Dolutegravir (1) – Tivicay®

• Clinical trials
  • The pharmaceutical manufacturer has submitted the SPRING-1, SINGLE, SAILING, VIKING-PILOT and VIKING-3 studies to demonstrate additional benefit.
  • The SPRING-1 study is a multicentre, randomised and controlled Phase IIb dose-finding study with a four-arm parallel design, in which partial blinding was employed.
  • The SINGLE study is a randomised, controlled, double-blind, multicentre Phase III study involving 844 treatment-naïve adults infected with HIV-1.
  • The assessment of the additional benefit of dolutegravir for antiretrovirally pre-treated adults for whom treatment with an integrase inhibitor is the first-line therapy is based on the multicentre, randomised and controlled, double-blind Phase III trial SAILING.

a) Adults who have not previously received antiretroviral therapy (treatment-naive)

• For adults who have not previously received antiretroviral therapy (treatment-naïve), there is proof of considerable additional benefit compared with the appropriate comparator therapy, a combination therapy comprising efavirenz in combination with two nucleoside/nucleotide analogues (tenofovir disoproxil plus emtricitabine or abacavir plus lamivudine).
• The certainty of the evidence (probability of additional benefit) is classified in the ‘Proof’ category.
• The G-BA classifies the extent of the additional benefit of dolutegravir for adults who have not previously received antiretroviral therapy (treatment-naïve) adults infected with the human immunodeficiency virus (HIV) as considerable, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the course of the disease and the therapeutic objective in the treatment of the condition.
• mortality
  • For the endpoint of overall mortality, which had a minor overall event rate, the differences in outcomes were not statistically significant either in the two individual studies or in the meta-analysis at the 96-week evaluation point.
  • There is no evidence of additional benefit or greater harm from dolutegravir compared with the appropriate comparator therapy, a combination therapy comprising efavirenz in combination with two nucleoside/nucleotide analogues (tenofovir disoproxil plus emtricitabine or abacavir plus lamivudine), is not proven for this endpoint.
• Morbidity – AIDS-defining events (CDC Class C events), supplemented by virological response (viral load < 50 HIV-1 RNA copies/ml) and CD4 cell count
  • For the endpoint under consideration here – AIDS-defining events – there was no statistically significant difference between the dolutegravir and control groups at the 96-week analysis point, neither in the individual studies nor in the meta-analysis.
  • Both in the individual studies and in the meta-analysis, a statistically significant effect in favour of dolutegravir was observed for the endpoint of virological response (meta-analysis: RR = 1.12 [1.04; 1.21]; ARR = –8.2%).
  • With regard to the CD4 cell count, a statistically significant increase in favour of dolutegravir was observed in the SINGLE study and in the meta-analysis of the two studies.
  • In conclusion, from the G-BA’s perspective, it can be stated that, for the validated, patient-relevant surrogate endpoint of virological response represents a moderate advantage of dolutegravir – significant in nature but moderate in magnitude – which constitutes a previously unattained moderate, and not merely minor, improvement in treatment-related benefit.
• Morbidity – HIV symptoms (Symptom Distress Module [SDM])
  • The SDM endpoint was assessed only in the SINGLE study.
  • No statistically significant difference was observed between the treatment groups, meaning that the additional benefit of dolutegravir over the appropriate comparator therapy is not proven.
• quality of life
  • No data on health-related quality of life were collected in the SPRING-1 study.
  • In the SINGLE study, the mean changes in the total score, based on the five dimensions and the visual analogue scale (VAS), were determined using the generic European Quality of Life-5 Dimensions (EQ-5D) instrument.
  • There are insufficient data available to assess health-related quality of life.
  • An additional benefit of dolutegravir compared with the appropriate comparator therapy is therefore not proven for health-related quality of life.
• Side effects
  • Whilst for severe adverse events, Grade 3–4 severe adverse events (DAIDS), psychiatric disorders, and musculoskeletal, connective tissue and bone disorders, it is not proven that dolutegravir causes greater or minor harm compared with the appropriate comparator therapy; however, the meta-analytical review of the endpoint category ‘non-serious/serious side effects’, there is proof that dolutegravir causes less harm for the endpoints ‘discontinuation due to AEs’, ‘skin rash’ and ‘neurological disorders’, each of which has a considerable extent.
  • For the endpoint ‘severe adverse events, grade 3–4 (DAIDS)’, no pooled estimate could be calculated due to the heterogeneity between the studies.
  • From the results presented in the dossier regarding discontinuations due to adverse events, the severity of these events cannot be determined for all patients.
• Conclusion
  • In light of these considerations, based on the information in the dossier, the results of the benefit assessment and the statements submitted, the G-BA assesses the results on side effects for the endpoints of discontinuation due to AEs, skin rash (PT) and nervous system disorders (SOC) for male patients, taking into account the findings regarding virological response and the further data on overall mortality, morbidity and quality of life, as representing, compared with the appropriate comparator therapy—a combination therapy of efavirenz in combination with two nucleoside/nucleotide analogues (tenofovir disoproxil plus emtricitabine or abacavir plus lamivudine)— a significant improvement in treatment-related benefit that has not yet been achieved, through the substantial avoidance of non-serious and severe side effects in treatment-naive (treatment-naïve) adults with HIV infection, particularly in the context of the disease course requiring lifelong therapy.

