BMS Data Update Dr Keith Aizen and Victoria Adamson Bristol-Myers Squibb Prescribing and adverse event reporting information can be found at the end of.

BMS Data Update

Dr Keith Aizen and Victoria Adamson

Bristol-Myers Squibb

Prescribing and adverse event reporting information can be found at the end of this presentationDate of preparation: July 2009

Job Bag No: HIV/0709/2983MC/HIV/ATR/0709/0008

BMS Virology Portfolio

VIdex®

Didanosine (ddI)

Zerit®

stavudine (D4T)

DDI and D4T safety update

Topics

• Peripheral neuropathy

• CV risk

• Hepatotoxicity

Peripheral neuropathy

0

20

40

60

80

100

0 24 48 72 96 120 144

Study 903% Patients < 50 Copies/mL

% P

atie

nts

wit

h H

IV-1

RN

A <

50

c/m

L

Weeks

73%69%

Intent to Treat (Missing=Failure)

TDF+3TC+EFV

d4T+3TC+EFV

Adapted from Gallant et al JAMA July 14 2004 vol 202 191-201

Study 903 Selected Toxicities Associated with Mitochondrial Dysfunction through Week 144

(All Grades) Week 48 Week 144 Week 48 Week 144

Patients (%) with Events 9 (3%)* 17 (6%)* 30 (10%)* 82 (27%)*

Peripheral Neuritis/

Neuropathy 6 (2%)** 9 (3%)* 20 ( 7%)** 31 (10%)*

Lipodystrophy + 3 (1%) 9 (3%)* 11 ( 4%) 57 (19%)*

Lactic Acidosis + 0 0 3 ( 1%) 3 ( 1%)

Pancreatitis 0 0 0 0+ Investigator Defined

* p value < 0.001; ** p = 0.013

TDF+3TC+EFV (n=299)

d4T+3TC+EFV(n=301)

Adapted from Gallant et al JAMA July 14 2004 vol 202 191-201

Do treatments for HIV drug induced peripheral neuropathy work ?

Pregabalin1

Improved pain but no better than placebo

Acetyl L Carnitine2

After 14 days no difference to placebo by ITT, but

significant difference by EE analysis

Simpson D IAC Aug 2008 abstract THAB0301Youle et al HIV Medicine (2007),8, 241-250

Morphological changes

What do BHIVA Guidelines recommend ?

Lipoatrophy• Replace D4T or AZT• Surgical intervention

Lipohypertrophy• Metformin if insulin resistance is present• GH – long term data required

Gazzard et al, HIV Medicine (2008) vol 9 563-608

CV risk

NRTIs and Risk of MI: Recent* Exposure to Each Drug

Lundgren JD, et al CROI Oral Abstract 44LB

* recent use = current or within the last 6 months** not shown (low number of patients currently on ddC)

1.9

1.5

1.2

1.0

0.8

0.6

RRyes/no95% CI

ZDV ddI ddC d4T 3TC ABC TDF

138,109 74,407 29,676 95,320 152,009 53,300 39,157523 331 148 405 554 221 139

#PYFU:#MI:

**

• Newly described

• Unknown cause in HIV infected Patients

• Postulated to be associated with DDI

Kovari et al Clinical infectious diseases 2009:49 626-635

Literature review of noncirrhotic portal hypertension


Study design

• Nested case control study

• 15 patients with NCPH and 75 controls in the Swiss HIV cohort study

• Matched by HIV duration, no viral hepatitis and follow up to at least the date of NCPH diagnosis


Definition of NCPH in this study

• Endoscopically confirmed varices

• Presenting symptoms include increased liver enzymes, heamatamesis or ascites



Bivariable odds ratios for the effect of DDI on NCPH and ORs for the covariables before and after adjustment for DDI


• Strong association between prolonged DDI exposure and development of NCPH

• “An important finding of this study is that long-term toxicity of antiretroviral drugs might emerge only after decades. As persons with HIV infection in industrialized countries live longer and ART exposure is prolonged, we need to be alert for novel clinical manifestations attributable to drug-related adverse events”

Study Conclusions


Naïve patients: BHIVA 2008: What to start with?

NNRTINNRTIEFVa

A

NNRTINNRTINVP*

PIPIATV/r ~

fAPV/rLPV/rSQV/r

BNRTINRTI

TDF+ ABC&

NRTIAZT>

ddI

““It is the Writing Group’s view that EFV should be considered first line in all It is the Writing Group’s view that EFV should be considered first line in all patients. This is Based upon its efficacy, durability, toxicity profile, convenience patients. This is Based upon its efficacy, durability, toxicity profile, convenience

and cost”and cost”

+

aexcept in women who may wish to become pregnant *Only when CD4 <250 cells/mm3 in females, <400 cells/mm3 in males ~ Where established cardiovascular disease risk factors and a PI required > Co-formulated as Combivir® & Co-formulated as Kivexa® + Co-formulated as Truvada®

preferredpreferred

alternative

CNRTINRTI

FTC 3TC

+

Gazzard et al, HIV Medicine (2008) vol 9 563-608

ACTG 5142 Study: Co-Primary Endpoint: Time to Virologic Failure (VF)

EFV + 2 NRTIsLPV/r + 2 NRTIsEFV + LPV/r

250253250

210210215

186185189

173168181

142140149

737473

191417

Adapted from: Riddler SA, et al. N Engl J Med. 2008;358:2095-2106.

Number of Patients0 24 48 72 96 120 144

Weeks After Randomization

EFV + 2 NRTIs vs LPV/r + 2 NRTIs : P=0.006EFV + LPV/r vs EFV + 2 NRTIs : P=0.49 (NS)EFV + LPV/r vs LPV/r + 2 NRTIs: P=0.13 (NS)

(threshold for significance P<0.014)

100

90

80

70

60

50

40

30

Pro

bab

ility

of

no

Vir

olo

gic

Fai

lure

(%

) EFV + 2 NRTIsLPV/r + 2 NRTIsEFV + LPV/r

║

0

║

EFV + 2 NRTIs arm had a statistically significantly longer time to virologic failure than the LPV/r + 2 NRTIs arm

903E Study: The Safety and Efficacy of Tenofovir DF (TDF) in Combination with Lamivudine (3TC) and Efavirenz (EFV) in Antiretroviral-naïve Patients Through 7 Years

Methods

• Patients in selected sites (Argentina, Brazil, and Dominican Republic) rolled over into a 7-year (336-week) open-label extension phase (903E)

• Data obtained from patients originally randomized to TDF and participating in 903E were analyzed

Study Design

TDF OD

EFV OD

3TC BID

d4t placebo BID

d4t BID

EFV QD

3TC BID

TDF placebo QD

TDF QD

EFV QD

3TC QD

(OPEN-LABEL)

Study 9033 Years

(144 Weeks)

Study 903E

7 Years(336 Weeks)

n = 86

Adapted from Madruga JVR, et al , ICDT 2008, Poster P4

903E Study: HIV-1 RNA, CD4, and Resistance

Resistance• 4 patients discontinued due to virologic

failure– 2 Wild type genotypes– 1 T69N, M184V, K103N at Week 240– 1 M184M/V, K103 K/N, V108V/I,

