The total 1-year costs of PrEP were €4271 (SD: €2446)/participant, of which 73% were drug costs. The other significant costs were consultations (€205), ELISA tests (€126), and diagnostic for other STIs (€262; Table 2). However, as previously stated in the methodology, the consultations were considered to be entirely protocol driven and thus not included in the total cost.
The yearly cost to avoid one infection calculated as the difference in costs divided by the difference in HIV infections based on trial results of 5.68 HIV infections averted/100 person-years (or 1/NNT) was €75 258/HIV infection averted. As the cost of the placebo arm was set to zero in the base case analysis, the numerator equates to the healthcare costs in the TDF-FTC arm (Table 4).
Using TDF-FTC at French generic prices (€179.9 for 30 tablets) reduced the 1-year cost of on-demand PrEP to €2271/participant and €39 970/HIV infection averted. Using TDF-FTC at fully discounted international market prices (€60/30 tablets) reduced the 1-year cost of on-demand PrEP to €1517/participant and €26 787/HIV infection averted. The results of the probabilistic sensitivity analysis using the overall NNT of 17.6 to estimate the number of infections averted are presented in Fig. 1a. All replications are in the upper right quadrant, indicating that on-demand PrEP was always more expensive and more effective than no PrEP. The uncertainty of the result was mostly because of the uncertainty of the clinical results, as shown by the length of the scatterplot on the horizontal axis. Because our hypothesis of a zero cost in the placebo arm was conservative (i.e. increased the potential cost difference and therefore the cost/infection averted), we increased the costs in the placebo arm to those of STI tests, or €262/participant and obtained a cost of €70 466/HIV infection averted.
The analyses were also run for the participants in the Paris region where the NNT was 13.2 and the results are presented in Fig. 1b. The yearly costs were predictably lower than for the overall population ranging from €58 397 to 20 961/HIV infection averted.
The estimate of the net benefit of using PrEP found that, at current drug prices, PrEP is cost saving up to 7.5 years of risk exposure, up to 13 years of risk exposure at generic price in France and up to 20 years at international market drug prices (Fig. 2).
We estimated the total average cost of using on-demand PrEP for high-risk MSM in France based on the results of the IPERGAY double-blind randomized controlled trial. We found that using on-demand PrEP cost on average €75 258 each year to avoid one HIV infection at current drug price and €42 222 at French generic price. From a strictly monetary viewpoint, the use of on-demand PrEP results in a net saving if the duration of the risk exposure is shorter than 7.5 years at current drug price, 13 years at generic price in France today, and 20 years at discounted prices.
Assuming that a decision would be based solely on cost neutrality is incorrect, however, as the health benefits of prevention include reduced transmission, reduced HIV- related morbidity, treatments of other STIs, and psychological benefits.
Our base-case estimate is conservative as we assumed a zero cost in the placebo arm, while MSM may benefit from counseling and testing even in the absence of PrEP. We also used in-trial costs which included laboratory tests which may not occur in routine use of PrEP. We, therefore, maximized the cost difference between PrEP and no PrEP assuming an increment in cost larger than what it may be in reality. This cost difference, however, was driven by the cost of PrEP (drug use and laboratory tests) which was the list price at the time of the trial and which was reduced from €500.88 to 179.9 when the generic became available in July 2017. We also ignored the possibility that avoiding HIV infection in one person may benefit to more than one person. A rapid estimate based on a 2–3 months period for high risk of transmission postinfection , with a transmission rate of 0.185/receptive unprotected anal intercourse during that period , using the IPERGAY trial results of 14 sexual partners over a 2-month period with an average number of 26 sexual acts out of which 70% were unprotected and a 0.7 probability of having an HIV-negative partner , then the expected number of secondary infections during the high infectivity period is 2.36. Using lower figures of transmission/anal intercourse [15,16] would reduce the number of secondary infections to 1.63. To these, other transmissions resulting from secondary infections and occurring before the treatment is initiated could be added. Thus, including in the calculation the cost of treating secondary HIV infections could make on-demand PrEP cost neutral at 1 year in this high-risk population, where the incidence is 6.6 HIV infections/100 person-years. As the cost/infection averted can be roughly estimated by multiplying the 1-year cost of PrEP by the NNT, it can be expected, however, that the net benefit will decrease over time as the incidence of HIV infection decreases. Also, implementing PrEP in a lower risk population might decrease the net benefit of PrEP.
We found that on-demand PrEP resulted in a net monetary benefit for a duration of exposure to risk and need for PrEP of 7.5 years or less at current drug price and 13 years or less at French generic price. Some patients in IPERGAY reported discontinuing the use of PrEP for various reasons including modifications in their sexual behavior. There are no data to date regarding the cumulative lifetime use of PrEP, but such periods without PrEP or avoidance of unprotected anal sex would reduce the overall cost of prophylaxis and increase the net benefit. Also, PrEP has been implemented only recently in high-risk population in France and other countries, and recent report suggest that a reduction in HIV incidence may be foreseen (https://www.gettingtozerosf.org/wp-content/uploads/2017/06/GTZ_Health-Commission_02MAY17_From-HC-website.pdf accessed September 2017).
The IPERGAY trial also found that providing PrEP to MSM allowed the diagnosis and treatment of other STIs which might be otherwise neglected. IPERGAY was not designed to demonstrate this benefit on other STIs as both arms benefited from the same active procedures of detection and treatment but we would argue that the access to on-demand PrEP is an additional tool for the healthcare system to better care for the population of MSM with high levels of sexual risk behaviors. Our economic evaluation was based on infections averted and net benefit because we used in-trial data only and did not extrapolate results. Based on the results of the Preexposure Prophylaxis Initiative (IPrEx) trial, American authors reported costs/infection averted as high as $500 000, or 20 times the cost of treating a person with HIV infection for 1 year but their computations assumed an NNT of 44 which is three times higher than our figures, and double our ‘on-demand’ drug costs . More recently the costs of averting one infection using continued PrEP was estimated at $679 878/infection averted, assuming a 44% reduction in the annual risk of HIV acquisition which is half the IPERGAY results . Translating our results into costs/quality adjusted life years (QALYs) with an NNT of 17.6 and a risk calculator would result in lifetime cost savings .
