Dr Graeme Moyle, London - British HIV Association · Dr Graeme Moyle, London. ... • Vioxx CV...

Second Joint Conference 0f the British HIV Association [BHIVA]

and the British Association for Sexual Health and HIV [BASHH]

20-23 April 2010, Manchester Central Convention Complex

Long term toxicities from antiretrovirals: an inevitable consequence?

Dr Graeme Moyle, London

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

Time since initiation of phase I trials (years)

”GOD” ”DOG” REALISTIC

Chronic liver disease

Cognitive disorders

Non-Aids cancers

Chronic renal disease

OsteoporosisCVD

Frailty

Depression

Diabetes mellitus


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”


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

http://www.mhra.gov.uk/Safetyinformation/Reportingsafetyproblems/Reportingsuspectedadversedrugreactions/Healthcareprofessionalreporting/Adversedrugreactions/CON051927.

Assessment of CausalityA medical judgement made by a qualified medical Practitioner, usually

(but not always) the PI.

Not Related 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.

Unlikely

Possibly Related Again temporal relationship, relative, however is reasonable but the event could be due to another, equally likely cause.

Probably Related Temporal relationship, relative, reasonable and more likely explained by the product than any other cause

Definitely Related Temporal relationship, relative, reasonable and there is no other cause to explain the event.

MHRA: Flow Diagram of Clinical Trial Reporting Requirements.Adverse

Event

Report to PI

Fatal/life-

threatening?

Listed in

Protocol?

Report to Sponsor ASAP.

Sponsor informs MHRA

within 15 days

Complete CRF as

per protocol

Report to Sponsor

ASAP. Sponsor

informs MHRA within

7 days

Assessment of

causality

Complete Trust SUSAR form

Follow up


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.

http://www.mhra.gov.uk/Safetyinformation/Generalsafetyinformationandadvice/Adviceandinformationforconsumers/Sideeffectsofmedicines/CON019606

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 - 1906

• Food, Drug, and Cosmetic Act - 1933

• Elixir sulfanilamide tragedy

• Required pre-market safety

• Kefauver-Harris Amendments - 1962

• Thalidomide

• Clinical studies supported by animal testing

• Special cases

• FIAU

• Testing of NRT inhibitors for hepatitis B in woodchucks

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 12-16 hr

• All survived with intensive cardiopulmonary support and dialysis for 1 month

• Some with permanent disability

Delayed Type A Events: Chronology of FIAU Studies

1990 FIAU is safe for 28d in woodchucks.

1990-1 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.

1991-2 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 0.05-0.5 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.

1992 -1993 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.

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

1994-5 Animals studies show delayed liver failure


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 .

0

1

2

3

4

5

6

7

8

9

Incid

ence

(%

)

3.4%

(27/803)

7.8%

(66/847)2.7%

(23/842)

OR 0.40

P < 0.0001

OR 0.03

P < 0.0001

Control arm

Prospective HLA-B*5701

screening arm

Clinically Suspected

HSRImmunologically Confirmed

HSR

Type B events: ABC HSRPREDICT 1: Clinically Suspected and Immunologically Confirmed HSR in ITT evaluable population

0.0%

(0/802)

(0.25, 0.62)

(0, 0.18)

Mallal S et al., IAS 2007; Poster #WESS101


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.

Pomeranz et al., JAMA, 1998;279:1200-1205

In the USA:

• ADRs are among the top 10 causes of death

• Annually 2 216 000 ADRs in inpatients and 106 000 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 90 523 deaths, lung diseases 101 077 deaths, stroke 150 108 deaths

Rationale for pharmacovigilance

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

13 000 patients for 3 cases

The number of patients involved in pre-marketing studies has been increasing but is still inadequate to provide information on less frequent ADR

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

VIGOR - Summary of GI Endpoints

†p < 0.001. * p = 0.005.

0

1

2

3

4

5

Confirmed ClinicalUpper GI Events

ConfirmedComplicated

Upper GI Events

All ClinicalGI Bleeding

RR: 0.46†

(0.33, 0.64)

RR: 0.43*(0.24, 0.78)

RR: 0.38†

(0.25, 0.57)

Rate

s p

er

100 P

atient-

Years

RofecoxibNaproxen

( ) = 95% CI.

Source: Bombardier, et al. � Engl J Med. 2000.

