Complications and adverse reactions associated with antiretroviral therapy

Transcription

1 13th International Workshop on Clinical Pharmacology of HIV Therapy Barcelona, April Complications and adverse reactions associated with antiretroviral therapy Esteban Martinez

2 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

3 Adverse effects come in two modalities Short-term/acute/early onset Metabolic GI disturbance HSR, etc Long-term/cummulative/late onset Lipodystrophy Cardiovascular Renal, etc Linked to immediate tolerability Well known and defined Impact on adherence Linked to individual drugs Usually easy to manage Linked to long-term use of durable, tolerable therapies Less known and less well defined Often synergistic with diseases of normal ageing More difficult to manage

4 Antiretroviral tolerability decreases with age Kaiser Permanente of Northern California chart review All adults who initiated antiretroviral therapy ( 3 drugs) from (N = 5090) Analysis of patients who developed grade 2-4 abnormality while on HAART Median follow-up: 3.8 years Parameter % with grade 2-4 abnormality All patients years years 50 years P value TC or LDL Glucose <.001 Creatinine NR Silverberg MJ et al. Arch Intern Med 2007;167:

5 The lower the CD4+ cell count, the higher the risk for co-morbidities Cohort study of HIV+ and HIV- Kaiser Permanente members Overall, increased risk of CHD (P <.001), MI (P <.001) in HIV+ vs HIVpatients CHD Risk By Most Recent CD4+* HIV Positive, Receiving ART HIV Positive, Not Receiving ART HIV Negative CD CD CD HIV Negative CD CD CD Lower Rate of CHD Higher Rate of CHD Rate Ratio (95% CI) Rate Ratio *Adjusted for age, race, sex, tobacco use, alcohol/drug abuse, obesity, diabetes, and use of lipid-lowering and antihypertensive therapy. The following factors were time varying in the analysis: ART, CD4+ count, age, diabetes, lipid-lowering therapy, antihypertensive therapy, remaining factors were fixed variables. Reference 0.9 (P =.38) 1.4 (P <.001) 1.7 (P <.001) Reference 1.3 (P =.19) 1.1 (P =.75) 1.5 (P =.29) Klein D, et al. CROI Abstract 810.

6 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

7 Randomized clinical trials show that EFV decreases vitamin D: SENSE study Rockstroh J ET AL. 12th Int Workshop Adverse Drug Reactions & Co-Morbidities in HIV, London, November 2010 [P17]

8 Randomized clinical trials show that EFV decreases vitamin D: ECHO study Patients with 25(OH)D deficiency (%) * * TMC278 EFV *p=0.032 (Fisher s Exact test) for treatment comparison in severe 25(OH)D deficiency at Week 48, irrespective of baseline Wohl D, et al. 18th CROI Abstract O-1014

9 EFV-induced vitamin D deficiency: Potential pathogenetic pathway EFV EFV induces 24-hydroxilase, a p450 enzyme that hydrolizes 25 (OH) vitamin D to the inactive 24,25(OH)2 vitamin D Conrado T et al. Arq Bras Endocrinol Metab 2010

10 How does this effect translates into the HIV+ population?

11 Similar prevalence of low vitamin D levels, but more severe in HIV+ patients EFV use in approximately 50% of HIV+ patients 63% 72% 14% 22% 20% 1% 2% Ross AC et al. 13th Int Workshop Adverse Drug Reactions and Co-morbidities in HIV 2011, Rome (abstract 10)

12 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

13 Initiation of ART leads to a decrease in BMD followed by a plateau Change in BMD from baseline (%) (irrespective of the antiretroviral drugs used) Change in BMD from baseline (%) Semanas Adapted from several references: Rivas P, et al. HIV Medicine 2008; Hansen et al, IAS 2009; Daar et al. CROI 2010

14 Initial decrease in BMD with ART is an immune reconstitution phenomenum TDF/FTC+LPV/r (n=20) Bone resorption markers (CTx, RANKL) increase from week 2. Maximal change for CTx +93% at week 12, and RANKL +162% at week 24 (both p<0.01) Change in Bone Resorption with HAART C-Terminal Telopeptide (% Change from Baseline) HAART (LPV/r + TDF/FTC) P<0.001 P< Time (Weeks) Ofotokun I, et al. 18th CROI; Boston, MA; February 27-March 2, Abst. 78

