Tailoring first line HIV therapy to avoid long term toxicities and drug-drug interactions

Transcription

1 Healthy living with HIV 2 3 September 2016, Barcelona, Spain Tailoring first line HIV therapy to avoid long term toxicities and drug-drug interactions Marta Boffito MD, PhD Head of Clinical Trials, St. Stephen s Centre (SSAT) Consultant Physician, Chelsea and Westminster Hospital Reader, Imperial College

2 EACS Guidelines Oct 2015: Initial Combination Regimen for ART-naïve Adult HIV-positive persons Class EACS Recommended Therapy Regardless of BL VL or CD4+ Count Alternative Regimens INSTI Boosted PI RAL + TDF/FTC* i EVG/COBI/TDF/FTC* i DTG/ABC/3TC ii DTG + TDF/FTC* i DRV/RTV + TDF/FTC* i RAL + ABC/3TC ii ATV/RTV + TDF/FTC* i ATV/COBI + TDF/FTC* i ATV/RTV + ABC/3TC ii ATV/COBI + ABC/3TC ii DRV/RTV + ABC/3TC ii DRV/COBI + ABC/3TC ii DRV/COBI + TDF/FTC* i LPV/r + TDF/FTC* i NNRTI RPV/TDF/FTC i# EFV/TDF/FTC i EFV + ABC/3TC Only for pts who are HLA-B*5701 negative; * Only for pts with egfr >70 ml/min; i Avoid TDF if pt has osteoporosis; ii Use this combination only if HBs Ag negative; IF TDF/FTC is not available, one alternative could be TDF+3TC as separate entities; # Not approved in pts with baseline HIV-1 RNA > 100,000 copies/ml and not recommended CD4+ cell counts < 200 cells/mm 3 In Europe, Atripla is not approved for the treatment of HIV-1 naïve patients

3 Incidence per 1000 person years EFV tolerability Possible dynamic cognitive changes over time during ART 1 Suicidality during 4 ACTG clinical trials of efavirenz (EFV) 2 ART 8.08 HIV RNA Cognitive function Protective Improvement Divergence Neurotoxic 1.22 Undetectable Time: T0 T1 T2 ACTG, AIDS Clinical Trials Group 1. Underwood J, et al. AIDS 2015;29: Mollan KR, et al. Ann Intern Med 2014;161:1 10

4 European integrase inhibitor SmPCs Drug Raltegravir Dolutegravir & Triumeq Elvitegravir & Stribild Genvoya Suicide/ideation Depression, including suicidal ideation & behaviors reported, particularly if pre-existing history of depression or psychiatric illness. Caution.with a pre-existing history of depression or psychiatric illness Uncommon ( 1/1,000 to <1/100): Suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness) Uncommon: suicidal ideation & suicide attempt (in patients with a pre-existing history of depression or psychiatric illness), depression, insomnia Uncommon: depression* *This adverse reaction was not observed in the Phase 3 clinical studies for Genvoya but identified from clinical studies for elvitegravir when used with other antiretrovirals All SmPC advice accessed from on 2 nd July 2016

5 European integrase inhibitor SmPCs Drug Raltegravir Dolutegravir & Triumeq Elvitegravir & Stribild Genvoya Suicide/ideation Depression, including suicidal ideation & behaviours reported, particularly if pre-existing history of depression or psychiatric illness. Caution.with a pre-existing history of depression or psychiatric illness Uncommon ( 1/1,000 to <1/100): Suicidal ideation or suicide attempt (particularly in patients with a pre-existing history of depression or psychiatric illness) Uncommon: suicidal ideation & suicide attempt (in patients with a pre-existing history of depression or psychiatric illness), depression, insomnia Uncommon: depression* *This adverse reaction was not observed in the Phase 3 clinical studies for Genvoya but identified from clinical studies for elvitegravir when used with other antiretrovirals All SmPC advice accessed from on 2 nd July 2016