b) adolescents aged 12 years and over who have not previously received antiretroviral therapy (treatment-naïve)

• For antiretroviral-naïve (treatment-naïve) adolescents aged 12 years and over who are infected with the human immunodeficiency virus (HIV), the additional benefit compared with the appropriate comparator therapy—efavirenz in combination with abacavir plus lamivudine—is deemed not proven.
• The pharmaceutical manufacturer has not submitted any data for this patient group; consequently, evidence of additional benefit compared with the appropriate comparator therapy—efavirenz in combination with abacavir and lamivudine—is not considered to have been provided for this patient population.

c) adults who have previously received antiretroviral therapy and for whom treatment with an integrase inhibitor is the first-line treatment option

• For antiretrovirally pre-treated adults for whom treatment with an integrase inhibitor is the first-line treatment option, there is an indication of a minor additional benefit compared with the appropriate comparator therapy, raltegravir in combination with an individualised backbone regimen, depending on prior therapy(ies) and taking into account the reason for the change in therapy, in particular treatment failure due to virological failure and any associated development of resistance, or due to side effects.
• The certainty of the finding (probability of additional benefit) is classified as ‘indication’.
• The G-BA assesses the extent of the additional benefit of dolutegravir for adults who have previously received antiretroviral therapy and for whom treatment with an integrase inhibitor is the first-line treatment option, as minor, based on the criteria set out in Section 5(7) of the AM-NutzenV, taking into account the course of the disease and the therapeutic goal in the treatment of the condition.
• mortality
  • The SAILING study shows no statistically significant result, with few events in terms of all-cause mortality.
  • No additional benefit or greater harm of dolutegravir compared with raltegravir is not proven for this endpoint.
• Morbidity – AIDS-defining events (CDC Class C events), supplemented by virological response (viral load < 50 HIV-1 RNA copies/ml) and CD4 cell count
  • The assessment of the morbidity data from the SAILING study is carried out in the same way as the evaluation criteria selected for the SPRING-1 and SINGLE studies, to which reference is made here.
  • For the endpoint under consideration here – AIDS-defining events – there was no statistically significant difference between the groups treated with dolutegravir and raltegravir at the 48-week analysis point, given the minor number of events.
  • For the endpoint of virological response, there is a statistically significant effect in favour of dolutegravir (RR = 1.14 [1.04; 1.24]; ARR = –7.2%).
  • With regard to CD4 cell count, there is no statistically significant difference between the treatment groups.
• Morbidity – HIV symptoms (Symptom Distress Module [SDM])
  • The endpoint ‘HIV symptoms’ (Symptom Distress Module [SDM]) was not assessed in the study.
  • Consequently, additional benefit from dolutegravir compared with the appropriate comparator therapy is not proven.
• quality of life
  • In the SAILING study, data on health-related quality of life were also collected using the generic European Quality of Life-5 Dimensions (EQ-5D) instrument.
  • The values recorded, which were based on the SINGLE study, do not allow for an adequate assessment of health-related quality of life.
  • An additional benefit of dolutegravir compared with the appropriate comparator therapy is not proven for health-related quality of life, even for the patient population of antiretrovirally pre-treated patients for whom treatment with an integrase inhibitor is the first-line therapy option.
• Side effects
