The Dawn of the TLD Era

Transcription

1 The Dawn of the TLD Era 20th September 2018 Mark Siedner Africa Health Research Institute Harvard Medical School

2 Outline: A Primer on Dolutegravir Do we really need more HIV drugs? The case for a new first-line regimen How Does it Work? Mechanism and pharmacology How Well Does it Work? Efficacy and clinical experience Is it all Roses and Rainbows? Toxicity and potential teratogenicity The W s of DTG in South Africa Who, when, why, and where Unanswered questions Yours and mine

3 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap No as dirt drug interactions (rifampin?) Potent Safe and high barrier to resistance in pregnancy Non-toxic

4 Do we really need more HIV drugs? The case for a new first-line regimen

5 Question 1 Approximately what proportion of people in South Africa are initially infected with a drugresistance virus? a. b. c. d. Approximately 1% Approximately 3% Approximately 5% Approximately 10%

6 Question 1 Approximately what proportion of people in South Africa are initially infected with a drugresistance virus? a. b. c. d. Approximately 1% Approximately 3% Approximately 5% Approximately 10%

7 Pre-treatment Drug Resistance in SSA Gupta et al, Lancet HIV 2017

8 Question 2 Approximately what proportion of people in South Africa have drug resistance at the time of detected virologic failure? a. b. c. d. Approximately 5% Approximately 20% Approximately 50% Approximately 80%

9 Question 2 Approximately what proportion of people in South Africa have drug resistance at the time of detected virologic failure? a. b. c. d. Approximately 5% Approximately 20% Approximately 50% Approximately 80%

10 At Failure, Resistance is the Rule Gregson et al, Lancet HIV 2016

11 Do we really need more HIV drugs? Emergence of pre-treatment and acquired drug resistance has provided an urgent need for newer classes of ART in the region

12 How does it work? Dolutegravir mechanism and pharmacology

13 Kumar et al, Mol Cell Ther, 2014

14 Smith et al, Retrovirology, 2018

15 Question 3 Which of the following drugs should not be used in combination with dolutegravir? a. b. c. d. e. Rifampin Metformin Efavirenz Warfarin All can be used with dolutegravir

16 Question 3 Which of the following drugs should not be used in combination with dolutegravir? a. b. c. d. e. Rifampin Metformin Efavirenz Warfarin All can be used with dolutegravir

17 Pharmacology ~100% hepatically metabolized and cleared No dose adjustment in moderate hepatic failure Not impacted by renal impairment Co-formulations with TDF do require renal dosing Separate DTG and TDF/XTC if GFR<50 12-hour half-life without need for boosting Once daily dosing adequate in most situations* Few meaningful drug interactions QD/BD dosing increases metformin levels by ~80%/~140% EFV and ETR both significantly decrease dolutegravir levels Kandel et al, Drug, Design Dev 2015;Song et al, J Acquir Defic Syndr, 2016; Song et al, Clin Pharm Drug Dev, 2013

18 Pharmacology Standard dose of 50mg daily Co-formulations in the United States and Europe ABC/3TC/DTG 600/300/50 RPV/DTG 25/50 Co-formulations in sub-saharan Africa TDF/3TC/DTG 300/300/50 Mylan pharmaceuticals Kandel et al, Drug, Design Dev 2015 TLD

19 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap No as dirt drug interactions (rifampin?) Potent Safe and high barrier to resistance in pregnancy Non-toxic

20 But what is the bottom line? Estimated Annual Cost/Patient ($) TLD TLE

21 Cost-Effectiveness of Dolutegravir No change GRT prior ART DTG prior ART Philipps et al, Lancet HIV, 2017 GRT for all DTG for all

22 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap as dirt No drug interactions (rifampin?) Potent Safe and high barrier to resistance in pregnancy Non-toxic

23 Dolutegravir-Rifampin Interactions Dolutegravir co-administration with rifampin Metabolized by UGT1A1 & CYP3A4 Both activated by rifampin Healthy volunteers DTG+RIF reduced DTG Ctau by 72% 50 DTG BID + RIF n DTG Concentration ng/ml (Cmin) Week Week DTG QD - RIF n DTG Concentration ng/ml (Cmin) Week Week Dooley et al, CROI, 2018

