integrase inhibitors in clinical practice in the Netherlands HIV Clinical Forum 2018 Kees Brinkman OLVG- Amsterdam The Netherlands
Disclosures relevant activities to dislose companies advisory boards Gilead Janssen MSD Viiv speaker virology education author UpToDate
content hiv care in the Netherlands role of integrase inhibitors in the Netherlands practical use of INSTI case report of naïve HIV patient choice of cart in ageing patient with co-morbidities HBV protection?
Netherlands (2015) population size: 17 milj area: 41.000 km 2 capital: Amsterdam 219 km 2 pop.size 840.000 BNI $ 46.400
NL 2016: 19.000 PLWHA known 0,11% estimated 0,13%?? Amsterdam 2016: known 0,68% estimated 0,73%
HIV in NL anti-retroviral treatment - cart introduced in 1996 (rapid licensing) - fully reimbursed in basic healthcare insurance outpatient pharmacy 1 st perscription by hiv center no hospital/regional budgets - 26 hiv treatment centers - 50% care by HIV trained nurses - obligatory monitoring - ATHENA cohort, now SHM - since 2016: used for quality assesment treatment center
Population monitored in NL: 2016 Men Women Total N % N % N % Total 15.275 81 3.591 19 18.866 100 Transmission MSM 11.616 76 - - 11.616 62 Hetero 2392 16 3117 87 5509 29 IDU 231 2 92 3 339 2 Blood 144 1 95 3 241 1 Other 892 6 287 8 1157 6 report 2016
organisation DUTCH ASSOC. HIV PHYSICIANS
guidelines web based based on DHHS / EACS /BHIVA etc EBM based adjustments in accordance with: availability national preference» cost? pharmacology clinical monitoring guidelines www.nvhb.nl
First-line ART Recommended, preferred regimens + ALTERNATIVE GUIDELINES NRTI BACKBONE NNRTI INSTI PI NRTI-REDUCING EACS (2017) 1 TAF/FTC TDF/FTC ABC/3TC* RPV* EFV DTG RAL EVG DRV/c or /r ATV/c or /r DRV/c or /r + RAL LPV/r + XTC DHHS (2017) 2 TAF/FTC TDF/FTC ABC/3TC* EFV RPV* DTG RAL EVG/c ATV/c or /r DRV/c or /r DRV/c or /r + RAL IAS USA (2016) 3 TAF/FTC ABC/3TC* EFV RPV DTG RAL EVG/c DRV /c or /r DRV/c or /r + RAL DRV/c or /r + DTG DRV/c or /r + XTC BHIVA (2016) 4 TAF/FTC TDF/FTC ABC/3TC* RPV* EFV DTG RAL EVG/c DRV/r ATV/r DRV/c or /r + RAL WHO (2016) 5 TDF/XTC AZT/XTC EFV EFV 400 NVP DTG *Use recommended only if baseline viral load <100,000 copies/ml. 3TC, lamivudine; ABC, abacavir; ATV, atazanavir; AZT, zidovudine; BHIVA, British HIV Association; c, cobicistat; DHHS, Department of Health and Human Services; DRV, darunavir; DTG, dolutegravir; EACS, European AIDS Clinical Society; EFV, efavirenz; EVG, elvitegravir; FTC, emtricitabine; IAS USA, International Antiviral Society USA; LPV, lopinavir; NNRTI, non-nucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; NVP, nevirapine; PI, protease inhibitor; r, ritonavir; RAL, raltegravir; RPV, rilpivirine; TAF, tenofovir alafenamide fumarate; TDF, tenofovir disoproxil fumarate; WHO, World Health Organization; XTC, FTC or 3TC. 1. EACS Guidelines Version 9.0. Available from: http://www.eacsociety.org/guidelines/eacs-guidelines/eacs-guidelines.html. Accessed January 2018; 2. DHHS Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Available from: https://aidsinfo.nih.gov/guidelines/html/1/adult-and-adolescent-arv/0. Accessed January 2018; 3. Günthard HF, et al. JAMA 2016;316:191 210; 4. BHIVA Guidelines. Available from: http://www.bhiva.org/documents/guidelines/treatment/2016/treatment-guidelines-2016-interim-update.pdf. Accessed January 2018; 5. WHO. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection. Available from: http://apps.who.int/iris/bitstream/10665/208825/1/9789241549684_eng.pdf?ua=1. Accessed January 2018.
