Long term toxicities from antiretrovirals: an inevitable consequence?

Transcription

1 Second Joint Conference 0f the British HIV Association [BHIVA] and the British Association for Sexual Health and HIV [BASHH] April 2010, Manchester Central Convention Complex Long term toxicities from antiretrovirals: an inevitable consequence? Dr Graeme Moyle, London

2 Declaration of Interests I am an Associate Specialist at Chelsea and Westminster NHS Foundation Trust I have no family or personal relationships with persons in the Pharma Industry I do not directly hold shares in Pharma companies involved in HIV care I have received honorarium for speaking or consultations from BMS, Gilead Sciences, Merck, Tibotec, Theratechnolgies, ViiV Healthcare I also have had research grants at SSAR from Abbott/Solvay, Ardea Biosciences, Bionor, GSK, Pfizer Enthusiasm for an agent as a function of time since first introduced Enthusiasm GOD DOG REALISTIC Time since initiation of phase I trials (years)

3 Non-Aids cancers CVD Osteoporosis Depression Diabetes mellitus Frailty Cognitive disorders Chronic liver disease Chronic renal disease Long term toxicities from antiretrovirals: an inevitable consequence? Definitions: Article 1 of Directive 2001/83/EC as amended defines a medicinal product as: a) Any substance or combination of substances presented as having properties for treating or preventing disease in human beings b) Any substance or combination of substances which may be used in or administered to human beings either with a view to restoring, correcting or modifying physiological functions by exerting a pharmacological, immunological or metabolic action, or to making a medical diagnosis

4 Long term toxicities from antiretrovirals: an inevitable consequence? Definitions: An adverse drug reaction (ADR) is an unwanted or harmful reaction experienced following the administration of a drug or combination of drugs under normal conditions of use, which is suspected to be related to the drug. Includes but not defined: Acute toxicity vs. chronic toxicity / late toxicity Permanent vs. transient toxicity Immediate vs. delayed toxicity Serious vs. Non-serious AEs drugreactions/con Assessment of Causality A medical judgement made by a qualified medical Practitioner, usually (but not always) the PI. Not Related Unlikely Temporal relationship of the onset of the event, relative to the administration of the product, is not reasonable or another cause can by itself explain the occurrence of the event. Possibly Related Probably Related Definitely Related Again temporal relationship, relative, however is reasonable but the event could be due to another, equally likely cause. Temporal relationship, relative, reasonable and more likely explained by the product than any other cause Temporal relationship, relative, reasonable and there is no other cause to explain the event.

5 MHRA: Flow Diagram of Clinical Trial Reporting Requirements. Adverse Event Report to PI Assessment of causality Listed in Protocol? Complete CRF as per protocol Report to Sponsor ASAP. Sponsor informs MHRA within 7 days Fatal/lifethreatening? Report to Sponsor ASAP. Sponsor informs MHRA within 15 days Complete Trust SUSAR form Follow up Long term toxicities from antiretrovirals: an inevitable consequence? Definitions: Describing risk in MHRA patient information leaflets: very common means that more than one in ten people taking the medicine are likely to have the side effect common means that between one in ten and one in 100 people are affected uncommon means that between one in 100 and one in 1,000 people are affected rare means that between one in 1,000 and one in 10,000 people are affected very rare means that fewer than one in 10,000 people are affected. ofmedicines/con019606

6 Different types of adverse events Type A effects ( drug actions ): due to pharmacological effects fairly common dose related (i.e. more frequent or severe with high doses) and may often be avoided by individualising doses can usually be reproduced and studied experimentally and are often already identified in pre-clinical or in dose escalation studies. Drug interactions - may be classified as Type A effects, although they are restricted to a defined sub-population of patients, i.e. those taking interacting drugs FDA Reactionary Regulatory Guidance Pure Food and Drug Act Food, Drug, and Cosmetic Act Elixir sulfanilamide tragedy Required pre-market safety Kefauver-Harris Amendments Thalidomide Clinical studies supported by animal testing Special cases FIAU Testing of NRT inhibitors for hepatitis B in woodchucks