P225P/H, T69A/T,K219K/R, K70K/E/G/R at Week 336

– No K65R

Proportion with HIV-1 RNA <400 copies/mL through 7 Years (M=F)

Mean Change from Baseline in CD4 through 7 Years

Proportion with HIV-1 RNA <50 copies/mL through 7 Years (M=F)

100

80

60

40

20

00 1 2 3 4 5 6 7

Years

% w

ith

HIV

RN

A <

400

co

pie

s/m

L

81%

n=86

100

80

60

40

20

00 1 2 3 4 5 6 7

Years

% w

ith

HIV

RN

A <

50

cop

ies

/mL

80%

n=86

500

200

150

100

50

00 1 2 3 4 5 6 7

Years

Mea

n C

ha

ng

e in

ce

lls/m

m3

+459450

250

300

350

400

n= 86 85 85 84 82 77 73 71


903E Study: Median Total Limb Fat (IQR) Years 2-7

aP-value for change from Year 2 using Wilcoxon Signed Rank test

12

10

8

6

4

2

00 1 2 3 4 5 6 7

Year

TDF + 3TC + EFV n = 69 69 65 61 59 58

Me

dia

n L

imb

Fa

t in

kg

8.0a

P<0.001a6.7


903E Study: Investigators’ Conclusions

Through 7 years of therapy in antiretroviral-naïve patients, TDF + 3TC+ EFV demonstrated the following:

• Sustained, durable antiretroviral efficacy

• Continued CD4 cell count increases

• No discontinuations due to renal adverse events

• No evidence of clinically relevant bone effects

• Significant increases in limb fat from Years 2 through 7

Madruga JVR, et al , ICDT 2008, Poster P4

26

Efficacy of boosted Reyataz ®

Atazanavir (ATV/r)in naïve patients

27

Screening/enrolment

CASTLE study designCASTLE study design

TDF/FTC 300/200 mg QD TDF/FTC 300/200 mg QD

(1:1)

HIV RNA 5000 c/mL, no CD4 cell count restrictionRandomization (n=883)

Stratified: HIV RNA <100 000 c/mL vs 100 000 c/mL; geographic region

ATV/r 300/100 mg QD (n=440) LPV/r 400/100 mg BID (n=443)

ATV/r, atazanavir/ritonavir; BID, twice daily; FTC, emtricitabine; LPV/r, lopinavir/ritonavir; QD, once daily; TDF, tenofovir

Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

Primary endpoint:Proportion of subjects with HIV RNA <50 c/mL at Week 48

Principal analysis: ITT-confirmed virological response (CVR) – (NC=F)

28

Primary efficacy endpoint: Primary efficacy endpoint: ITT-confirmed virological response (NC=F)ITT-confirmed virological response (NC=F)

ATV/r (n=440)LPV/r (n=443)

ATV/r has noninferior antiviral efficacy compared with LPV/r

HIV RNA <50 c/mL: 78% ATV/r vs 76% LPV/rDifference estimate: 1.7 (95% CI, -3.8%, 7.1%)

Supporting analyses:ITT–TLOVR: HIV RNA <50 c/mL: ATV/r 78%, LPV/r 76%; 1.9 (-3.6, 7.4)OT–VROC: HIV RNA <50 c/mL: ATV/r 84%, LPV/r 87%; -3.5 (-8.7, 1.8)

Res

po

nd

ers,

% (

SE

)

0

20

40

60

80

100

Time (weeks)BL 12 24 36 484

Adapted from Molina J-M, et al. Lancet 2008;372:646−655

29

Week 96 ResultsWeek 96 ResultsHIV RNA <50 c/mL (CVR NC=F)HIV RNA <50 c/mL (CVR NC=F)

* p<0.05

ATV/r (n=440)LPV/r (n=443)

ATV/r has noninferior antiviral efficacy compared with LPV/r

HIV RNA < 50 c/mL: 74% ATV/r vs 68% LPV/rDifference estimate: 6.1 (95% CI, 0.3%–12.0%)*

Supporting analyses:ITT–TLOVR: HIV RNA <50 c/mL: ATV/r 70%, LPV/r 63%; 6.6 (0.4, 12.7)OT–VROC: HIV RNA <50 c/mL: ATV/r 89%, LPV/r 88%; 1.6 (-3.1, 6.2)

Res

po

nd

ers

(%)

0

20

40

60

80

100

Time (weeks)BL 12 24 36 484 60 72 84 96


30

As randomised: Week 96 CD4 mean As randomised: Week 96 CD4 mean change from baselinechange from baseline

Increase in mean CD4 cells/mm3: 268 ATV/r vs 290 LPV/r

Estimated difference: -21.2 (95% CI: -43.3, 0.9)

CD

4 m

ean

ch

ang

e (c

ells

/mm

3 )

Time (weeks)BL 12 24 36 484 60 72 84 96

ATV/r (n=440)LPV/r (n=443)


0

50

100

150

200

250

300

31

Adverse events: SummaryAdverse events: Summary

ATV/r(n=441)n (%)

LPV/r(n=437)n (%)

Serious adverse events 63 (14) 50 (11)

Grade 2–4 treatment-related AEsa 133 (30) 140 (32)

Grade 2–4 treatment-related AEs 3%a,b

Jaundice 18 (4) 0

Nausea 18 (4) 33 (8)

Diarrhoea 11 (2) 54 (12)

• 3 discontinuations on ATV/r due to jaundice/hyperbilirubinaemia

– None between Weeks 48 & 96

• 7 subjects discontinued due to diarrhoea (all on LPV/r)

– 2 between Weeks 48 and 96

• 39 (9%) of subjects on ATV/r versus 96 (22%) on LPV/r initiated antidiarrhoeal medications

• Renal all grade AEs: 4% in both arms

– 1 discontinuation due to renal AE in each arm aThrough 96 weeks

bExcluding laboratory abnormalitiesreported as AEs

Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d

32

Grade 2−4 diarrhoea through 96 weeksGrade 2−4 diarrhoea through 96 weeks


2

12

0

2

4

6

8

10

12

14

ATV/r (n=441) LPV/r (n=437)

Pat

ien

ts (

%)

33

Fasting lipids: NCEP and ratiosFasting lipids: NCEP and ratios

ATV/r(n=441)

LPV/r(n=437)

NCEP shifts up (≥1 category)

Total cholesterol 16% 29%

LDL cholesterol 32% 40%

Triglycerides 23% 49%

Baseline Week 96 Baseline Week 96

Total: HDL cholesterol ratio >5 23% 17% 27% 27%

2% of subjects on ATV/r versus 9% of subjects on LPV/r initiated lipid-lowering drugs on study


34

Findings from CASTLE sub-analysesFindings from CASTLE sub-analyses

Boosted Reyataz wasefficacious & generally well-tolerated

irrespective of race

Boosted Reyataz resulted in improvements in

patients’ quality of life

Mc Grath et al, IAC 2008August 2008, Poster # TUPE0058

Boosted Reyataz was efficacious & generally well-toleratedirrespective of gender

Boosted Reyataz was efficacious & generally well-tolerated irrespective

of HBV/HCV status

Perez-Elias MJ, et al. IAS 2005 Poster TuPe1.1C25Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136

