Emtricitabin / Rilpivirin / Tenofovirdisoproxil (1) – Eviplera®

• Clinical trials
  • In its dossier, the pharmaceutical manufacturer submitted meta-analyses of the results of two randomised controlled trials to address the research question: C209 (Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naïve adults infected with HIV-1, ECHO) and C215 (Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naïve adults infected with HIV-1, THRIVE).
  • Meta-analyses including study C204 (A phase IIb randomised, partially blinded, dose-finding trial of TMC278 in antiretroviral-naïve HIV-1-infected subjects) were only submitted as part of the commenting procedure.

HIV-1 infection: antiretroviral-naïve adult patients with a viral load of ≤ 100,000 HIV-1 RNA copies/ml

• The G-BA classifies the extent of the additional benefit of emtricitabine, rilpivirine and tenofovir disoproxil as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV.
• Compared with the appropriate comparator therapy ‘efavirenz in combination with tenofovir plus emtricitabine’ , in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this represents a previously unattained moderate improvement in treatment-related benefit, as it achieves a significant reduction in dermatological and neurological side effects.
• Morbidity – Virological response (viral load)
  • For the endpoint “virological response (viral load)”, rilpivirine offers no additional benefit compared with the appropriate comparator therapy.
  • The endpoint ‘virological response (viral load)’ is patient-relevant for the indicated therapeutic indication.
  • The week 48 data show no statistically significant result in favour of emtricitabine, rilpivirine and tenofovir disoproxil (88.9% vs. 84.9%; RR 0.76 [0.48; 1.21]; p = 0.246).
  • A gender-specific difference is suggested for this endpoint (IQWiG Addendum, interaction test p = 0.104).
  • When analysed by gender, there is a statistically significant result in favour of emtricitabine, rilpivirine and tenofovir disoproxil for men (91.4% vs. 84.5%; AD = 6.9%; RR 0.56 [0.33; 0.95]; p = 0.033), but not for women (81.6% vs. 85.9%; RR 1.20; [0.57; 2.55]; p = 0.633).
  • In the light of previous experience with HIV therapy, a gender-specific difference appears neither virologically plausible nor medically justified.
  • Therefore, the assessment of the endpoint ‘virological response’ is not carried out separately by gender.
  • Consequently, there is no additional benefit for the endpoint ‘virological response (viral load)’ for the combination of rilpivirine, emtricitabine and tenofovir compared with the appropriate comparator therapy of efavirenz, emtricitabine and tenofovir.
• Side effects – skin reactions
  • With regard to dermatological side effects, there is a minor additional benefit for rilpivirine in combination with emtricitabine and tenofovir compared with the appropriate comparator therapy.
  • No heterogeneity was observed between the studies for the endpoint “skin events”.
  • Based on the meta-analysis, there is a statistically significant result in favour of the rilpivirine combination with emtricitabine and tenofovir.
  • According to the EPAR (European Public Assessment Report), the most common adverse skin events in the treatment and control arms of studies C209 and C215 were “skin rashes” and “itching”.
  • Even when taking into account the severity of HIV, the observed skin events do not, by their nature, constitute serious or severe health impairments.
  • To characterise the dermatological side effects, the pharmaceutical manufacturer described two endpoints: the endpoint ‘skin events’ and the endpoint ‘skin rashes’ as a subgroup of ‘skin events’.
  • The endpoint “skin events” is used as the primary endpoint for assessing the additional benefit of emtricitabine, rilpivirine and tenofovir.
  • In operational terms, the ‘skin events’ endpoint comprises several MedDRA preferred terms for dermatological events, which were not clearly pre-specified in the respective studies and were not identical across studies.
  • Consequently, the potential for bias in this analysis is classified as high.
  • Due to the small effect size of the results and the high potential for bias at the endpoint level, the certainty of the proof is downgraded from ‘proof’ to ‘indication’.
  • There is therefore an indication of a minor additional benefit for the endpoint ‘skin events’ for the combination of active substances emtricitabine, rilpivirine and tenofovir compared with the appropriate comparator therapy of efavirenz, emtricitabine and tenofovir.
• Side effects – disorders of the nervous system (SOC)
  • Taking the neurological side effects into account, the G-BA assesses the extent of the added benefit of the rilpivirine combination compared with the appropriate comparator therapy for the endpoint “disorders of the nervous system (SOC)” as minor.
  • The study results show a statistically significant, clinically relevant reduction in neurological side effects for the rilpivirine combination compared with the appropriate comparator therapy.
  • The reduction in neurological side effects is of direct relevance to patients.
  • According to the EPAR, the most common adverse neurological events in the treatment and comparator arms of studies C209 and C215 were “dizziness”, “headache”, “somnolence” and “difficulty concentrating”.
  • To capture neurological side effects, the pharmaceutical manufacturer described two endpoints: the endpoint “Neurological events” and the endpoint “Disorders of the nervous system (SOC)”.
  • In its operationalisation, the ‘Neurological events’ endpoint comprises several MedDRA preferred terms for neurological events, which were not clearly pre-specified in the respective studies and were not identical across studies.
  • Consequently, the potential for bias in this analysis is classified as high.
  • In contrast, the ‘Disorders of the Nervous System (SOC)’ endpoint does not involve any retrospective selection of specific events.
  • With the exception of those events assigned to the priority primary SOCs ‘Infections’ and ‘Neoplasms’, all events falling under the SOC ‘Diseases of the Nervous System’ are recorded.
  • Overall, the potential for bias arising from the operationalisation of the endpoint ‘Disorders of the nervous system (SOC)’ is assessed as lower than for the endpoint ‘Neurological events’; consequently, the endpoint ‘Disorders of the nervous system (SOC)’ is used to assess the additional benefit of the rilpivirine combination.
  • The certainty of evidence from the present meta-analysis on this endpoint is classified as sufficient as proof.
• Health-related quality of life
  • Based on the data provided, no added benefit can be demonstrated for the “health-related quality of life” (physical and mental health, SF-36v2). No additional benefit can be identified for the Rilpivirin combination with Emtricitabin and Tenofovir compared to the appropriate comparator therapy.
  • Furthermore, the reduction in side effects did not lead to a relevant improvement in quality of life.

Courtesy translation only, please refer to the German original.