6 ECHO and THRIVE Week 96 Safety: TTCA Summary of Psychiatric AEs Incidence, n (%) RPV N=686 EFV N=682 P Any psychiatric AE (any cause) 190 (28) 217 (32) a Any serious psychiatric AE (any cause) Leading to permanent discontinuation (any cause) 9 (1) 9 (1) NS 11 (2) 15 (2) NS Any treatment-related psychiatric AE b,c 107 (16) 166 (24) < a Abnormal dreams/nightmares 57 (8) 90 (13) a Insomnia 35 (5) 41 (6) NS Depression 15 (2) 18 (3) NS Sleep disorder 9 (1) 22 (3) NS Anxiety 4 (0.6) 15 (2) NS a RPV vs. EFV, Fisher s Exact test, pre-planned analysis; b Reported in 2% of patients in either group; c Judged by the investigator to be at least possibly related to treatment 6 ; NS, not significant, Fisher s Exact test, post hoc analysis; AE, adverse event

7 Fracture prevalence/ 100 persons Fracture prevalence/ 100 persons Hazard Ratio PLWHIV are at increase of low BMD and fractures Increased BMD issue risk from HIV infection Increased BMD issue risk from HIV treatment Fracture prevalence PLWHIV and non-infected controls 3* Female 7.0 p= (overall comparison) Age HIV Male 7.0 p< (overall comparison) Age Non-HIV Antiretroviral exposure and risk of osteoporotic fractures: TDF ABC ZDV/D4T NNRTI rpi *U.S. healthcare system data PLWHIV have lower bone mineral density (BMD) than the uninfected population 1 Prevalence of fractures of the spine, hip, and wrist, sites commonly associated with osteoporosis can be 60% higher in PLWHIV compared ARVs can exacerbate low BMD issues Initiation of therapy is associated with a 2 6% decrease in BMD over the first two years of treatment 2 with the uninfected 3 1. Anastos K et al. Antivir Ther 2007;12(7): , 2. McComsey GA et al. Clin Infect Dis 2010;51(8):937 46, 3. Triant VA et al. J Clin Endocrinol Metab 2008;93(9): , 4. Bedimo R et al. AIDS 2012;26:825 31

8 D.A.D: ARVs & CKD development in pts with initial normal renal function Determination of whether the reported association between ARVs (TDF, ATV+RTV, LPV/r, other PI+RTV and ABC) 1-4 and CKD (egfr <60 ml/min/1.73m 2 >3 months apart) is cumulative among persons with normal renal function Overall <1% (201/23,350) of patients developed CKD after a median of 6.3 years who had an initial median egfr 102 ml/min Incidence Rate Ratio per Year Cumulative Risk of CKD of Additional Exposure to ARVs (95%CI) TDF ATV+RTV LPVr year years years Univariate Multivariate* TDF ATV+RTV LPV/r *Adjusted for fixed variables at baseline (gender, race, HIV exposure, study, prior CVD, age, baseline date, baseline egfr and CD4 nadir) and time-updated covariates (HBV and HCV status, smoking status, BMI, family history of CVD, HIV RNA, CD4 count, anaemia, diabetes, hypertension, starting ART, and an AIDS diagnosis within previous 12 months) Increased cumulative risk of CKD with longer exposure to ATV+RTV > LPV/r > TDF 1 Ryom JID 2013; 2 Mocroft AIDS 2010; 3 Scherzer AIDS 2012; 4 Hamada CID 2012

9 D:A:D link between ART choice and risk of MI D:A:D study population of 33,308 PLWHIV followed up from enrolment until the first myocardial infarction (MI) event, first February 2008 or 6 months after the patient s last clinic visit Relative risk of MI for different ART 580 patients experienced an MI 3.2 events per 1000 PYFU Some specific NRTIs and PIs are correlated with increased MI risk with recent and/or cumulative exposure PYFU, patient-years of follow up; *Current or within last 6 months; **not shown (low number of patients currently on ddc); Approximate test for heterogeneity: P= Worm SW et al. J Infect Dis Feb 1;201(3): ; 2, D:A:D Study Group Lancet Apr 26;371(9622):