  • The SAILING study provides an indication of a minor incidence of adverse effects with dolutegravir compared with the appropriate comparator therapy.
  • For the endpoint ‘nervous system disorders’ (SOC), no statistically significant difference was observed.
  • However, there is proof in each case of an effect modification by the characteristics of age and ethnicity.
  • For those aged over 50, there is an indication of minor harm associated with dolutegravir (RR = 0.45 [0.23; 0.89]; ARR = 14.0 %).
• Conclusion
  • Based on these considerations, the information in the dossier, the results of the benefit assessment and the statements received, the G-BA assesses the results for the endpoints ‘virological response’, ‘severe adverse events, grade 3–4’ (DAIDS) and nervous system disorders (SOC) for the patient population of those aged over 50 – taking into account the data on overall mortality, morbidity and quality of life as a moderate—and more than just minor—improvement in treatment-related benefit that has not yet been achieved compared with the appropriate comparator therapy, raltegravir in combination with an individualised backbone therapy, primarily attributable to the significant reduction in side effects for antiretrovirally pre-treated adults for whom treatment with an integrase inhibitor is the first-line therapy option, particularly in the context of the disease course requiring lifelong treatment.

d) antiretroviral-treated adults for whom treatment with an integrase inhibitor is a secondary treatment option

• For adults who have previously received antiretroviral therapy and for whom treatment with an integrase inhibitor is a secondary treatment option, there is no proof of additional benefit compared with the appropriate comparator therapy: individualised antiretroviral therapy depending on prior therapy(ies) and taking into account the reason for the change in therapy, in particular treatment failure due to virological failure and any associated development of resistance, or due to side effects.
• Compared with the appropriate comparator therapy—individualised antiretroviral therapy based on prior therapy(ies) and taking into account the reason for the change in treatment, in particular treatment failure due to virological failure and any associated development of resistance, or due to side effects, the pharmaceutical manufacturer has, for antiretroviral-treated adults for whom treatment with an integrase inhibitor represents a second-line treatment option, no data comparing dolutegravir with the appropriate comparator therapy, meaning that evidence of additional benefit in this patient population is deemed not to have been established.

e) antiretrovirally pre-treated adolescents aged 12 years and over

• For antiretrovirally pre-treated, HIV-1-infected adolescents aged 12 years and over, the additional benefit compared with the appropriate comparator therapy – individualised antiretroviral therapy depending on prior therapy(ies) and taking into account the reason for the change in therapy – in particular treatment failure due to virological failure and any associated development of resistance, or due to side effects, does not provide proof.
• Compared with the appropriate comparator therapy—individualised antiretroviral therapy depending on prior therapy(ies) and taking into account the reason for the change in treatment— in particular treatment failure due to virological failure and any associated development of resistance, or due to side effects, the pharmaceutical manufacturer has not provided any data for a comparison of dolutegravir with the standard of care for antiretrovirally pre-treated, HIV-1-infected adolescents aged 12 years and over, so that the evidence of additional benefit in this patient population is regarded as not having been established.

Courtesy translation only, please refer to the German original.