Dolutegravir-Rilpivirine (Juluca

Dolutegravir-Rilpivirine (Juluca)

Last Updated: November 30, 2017

David H. Spach, MDClinical Director, MW AETCProfessor of MedicineDivision of Infectious DiseasesUniversity of Washington

Dolutegravir-RilpivirineJuluca (Jah-LOO-kah)

ANTIRETROVIRAL THERAPY

Disclosures

Dr. Spach has no conflicts of interest


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


Photograph courtesy of ViiV

Dolutegravir-Rilpivirine

INSTI NNRTI

50 mg 25 mg

Dose: 1 tablet once daily with a meal

HIV: Antiretroviral Therapy

Integrase Inhibitors

Non-Nucleoside RTI

HIV




INSTI NNRTI

50 mg 25 mg


HIV Integration Into Host DNA

Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

Host DNA

IntegraseIntegrase

HIV DNA



HIV DNA

Host DNA Host DNA


HIV DNA

Host DNA Host DNA


Host DNA Host DNA

Proviral HIV DNA

HIV Integration Integrase Strand Transfer Inhibitor


Integrase Strand Transfer Inhibitor

HIV Integrase



Host DNA

Integrase

HIV DNA

Integrase Strand Transfer Inhibitor




INSTI NNRTI

50 mg 25 mg


HIV Reverse TranscriptionConversion of HIV RNA to HIV DNA


HIV DNAHIV RNA

Reverse Transcriptase

Nucleotides (human)

Inhibition of HIV Reverse TranscriptionNonnucleoside Reverse Transcriptase Inhibitor (NNRTI)



NNRTI Binding Pocket

Polymerase Active Site




Polymerase Active Site

NNRTI Inhibitor

NNRTI BindingPocket


Hyperextended thumb region



NNRTI Inhibitor

Altered Polymerase Active Site

Dolutegravir plus Rilpivirine as Maintenance Dual TherapySWORD-1 and SWORD-2

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


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)


• 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


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


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

Questions

Dolutegravir-Rilpivirine (Juluca

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