GI outcomes VIGOR

NEJM, 11/00

17/1000 p-yrs

Patients with Events (Rates per 100 Patient-Years)

Event CategoryRofecoxibN=4047

NaproxenN=4029

Relative Risk(95% CI)

Confirmed CV events

45 (1.7) 19 (0.7) 0.42(0.25, 0.72)

Cardiac events

28 (1.0) 10 (0.4) 0.36(0.17, 0.74)

Cerebrovascular events

11 (0.4) 8 (0.3) 0.73(0.29, 1.80)

Peripheral vascular events

6 (0.2) 1 (0.04) 0.17(0.00, 1.37)

VIGOR - Confirmed Thrombotic Cardiovascular Events

Source: Data on file, MSD

0.0

0.5

1.0

1.5

2.0

2.5

3.0

3.5

Months of Follow-up

0 2 4 6 8 10 12 14

Cum

ula

tive I

ncid

ence %

Rofecoxib (OA)

Investigator-Reported Thrombotic Cardiovascular Events in the VIGOR Study Compared with Phase IIb/III OA Study

Rofecoxib (VIGOR)

Naproxen (VIGOR)

FDA files

Ibuprofen, Diclofenac,

Nabumetone (OA)

Summary: Selected CV Endpoints

Large Vioxx Databases

PTY risk 1

VIGOR

Vioxx 50 Naprox

N=2697 N=2698

Alzheimer’s

Vioxx 25 Placebo

N=1699 N=1930

APPROVe

Vioxx 25 Placebo

N=3070 N=3334

APTC events

n

PY-rate 235

1.30

18

0.77

32

1.88

40

2.07

34

1.11

18

0.54

Myocardial Infarction (fatal and non-fatal)

n

PY-rate 220

0.74

4

0.14

15

0.88

15

0.77

21

0.68

9

0.27

All cause mortality (on drug)

n

PY-rate 222

0.82

15

0.56

36

2.12

19

0.98

10

0.36

10

0.30

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

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.

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

0.1 0.5 0.75 1 1.25 1.5 1.75

Male health workersMale health workers

Social insurance, menSocial insurance, men

Male chemical workersMale chemical workers

Hyperlipidaemic menHyperlipidaemic men

Nursing home residentsNursing home residents

Social insurance, womenSocial insurance, women

Male physiciansMale physicians

Male smokersMale smokers

(Ex)(Ex)--smokers, asbestos workerssmokers, asbestos workersTrials

Trials

Cohorts

Cohorts

Skin cancer patientsSkin cancer patients

USAUSA

FinlandFinland

SwitzerlandSwitzerland

USAUSA

USAUSA

FinlandFinland

FinlandFinland

USAUSA

USAUSA

USAUSA

Relative risk (95% CI)

Egger et al. BMJ 1998

Observations in Cohort studies vs. RCTs

Beta-carotene intake and cardiovascular mortality

EuroSIDA: Incidence of non-AIDS death 1994-2004Excluding death from unknown causes

Philips A CROI 2008 EuroSIDA; Mocroft,

0

1

2

3

4

5

6

7

8

9

1995

1996

1997

1998

1999

2000

2001

2002

2003

2004

Year

Ra

te p

er

10

0 P

ers

on

Ye

ars

Test for trend: p < 0.0001

Breakdown of Causes of Death: France 2005

Philips A CROI 2008

Lewden et al, CROI 2007

ANRS EN19 Mortalité 2005

0 5 10 15 20 25 30 35 40

Unknown

Other

Psychiatric

Metabolic

Iatrogenic

Digestive

Pulmonary

Renal

Neurologic

OD/drug

Liver disease

Hepatitis B

Accident

Non-AIDS

Suicide

CVD

Hepatitis C

Cancer

AIDS

Percent

N = 937 deaths

CVD

Cancer

Substance Abuse

Other

Adapted from Sackoff J, et al Ann Intern Med 2006;145:397-406.

