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The federal government may have contributed far more to the development of HIV pre-exposure prophylaxis (PrEP) than previously estimated, researchers reported.

While previous estimates said the federal government spent $50 million on the development of combination tenofovir/emtricitabine, or TDF/FTC (Truvada), it actually spent at least $143 million, according to a new estimate by Frazer Tessema, a medical student at the University of Chicago, and colleagues from the Program on Regulation, Therapeutics, and Law (PORTAL) at Brigham and Women's Hospital and Harvard University in Boston.

That's a conservative estimate, as including additional work adds $314 million to total federal spending, they noted in their study .

Although generic TDF-FTC is now available, "our piece is particularly concerned with the period from July 2012 to October 2020, where TDF-FTC for PrEP was only available in the U.S. as a high-price, brand-name product and likely, as a result, many Americans contracted HIV who otherwise would not have if the price was lower," Tessema told MedPage Today in an email.

Hussain Lalani, MD, MPH, who is also a member of PORTAL but was not an author on the paper, noted that "this study is part of a consistent and large theme in which the U.S. government invests in basic science and translational research through the NIH, CDC, and other governmental agencies and these investments lead to life-saving discoveries that are commercialized and sold for high prices by the pharmaceutical industry."

Tessema said that other high-priced therapies have benefited from significant taxpayer investment, including sofosbuvir (Sovaldi) for hepatitis C, pregabalin (Lyrica) for diabetic neuropathy, and buprenorphine (Suboxone) for opioid use disorder.

The FDA approved TDF-FTC in July 2012 as PrEP to prevent HIV infection. Tenofovir disoproxil fumarate (Viread) was originally approved in 2001 and emtricitabine (Emtriva) was originally approved in 2003 to treat HIV, and the combination therapy was approved as Truvada in 2004 for treating HIV.

Although it's highly effective for PrEP, its uptake in the U.S. remains low, with just 363,000 people currently on the regimen, even though more than a million people are at risk for HIV infection, the researchers said.

One of the reasons for its underuse is its high cost, they added. The 2018 list price for Truvada was more than $20,000 for a 1-year supply. In contrast, a year's worth of treatment in Australia costs just over $70.

Some have argued that the price shouldn't be so high, given the significant investment in the development of the therapy by U.S. taxpayers. Tessema and colleagues wrote that CDC researchers discovered the treatment and received three patents for their related work. Based on their findings and other supporting work, the NIH funded several trials for the combination therapy for the prevention of HIV.

Preliminary results of those trials were presented at a conference in 2006, and two large PrEP trials subsequently changed their intervention to use the combination instead of tenofovir only, including the , which had substantial U.S. public sector support.

In November 2019, the U.S. government sued drugmaker Gilead for patent infringement related to combination therapy PrEP, and in April 2020, Gilead counter-sued for breach of contract, Tessema and colleagues noted. Gilead has argued that the CDC patents are invalid because use as PrEP was widely known at the time of filing in 2006, but the CDC countered it wasn't widely known as a PrEP regimen at the time.

There has been ongoing litigation between HHS and Gilead over the ownership of key patents on the drug and its use in HIV prevention, the researchers said.

To get a better sense of federal investment in the therapy, Tessema and colleagues identified NIH awards using the FDA's summary review document, published research trials, the FDA's "Orange Book" to identify key patents, and Westlaw to review court filings for disputed patents.

From there, they created a list of 46 key search terms to identify government awards related to the development of the combination therapy for prevention. Ultimately, they came up with a list of 28 clinical investigators, six CDC patent holders or researchers, three people involved with the material transfer of compounds between Gilead and the CDC, and nine iterations of the drug's name or its components.

They found a total of 73 awards that were "highly" or "potentially" related to its development between 1998 and 2012.

The 37 "highly" related awards totaled $143 million in 2022 inflation-adjusted dollars, while the 36 "potentially" related awards totaled $314 million.

That's a much larger figure than the often-cited estimate of $50 million, based solely on funding for the iPrEx study, the researchers wrote.

At least four of the pivotal trials for the therapy -- iPrEx, VOICE, Partners PrEP, and FEM PrEP -- were partially or fully funded by the NIH.

"The substantial public funding raises questions about the high price charged by the drug's manufacturer, which reduced its affordability and limited its accessibility as HIV preventive therapy," Tessema and colleagues wrote.

They said there are ongoing pricing issues with combination PrEP therapy, as Gilead introduced a follow-on formula for PrEP of tenofovir alafenamide plus emtricitabine (Descovy), which was approved in October 2019 -- ahead of generics becoming available in October 2020.

Gilead made "substantial efforts to transition PrEP patients from Truvada to Descovy," the researchers wrote. Tessema said the strategy is known as a "product hop."

"After 14 months of marketing, Gilead announced that 46% of U.S. PrEP users had switched to Descovy," they wrote. "Although at this time Gilead controls the intellectual property of Descovy until 2031, future pricing negotiations should recognize that Gilead would not have been able to so readily market this drug for PrEP without the groundbreaking publicly funded work conducted or supported by the CDC and the NIH related to TDF-FTC."

The launch price was about $20,000 for 1 year, the authors noted.

"No matter how this litigation concludes, our research findings bolster the claim that federal government support was extensive in both basic science and clinical trials," Tessema and team concluded. "Better policies are needed to ensure the appropriate pricing of products for patients when U.S. taxpayers contribute essential funding."

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