Tenofovir alafenamide fumarate at what price? No more than $1000 a year above existing tenofovir formulation, says model

The superior safety of the tenofovir analogue tenofovir alafenamide fumarate (TAF) over tenofovir disoproxil fumarate (TDF) would justify a price premium of at most $1,010 per patient per year, according to an analysis published in the online edition of Clinical Infectious Diseases. The authors used pessimistic assumptions about the toxic effect of TDF on kidney function and bone mineral density, so this figure could be revised downwards if it causes fewer serious side effects. Moreover, price comparisons were made between TAF- and branded TDF-containing regimens, and the analysis will need to be repeated when TDF comes off patent in 2017.

“The clinical case for TAF over TDF appears solid,” comment the authors. “But ‘better’ does not necessarily imply ‘worth it.’ Society cannot and should not be willing to pay any price for TAF’s clinical superiority. The toxicities associated with TDF…are both infrequent and most often managed by substituting another antiretroviral agent without the general interruption of HIV therapy.”

Approximately 84% of patients taking antiretroviral therapy in the US are treated with a TDF-containing regimen. TDF was first approved in 2001 and has a potent anti-HIV effect. The drug also has an excellent safety profile, its main short-term side-effects being nausea, diarrhoea and headache. But longer-term therapy has been associated with rare cases of kidney toxicity and reductions in bone mineral density. The overall impact of these metabolic side-effects is thought to be clinically meaningful but generally low. One editorial on this subject had the sub-title, “Does statistically significant mean clinically significant?” Indeed, the tolerability of TDF is one of the reasons why it is used as HIV pre-exposure prophylaxis (PrEP).

Glossary

toxicity

Side-effects.

formulation

The physical form in which a drug is manufactured or administered. Examples of formulations include tablets, capsules, powders, and oral and injectable solutions. A drug may be available in multiple formulations.

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.

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.

bone mineral density (BMD)

The higher your bone mineral content, the denser your bones are. And the denser your bones, the stronger they are and the less likely they are to break. A bone density test uses X-rays to measure how many grams of calcium and other bone minerals are packed into a segment of bone. The bones that are most commonly tested are in the spine, hip and sometimes the forearm. 

TAF is an analogue of TDF. It has long been known that it achieves higher intracellular levels of tenofovir at lower plasma levels, requiring just 10% of the active drug compared to TDF. This achieves a more favourable safety profile.

In November 2015, the US Food and Drug Administration (FDA) approved TAF as a lower-toxicity alternative to TDF; indeed, approved hinged on the favourable toxicity profile of TAF.

TAF was approved as component of the co-formulated therapy elvitegravir/cobicistat/emtricitabine/TAF (Genvoya). Gilead, the manufacturer of both TAF and TDF has priced Genvoya at an Average Wholesale Price (AWP) of $37,118 per patient, per year. This is competitive with the price for co-formulated elvitegravir/cobicistat/emtricitabine/TDF (Stribild).

A team of investigators developed a cost-effectiveness model to calculate the premium that should be payable for TAF; a drug that is just as effective but less toxic than TDF.

The analysis assumed that all US patients taking TDF-containing therapy could switch immediately to comparable TAF-containing combinations. It was also assumed that 0.5% of patients taking TDF would have renal toxicities requiring cessation of the therapy. The authors calculated that a quarter of these individuals would require dialysis, each case costing $87,600 a year. Kidney disease and dialysis were both assumed to have a significant impact on quality of life.

The model also assumed that a third of TDF-treated individuals would have bone loss at the hip and 19% at the vertebrae. It was assumed that 5% of those experiencing TDF-related bone loss would experience a fracture in the current year. Fractures were assumed to have a significant impact on quality of life.

Based on these assumptions, the investigators calculated that the maximum permissible price increase for TAF-containing therapy over TDF-containing treatment was approximately $1,000 per year. They note that their estimates about the toxicity of TDF were pessimistic and more favourable assumptions would reduce the permissible premium for TAF.

The patent for TDF expires in 2017 and it is likely that generic versions of the drug will be co-formulated with lamivudine, which is already off-patent. The investigators therefore caution that, “in the presence of generically available TDF, there does not exist a TAF premium over the current $38,740 AWP for branded TDF-based regimens that society ought to be willing to pay.”

They conclude, “while we should be prepared to pay more for safety, efficacy, and dosing improvements, we must also insist, whenever possible, on judicious cost containment…we find that an annual premium of up to $1,010 over the current AWP for TDF-based formulations can be justified.” However, a more restrictive amount will apply once generic TDF becomes available.

References

Walensky RP et al. The epi-TAF for TDF? Clin Infect Dis, online edition, 2015.