24 Dolutegravir-Rifampin Interactions 24-week Snapshot DTG 50 BID + 2 NRTIs (n=69) EFV + 2 NRTIs (n=44) Dooley et al, CROI, 2018

25 Dolutegravir-Rifampin Interactions Preliminarily appears safe and effective with rifampin Dosing when co-administered with rifampin DTG at dose of 50 bid In practice: TLD 300/50/50 qpm DTG 50mg qam

26 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap as dirt No drug interactions (rifampin?) Potent Safe and high barrier to resistance in pregnancy Non-toxic

27 How well does it work? Clinical efficacy of dolutegravir

28 Question 4 What proportion of ART-naïve individuals in randomized trials starting dolutegravir-based ART have developed documented INSTIresistance? a. b. c. d. 0% 3% 5% 10%

29 Question 4 What proportion of ART-naïve individuals in randomized trials starting dolutegravir-based ART have developed documented INSTIresistance? a. b. c. d. 0% 3% 5% 10%

30 Dolutegravir in ART Naive Walmsly et al, JAIDS, 2015

31 SPRING-21 (to Week 96)* Subjects with persistent virologic failure, n (%) Genotypic results at time of failure, n (%) INSTI-resistant mutations, n (%)* RT genotypic results available at time of PDVF, n NRTI-resistant mutations, n (%)* SINGLE2 (to Week 144)* FLAMINGO3 (to Week 96) ARIA4 (to Week 48) DTG + 2NRTI (n=411) RAL + 2NRTI (n=411) DTG + ABC/3TC (n=414) EFV/ TDF/FTC (n=419) DTG + 2NRTI (n=242) 20 (5) 28 (7) 39 (9) 33 (8) 2 (<1) 4 (2) 6 (2) 4 (2) (0) 1 (6) 0 (0) 0 (0) 0 (0) 0 (0) (0) 4 (21) 0 1 ( K65K/R) 0 (0) 0 (0) 0 (0) 1 (M184V) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) 0 (0) NNRTI-resistant mutations, n (%)* 0 6 (K101E, K103N, K103K/N, G190G/A) PI-resistant mutations, n (%) 0 0 (0) Raffi et al. Lancet Infect Dis 2013;13:927 35; Walmsley et al. J Acquir Immune Defic Syndr 2015;70:515 19; Molina et al. Lancet HIV 2015;2:e127 36; Orrell et al. Lancet HIV 2017; 4(12):e DRV/r + DTG/ABC/3T 2NRTI (n=242) C (n=248) ATV/r + TDF/FTC (n=247) Slide Courtesy of Ravi Gupta

32 Dolutegravir at First-Line Failure HIV-1 RNA <50 c/ml, % DTG + 2 NRTIs (ITT-E, n=312) 60 LPV/RTV + 2 NRTIs (ITT-E, n=312) 40 DTG + 2 NRTIs (PP, n=282) 20 LPV/RTV + 2 NRTIs (PP, n=275) 0 Virologic Aboud et al, IAS, 2017

33 Dolutegravir at First-Line Failure DTG + 2 NRTIs (n=8) LPV/RTV + 2 NRTIs (n=24) INSTI 0 0 NRTI 0 3* K70R 0 2 M184V 0 1 K219Q 0 1 K219E Resistance analysis PI No subject receiving DTG + 2 NRTIs developed INSTI or NRTI resistance-associated mutations. Aboud et al, IAS, 2017

34 Dolutegravir as Salvage Therapy Cahn et al, Lancet HIV 2017

35 Proportion Dolutegravir in INSTI-experienced Viral Suppression <50 at 24 weeks DTG 50 QD Eron et al, J Infect Dis 2013 Emergent INSTI Resistance DTG 50 BD

36 Dolutegravir Efficacy Summary Highly potent as first-line therapy Outperforms EFV and ATV/R due to less toxicity Similar in efficacy to RAL and DRV/R Potent and efficacious as second-line Outperforms LPV/R Very high barrier to resistance in those without prior INSTI experience Efficacy as third line regimen Most recommend 50mg bid dosing for prior INSTI experience

