Antiretroviral treatment (ART) has changed the human immunodeficiency virus (HIV) disease's natural course, and made possible a patients’ life expectancy similar to that of the general population.1 ART is usually based on a three-drug approach with the goal of lowering the plasma viral load to undetectable levels, i.e., below a threshold of less than 50copies/mL, and keep it suppressed as long as possible. In most cases, current ART regimens lead to a partial restoration of the immune system, both in quantity and quality, depending in part on the degree of baseline immunodeficiency levels.2 Thus, ART is one of the top medical interventions in medical history in terms of cost/efficacy ratios, including developing countries.3

An expert panel formed by members from the AIDS Study Group (GESIDA for its Spanish acronym) of the Spanish Society of Infectious Diseases and Clinical Microbiology (SEIMC for its Spanish acronym) and from the (Spanish) AIDS National Plan (PNS for its Spanish acronym) have issued their 2018 treatment guidelines. Their recommendations include 4 preferred regimens (PR), 4 alternative regimens (AR), and 6 referred as other regimens (OR) according to the scientific evidence from randomized clinical trials (RCT) and the expert panel's opinion.4 However, in the context of limited resources any therapeutic intervention must be applied efficiently. Thus, both costs incurred and outcomes obtained by the different ART must be examined to identify the most efficient regimens within those recommended by the GESIDA/PNS guidelines. There are other costs to consider, in addition to the drugs, including those incurred while managing adverse effects (AE) or the costs of drug-resistance studies, among others. Studies published between 2011 and 2017 evaluated the efficiency of ART recommended regimens by GESIDA/PNS.5 Regimens recommended for 2018 differ from those recommended in previous years. In addition, new scientific evidence and changes in costs suggest the need of a new and updated economic evaluation for the current ART recommendations.

Consequently, the objective of this study is to evaluate the costs and the efficiency (cost/efficacy) of the ART regimens proposed by the GESIDA/PNS 2018 guidelines as preferred and alternative initial therapies for HIV-infected patients who have not received previous ART (treatment-naïve patients).

The first step was to form a scientific committee (SC) of 17 Spanish experts identified by GESIDA (this paper's authors except AJB and PL) with experience in the clinical management of HIV-infected patients. SC's tasks included providing general advice, validating the assumptions made as part of the economic evaluation, supplying the RCTs used as scientific evidence, and providing expert opinion when the scientific evidence was insufficient.

Models of economic evaluation

The model of economic analysis consists of as many decision trees as PR and AR. Each decision tree was built based on the data from the RCTs assessing the corresponding regimen and it reproduces the regimen's characteristics in terms of efficacy, AE, and reasons for withdrawal (Table 1 and Fig. 1).

Fig. 1.

Structure of the economic evaluation model for each regimen of antiretroviral treatment (ART). SR: substitution regimen.

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Eighteen RCTs were included: GS-US-380-1489,10 SINGLE,11 FLAMINGO,12 SPRING-2,13,14 GS-US-380-1490,15 ONCEMRK,16 STARTMRK,17 QDMRK,18 GS-US-292-0104/0111,19 GS-US-236-0102,20 GS-US-236-0103,21 WAVES,22 AMBER,23 ARTEMIS,24 ACTG 5257,25 NEAT001/ANRS143,26 ECHO27 and STAR.28,29 ACTG525725 and NEAT001/ANRS14326 provide information on outcomes and AE for the week 96. Since our analyses have a time horizon of 48 weeks, we requested the 48 weeks data to the authors. In both cases, formally and confidentially, the authors sent to us the required data. With the available scientific evidence, all the PR and AR regimens could be evaluated (Table 1), except TAF/FTC+RAL qd (1200mg), since Isentress® 600mg is not commercialized in Spain and its prize is not available. For regimens that use TAF as nucleotide reverse transcriptase inhibitors, the RCTs with tenofovir DF (TDF) were included, since the efficacy and safety of TDF and TAF could be considered the same at 48 weeks.19,23

Costs of the ART regimens at 48 weeks varied between 6724 and 10,690 Euros, for TAF/FTC/RPV (AR) and TAF/FTC+RAL (PR), respectively (Table 1, Fig. 2B). The cost of initiating ART, in the base case scenario, varied between 6788 Euros for TAF/FTC/RPV (AR) and 10,649 Euros for TAF/FTC+RAL (PR). Within the most favourable scenario, costs varied between 6766 and 10,644 Euros for TAF/FTC/RPV (AR) and TAF/FTC+RAL (PR), respectively. Within the least favourable scenario, costs fluctuated between 6816 and 10,655 Euros for TAF/FTC/RPV (AR) and TAF/FTC+RAL (PR) (Table 4 and Fig. 2A and B).

Fig. 2.

