Dolutegravir-Rilpivirine (Juluca)
Last Updated: November 30, 2017
David H. Spach, MDClinical Director, MW AETCProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington
Dolutegravir-Rilpivirine (Juluca)
Source: Juluca Prescribing Information
IndicationComplete regimen to replace current ARV in those who are:- Virologically suppressed (HIV-1 RNA <50 copies per mL) - On a stable antiretroviral regimen for ≥6 months- No history of treatment failure- No known resistance to dolutegravir or rilpivirine
Dolutegravir-Rilpivirine (Juluca)
Photograph courtesy of ViiV
Dolutegravir-Rilpivirine
INSTI NNRTI
50 mg 25 mg
Dose: 1 tablet once daily with a meal
Dolutegravir-Rilpivirine (Juluca)
Photograph courtesy of ViiV
Dolutegravir-Rilpivirine
INSTI NNRTI
50 mg 25 mg
Dose: 1 tablet once daily with a meal
HIV Integration Into Host DNA
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
Host DNA
IntegraseIntegrase
HIV DNA
HIV Integration Into Host DNA
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
HIV DNA
Host DNA Host DNA
HIV Integration Integrase Strand Transfer Inhibitor
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
Integrase Strand Transfer Inhibitor
HIV Integrase
HIV Integration Into Host DNA
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
Host DNA
Integrase
HIV DNA
Integrase Strand Transfer Inhibitor
Dolutegravir-Rilpivirine (Juluca)
Photograph courtesy of ViiV
Dolutegravir-Rilpivirine
INSTI NNRTI
50 mg 25 mg
Dose: 1 tablet once daily with a meal
HIV Reverse TranscriptionConversion of HIV RNA to HIV DNA
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
HIV DNAHIV RNA
Reverse Transcriptase
Nucleotides (human)
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
Reverse Transcriptase
NNRTI Binding Pocket
Polymerase Active Site
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
Reverse Transcriptase
Polymerase Active Site
NNRTI Inhibitor
NNRTI BindingPocket
Reverse Transcriptase
Hyperextended thumb region
Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)
Ilustration: David Ehlert (Cognition Studio) and David Spach, MD
NNRTI Inhibitor
Altered Polymerase Active Site
Dolutegravir plus Rilpivirine as Maintenance Dual TherapySWORD-1 and SWORD-2: Design
Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.
Early Switch Phase
Early SwitchDTG + RPV
(n = 513)
Continue 3-4-Drug ART
(n = 511)
Late SwitchDolutegravir
(n = 511)
52 weeks 96 weeks
*Primary endpoint for early switch phase: week 48 HIV RNA <50 copies/mL by FDA snapshot analysis
Late switch phaseStudy Design: SWORD-1 and Sword-2• Background: Identical randomized,
multinational, open-label, industry-sponsored, parallel-group, non-inferiority studies of dolutegravir plus rilpivirine to maintain virologic suppression
• Inclusion Criteria:- Age ≥18 years of age- On stable 3-4 drug ART ≥6 months- No history of virologic failure - No resistance to DTG or RPV - 1st or 2nd regimen - HIV RNA <50 copies/mL in prior 12months- HIV RNA <50 copies/mL at screening- No HBV co-infection
• Regimen (Once daily)- Dolutegravir 50 mg + Rilpivirine 25 mg
Dolutegravir plus Rilpivirine as Maintenance Dual TherapySWORD-1 and SWORD-2: Baseline Characteristics
Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.
Baseline Characteristic DTG + RPV (n=513)
3 or 4-Drug ART (n=511)
Age (mean) 43 43
Age >50 years 147 (29%) 142 (28%)
Female 120 (23%) 108 (21%)
Race, non-white 92 (18%) 111 (22%)
CD4 count (median) 611 638
Baseline PI 133 (26%) 136 (27%)
Baseline NNRTI 275 (54%) 278 (54%)
Baseline INSTI 105 (20%) 97 (19%)
Baseline TDF 374 (73%) 359 (70%)
ART duration (median) 51 months 53 months
95 95
0
20
40
60
80
100
HIV
RN
A <5
0 co
pies
/mL
(%)
Dolutegravir + Rilpivirine Continued 3 or 4-Drug ART
Dolutegravir plus Rilpivirine as Maintenance Dual TherapySWORD-1 and SWORD-2: Pooled Results at Week 48
Week 48 Virologic Response (by FDA Snapshot Analysis)
Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.
• Confirmed virologic withdrawal: 2 (<1%) in each arm• One NNRTI resistance mutation (K101K/E) detected in DTG + RPV arm• No integrase resistance occurred
486/513 485/511
Dolutegravir plus Rilpivirine as Maintenance Dual TherapySWORD-1 and SWORD-2: Pooled Results at Week 48
Week 48: Change in Plasma Lipids from Baseline
Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.
0.1
1.01.5
-1.8
0.5
-1.0
1.3 1.1
-3
-2
-1
0
1
2
3
Total Cholesterol LDL HDL Triglycerides
Cha
nge
in M
ean
Valu
e (m
g/dL
)
Dolutegravir + Rilpivirine Continued 3 or 4-Drug ART
Dolutegravir plus Rilpivirine as Maintenance Dual TherapySWORD-1 and SWORD-2: Conclusion
Source: Llibre JM et al. Abstract 44LB. CROI 2017. Seattle, WA.
Conclusion: “A switch to a novel, once daily [2-drug regimen] of dolutegravir plus rilpivirine demonstrated high efficacy and was non-inferior to the continuation of [current ART] in virologically suppressed HIV-1-infected adults. The safety profiles of both dolutegravir and rilpivirine were consistent with the respective labels. A dolutegravir plusrilpivirine [2-drug regimen] offers the potential for reduction in cumulative ART exposure, without an increased risk of virologic failure.”
Dolutegravir and Inhibition of Tubular Secretion of Creatinine
Tubular Secretion
Excretion
Peritubular capillary
Dolutegravir
Decreases tubular secretion of creatinine via inhibition of OCT2
Organic Cation Transporter 2 (OCT2)Dolutegravir
Rilpivirine
Rilpivirine
Dolutegravir-Rilpivirine (Juluca)Impact on Serum Creatinine
• Dolutegravir: increase 0.1-0.15 mg/dL
• Rilpivirine Studies: increase 0.1 mg/gL
• Dolutegravir plus Rilpivirine Studies: increase 0.09 mg/dL
Dolutegravir-Rilpivirine (Juluca)Summary
• Main use as 2-drug step-down maintenance regimen
• Important to use only in carefully selected individuals
• Do not use as initial antiretroviral regimen
• Do use use with proton pump inhibitors (rilpivirine)
• Potential cost savings of long-term 2-drug regimens
• Additional use as component of salvage regimens