BOSTON — Margaret Russell, MD, assumed that when the combination of tenofovir alafenamide (TAF) and emtricitabine (Descovy, Gilead Sciences) was approved for HIV prevention by the US Food and Drug Administration (FDA), she and her colleagues would switch most patients using pre-exposure prophylaxis (PrEP) to the new drug. That's what she'd done with Descovy for HIV treatment.

But then she learned — from after-market research and FDA data — that people who used Descovy for PrEP rather than its cousin, the combination of tenofovir disoproxil fumarate (TDF) and emtricitabine (Truvada, Gilead Sciences), had a small but notable increase in statin use.

"I was a little surprised," said Russell, a family physician and HIV provider at a federally qualified health center in Chicago who counsels about three people a week about PrEP. "We had been so focused on the kidney and bone effects of Truvada," she explained, that weight and lipid changes were "not on my radar."

She's not alone. Since its FDA approval last year, about 27% of PrEP prescriptions have been for Descovy, according to Gilead data. The company predicts that 40% to 45% of PrEP users will be on the new pill by the end of 2020.

But those predictions have been met with resistance from clinicians, scientists, and even public health agencies, urging physicians to keep Truvada as their first-line prevention pill for HIV, especially because generic Truvada will be available by the end of the year.

With the Conference on Retroviruses and Opportunistic Infections (CROI) 2020 set to begin virtually on Sunday, Douglas Krakower, MD, from the Beth Israel Deaconess Medical Center and Atrius Health in Boston, said he hopes researchers will address the statin signal when they present the final 96-week findings from the DISCOVER trial of Descovy as PrEP.

"The DISCOVER statin signal needs to be explored further," said Krakower. But more than that, he said he hopes the conference will be a place to talk about taking a more balanced view of the two drugs, their safety profiles, and the trade-offs that accompany each combination.

"There's reflexive thinking by clinicians and the patient communities they serve that Descovy is safer for HIV treatment so it's better for HIV PrEP," he said. But it isn't necessarily better; "there are differences in safety profiles."

This could be a pivotal moment for Gilead and HIV prevention medicines.

The company has been embroiled in a lawsuit with the federal government since activists revealed last year that the US government owns the patent, not the California-based drug giant.

And Facebook removed advertisements last year when activists and researchers pointed out that they overstated negative renal and bone mineral density events related to Truvada, putting people off HIV prevention at a time when the Centers for Disease Control and Prevention estimates that 1.1 million Americans are at high risk for HIV.

And then there's the Descovy marketing push Gilead started after FDA approval, which Rochelle Walensky, MD, chief of infectious diseases at Massachusetts General Hospital in Boston, called a "marketing blitzkrieg."

In just the past 2 weeks, two medical journals she subscribes to "arrived covered in Gilead ads," Walensky reported.

Krakower said that he has received multiple marketing emails from Gilead in support of Descovy for PrEP, as well as "a poster on Descovy to hang on the clinic wall that I did not request" and multiple invitations to Gilead-sponsored dinners on Descovy vs Truvada for PrEP.

"The materials I've received from Gilead have been focused much more on the renal and bone-safety issues, not a balanced approach where they also mention weight and lipid changes," he told Medical Medscape News. "It's not to say that some of the conversations we had haven't gone in to those areas, but that was mostly because I brought them up."

For its part, Gilead said in a statement that its marketing materials for Descovy "are consistent with the results of the DISCOVER trial," and that "safety data are presented in an objective and balanced manner, including appropriate context to help ensure that the safety profile of Descovy for PrEP is accurately presented to providers and consumers."

Either way, the marketing is markedly different from Gilead's silence when the FDA approved Truvada for PrEP in 2012, said Lindsay Dawson, associate director of HIV policy at the Kaiser Family Foundation.

"Gilead is clearly trying to move people from Truvada to Descovy," Dawson said. "From their perspective, it's a safety issue, at least that's what they're saying. But from a financial perspective, there will be a generic Truvada available later this year."

"Truvada Is Still the Gold Standard"

Right now, both drugs cost nearly $2000 a month, Dawson said. There's no way to know how much Truvada will cost when it goes generic. Sometimes it takes three or four generic drugs to drive down the price of a medicine, she pointed out.

"There's going to be a lot to figure out, including whether generic drug uptake lowers the cost, whether people move from Truvada to Descovy, and whether the availability of the generic enhances access to PrEP."

That's exactly what worries Julia Marcus, PhD, and epidemiologist at Harvard Medical School in Boston.

"My priority is improving PrEP access," she said. "If Truvada is stigmatized as being a lesser medicine, it will impede access to PrEP."

Marcus has spent her career studying how to move PrEP from clinical trial to full implementation. And although Gilead provides multiple drug- and copay-assistance programs, she said the data show that one of the reasons people stop Truvada now is cost or the perception of cost.

That's why Marcus and Krakower have contributed essays on Truvada and Descovy as PrEP, one of which was published in the Annals of Internal Medicine. It encourages clinicians to consider whether Descovy is better than Truvada and to look at the possible statin issue related to Descovy.

And they're not alone. Since the approval of Descovy for PrEP, the New York Department of Health and Mental Hygiene, Kaiser Permanente Northern California, and the Howard Brown Health Clinic network have all issued guidance to clinicians to consider Truvada as the first-line for the prevention of HIV and to help them understand the trade-offs between the two options and how to prescribe them.