Absalon J, et al. XVII IAC, Mexico City, 3−8 August 2008, Poster # TUPE0062

Su et al, IAC 2008August 2008, POSTER # TUPE0060

Boosted Reyataz was an effective and well-tolerated in advanced HIV-infected

treatment-naïve patients

Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008. Poster H-1250d

35

Boosted Reyataz was efficacious & generally Boosted Reyataz was efficacious & generally well-tolerated well-tolerated irrespective of raceirrespective of race

Mc Grath et al, IAC 2008

36

Efficacy

• ATV/r QD demonstrated noninferior antiviral efficacy to LPV/r BID (both +TDF/FTC) in ARV-naïve patients

• Virological response rates were consistently high in men and women

• Both regimens were associated with robust increases in CD4 cell count regardless of gender

Gender

HIV RNA <50 copies/mL

(CVR NC=F) at Week 48:

Responder/evaluable (%)

Mean CD4 cell count

change from baseline

(SE), cells/mm3

Mean absolute CD4 cell

count at Week 48

(SE), cells/mm3

ATV/r LPV/r ATV/r LPV/r ATV/r LPV/r

Female 105/138 (76) 101/139 (73) 199 (11.8) 221 (12.5) 406 (16.5) 417 (15.4)

Male 238/302 (79) 237/304 (78) 205 (8.7) 219 (8.9) 418 (12.2) 448 (12.0)

Absalon J, et al. XVII IAC, Mexico City, 3−8 August 2008, Poster # TUPE0062

Boosted Reyataz was efficacious & generally well-tolerated irrespective of gender

37

Boosted Reyataz was efficacious & generally Boosted Reyataz was efficacious & generally well-tolerated well-tolerated irrespective of HBV/HCV statusirrespective of HBV/HCV status

CASTLE: ATV/r Liver Function and BilirubinCASTLE: ATV/r Liver Function and BilirubinBilirubin and ALT levels

Perez-Elias MJ, et al. IAS 2005 Poster TuPe1.1C25

0.4 mg/dL

1.8 mg/dL

Baseline Month 60

5

1

2

3

4

Su

bje

cts

wit

hm

od

erat

e-to

-sev

ere

AL

T e

leva

tio

n (

%)

0%† 0%†

*†p=NS

To

tal b

iliru

bin

(m

g/d

L)

0.6 mg/dL

1.9 md/dL

0

0.4

0.8

1.2

1.6

2.0

2.4

Baseline Month 6

1.10 %*

1.90 %*

ALT >200 UI/mL or ALT>3.5 x baseline abnormal levels

Median total bilirubin

Coinfected Not coinfected

n=subjects with measurements

n=176 n=116 n=107 n=75 n=176 n=107n=116 n=75

38

CASTLE: Efficacy by Hepatitis B/C coinfectionCASTLE: Efficacy by Hepatitis B/C coinfection

• Virological and immunological responses at Week 48 were similar in hepatitis uninfected and coinfected patients in the ATV/r and LPV/r arms

• Responses were comparable in coinfected patients treated with ATV/r or LPV/r

HIV RNA <50 copies/mL

(CVR NC=F) at Week 48:

n/N (%)

Mean CD4 cell count

change from baseline

(SE), cells/mm3

ATV/r LPV/r ATV/r LPV/r

HBV/HCV− 300/378 (79) 301/391 (77) 204 (7.2) 291 (7.7)

HBV/HCV+ 42/61 (69) 37/51 (73) 196 (26.1) 228 (21.7)

Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136

39

CASTLE: Adverse Events by Hepatitis B/C CASTLE: Adverse Events by Hepatitis B/C CoinfectionCoinfection

Grade 2–4 treatment-related AEs through Week 48: As-treated patients, n (%)

Absalon J, et al. ICDT, Glasgow, UK, 9−13 November 2008, Poster 136

• Hepatitis uninfected and coinfected patients treated with ATV/r had a more favourable lipid profile compared with LPV/r-treated patients

• Lipid profiles were similar in hepatitis uninfected and coinfected patients in both the ATV/r and LPV/r treatment arms

ATV/r LPV/r

HBV/HCV−

(n=380)

HBV/HCV+

(n=60)

HBV/HCV−

(n=385)

HBV/HCV+

(n=51)

Any AE 99 (26) 16 (27) 110 (29) 19 (37)

GI disorders 36 (9) 3 (5) 71 (18) 11 (22)

Hyperbilirubinaemia 23 (6) 10 (17) 1 (<1) 0

Jaundice 16 (4) 2 (3) 0 0

40

Summary: RSummary: Role of ATV in Coinfected Patientsole of ATV in Coinfected Patients

1. Lapadula G, et al. EACS 2007, Poster 9.6/03; 2. Lankisch TO, et al. Hepatology 2006;44:1324–1332,3. http://www.emea.europa.eu/humandocs/Humans/EPAR/reyataz/reyataz.htm

• ATV hyperbilirubinaemia is common in clinical practice, particularly when ATV is used with RTV (boosting) and among patients with altered bilirubin levels at baseline1

• Pre-existing Gilbert’s syndrome predisposes patients to higher bilirubin levels with ATV2

• Severe hyperbilirubinaemia occurs in only a minority of patients1

• Neither HBV nor HCV co-infection seemed to increase the risk of hyperbilirubinaemia and hyperbilirubinaemia did not seem to increase risk of flares in liver transaminases1

• Results confirm that hyperbilirubinaemia is manageable in clinical practice and an ‘innocent’ phenomenon in most cases as far as liver tolerability is concerned1

• Patients with hepatic impairment: ATV/r should be used with caution in patients with mild hepatic impairment. ATV should not be used in patients with moderate to severe hepatic impairment3

41

Boosted Reyataz was Boosted Reyataz was an effective and well-tolerated an effective and well-tolerated in in advanced HIV-infectedadvanced HIV-infected treatment-naïve patients treatment-naïve patients

Egger M, 14th CROI, 2007, Abstract 62. ART Cohort Collaboration http://www.art-cohort-collaboration.org

2003–2005

• 42 countries, 176 sites,33 008 patients

• Low CD4 count at start of treatment suggests that many patients have advanced disease

42

CASTLE: 96-Week Efficacy According to CASTLE: 96-Week Efficacy According to Baseline Viral LoadBaseline Viral Load

0

10

20

30

40

50

60

70

80

90

100

ATV/rLPV/r

HIV RNA <100 000 copies/mL

HIV RNA ≥100 000 copies/mL

7570 74

66

Res

po

nd

ers

(%)

<50

c/

mL

Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008, Poster H-1250d

ITT-confirmed virological response (NC=F) at Week 96 by qualifying HIV viral load

n=225n=218 n=223n=217

43

CASTLE: 96-Week Efficacy by Baseline CD4 CASTLE: 96-Week Efficacy by Baseline CD4 Cell CountCell Count

