Dolutegravir-Rilpivirine (Juluca)

Transcription

1 Dolutegravir-Rilpivirine (Juluca) David H. Spach, MD Clinical Director, MW AETC Professor of Medicine Division of Infectious Diseases University of Washington Last Updated: November 30, 2017

2 ANTIRETROVIRAL THERAPY Dolutegravir-Rilpivirine Juluca (Jah-LOO-kah)

3 Disclosures Dr. Spach has no conflicts of interest

4 Dolutegravir-Rilpivirine (Juluca) Indication Complete 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 Source: Juluca Prescribing Information

5 Dolutegravir-Rilpivirine (Juluca) Dolutegravir-Rilpivirine 50 mg 25 mg INSTI NNRTI Dose: 1 tablet once daily with a meal Photograph courtesy of ViiV

6 HIV: Antiretroviral Therapy HIV Integrase Inhibitors Non-Nucleoside RTI

7 Dolutegravir-Rilpivirine (Juluca) Dolutegravir-Rilpivirine 50 mg 25 mg INSTI NNRTI Dose: 1 tablet once daily with a meal Photograph courtesy of ViiV

8 HIV Integration Into Host DNA HIV DNA Integrase Integrase Host DNA Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

9 HIV Integration Into Host DNA HIV DNA Host DNA Host DNA Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

10 HIV Integration Into Host DNA HIV DNA Host DNA Host DNA

11 HIV Integration Into Host DNA Proviral HIV DNA Host DNA Host DNA

12 HIV Integration Integrase Strand Transfer Inhibitor Integrase Strand Transfer Inhibitor HIV Integrase Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

13 HIV Integration Into Host DNA HIV DNA Integrase Integrase Strand Transfer Inhibitor Host DNA Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

14 Dolutegravir-Rilpivirine (Juluca) Dolutegravir-Rilpivirine 50 mg 25 mg INSTI NNRTI Dose: 1 tablet once daily with a meal Photograph courtesy of ViiV

15 HIV Reverse Transcription Conversion of HIV RNA to HIV DNA Nucleotides (human) HIV DNA HIV RNA Reverse Transcriptase Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

16 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) Polymerase Active Site NNRTI Binding Pocket Reverse Transcriptase Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

17 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) NNRTI Inhibitor Polymerase Active Site NNRTI Binding Pocket Reverse Transcriptase Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

18 Inhibition of HIV Reverse Transcription Nonnucleoside Reverse Transcriptase Inhibitor (NNRTI) NNRTI Inhibitor Hyperextended thumb region Altered Polymerase Active Site Reverse Transcriptase Ilustration: David Ehlert (Cognition Studio) and David Spach, MD

19 Dolutegravir plus Rilpivirine as Maintenance Dual Therapy SWORD-1 and SWORD-2

20 Dolutegravir plus Rilpivirine as Maintenance Dual Therapy SWORD-1 and SWORD-2: Design Study Design: SWORD-1 and Sword-2 Background: Identical randomized, multinational, open-label, industrysponsored, 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 - 1 st or 2 nd regimen - HIV RNA <50 copies/ml in prior 12 months - HIV RNA <50 copies/ml at screening - No HBV co-infection Regimen (Once daily) - Dolutegravir 50 mg + Rilpivirine 25 mg Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA. Early Switch Phase 52 weeks 96 weeks Continue 3-4-Drug ART (n = 511) Early Switch DTG + RPV (n = 513) Late switch phase Late Switch Dolutegravir (n = 511) *Primary endpoint for early switch phase: week 48 HIV RNA <50 copies/ml by FDA snapshot analysis

21 Dolutegravir plus Rilpivirine as Maintenance Dual Therapy SWORD-1 and SWORD-2: Baseline Characteristics Baseline Characteristic DTG + RPV (n=513) 3 or 4-Drug ART (n=511) Age (mean) Age >50 years 147 (29%) 142 (28%) Female 120 (23%) 108 (21%) Race, non-white 92 (18%) 111 (22%) CD4 count (median) 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 Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

22 Dolutegravir plus Rilpivirine as Maintenance Dual Therapy SWORD-1 and SWORD-2: Pooled Results at Week 48 Week 48 Virologic Response (by FDA Snapshot Analysis) HIV RNA <50 copies/ml (%) Dolutegravir + Rilpivirine / /511 Continued 3 or 4-Drug ART Confirmed virologic withdrawal: 2 (<1%) in each arm One NNRTI resistance mutation (K101K/E) detected in DTG + RPV arm No integrase resistance occurred Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

23 Dolutegravir plus Rilpivirine as Maintenance Dual Therapy SWORD-1 and SWORD-2: Pooled Results at Week 48 Week 48: Change in Plasma Lipids from Baseline Change in Mean Value (mg/dl) Dolutegravir + Rilpivirine Continued 3 or 4-Drug ART Total Cholesterol LDL HDL Triglycerides Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

24 Dolutegravir plus Rilpivirine as Maintenance Dual Therapy SWORD-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 noninferior 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 plus rilpivirine [2-drug regimen] offers the potential for reduction in cumulative ART exposure, without an increased risk of virologic failure. Source: Llibre JM et al. Abstract 44LB. CROI Seattle, WA.

25 Dolutegravir and Inhibition of Tubular Secretion of Creatinine Tubular Secretion Peritubular capillary Organic Cation Transporter 2 (OCT2) Dolutegravir Rilpivirine Dolutegravir Rilpivirine Decreases tubular secretion of creatinine via inhibition of OCT2 Excretion

26 Dolutegravir-Rilpivirine (Juluca) Impact on Serum Creatinine Dolutegravir: increase mg/dl Rilpivirine Studies: increase 0.1 mg/gl Dolutegravir plus Rilpivirine Studies: increase 0.09 mg/dl

27 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

28 Questions