P.S. I’m HIV positive

It’s all about living, not living with HIV

Prescribing information and adverse event reporting can be found on last page

P.S. I’m HIV positive

Unbeaten virological control?

Sustained virological control?

Increasing CD4 count over the long-term?

A favourable long-term tolerability profile?

Reassuring MI data?

Minimal pill burden?

What helps put their HIV into

perspective?

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It’s all about living, not living with HIV

Longer virological control than LPV/r1

EFV + LPV/r 250 215 189 181 149 73 17LPV/r + 2 NRTIs 253 185 140 74 14210 168

EFV + 2 NRTIs 250 210 186 173 142 73 19

Weeks after Randomisation

Prob

abili

ty o

f no

viro

logi

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ailu

re (%

) 100

70

80

90

60

50

40

20

10

30

1441209672482400

No. of patients

EFV + 2 NRTIs

LPV/r + 2 NRTIsLPV/r + EFV

p=0.006

Primary endpoint: time to virological failure1

Adapted from Riddler SA, et al. NEJM 2008; 358: 2095-2106. ACTG 5142 study design1: Phase III, randomised, open-label study comparing outcomes of antiretroviral therapy with EFV + 2 NRTIs [1st NRTI (all patients): 3TC (150mg bd or 300mg od): 2nd NRTI (investigator selection): ZDV 300mg bd or TDF 300mg od or d4T XR od*]; LPV/r + 3TC (+ZDV, d4T XR or TDF) or LPV/r + EFV in 753 antiretroviral-naïve patients. Median follow-up was 112 weeks. (*d4T XR was an investigational formulation of stavudine that is not commercially available. Dosing was 100mg od or 75mg if subject weighed <60kg). Sustiva safety profile in these studies was in line with already known data.

● Sustiva + 2 NRTIs demonstrates a significantly longer time to virological failure than LPV/r + 2 NRTIs (p=0.006)1

● Longer time to virological failure than LPV/r + 2 NRTIs in patients with HIV-1 RNA ≥100,000 copies/mL at baseline (p=0.01)1

Stronger virological control than LPV/r in terms of undetectable viral load1

● Higher proportion of patients with plasma HIV-1 RNA <50 copies/mL at week 96 (89% for Sustiva + 2 NRTIs and 77% for LPV/r + 2 NRTIs) (p=0.003)1

ITT analysis Missing = Ignored

Significantly reduced virological failures compared to NVP2

NEW STUDY (2008): Designed to demonstrate non-inferiority of treatment failure with nevirapine (NVP) twice daily vs. Sustiva at 48 weeks2

20

25

15

10

5

0SUSTIVA + 2 NRTIs

(n=1,822)

13.8%

p<0.001

NVP + 2 NRTIs(n=995)

20.4%

% p

atie

nts

with

viro

logi

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ailu

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HIV-1 RNA > 400 copies/mL

Proportion of patients with virological failure after 2 years’ follow-up2

Adapted from Nachega et al. AIDS 2008; 22: 2117–2125. Nachega et al, study design2: observational cohort study in 2,817 HIV-infected, HAART-naïve adults who began NVP- (n=995) or SUSTIVA-based (n=1,822) therapy via a private-sector HIV/AIDS programme in nine countries of southern Africa. The primary outcome was time to virological failure (two measurements of viral loads ≥ 400 copies/mL). Median follow-up period was 2 years. Sustiva safety profile in these studies was in line with already known data.

Sustiva helps give me unbeaten virological control

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It’s all about living, not living with HIV

7 year proven virological control Undetectable virological control maintained3

Time (years)

Patie

nts

with

HIV

RNA

<50

cop

ies/

mL

(%) 100

70

80%(n=86)

90

80

60

50

40

20

10

0

30

0 1 764 532

Virological response (<50 copies/mL) through 7 years (M=F)3

Adapted from Cassetti I, et al. IAC 2008, Abstract TUPE0057. Study 903E3 is a Phase III trial with an ongoing 336-week open-label extension phase and a completed 144-week randomized, double-blind phase designed to evaluate TDF compared to stavudine (d4T) in combination with 3TC and EFV in antiretroviral-naive patients (n=86). 15 patients discontinued from the study prior to Year 7.

No. of patients 86 85 85 84 82 77 73 71

Time (years)

Mea

n ch

ange

in C

D4 c

ells

/mm

3

0

500

350

450

400

300

250

200

100

50

0

150

1 764 532

+459

Mean change from baseline in CD4 count through 7 years3

Adapted from Cassetti I, et al. IAC 2008, Abstract TUPE0057. Study 903E3 (n=86) is an ongoing 336-week open-label extension phase and a completed 144-week randomized, double-blind phase III trial designed to evaluate TDF compared to stavudine (d4T) in combination with 3TC and EFV in antiretroviral-naïve patients. All patients in Study 903E received EFV+3TC+TDF. Mean baseline CD4 count = 299 cells/mm3. 15 patients discontinued from the study prior to Year 7.