7671 71

78

69 70 69

58

ATV/r LPV/r

n= 222 106 45 58 228 134 29 48

Res

po

nd

ers

(%)

<50

c/

mL

Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008. Poster H-1250d

0

10

20

30

40

50

60

70

80

90

100 p=ns p=ns

100–<200 cells/mm3

≥200 cells/mm3

50–<100 cells/mm3

<50 cells/mm3

Treatment Experienced patients

Evolving goal of antiretroviral therapy for all HIV-positive patients regardless of the extent of previous treatment experience

• Achieve and maintain an undetectable VLAchieve and maintain an undetectable VL1,2 1,2

– Achievable for majority of patients with currently available agents

Patients with therapy options

• Consider changing regimen sooner rather than later

• Change ≥ 2 drugs in the regimen to active agents

• The use of an agent from a new drug class is likely to be effective

1. Hammer SM, et al. JAMA. 2006;296:827-843.2. BHIVA website: http://www.bhiva.org/files/file1030835.pdf (Pre-press version of 2008 BHIVA Guidelines for HIV Anti-Retroviral Treatment; on page 11-Accessed on 04 September 2008)

Evolution of Once-daily ATRIPLA® Dosing

Sustiva SmPC, September 2008Viread SmPC, September 2008Emtriva SmPC, September 2008Truvada SmPC, December 2008ATRIPLA SmPC, December 2008

Efavirenz (Sustiva®)

Emtricitabine(Emtriva®)

Tenofovir DF(Viread®)

Truvada®

ATRIPLA®

The pills shown are not the actual size

The ATRIPLA® Indication in Europe

ATRIPLA SmPC

• ATRIPLA® is a fixed‑dose combination of efavirenz, emtricitabine and tenofovir disoproxil fumarate

– It is indicated for the treatment of HIV‑1 infection in adults with virological suppression to HIV‑1 RNA levels of <50 copies/mL on their current combination antiretroviral therapy for >3 months

– Patients must not have experienced virological failure on any prior ART and must be known not to have harboured virus strains with mutations conferring significant resistance to any of the three components contained in ATRIPLA® before initiation of their first ART regimen

• The demonstration of the benefit of ATRIPLA® is primarily based on 48‑week data from a clinical study in which patients with stable virological suppression on a combination ART changed to ATRIPLA®

– No data are currently available from clinical studies with ATRIPLA® in treatment‑naïve or heavily pretreated patients

Efficacy of ATRIPLA®

Study AI266073 Design

• Stable ARV Regimen

(PI or NNRTI + 2 NRTIs) for ≥ 3 months

• VL <200 copies/mL

• No History of Virologic Failure

EFV/FTC/TDF Once Daily

Stayed on Baseline Regimen*

*SBR: stayed on baseline regimen

Switch

Continue

Primary Endpoint: assess non-inferiority of EFV/FTC/TDF vs. SBR in terms of maintenance of HIV-1 RNA <200 copies/mL through Week 48 by TLOVR**analyses

**Time to loss of Virologic Response Algorithm

Phase IV, multicentre (55 US sites), open-label study (N = 300)

Randomisation

2:1

Stratify byPI or NNRTI

0 24 48 Week

Adapted from Young B, et al., Glasgow 2008; Poster #P061 ATRIPLA® is not indicated for treatment-naïve patients in the EU

ARV Baseline Regimen

EFV 36%

NVP 11%ATV/r 15%

LPV/r 13%FPV/r (9%)

SQV/r (2%)

IDV (2%)

NFV (7%)

ATV (2%)FPV (3%)

a. Most frequent NNRTI regimens were: EFV+AZT/3TC (16%), EFV+ABC/3TC (6%), EFV+TDF+3TC (5%) b. Most frequent PI regimens were: ATV/r + FTC/TDF (13%), LPV/r + FTC/TDF (6%), FPV/r+ABC/3TC (4%)

PIs (53%) NNRTIs (47%)

Adapted from DeJesus EACS 2007, Madrid, Spain ATRIPLA® is not indicated for treatment-naïve patients in the EU

Primary Endpoint Analysis: Percentage of Patients with HIV-1 RNA <200 copies/mL Through 48 Weeks (TLOVR)

0

20

40

60

80

100

% <200 copies/mL

EFV/FTC/TDF SBR

Pe

rce

nt

wit

h V

iro

log

ic R

es

po

ns

e

88%89%

Treatment Difference (EFV/FTC/TDF – SBR) and 95% CI:1.1% (–6.7%, 8.8%)

• The primary endpoint of non-inferiority of EFV/FTC/TDF to SBR was demonstrated


Efficacy Analysis by Prior Treatment Stratum: Week 48

Stratum at Baseline

Patients Below HIV-1 RNA Threshold (%)

Prior NNRTI Prior PI

EFV/FTC/TDF(N = 95)

SBR(N = 45)

EFV/FTC/TDF(N = 108)

SBR(N = 52)

<200 copies/mL

TLOVRa 92% 84% 87% 90%

M=Eb 100% 100% 100% 100%

<50 copies/mL

TLOVR 92% 82% 83% 87%

M=E 100% 97% 98% 98%a. Time to loss of virologic response algorithm (NC=F)b. Missing data (for any reason) was excluded in this analysisP=NS for all comparisons in both strata


Discontinuations Due to Adverse Events

N (%)EFV/FTC/TDF

(N=203)SBR

(N=97)

Any Adverse Event 10 (5%) 1 (1%)

Nervous system symptoms (NSS)a 5 (2%) 0

Increased creatinineb 2 (<1%) 0

Acute hepatitis 1 (<1%) 0

AST/ALT elevation 1 (<1%) 0

Acute pancreatitis 1 (<1%) 0

Gastritis 0 1 (1%)a. All patients were in the PI stratum. 4/5 patients experienced >1 NSS AE; NSS AE

(number of patients) were: headache (1), dizziness (3), insomnia (2), somnolence (1), personality change (1), mood disturbance (2). 8/10 NSS AE were Grade 2 (moderate), 2/10 (dizziness, headache) were Grade 3 (severe)

b. 1 patient had baseline Scr = 2.4 mg/dL and discontinued at Week 6 with Scr = 2.3 mg/dL; 1 patient had baseline Scr = 1.4 mg/dL and discontinued at Week 21 with Scr = 1.3 mg/dL. Neither patient experienced a Scr elevation while on study in excess of their baseline value


Patient Preference Studies

Study AI266073

ADONE

ATRIPLA® is not indicated for treatment-naïve patients in the EU

Study AI266073 Methods

• The following patient reported outcomes were collected in both treatment arms:

– Adherence by Visual Analog Scale

– Quality of Life (QOL) by SF-36 (v2) survey

– HIV Symptoms Index by a 20-item survey– Perceived Ease of the Regimen for Condition

(PERC) questionnaire

• In the Atripla arm only, a Preference of Medication (POM) questionnaire was completed

Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU

HIV Symptoms Index: Statistically Significant Improvements in Patients Randomised to EFV/FTC/TDF