10 ATV/COBI and DRV/COBI Clinical Program Virologic Suppression Virologic Failure ATV/COBI Study 105: Head-to-head Phase II Study 114: Head-to-head Phase III Bioequivalence 85% vs 87% at 48 weeks 72% vs 74% at 144 weeks Consistent results regardless of baseline characteristics 5.8% vs 4% at 48 weeks 8% vs 5% at 144 weeks Consistent results regardless of baseline characteristics DRV/COBI QUAD: 48-week Phase II study Study 130: Single-arm Phase 3b safety study Bioequivalence QUAD: DRV/COBI/TVD: 84% at 48 weeks Study 130: 81% at 48 weeks No long-term data QUAD: DRV/COBI/TVD: 12% at 48 weeks Study 130: 11% at 48 Weeks (8% in naives) - 15% in VL>100,000 vs 8% in VL<100,000 No long-term data Safety Similar to ATV/r at 48 weeks and 144 weeks1 Similar to DRV/r at 48 weeks Drug Levels Healthy adults: No change HIV patients: C min = 6% drop C min = 60x above EC 90 (14 ng/ml) Healthy adults non-fdc: 31% drop in C trough Healthy adults FDC: 26% drop in C min HIV patients: Consistent to healthy adults C min = 6.5x above EC 90 (200 ng/ml) 1Gallant et al Brief Report: Cobicistat Compared With Ritonavir as a Pharmacoenhancer for Atazanavir in Combination With Emtricitabine/Tenofovir Disoproxil Fumarate: Week 144 Results. J Acquir Immune Defic Syndr Jul 1;69(3):

11 Benefits Enhances drug exposure Prevents/overcomes resistance; high genetic barrier Less frequent dosing Potentially improves adherence Risks DDIs Tolerability Serum creatinine CVR Boffito M, et al. AIDS 2015;29:

12 Antiretrovirals and interaction potential Higher potential Moderate Potential Lower Potential Boosted PIs Perpetrators enzyme and transporter Inhibition Victim - absorption (ATV); induction EVG/cobi Perpetrator enzyme and transporter inhibition Victim - absorption; induction Rilpivirine Victim of enzyme inhibition and induction. Also absorption. Maraviroc Victim of enzyme inhibition and induction. Raltegravir Victim of few induction and absorption interactions Most NRTIs Victim of some transporter mediated interactions Efavirenz, (Nevirapine, Etravirine) Perpetrators enzyme and transporter induction Dolutegravir Victim of enzyme induction and absorption interactions Perpetrator of renal interaction Based on

13 Focus on the effects of pharmacokinetic boosting

14 Mean (±95% CI) EVG concentration (ng/ml) Ramanathan S, et al. Clin Pharmacokinet 2011;50: Boosting with RTV or COBI increases plasma concentration of other drugs Unboostd Short t 1/2 (~3.5 hours) High dose and/or BID dosing necessary Boosted Unboosted Boosted exposures (AUC tau ) Long t 1/2 (~9.5 hours) C min >> IC 95 Potential for low QD dose IC 95 * IC 50 * Time (hours) EVG 100 mg. *Protein binding adjusted

15 Bioequivalent exposure of EVG, darunavir and atazanavir with ritonavir (RTV, 100 mg) and cobicistat (COBI, 150 mg) Given both boosters inhibit CYP3A4, there will be DDIs COBI inhibits some CYPs and transporters more selectively than ritonavir COBI does not have enzyme-inducing properties in contrast to RTV Co-medications should be systematically reviewed when switching the pharmacokinetic enhancer to anticipate potential dosage adjustments

16 EACS Guidelines Oct 2015: Initial Combination Regimen for ART-naïve Adult HIV-positive persons Class EACS Recommended Therapy Regardless of BL VL or CD4+ Count Alternative Regimens INSTI Boosted PI RAL + TDF/FTC* i EVG/COBI/TDF/FTC* i DTG/ABC/3TC ii DTG + TDF/FTC* i DRV/RTV + TDF/FTC* i 10 of the 17 regimens have boosters RAL + ABC/3TC ii ATV/RTV + TDF/FTC* i ATV/COBI + TDF/FTC* i ATV/RTV + ABC/3TC ii ATV/COBI + ABC/3TC ii DRV/RTV + ABC/3TC ii DRV/COBI + ABC/3TC ii DRV/COBI + TDF/FTC* i LPV/r + TDF/FTC* i NNRTI RPV/TDF/FTC i# EFV/TDF/FTC i EFV + ABC/3TC Only for pts who are HLA-B*5701 negative; * Only for pts with egfr >70 ml/min; i Avoid TDF if pt has osteoporosis; ii Use this combination only if HBs Ag negative; IF TDF/FTC is not available, one alternative could be TDF+3TC as separate entities; # Not approved in pts with baseline HIV-1 RNA > 100,000 copies/ml and not recommended CD4+ cell counts < 200 cells/mm 3 In Europe, Atripla is not approved for the treatment of HIV-1 naïve patients

