Antiretroviral treatment (ART) has changed the human immunodeficiency virus (HIV) disease's natural course,1,2 and has made it possible for patients’ life expectancy to approach that of the general population.3,4 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 50 copies/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.5–8 Thus, as a whole, ART is considered one of the top medical interventions in medical history in terms of cost/efficacy ratios, including developing countries.9–16

Expert panels 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 the (Spanish) AIDS National Plan (PNS for its Spanish acronym) have issued their 2016 treatment guidelines. Their recommendations include 4 preferred regimens (PR), 7 alternative regimens (AR), and 8 referred as other regimens (OR) according to the scientific evidence from randomized clinical trials (RCT) and the expert panel's opinion.17 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 2015 evaluated the efficiency of ART recommended regimens by GESIDA/PNS.18–22 Regimens recommended for 2016 differ from those recommended in previous years. In addition, new scientific evidence and changes in costs suggest the appropriateness of a new and updated economic evaluation of the current ART recommendations.

Consequently, the need for this new cost evaluation arose. The purpose of this study is to evaluate the costs and the efficiency (cost/efficacy) of the ART regimens proposed by the GESIDA/PNS 2016 guidelines as recommended initial therapies for HIV-infected patients who have not received previous ART, i.e., treatment-naïve patients.

The first step was to form a scientific committee (SC) of 16 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 recommended regimens. 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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The 25 RCTs included in the 2015 study22 were: GS-934,26 ARTEMIS,27 CASTLE,28 ARTEN,29 ABT730,30 GEMINI,31 HEAT,32 KLEAN,33 CNA30024,34 ECHO,35 QDMRK,36 VERxVE,37 PROGRESS,38 ACTG5202,39 GS-US-236-0102,40 GS-US-236-0103,41 GS-US-216-0114,42 SINGLE,43 SPRING-2,44,45 STAR,46,47 FLAMINGO,48 STARTMRK,49 GARDEL,50 ACTG5257,51 and NEAT001/ANRS143.52 These two last articles 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. In addition, the SC selected three additional RCTs that evaluate the efficacy of regimens recommended in the 2016 GESIDA/PNS consensus paper17: WAVES,53 GS-US-292-0104/0111,54 and ENCORE 1.55 From these studies, the ENCORE 155 does not meet one of the inclusion criteria (results at 48 weeks are not described). Finally, with the available scientific evidence, the 18 recommended regimens could be evaluated (Table 1). For regimens that may use ritonavir or COBI as farmacoenhancer, the efficacy and safety of ritonavir and COBI were considered the same.42

Costs of the ART regimens at 48 weeks varied between 4610 and 10,916 Euros, for 3TC+LPV/r (OR) and TDF/FTC+RAL (PR), respectively (Table 1, Fig. 2B). The cost of initiating ART, in the base case scenario, varied between 4663 Euros for 3TC+LPV/r (OR) and 10,894 Euros for TDF/FTC+RAL (PR). Within the most favourable scenario, costs varied between 4638 and 10,888 Euros for 3TC+LPV/r (OR) and TDF/FTC+RAL (PR), respectively. Within the least favourable scenario, costs fluctuated between 4692 and 10,904 Euros for 3TC+LPV/r (OR) and TDF/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 RNA of HIV/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 RNA of HIV 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; ATV: atazanavir; COBI: cobicistat; DRV: darunavir; DTG: dolutegravir; EFV: efavirenz; EVG: elvitegravir; FTC: emtricitabine; LPV: lopinavir; NVP: nevirapine;/r: ritonavir-boosted; RAL: raltegravir; RPV: rilpivirine; TDF: tenofovir DF; 3TC: lamivudine. PR: Regimen designated as “Preferred” by the expert panel of GESIDA and the 2016 AIDS National Plan.17 AR: Regimen designated as “Alternative” by the expert panel of GESIDA and the 2016 AIDS National Plan.17 OR: Regimen designated as “Other” by the expert panel of GESIDA and the 2016 AIDS National Plan.17