37

52

42 41

3331

24

32

0

10

20

30

40

50

60

Diarrhea or loose bowel movements Bloating, pain, or gas in the stomach Changes in the way their bodylooked

Problems having sex

Baseline Week 48

Perc

ent e

xper

ienc

ing

HIV

-rel

ated

sym

ptom

HIV Symptom Indices

*p-values compare change from baseline to Week 48 in patients switched to EFV/FTC/TDF

PRIOR PI STRATUM OVERALL

*

** *

(p = 0.002) (p = 0.002) (p = 0.002) (p = 0.032)

Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU

HIV Symptoms Index: Proportion of Patients Reporting Dizziness & Lightheadedness

Perc

ent E

xper

ienc

ing

Sym

ptom

s of

D

izzi

ness

or L

ight

head

edne

ss

*

**

* = p < 0.002 ** = p < 0.0014

Baseline Week 4 Week 12 Week 24 Week 36 Week 48

28 %

30 %

39 %

23 %

32 %

24 % 24 %

16 %

24 %

32 %30 %30 %

35 %

46 %

25 % 27 % 26 % 28 %

0

5

10

15

20

25

30

35

40

45

50

EFV/FTC/TDF Overall

EFV/FTC/TDF (prior NNRTI)

EFV/FTC/TDF (prior PI)

SBR

26%


Perceived Ease of the Regimen for Condition (PERC)

% o

f pat

ient

s w

ho c

onsi

dere

d th

eir r

egim

en"v

ery

easy

" to

take

How Easy Did Patients Consider their Regimen?

n = 202 96 199 93 194 93 187 89 178 83 178 86

* = p< 0.001p-values compare treatment arms at each timepoint

* * * * *95949492

68

97

8175

79777875

0

10

20

30

40

50

60

70

80

90

100

Baseline Week 4 Week 12 Week 24 Week 36 Week 48

EFV/FTC/TDF

SBR


Preference of Medication (POM) Questionnaire in Patients Randomised to EFV/FTC/TDF

64 %

74 %79 % 80 %

85 %

0

10

20

30

40

50

60

70

80

90

100

Week 4 Week 12 Week 24 Week 36 Week 48n = 116 139 146 143 146n = total number of patients taking the questionnaire

% re

port

ing

that

EFV

/FTC

/TD

F w

as "

muc

h be

tter"

tha

n th

eir p

revi

ous

regi

men


Doses consumed last month

ad

her

ence

% a

nd

95%

CI

P = 0.042 P = 0.042

Baseline

1 month post switch

2 months post switch

Doses consumed right time last month

Doses consumed last week

Doses consumed right time last week

ADONE study Self reported adherence

92

93

94

95

96

97

98

99

100

Adapted from Maggiolo F et al. HIV9, November 2008, Glasgow. Poster# P-167.ATRIPLA® is not indicated for treatment-naïve patients in the EU

ADONE study Conclusions

• These preliminary data suggest that switching to a FDC of TDF/FTC/EFV, even with a small reduction in the daily pill burden, may positively affect adherence

• The compact one pill, once-a-day, FDC based HAART is well accepted by patients that score it as highly preferable in terms of simplicity, convenience, tolerability and potency

• Both the immunological status and well-being of patients improve after switching to the simplified, FDC-based HAART

Maggiolo F et al. HIV9, November 2008, Glasgow. Poster# P-167. ATRIPLA® is not indicated for treatment-naïve patients in the EU

Thank you

Questions

DRUG INTERACTIONS: Co‑administration of REYATAZ with the following agents is not recommended: simvastatin, lovastatin, nevirapine efavirenz or proton pump inhibitors Oral contraceptives: Use with oral contraceptives should be avoided.

Co‑administration of REYATAZ/ritonavir is not recommended for the following unless justified by the benefit/risk ratio; voriconazole fluticasone or other glucocorticoids that are metabolized by CYP3A4. PREGNANCY AND LACTATION: Avoid use in pregnancy and lactation. UNDESIRABLE EFFECTS: Common: nausea, headache, ocular icterus, vomiting, diarrhoea, dyspepsia, abdominal pain, jaundice, insomnia, asthenia, peripheral neurologic symptoms, rash, fatique and lipodystrophy Serious: pancreatitis, myopathy, hepatitis, nephrolithiasis. LABORATORY ABNORMALITIES Elevated bilirubin, creatinine kinase LEGAL STATUS: POM. PACKAGE QUANTITIES AND BASIC NHS PRICE: Carton of 60 hard capsules, 150mg: £303.38, 200mg: £303.38, carton of 30 capsules, 300mg: £303.38 MARKETING AUTHORISATION NUMBERS: EU/1/03/267/003 - 150mg Bottle; EU/1/03/267/005 - 200mg Bottle. EU/1/03/267/008 -300mg Bottle

MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG, BMS House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex. UB8 1DH. Telephone: 0800-731-1736. DATE OF PI PREPARATION: January 2009

REY/0109/2630

PRESENTATION: Hard capsules: 150mg, 200mg, 300mg atazanavir. INDICATION: Antiretroviral combination treatment of HIV-1 infected, adults. DOSAGE AND ADMINISTRATION: Oral. 300mg with ritonavir 100mg once-daily with food. If co‑administered with didanosine, recommend didanosine be taken two hours after Reyataz with ritonavir with food. Hepatic impairment: use caution in patients with mild hepatic insufficiency. CONTRAINDICATIONS: Hypersensitivity to atazanavir or any excipient. Moderate to severe hepatic insufficiency. Do not use in combination with rifampicin or products that are substrates of CYP3A4 and have a narrow therapeutic windows or products containing St. John’s wort. SPECIAL WARNINGS AND PRECAUTIONS: Patients with chronic hepatitis B or C treated with combination antiretroviral therapy are at increased risk for severe and potentially fatal hepatic adverse events. Patients with pre-existing liver dysfunction must be monitored according to practice. In worsening liver disease consider interruption or discontinuation of treatment. Reyataz may induce PR prolongations. Caution with medicines that may increase QT interval. Caution in haemophiliac patients. Combination antiretroviral therapy has been associated with lipodystrophy and metabolic abnormalities. In clinical studies, Reyataz (with or without ritonavir) has been shown to induce dyslipidemia to a lesser extent than comparators. Hyperbilirubinaemia has occurred in patients receiving Reyataz; no dose reduction is recommended. Nephrolithiasis has been reported in patients receiving Reyataz. If signs or symptoms occur, temporary interruption or discontinuation of treatment may be considered. On initiation of combination therapy immune reactivation syndrome may occur.

