Discussion
This budget impact model using an ABM, highlights the fact that the potential economic savings between 2019 and 2023 due to the introduction of generic ARVs are significant and mostly driven by the penetration rate of generics. They range from €309 million to €1.5 billion as penetration rates vary between 10 and 70%, from €894 million to €993 million as the time between patent and generic MAD varies between 10 and 15 years, and from €965 million to €993 million as generic NPUs vary between 40 and 50% of patent ARVs NPUs.
Only two studies were found in which models were used to estimate the economic impact of new generic antiretrovirals. Restelli et al. [
12] developed a BIM to forecast the rates of use of brand and generic ARVs and their impact on the Italian National Health Service budget from 2015 to 2019. They estimated the five-year economic savings at €187 million. They used expert opinions to drive their model and to develop scenarios according to the introduction of generic drugs or new brand drugs. However, they did not consider the generic and brand drug costs and changes in penetration rates over time, the variability in generic drug marketing authorisation dates, or the patients’ individual characteristics and their ability to switch from one treatment to another several times. Contrary to this method, the one developed in our study puts individuals at the heart of predictions. Instead of learning, predicting, and applying ARV consumption rates to a population, regardless of individual specificities, it rather uses data from medical histories to learn and predict the changes in each individual’s characteristics and treatments. Therefore, this way of assigning treatments over time is closer to the constrained allocation of ARVs observed in real-life management of HIV. Hill et al. [
13] estimated the economic impact of generics at €1.25 billion, using a comparison between two scenarios. In their basic case scenario, every patient was assigned to brand-name antiretrovirals while in the second scenario, they all switched to generic drugs. They used a UK Collaborative HIV Cohort database to estimate the proportions of patients taking each drug and the British National Formulary database to estimate drug costs. This study provides deterministic results without a sensitivity analysis. Nevertheless, this study was an oral presentation, and therefore, the limited amount of available information prevents us from making a more thorough comparison with our work.
The agent-based method proposed here in the context of health economics research has four major advantages. First, it makes it possible to integrate many more parameters in the prediction of cost savings, especially individual parameters together with their correlation structures, which makes the predictions more realistic. Second, the effect of time can be examined through longitudinal models. Third, the precision of predictions can be assessed by incorporating randomness into the dynamics of the system. This precision can be evaluated or illustrated by means of bootstrap confidence intervals derived from the distribution of the predictions obtained through several simulation runs. It is a precious tool in this context to compare and identify the main sources of randomness. Fourth, the individual behaviour of patients can be examined and therefore the conclusion can be modulated in terms of population together with individuals. The main drawback is usually modelling and comes from the choice of models and the performance of the calibration of such models. The choice of models is driven by the data and the clinical input on the disease. For this study, we benefited significantly from the help of the Dat’Aids scientific committee, comprised of experts in the management of HIV-infected patients.
This study has several limitations that must be discussed. The time required to clean the Dat’Aids database, design the ABM, and implement it was much more than we had imagined. Consequently, by the time we were able to produce the first results, we were near the end of the period during which we had initially planned to carry out simulations. Therefore, as the ABM was built for predictive purposes, we decided to change the simulation period to 2019–2023. We are aware that doing so with a model trained on 2015 data presents major drawbacks. First, we were unable to consider the ARVs that entered the French market after 2015 as we lacked the necessary data. This could lead to an overestimation of the cost savings as these new patent ARVs will not be genericised during the course of the study. Second, the baseline characteristics and treatments of the simulated patients were taken from the 2015 Dat’Aids data. Overcoming this limitation would entail retraining and running the model on a more recent extraction of the Nadis cohort, which, unfortunately, we were unable to do within a reasonable time frame. However, we were able to perform analyses on a 2019 Nadis extraction, and found that the distribution of the PHIVs’ characteristics did not differ from those of PHIVs included in the 2015 extraction. We also estimated that 18.9% of the PHIVs included in the 2019 Nadis extraction had treatment regimens containing an ARV that entered the French Market between 2016 and 2019. Approximately 83.5% were on an STR containing tenofovir alafenamide (TAF), and this was 15.8% of the PHIVs included in the 2019 Nadis extraction. The proportion of patients that switches from tenofovir disoproxil (TDF) to TAF can be expected to increase in the future as TAF has a lower toxicity than TDF, but we were unable to evaluate the share of patients that would have made that switch by 2023. Still, in light of these findings, using the 2015 PHIV data as a baseline for the simulations that start in 2019 is not likely to affect the model outcomes. In addition, we gathered the exact information on MADs, NPUs, and penetration rates for every generic ARV that entered the French market between 2015 and 2019. To stay as consistent as possible with the study period, the version of ARVs consumed by each PHIV in the cohort was randomly selected between patent and generic product according to the penetration rates of 2019.