15 TDF associated with small (but significant) BMD decrease in naïve patients 903 study (144 weeks) Powderly W et al. CROI 2005

16 Increasing age potentiates the risk of fractures 20 Age (yrs) T-score (SD) Kanis JA et al Osteoporosis Int 2002;13:

17 Incidence of bone fractures: relative increase, but absolute low numbers Higher proportion of patients on effective treatment Increased survival and increased fracture rates Fracture Rate per 1000 Patient-Years Pre-HAART Era: 1.61 Events/1000 PY Fracture Rate by Year HAART Era: 4.09 Events/1000 PY Year of Fracture Diagnosis Bedimo R et al. 13th Int Workshop Adverse Drug Reactions and Co-morbidities in HIV 2011, Rome

18 TDF and PIr exposure associated with a higher risk of osteoporotic fractures 1,3 1,2 Hazard Ratio 1,1 1,0 0,9 0,8 MV Model 1: Controlling for CKD, age, race, tobacco use, diabetes and BMI; MV Model 2: Controlling for Model 1 variables + concomitant exposure to other ARVs. Bedimo R et al. 13th Int Workshop Adverse Drug Reactions and Co-morbidities in HIV 2011, Rome

19 Interaction between TDF and PIr exposure for osteoporotic fractures risk Concomitant exposure to both TDF and rpi associated with a greater OF risk than exposure to either TDF without rpi or rpi without TDF 1,4 1,2 Hazard Ratio 1,0 0,8 0,6 TDF rpi TDF + rpi Bedimo R et al. 13th Int Workshop Adverse Drug Reactions and Co-morbidities in HIV 2011, Rome

20 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

21 Increasing age potentiates the risk of kidney failure Estimated GFR (ml/min/1.73m 2 ) General population Inulin (Davies and Shock, 1950) 20 NHANES III Estimated GFR (median, 95th percentiles) Age (years) National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease. Am J Kidney Dis 2002

22 Creatinine 1.3 mg/dl Man 50 years old

23 Creatinine 1 mg/dl Woman 50 years old

24 Increasing age is a risk factor for TDFassociated kidney toxicity Data from the Tenofovir Expanded Access Program after 4 years of FU Grade 1 or more ( 0.5 mg/dl or 44 µmol/l from baseline): OR (95%CI) P value Age (years) 1.05 ( ) Low CD4 cells/µl (<50, , >100) 2.17 ( ) <0.001 (<50, , >100 cells/µl) Low baseline weight (kg) 1.06 ( ) <0.001 Nephrotoxic medication at baseline 2.40 ( ) Grade 2 or more ( 2 mg/dl or 177 µmol/l from baseline ): OR (95%CI) P value High baseline creatinine (mg/dl) 17.4 ( ) Low baseline weight (kg) 1.14 ( ) n=911 patients with baseline and follow-up serum creatinine and relevant information on risk factors available Adapted from Nelson M et al. AIDS 2007; 21:

25 Low weight is a risk factor for TDFassociated kidney toxicity Time to 25% egfr reduction according to baseline weight categories n=160 n=168 n=167 Log-rank test <59kg vs >67kg 59-67kgvs >67kg p=0.002 p=0.073 Nishijima P et al. 13th Int Workshop Adverse Drug Reactions and Co-morbidities in HIV 2011, Rome

26 TDF and PIr exposure associated with a higher risk of CKD: EuroSIDA study 6843 HIV-infected pts with 3 serum creatinine measures and corresponding body weight measures from EuroSIDA study 21,482 pt-yrs of follow-up Cumulative exposure to TDF, ATV, LPV/RTV, or IDV each associated with increased risk of CKD Risk of CKD after stopping TDF remained elevated for 1 yr Within 12 mos, IRR: 4.05 ( ) After 12 mos, IRR: 1.12 ( ) Risk of CKD after stopping ATV or LPV/RTV similar to pts never exposed Agent TDF IDV ATV LPV/RTV Adjusted* IRR per Yr of Exposure (95% CI) Cockcroft-Gault (n = 225) MDRD (n = 277) CKD-EPI (n = 258) INSIGHT def (n = 129) *Adjusted for baseline egfr, AIDS during follow-up, use of nephrotoxic drugs, current CD4+, age, HIV-1 RNA, any CV event, arterial hypertension, diabetes, HCV coinfection, non-aids malignancy, and pt sex. Kirk O, et al. CROI Abstract 107LB.