Other authors have reported that taken daily ‘PrEP is unsustainably expensive’ and identified the high cost of the drug as a barrier to the wide adoption of prevention . With TDF-FTC at the current list price the strategy of providing on-demand PrEP, together with counseling and testing other STIs, is nearly four times higher than the cost of treating a patient with HIV infection for 1 year. Using the discounted TDF-FTC costs (€60/30 tablets on the internet, which could become the price of generic TDF-FTC in France in the future), however, PrEP could become cost neutral, which means that the additional drug costs are completely offset by savings at 1 year. The difference in results is explained also by the use of on-demand versus daily PrEP. Although equally effective, on-demand PrEP halved drug costs and appears, therefore, more efficient than systematic PrEP in European countries [6,21]. This would allow using PrEP on a larger population or for a longer duration.
Our calculations included the cost of counseling which is roughly 17% of total costs at the current drug price and 50% at the generic drug price. To further reduce costs, the current protocol could be altered based on the counseling interventions of proven effectiveness.
Compared to other economic evaluations, our results are short term and based on the results of a single trial [7,22]. Most publications on the cost-effectiveness of daily PrEP in MSM have used models to extrapolate the long term of lifetime effects of PrEP. Although this approach fits well the natural history of the disease and the lifetime benefits of not being infected, the uncertainty on the long-term costs and effects is reflected in the wide range of cost-effectiveness ratios, from zero to $1 474 000/QALY [23,24]. A recent modeling of cost-effectiveness of on-demand PrEP in the Netherlands over a 10-year period found a low €2000/QALY, using a yearly cost of on-demand PrEP of €3850, which was less than our cost . These Dutch findings support the use of on-demand PrEP for HIV prevention among MSM. The main political advantage of our trial-based estimates is that they present the more recent estimates given the current situation of HIV incidence, PrEP efficacy and costs and allow policy makers to directly compare the cost of treating HIV infections to the cost of averting HIV infections in France.
Additional evidence on the sustained benefit of on-demand PrEP in a larger population would be useful, although it is not clear that such trials would now be feasible. Strategies based on detection and treatment of HIV infection appear to be insufficient to eradicate HIV and should be complemented by PrEP. Based on IPERGAY data, on-demand PrEP has been approved in France and a generic TDF-FTC has been recently available: further documentation of benefits on HIV infection might be based on large database and analysis of real life data which should be soon available.
We gratefully acknowledge the contribution of Ms Meryl Darlington to the revision of the manuscript.
Ethical approval (CNIL CPP): the protocol was approved by public health authorities and by ethics committees in France (CPP Paris Saint-Louis) and Canada (CER Montreal). All study participants provided written informed consent. The study protocol is available at NEJM.org.
The study was sponsored by the ANRS (France Recherche Nord & Sud Sida-HIV Hépatites) and funded by ANRS, the Canadian HIV Trials Network, the Fonds de dotation Pierre Bergé pour la Prévention – SIDACTION, Gilead Sciences, and the Bill and Melinda Gates Foundation.
Substantial contributions to the conception or design of the work (I.D-Z, J.M. M., C.C., C.T., B.S., G.P., L.M., L.C.); The acquisition, analysis, or interpretation of data for the work (P.M., I.D-Z., I.C., J.C., C.T., C.Ch., L.C., J.M.M., C.Ca., L.M.) and drafting the work or revising it critically for important intellectual content (all); final approval of the version to be published (all); and agreement to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved (all).
I.D-Z. reports receiving support from Pfizer, Janssen, Merck, Abbvie; B.S. reports receiving support as an advisor for Gilead Sciences, Merck, and Janssen, Bristol and research grants from Gilead Sciences and Merck; C.Ch. reports receiving support as an advisor for Gilead, Pfizer, Janssen, and Astellas; C.T. reports receiving support from Gilead Sciences and Pfizer;
J.M.M. reports receiving support as an advisor for Gilead Sciences, Merck, Janssen, Bristol Myers Squib and ViiV, and research grants from Gilead Sciences and Merck; L.C. reports research grants from MSD and ViiV Healthcare and support from AbbVie, Bristol Myers Squib, Gilead Sciences, Janssen, MSD, and ViiV Healthcare.
ANRS IPERGAY Study Group: Members of the Scientific Committee: J.M.M. (Chair), Mark Wainberg, Benoit Trottier, C.T., Jean-Guy Baril, G.P., L.C., Antoine Chéret, Armelle Pasquet, Eric Cua, Michel Besnier, Willy Rozenbaum, C.Ch., Constance Delaugerre, Nathalie Bajos, Julie Timsit, Gilles Peytavin, Julien Fonsart, I.D-Z., L.M., Jean-Pierre Aboulker, B.S., Marie Suzan-Monti, Gabriel Girard, D.R., Marie Préau, Michel Morin, David Thompson, C.Ca., Lucie Marchand, Véronique Doré, Marie-Christine Simon, Isabelle Charreau, Joanne Otis, France Lert, Alpha Diallo, Séverine Gibowski, and Cecile Rabian.
Conflicts of interest
There are no conflicts of interest.
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Keywords:Copyright © 2018 Wolters Kluwer Health, Inc.
cost-benefit analysis; economics; HIV; intermittent; MSM; preexposure prophylaxis; prevention