Representation of the base case scenario. (A) Cost: cost of initiating a regimen including all potential consequences of initiating ART with that regimen (Adverse effects (AE) and changes to other regimens) that may occur within 48 weeks. Efficacy: proportion of patients with undetectable plasma viral load (<50copies of HIV-RNA/mL) at 48 weeks. The slope between the y-intercept and the coordinates for each regimen represents the efficiency (cost/efficacy). The slope reflects the cost of achieving one responder by week 48 from the payer perspective: The National Health Service (NHS). (B) ART Cost: Drug costs for each regimen for 48 weeks (laboratory sale price (LSP)+4% VAT – 7.5% reduction). Cost of initiating ART: cost of initiating a regimen including all potential consequences of initiating ART with that regimen (Adverse effects (AE) and changes to other regimens) that may occur within 48 weeks. Cost per Responder: Cost of achieving one responder (<50copies of HIV-RNA per mL of plasma) by week 48 from the payer (NHS) perspective, calculated as the cost of initiating ART divided by its efficacy. ABC: abacavir; COBI: cobicistat; DRV: darunavir; DTG: dolutegravir; EVG: elvitegravir; FTC: emtricitabine; /r: ritonavir-boosted; RAL: raltegravir; RPV: rilpivirine, TAF: tenofovir alafenamide; 3TC: lamivudine. PR: Regimen designated as “Preferred” by the expert panel of GESIDA and the 2018 AIDS National Plan.4 AR: Regimen designated as “Alternative” by the expert panel of GESIDA and the 2018 AIDS National Plan.4

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The efficacy in base case scenario ranged between 0.82 (82% response rate at 48 weeks) for TAF/FTC+DRV/r (AR) and 0.91 for TAF/FTC+DTG (PR). Within the most favourable scenario, the efficacy varied between 0.84 for TAF/FTC+DRV/r (AR) and 0.93 for TAF/FTC+DTG (PR). The least favourable scenario shows a variation in efficacy ranging from 0.80 for TAF/FTC+DRV/r (AR) and 0.89 for TAF/FTC+DTG (PR) and TAF/FTC/EVG/COBI (AR) (Table 4 and Fig. 2A).

The efficiency (cost/efficacy), in the base case scenario, varied between 7814 and 12,412 Euros per responder for ABC/3TC/DTG (PR) and TAF/FTC+RAL (PR), respectively. The efficiency values, in the most favourable scenario, ranged between 7595 and 12,177 Euros per responder for ABC/3TC/DTG (PR) and TAF/FTC+RAL (PR), respectively. Within the least favourable scenario, these same estimates varied between 8049 and 12,659 Euros per responder for ABC/3TC/DTG (PR) and TAF/FTC+RAL (PR), respectively. When initiating ART with the regimen TAF/FTC+RAL (PR), the cost per responder was 58.8% higher than with the regimen ABC/3TC/DTG (PR) in the base case scenario, 60.3% higher in the most favourable scenario, and 57.3 higher in the least favourable scenario.

The GESIDA/PNS panel stratified the recommended regimens in PR, AR and OR according to reasons widely justified and discussed in the original report.4 Of the ART regimens recommended by GESIDA/PNS in their 2018 consensus paper4 as PR or AR for naïve patients, TAF/FTC/RPV (AR) emerged as the least expensive whether considering the ART cost alone or considering all the additional costs derived from the decision of initiating treatment with an ART regimen (AE management, drug resistance tests, HLA B*5701 test, and regimen change). However, the most efficient was ABC/3TC/DTG (PR) because of its higher efficacy and similar cost. Some regimens present a high efficacy but are less efficient due to their high cost (e.g., TAF/FTC+DTG).

The cost of initiating a treatment with a regimen is the real costs to the NHS because it includes ART costs and the costs of the consequences (e.g., AE management or switching the regimen); whereas for the hospital's pharmacy the cost consists of only the ART. The ratio cost/efficacy represents the NHS cost of achieving one responder, at 48 weeks in our case. In certain cases, the physician and/or the patient may prefer a triple therapy regimen based on a non-nucleoside, a PI/r, or an integrase inhibitor, or even a dual therapy, for clinical reasons or personal preferences. In such cases, the costs of initiating treatment, its efficacy, and the cost/efficacy ratio would have to be considered within each of these regimens and might not necessarily be the major driver in the decision-making process.

For all regimens, the main cost of initiating treatment is the ART due to its high price. In contrast, the costs related to managing AE are low since only a very small percentage of patients present AE and the involved costs are low.