REYATAZ® HARD CAPSULES PRESCRIBING INFORMATIONSee summary of product characteristics prior to prescribing

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk. Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd

Medical Information on 0800 731 1736, [email protected]

SUSTIVA® 600mg FILM-COATED TABLETS PRESCRIBING INFORMATIONSee Summary of Product Characteristics prior to prescribing

PRESENTATION: Film‑coated tablets: 600mg efavirenz. INDICATIONS: Antiretroviral combination treatment of HIV-1 infected adults, adolescents and children 3 years of age and older. Sustiva has not been adequately studied in advanced HIV disease. DOSAGE AND ADMINISTRATION: Oral. Sustiva must be given in combination with other antiretroviral medications. Adults and adolescents over 40kg: 600mg once daily preferably at night and on an empty stomach. CONTRAINDICATIONS: Hypersensitivity to contents. Severe hepatic impairment (Child Pugh Grade C). Do not use in combination with St. John’s wort or products that are substrates of CYP3A4 See SPC for details. WARNINGS AND PRECAUTIONS: Not for sole use. Co-administration of efavirenz with Atripla is not recommended. Discontinue use if severe rash associated with blistering, desquamation, mucosal involvement or fever develops. Advise immediate contact with doctor if experience severe depression, psychosis or suicidal ideation. Nervous system symptoms generally resolve after the first 2 - 4 weeks. Immune reactivation syndrome may arise with severe immune deficiency. Given lipodystrophy association with combination antiretroviral therapy, consider monitoring fasting serum lipids and blood glucose and manage as appropriate. Patients with hereditary disorders of galactosaemia or glucose/galactose malabsorption syndrome should not take Sustiva. Caution needed in mild to moderate liver disease or chronic Hepatitis B or C infection. Where evidence of worsening liver disease, interruption or discontinuation of treatment must be considered. Close safety monitoring is recommended in patients with severe renal failure. Caution if history of seizures. DRUG INTERACTIONS: Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP isozymes including

CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz exposure may alter when given with medicinal products or foods (e.g. grapefruit) which affect CYP3A4 activity (see Contraindications above). See SPC for full drug interaction details for protease inhibitors, NRTIs, NNRTIs, anticonvulsants, lipid-lowering agents, antacids, methadone, St.John's Wort, antidepressants, the H1-antihistamine cetirizine, lorazepam, antimicrobial and antifungal agents, (efavirenz dose should be reduced when co-administered with voriconazole and increased when co-administered with rifampicin). Potential of interaction with oral contraceptives has not been fully characterised. PREGNANCY AND LACTATION: Avoid use in pregnancy and lactation. Barrier contraception should always be used in combination with other methods of contraception. UNDESIRABLE EFFECTS: Common: rash, pruritus, anxiety, depression, nervous system symptoms, psychiatric symptoms, immune reactivation syndrome, gastrointestinal, skin and subcutaneous tissue disorders, fatigue. Serious: Stevens-Johnson syndrome, lipodystrophy and metabolic abnormalities, acute hepatitis, acute pancreatitis. Laboratory abnormalities for liver enzymes, amylase, lipids, and false positive cannabinoid test results. See SPC for full details of side effects. LEGAL STATUS: POM. PACKAGE QUANTITIES AND BASIC NHS PRICE: Blister packs of 30 tablets: £200.27. MARKETING AUTHORISATION NUMBERS: EU/1/99/110/009. MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG, BMS House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex. UB8 1DH Telephone: 0800-731-1736. DATE OF PI PREPARATION: February 2009

SUS/0209/2280



ZERIT® PRESCRIBING INFORMATIONSummary of Product Characteristics prior to prescribing

PRESENTATION: Capsules: 20mg, 30mg, or 40mg stavudine. Powder for Oral Solution 200mg. INDICATIONS: Antiretroviral combination treatment of HIV infected patients. DOSAGE: Oral, at least an hour before a meal, or, if not possible, with a light meal. Adults: <60kg - 30mg twice daily, ≥60kg - 40mg twice daily. Adolescents, children and infants: birth to 13 days old - 0.5 mg/kg twice daily; at least 14 days old and < 30 kg - 1mg/kg twice daily; patients 30kg - adult dosing. Patients with renal impairment - see SPC. CONTRAINDICATIONS: Hypersensitivity to any of the constituents. WARNINGS & PRECAUTIONS: Patients with a history of peripheral neuropathy, pancreatitis or liver disease should be closely monitored. Lactic acidosis, sometimes fatal, usually associated with hepatomegaly and hepatic steatosis has been reported after a few or several month’s treatment and should be closely monitored. Children exposed in-utero or post-natally to nucleoside analogues should be fully investigated for possible mitochondrial dysfunction. Lipodystrophy has been linked with combination antiretroviral therapy. Immune reactivation syndrome may arise in patients with severe immune deficiency at time of institution of combination antiretroviral therapy (see SPC). Unsuitable for individuals with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency or glucose-galactose malabsorption. DRUG INTERACTIONS: Other drugs actively secreted by renal tube e.g. trimethoprim. Use of stavudine in combination with zidovudine is not recommended. In vitro studies indicate activation of stavudine is inhibited by doxorubicin and ribavirin. PREGNANCY & LACTATION: Use should be considered only if clearly indicated and only when the potential benefit outweighs the possible risk. Women taking stavudine should not breast feed. Lactic acidosis, sometimes fatal, has been reported in pregnant women.

UNDESIRABLE EFFECTS: Common: Diarrhoea, nausea, abdominal pain, dyspepsia, fatigue, lipoatrophy, lipodystrophy, peripheral neuropathy and other peripheral neurologic symptoms, dizziness, headache, insomnia, abnormal dreams, depression, rash, and pruritus. Less commonly, pancreatitis, hepatitis, liver failure or jaundice, lactic acidosis, gynaecomastia, immune reactivation syndrome, metabolic abnormalities, vomiting, asthenia, anorexia, arthralgia, myalgia, anxiety, emotional lability, urticaria, laboratory abnormalities, motor weakness, mitochondrial dysfunction. LEGAL STATUS: POM PACK QUANTITY & BASIC NHS PRICE: Packs of 56 capsules, 20mg: £142.28, 30mg: £149.20, 40mg: £153.70. Powder for Oral Solution 200ml: £23.40 per pack. MARKETING AUTHORISATION NUMBERS: EU/1/96/009/004(20mg), EU/1/96/009/006 (30mg), EU/1/96/009/008(40mg), EU/1/96/009/009 (Powder for Oral Solution). MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH. For further information free-phone: 0800-731-1736. DATE OF PI PREPARATION: May 2009. Further information is available on request from Bristol-Myers Squibb Pharmaceuticals Ltd., Bristol-Myers Squibb House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH. Telephone: 0800-731-1736.