7 Type A Events: TGN1412 CD28 agonist antibody Enhanced regulatory T cell activity T cell activation Standard repeated dose program in Cynomolgus monkey Transient increase in circulating T cells Low to moderate increases in IL-2, 5, and 6 but not IL-4, TNFα, or INFγ No clinical signs suggestive of cytokine release Low level signals evident on retrospective analysis TGN1412 What happened Six healthy male volunteers given TGN1412 simultaneously in a Phase I study Systemic inflammatory response 90 min after dose Headache, myalgia, nausea, diarrhea, erythema, vasodilation, and hypotension Pulmonary infiltrates, renal failure, and DIC within hr All survived with intensive cardiopulmonary support and dialysis for 1 month Some with permanent disability

8 Delayed Type A Events: Chronology of FIAU Studies 1990 FIAU is safe for 28d in woodchucks ACTG 122B: Oral FIAU in 10 HIV-infected pts at 1mg/kg x 14d. Nausea and fatigue at 1.7 mg/kg/d are dose-limiting. 6 HBV/HIV-infected pts treated at NIH. Marked suppression of HBV levels, acceptable AEs Dose de-escalation studies in 43 pts with HBV/HIV confirm short-term tolerance and antiviral activity down to 0.1 mg/kg/d. 3/4 NIH pts die 2-5 months after retreatment: pancreatitis on ddi; 2 with liver failure. Autopsies no microvesicular fat. Chronology of FIAU Studies 1992 NIH trial in 24 HIV-negative HBV pts: FIAU mg/kg/d x 28d. Dose-related inhibition of HBV DNA. AEs: peripheral neuropathy, cholecystitis 4 mo after FIAU; neuropathy and hepatic failure 3 mo after treatment - dies 2 mo later. Autopsy - microvesicular fat Eli Lilly assumes FIAU development. Multi-center trial of 0.1 vs 0.25 mg/kg/d x 90d. NIH 180d trial: 15 HIV/HBV pts enrolled; May 1993: Dose reduced or stopped for GI upset in 3 pts and neuropathy in one subject. June 1993 One pt admitted for fatigue and nausea. June 26,1993 Pt presents with lactic acidosis. Trial is stopped.

9 Chronology of FIAU Studies July 1993 Despite termination of FIAU, 5 pts die of progressive liver failure, lactic acidosis, pancreatitis, myopathy and neuropathy. Two survive with emergency liver transplantation. Five suffer reversible effects. Three remained well Animals studies show delayed liver failure Different types of adverse events Type B effects ( patient reactions ): occur in only a minority of predisposed, intolerant patients, little or no dose relationship, generally rare and unpredictable, sometimes serious, difficult to study.

10 Type B events: ABC HSR PREDICT 1: Clinically Suspected and Immunologically Confirmed HSR in ITT evaluable population Incidence (%) % (66/847) OR 0.40 (0.25, 0.62) P < % (27/803) Clinically Suspected HSR Control arm Prospective HLA-B*5701 screening arm 2.7% (23/842) OR 0.03 (0, 0.18) P < % (0/802) Immunologically Confirmed HSR Mallal S et al., IAS 2007; Poster #WESS101 Different types of adverse events Type C effects: the use of a drug increases the frequency of a spontaneous disease, may be both serious and common (and include malignancy, CV events, DM) often relate to long term use, there is often no suggestive time relationship and the connection may be very difficult to prove.

