The natural history of infection by human immunodeficiency virus (HIV) is characterized by a progressive decrease of CD4+ cells and immune function, promoting the occurrence of infections and AIDS-defining malignancies. It is estimated that there are 36.7 million HIV-infected people worldwide and that 1.1 million deaths occur annually from the disease1. In Spain, it affects about 148,785 people2 and its estimated annual mortality is approximately 845 deaths per year3.

Since the introduction of highly active antiretroviral therapy (HAART) as a combination of three antiretroviral drugs, control and maintenance of the disease has been achieved in HIV-infected patients and morbidity and mortality have markedly decreased, converting HIV infection into a chronic disease4.

Although Spanish guidelines have been recommending an initial treatment including two nucleoside reverse transcriptase inhibitors (NRTIs) combined with an integrase inhibitor (INI), a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor boosted with ritonavir (PI/r), currently only INI-based regimens are preferentially recommended5.

Fixed-dose combinations of antiretroviral drugs have meant an important step forward in simplifying treatment and improving compliance. Better compliance has led to a lower risk of treatment errors and decreased resistance selection, which results in an increased effectiveness of therapy with the consequent decrease in viral load and improvement in quality of life of patients6.

Dolutegravir (DTG) is an integrase inhibitor whose clinical development has shown good tolerability and safety, a high barrier to resistance and a lack of relevant drug interactions. The single-tablet formulation with abacavir and lamivudine (DTG/ABC/3TC) obtained European approval in September 2014 and has been marketed in Spain since May 2015.

To assist in the inclusion of the drug on the formulay, the study objective was to assess the incremental cost-utility ratio (ICUR) in €/QALY of the fixed-dose combination of (DTG/ABC/3TC) versus the combinations Emtrici- tabine/Tenofovir/Efavirenz (FTC/TDF/EFV), and darunavir/r (DRV/r) or Ralte- gravir (RAL) with Emtricitabine/Tenofovir (FTC/TDF) or Abacavir/Lamivudine (ABC/3TC) as initial antiretroviral therapy in patients infected with HIV-1 from the perspective of the Spanish National Health System.

Since the introduction of HAART, control and maintenance of HIV infection has been achieved, decreasing its morbidity and reducing costs associated with its medical care. However, the increased survival produced causes costs of treatment and patient care to occur over a much longer time period, normally causing overall costs to become larger than other treatment alternatives and making it necessary to evaluate its cost-effectiveness.

The ARAMIS model used for this adaptation has been verified and previously used in several studies7-8. This is the first research that uses microsimulation to assess the cost-utility of a VIH fixed dose combination in Spain. The stochastic approach used in this study enabled us to show the biological variability and to determine that the fixed-dose combination DTG/ABC/3TC is the most efficient alternative among the initial treatment regimens evaluated. It was to be the dominant strategy in the comparisons considered as the base case and in 14 of 18 sensitivity analyses, and was cost-effective in the remaining four.

This greater efficiency is determined by the savings derived from starting treatment with DTG/ABC/3TC and because this alternative was the most efficient in all cases, except in the sensitivity analyses without discounting and using the lower efficacy level of the trials with dolutegravir (DTG) when compared to the alternatives RAL and DRV. In these cases, the lower efficacy of the alternative to starting with DTG/ABC/3TC was shown to be marginal with values between -0.04 and 0.03 QALYs, which over the lifetime of the patient are equivalent to a lifetime benefit of between 10 days and two weeks. This marginality of the unprovided benefit causes the savings produced to make the alternative appear cost-effective with respect to the compared alternatives.

This effectiveness is consistent with the proposed treatment algorithms since all alternatives are favoured by having treatments including DTG in subsequent lines. Thus, the effectiveness shown in the first lines of treatments is consistent with the efficacy results of the comparative clinical trials of the treatments evaluated12-17. And this dominance is consistent with the results of previous research compararing DTG with ABC/3TC or FTC/ TDF in Canada29.

As shown in Table 5, this efficiency of the first lines of the alternative to starting with DTG/ABC/3TC is boosted by a lower mean monthly cost of treatment than the other compared strategies. Furthermore, it can be seen how other alternatives are benefited by the use of DTG/ABC/3TC in the second lines of treatment.

Although the model has limitations due to the lack of data on the efficacy of subsequent treatment lines and the costs derived from visits in actual clinical practice, these have been treated conservatively. Thus, the high efficacy applied to treatments after the first failure will mean that patients continue with high CD4+ levels. Hence, the benefit of postponing the change of initial treatment shown in the alternative to starting with DTG/ABC/3TC is masked by the effect of subsequent lines. With regard to the case to imputing only protocol visits, this is also a consequence of a conservative approach because it does not consider unexpected visits occurring in actual clinical practice as a result of adverse effects and interactions, regardless of whether or not it involves discontinuation. It is considered that this assumption could penalize the strategy of starting with DTG/ABC/3TC since it safety profile, tolerability and interactions suggests that this treatment generates a lower number of these visits, which leads to underestimating the costs attributable to the other compared strategies. Finally, another limitation has been that the study has not taken into account the subsequent introduction of the generic ABC/3TC

Cost-utility analyses of these alternatives based on real World data of their clinical effectiveness and associated resource consumption will be recommended in the future.

Since the results obtained with this model are favourable to the strategy of starting with DTG/ABC/3TC, it may be concluded that, this is the most efficient option of the alternatives evaluated for the Spanish National Health System. This result could assist informed decision-making about inclusion of the fixed-dose combination DTG/ABC/3TC into the hospital formularies.