HIV/0509/2893

Adverse events should be reported. Reporting forms and information can be found atwww.yellowcard.gov.uk. Adverse events should also be reported to Bristol-Myers Squibb Pharmaceuticals Ltd


VIDEX® EC PRESCRIBING INFORMATIONPlease refer to Summary of Product Characteristics prior to prescribing

PRESENTATION: Gastro-resistant hard capsules: 125mg, 200mg, 250mg or 400mg didanosine. INDICATIONS: Antiretroviral combination treatment of HIV-1 infected adults, adolescents or children over 6 years. DOSAGE: Oral. Administer once or twice daily at least 2 hours before or after a meal with 100ml of water. Adults: Recommended daily dose: 400mg for patients weighing 60kg and 250mg for patients weighing <60kg. Children (over 6 years): recommended daily dose based on body surface area is 240mg/m2 (180mg/m2 in combination with zidovudine). Dose adjustment required for patients with renal impairment. Refer to SPC for full details. CONTRAINDICATIONS: Hypersensitivity to contents. Children younger than 6 years. SPECIAL WARNINGS AND PRECAUTIONS: Not for sole use. Extreme caution in patients with history of pancreatitis. Where possible suspend dosing until a diagnosis of pancreatitis has been excluded and when treatment with other drugs known to cause pancreatic toxicity is required, suspend didanosine wherever possible. Dose suspension should be considered when biochemical markers of pancreatitis have increased, even in the absence of symptoms. Patients on didanosine may develop toxic peripheral neuropathy. Suspend Videx EC until resolution of symptoms. A reduced dose may then be tolerated. Liver failure has occurred rarely. Observe for liver enzyme elevations and suspend treatment if enzymes rise >5 times above the upper limit of normal. Re-challenge only if the potential benefits clearly outweigh the potential risks. Lactic acidosis has been reported with the use of nucleoside analogues. Retinal or optic nerve changes may occur rarely. Children should have a retinal examination every 6 months or if a change in vision occurs. Given lipodystrophy association with combination antiretroviral therapy, consider monitoring fasting serum lipids and blood glucose and manage as appropriate. Nucleoside and nucleotide analogues have been reported to cause mitochondrial dysfunction in HIV-negative infants exposed in-utero and/or post-natally. DRUG INTERACTIONS: Co-administration with drugs known to cause peripheral neuropathy or pancreatitis may increase the risk of these toxicities.

Co-administration of didanosine and tenofovir disoproxil fumarate results in a 40-60% increase in systemic exposure to didanosine and is therefore not recommended. Co-administration of didanosine with xanthine oxidase inhibitors, such as allopurinol, may result in increased systemic exposure to didanosine, therefore patients should be carefully monitored for didanosine-related adverse events.

PREGNANCY & LACTATION: Avoid use in pregnancy and lactation. Use only when the potential benefit outweighs the possible risk. UNDESIRABLE EFFECTS: Common: Pancreatitis, peripheral neurologic symptoms, lipodystrophy and metabolic abnormalities, diarrhoea, nausea, vomiting, abdominal pain, rash, fatigue, allergic reactions, asthenia, headache, neutropenia. Increased uric acid, liver enzymes, bilirubin level. Rarely reported events post marketing are: chills and fever, flatulence, parotid gland enlargement, dry mouth, lactic acidosis, anorexia, diabetes mellitus, hypoglycaemia, hyperglycaemia, alopecia, hepatitis, liver failure, hepatic steatosis, sialoadenitis, anaemia, leukopenia, thrombocytopenia, anaphylactic reaction, dry eyes, retinal depigmentation, optic neuritis, myalgia, rhabdomyolysis. LEGAL STATUS: POM. PACK QUANTITY & BASIC NHS PRICE: Blister packs of 30 capsules: 125mg: £49.16, 200mg: £78.65, 250mg: £98.31, 400mg: £157.30 MARKETING AUTHORISATION NUMBERS: 11184/0083 125mg, 11184/0084 200mg, 11184/0085 250mg, 11184/0086 400mg. MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharmaceuticals Limited, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH. DATE OF PI PREPARATION: May 2009. Further information is available on request from Bristol-Myers Squibb Pharmaceuticals Ltd., Bristol-Myers Squibb House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB8 1DH. Telephone: 0800-731-1736.

HIV/0509/2892



ATRIPLA® PRESCRIBING INFORMATIONPresentation: Atripla film-coated tablet. Each tablet contains 600mg of efavirenz, 200mg of emtricitabine and 245mg of tenofovir disoproxil (as fumarate). Indications: For treatment of HIV-1 infected adults with virologic suppression to HIV-1 RNA levels of <50 copies/ml on their current combination therapy for more than 3 months. Patients must not have experienced virological failure on prior antiretroviral therapy and must not have resistance to any of the three components of Atripla.Dosage & Administration: Therapy should be initiated by a physician experienced in the management of HIV infection. Adults: One tablet once daily taken orally on an empty stomach at bedtime. Children and adolescents: not recommended. Elderly: Insufficient data are available on which to make dose recommendations for patients over the age of 65 years – caution should be exercised. Not recommended in patients with moderate or severe renal impairment (CrCl <50ml/min). No dose modification necessary in patients with mild to moderate liver disease. Contraindications: Hypersensitivity to efavirenz, emtricitabine, tenofovir, tenofovir disoproxil fumarate, or any of the excipients. Atripla must not be used in patients with severe hepatic impairment. It must not be administered concurrently with terfenadine, astemizole, cisapride, midazolam, triazolam, pimozide, bepridil or ergot alkaloids, because competition for CYP3A4 by efavirenz could result in inhibition of metabolism and create the potential for serious and/or life-threatening undesirable effects (e.g. cardiac arrhythmias, prolonged sedation or respiratory depression). Herbal preparations containing St. John’s wort must not be used while taking Atripla due to the risk of decreased plasma concentrations and reduced clinical effects of efavirenz. Atripla must not be administered concurrently with voriconazole because efavirenz significantly decreases voriconazole plasma concentrations, while voriconazole significantly increases efavirenz plasma concentrations. Warnings and Precautions: Atripla should not be administered concomitantly with other medicinal products containing any of the same active components, with other cytidine analogues such as lamivudine or with adefovir dipivoxil. Patients switched to Atripla from a PI-based regimen may have a reduced response to therapy – monitor viral load and adverse reactions. Appropriate precautions must be used to prevent the risk of transmission of HIV to others through sexual contact or contamination with blood. Hepatic: Discontinue Atripla in patients developing symptomatic hyperlactataemia, metabolic/lactic acidosis, progressive hepatomegaly or rapidly elevating aminotransferase levels. Use with caution in patients with hepatomegaly, hepatitis, other risk factors for liver disease and hepatic steatosis, co-infection with HCV and treatment with alpha interferon and ribavirin – monitor closely. Caution in administering Atripla to patients with mild or moderate liver disease. Patients with pre-existing liver dysfunction should be monitored; interruption or discontinuation of treatment must be considered if evidence of worsening liver disease or persistent elevations of serum transaminases >5 times ULN. HBV Co-infection: Patients with HIV co-infected with either HBV or HCV treated with combination antiretroviral therapy are at increased risk of severe and potentially fatal hepatic adverse reactions. Discontinuation of therapy may be associated with severe acute exacerbations of hepatitis. Co-infected HIV/HBV patients should be closely monitored for at least four months following discontinuation of Atripla for symptoms of severe acute exacerbations of hepatitis. Psychiatric: Advise patients to contact their doctor immediately if they experience psychiatric symptoms such as severe depression, psychosis or suicidal ideation. Nervous system symptoms such as dizziness, insomnia, somnolence, impaired concentration and abnormal dreams may begin during the first 1 or 2 days of therapy and generally resolve after the first 2 - 4 weeks. Exercise caution in any patient with a history of seizures. Renal: Atripla is not recommended for patients with moderate or severe renal impairment. Avoid use of Atripla with concurrent or recent use of nephrotoxic medicinal product. If concomitant use of Atripla with a nephrotoxic agent is unavoidable, monitor renal function weekly. Renal failure and impairment, elevated creatinine, hypophosphataemia and proximal tubulopathy (including Fanconi syndrome) have been reported with use of tenofovir disoproxil fumarate in clinical practice. It is recommended that CrCl is calculated in all patients prior to therapy initiation and renal function monitored every 4 weeks for the first year and every 3 months thereafter. In patients at risk of renal impairment, consideration should be given to more frequent monitoring of renal function. If CrCl is decreased to <50ml/min or serum phosphate is decreased to <1.5mg/dl, renal function should be re-evaluated within one week. Treatment with Atripla should be interrupted if CrCl is confirmed to be <50ml/min or if serum phosphate is decreased to <1mg/dl. Refer to SPC for further recommendations regarding monitoring, dose adjustment and discontinuation of therapy. Skin reactions: Discontinue Atripla in patients who develop severe rash associated with blistering, desquamation, mucosal involvement or fever. Lipodystrophy and metabolic: Combination antiretroviral therapy has been associated with lipodystrophy in HIV patients. Consider monitoring fasting serum lipids and

