press conference.

However, as an approximate comparison, the researchers used CDC surveillance data on the rate of new infections among at-risk gay men in some of the same cities as the DISCOVER study sites, finding it was many times higher.

Having multiple safe and effective prevention options to choose from is not a problem, but it does raise concerns about how prevention trials will be conducted in the PrEP era. When comparing two interventions that are highly effective, there may be too few infections in either group to show that one is significantly better. Seeing a real difference would require a large number of study participants followed for a long time—maybe too large and too long to be practical in the real world.

Plus, some advocates question whether it’s worth putting resources into trials to approve prevention tools that are similar to what we already have. Others are concerned about the individual and public health costs of Descovy, pointing out that the patent on Truvada will expire in a couple years, likely paving the way for cheaper generic versions.

“Count me as profoundly unexcited about a second safe and effective daily pill for HIV prevention,” longtime HIV prevention advocate Jim Pickett of the AIDS Foundation of Chicago told POZ. “We’ve had one since 2012—another is not needed. What we do need are other types of prevention products, such as rectal douches, long-acting injectables, fast-dissolving inserts and implants.” Pickett also noted that it’s “deeply problematic to recruit mostly white gay men into a huge prevention trial when the majority of the epidemic’s impact is on the shoulders of black gay men and trans women.”

Click here to read the CROI study abstract.

Click here to learn more about PrEP.