We did not consider the changes in the value of the euro across the study period. In fact, drug NPUs in France are negotiated with the government. Therefore, it seemed improbable that they would be impacted by fluctuations in the euro. However, we accounted for changes in drug NPUs by applying a 3.8% yearly discount based on rates observed from 2013 to 2018.
This study only focused on ARV costs. It does not include all resources consumed by PHIVs such as other direct medical and non-medical costs, indirect or informal costs. The results presented here are based on the assumptions underlying the execution models which are detailed in the associated section in
supplementary materials. Please note that we did not consider the ability of some patients to break their Single Tablet Regimen (STR) (i.e., switch from a one-pill combination of several medicines to several pills) as this would have resulted in a much higher complexity in the algorithm. Such a consideration ensures that when the generic version of a medicine that is also part of a combination is available, but the combination itself is not, patients are prevented from breaking it up to take the generic. Therefore, resulting cost savings may be underestimated. In addition, we conducted no analysis on the efficacy of generic drugs or their impact on health as we considered both the efficacy and the safety to be similar between brand-name and generic drugs. Walensky et al. [
32] and Sweet et al. [
33] used simulation models to compare both cost and efficacy between STRs based on a foundation of emtricitabine and tenofovir (FTC/TDF) and their multiple-tablet counterparts, including generics when available and exchanging lamivudine for emtricitabine (e.g., EFV/TDF/FTC vs. generic EFV + TDF + generic lamivudine). Both studies demonstrated a higher efficacy of brand-name STRs compared to generic-based multi-tablet regimens (gMTRs), mainly as a result of poorer adherence to gMTRs than to STRs because of the pill burden and a lower efficacy of lamivudine compared to emtricitabine. However, their cost evaluation differs significantly from ours as only a few brand-name STRs were studied, the focus was on the breaking of STR, and in both studies, the two scenarios that were compared were everyone taking a brand-name STR or everyone taking a gMTR.
Acknowledgements
STUDY GROUP DAT’AIDS:
Besançon: C. Chirouze, C. Drobacheff-Thiébaut, A. Foltzer, K. Bouiller, L. Hustache- Mathieu, Q. Lepiller, F. Bozon, O Babre, AS. Brunel, P. Muret, E. Chevalier,
Clermont-Ferrand: C. Jacomet, H. Laurichesse, O. Lesens, M. Vidal, N. Mrozek, C. Aumeran, O. Baud, V. Corbin, E. Goncalvez, A Mirand, A brebion, C Henquell.
Guadeloupe: I. Lamaury, I. Fabre, E. Curlier, R. Ouissa, C. Herrmann-Storck, B. Tressieres, MC. Receveur, F. Boulard, C. Daniel, C. Clavel, PM. Roger, S. Markowicz, N. Chellum Rungen.
La Roche sur Yon: D. Merrien, P. Perré, T. Guimard, O. Bollangier, S. Leautez, M. Morrier, L. Laine, D. Boucher, P. Point.
Lyon:: L. Cotte, F. Ader, A. Becker, A. Boibieux, C. Brochier F, Brunel-Dalmas, O. Cannesson, P. Chiarello, C. Chidiac, S. Degroodt, T. Ferry, M. Godinot, J.M. Livrozet, D. Makhloufi, P. Miailhes, T. Perpoint, M. Perry, C. Pouderoux, S. Roux, C. Triffault-Fillit, F. Valour, C. Charre, V. Icard, J.C. Tardy, M.A. Trabaud.
Marseille IHU Méditerrannée: I. Ravaux, A. Ménard, AY. Belkhir, P. Colson, C. Dhiver, A. Madrid, M. Martin-Degioanni, L. Meddeb, M. Mokhtari, A. Motte, A. Raoux, C. Toméi, H. Tissot-Dupont.
Marseille Ste. Marguerite: I. Poizot-Martin, S. Brégigeon, O. Zaegel-Faucher, V. Obry-Roguet, H Laroche, M. Orticoni, M.J. Soavi, E. Ressiot, M.J. Ducassou, I. Jaquet, S. Galie, H. Colson, A.S. Ritleng, A. Ivanova, C. Debreux, C. Lions, T Rojas-Rojas.
