Added Benefit for HIV Drug Combination Unproven

Although the FDA has approved the combination of emtricitabine/tenofovir alafenamide plus other antiviral agents in adults and adolescents infected with HIV-1, an early benefit assessment revealed that this combination did not provide additional benefits over the comparator therapy.

The Federal Joint Committee (G-BA) differentiated between 4 groups of patients by age and treatment status. Two of the groups that consisted of pretreated and treatment-naïve adolescents were not considered in the drug manufacturer’s dossier.

In the German Institute for Quality and Efficiency in Health Care (IQWiG) assessment, researchers did not follow the manufacturer’s justification that the guideline recommendations did not differentiate between adults and adolescents, or that adolescents constituted less than 1% of the target population.

Although a search for corresponding studies in adolescents did not have any results, it was concluded that an added benefit of emtricitabine/tenofovir alafenamide in comparison to the appropriate comparator therapy was not proven for pretreated or treatment-naïve adolescents.

For treatment-naïve adults, the dossier did not contain any suitable data. The G-BA stated that in the comparator arm, these patients should be treated with NRTI backbone therapy.

But in the submitted studies by the manufacturer, elvitegravir/cobicistat was added to the new combination in the test arm, and the NRTI backbone therapy emtricitabine/tenofovir disoproxil was combined with elvitegravir/cobicistat in the comparator arm. As for the third combination elvitegravir/cobicistat, it did not comply with the appropriate comparator therapy.

This was supported by the manufacturer with 3 arguments that were not followed by IGWiG. But, the third combination partner was not methodologically relevant for a comparison between 2 NRTI backbone therapies, according to the first argument. The effect modification by the third partner cannon be excluded, but corresponding subgroup analyses would be required for this.

The manufacturer’s second argument was that elvitegravir/cobicistat was at least equivalent to 1 of the 3 combination partners named by the G-BA, particularly efavirenz. This can be inferred from a G-BA decision, in which there is no sufficient proof of an added benefit, or less benefit of a combination with elvitegravir/cobicistat in comparison with a combination with efavirenz, according to the manufacturer.

Although inequivalence was unproven, that does not mean that equivalence was established. In fact, the comparison the G-BA decision was based off of showed disadvantages of elvitegravir/cobicistat compared with efavirenz for individual outcomes.

The third argument stated that the use of elvitegravir/cobicistat as a third combination partner is appropriate because those comparator therapies are to be preferred for which the G-BA has already established a patient-relevant benefit.

For pretreated adults, the appropriate comparator therapy was individual antiretroviral therapy. The manufacturer differentiated between patients with indication for a treatment switch.

There was no available data for the first group, meaning the added benefit of emtricitabine/tenofovir alafenamide in comparison with the appropriate comparator therapy for this group was not proven.

Lastly, the analyses did not provide any hints of added benefit for the new combination in comparison with continuation of ongoing treatment for mortality, morbidity, and health-related quality of life.

There were also negative effects in the side effects outcome category. Furthermore, there appeared to be a hint of greater harm with the new combination.

Overall, in each of the 4 research questions, the added benefit of emtricitabine/tenofovir alafenamide in comparison with the appropriate comparator therapies was not proven. Additionally, pretreated adults without indication for a treatment switch could undergo greater harm from the combination than from continuation of their ongoing treatment.