The study results should be interpreted in the context of its limitations. A potential limitation is that the analyses are based on RCTs performed in different countries, during different periods of time, with slightly different inclusion and exclusion criteria. Thus, results may have differed if all regimens had been administered in similar populations and time periods. In fact, more recent studies include lower percentages of patients with poor prognosis, i.e., those with low CD4 counts (<200cells/μL) and high plasma viral load (>100,000copies/mL). This leads to results with higher levels of efficacy than those reported in previous studies and may offer an advantage to drugs assessed recently for the first time. In addition, there are drugs with restricted use. For instance, RPV is only approved for individuals with baseline plasma viral loads <100,000copies/mL. RPV efficacy results in patients with plasma viral load <100,000copies/mL are better than the average efficacy from the RCTs included in this analysis. However, these studies included patients similar to those participating in studies of the other drugs, thus, efficacy data refer to comparable patient groups. Moreover, we have assumed that at 48 weeks the efficacy and the clinically relevant side effects are similar for TDF/FTC as compared with TAF/FTC.

Another limitation is that some RCTs do not to specify which AE were ART-related, such lack of information was completed with the experts’ opinion. Similarly, for lack of other scientific evidence, i.e., resources needed for AE management and the substitution regimens used when the initial regimen was suspended were estimated based on experts’ opinion. The AMBER23 provides information on AE occurring in over 5% of patients instead in over 2%, so the cost of managing their AE could be slightly higher. We have considered only the cost of managements of those side effects reported in the clinical trials but we recognize as a limitation that sometimes additional side effects able to generate additional costs are identified in a real life setting when a drug is widely utilized. At the time of writing the manuscript, the combinations TAF/FTC/DRV/COBI and TAF/FTC/RPV are not commercialized in Spain and, consequently, their billing prices are not available. For these reason, the cost of those regimens has been calculated as the sum of TAF/FTC+DRV/COBI and TAF/FTC+RPV, respectively.

Additionally, although the study's methodology ensures agreement at a national level, calculations may differ in other countries. Regimens’ efficacy was evaluated using the ITT-E analytical approach assigning missing or incomplete follow-ups as failures (“missing or non-completer=failure”). This method of evaluation may not coincide with the main end-point in some of the studies, though the data published in the reports do allow for the necessary calculations. In other words, results may have differed if other analytical methods of measuring efficacy had been used instead. Also, when more than one RCT assessed the same regimen, a metanalysis could not be performed because of the absence of a common comparator. Another limitation would be that these findings are applicable only to Spain and taking into account the Spanish official drug prices in February 2018, not considering potential local discounts even when they could be substantial and not uncommon as in the case of RAL. Thus, results should be interpreted cautiously especially in environments where prices differ substantially from the Spanish average. GESIDA recommend single tablet regimens when available irrespective of whether or not the same combination can be built using two or more tablets including generics and with a potentially lower cost. Moreover to using the downloadable application cost-efficacy can be recalculated using the cost of generics instead of the branded drugs.

Major strengths of this study include the use of the best scientific evidence available and the sensitivity analyses performed to best capture the underlining uncertainty in costs and outcomes. Further, the models use efficacy estimators, with universal validity, which, added to the fact that the methodology is applicable to any environment, would make the results valid in other contexts as long as local costs could be entered into the models.

In order to facilitate the use of this methodology in other centres or countries with different ART- or HIV management-related costs or to take into account the potential future use of generic drugs, a software application was developed and made available free of charge at http://gesida-seimc.org/category/guias-clinicas/antirretroviral-vigentes/. This application allows the calculations of ART costs, initiating ART costs, efficiency (cost/efficacy), and the relative efficiency of initiating treatment with the different regimens based on local costs of the medicines and the management of side effects. This application will aid any centre interested in computing its own estimates based on the model developed here.

The ideal study design to determine ART efficiency in regular clinical practice would be a prospective cohort cost/effectiveness study with a long follow-up period, but these studies are unlikely to be carried out. When lacking such studies, cost/efficacy models provide a very useful tool to examine costs and ART efficiency based on the best scientific evidence available.

Current study findings are relevant because the mission of any health care system is to maximize the population's health outcomes in a context of inherently limited resources. In such context, guaranteeing the system's sustainability requires an efficient use of the limited resources.30

At the patient-physician level, the drug efficiency is an important characteristic of therapy but not necessary the most important driver when choosing an antiretroviral combination as initial therapy, because other features must be taken into consideration as efficacy, tolerability, safety, convenience, drug-drug interactions and resistance profile. So, results might be cautiously interpreted, as the most efficient combination may not be the best one for a particular patient. For this reason, periodic economic evaluation studies, such as this one, have the potential of facilitating the decision-making process of health professionals, managers, and policy decision-makers in the field of HIV-infection management.

José Antonio Pérez-Molina has received consultancy fees from Bristol-Myers Squibb, ViiV Healthcare, and Gilead Sciences, and speaker fees from Bristol-Myers Squibb, ViiV Healthcare, and Merck Sharp & Dohme.

