Dolutegravir / Rilpivirin (1) – Juluca®

• Clinical trials
  • To assess the additional benefit for the patient group of antiretrovirally pre-treated (treatment-experienced) adults, the pharmaceutical manufacturer has drawn on the two open-label, parallel, randomised, controlled trials, SWORD-1 and SWORD-2, which have an identical design.
  • In the trials, dolutegravir/rilpivirin was compared with continuation of the previous treatment regimen consisting of two NRTIs and a third combination partner (NNRTI, PI or an INI).

Adult HIV-1 patients who are virologically suppressed and for whom the antiretroviral regimen has been discontinued for at least six months, have no history of virological failure and no known or suspected resistance to non-nucleoside reverse transcriptase inhibitors or integrase inhibitors.

• The additional benefit is not proven.
• mortality
  • The meta-analysis of the SWORD-1 and SWORD-2 studies shows no statistically significant difference between the treatment groups for the endpoint of overall survival.
  • Consequently, the additional benefit of dolutegravir/rilpivirine compared with continuing the previous therapy for the endpoint of mortality is not proven.
• Morbidity – AIDS-defining events (CDC Class C)
  • For the endpoint ‘AIDS-defining events’ (CDC Class C), the meta-analysis of the SWORD-1 and SWORD-2 studies shows no statistically significant difference between the treatment groups.
• Morbidity – Virological response/virological failure
  • For the endpoints of virological response and virological failure, the meta-analysis showed no statistically significant difference between the treatment arms.
• Morbidity – CD4 cell counts
  • For CD4 cell counts, the meta-analysis of the two studies, SWORD-1 and SWORD-2, showed no statistically significant difference between the treatment arms.
• Morbidity – HIV-associated events (CDC Class B)
  • For the endpoint of HIV-associated events (CDC Class B events), the meta-analysis showed no statistically significant difference between the treatment groups; therefore, additional benefit is not proven.
• Morbidity – Health status measured using the EQ-5D VAS
  • For the endpoint of health status assessed using the EQ-5D VAS, the meta-analysis shows no statistically significant difference between the treatment groups.
  • There is therefore no proof of additional benefit for this endpoint.
• Morbidity – HIV symptoms measured using the HIV Symptom Index (HIV-SI)
  • The meta-analysis revealed a statistically significant difference in favour of dolutegravir/rilpivirine (MD [95% CI]: -1.30 [-2.34; -0.26]; p=0.014).
  • To assess clinical relevance, the effect size is considered using Hedges’ g ([95% CI]: -0.17 [-0.30; -0.03]).
  • The 95% confidence interval does not lie entirely outside the irrelevance range of -0.2 to 0.2.
  • It cannot therefore be concluded that the effect is clinically relevant.
  • No additional benefit of dolutegravir/rilpivirine over the appropriate comparator therapy can be inferred.
• quality of life
  • The SWORD-1 and SWORD-2 studies did not investigate endpoints in the health-related quality of life category.
  • Consequently, the additional benefit of dolutegravir/rilpivirine compared with continuing the previous treatment is not proven for the quality of life endpoint.
• Side effects
  • For the endpoints of serious adverse events (SAEs) and severe adverse events (AEs; Division of AIDS (DAIDS) Grade 3–4), the meta-analysis showed no statistically significant difference between the treatment groups in either case.
  • For the endpoint of discontinuation due to AEs, the meta-analysis revealed a statistically significant difference to the detriment of dolutegravir/rilpivirin.
  • At the level of individual events considered relevant in the therapeutic indication for HIV, classified according to MedDRA terms SOC (System Organ Class) and PT (Preferred Term), statistically significant differences to the detriment of dolutegravir/rilpivirin were observed for the endpoints gastrointestinal disorders (SOC), nervous system disorders (SOC), psychiatric disorders (SOC) and disorders of the skin and subcutaneous tissue (SOC), each showed statistically significant differences to the detriment of dolutegravir/rilpivirin compared with continuation of previous therapy.
• Overall assessment
  • Overall, no data are available for patients with an indication for switching.
  • For patients without an indication for switching, the SWORD-1 and SWORD-2 studies provide results on mortality, morbidity and side effects.
  • In the morbidity category, a statistically significant advantage was observed for the endpoint ‘symptoms measured using the HIV Symptom Index’.
  • No clinical relevance can be inferred from this difference.
  • For the endpoints serious adverse events (SAE) and severe adverse events (AE; Division of AIDS (DAIDS) Grade 3–4), the meta-analysis showed no statistically significant difference between the treatment groups in either case.
  • For the endpoint ‘discontinuation due to AEs’, the meta-analysis revealed a statistically significant difference to the detriment of dolutegravir/rilpivirine.
  • For patients without an indication for treatment switch, a statistically significant difference to the detriment of dolutegravir/rilpivirin was identified in the meta-analysis in the ‘side effects’ category, at the level of individual events considered relevant in the therapeutic indication for HIV, for the endpoints of gastrointestinal disorders, nervous system disorders, psychiatric disorders and disorders of the skin and subcutaneous tissue, a statistically significant difference to the detriment of dolutegravir/rilpivirin was found in the meta-analysis.
  • Overall, however, it is questionable whether, in clinical practice, a switch from the current treatment would be initiated for patients for whom there are no medical reasons for a change in therapy.
  • A clear distinction between patients with and without an indication for switching is not readily transferable to everyday healthcare situations.
  • Furthermore, the generalisability of the results from the patient group without an indication for switching to the overall population of treatment-experienced adults is unclear.
  • The assessment of additional benefit is therefore carried out for the overall population of treatment-experienced adults.
  • In summary, for previously treated, HIV-1-infected adult patients, an overall assessment of the results regarding mortality, morbidity and side effects shows no additional benefit of dolutegravir/rilpivirin compared with the appropriate comparator therapy.

Courtesy translation only, please refer to the German original.