27 Plasma TDF levels may increase with some commonly used PI/r ATV 400 mg TDF 300 mg TDF alone 80 Tenofovir Concentration (ng/ml) 100 TDF AUC 34% TDF + LPV/r % change from when dosed alone Cmax AUC Cmin -20% -25% -40% 14% 24% 22% mean ± 95%CI Time (hr) -60 Light meal Kearney B et al. ICAAC 2003, poster #A-1617 Kaul S, et al. ICAAC, 2003calibri

28 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

29 D:A:D study: Recent and/or cumulative antiretroviral exposure and risk of MI RR of recent* exposure yes/no 95%CI ZDV ddi ddc d4t 3TC ABC TDF # PYFU: 138,109 74,407 29,676 95, ,009 53,300 39,157 # MI: RR of cumulative exposure/year 95%CI PI NRTI NNRTI IDV NFV LPV/RTV SQV NVP EFV # PYFU: 68,469 56,529 37,136 44,657 61,855 58,946 # MI: *Current or within last 6 mos. Approximate test for heterogeneity: P = Lundgren JD, et al. CROI Abstract 44LB

30 PI-based ART leads to higher cimt than NNRTI-based ART after 2 years Two-year carotid artery intima-media thickness (CIMT) progression, human immunodeficiency virus (HIV) RNA viral load and baseline combined antiretroviral therapy (cart) use among Study to Understand the Natural History of HIV/AIDS in the Era of Effective Therapy (SUN Study) participants (n = 389). Baker JV et al. Clin Infect Dis 2011

31 Contribution of dyslipidaemia to MI risk HDL cholesterol (per mmol/l) Triglycerides (per log 2 mmol/l higher) Total cholesterol (per mmol/l) PI exposure 1.15 (1.06, 1.25) (per additional year) NNRTI exposure 0.94 (0.74, 1.19) (per additional year) 0.72 ( ); P=0.05* 1.58 ( ); P< ( ); P<0.001* 1.10 ( ); P=0.002 * 1.00 ( ); P=0.92* Relative Rate of MI* (95% CI) *Adjusted for conventional risk factors (sex, cohort, HIV transmission group, ethnicity, age, BMI, family history of CVD, smoking, previous CVD events, lipids, diabetes, and hypertension). Friis-Møller N et al. N Engl J Med 2007 Unadjusted model.

32 Factors contributing to CV disease in HIVinfected patients: where ABC could act? Age, sex Smoking BP Weight Lipids Glucose Renal HIV Atheroma formation and growth INFLAMMATION Plaque instability and rupture Thrombosis Lipids Glucose Adipose tissue Renal ART ABC? Adapted from Reiss P. CROI 2009

33 Myocardial infarction was not recognised as part of ABC hypersensitivity reaction Percent of Cases Signs and Symptoms of Abacavir Hypersensitivity Reaction (n=636) Hetherington S et al. 7 th CROI 2000

34 The pathogenetic link between ABC and MI remains controversial ICAM-1 Mac-1 Leukocytes Platelets Endothelial cells ABC in vitro: induces Mac-1 on leukocytes, which interacts with ICAM-1 on endothelial cells 1 increases platelet activity through inhibition of soluble guanylyl cyclase 2 facilitates collagen-induced platelet aggregation 3 ABC in patients: STEAL Study 4 WIHS and HOPS Cohort 5 BICOMBO Study 6 HEAT Study 7 No differences in biomarkers (hscrp, IL-6, D-dimer, MCP-1 ) 1 de Pablo CROI 2010 #716; 2 Baum CROI 2010 #717; 3 Satchell CROI 2009 #151LB7; 4 Martin CROI 2010, #718; 5 Palella AIDS 2010; 6 Martinez AIDS 2010; 7 McComsey CROI 2009 # 732

35 FDA meta-analysis of risk of MI in abacavir trials: no proven association Current analysis: 26 controlled trials in which ABC use was randomized; source data obtained for analysis No significant relationship between ABC use and risk of MI Academic Center Trials Mantel-Haenszel Risk Difference, % (95% CI) MI Frequency (Events/Subjects) Abacavir No Abacavir 6/702 4/863 NIH (ACTG) Trials /1985 9/1610 Manufacturer Trials /2341 9/2367 All Trials / / Ding X, et al. CROI Abstract 808