Esteban Martínez has received honoraria as consultant for AbbVie, Boehringer Ingelheim, BristolMyers Squibb, Gilead Sciences, GlaxoSmithKline, Merck Sharp & Dohme, Theratechnologies y ViiV Healthcare; he has received grants for research from Merck Sharp & Dohme, and he has received support for educational activities from AbbVie, BristolMyers Squibb, Gilead Sciences, GlaxoSmithKline, MerckSharp & Dohme, y ViiV Healthcare.

Antonio Javier Blasco has no potential conflicts of interest related to this study.

José Ramón Arribas receives advisory fees, speaker's fees, or grant support from Viiv Healthcare, Janssen, Gilead Sciences and Merck Sharp & Dohme.

Pere Domingo has received honoraria for consultancy from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Janssen, and ViiV Healthcare. He has also received research grants (money for Institution) from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Pfizer Inc and ViiV Healthcare. He had also received honoraria for speech from AbbVie, Boehringer Ingelheim, Bristol-Myers Squibb, Merck Sharp & Dohme, Gilead Sciences, Janssen, and ViiV Healthcare. Dr. Domingo is recipient of a grant from the Programa de Intensificación from FIS in the year 2013 (INT12/383).

José Antonio Iribarren has no potential conflicts of interest related to this study.

Hernando Knobel has done consultancy work for Abbott Laboratories, Abbvie Laboratories, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme and ViiV Healthcare and has received compensation for lectures from Abbott Laboratories, Bristol-Myers Squibb, Gilead Sciences, Janssen and ViiV Healthcare.

Pablo Lázaro has no potential conflicts of interest related to this study.

José López-Aldeguer has received speaker fees from Gilead Sciences.

Fernando Lozano has disclosed that he has served as an advisor or consultant for Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Janssen, Merck-Sharp & Dohme, Roche Pharmaceuticals and ViiV Healthcare, and has also served on the speaker's bureaus for, as well as received support for educational activities from Abbvie, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Gilead Sciences, Janssen, Merck Sharp & Dohme, Roche Pharmaceuticals and ViiV Healthcare.

Ana Mariño has received support to attendance to conferences from Bristol-Myers Squibb, Gilead Sciences, Janssen Cilag and ViiV Healthcare.

José M. Miró has received honoraria for consultancy from AbbVie, Angelini, Bristol- Myers Squibb, Genentech, Gilead Sciences, Jansen, Medtronic, Merck Sharp & Dohme, Novartis, Pfizer and ViiV Healthcare. He has also received research grants from Cubist, Merck Sharp & Dohme, Novartis, ViiV Healthcare, Fondo de Investigaciones Sanitarias (FIS) from the Instituto de Salud Carlos III (Madrid), Fundación para la Investigación y Prevención del Sida en España (FIPSE, Madrid), Ministerio de Sanidad, Política Social e Igualdad (MSPSI, Madrid), National Institutes of Health (NIH, Bethesda, MA, EE, UU.) He had also received honoraria for speech from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme, Novartis and ViiV Healthcare. Dr. Miró is recipient of a personal 80:20 research grant from the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain during 2017–2019.

Santiago Moreno has been involved in speaking activities and has received grants for research from Abbott, Boehringer Ingelheim, Bristol-Myers Squibb, Gilead, Glaxo Smith Kline, Janssen Cilag, Merck Sharp & Dohme, Pfizer, Roche, and Schering Plough.

Eugenia Negredo receives advisory fees, speaker's fees, or grant support from Viiv Healthcare, Merck Sharp & Dohme, Janssen and Gilead Sciences.

Federico Pulido receives advisory fees, speaker's fees, or grant support from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck Sharp & Dohme and Viiv Healthcare.

Rafael Rubio reports grants from Abbott and Janssen, and payment for lectures from Abbott, Bristol-Myers Squibb, ViiV, Gilead, Janssen, and Merck Sharp & Dohme.

Jesús Santos has received honoraria as consultant for Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag and Merck Sharp & Dohme; has received grants for research from Gilead Sciences, GlaxoSmithKline, Janssen Cilag and speaker fees from Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme and ViiV Healthcare.

Javier de la Torre has received consultancy fees from ViiV Healthcare, Gilead Sciences, and speaker fees from Abbott Laboratories, Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, GlaxoSmithKline, ViiV Healthcare, Janssen, Merck Sharp & Dohme and Roche Pharmaceuticals.

Montserrat Tuset has received grants from Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Janssen and speaker fees from Janssen, Merck Sharp & Dohme, and participating in Advisory Boards from ViiV Healthcare.

Miguel A. von Wichmann has received has received consultancy fees from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen Cilag, Merck Sharp & Dohme and ViiV Healthcare, and speaker fees from Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen Cilag, Merck Sharp & Dohme.

Josep M. Gatell has received honoraria for speaking or participating in Advisory Boards and/or research grants (his institution) from Merck Sharp & Dohme, Gilead Sciences, Janssen and ViiV Healthcare.