The Use of Integrase Inhibitors In Latin America: From Guidelines to the Real World Ernesto Martínez B., MD Internal Medicine, Infectious Diseases

Transcription

1 De afbeelding kan niet worden weergegeven. The Use of Integrase Inhibitors In Latin America: From Guidelines to the Real World Ernesto Martínez B., MD Internal Medicine, Infectious Diseases

2 DISCLOSURE C.O.I. 1. Honorary as speakers from MSD, ViiV, GSK, Gilead, Stendhal, Janssen and Abbvie 2. Honorary in Advisory Boards from MSD, ViiV/GSK, Gilead and Stendhal 3. Research Grants from ViiV/GSK. 4. Financial Support for medical Education foundations and networking from GSK, MSD, Stendhal, Abbvie and Janssen

3 Introudcton of INSTI into practice in the HIV treatment history UCHCC: UNC CFAR HIV Clinical Cohort (University of North Carolina) Percent 100% 90% 80% 70% 60% 50% 40% 30% 20% NRTI Only Initial Antiretroviral Therapy, UCHCC Other (including unboosted and other bpi) NNRTI bpi (LPV/r, DRV/r, ATV/r) 10% INSTI 0% Calendar Year RAL Oct, 2007 Stribild Aug, 2012 Triumeq Aug, 2014 Modified from Joe Eron

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6 A R T 1st World INSTI LATAM

7 WHO, 2013 EACS, 2013 BHIVA, 2013 GESIDA,2014 IAS, 2014 DHHS, 2014 ABC/3TCTDF/FTC EFV NVP RPV/TDF/FTC LPV/r ATV/r FPV/r DRV/r RAL DTG EVG/cobi/ TDF/FTC Otros AZT MVC Preferred Alternative Conditioned ABC/3TCTDF/FTC EFV NVP RPV/TDF/FTC LPV/r ATV/r FPV/r DRV/r RAL DTG EVG/cobi/ Otros WHO, 2015 EFV-400 AZT EACS, 2017 or TAF or ATV/c or DRV/c or STR BHIVA, 2016 or TAF GESIDA,2016 or TAF or ATV/c or DRV/c or STR IAS, 2016 TAF! o DRV/c or STR TAF! DHHS, 2016 o TAF or STR +/- TAF TDF/FTC

8 Country, year AZT/3TCABC/3TC TDF/FTC EFV NVP RPVc LPV/r ATV/r FPV/r DRV/r RAL DTG EVGc Ecuador, 2012 Chile, 2013 Venez, 2014 Colombia,2014 Argent, TDF/F +/- TAF Brazil, TDF/3 +TDF/3 Mexico, 2017 o STR TAF!

9 Country, year AZT/3TCABC/3TC TDF/FTC EFV NVP RPVc LPV/r ATV/r FPV/r DRV/r RAL DTG EVGc Ecuador, 2012 Chile, 2013 Venez, 2014 Colombia,2014 o STR Argent, 2016 STR STR o ATV/c +TDF/F +/- TAF Brazil, DTG +TDF/3 +TDF/3 +TDF/3 Mexico, DTG TAF! o STR STR o ATV/c o STR TAF! Up to 3 year delay in the adoption of new therapies (INSTI, STR, TAF)

10 Comparative efficacy and safety of first-line antiretroviral therapy: a systematic review and network meta-analysis Network of eligible comparisons between treatments Kanters S., et al. Lancet HIV 2016; 3: e510 20

11 Kanters S., et al. Lancet HIV 2016; 3: e510 20

12 Kanters S., et al. Lancet HIV 2016; 3: e510 20

13 Late presentation by age in L Am 80,0% 70,0% 60,0% 50,0% 40,0% 30,0% 20,0% 10,0% 0,0% < > >69 Beltran C, et al. HIV Hepatitis Americas Brazil P042

14 ART options Risk of DDI IP/r, Cobi RAL, DTG, RPV ABC, LPV, FPV, EFV CVD IP/r, Cobi RAL, DTG, TDF, RPV, LPV, FPV, EFV RAL, DTG ABC, LPV, FPV, EFV Cancer Lipid Dis. IP/r, Cobi TDF/FTC, 3TC, ABC, RAL, DTG, NVP, LPV, EFV IP/r, Cobi HBV, HCV Coinf. TB Coinf. EFV, RAL, TDF, ABC, NVP, DTG IP/r, RPV RAL, ABC, TDF, ATV, LPV IP/r, Cobi, DTG, RPV Renal Dysfn RAL, DTG ABC, IP/r Bone metab. HAND IP/r, Cobi, EFV RAL, DTG, DRV, MVC, EFV, TDF, LPV IP/r, Cobi