11 Rationale for pharmacovigilance Pomeranz et al., JAMA, 1998;279: In the USA: ADRs are among the top 10 causes of death Annually ADRs in inpatients and deaths possibly related to use of pharmaceuticals in USA In 1994, 4.6% of all deaths in USA may be due to pharmaceuticals Comparison: accidents deaths, lung diseases deaths, stroke deaths Rationale for pharmacovigilance To be sure to detect an ADR that occurs once per 2000 patients treated, we need to treat: 6000 patients for 1 case 9600 patients for 2 cases patients for 3 cases The number of patients involved in premarketing studies has been increasing but is still inadequate to provide information on less frequent ADR

12 FDA Withdrawal of Drugs 20 drugs withdrawn since inception of FDA in 1936 Omniflox antibiotic that causes hemolytic anemia Rezulin diabetes drug that causes acute liver failure Fen-Phen and Redux weight loss drugs that cause heart valve injury PPA (Phenylpropanolamine) OTC decongestant and weight loss drug that caused hemorrhagic stroke in women Rovan antibiotic that cause acute liver failure Lotronex drug for IBS that caused ischemic colitis Baycol cholesterol-lowering drug that caused severe muscle injury, kidney failure, and death Seldane antihistamine that caused heart arrhythmias and death Propulsid drug for nighttime heartburn that caused heart arrhthythmias and death Vioxx and Bextra- COX-2 inhibitors associated with CV risk Type C AEs: Vioxx COX-II Inhibitor Anti-inflammatory with less adverse effects, especially GI events. Potential toxicities: kidney and platelets - increased risk of thrombotic events Role in Cancer prevention Role in Alzheimer s disease

13 VIGOR - Summary of GI Endpoints Rates per 100 Patient-Years RR: 0.46 (0.33, 0.64) Confirmed Clinical Upper GI Events p < * p = ( ) = 95% CI. RR: 0.43* (0.24, 0.78) Confirmed Complicated Upper GI Events RR: 0.38 (0.25, 0.57) Rofecoxib Naproxen All Clinical GI Bleeding Source: Bombardier, et al. Engl J Med GI outcomes VIGOR 17/1000 p-yrs NEJM, 11/00

14 VIGOR - Confirmed Thrombotic Cardiovascular Events Patients with Events (Rates per 100 Patient-Years) Event Category Confirmed CV events Cardiac events Cerebrovascular events Peripheral vascular events Rofecoxib N=4047 Naproxen N=4029 Relative Risk (95% CI) 45 (1.7) 19 (0.7) 0.42 (0.25, 0.72) 28 (1.0) 10 (0.4) 0.36 (0.17, 0.74) 11 (0.4) 8 (0.3) 0.73 (0.29, 1.80) 6 (0.2) 1 (0.04) 0.17 (0.00, 1.37) Source: Data on file, MSD Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA Study 3.5 Cumulative Incidence % Rofecoxib (VIGOR) Ibuprofen, Diclofenac, Nabumetone (OA) Rofecoxib (OA) Naproxen (VIGOR) Months of Follow-up FDA files

15 Summary: Selected CV Endpoints Large Vioxx Databases PTY risk 1 APTC events VIGOR Vioxx 50 Naprox N=2697 N=2698 Alzheimer s n PY-rate Myocardial Infarction (fatal and non-fatal) n 20 PY-rate All cause mortality (on drug) n 22 PY-rate Vioxx 25 Placebo N=1699 N= APPROVe Vioxx 25 Placebo N=3070 N= n= events. 1 PYR patient years at risk, assuming constant overall risk. 2 PY-rate: Overall rate per 100 patient years. FDA files Challenges in Interpreting Vioxx CV Safety Vioxx CV signal was clear when compared to naproxen (excess approximately 6/1000pts yrs in OA) In VIGOR this was balanced by a reduced risk of GI bleeds (excess 17/1000pts years) CV findings inconsistent when compared to placebo (APPROVe different from Alzheimer s) In APPROVe excess of thrombotic events was approximately 6/1000pt yrs Mechanism: decreased prostacyclin from COX2 inhibition tilts toward platelet aggregation Net increase in thrombotic tendency, especially in people at higher risk (predisposed) Extent of role of BP on CV/T events with Vioxx is unclear Role of low dose ASA in protecting for CV/T events with Vioxx unknown Note: Data re derived from RCTs

16 Toxicity - ways of detection Randomised trials: randomised phase open-label follow-up Passive surveillance Spontaneous reporting systems Active surveillance: cohort studies Randomized Controlled Trials RCTS rarely done to assess the harmful impact of a treatment, however if harm is shown, can generally be confident of the result If study is properly randomized, both known and unknown confounders should be randomized to each group.