Martinique: A. Cabié, S. Abel, J. Bavay, B. Bigeard, O. Cabras, L. Cuzin, R. Dupin de Majoubert, L. Fagour, K. Guitteaud, A. Marquise, F. Najioullah, S. Pierre-François, J. Pasquier, P. Richard, K. Rome, JM Turmel, C. Varache.
Montpellier: J. Reynes, A. Makinson.
Nancy: B. Lefèvre, E. Jeanmaire, S. Hénard, E. Frentiu, A. Charmillon, A. Legoff, N. Tissot, M. André, L. Boyer, MP. Bouillon, M. Delestan, F. Goehringer, S. Bevilacqua, C. Rabaud, T. May.
Nantes: F. Raffi, C. Allavena, O. Aubry, E. Billaud, C. Biron, B. Bonnet, S. Bouchez, D. Boutoille, C. Brunet-Cartier, C. Deschanvres, B.J. Gaborit, A. Grégoire, M. Grégoire, O. Grossi, R. Guéry, T. Jovelin, M. Lefebvre, P. Le Turnier, R. Lecomte, P. Morineau, V. Reliquet, S. Sécher, M. Cavellec, E. Paredes, A. Soria, V. Ferré, E. André-Garnier, A. Rodallec.
Nice: P. Pugliese, S. Breaud, C. Ceppi, D. Chirio, E. Cua, P. Dellamonica, E. Demonchy, A. De Monte, J. Durant, C. Etienne, S. Ferrando, R. Garraffo, C. Michelangeli, V. Mondain, A. Naqvi, N. Oran, I. Perbost, M. Carles, C. Klotz, A. Maka, C. Pradier, B. Prouvost-Keller, K. Risso, V. Rio, E. Rosenthal, I. Touitou, S. Wehrlen-Pugliese, G. Zouzou.
Orléans: L. Hocqueloux, T. Prazuck, C. Gubavu, A. Sève, S. Giaché, V. Rzepecki, M. Colin, C. Boulard, G. Thomas.
Paris APHP Bicètre: A. Cheret, C. Goujard, Y. Quertainmont, E. Teicher, N. Lerolle, S. Jaureguiberry, R. Colarino, O. Deradji, A. Castro, A. Barrail-Tran.
Paris APHP Bichat: Y. Yazdanpanah, R. Landman, V. Joly, J. Ghosn, C. Rioux, S. Lariven, A. Gervais, FX. Lescure, S. Matheron, F. Louni, Z. Julia, S. Le GAC C. Charpentier, D. Descamps, G. Peytavin,
Paris APHP Necker Pasteur: C. Duvivier, C. Aguilar, F. Alby-Laurent, K. Amazzough, G. Benabdelmoumen, P. Bossi, G. Cessot, C. Charlier, P.H. Consigny, K. Jidar, E. Lafont, F. Lanternier, J. Leporrier, O. Lortholary, C. Louisin, J. Lourenco, P. Parize, B. Pilmis, C. Rouzaud, F. Touam.
Paris APHP Pitié Salpetrière: C. Katlama, MA Valantin, R. Palich.
Reims: F. Bani-Sadr, JL. Berger, Y. N’Guyen, D. Lambert, I. Kmiec, M. Hentzien, A. Brunet, J. Romaru, H. Marty, V. Brodard,
Rennes: C. Arvieux, P. Tattevin, M. Revest, F. Souala, M. Baldeyrou, S. Patrat-Delon, J.M. Chapplain, F. Benezit, M. Dupont, M. Poinot, A. Maillard, C. Pronier, F. Lemaitre, C. Morlat, M. Poisson-Vannier, T. Jovelin, JP. Sinteff.
St Etienne: A. Gagneux-Brunon, E. Botelho-Nevers, A. Frésard, V. Ronat, F. Lucht.
Strasbourg: D. Rey, P. Fischer, M. Partisani, C. Cheneau, M. Priester, ML. Batard (à remplacer par C. Mélounou au 01/04/20), C. Bernard-Henry, E. de Mautort, S. Fafi-Kremer.
Toulouse: P. Delobel, M. Alvarez, N. Biezunski, A. Debard, C. Delpierre, G. Gaube, P. Lansalot, L. Lelièvre, M. Marcel, G. Martin-Blondel, M. Piffaut, L. Porte, K. Saune.
Tourcoing: O. Robineau, F. Ajana, E. Aïssi, I. Alcaraz, E. Alidjinou, V. Baclet, L. Bocket, A. Boucher, M. Digumber, T. Huleux, B. Lafon-Desmurs, A. Meybeck, M. Pradier, M. Tetart, P. Thill, N. Viget, M. Valette.