● CD4 count rose by 459 cells/mm3 from a mean baseline CD4 count of 299 cells/mm3.3

Sustiva helps give me sustained virological control

Continuing improvement in CD4 count over 7 years3

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Sustiva gives them the added reassurance of long-term tolerability

Favourable long-term tolerability profile4,5,11

Lipid profile

In the STARTMRK Study,

● Sustiva + TDF/FTC exerted only modest effects on serum lipids over 96 weeks4

● The change from baseline in the T Chol:HDL-C ratio was similar for the Sustiva and RAL arms over 48 weeks (-0.1 vs -0.3 respectively, p=0.292)5

Many studies show that the total cholesterol/HDL cholesterol ratio is a powerful predictor of CHD risk6-10

Reassuring Myocardial Infarction (MI) data

Sustiva was not associated with increased relative risk of MI unlike LPV/r11

1.2

1.15

1.05

0.95

1.1

0.9IDV NFV LPV/r SAQ NVP EFV

1.0

PI NNRTI*

#PYFU (Person-years of follow up):

#MI (Myocardial Infarction):

68,469

298

56,529

197

37,136

150

44,657

221

61,855

228

58,946

221

RR/y

ear 9

5% C

I

p=0.0009

PIs/NNRTIs and risk of MI: cumulative exposure to each drug11

Adapted from Lundgren JD, et al. CROI 2009; Presentation and Abst 44LB. D:A:D study design11: Multicentre, 11 cohort, 33,308 patient study examining the relative risk of Myocardial Infarction following exposure to specific antiretroviral therapy from the PI, NNRTI, and NRTI Drug Classes. Approximate test for heterogeneity: p=0.02. Atazanavir (ATZ) was not included in this study as it did not meet the number threshold.

Cumulative exposure

● No association with an increased relative risk of MI was seen with cumulative exposure to Sustiva11

● Cumulative (but not recent) exposure to LPV/r was associated with an increased relative risk of MI (relative rate [RR]: 1.13/year)11

And:

Increased risk of MI with LPV/r was only partly explained by dyslipidaemia11

Favourable long-term tolerability profile3,5,12,13

Limb fat

● Although there were more patients with protocol-defined 20% loss of peripheral fat in ACTG 5142, this was mainly associated with thymidine analogue-containing regimens compared to TDF-containing regimens12

10

8

12

6

4

2

0

0 1 2

69 69 65 61 59 58

3 4 5 6 7

Med

ian

Lim

b Fa

t in

kg

YearTDF+3TC+EFV n =

* p-value for change from year 2 using Wilxcoxon Signed Rank test

p<0.001

6.7

8.0*

Study 903E: median total limb fat (IQR) years 2 - 73

Adapted from Cassetti I, et al. IAC 2008, Abstract TUPE0057.

● Study 903E3 showed significant and continued increases in limb fat between years 2 and 7 with Sustiva +TDF/FTC3

● In the STARTMRK Study, both the Sustiva and RAL arms showed no patterns of fat loss over 48 weeks5

Lon

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It’s all about living, not living with HIV

CNS symptoms in perspectiveCNS symptoms generally resolve after the first 2-4 weeks14,15

non-SUSTIVA

EFV group, n = 191 186 185 176

Non-EFV group, n = 99 99 98 93

SUSTIVA

2412410

Weeks

EFV

sym

ptom

sco

re c

hang

es

-2

0

2

4

6

8

Sustiva-associated neurologic symptoms (excluding depression and anxiety) compared with non-Sustiva therapies15

Adapted from Clifford DB, et al. Ann Intern Med 2005; 143: 714–721. A5097s study design15: from the double-blind, randomised, controlled A5097 trial, a substudy compared neurological changes from baseline in patients who received SUSTIVA (n=200) with non-SUSTIVA patients (n=103). Neuropsychological performance and patient status was evaluated with a symptom questionnaire, which included SUSTIVA-focused score change and general symptoms. Mean changes from baseline over time with 95% CIs were evaluated.

● CNS symptoms of moderate-to-severe intensity were experienced by 19.4% of patients14 but resulted in a low number of discontinuations (2.1%)14

● CNS symptoms are generally mild, normally begin during the first one or two days of therapy and usually resolve after the first 2-4 weeks14

Because Sustiva offers…

Unbeaten virological control1,2

Sustained virological control3

Increasing CD4 count over the long-term3

A favourable long-term tolerability profile3-5,11-13

Reassuring MI data11

Minimal pill burden14

…and is therecommended/preferred

NNRTI for treatmentinitiation across many

international guidelines…

● EACS16 ● DHHS17 ● IAS18 ● BHIVA19 ● GESIDA20 ● ANRS21

…Sustiva helps put patients’ HIV into perspective

Su

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a s

um

mary

It’s all about living, not living with HIV

SUSTIVA® 600mg FILM-COATED TABLETS PRESCRIBING INFORMATION See 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. 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. Patients should be advised to seek medical advice if they experience joint aches & pain, joint stiffness of difficulty in movement. 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. Efavirenz should not be given to patients below 3 years or weigh less than 13kg. 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 with antiretrovirals, antimicrobials, anticonvulsants, lipid-lowering agents, antacids, opiods,

