Rilpivirin (1) – Edurant®

• Clinical trials
  • In its dossier, the pharmaceutical manufacturer presented a meta-analysis of the results of three randomised controlled trials to address the research question: trial C204 (a phase IIb randomised, partially blinded, dose-finding trial of TMC278 in antiretroviral-naive HIV-1-infected subjects), C209 (Rilpivirine versus efavirenz with tenofovir and emtricitabine in treatment-naive adults infected with HIV-1, ECHO) and C215 (Rilpivirine versus efavirenz with two background nucleoside or nucleotide reverse transcriptase inhibitors in treatment-naive adults infected with HIV-1, THRIVE).

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

• For antiretrovirally untreated adult patients with a viral load of ≤ 100,000 HIV-1 RNA copies/ml, there is proof of a minor additional benefit compared with the appropriate comparator therapy.
• The G-BA classifies the extent of the additional benefit of rilpivirine as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the severity of the disease and the therapeutic objective in the treatment of the disease.
• Compared with the appropriate comparator therapy “efavirenz in combination with two NRTIs (tenofovir plus emtricitabine or abacavir plus lamivudine)” , in accordance with Section 5(7) in conjunction with Section 2(3) of the AM-NutzenV, this represents a previously unachieved moderate improvement in treatment-related benefit, as it results in a significant reduction in 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 a statistically significant result in favour of rilpivirine (89.3% vs. 83.4%; AD = 5.9%; RR 0.65 [0.45; 0.93]; p = 0.017), for which there is an indication of a gender-specific difference (p = 0.05; I = 73.5% (dossier) and p = 0.048; I = 74.3% (IQWiG A12-04, p. 31)).
  • When analysed by gender, there is a statistically significant result in favour of rilpivirine for men (91.3% vs. 82.4%; AD = 8.9%; RR 0.50 [0.32; 0.77]; p = 0.002), but not for women (84.5% vs. 86.0%; RR 1.06; [0.58; 1.96]; p = 0.845) (IQWiG A12-04 p. 31).
  • The Week 96 data show a reduction in the subgroup difference for the characteristic of sex (p = 0.21; I = 36.5 %), the effect size and the difference in effect between the rilpivirine and efavirenz groups.
  • The result is still statistically significant for men (85.7% vs. 78.5%; AD = 7.2%; RR 0.67 [0.44; 1.00]; p = 0.05); but is no longer statistically significant for the overall group (83.2% vs. 78.5%; RR 0.78 [0.57; 1.06]; p = 0.12).
  • As the subgroup difference for the characteristic of sex at week 96 can now only be classified as minor to moderate, and given that, based on previous experience in HIV therapy, a gender-specific difference does not appear virologically plausible or medically justified, the assessment of the endpoint ‘virological response’ is not carried out separately by gender.
  • For the overall group, the week 96 data show no statistically significant result. There is therefore no additional benefit for rilpivirine over the appropriate comparator therapy for the endpoint ‘virological response (viral load)’.
• Morbidity – Virological failure (resistance)
  • For the endpoint ‘virological failure (resistance)’, the interaction test indicates a moderate influence of the background therapy on the study results (p = 0.11; I = 55.6% (dossier; studies C209 and C215 only)).
  • The summary analysis was therefore not taken into account.
  • When examining the study results for the background therapies of the appropriate comparator therapy, the results are not statistically significant.
  • It is not possible to conclude from the available data whether rilpivirine causes minor or major harm compared to efavirenz.
• Diseases of the nervous system (SOC)
  • With regard to neurological side effects, the G-BA assesses the extent of the added benefit of rilpivirine compared with the appropriate comparator therapy for the endpoint ‘nervous system disorders (SOC)’ as minor.
  • The study results show a statistically significant, clinically relevant reduction in neurological side effects for rilpivirine compared with the appropriate comparator therapy.
  • The prevention of neurological side effects is of direct relevance to patients.
  • According to the EPAR (European Public Assessment Report), 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 included within the SOC ‘Diseases of the Nervous System’ are recorded.
  • Overall, the potential for bias arising from the operationalisation of the ‘nervous system disorders (SOC)’ endpoint is assessed as lower than for the ‘neurological events’ endpoint; consequently, the endpoint ‘Disorders of the nervous system (SOC)’ is used to assess the additional benefit of rilpivirine.
  • The certainty of evidence from the present meta-analysis on this endpoint is classified as sufficient as proof.
  • The comparison of the week 48 data (32.6% vs. 47.4%; AD = 14.8%; RR 0.69 [0.58; 0.82]; p < 0.0001) with the Week 96 data (35.2% vs. 49.1%; AD = 13.9%; RR 0.72 [0.61; 0.84]; p < 0.0001) shows a slight increase in effect size and a slight reduction in the difference in effect for the registration population, whilst the result remains statistically significant.
  • The inclusion of the Week 96 data does not lead to a change in the assessment.
• Health-related quality of life
  • Based on the data presented, no additional benefit for rilpivirine compared with the appropriate comparator therapy can be inferred for the ‘health-related quality of life’ dimension (physical and mental health, SF-36v2).
  • Furthermore, the reduction in side effects has not led to a relevant improvement in quality of life.

Courtesy translation only, please refer to the German original.