Our newest HIV pre-exposure prophylaxis (PrEP) regimen is, at best, only marginally more valuable than the old PrEP regimen—and with a generic version of the old regimen looming on the horizon, the new regimen’s cost is way too high, according to a new research analysis. That conclusion, which was reached by a team of respected U.S. HIV researchers and advocates, could fuel a simmering debate over PrEP pricing and access.
Until late last year, the fixed-dose combination drug emtricitabine/tenofovir disoproxil fumarate (F/TDF, Truvada) was the only U.S. Food and Drug Administration–approved option for PrEP. In October 2019, emtricitabine/tenofovir alafenamide (F/TAF, Descovy) joined F/TDF on the PrEP menu. However, F/TAF arrived as a new PrEP option alongside a torrent of criticism and questions over tenofovir patent protections, price tags, and the necessity of switching to the newer regimen.
This new research analysis may deepen that criticism. Presented on March 9 during CROI 2020, a major HIV research conference, the study finds that the highest possible fair price for F/TAF as PrEP in the U.S. is $8,670 per year—i.e., roughly half its current list price—and that when a generic version of F/TDF rolls out over the next year, F/TAF won’t be cost effective unless its price point is extremely close to that of generic F/TDF.
The study was led by two veterans of HIV science from different corners of the field: Rochelle Walensky, M.D., M.P.H., a professor of medicine at Harvard Medical School, and Tim Horn, M.S., the director of medication access and pricing at the public health advocacy organization NASTAD.
Modeling a Best Possible Theoretical Scenario for F/TAF PrEP
Walensky, Horn, et al conducted their cost-effectiveness analysis based on previously published research. Since F/TDF and F/TAF have similar efficacy as PrEP, they focused specifically on two areas in which the drugs appear to significantly differ: their bone and kidney safety profiles. F/TAF has been shown to be friendlier toward bone and renal markers than F/TDF, suggesting a lower long-term risk of developing fractures and kidney disease.
Accordingly, their study pulled together the following data points:
- The number of men who have sex with men (MSM) using PrEP in the U.S. (MSM are the only group for whom F/TAF is officially approved and for whom PrEP usage data are readily available.)
- Long-term fracture incidence risk among people receiving F/TDF.
- Differences in creatinine levels and estimated glomerular filtration rate in people receiving F/TDF PrEP versus F/TAF PrEP.
- Reported cost estimates for the most severe outcomes: hip fracture and hemodialysis (due to onset of end-stage renal disease [ESRD]).
- Official Federal Supply Schedule pricing for F/TAF.
To set a maximum benefit point for F/TAF and simplify their analysis, the researchers then made the following broad-stroke assumptions:
- Once collated, all fractures were reclassified as hip fractures. The decision was an effort to maximize the benefit of the doubt given to F/TAF as a cost-effective replacement, since hip fractures generally incur the greatest cost to treat and have the greatest impact on a person’s quality of life.
- F/TAF was presumed to cause zero incidence of hip fracture.
- F/TDF’s effects on the kidneys were presumed to be a worst-case scenario in every case: an inevitable and accelerated progression toward ESRD.
- F/TAF was presumed to cause zero cases of end-stage renal disease and require no hemodialysis.
- Despite signals in some studies that F/TAF use may be associated with lipid increases, weight gain, and cardiovascular risk, zero costs or effects of such risks (e.g., statin use, hospitalization, reduced quality of life) were taken into account.
The goal of all these assumptions was to create the most extreme plausible scenario in which F/TAF exceeded safety expectations while F/TDF yielded the worst possible safety outcomes. That, in turn, allowed the researchers’ cost-effectiveness analysis to focus on the most optimistic picture possible for F/TAF.
The Best-Case Results: Modest Gains on F/TAF at Tremendous Cost
The researchers projected these numbers out over a five-year period using the cohort of all 123,610 MSM currently on PrEP in the U.S., and compared outcomes in two theoretical scenarios: 1) all of the MSM take F/TDF throughout that five-year span, and 2) all of the MSM take F/TAF throughout that span.
The analysis found that, in a best-case scenario, exclusive F/TAF use would prevent 2,101 fractures and 25 ESRD cases compared to exclusive F/TDF use. The resulting impact on life expectancy was estimated to be modest: a total of 690 quality-adjusted life-years (QALYs).
The impact on cost, on the other hand, was found to be massive—fueled almost entirely by the impending arrival of generic F/TDF in the U.S. within the next year.
At the time of this analysis, the Federal Supply Schedule list price for F/TAF was $16,600 per person per year, assuming daily dosing. The future price of a generic F/TDF is currently unknown, but based on a historical analysis of generic drug pricing (which yielded price reductions of 66% on average in the first year of generic availability, increasing to 80% reductions by year five), the researchers conservatively estimated that generic F/TDF would be 50% cheaper than F/TAF, or $8,300 per person per year.
Switching all MSM from F/TDF to F/TAF would thus result in a total cost of roughly $10.3 billion, or an increase of about $5 billion over a scenario in which all MSM took generic F/TDF. That results in an incremental cost-effectiveness ratio (ICER) of $7.2 million per QALY.
The researchers acknowledged that there is no commonly accepted threshold for what level of ICER is considered ideal, or even acceptable. After examining a range of expert analyses on the subject, they settled on $100,000 per QALY, which was at the high end of the range they observed. F/TAF’s ICER thus exceeded the maximum acceptable cost by more than $7 million per QALY.
This cost was heavily affected by the age of the person taking PrEP, however. The younger the recipient, the less cost-effective F/TAF was, due to the lower overall likelihood of those people developing fractures or ESRD within the five-year study period; the ICER for F/TAF among people under the age of 35 was more than $16 million per QALY. By contrast, the ICER for F/TAF among people over the age of 54 was $3.8 million per QALY—still very high compared to the $100,000 threshold, but relatively less so.
What F/TAF Cost Would Be Acceptable?
Working with the data they had generated, Walensky, Horn, et al attempted to set a new maximum price for F/TAF that would allow it to be as cost-effective as F/TDF. Their calculations yielded a cost of $8,670 per person per year—or $370 more than the cost of a generic F/TDF that was conservatively set at 50% of F/TAF’s current sticker price. At a more aggressive price reduction of 75% for generic F/TDF, F/TAF would need to be priced at $4,520 per person per year.
Even at that price, however, the researchers noted that current spending on the federal government’s “Ending the HIV Epidemic” plan doesn’t even come close to matching these drug pricing levels. The federal plan’s complete budget currently sits at roughly $900 million; if F/TAF at a heavily discounted $4,520 was prescribed to every one of the 1.2 million Americans who are estimated to be indicated for PrEP due to their HIV risk levels, the resulting $5.4 billion cost would utterly engulf the entire plan.
In their conclusion, the study authors put the results of their analysis in stark terms. “At current F/TAF prices, F/TAF compared with generic F/TDF will not be cost-effective in the United States, even in populations at highest risk for F/TDF adverse events,” they wrote. “There is no urgency and no reason to switch PrEP regimens now, and it would be hard to switch back later.”
Once generic F/TDF hits the U.S. market, the authors suggested, “payers should consider the $370 premium ceiling estimated here in assessing whether to recommend that patients switch to F/TAF.”
In addition to their presentation at CROI 2020, the study was also published on March 10 in the Annals of Internal Medicine.