St. John’s Wort, antidepressants, hormonal contraceptives, calcium channel blockers, immunosuppressants, the H1-antihistamine cetirizine, lorazepam, and antifungal agents, (efavirenz dose should be reduced when co-administered with voriconazole). 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: disturbance in attention, dizziness, headache, somnolence, abdominal pain, diarrhoea, nausea, vomiting, rash, pruritus, fatigue, abnormal dreams, anxiety, depression, insomnia. Serious: psychiatric adverse reactions, immune reactivation syndrome, lipodystrophy and metabolic abnormalities, osteonecrosis, 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: July 2009 SUS/0709/2317

Date of preparation: October 2009

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, medical.information@bms.com

References:

1. Riddler SA, et al. Class-sparing regimens for initial treatment of HIV-1 infection. NEJM 2008; 358: 2095-2106. 2. Nachega JB, et al. Efavirenz versus nevirapine-based initial treatment of HIV infection: clinical and virological outcomes in Southern African adults. AIDS 2008; 22: 2117–2125. 3. Cassetti I, et al. IAC 2008, Abstract TUPE0057; Conference reports for NATAP: www.natap.org/2008/IAS/IAS_66.htm. 4. Lennox J, et al. Raltegravir Demonstrates Durable Efficacy through 96 Weeks: Results from STARTMRK, A Phase III Study of Raltegravir (RAL)-based vs Efavirenz (EFV)-based Therapy in Treatment-Naïve HIV+ Patients. September 2009. Poster #H924b, ICAAC, San Francisco, CA. 5. DeJesus E, et al. Metabolic Profiles and Body Composition Changes in Treatment-HIV-Infected Patients Treated with Raltegravir 400 mg bid-based vs. Efavirenz 600 mg qhs-based combination therapy: 48-week data. September 2009. Poster #H1571b, ICAAC, San Francisco, CA. 6. Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III or ATP III). National Cholesterol Education Program (NCEP) Guidelines 2009. 7. Hong MK, Romm PA, Reagan K, Green CE, Rackley CE. Usefulness of the total cholesterol to high-density lipoprotein cholesterol ratio in predicting angiographic coronary artery disease in women. Am J Cardiol 1991;68:1646-50. 8. Castelli WP, Anderson K, Wilson PWF, Levy D. Lipids and risk of coronary heart disease: the Framingham Study. Ann Epidemiol 1992;2:23-8. 9. Kinosian B, Glick H, Preiss L, Puder KL. Cholesterol and coronary heart disease: predicting risks in men by changes in levels and ratios. J Investig Med 1995;43:443-50. 10. Criqui MH, Golomb BA. Epidemiologic aspects of lipid abnormalities. Am J Med 1998;105: 48S-57S. 11. Lundgren JD, et al. CROI 2009; Presentation and Abst 44LB. 12. Haubrich RH, Riddler SA, DiRienzo G, et al. Metabolic outcomes of ACTG 5142: A prospective, randomized, phase III trial of NRTI-, PI-, and NNRTI sparing regimens for initial treatment of HIV-1 infection. 14th Conference on Retroviruses and Opportunistic Infections, 2007; Oral Presentation 38. 13. Arribas JR, Pozniak AL, Gallant JE, et al. Three year Safety and Efficacy of Emtricitabine (FTC)/ Tenofovir DF (TDF) and Efavirenz (EFV) Compared to Fixed Dose Zidovudine/Lamivudine (CBV) and EFV in Antiretroviral Treatment-Naïve Patients. 4th International AIDS Society Conference on HIV Pathogenesis, Treatment, and Prevention, Sydney, Australia, 2007; Poster.] 14. Sustiva® (efavirenz, Bristol-Myers Squibb Pharma EEIG). Summary of Product Characteristics: Last modification – September 2009. http://emc.medicines.org.uk/emc/assets/c/html/displaydoc.asp?documentid=11284 Accessed October 2009. 15. Clifford DB, et al. Impact of efavirenz on neuropsychological performance and symptoms in HIV-infected individuals. Ann Intern Med 2005; 143: 714–721. 16. European AIDS Clinical Society (EACS) Guidelines for the clinical management and treatment of HIV infected adults in Europe. 2008.http://www.eacs.eu/guide/index.htm. 17. DHHS guidelines, Nov 2008. http://AIDSinfo.nih.gov. 18. Hammer SM et al. Antiretroviral treatment of adult HIV infection: 2008 Recommendations of the International AIDS Society USA Panel. JAMA 2008; 300(5): 555–570. 19. Gazzard B. British HIV Association (BHIVA) Guidelines for the treatment of HIV-1-infected adults with antiretroviral therapy. HIV Medicine 2008;9: 563–608. 20. Recommendations of GESIDA/Spanish AIDS. Plan on antiretroviral therapy in adults infected by the human immunodeficiency virus (updated January 2007). 21. Rapport du Groupe d’Experts 2008 sur la prise en charge médicale des patients infectées par le VIH, sous la direction du Prof. Patrick Yeni.

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