Trial Designs

Dolutegravir-based regimens have been evaluated in three Phase 3, active-control, noninferiority, treatment-naïve trials1-4

  • Baseline characteristics: Median age was 35 years, 84% of patients were male, 24% were of African American/African heritage, 68% were white, 32% had HIV-1 RNA >100,000 copies/mL, 53% had CD4+ T-cell counts <350 cells/mm3, 7% had hepatitis C virus co-infection,* and 4% were CDC Class C (AIDS)
     
  • Primary endpoint: Proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 using FDA snapshot analysis with 10% noninferiority margin with prespecified tests for superiority

*Hepatitis B virus co-infection was an exclusion criterion.

ABC/3TC=abacavir/lamivudine; TDF/FTC=tenofovir/emtricitabine; CrCl=creatinine clearance; CDC=Centers for Disease Control and Prevention.

  • Baseline characteristics: Median age was 36 years, 87% of patients were male, 11% were of African American/African heritage, 85% were white, 28% had HIV-1 RNA >100,000 copies/mL, 48% had CD4+ T-cell counts <350 cells/mm3, 11% had hepatitis B and/or C virus co-infection, 2% were CDC Class C (AIDS), and 39% received ABC/3TC
  • Primary endpoint: Proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 using FDA snapshot analysis with 10% noninferiority margin with prespecified tests for superiority

808 patients included in the efficacy and safety analyses.

  • Baseline characteristics: Median age was 34 years, 85% of patients were male, 23% were of African American/African heritage, 72% were white, 25% had HIV-1 RNA >100,000 copies/mL, 35% had CD4+ T-cell counts <350 cells/mm3, 10% had hepatitis B and/or C virus co-infection, 3% were CDC Class C (AIDS), and 33% received ABC/3TC
  • Primary endpoint: proportion of patients with HIV-1 RNA <50 copies/mL at Week 48 using FDA snapshot analysis with 12% noninferiority margin with prespecified tests for superiority

484 patients included in the efficacy and safety analyses.

*Hepatitis B virus co-infection was an exclusion criterion.

ABC/3TC=abacavir/lamivudine; TDF/FTC=tenofovir/emtricitabine; CrCl=creatinine clearance; CDC=Centers for Disease Control and Prevention.

808 patients included in the efficacy and safety analyses.

484 patients included in the efficacy and safety analyses.

Virologic Response

Proven virologic response for patients taking dolutegravir-based regimens (snapshot analysis: proportion of patients with HIV-1 RNA <50 copies/mL)4

Statistically superior difference:
  • Treatment difference (8.3% [95% CI; 2.0%, 14.6%]) was driven primarily by rates of discontinuation due to adverse events (4% for the regimen with TIVICAY vs 14% for efavirenz/TDF/FTC)
Noninferior difference:
  • Treatment difference was 4.9% (95% CI; –0.6%, 10.3%)
Statistically superior difference:
  • Treatment difference (12.4% [95% CI; 4.7%, 20.2%]) was driven primarily by treatment difference in the HIV-1 RNA >100,000 copies/mL viral load stratum (82% for the regimens with TIVICAY and 52% for the darunavir/ritonavir regimens), rates of discontinuation due to AEs (2% vs 5%, respectively), and rates of discontinuation due to other reasons (protocol deviation, lost to follow-up, or withdrew consent; 8% vs 12%, respectively)
  • Direct comparisons across trials should not be made due to differing trial designs

Resistance Results

High barrier to resistance with dolutegravir is supported by treatment-naïve results4

  • In SINGLE, no patients receiving TIVICAY had detectable decreases in susceptibility to dolutegravir or background NRTIs (ABC/3TC) in the resistance analysis data set (n=11 with confirmed HIV-1 RNA >400 copies/mL at failure or last visit and having resistance data)

Number of patients with treatment-emergent INSTI, NNRTI, or NRTI substitutions with decreased susceptibility to ARVs studied based on the resistance analysis data set through 144 weeks4

INSTI=integrase strand transfer inhibitor; NNRTIs=non-nucleoside reverse transcriptase inhibitors; NRTI=nucleoside reverse transcriptase inhibitor; ARVs=antiretrovirals.