Age-Adjusted Deaths per 100,000

Leading Specific Causes of Non-HIV Deaths Among Persons With AIDS, by Race

15.7

13.6

12.7

9.2

4.4

4.3

12.9

10.0

6.0

5.5

4.3

4.1

15.3

12.1

8.2

4.5

3.4

0 5 10 15 20 25

Chronic ischemic heart disease

Lung cancer

Drug abuse and dependence

Hypertensive diseases

Chronic obstructive pulmonary disease

Acute myocardial infarction



Lung cancer

Hypertensive diseases


Alcohol abuse and dependence



Lung cancer


Intentional self-harm (suicide)

Black

Hispanic

White and Other

Population-based cohort analysis (New York City) All PLWA ≥13 years old (1999 2004) reported to New York City HIV/AIDS

Reporting System and Vital Statistics Registry through 2004 (n = 68 669)

•Adapted from Weber R et al. Arch Int Med 2006;166:1632–1641; Pantazis N et al. AIDS 2008;22:2441–2450; Baker JV et al. AIDS 2008;22:841–848. d’Arminio Monforte. AIDS 2008;22:2143–2153

Re

lative R

isk

>500

1.0

10

HIV/AIDS

Cancer

Heart

Liver

<50 50–99 100–199 200–349 350–499

100

CD4+ Cells/mm3

Low CD4 on therapy predicts risk of AIDS and more importantly the risk of non-AIDS events (DAD)

Unadjusted Rate of MI/1000 P-Y in D:A:D 2009

3.8

4.4

5

4.2

3.6

4.1

3.5

0

1

2

3

4

5

6

ZDV ddI ddC d4T 3TC ABC TDF

# MI/1000 PYFU

Lundgren JD et al., CROI 2009; Abst 44LB

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

NRTIs and MI Risk in D:A:D

Lundgren J, et al. CROI 2009, abstract 44, 2/8/2009

1.9

1.5

1.2

1

0.8

0.6

1.9

1.5

1.2

1

0.8

0.6

RR Yes/No (95%CI)

RR Per Year (9

5%CI)

ZDV ddl ddC d4T 3TC ABC TDF

**

138,109

523

74,407

331

29,676

148

95,320

405

152,009

554

53,300

221

39,157

139

#PYFU:

#MI:

*Recent use=current or within the last 6 months.

**Not shown (low number of patients currently on ddC)

Observed Rate of MIs in D:A:D Cohort Study4

Predicted 10 yearFramingham Risk

Observed rate of MI (events/1000 patient years)

Difference*

(events/1000 patient yearsi.e 100pts for 10yrs))

No ABC ABC

LOW ≤10% 1 2.9 1.9

MEDIUM >10% - <20% 5.9 7.7 1.8

HIGH ≥20% 15.9 32.5 16.6

*Additional observed MIs in the recent use of ABC group as compared to no recent use of ABC group

D:A:D Study Group Results [2008 publication]

Based on unadjusted data

1. D:A:D Study Group. Published on line April 2 2008 DOI:10.1016/50140-6736(08)60423-7

Rate of Vascular events/1000 P-Y in ACTG5202Defined as coronary artery disease, infarct, ischemia, angina, cerebrovascular accident, transient ischemic attack or peripheral vascular disease.

1.4

2.5

0

1

2

3

4

5

6

ABC TDF

# MI/1000 PYFU

Daar E, et al. 17th CROI; San Francisco, CA; February 16-19, 2010. Abst. 59LB.

Risk Ratio: 1.75!

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)

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

ACTG5202 CV events

CV events per 100 patients with ABC/3TC

CV events per 100 patients with TDF/FTC





12 months 5 years 10 years

0.14 0.25(0.1 extra)

0.7 1.3(0.5 extra)

1.4 2.5(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 m2, fall to <60

• If baseline eGFR <60 mL/min/1.73 m2, fall by 25%

• 225 (3.3%) progressed to CKD

• 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, 2010. Abst. 107LB.

Multivariable

IRR/year 95% CI P-value

Tenofovir 1.16 1.06-1.25 <0.0001

Indinavir 1.12 1.06-1.18 <0.0001

Atazanavir 1.21 1.09-1.34 0.0003

Lopinavir/r 1.08 1.01-1.16 0.030

Cumulative Exposure to ARVs and Risk of CKD

Balancing Risks

• Incidence of MI: 3.3 (3.0-3.6)/1000 PYFU [DAD]

• Incidence of CKD: 1.1 (0.9–1.2)/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


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)

Dr Graeme Moyle, London - British HIV Association · Dr Graeme Moyle, London. ... • Vioxx CV...

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