available as single tablet regimen (STR) TRIPLE 2DR DRUG ATRIPLA 1 EVIPLERA 2 STRIBILD 3 TRIUMEQ 4 GENVOYA 5 ODEFSEY 6 SYMTUZA 7 BIKTARVY 8 JULUCA 9 COMPONENTS Generic FDC TDF/XTC/EFV TDF/FTC/RPV TDF/FTC/EVG/c ABC/3TC/DTG TAF/FTC/EVG/c TAF/FTC/RPV TAF/FTC/DRV/c TAF/BIC/FTC DTG/RPV CONSIDERATIONS Premorbid Psychiatric VL <100,000 Drug drug interactions HLAB*5701 co-infection Drug drug interactions VL <100,000 Drug drug interactions Long-term data Gastric ph Licensed once-daily fixed-dose combinations. Pill sizes are not to scale. Filed for licensing: TDF/3TC/DOR (1439A) 1. Atripla SmPC. Available from: https://www.medicines.org.uk/emc/medicine/20505. Updated May 2017. Accessed October 2017; 2. Eviplera SmPC. Available from: https://www.medicines.org.uk/emc/medicine/25518. Updated June 2017. Accessed October 2017; 3. Stribild SmPC. Available from: https://www.medicines.org.uk/emc/medicine/27810. Updated June 2017. Accessed October 2017; 4. Triumeq SmPC. Available from: https://www.medicines.org.uk/emc/medicine/29178. Updated January 2017. Accessed October 2017; 5. Genvoya SmPC. Available from: https://www.medicines.org.uk/emc/medicine/31225. Updated September 2017. Accessed October 2017; 6. Odefsey SmPC. Available from: https://www.medicines.org.uk/emc/medicine/32117. Updated September 2017. Accessed October 2017; 7. Symtuza SmPC. Available from: http://www.medicines.org.uk/emc/medicine/34148. Updated September 2017. Accessed October 2017; 8. Biktarvy PI. Available from: https://www.accessdata.fda.gov/drugsatfda_docs/label/2018/210251s000lbl.pdf. Accessed February 2018; 9. Juluca SmPC. Available from: https://www.viivhealthcare.com/our-medicines/juluca.aspx. Updated November 2017. Accessed December 2017.
Shifts in 1 st line cart regimens 2011-2016 TDF/FTC/RAL TAF/FTC/EVGc ABC/3TC/DTG TDF/FTC/DTG TDF/FTC/EFZ TDF/FTC/EVG/c
cart use in the Netherlands in 2015 NNRTI PI INSTI
everyone on cart after entry: more rapid initiation of cart over time within 21-31 days within 14-20 days within 7-13 days within 1 week Same day 2016: 75% within 1 month
Universal treatment initiation of cart in NL fairly uniform across all 26 centres Proportion of patients started on cart within 6 months after entering care, by year & treatment center size report 2016 care for > 600 pts care for 300-600 pts 2012 2013 2014 care for < 300 pts
Viral suppression rates on cart in NL high across all 26 centres report 2016 2012 2013 2014 2015 Percentages of treatment-naive patients with a plasma HIV RNA level <400 copies/ml at 6 months (minimum and maximum: 3-9 months) after the start of combination antiretroviral therapy (cart) across all HIV treatment centres.
Continuum of care in NL 2016: 89%-92%-95% in total 77% suppressed 100% 89% 84% 81% 77% 2,600 undiagnosed (95% CI 2,100-3,200) 89% 92% 95% 90-90-90 by 2020 MSM in NL: 90%-94%-96% (=88% suppressed)
NL: observed decrease in new infections Annual number of newly-acquired HIV infections as estimated using ECDC modelling tool 450 (95% CI 200-750) in 2015 PMTCT: no vertical transmissions in 2016 in NL
Amsterdam: HIV care continuum 94%-90%-94% in 2015 Total population 94% 90% 94% Prins ea - IAS2017
Amsterdam: decrease new HIV infections main 95% CI 70 (95% CI, 30 180) new HIV infections in 2015. Average time from infection to diagnosis: 2.9 (2.3 3.7) years. including corrections for reporting delay in 2014 (+3%) and 2015 (+11%)
mr P, 1960 age diabetes type 1 (1986) insulin-pump/sensor; HbA1c 7%; gluc 2-20 mmol/l micro-albuminuria and retinopathy kreatinin 105 umol/l (egfr 55 ml/min) total cholesterol 5,2 mmol/l, HDL 1,2 mmol/l med: omeprazol, simvastatin, lisinopril 10, insulin RR 148/86; BMI 24 kg/m 2 ; smoker 2014(oct) HIV-1 positive (MSM) (2012 neg) regular STD s CD4 240/mm3, HIV load 88.000, no RAM HLA-B57 negative serology: ahbs, ahbc, ahcv negative co-morbidity renal function CVD risk? HBV risk?