15 CVD Lipid Dis.

16 Martinez E., et al. AIDS 2012, 26: CVD Lipid Dis.

17 Martinez E., et al. AIDS 2012, 26: CVD Lipid Dis.

18 CVD Lipid Dis.

19 CVD

20 TB Coinf. Grinsztejn B, et al., ANRS Reflate TB study group. Lancet Infect Dis Jun;14(6):459-67

21 HAND Raltegravir Concentrations in Cerebrospinal Fluid RAL concentrations in CSF exceeded the IC50 for wild-type HIV in all specimens by a median of 4.5-fold. Croteau D., et al. Antimicrob Agents and Chemther, Dec. 2010, p Letendre S., Top Antivir Med November ; 19(4):

22 HAND Dolutegravir Concentrations in Plasma and Cerebrospinal Fluid The DTG concentrations in CSF were similar to unbound plasma concentrations and exceeded the in vitro 50% inhibitory concentration for wild-type HIV (0.2 ng/ml), suggesting that DTG achieves therapeutic concentrations in the central nervous system. The HIV-1 RNA reductions were similar in CSF and plasma Letendre S., et al. Clinical Infectious Diseases 2014;59(7):1032 7

23 Bone metab. RAL + TDF/FTC (n = 603), ATV/RTV + TDF/FTC (n = 605), or DRV/RTV + TDF/FTC (n = 601) All arms associated with significant loss of BMD through Wk 96 (P <.001) At hip and spine, similar loss of BMD in the PI arms Significantly greater loss in the combined PI arms than in the RAL arm Loss of BMD (%) Total Hip P = P =.005 Total Spine P = P <.001 ATV/RTV + TDF/FTC RAL + TDF/FTC DRV/RTV + TDF/FTC Combined PI arms Brown TT, et al. J Infect Dis. 2015;[Epub ahead of print].

24 SINGLE: bone turnover markers Bone metab. Greater change in bone turnover markers for Efavirenz(TDF/FTC vs Dolutegravir/ABC/3TC in antiretroviral therapy-naive adults over 144 weeks Tebas P., et al. AIDS 2015, 29:

25 Renal Dysfn DTG inhibits creatinine secretion, increasing creatinine levels, but does not affect egfr Mean Change From Baseline of Creatinine (mg/dl) DTG 50 mg QD (n = 411) RAL 400 mg BID (n = 411) Change in Serum Creatinine, Change in CrCl, Mean (± SD) [1,2] Mean (± SD) [1] Mean Change From Baseline (ml/min) BL Wk Wk Baseline (mg/ml): DTG 0.85 vs RAL 0.85 Baseline (ml/min): DTG 125 vs RAL Raffi F, et al. Lancet. 2013;381: Curtis LD, et al. IAS Abstract TUPE282.

26 Renal Dysfn Data on file. Gilead Sciences, Inc.

27 HCV Coinf. Drug-drug Interactions between DAAs and ARVs

28 Cancer Makinson A., et al. J Thorac Oncol. 2010;5:

29 Women Pooled data from Phase III clinical trials Squires K., et al. 4th International Workshop on HIV and Women January 13-14, Washington DC

30 Women

31 Squires K, et al. IAS Abstract MOLBPE08. Reproduced with permission. Women HIV-1 RNA < 50 c/ml (%) EVG/COBI/TDF/FTC ATV/RTV + TDF/FTC n = Overall 100,000 > 100,000 HIV-1 RNA (copies/ml) Emergent Resistance Resistance analysis population Developed resistance mutations to study drugs 86 EVG/COBI/FTC/TD F (n = 289) ATV/RTV + TDF/FTC (n = 286) EVG/COBI/FTC/TDF superior to ATV/RTV + TDF/FTC Overall treatment difference 6.5% (95% CI: 0.4%-12.6%) No significant differences between arms in change from BL for egfr, spine or hip BMD, LDL or HDL cholesterol, total cholesterol to HDL ratio, or triglycerides Significantly greater increase in total cholesterol with EVG/COBI/TDF/FTC Lower rate of discontinuations due to AEs with EVG/COBI/TDF/FTC vs ATV/RTV + TDF/FTC (2.4% vs 7.0%)

32 Women

33 Condition WHO EACS 2016 GESIDA 2016 BHIVA 2016 IAS 2016 DHHS 2016 Late presenter Women > 50 y/o TB Coinf. HepB Coinf. HepC Coinf. Renal Dis. CVD or risk Dyslipidemias NC Disorders Cancer

34 Condition WHO EACS 2016 GESIDA 2016 BHIVA 2016 IAS 2016 DHHS 2016 Late presenter Women No AZT,ddI,d4T,NVP > 50 y/o TB Coinf. TDF/FTC + EFV o RAL ABC/3TC o TDF/FTC + EFV Alt: RAL o MVC TDF/FTC + EFV ALT: RAL o DTG ABC/3TC o TDF/FTC + EFV o RAL HepB Coinf. TDF + FTC o 3TC TDF +/- FTC o 3TC TDF/TAF TDF o TAF + FTC o 3TC HepC Coinf. ABC/3TC o TDF o TAF(+FTC) + RAL o DTG Renal Dis. ABC/3TC + ITRNN o INI o DRV/r No TDF, ATV ABC, No TDF CVD or risk Dyslipidemias NC Disorders No EFV Cancer RAL, Alt: DTG No RTV