37 Dolutegravir as Monotherapy (Never say never) Wijting et al, Lancet HIV 2017

38 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap as dirt No drug interactions (rifampin?) Potent and high barrier to resistance Safe in pregnancy Non-toxic

39 Is it all roses and rainbows? Toxicity and potential teratogenicity

40 Question 5 Which of the following potential toxicities have been reported with dolutegravir? a. b. c. d. Weight gain Abnormal dreams Increase in creatinine Neural tube defects among women taking it at the time of conception e. All of the above

41 Question 5 Which of the following potential toxicities have been reported with dolutegravir? a. b. c. d. Weight gain Abnormal dreams Increase in creatinine Neural tube defects among women taking it at the time of conception e. All of the above

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43 DTG and Neural Tube Defects

44 Zash et al, NEJM 2018

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47 Women presenting in pregnancy* Zash et al, Lancet GH, 2018 *Median gestation at ART initiation: 19 vs 21 weeks

48 Women presenting in pregnancy* Orrell et al, AIDS 2018 *After 28 weeks gestation

49 Modeling DTG use in pregnancy Phillips et al, AIDS 2018

50 Modeling DTG use in pregnancy Outcome* EFV DTG Outcomes among women Number of deaths among 314, ,800 women Outcomes among children Pediatric HIV infections 21,400 16,100 Neural tube defects 600 8,200 Cumulative pediatric deaths** 100, ,200 Combined outcomes among women and children Cumulative deaths among 414, ,000 women and children Δ 31,600 5,300 7,600 5,900 25,700 *Out of projected 3.7 million women ever on first-line ART and 1.2 million HIV-exposed children. **Cumulative pediatric deaths = non-neural tube defect-related + neural tube defect-related deaths Dugdale et al, AIDS 2018

51 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap as dirt No drug interactions (rifampin?) Potent and high barrier to resistance Safe in pregnancy Non-toxic?

52 DTG Use in Children Early, promising, but still limited data Appears relatively safe and well tolerated in Adolescents Children 2-6 years old Odyssey Study forthcoming Ruel et al, CROI 2017 Wiznia et al, CROI 2016 Viani et al, Pediatr Infect Dis J, 2015

53 DTG versus other INSTI Dosing Boosting Required? Barrier to Resistance Generic Once Daily Coformulation Raltegravir Twice daily No Low No Likely Elvitegravir Once daily Yes High No? Bicegravir Once daily No High No? Once daily No High Yes? INSTI Dolutegravir Safety in Pregnancy

54 Toxicity of DTG in Clinical Trials

55 Toxicity of DTG in Clinical Trials Walmsly et al, NEJM, 2013

56 Toxicity of DTG in Clinical Trials Raffi et al, Lancet, 2013

57 Other Considerations: Increased Cr Walmsly et al, NEJM, 2013

58 Toxicity in Real World: Psych Effects? Hoffmann et al, HIV Med, 2017 Yagura et al, CROI, 2017

59 Toxicity in Real World: Weight Gain? Norwood et al, JAIDS, 2017

60 Toxicity in Real-World: IRIS? Wijting et al, CROI, 2017

61 Event rate/100 PY(hazard) Randomized to: 2 NRTI + NNRTI 2 NRTI + NNRTI + RAL IRIS Events 0 REALITY trial: ART naïve adults/children in Africa, CD4 <100 (n=1805) Median CD4 <50; 74% with VL >100K 150 Toxicity in Real-World: IRIS? 0 More rapid decline in VL in RAL group Week since randomisation (ART initiation) Standard Raltegravir-intensified No difference in IRIS Gibbs DA et al, CROI 2018 (Slide Courtesy of Raj Gandhi) IRIS ART + RAL ART 9.9% 9.5% 48

62 Dolutegravir Toxicity Summary Very well tolerated in clinical trials Non-significant increase in Cr without GFR change But beware the T of TLD In observational cohort studies Weight gain Abnormal dreams/psychiatric effects IRIS