36 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

37 Lipodystrophy is a predictor of subclinical atherosclerosis Prevalence of coronary disease measured by CAC* according to different phenotypes n = 6 n = 38 No lipodistrophy n = 47 n = 108 Lipoatrophy n = 57 n = 73 Mixed form n = 24 n = 19 Lipoaccumulation X²-test p-value < 0,001 CAC : Coronary artery calcium score Guaraldi G et al. Atherosclerosis 2009

38 Limb fat loss still present with contemporary regimens ACTG 5224s: Limb fat changes 10% Limb Fat Loss From BL to Wk 96 (%) n = Limb Fat Primary Endpoint TDF/FTC + EFV ABC/3TC + EFV TDF/FTC + ATV/RTV ABC/3TC + ATV/RTV P = NS Study Arm Similar absolute and % increases in limb fat with ABC/3TC and TDF/FTC in ITT analysis (P > 0.1) Greater absolute and % increases in limb and trunk fat with ATV/r vs EFV in ITT and as-treated analyses (P <.05) McComsey G, et al. CROI Abstract 106LB.

39 How much fat is normal fat?: Fat percent in general population relatively stable National Health and Nutrition Examination Survey (NHANES) Race: white (45%), black (26%), hispanic (29%). Age: 8->85 a men and women BMI: < 18,5 (3,1%) up to > 40 (26,3%) Kelly TL, et al. PLoS ONE 2009

40 Fat mass ratio (% trunk fat / % leg fat) in the general population Kelly TL, et al. PLoS ONE 2009

41 FMR: % trunk fat/ % leg fat(bonnet E et al. J Clin Densitom 2005) Lipodistrophy >1.5 (1 DS en VIH negativos) Normal <1

42 FMR= 30.7 / 33.1 = 0.93

43 FMR= 25.5 / 7.3 = 3.49

44 Less limb fat gain with DRV/r + NRTIs (mostly non-thymidine) vs DRV/r: MONOI Valantntin MA et al. 17th CROI 2010; San Francisco. Abstract #721.

45 Abdominal lipoaccumulation remains prevalent among HIV+ patients Group 1 ART < 2005 N= 723 Group 2 ART > 2005 N= 115 p Age (Median; IQR) 46 (42-51) 44 (36-51) 0,004 Male 510 (70.6%) 85 (74.0%) BMI Kg/m ( ) ( ) Waist Circumference (Median;IQR) 88 (81-95) 88 (80-97) 0, cm (IDF) 149 (29.2%) 32 (37.6%) 0,118 >102 cm (NCEP ATPIII) 65 (12.7%) 10 (11.8%) Female 213 (29.4%) 30 (26.0%) BMI Kg/m ( ) 23 ( ) < Waist Circumference (Median; IQR) 80 (73-88) 87 (80-97) cm (IDF) 112 (52.6%) 23 (76.7%) > 88 cm (NCEP ATPIII) 52 (24.4%) 13 (43.3%) Poizot-Martin I, et al. EACS 2009, abstract PS11/1

46 VAT is correlated with LPS in chronically treated patients Correction for TGs, HDL-C, adiponectin, leptin, HOMA-IR, and stnfr2 each attenuated the relationship between LPS and VAT r=.32 p=.03 N=46 Dubé M et al. 13th Int Workshop Adverse Drug Reactions and Co-morbidities in HIV 2011, Rome

47 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

48 Late switches from TDF/FTC/EFV due to CNS adverse effects Retrospective chart review of patients who initiated ART with fixed-dose TDF/FTC/EFV at Chelsea & Westminster Hospital in London (N = 472) Data collected on timing and reasons for discontinuing TDF/FTC/EFV 89 patients (19%) discontinued TDF/FTC/EFV after median of 294 days (IQR: ) 71% of discontinuations due to CNS toxicity Among patients discontinuing due to CNS toxicity, most did so after 3 mos 16% after 0-12 wks; 48% after wks; 36% after wks Zheng J, et al. ICAAC Abstract H2-783.