17 Mechanism of pharmacokinetic drug drug interactions (DDIs) Inhibition/induction of hepatic cytochromes, glucuronidation, or drug transporters Metabolism Systemic circulation Inhibition/induction of intestinal cytochromes or drug transporters Absorption Gastric ph Liver Bile Food, mineral supplements Inhibition of renal drug transporters Portal vein Excretion Kidney Enterocyte Small intestine Adapted from Roden DM & George AL, Jr. Nat Rev Drug Discov 2002;1:37 44;; DHHS. Drug interactions. Available at: (accessed June 2016)

18 Focus on DDIs that affect drug absorption

19 A range of pharmacokinetic interactions affect drug absorption Extent of oral absorption of drugs can be affected by: Gastric environment: Acid-reducing agents (e.g. PPIs, H2 antagonists, antacids) can reduce the absorption of ARVs that require gastric acidity for optimal absorption (i.e. ATV and RPV) Polyvalent cations in some products (e.g. Al3+-, Ca2+-, Mg2+-containing antacids/supplements/iron products) can bind to integrase inhibitors and reduce their absorption Drugs that induce/inhibit the enzyme CYP3A4 or the efflux transporter P-glycoprotein in the intestines may reduce/promote the absorption of other drugs DHHS guidelines. Updated April Available at

20 Mean (SD) plasma concentration (ng/ml) Antacids decrease plasma concentrations of EVG 1000 EVG/r alone EVG/r + antacid (Al/Mg) Time (hours) Ramanathan S, et al. J Acquir Immune Defic Syndr 2013;64:45 50

21 Focus on DDIs that affect drug distribution

22 Pharmacokinetic interactions that affect drug distribution in the liver MRP1 (ABCC1) MRP3 (ABCC3) MRP4 (ABCC4) Blood Efflux transporter: OATP1B1(OATP2/ OATP-C) OATP1B3 (OATP8) OATP2B1 (OATP-B) OAT2 MDR1 (ABCB1) MDP2 (ABCC2) MDR3 (ABCB4) Bile canaliculus Uptake transporter: OCT1 NTCP Sinusoidal membrane BCRP (ABCG2) BSEP (ABCB11) Canalicular membrane Adapted from Giacomini KM & Sugiyama Y. In Goodman & Gilman s The Pharmacological Basis of Therapeutics (12th ed), Brunton LL (ed), McGraw-Hill:pp

23 ROS concentration (ng/ml) Lopinavir/ritonavir increases serum concentrations of rosuvastatin Rosuvastatin (ROS) 16 Only 10% hepatic metabolism CYP2C9 >> CYP2C19, 3A4, 2D ROS AUCs for subjects on: ROS alone ROS + LPV/r Lopinavir/ritonavir (LPV/r) caused: x increase in ROS C max 2.1x increase in ROS AUC C min unchanged Interaction occurs at transporter level Time (hours) Kiser JJ, et al. J Acquir Immune Defic Syndr 2008;47:

24 61 year old asymptomatic MSM diagnosed with HIV CD4 count 230 cells/mm 3 Plasma viral load: 80,000 copies/ml

25 Co-morbidities, co-medications, recreational drugs and supplements Co-morbidities Hypertension Benign prostatic hyperplasia Hypercholesterolemia Asthma Depression (not on treatment) Co-medications Amlodipine 10mg OD Tamsulosin 0.4mg OD Simvastatin 20mg OD Fluticasone/formoterol inhaler The patient is already on polypharmacy! Other Multivitamin* Mephedrone every other weekend *Contains: magnesium 60mg, iron 6mg, zinc 15mg, copper 1,000µg, manganese 3mg, selenium 150µg, chromium 50µg, iodine 150µg, silicon 10mg

26 Test results Test ALT Baseline resistance test egfr Anti-HBs HBcAb HBsAg Hepatitis C antibodies HLA B*5701 Result 69 IU/L Wild type 72 ml/min Positive Negative Negative Negative Positive Anti-HBs: hepatitis B surface antibody; ALT: alanine aminotransferase; egfr: estimated glomerular filtration rate; HBcAb: hepatitis B core antibody; HBsAg: hepatitis B surface antigen; HLA: human leucocyte antigen

27 Patient consultation Please may I have a once a day combination, with no side effects? Treatment options to consider: 2 NRTI + RAL BD 2 NRTI + 1 NNRTI EFV / NVP / RPV Is it essential for the patient to have a single tablet regimen?