New York City is urging physicians to keep Truvada as first-line treatment. And Kaiser Permanente Northern California sent a letter to every PrEP patient that outlined the trade-offs between the two drugs. It concludes that "since both medicines work extremely well with very low rates of side effects, we continue to recommend Truvada as our preferred medication for PrEP."

In other words, "Truvada is still the gold standard," Krakower said.

Trade-Offs

Most of the clinical data presented from DISCOVER have focused on renal and bone mineral density improvements related to the use of Descovy for PrEP.

The presentation at CROI 2019 included slides on bone mineral density and renal biomarkers but not on lipid levels, which the study showed to be higher in people on Descovy. The conclusion slide called Descovy "a safer option for PREP" for men and transgender women who have sex with men.

And DISCOVER research presented at the International AIDS Society Conference on HIV Science (IAS) 2019 showed that the lower transmission rate of HIV in the Descovy group than in the Truvada had only a three in 1000 chance of being a coincidence. This was after CROI presenter Brad Hare, MD, from Kaiser Permanente San Francisco, told Medscape Medical News that the fact that they only had 22 infections meant that "if those 22 infections had been more evenly distributed, we couldn't have shown noninferiority." Data on fasting lipids and weight gain were presented only on slides shown during the Q&A section.

Separate research presented at IAS 2019 showed that people living with HIV who took Descovy plus dolutegravir gained 3 pounds more than those taking Truvada plus dolutegravir. This led researcher Michelle Moorhouse, MB BCh, from the Wits Reproductive Health and HIV Institute in Johannesburg, South Africa, to ask, rhetorically: "Is there a protective effect of TDF? Is there an aggravating effect of TAF? I think we just don't know."

The concluding DISCOVER slide presented at IAS 2019 stated: "F/TAF is a safer, potentially more efficacious option than F/TDF."

The DISCOVER data presented at IDWeek 2018 also focused on renal function and safety. Researchers showed that, at 48 weeks, biomarkers for renal issues were lower in the Descovy than in the Truvada group, but presented no data on weight gain or lipid levels.

And 96-week data presented at the 2019 European AIDS Society Conference showed that the renal and bone mineral density changes were statistically significant in favor of Descovy, but there were no changes in clinical outcomes. It did not address lipid levels or weight gain.

Biomarkers, Clinical Impacts, and Cost

Final DISCOVER findings have yet to be published, so it's hard to compare Descovy and Truvada for PrEP.

But in August 2019, the FDA issued a research brief with more details from the study. It states that Descovy is not superior to or, really, safer than Truvada.

Even though there are noticeable differences in glomerular filtration between Descovy and Truvada, the brief notes that "there were no notable differences (i.e., no risk differences of greater than 1%)" between the two drugs on renal measures.

Five people on Descovy developed acute kidney injury and one developed nephrotic syndrome. Two people on Truvada developed acute kidney injury and one developed Fanconi syndrome.

"In summary, interim results from the DISCOVER trial indicate that use of F/TAF as PrEP has favorable effects on biomarkers of renal tubular function relative to F/TDF at 48 weeks," the FDA reviewers write. "But the clinical impact of these differences is less clear."

There were also "no discernable differences between the treatment groups in the frequency or type of fracture events or other events related to bone health."

There might be clinical differences, but we don't have data to show that yet, Russell told Medscape Medical News.

Fasting lipids dropped in the Truvada group but increased in the Descovy group in the DISCOVER trial. This was consistent with other trials comparing TDF with TAF for the treatment of HIV. Still, the ratio of total to HDL cholesterol, which is an important marker of cardiovascular risk, was essentially the same between Descovy and Truvada in DISCOVER, with no statistically significant changes in weight between the two groups.

Because conference attendees have been interested in weight gain, researchers at IAS 2019 reported that weight gain related to TAF in previous PrEP trials has been about 1 kg.

And as with the renal findings, the increase in fasting lipid levels seen with Descovy "were not associated with any difference in cardiovascular or cerebrovascular events" between the two groups, the FDA brief states. One of the few clinical differences was in statins. Twice as many people started on statins in the Descovy group than in Truvada group (43 vs 21; 1.6% vs 0.8%).

In a statement, Gilead Sciences reported that at 48 weeks, statin use was 1.6% in the Descovy groups and 1.0% in the Truvada group.

"It's still a rare event," said Krakower. "But it goes back to what Julia and I tried to convey in our articles: There are differences in safety profiles, with renal and bone markers on one side for Truvada, and weight changes and lipid levels on the other."

Back to the Clinic

When a patient asks about starting or switching to Descovy, Russell said she has much more of a conversation about trade-offs than she had anticipated. On one hand, Truvada is associated with biomarker changes in renal health and bone mineral density. On the other, Descovy, at least so far, has been associated with some weight gain, changes in lipid profiles, increases in A1C, and increases in statin use.

Her patients, for the most part, have decided to stay with Truvada, she reported.

And Krakower said he is finding the same thing.

"People have felt very averse to any possibility of weight gain, even small amounts," he said. "My sense is that when you allow people to openly express their personal preferences, people's values emerge."

Conference on Retroviruses and Opportunistic Infections (CROI) 2020

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