49 Discontinuations of study drugs due to specific adverse effects: NEFA study N ev i r a pin e ( n= 155) E fa v i r en z ( n= 156) A ba c avi r ( n= 149) A t 1 y ea r A t 3 y ea r A t 1 y ea r A t 3 y ea r A t 1 y ea r A t 3 y ea r C lin i cal ( a ny) N eu r op s yc h iat r ic C uta n eous G ast r oi n testi n al S y s temi c a O the r La b o r ato r y ( a ny) In c r e as e d t r an s ami n ase s H yp e r g lyc e mia Tot a l 2 6 (17 % ) 2 9 (19 % ) 2 7 (17 % ) 3 9 (25 % ) 9 ( 6 %) 1 3 (9%) P=0.013 P=0.005 Martinez E et al. AIDS 2007

50 Does EFV affrect NC function? 146 patients 129 (88.4%) were on cart 69 (47%) were classified as cognitively impaired 35.6% asymptomatic 11.6% mild neurocognitive impairment Variable β OR 95% CI P-value β OR 95% CI P-value Univariate Multivariate Gender (male versus female) ( ) Age per 10 years ( ) ( ) Education per year ( ) ( ) Non-Italian born versus Italian born ( ) ( ) IVDU ( ) 0.78 HCV ( ) Time since HIV diagnosis per year ( ) AIDS defining illness ( ) CD4 nadir per 100 cells ( ) Time on cart per one year increase ( ) Efavirenz use ( ) ( ) CPE rank > ( ) HIV RNA per log increase ( ) HIV RNA < 50 copies/ml ( ) CD4 cell count per 100 cell increase ( ) 0.42 Ciccarelli N et al. Neurology 2011; 76:

51 Neuronal damage and ART: how this data translates into the clinic? Neurons stained for microtubuleassociated protein-2 (MAP-2): (A) normal untreated cultures (B) dendritic beading (C) pruning of dendrites (D) loss of neuron density Following 6 days exposure to ARVs at reported plasma concentrations: (B) and (C) cultures treated with atazanavir (D) maximal damage seen with efavirenz Liner J et al. CROI 2010, poster 435

52 Zidovudine, Lamivudine, Indinavir, and Abacavir

53 Increased deposition of amyloid in patients with access to HAART Age 24-75, mean age in mid 40s UCSD and UCLA brain banks Green, Masliah et al AIDS 2005

54 1. Long-term adverse effects or co-morbitities: Impact of age and immunodeficiency 2. Efavirenz and low vitamin D 3. TDF / PIr and bone problems 4. TDF / PIr and kidney problems 5. Antiretrovirals and CV disease 6. Lipodystrophy: still matters? 7. Neurotoxicity 8. Hepatotoxicity

55 ART and hepatotoxicity RTV ddi d4t NVP TPV AZT EFV ETV MRV APV DRV ABV TDF ATV LPV RAL 3TC FTC SQV ENF NRTI NNRTI PI New ARVs Soriano V et al. AIDS 2008

56 Hepatotoxicity of antiretrovirals more common with greater liver fibrosis 102 HIV/HCV coinfected patients on long-term HAART 100 Cumulative Incidence of Hepatic Events (%) Yes No F3-F4 (n=41) Log Rank: 6.48 (p=0.01) F0-F2 (n=62) 0 follow-up (months) no. of patients Labarga P et al. J Infect Dis 2007

57 Non-cirrotic portal hypertension Unexplained: platelets transaminases alkaline phosphatase liver stiffness (Fibroscan) HIV High intraportal drug concentration Hypercoagulability? Endothelial dysfunction? Mitochondrial damage? Heterogeneous liver perfusion Periportal fibrosis Partial nodular transformation Nodular regenerative hyperplasia Non-cirrhotic portal hypertension Slide courtesy of Vicente Soriano

58 NVP well tolerated in experienced patients with high CD4 if plasma HIV undetectable N=3051 N=796 N=1865 N=1349 N=853 N=2272 TOXPC: discontinuation of NVPc due to toxicities or patient/physician choice at any time. TOXPC 18 weeks: TOXPC occurring within 18 weeks HSR: discontinuations due to hypersensitivity reactions Kesselring A et al. AIDS 2009

59

60 May an adverse effect be ultimately good for health?

61 Summary Short-term AEs scarce and predictable Long-term AEs also scarce but more difficult to predict With aging, co-morbidities are increasingly apparent Despite low long-term AEs, potential negative impact on co-morbitities of certain antiretrovirals ART should be chosen not only for providing long-term efficacy but also for having the lowest impact on co-morbidities