  • While there were no detectable decreases in susceptibility to dolutegravir or background NRTIs (ABC/3TC), 2 patients with virologic failure assigned to dolutegravir had treatment-emergent G/D/E193D and G193G/E integrase substitutions at Week 84 and Week 108, respectively, and 1 subject with 275 copies/mL HIV-1 RNA had a treatment-emergent Q157Q/P integrase substitution detected at Week 24
  • In SPRING-2, no patients receiving TIVICAY had detectable decreases in susceptibility to dolutegravir or background NRTIs (ABC/3TC or TDF/FTC) in the resistance analysis data set (n=1 with confirmed HIV-1 RNA >400 copies/mL at failure or last visit and having resistance data)

Number of patients with treatment-emergent INSTI or NRTI substitutions with decreased susceptibility to ARVs studied based on the resistance analysis data set through 96 weeks4

  • In FLAMINGO, no patients receiving TIVICAY had detectable decreases in susceptibility to dolutegravir or background NRTIs (ABC/3TC or TDF/FTC) in the resistance analysis data set (n=2 with confirmed HIV-1 RNA >400 copies/mL at failure or last visit and having resistance data)

Number of patients with treatment-emergent INSTI, PI, or NRTI substitutions with decreased susceptibility to ARVs studied based on the resistance analysis data set through 96 weeks4

PI=protease inhibitor.

 

  • Direct comparisons across trials should not be made due to differing trial designs

Discontinuations Due to AEs

Proportion of patients who discontinued due to adverse events in treatment-naïve trials4

AEs=adverse events.



  • Direct comparisons across trials should not be made due to differing trial designs

Adverse Drug Reactions

Grades 2 to 4 treatment-emergent adverse drug reactions in treatment-naïve trials (≥2% frequency)4

Grade 1 insomnia rates:

  • 7% and 4% in patients receiving TIVICAY and efavirenz/TDF/FTC, respectively
  • These events were not treatment limiting

Grade 1 insomnia rates:

  • 1% and <1% in patients receiving TIVICAY and raltegravir, respectively
  • These events were not treatment limiting

Grade 1 insomnia rates:

  • 1% and 2% in patients receiving TIVICAY and darunavir/ritonavir, respectively1
  • These events were not treatment limiting

§Includes pooled terms: rash, rash generalized, rash macular, rash maculopapular, rash pruritic, and drug eruption.

 


  • Direct comparisons across trials should not be made due to differing trial designs

Please see full Prescribing Information for TIVICAY.

 

References

  1. Walmsley S, Baumgarten A, Berenguer J, et al. Dolutegravir plus abacavir/lamivudine for the treatment of HIV-1 infection in antiretroviral therapy-naive patients: week 96 and week 144 results from the SINGLE randomized clinical trial. J Acquir Immune Defic Syndr. 2015;70:515-519.
  2. Raffi F, Jaeger H, Quiros-Roldan E, et al; on behalf of the SPRING-2 Study Group. Once-daily dolutegravir versus twice-daily raltegravir in antiretroviral-naive adults with HIV-1 infection (SPRING-2 study): 96 week results from a randomised, double-blind, non-inferiority trial. Lancet Infect Dis. 2013;13(11):927-935.
  3. Molina J-M, Clotet B, van Lunzen J, et al. Once-daily dolutegravir versus darunavir plus ritonavir for treatment-naive adults with HIV-1 infection (FLAMINGO): 96 week results from a randomized, open-label, phase 3b study. Lancet HIV. 2015;2:e127-e136.
  4. Data on file. ViiV Healthcare group of companies. Research Triangle Park, NC.