Dolutegravir / Abacavir / Lamivudin (1) – Triumeq®

• Clinical trials
  • To demonstrate additional benefit, the pharmaceutical manufacturer submitted the SPRING-1, SINGLE and SAILING to demonstrate added benefit; these studies also formed the basis for the benefit assessment of the single substance dolutegravir (G-BA resolution on the benefit assessment of dolutegravir dated 7 August 2014).
  • 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-naive adults infected with HIV-1.

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

• For adults who have not previously received antiretroviral therapy (treatment-naive), there is an indication of a considerable additional benefit.
• The certainty of the evidence (probability of additional benefit) is classified as ‘indication’.
• The G-BA classifies the extent of the additional benefit of dolutegravir/abacavir/lamivudine 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 all-cause mortality, the differences at the 96-week evaluation point were not statistically significant, given the minor event rate.
  • There is no evidence of additional benefit or greater harm from dolutegravir/abacavir/lamivudine 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 dolutegravir/abacavir/lamivudine and the comparator group at the 96-week analysis time point, given the small number of events that occurred.
  • For the endpoint of virological response, a statistically significant effect in favour of dolutegravir/abacavir/lamivudine was observed (RR = 1.10 [1.02; 1.20]; ARR = −7.2%).
  • The lower limit of the 95% confidence interval for the effect estimate for dolutegravir/abacavir/lamivudine is close to that of the comparator.
  • When considering the sensitivity analysis conducted by the IQWiG on virological non-responders at the same assessment time point, no significant effect was observed between the treatment arms (RR = 1.01 [0.67; 1.52]).
  • A statistically significant increase in the CD4 cell count was observed in favour of dolutegravir/abacavir/lamivudine.
  • In this specific case, it remains unclear whether the statistically significant difference also represents a clinically relevant difference.
  • In conclusion, from the G-BA’s perspective, it can be stated that the significant—albeit moderate in magnitude—advantage of dolutegravir/abacavir/lamivudine for the validated, patient-relevant surrogate endpoint of virological response represents a moderate—and not merely minor—improvement in treatment-related benefit that has not been achieved to date.
• Morbidity – HIV symptoms (Symptom Distress Module [SDM])
  • To assess the impact of disease symptoms on the patient, the Symptom Bother Score is used for the benefit assessment.
  • No statistically significant difference was observed between the treatment groups in this regard; consequently, an additional benefit of dolutegravir/abacavir/lamivudine over the appropriate comparator therapy is not proven.
• Morbidity – Health status (EQ-5D VAS)
  • Analysis of the visual analogue scale (VAS) of the standardised European Quality of Life-5 Dimensions (EQ-5D) index tool shows no statistically significant difference between the treatment groups.
  • Consequently, for this endpoint, the additional benefit of dolutegravir/abacavir/lamivudine over the appropriate comparator therapy is not proven.
• quality of life
  • There are insufficient data available to assess health-related quality of life.
  • An additional benefit of dolutegravir/abacavir/lamivudine compared with the appropriate comparator therapy is therefore not proven for health-related quality of life.
• Side effects
  • Whilst no evidence exists to demonstrate that dolutegravir/abacavir/lamivudine compared with the appropriate comparator therapy, there is evidence in the endpoint category of non-serious/severe side effects that indicate that dolutegravir/abacavir/lamivudine causes less harm for the endpoints of treatment discontinuation due to AEs, skin rash, and for nervous system disorders, in each case of considerable extent.
  • For the endpoint of severe adverse events (Grade 3–4, DAIDS), the impact of the missing results from the SPRING-1 study is considered significant for the relevant patient population, given the existing heterogeneity with opposing effects observed in the SINGLE and SPRING-1 studies.
  • Consequently, there is not enough proof of greater or minor harm from dolutegravir/abacavir/lamivudine for this endpoint.
• 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 findings on side effects for the endpoints ‘discontinuation due to AEs’, skin rash (PT) and nervous system disorders (SOC) in male patients, taking into account the findings on 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 and the need for lifelong therapy.

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

• For adolescents aged 12 years and over who have not previously received antiretroviral therapy (treatment-naïve) and who are infected with the human immunodeficiency virus (HIV), additional benefit is not proven.
• For this patient group, no data are available comparing dolutegravir/abacavir/lamivudine with the appropriate comparator therapy, efavirenz in combination with abacavir plus lamivudine.

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

• For antiretrovirally pre-treated adults for whom combination therapy with an integrase inhibitor is the first-line treatment option, there is no evidence of additional benefit compared with the appropriate comparator therapy—a combination of raltegravir with an individualised backbone therapy depending on prior treatment(s) 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.
• The SAILING study is not suitable for the evaluation of the fixed-dose combination of dolutegravir/abacavir/lamivudine.
• For antiretrovirally pre-treated adults for whom combination therapy with an integrase inhibitor is the first-line treatment option, there is therefore no evidence of additional benefit from dolutegravir/abacavir/lamivudine.

d) antiretrovirally pre-treated adults for whom combination therapy with an integrase inhibitor is a secondary treatment option

• For antiretroviral-treated adults for whom combination therapy with an integrase inhibitor is a secondary treatment option, an additional benefit is not proven.
• Compared with the appropriate comparator therapy – an individualised antiretroviral regimen 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, there are no data are available for dolutegravir/abacavir/lamivudine.

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

• An additional benefit is not proven for antiretrovirally pre-treated, HIV-1-infected adolescents aged 12 years and over.
• Compared with the appropriate comparator therapy—an individualised antiretroviral regimen 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, no data are available for dolutegravir/abacavir/lamivudine in antiretrovirally pre-treated, HIV-1-infected adolescents aged 12 years and over.

Courtesy translation only, please refer to the German original.