Purpose Methods Demographics of patients in the study Outcome. Efficacy Adverse Event. Limitation

Transcription

1 ANDREW LEE

2 Purpose Methods Demographics of patients in the study Outcome Efficacy Adverse Event Limitation

3 Dolutegravir Integrase inhibitor Plasma half life 14hours Tivicay FDA (US)- 13 August mg once daily

4 Purpose TO compare efficacy Dolutegravir vs Darunavir and Boosted Ritonavir (recommended as one the of the 1 st line treatment for HIV- 1, treatment naïve patient)

5 IDENTIFIED INCIDENCE AND SEVERITY OF ADVERSE EVENTS CHANGES IN LABORATORY VARIABLES TIME TO VIROLOGICAL SUPPRESSION MEASURE OUTCOME OF QUALITY OF LIFE TREATMENT EMERGENT GENOTYPIC OR PHENOTYPIC EVIDENCE OF RESISTANCE

6 METHODS Multicentre Open label Phase 3b, non inferiority study HIV 1 RNA infected antiretroviral therapy naïve adults with at least HIV 1 RNA of 1000 copies NO Anti Retroviral Therapy resistance at screening

7 64 research centres in 9 countries worldwide USA RUSSIA PUERTO RICO

8 GERMANY SWITZERLAND FRANCE ROMANIA SPAIN ITALY

9 Patients are randomly assigned with the intention to treat (1:1) Dolutegravir 50mg ONCE Daily Investigator-(discretion) Darunavir 800mg + Ritonavir 100mg Once daily Tenofoviremtricitabine Abacavir- Lamivudine Further randomly stratified to: HIV RNA < HIV RNA >

10 Recruitment begin on 31/10/2011 to 24/5/2012

11 BASELINE DEMOGRAPHICS OF PATIENTS IN STUDY

12 Follow up done at Week 2, 4, 8, 12, 16, 24, 36, 48 Last finding of 48 weeks analysis on 22/4/2013

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15 In patients with baseline HIV RNA of > copies per ml, the response rate was higher for patients in the dolutegravir treatment group than for patients in the darunavir + ritonavir treatment group(70%), irrespective of the background dual NRTI given. Number of participants is too small to draw definitive conclusion (25% of total patients in each group)

16 CD4 increment at week 48 from baseline DOLUTEGRAVIR Median 210 (IQR ) DARUNAVIR + RITONAVIR Median 210 (IQR )

17 Other positive outcomes

18 Changes in lipid profile through week 48 were more favourable for dolutegravir compared with darunavir + ritonavir Mean increase in fasting LDL cholestrol at week 48 was significantly lower in the dolutegravir group than in the darunavir plus ritonavir group. Adjusted mean difference, -0.30, 95% CI, -042 to 0.19, p<0.0001)

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20 PROTOCOL DEFINED VIROLOGICAL DOLUTEGRAVIR (tenofovir-emtricitabine) FAILURE HIV 1 RNA VIRAL LOAD NUMBER OF WEEK 1 st 2270 WEEK 24 2 nd 668 WEEK 24 Darunavir + Ritonavir (abacavir- lamivudine) 1 st 218 WEEK 48 2 nd WEEK 36

21 No patients developed resistance in these 2 arms

22 Adverse Events

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26 SERUM CREATININE CHANGE FROM THE BASELINE VALUE dolutegravir darunavir plus ritonavir 24.8 to 48.6micromol/L -24 to 37.1 micromol/l Increase in serum creatinine were evident in the dolutegravir group by week 2 but remained stable after week 2 to week 48. No patients had grade 3 or 4 toxic effects

27 DECREASE TUBULAR SECRETION OF CREATININE DOLUTEGRAVIR - INCREASE SERUM CREATININE CONCENTRATION

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29 TRANSAMINITIS MAXIMUM TREATMENT EMERGENCE AMINO TRANSFERASE (> 3x UPPER LIMIT OF NORMAL) MET TREATMENT STOPPING CRITERIA FOR HEPATOTOXICITY DOLUTEGRAVIR 9/243 (4%) 1 PATIENT(<1%) (PATIENT HAD BARBITURATE) DARUNAVIR + RITONAVIR 6/242 (2%) 4 PATIENTS (2%) (CHRONIC HEP B, ACUTE HEP C)

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31 Limitations Low number of the non-white, female, and co-infected (HIV and hepatitis B or HIV and hepatitis C Not fully representative of HIV global epidemic Good baseline immunity in most of the patients in the study (CD4 count around 400) Well known fact, Integrase Inhibitor tends to reduce the viral load quickly less than 8weeks, protease inhibitor tends to reduce viral load slowly(detectable but falling viral load even after 48weeks) Therefore longer follow up needed, spring 2b 96weeks follow up SELECTIVE BIAS- from patients and investigators There is no virological data for 4% of patients in dolutegravir arm and 10% of patients in darunavir + ritonavir arm

32 This regime Not be used in HLA-B*5701 group

33 Conclusion Data- Dolutegravir superior to rdrv. Would you start using Kivexa/ DLG in all treatment-naïve patients?

34 IN MY OPINION, Not in Singapore Was not well study in Asian and female population Unknown long term efficacy (>1 year) Still undergoing longer period of Phase IIIb trial Unknown efficacy in patients with AIDS/CD4 count less than 200

35 UNDENIEDBLY, Appealing treatment option- able to reduce viral load rapidly in vivo May consider this treatment in Caucasian male

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37 Additional comments When evaluating RCT, use Patient Intervention Comparator Outcome

38 Main caution - Outcome Benefit extremely dependent on rate of discontinuation in comparator arm (virologic efficacy no difference): Open label study can affect the above. Subjective adverse effects (e.g. giddiness) may be dependent on sociocultural context. Clinically we are concerned with long-term virologic suppression. Is 48 wk < 50 c/ml ITT the most clinically relevant outcome? Likely no in real-world clinical practice where we can switch regimens in small proportion for adverse effects.

39 Overall Still EFV-based regimen as first-line barring contraindications.