blood glucose and manage lipid disorders as appropriate. Other: Administration of Atripla with food may increase efavirenz exposure. Mitochondrial dysfunction. Immune Reactivation Syndrome. Osteonecrosis. Decreased bone mineral density and bone abnormalities (infrequently contributing to fractures), which may be associated with proximal renal tubulopathy. Co-administration of Atripla and didanosine is not recommended as exposure to didanosine is significantly increased. Avoid in antiretroviral experienced patients with strains harbouring K65R, M184V/I or K103N mutations. Contains sodium – consider in patients on sodium-restricted diet.Interactions: Efavirenz is an inducer of CYP3A4 and an inhibitor of some CYP450 isoenzymes including CYP3A4. Other compounds that are substrates of CYP3A4 may have decreased plasma concentrations when co-administered with efavirenz. Efavirenz exposure may also be altered when given with medicinal products or foods (e.g. grapefruit juice) which affect CYP3A4 activity – see contraindications above. Atripla should not be co‑administered with adefovir dipivoxil, lamivudine, atazanavir/ritonavir or didanosine. Avoid co-administration of Atripla with medicinal products that reduce renal function or compete for active tubular secretion (e.g. cidofovir). Avoid use of Atripla with concurrent or recent use of nephrotoxic medicinal product. Refer to SPC for drug interaction details for protease inhibitors, NRTIs, NNRTIs, antimicrobial and antifungal agents, anticonvulsants, antidepressants, cardiovascular agents, lipid-lowering agents, hormonal contraceptives, opioids and herbal products. Use in pregnancy and lactation: Atripla should not be used in pregnancy unless clearly necessary. Barrier contraception should always be used in combination with other methods of contraception. Avoid breast-feeding. Side effects: Very commonly reported adverse events (≥1/10): dizziness, headache, diarrhoea, nausea, vomiting, elevated creatine kinase, rash (all grades), hypophosphataemia*. Commonly reported adverse events (≥1/100, <1/10): anorexia, neutropenia, stupor, lethargy, disturbance of attention somnolence, dyspepsia, abdominal pain and distension, flatulence, dry mouth, elevated serum lipase, elevated amylase including elevated pancreatic amylase, allergic reaction, pruritus, maculopapular rash, urticaria, vesiculobullous rash, pustular rash, skin hyperpigmentation, dermatitis, night sweats, blood creatinine increased, increased energy, decreased or increased appetite, hypertriglyceridaemia, hyperglycaemia, hot flush, fatigue, fever, pain, asthenia, hyperbilirubinaemia, increased AST and ALT, anxiety, depression (including severe), nightmares, abnormal dreams, insomnia, sleep disorder, altered mood (euphoric or depressed), vertigo. Uncommonly reported adverse events (≥1/1,000, <1/100): Stevens-Johnson syndrome, erythema multiforme, suicide ideation (except in patients with a history of psychiatric disorders), acute pancreatitis and acute hepatitis. Refer to SPC for full list. Adverse events of unknown frequency: renal failure (acute and chronic), acute tubular necrosis, proximal tubulopathy including Fanconi syndrome, nephritis (including acute interstitial nephritis), nephrogenic diabetes insipidus, proteinuria, photoallergic dermatitis, rhabdomyolysis*, osteomalacia* (manifested as bone pain and infrequently contributing to fractures), muscular weakness*, myopathy*, osteonecrosis (particularly in patients with generally acknowledged risk factors, advanced HIV disease or long‑term exposure to CART), lactic acidosis, hypokalaemia*, hepatitis, hepatic steatosis, hepatic failure, completed suicide, psychosis, neurosis, cerebellar coordination and balance disturbances. The side effects marked * may occur as a consequence of proximal renal tubulopathy. Combination antiretroviral therapy has been associated with metabolic abnormalities including hypercholesterolaemia, insulin-resistance and hyperlactataemia as well as lipodystrophy. HIV patients with severe immunodeficiency at the time of initiation of CART may experience Immune Reactivation Syndrome. Refer to SPC for further information on adverse events. Overdosage: If overdosage occurs, monitor for evidence of toxicity. Apply standard supportive treatment if necessary. Emtricitabine and tenofovir, but not efavirenz, can be removed by haemodialysis. Administration of activated charcoal may be used to aid removal of unabsorbed efavirenz.Pharmaceutical Precautions: No special requirements for use and handling. Store in the original package in order to protect from moisture. Keep the bottle tightly closed. Legal Category: POM. Package Quantities: Bottle of 30 film-coated tablets. Price: UK NHS £ 626.90.Marketing Authorisation Number: EU/1/07/430/001. The Marketing Authorisation Holder is Bristol‑Myers Squibb and Gilead Sciences Limited, Unit 13, Stillorgan Industrial Park, Blackrock, Co. Dublin, Ireland. Further information is available from the local representative of the Marketing Authorisation Holder: Gilead Sciences International Ltd, Flowers Building, Granta Park, Abington, Cambs, CB21 6GT. Telephone: 01223 897555. e-mail: [email protected] THE SUMMARY OF PRODUCT CHARACTERISTICS BEFORE PRESCRIBING PARTICULARLY IN RELATION TO SIDE EFFECTS, PRECAUTIONS AND CONTRAINDICATIONS.Atripla is a registered trademark

Date of PI Preparation: April 2009. 177/UKM/09-04/SM/1052 Atripla PI version April 09

Adverse events should be reported. Reporting forms and information can be found at www.yellowcard.gov.uk.

Adverse events should also be reported to Bristol Myers Squibb Pharmaceuticals Ltd

Medical Information on 08007311736 or [email protected]

ATRIPLA PRESCRIBING INFORMATION

BMS Data Update Dr Keith Aizen and Victoria Adamson Bristol-Myers Squibb Prescribing and adverse event reporting information can be found at the end of.

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