63 What do we want from 1st line ART? Easy to take (one pill/once per day) Cheap as dirt No drug interactions (rifampin?) Potent and high barrier to resistance Safe in pregnancy Non-toxic? (mostly)

64 The W s of DTG use in South Africa Who, when, why, and where

65 2017 WHO Guidance WHO Policy Brief, 2017

66 Current WHO Guidelines Population Preferred Alternatives Adult men and adolescent boys Pregnant (from eight weeks after conception) and breastfeeding women and adolescent girls TDF/3TC/DTG TDF/3(F)TC/EFV (400 or 600) Women and adolescent girls with effective contraception or not of childbearing potential Women and adolescent girls of childbearing potential who want to become pregnant and have no effective contraception WHO Treatment Guidelines, 2018 TDF/3(F)TC/EFV TDF + 3TC/FTC + PI/r

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68 Who Decides Who Gets TLD?

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70 DTG use in South Africa What? First-line therapy Who? Most everyone TBD: women of child bearing age When? Likely by April 2019

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72 Unanswered Questions (mine) Safety at conception, safety at conception, safety at

73 Unanswered Questions (mine) Safety What at conception, safety at conception, safety at about those on TLE? VL before switch? Window period? GRT before switch?

74 Unanswered Questions (mine) Safety What at conception, safety at conception, safety at about those on TLE? VL before switch? Window period? GRT before switch? A bit more on efficacy and safety in children (Odyssey)

75 Unanswered Questions (mine) Safety What at conception, safety at conception, safety at about those on TLE? VL before switch? Window period? GRT before switch? A bit more on efficacy and safety in children (Odyssey) Will TLD be as effective and immune to resistance: With multi-class resistance at time of switch? In non-clade B viruses? With TDF as partner drug? In the public sector in a very different epidemic

76 Unanswered Questions (mine) Safety What at conception, safety at conception, safety at about those on TLE? VL before switch? Window period? GRT before switch? A bit more on efficacy and safety in children (Odyssey) Will TLD be as effective and immune to resistance: With multi-class resistance at time of switch? In non-clade B viruses? With TDF as partner drug? In the public sector in a very different epidemic Role for INSTI both as PrEP and treatment?

77 Unanswered Questions (mine) Which No line is it? studies of DTG in people currently or previoulsy failing DTG

78 Question 6 In which populations would you consider use of DTG 50mg twice daily dosing? a. b. c. d. e. f. g. h. First-line NNRTI failure Concomitant use of rifampin Pregnancy Weight > 100kg Viral load > 100,000 copies/ml Prior exposure to integrase inhibitors All of the above b and f

79 Question 6 In which populations would you consider use of DTG 50mg twice daily dosing? a. b. c. d. e. f. g. h. First-line NNRTI failure Concomitant use of rifampin Pregnancy Weight > 100kg Viral load > 100,000 copies/ml Prior exposure to integrase inhibitors All of the above b and f

80 Question 7 What additional steps should one consider with use of DTG in women of child bearing age a. Pregnancy test before initiating therapy b. Council women on the risks and benefits of DTG use c. Before initiation, discussion of contraception use and desires for pregnancy d. Consider alternative therapy for those intending to become pregnant or known to be pregnant in first trimester e. Consider continuing therapy for those pregnant in the second trimester or later f. Ask about pregnancy intentions and contraception use at each visit for those currently on DTG-based therapy g. All of the above

81 Question 7 What additional steps should one consider with use of DTG in women of child bearing age a. Pregnancy test before initiating therapy b. Council women on the risks and benefits of DTG use c. Before initiation, discussion of contraception use and desires for pregnancy d. Consider alternative therapy for those intending to become pregnant or known to be pregnant in first trimester e. Consider continuing therapy for those pregnant in the second trimester or later f. Ask about pregnancy intentions and contraception use at each visit for those currently on DTG-based therapy g. All of the above

82 Thank you Henry Sunpath Ansuri Singh Raj Gandhi Vince Marconi Andrea Ciaranello Francois Venter Conference Organizers

83 Unanswered Questions (yours!)