17 Cohort Studies Cohort studies are large prospective observational studies Exposure to the harmful agent may not be random, exposed patients are not randomly allocated Compensated by adjustment for known (and collected) confounders Associations not causations Hypothesis generating Case Control studies Case control studies are a useful way to evaluate harm when the adverse event is rare or the time to event is long Controls are selected to be similar to the cases in all aspects Cases and controls are the retrospectively studied to determine the exposure status to the putative agent

18 Observations in Cohort studies vs. RCTs Beta-carotene intake and cardiovascular mortality Cohorts Male health workers Social insurance, men Social insurance, women Male chemical workers Hyperlipidaemic men Nursing home residents USA Finland Finland Switzerland USA USA Trials Male smokers Skin cancer patients (Ex)-smokers, asbestos workers USA Male physicians Finland USA USA Relative risk (95% CI) Egger et al. BMJ 1998 EuroSIDA: Incidence of non-aids death Excluding death from unknown causes Rate per 100 Person Years Test for trend: p < Year Philips A CROI 2008 EuroSIDA; Mocroft,

19 Breakdown of Causes of Death: France 2005 AIDS Cancer Hepatitis C CVD Suicide Non-AIDS Accident Hepatitis B Liver disease OD/drug Neurologic Renal Pulmonary Digestive Iatrogenic Metabolic Psychiatric Other Unknown Philips A CROI 2008 N = 937 deaths Percent Lewden et al, CROI 2007 ANRS EN19 Mortalité 2005 Leading Specific Causes of Non-HIV Deaths Among Persons With AIDS, by Race Population-based cohort analysis (New York City) All PLWA 13 years old ( ) reported to New York City HIV/AIDS Reporting System and Vital Statistics Registry through 2004 (n = ) CVD Cancer Substance Abuse Other Chronic ischemic heart disease Lung cancer Drug abuse and dependence Hypertensive diseases Chronic obstructive pulmonary disease Acute myocardial infarction Black Drug abuse and dependence Chronic ischemic heart disease Lung cancer Hypertensive diseases Acute myocardial infarction Alcohol abuse and dependence Hispanic Chronic ischemic heart disease Drug abuse and dependence Lung cancer Acute myocardial infarction Intentional self-harm (suicide) Adapted from Sackoff J, et al Ann Intern Med 2006;145: Age-Adjusted Deaths per 100, White and Other

20 Low CD4 on therapy predicts risk of AIDS and more importantly the risk of non-aids events (DAD) 100 Relative Risk 10 HIV/AIDS Cancer Heart 1.0 Liver < >500 CD4+ Cells/mm 3 Adapted from Weber R et al. Arch Int Med 2006;166: ; Pantazis N et al. AIDS 2008;22: ; Baker JV et al. AIDS 2008;22: d Arminio Monforte. AIDS 2008;22: # MI/1000 PYFU Unadjusted Rate of MI/1000 P-Y in D:A:D ZDV ddi ddc d4t 3TC ABC TDF After adjustment for: Demographics, cardiovascular risk factors, and use of other ARV drugs and further analyses included adjustment for: Latest measure of lipids, metabolic parameters, CD4, and HIV-RNA RR for current ABC use was 1.68 vs. other NRTI Lundgren JD et al., CROI 2009; Abst 44LB

21 NRTIs and MI Risk in D:A:D RR Yes/No (95%CI) ** RR Per Year (95%CI) ZDV ddl ddc d4t 3TC ABC TDF #PYFU: #MI: 138, , , , , , , Lundgren J, et al. CROI 2009, abstract 44, 2/8/2009 *Recent use=current or within the last 6 months. **Not shown (low number of patients currently on ddc) D:A:D Study Group Results [2008 publication] Observed Rate of MIs in D:A:D Cohort Study 4 Predicted 10 year Framingham Risk Observed rate of MI (events/1000 patient years) Difference * (events/1000 patient years i.e 100pts for 10yrs)) No ABC ABC LOW 10% MEDIUM >10% - <20% HIGH 20% Based on unadjusted data * Additional observed MIs in the recent use of ABC group as compared to no recent use of ABC group 1. D:A:D Study Group. Published on line April DOI: / (08)