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The efficacy in base case scenario ranged between 0.66 (66% response rate at 48 weeks) for ABC/3TC+LPV/r (OR) or ABC/3TC+ATV/r (AR), and 0.89 for TDF/FTC/EVG/COBI (AR) and TDF/FTC+DTG (PR). Within the most favourable scenario, the efficacy varied between 0.70 for ABC/3TC+ATV/r (AR) or ABC/3TC+LPV/r (OR) and 0.93 for ABC/3TC+DRV/r (OR) or 3TC+LPV/r (OR). The least favourable scenario shows a variation in efficacy ranging from 0.61 for ABC/3TC+ATV/r (AR) and 0.88 for TDF/FTC/EVG/COBI (AR) (Table 4 and Fig. 2A).

The efficiency (cost/efficacy), in the base case scenario varied between 5280 and 12,836 Euros per responder for 3TC+LPV/r (OR) and RAL+DRV/r (OR), respectively. The efficiency values in the most favourable scenario ranged between 5008 and 12,497 Euros per responder for 3TC+LPV/r (OR) and TDF/FTC+RAL (PR), respectively. Within the least favourable scenario these same estimates varied between 5585 and 13,968 Euros per responder for 3TC+LPV/r (OR) and RAL+LPV/r (OR), respectively. Among the PR and AR, the most efficient regimen, selected with a relative cost/efficacy of 1, was ABC/3TC/DTG (PR) with a cost per responder of 7929 Euros in the base case scenario. When initiating ART with the regimen TDF/FTC+RAL (AR), each responder was 61.0% more expensive than with the regimen ABC/3TC/DTG (PR) if using the base case scenario, 63.2% more expensive in the most favourable scenario, and 58.6% more expensive in the least favourable scenario

Considering all regimens, initiating ART with 3TC+LPV/r (OR), to obtain one responder was 33.3% less expensive than ABC/3TC/DTG (PR) if using the base case scenario, 34.6% less expensive in the most favourable scenario, and 32.1% less expensive in the least favourable scenario (Table 4 and Fig. 2A and B).

In the base case scenario, among the regimens containing non-nucleoside reverse transcriptase inhibitors, the least efficacious (68% of response rate), least expensive, and most efficient (cost per responder 7536 Euros) was ABC/3TC+EFV (OR), while TDF/FTC/RPV (AR) was the most efficacious (84% of response rate) and a little bit less efficient (cost per responder 8181 Euros). Among the regimens including PI/r, the most efficacious (88% of response rate), least expensive and most efficient (cost per responder 5280 Euros) was 3TC+LPV/r (OR), while the least efficient (cost per responder 12,836 Euros) was RAL+DRV/r (OR). Finally, among the regimens including integrase inhibitors, the most efficacious regimens (89% of response rate) were TDF/FTC+DTG (PR) and TDF/FTC/EVG/COBI (AR), while ABC/3TC/DTG (PR) was the most efficient (7929 Euros per responder) (Table 4 and Fig. 2A and B).

The GESIDA/PNS panel stratified the recommended regimens in PR, AR and OR according to reasons widely justified and discussed in the original report.17 Of the ten ART regimens recommended by GESIDA/PNS in their 2016 consensus paper17 as PR or AR for naïve patients considered in this analysis, TDF/FTC/EFV (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). Considering all the regimens, 3TC+LPV/r, classified as “other” by the GESIDA/PNS consensus group, was the least expensive, one of the most efficacious (88% of response rate) and the most efficient (5280 Euros per responder in the base case scenario). Some regimens present a high efficacy but are less efficient due to their high cost (e.g., TDF/FTC/EVG/COBI) while in others (e.g., ABC/3TC+ATV/r or ABC/3TC+LPV/r) the low efficiency is due to their low efficacy. Lack of experience, pill burden and toxicity issues in real clinical practice may be among the reasons why the GESIDA/PNS panel qualifies 3TC+LPV/r as OR despite being the less costly and the most efficient. The regimen TAF/FTC/EVG/COBI, one of four recommended as PR by GESIDA, has not been considered in the analysis. The reason is that the official price of the regimen in Spain was not available when the economic calculations were made. At the time of writing the manuscript, it is confirmed that the price is similar to the TDF/FTC/EVG/COBI combination. Since its tolerance is better and its effectiveness is equal or higher54 it could be foreseen that the cost-efficacy (efficiency) ratio will be good when next year is included in the analysis.