Increasing age of people in care In 2016: Median age of HIV+: 49 years 50+ years:46% 60+ years:16%
Comorbidity and multimorbidity increasingly prevalent with rise in age. Adult population in care in 2016. The numbers on top of each bar represent the number of individuals contributing data to that age category
mr P, 1960 diabetes type 1 (1986) insulin-pump/sensor; HbA1c 7%; gluc 2-20 mmol/l micro-albuminuria and retinopathy kreatinin 120 umol/l (egfr 51 ml/min) total cholesterol 5,2 mmol/l, HDL 1,2 mmol/l med: simvastatin 20, lisinopril 10, insulin RR 148/86; BMI 24 kg/m 2, smoker CVD risk? 2014(oct) HIV-1 positive (MSM) (2012 neg) regular STI CD4 240/mm3, HIV load 88.000, no RAM HLA-B57 negative serology: ahbs, ahbc, ahcv negative
10 years risk: 41,7%
quit smoking: 10 years risk: 27,7%
quit smoking & better RR en lipids: 10 years risk: 14,1%
Selecting ART Components for Pts With Comorbidities or Polypharmacy Component May Be Suboptimal for Pts With: Key drug-drug-interactions NRTI Backbone ABC/3TC CKD CVD Not for use when CrCl < 50 ml/min Possible increased CVD risk FTC/TAF CKD Not for use when CrCl < 30 ml/min Rifamycins FTC/TDF Additional Agents CKD Osteoporosis Not for use when CrCl < 50 ml/min Smaller BMD declines with TAF and ABC Boosted PIs Hyperlipidemia Other agents have lower lipid effects Statins, steroids DTG Antacids, metformin EVG/COBI Hyperlipidemia Other agents have lower lipid effects Statins, steroids, antacids RAL Antacids RPV *Consider www.hiv-druginteractions.org to assist with identifying potential interactions for all regimens. Polyvalent cation containing antacids. PPIs References in slidenotes. Slide credit: clinicaloptions.com
mr P, 1960 started on ABC/3TC/DTG (triumeq ) co-med: simvastatin, lisinopril, insulin BL 4 weeks 12 weeks hiv load 88.000 bld bld CD4 count 240 320 kreatinin 105 115 113 HBV vaccination: failed initially doing well except for sleeping disturbances and anxiety
abstract 948 Unexpectedly High Rate of Intolerance for Dolutegravir in Real Life Setting Guido van den Berk, Josephine Oryszczyn, Willem Blok, Narda van der Meche, Rosa Regez, Daoud Ait Moha, Kees Brinkman dept internal medicin OLVG, Amsterdam, The Netherlands k.brinkman@olvg.nl background - Integrase inhibitors (INSTI)are now preferred antiretrovirals in first line cart. - Dolutegravir (DTG) is possibly considered as one of the most efficacious, convenient and tolerated INSTI, with hardly any chance for drug-drug interactions. - Since we encountered many patients who stopped DTG because of intolerance, we analyzed the experience with DGV in our whole patient population since licensing in the Netherlands (aug 2014) methods - OLVG cohort: ±3000 patients, (97,4% on cart) - retrospective analysis of all patients who started DTG, either as initial therapy or after switching from other antiretrovirals for any reason. - Baseline characteristics at the moment of DTG start were recorded. - We calculated the proportion of patients who stopped DTG, analyzed the reason for interruption and evaluated potential risk factors. - Chi-squared test and Z-score to check for significant differences between groups and proportions. results total (N=387) naives(n=65) non-naives (N=322) median age (IQR) 48 46 (22) 48 (13) ns female 44 11,4% 8 12,3% 36 11,2% ns dutch origin 136 35,1% 28 43,1% 108 33,5% ns median CD4/mm3 (IQR) 650 530 (395) 655 (345) ns median DTG days (IQR) 220 196 (147) 221 (148) ns DTG separate.. 