35 Condition ECUADOR CHILE VENEZUELA COLOMBIA ARGENTINA BRAZIL MEXICO Late presenter Women > 50 y/o TB Coinf. HepB Coinf. HepC Coinf. Renal Dis. CVD or risk Dyslipidemias NC Disorders Cancer

36 Condition ECUADOR CHILE VENEZUELA COLOMBIA ARGENTINA BRASIL MÉXICO Late presenter TDF/3TC + RAL Women Same as males > 50 y/o TB Coinf. TDF/(3TC or FTC) + EFV TDF/FTC + EFV or NVP 2 ITRN + EFV or RAL TDF/3TC + EFV or RAL HepB Coinf. TDF/FTC TDF +/- FTC or 3TC TDF/FTC, TDF/3TC or TAF/FTC TDF/(FTC o 3TC) or TAF/FTC HepC Coinf. TDF/(3TC o FTC) + 3rd w/o DDI Renal Dis. ABC/3TC + EFV No TDF CVD or risk Dyslipidemias (ABC ó TDF)/Xtc + RAL (Alt: ATV/r or DRV/r) TDF/FTC+RAL o DRV/r or ATV/r TDF/FTC o ABC/3TC + RAL o MVC or ATV-400 Switch PI/r to EFV, NVP, RAL or TV ATV ± r o DRV/r, no AZT, ABC nor EFV NC Disorders Cancer

37 It s recommended that all ART be individualized basedon characteristics such as sex, age, coinfections, comorbidities, risk for DDI, baseline CD4 and VL, life styles and likelihood of adherence, and knowing that there is not an only ART régimen that fits all individuals.

38 Scenario 1st line Alternative Not recommended General recomm. Late presenter Pregnancy Women (TDF o TAF)/FTC o ABC/3TC + INSTI or EFV or RPV or ATV/r or DRV/r EFV, DTG, RAL, EVG/c/TDF/FTC ABC/3TC or TDF/FTC or 3TC + ATV/r or DRV/r or RAL TDF/ FTC+EVG/c, ABC/3TC+DTG DRV/r AZT/3TC + LPV/r or EFV or RPV ATV/r or ATV/c; DRV/r or DRV/c, EFV AZT, ddi, d4t, NVP Otros IP/r > 50 y/o INSTI, ATV/r, DRV/r, RPV EFV TB Coinfection TDF/FTC or ABC/3TC + EFV or RAL HepB Coinfection TDF/FTC, TDF/3TC or TAF/FTC NVP HepC Coinfection RAL or DTG NVP

39 Scenario 1st line Alternative Not recommended Renal Disease ABC + 3TC, RAL DTG, DRV/r CVD or high risk Dyslipidemias Neurocogn. Dis. Cancer TDF/FTC + RAL or DTG or RPV RPV/TDF/FTC or RAL or DTG Uncertain: INSTI, DRV/r, ABC/3TC? Individualize (DDI, Adv ev. etc.) TDF and fixed coformulations; LPV/r, ATV ABC, EVG/Cobi, IP/r EFV, IP/r, coform with cobicistat EFV, RPV

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41 Trends in the use of ART regimens in LATAM,

42 Comparison of selection of 3rd agent in the 1st ART regimen between < and > 50 yo. New admissions, Grupo VIHCOL, ,0% 40,0% 38,2% 36,4% 35,0% 30,0% 25,0% 20,0% 15,8% 15,9% 14,5% 14,5% 12,7% 13,6% 15,0% 9,8% 8,2% 10,0% 2,2% 3,1% 2,7% 3,6% 5,0% 0,9% 0,7% 0,9% 1,8% 1,8% 2,7% 0,0% < 50 años > 50 años 60,0% 49,8% 50,0% 43,8% 40,0% 30,0% 20,0% 10,0% 0,0% 1,9% 11,6% 16,7% 10,9% 8,6% 10,7% 11,7% 4,3% 6,2% 2,9% 4,9% 6,2% 1,5% 1,1% 1,2% 2,5% 2,5% < 50 años > 50 años ,0% 50,0% 40,0% 50,6% 42,9% 30,0% 20,0% 10,0% 0,0% 8,4% 10,5% 12,2% 7,8% 8,7% 5,4% 7,5% 7,5% 6,1% 3,1% 4,8% 4,8% 6,8% 6,1% 1,3% 2,1% 2,0% 1,4% < 50 años > 50 años

43 And a simple question... (just for yourself) What would I be willing to take if I were HIV positive?...

44 What is needed to do? HIV infection is a chronic incurable condition. To provide each individual with the best treatment option requires: 1. Timely updates of national guidelines with the best quality evidence 2. A tireless interaction with the health regulatory authorities 3. A price strategy affordable for our countries (economy of scale) But above all: A strong conviction of who prescribes! Otherwise, we will continue to be simply academic!