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Editorial Comment

Antiretroviral treatments’ durability and costs

important elements in the choice of first-line therapy

Restelli, Umberto; Croce, Davide; Rizzardini, Giuliano

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doi: 10.1097/QAD.0000000000001210
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HIV epidemiologic transition, from a fatal to a chronic condition [1], is today considered in the management of the infection. The choices concerning the antiretroviral treatments (ARTs) to be prescribed to HIV-infected patients are based on a long-term therapeutic strategy. One of the elements that should be considered when evaluating the opportunity to use an antiretroviral regimen as first-line choice is its durability, which is also among the most important attributes evaluated by patients [2].

Treatment durability, the importance of which to achieve long-term treatment success was already discussed in literature [3], was used as an effectiveness parameter in a cost-effectiveness analysis presented by Eaton et al.[4] in this issue of AIDS. The authors analyzed the cost-effectiveness of five first-line ARTs [Emtricitabine + Tenofovir + Efavirenz (EFV); Emtricitabine + Tenofovir + Rilpivirine (RPV); Emtricitabine + Tenofovir + Atazanavir + ritonavir; Emtricitabine + Tenofovir + Raltegravir; Emtricitabine + Tenofovir + Darunavir + ritonavir] in a real-world clinical setting in the United States (therefore the generalizability of the results should be tested in countries with public-oriented National Health Services, distinct from the largely private model of the United States). Durability was chosen as it incorporates implicit information on the absence of therapy-related adverse events and on the capability of the antiretroviral regimen to maintain virologic suppression.

With their valuable analysis, the authors concluded that Raltegravir-based and Efavirenz-based regimens were the most cost-effective options for naïve patients and that the incremental cost-effectiveness ratio of Raltegravir-based regimen vs. Efavirenz-based regimen was 47 US$ per month of additional therapy [4].

An important topic raised by the authors, along with the efficiency of the allocation of resources, is that of the sustainability of ART drug expenditures. The use of new antiretroviral drugs (often more effective and more expensive than the ones already available, even though Eaton et al.[4] showed that effectiveness might still be higher for therapies including older drugs) is not always a sustainable choice for National Health Services and the most effective choice for patients.

A further element that should be considered concerning the analysis presented is the importance of analyzing costs and effectiveness related to antiretroviral therapies within real-world clinical settings. The assessment of durability, however, might require several years of observation in a real-life setting, which might not be compatible with the need to make new technologies promptly available to patients, especially in a field as that of HIV treatment, in which several developments were observed in the last few years [5]. However, the results of observational analyses, even if they provide a lower level of evidence compared with randomized controlled trials, might provide valuable information to confirm or update clinical guidelines and should be considered along with the results of randomized controlled trials. A further element to be considered concerning the use of durability as an effectiveness parameter is related to potential biases. Within the analysis presented by Eaton et al.[4], for example, two of the comparators considered were not available in the market at the beginning of the observation window. Furthermore, some switching of therapies may be due to the cessation of external factors that led to the choice of the first ART (i.e. active substance abuse, not compatible with different, preferred ART). Further analyses of this kind, based on retrospective data collected from clinic or health service databases (such as the one conducted by Abgrall et al.[6]), should be encouraged as real-life data may provide further information to confirm or lead to a revision of the choices made on the basis of controlled trials. In particular, the assessment of durability is relevant considering chronic disorders. In fact, the use of short-term or medium-term effectiveness parameters might result in incomplete information, on which prescription decisions might be based.

Future analyses should, where possible, include the assessment of direct health costs related to monitoring activities and the management of adverse events.

In healthcare settings, characterized by the availability of limited resources, to keep ART regimens with generic drugs options for specific clusters of patients within national guidelines for the treatment of HIV patients might lead to the sustainability of investments in the use of more expensive ARTs for patients without treatment alternatives [7,8] (also considering the increased HIV prevalence worldwide [9], leading to the need to treat an increasing number of patients, and the likely increase of patient adherence to therapies due to a decrease of cost sharing in terms of out-of-pocket copayment, where applicable, i.e. the United States [10]).

National guidelines for the treatment of HIV patients should therefore continue to consider, for each setting of reference, the therapeutic strategies that allow the highest clinical effectiveness for patients in the medium and long term (i.e. the likelihood to develop resistance mutations) and the highest sustainability for the National Health Service to maintain or increase the therapeutic coverage of ARTs among the HIV-infected population (i.e. promoting the use of cost-saving therapeutic strategies as simplification to dual and monotherapies and the prescription of generic drugs [11–14]).

Most recent national guidelines show different choices in the recommendation of first-line ART. Eaton et al. [4] argue that the choice not to incorporate EFV and RPV among first-line choices should be reconsidered on the basis of cost-effectiveness results. Among those cited upon, the most recent US guidelines on the use of antiretroviral agents in HIV-1-infected adults and adolescents [11] recommend as first-line therapies only integrase strand transfer inhibitors (INSTIs) and protease inhibitors. British guidelines [14], alongside INSTI and protease inhibitors, recommend RPV, whereas Italian guidelines [12] recommend the use of INSTI and RPV (protease inhibitors are recommended only under special conditions). Most recent French guidelines [13] dating from 2013 recommend protease inhibitors and both EFV and RPV. However, it is difficult to understand the role of cost considerations in these recommendations.

Although the issue of cost is mentioned within the aforementioned guidelines (i.e. in British guidelines, it is stated that cost should be considered alongside side effects, comorbidities and individual preference in the choice of the therapy to be administered and that recommendations should be revised if cost pressures become a driving factor rather than, e.g. coformulation [14]; in French guidelines, Raltegravir as a third agent should not be preferred, although efficacy and safety have been demonstrated, due to its high cost [13]), cost-effectiveness results are explicitly considered only to recommend simplification to monotherapy [12,14].

In some cases (i.e. Italian guidelines [12]), the need to assess new drugs through multidimensional approaches, as Health Technology Assessment, before recommending them within guidelines, is also mentioned.

The elements to take into account in the choice of first-line ARTs are several and with many interconnections among each other. The study presented by Eaton et al. [4] shows how a pragmatic approach can contribute to the choice of the therapies to be used, both considering the effectiveness of therapies and their costs.

Acknowledgements

Conflicts of interest

There are no conflicts of interest.

References

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Keywords:

antiretroviral therapy; cost-effectiveness; durability; HIV

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