156 15 141 DTG in STR.. 231 50 181 DTG stopped 62 16,0% 13 20,0% 49 15,2% ns median DTG days (IQR) 78 81 (71) 75 (99) ns female 5 11,4% 3 37,5% 2 5,6% p=0.01 DTG separate 24 15,4% 1 6,7% 23 16,3% ns DTG in STR 38 16,6% 12 24,0% 26 14,4% ns reason for interruption other than toxicity* 6 9,7% 1 7,7% 5 10,2% toxicity 56 90,3% 12 92,3% 44 89,8% ns sleeping.. 19 31,3% 5 38,5% 14 28,6% ns gastro-intestinal.. 18 29,5% 4 30,8% 14 28,6% ns neuro-psychiatric.. 12 19,7% 3 23,1% 9 18,4% ns paresthesia.. 6 9,7% 0 0,0% 6 12,2% ns headache.. 8 12,9% 0 0,0% 8 16,3% ns fatigue.. 9 14,6% 1 7,7% 8 16,3% ns allergy.. 1 1,7% 1 7,7% 0 0,0% ns other.. 5 8,2% 1 7,7% 4 8,2% ns *LTFU, HBV protection, insurance, induction, patient request, interaction results DTG treatment was stopped in 62/387 (16,0%) patients. There were no virological failures. Main reason for DGV interruption was intolerance in 56/62 (90,3%) patients: 19/56 (31,3%) sleeping problems, 18/56 (29,5%) gastrointestinal problems, 12/56 (19,7%) psychiatric problems, 8/56(12,9%) headache, 9/56 (14,6%) fatigue and 6/55 (10,9%). Some patients reported more than one toxicity. Psychiatric reason to stop (n=12) varied from anxiety, depression and agitation to psychosis (n=2) conclusion In a real life setting a substantial proportion of patients unexpectedly interrupted DTG treatment for reasons of intolerance, in particular sleeping, gastrointestinal and psychiatric problems. This was much higher than reported in clinical trials.
similar experience LUMC combined analysis AIDS 2016; 30: 2831 -
similar experience LUMC combined analysis DGV without ABC DGV with ABC AIDS 2016; 30: 2831 -
switching 1st line regimens (by 3rd component) any reason vs toxicity report 2016 in general: well tolerated...
integrase inhibitors(insti) comparison raltegravir elvitegravir dolutegravir dosing 400 bid 150 QD (+ booster) STR? no yes (only) yes 50 QD (50 bid INSTI-R) T 1/2 9 hrs 13 hrs (b) 14 hrs metabolism UGT1A1 CYP3A (major) UGT1A/3 (minor) UGT1A1 (major) CYP3A (minor) elimination renal ( 9%) renal ( 7%) renal ( <1%) interactions minimal serious minimal side effects minimal few GI few CNS, GI
abacavir: increased RR for myocardial infarction?? CROI 2018: NA-ACCORD
mr P, 1960 switched to TAF/FTC/RAL(1200) within one week: insomnia disappeared what to do with HBV protection??
How often does HBV occur in HIV patients? CROI 2014 all patients all: N=2942 MSM: N = 2280 1 st sample HBV susceptible all: N = 871 (29,6%) MSM: N = 590 HBV infected N = 1498 (50,9%) HBV vaccinated N = 389 (13,2%) not tested N =184 (6,3%) 2 nd sample HBV susceptible all: N = 530 (72,0%) MSM: N = 349 HBV infected all: N = 35 (4,8%) MSM: N = 33 HBV vaccinated all: N = 171 (23,2%) MSM: N = 136 not available N = 135 MSM: N=72 Heuft et al; AIDS. 2014 Apr 24;28(7):999-
HBV free survival (MSM) protective effect of TDF = HBV - PrEP log-rank p = 0,004 p < 0,001 --- no treatment --- HBV active treatment, no TDF --- HBV active treatment, with TDF log rank p< 0,001 Heuft et al; AIDS. 2014 Apr 24;28(7):999-0 6000
INSTI in clinical practice additional remarks INSTI: rapid decrease of viral load pregnancy last trimester pre-operative (to reduce risk of transmission) Dolutegravir: neural tube defects in 1 st trimester? end of 2018 in NL: bictegravir only available as STR (B/F/TAF) profile dolutegravir
rapid uptake in Netherlands highly effective, well tolerated side effects do occur most INSTI: few interactions except for elvitegravir INSTI in clinical practice conclusion price... (no generics yet)
acknowledgments: Peter Reiss, Ard v Sighem, Cloë Orkins k.brinkman@olvg.nl