Rilpivirine for HIV: added benefit also proven for the combination product

Since the start of 2012, a new drug called rilpivirine has been available for adult patients infected with the human immunodeficiency virus type 1 (HIV-1). It is marketed both as a single agent and also as a fixed combination with other HIV drugs (trade name Eviplera®). Because important data were missing in the first dossier assessment of Eviplera® that was completed in April 2012 pursuant to the Act on the Reform of the Market for Medicinal Products (AMNOG), the German Institute for Quality and Efficiency in Health Care (IQWiG) was initially unable to accord an added benefit to the combination product.

But on the inclusion of additional study data (e.g. on subgroup analyses) that the drug manufacturer subsequently provided in the commenting procedure conducted by the Federal Joint Committee (G-BA), the Institute came to a different conclusion: there is now proof that also in the fixed combination with emtricitabine and tenofovir disoproxil, rilpivirine offers a considerable added benefit for men infected with HIV-1. For women, the available studies provide corresponding indications. This matches the result of the dossier assessment of April 2012 on rilpivirine as a single agent.

Studies on the single drug product also relevant for the fixed combination

In each case, the G-BA specified efavirenz-based therapy in combination with a "backbone therapy” consisting of other drugs, as the appropriate comparator therapy. For the assessment of the fixed combination, data specifically on efavirenz in combination with emtricitabine and tenofovir disoproxil were used. Results from a total of 3 studies were available. Since, at the time of the assessment, only analyses after 48 weeks were fully available for the two largest studies, IQWiG's assessment was based on these analyses.

In all three studies, rilpivirine was tested as a single drug and not in a fixed combination. Nevertheless, the results are also relevant for the assessment of the combination product, because the dose of rilpivirine, emtricitabine and tenofovir disoproxil that was given in these studies corresponds to the dose in the fixed combination.

Viral load is a sufficiently valid surrogate parameter

The manufacturer did not submit any data on the patient-relevant outcome of "AIDS-defining diseases/death", i.e. on the outbreak of AIDS and on survival. Instead, the manufacturer used results of "viral load” in order to prove the added benefit. Viral load denotes the number of components of a virus present in the blood and it shows how active HIV is.

In principle, IQWiG considers this "surrogate parameter” as valid, i.e. meaningful, because patients in whom the number of viruses can be persistently suppressed below the limit of detection have, according to the current state of knowledge, a lower risk of developing AIDS or of dying. However, it is unclear whether a treatment has just as great an effect on the patient-relevant outcome as on the surrogate parameter.

Drug combination reduces viral load in men

There was an indication in the studies that the effects on the reduction in viral load in men and in women are different and therefore the data should be considered separately. For this outcome, the three studies showed a statistically significant difference in favour of the rilpivirine combination for male patients. IQWiG therefore considers there is proof of an added benefit in HIV-1-infected men, but not in women, for this outcome. Because of the uncertainty described regarding the size of the effect with respect to the patient-relevant outcome, the extent of this added benefit cannot be quantified (is "non-quantifiable").

Fewer neurological side effects

Rilpivirine as a combination product also has advantages in terms of side effects, in that "neurological events" such as headaches or insomnia occurred less frequently. In this case there were no differences between men and women. However, the analysis presented by the manufacturer contains a few uncertainties, which is why IQWiG considers that here there is no proof, but only an indication of a lesser harm from rilpivirine compared to efavirenz, in each case combined with emtricitabine and tenofovir disproxil.

Based on the overall results on side effects and viral load, the Institute considers that for male patients, there is proof of a considerable added benefit and for female patients a corresponding indication.

G-BA decides on the extent of added benefit

The dossier assessment is part of the overall procedure for early benefit assessment conducted by the G-BA. After publication of the manufacturer's dossier and the IQWiG dossier assessment, the G-BA conducted a commenting procedure, in which the manufacturer submitted additional information. The G-BA subsequently (7th June 2012) commissioned IQWiG to undertake a new assessment, with the additional data included.

If, in the course of the discussions on a commission of the G-BA, a need for further revision arises, IQWiG presents a report in the form of an addendum. The Institute sent this addendum to the contracting agency on 22nd June 2012. The G-BA decides on the extent of the added benefit, thus completing the early benefit assessment.

An overview of this benefit assessment pursuant to AMNOG (addendum) is given by the following English-language extract.

Contact: Tel. +49(0)221-35685-0, presse@iqwig.de