22 Rate of Vascular events/1000 P-Y in ACTG5202 Defined as coronary artery disease, infarct, ischemia, angina, cerebrovascular accident, transient ischemic attack or peripheral vascular disease. EFV (n=465) ATV/r (n=463) EFV (n=464) ATV/r (n=465) ABC/3TC TDF/FTC Cardiovascular, n (%) Vascular event * 29 (6) 2 (<1) 29 (6) 2 (<1) 35 (8) 6 (1) 20 (4) 1 (<1) Non-AIDS malignancies, n (%) 20 (4) 18 (4) 18 (4) 17 (4) Renal, n (%) 12 (3) 14 (3) 5 (1) 12 (3) Bone fractures, n (%) 22 (5) 16 (3) 21 (5) 21 (5) # MI/1000 PYFU Risk Ratio: 1.75! ABC Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 59LB. 2.5 TDF ACTG5202 Vascular events Absolute risk increase with TDF/FTC = 0.32% (0.75% 0.43%) NNH during this trial with median treatment duration of 3 years = 100/0.32 = 312 i.e. for every 312 patients treated in this trial with TDF/FTC vs ABC/3TC over 3yrs, one additional patient will experience a Vascular event

23 ACTG5202 CV events CV events per 100 patients with ABC/3TC CV events per 100 patients with TDF/FTC CV events per 100 patients with ABC/3TC CV events per 100 patients with TDF/FTC CV events per 100 patients with ABC/3TC CV events per 100 patients with TDF/FTC 12 months 5 years 10 years (0.1 extra) (0.5 extra) (1.1 extra) Note: data on Framingham risk not available in ACTG5202 CROI 2010 presentation Note: 5year and 10year risk are calculated by extrapolation EuroSIDA Study: Risk for Chronic Kidney Disease Analysis of patients with 3 creatinine measurements + weight 6,842 patients with 21,482 person-years of follow-up Definition of CKD (egfr by Cockcroft-Gault) If baseline egfr 60 ml/min/1.73 m 2, fall to <60 If baseline egfr <60 ml/min/1.73 m 2, fall by 25% 225 (3.3%) progressed to CKD Cumulative Exposure to ARVs and Risk of CKD Multivariable IRR/year 95% CI P-value Tenofovir < Indinavir < Atazanavir Lopinavir/r Incidence of CDK: No TDF: 0.7/100 p-yrs (0.5 to 0.8) 4 years TDF: 2.4/100 p-yrs (1.7 to 3.0) Risk factors for CKD on TDF: age, HTN, HCV, lower egfr, lower CD4+ count Kirk O, et al. 17th CROI; San Francisco, CA; February 16-19, Abst. 107LB.

24 Balancing Risks Incidence of MI: 3.3 ( )/1000 PYFU [DAD] Incidence of CKD: 1.1 ( )/100 PYFU [Eurosida] 3 years of exposure ABC: 90% increased risk of MI (DAD, current/recent use] TDF: 56% increased risk of CKD (Eurosida: assuming risk continues to accumulate) 10 years of exposure ABC: 90% increased risk of MI (DAD, current/recent use] TDF: 441% increased risk of CKD (Eurosida: assuming risk continues to accumulate) Ole Kirk: Personal Communication Long term toxicities from antiretrovirals: an inevitable consequence? Summary AEs will be reported increasingly in persons aging with HIV Pharmacovigilance via RCTs, meta-analysis, active cohort and passive reporting systems contribute to identifying possible ART contributions Challenges are to separate signal from noise In cohorts, association is NOT causation Randomized trial data provides best comparison of exposure Always interpret risk estimates in context of confidence intervals and magnitude of risk (NNH)