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 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 three regimen types56 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 different inclusion and exclusion criteria, and even with different presentations for the same drug in regimens with LPV (capsules and pills) or NVP (normal formula or extended-release). 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 (<100/200 cells/μL) and elevated plasma viral load (>100,000 copies/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, NVP should only be initiated on women with CD4 <250cells/μL or on men with CD4 <400cells/μL. Also, RPV is only approved for individuals with baseline plasma viral loads <100,000copies/mL, and TDF/FTC/EVG/COBI is only approved for patients with estimated glomerular filtration rate >70ml/min. 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.

Further, NVP studies reviewed (ARTEN29 and VERxVE37) included only patients with low CD4 counts (<250cells/μL in women and <400cells/μL in men) which may explain the poorer results regarding efficacy compared to other regimens. However, because those are the drug label's approved criteria, such trials were included in the analysis. Also, study ACTG 520239 did not provide AE data at 48 weeks, so AE data at 96 weeks were included instead under the assumption that most AE do occur during the first 48 weeks. 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. Additionally, although the study's methodology ensures agreement at a national level, calculations may differ in other countries. Finally, 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. Finally, another limitation would be that these findings are applicable only to Spain and taking into account the Spanish official drug prices in February 2016, 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.

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,57 a software application was developed and made available free of charge at https://dl.dropboxusercontent.com/u/35731022/coste-eficacia-2016/Aplicaci%C3%B3n-TARV-VIH-GESIDA-2016.exe or at http://www.gesida-seimc.org/guias_clinicas.php?mn_MP=406&mn_MS=407. 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.58,59

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, the results should be interpreted by experts and the most efficient combination may not be the best one, or even may not be a “preferred” one, as it happens in this analysis. 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 political decision-makers in the field of HIV-infection management.

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

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.

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, Tibotec, Janssen, Abbvie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, and Tobira.

Manuel Crespo has received consultancy fees from AbbVie, Bristol-Myers Squibb, Gilead Sciences, Merck Sharp & Dohme, Janssen, and ViiV Healthcare. Dr Crespo has also received research grants from AbbVie, Pfizer, Gilead Sciences and ViiV Healthcare.

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).

Vicente Estrada has received honoraria, speakers’ fees and/or funds for research from Abbvie, Gilead, Merck Sharp & Dohme, Bristol-Myers Squibb, ViiV Healthcare and Janssen.

José Antonio Iribarren has disclosed that he has served as an advisor or consultant for Abbvie, Gilead and Janssen; grant support from Abvvie, BMS, MSD, Basque Government, FIPSE and FISS, and support to attendance to conferences from Abbvie, BMS, Gilead, Janssen, MSD, and ViiV Healthcare.

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 Jose López Aldeguer has received consultancy and speaker fees from Abbott Laboratories, ViiV Healthcare, Gilead Sciences, Janssen Pharmaceuticals and Merck Sharp & Dohme.

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.

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.

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

Juan Antonio Pineda has received honoraria as consultant for Abbvie, Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag and Merck Sharp & Dohme; has received grants for research from Boehringer Ingelheim Pharmaceuticals, Bristol-Myer Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme, Roche Pharma and ViiV Healthcare; and speaker fees from Boehringer Ingelheim Pharmaceuticals, Bristol-Myers Squibb, Gilead Sciences, GlaxoSmithKline, Janssen Cilag, Merck Sharp & Dohme, Roche Pharma and ViiV Healthcare.

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.

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 ViiV Healthcare.

Josep M. Gatell has received honoraria for speaking or participating in Advisory Boards and/or research grants from Bristol-Myers Squibb, Merck Sharp & Dohme, Tobira, Gilead, BI, Janssen, ViiV Healthcare and Abbvie.