28 DHHS guideline recommendations When prescribing or switching one or more drugs in an ARV regimen, clinicians must consider the potential for drug drug interactions that affect ARVs and non-arvs Recommendations for managing a particular drug interaction may differ depending on whether a new ARV is being initiated in a patient on a stable concomitant medication or a new concomitant medication is being initiated in a patient on a stable ARV regimen When prescribing interacting drugs is necessary, clinicians should be vigilant in monitoring for therapeutic efficacy and/or concentration-related toxicities US Department of Health and Human Services (DHHS). Guidelines for the Use of Antiretroviral Agents in HIV-1-Infected Adults and Adolescents, January Available at: (accessed June 2016)

29 Amlodipine drug drug interactions I Co-administration with ARVs has not been studied (only RAL) Amlodipine metabolised by cytochrome P450 3A4 (CYP3A4) PI/r may potentially increase exposure Caution warranted and clinical monitoring of therapeutic and adverse effects recommended Amlodipine should be started at a low dose with careful titration Calcium channel blockers Amlodipine PI/r Potential interaction may require close monitoring, alteration of drug dosage or timing of administration Gilead Sciences Europe Ltd. STRIBILD (elvitegravir/cobicistat/emtricitabine/tenofovir disoproxil), Summary of Product Characteristics, May 2016; HIV drug interactions, interactions with entry and integrase inhibitors. Available at: (accessed July 2016)

30 Amlodipine drug-drug inteactions II Coadministration has not been studied Amlodipine is metabolized by CYP3A4 Efavirenz and nevirapine are inducers of CYP3A4 They could potentially decrease amlodipine exposure Monitor clinical effect and increase dose if needed. Calcium channel blockers Amlodipine EFV - NVP Potential interaction may require close monitoring, alteration of drug dosage or timing of administration

31 Steroid drug drug interaction profile DTG PI/r EFV - NVP RAL Beclometasone Betamethasone - Budesonide - Clobetasol - Dexamethasone - Fludrocortisone - Fluocinolone - Fluticasone - Hydrocortisone (oral) - Hydrocortisone (topical) - Megestrol acetate - Methylprednisolone - Mometasone - Nandrolone - Oxandrolone - Prednisolone - Prednisone - Stanazolol - Testosterone - Triamcinolone - HIV drug interactions, interactions with entry and integrase inhibitors. Available at: (accessed July 2016)

32 Clinical cases of iatrogenic adrenal suppression after co-administration of RTV or COBI and corticosteroids: examples

33 % who have used drug Recreational drugs may be another source of drug drug interactions in HIV-positive patients Levels of drug use among Asian MSM Crystal meth Ecstasy Cocaine Poppers Cannabis GHB Ketamine 1. Antoniou T, Tseng A. Ann Pharmacother. 2002;36: Bourne A. Drug use among men who have sex with men: Implications for harm reduction. In: The Global State of Harm Reduction. Available at: (accessed July 2016)

34 Bracchi M, et al. AIDS 2015;29:

35

36 Mephedrone Mephedrone is a synthetic stimulant drug of the amphetamine and cathinone classes Slang names include drone, M-Cat, and meow meow Chemically similar to the cathinone compounds found in the khat plant of eastern Africa Tablets or powder can be swallowed, snorted or injected, producing similar effects to MDMA, amphetamines and cocaine Metabolised by three phase I pathways (involving CYP2D6) Dunne FJ, et al. Bri J Med Pract 2015;8:a801; Gregg RA, Rawls SM. Life Sci 2014;97:27 30; Pedersen AJ, et al. Drug Test Anal 2013;5:430 8

37 Daskalopoulou M, et al. Lancet HIV 2014;1:e22 31

38 Conclusions All ARVs may be associated to toxicity Let s listen and learn Drug-drug interactions are not going away and may affect people well being in patients being treated in co-infection rates e.g. HCV Online access drugs Different prescribers Fewer clinic visits? Polypharmacy Recreational drugs in OTC medication Ageing