Скачать презентацию BMS Data Update Dr Keith Aizen and Victoria Скачать презентацию BMS Data Update Dr Keith Aizen and Victoria

7a9e85bcd1a3920a6a807a13aac0690c.ppt

  • Количество слайдов: 65

BMS Data Update Dr Keith Aizen and Victoria Adamson Bristol-Myers Squibb Date of preparation: BMS Data Update Dr Keith Aizen and Victoria Adamson Bristol-Myers Squibb Date of preparation: July 2009 Job Bag No: HIV/0709/2983 MC/HIV/ATR/0709/0008 Prescribing and adverse event reporting information can be found at the end of this presentation

BMS Virology Portfolio VIdex® Didanosine (dd. I) Zerit® stavudine (D 4 T) BMS Virology Portfolio VIdex® Didanosine (dd. I) Zerit® stavudine (D 4 T)

DDI and D 4 T safety update DDI and D 4 T safety update

Topics • Peripheral neuropathy • CV risk • Hepatotoxicity Topics • Peripheral neuropathy • CV risk • Hepatotoxicity

Peripheral neuropathy Peripheral neuropathy

% Patients with HIV-1 RNA < 50 c/m. L Study 903 % Patients < % Patients with HIV-1 RNA < 50 c/m. L Study 903 % Patients < 50 Copies/m. L Intent to Treat (Missing=Failure) 73% 69% TDF+3 TC+EFV d 4 T+3 TC+EFV Weeks Adapted from Gallant et al JAMA July 14 2004 vol 202 191 -201

Study 903 Selected Toxicities Associated with Mitochondrial Dysfunction through Week 144 d 4 T+3 Study 903 Selected Toxicities Associated with Mitochondrial Dysfunction through Week 144 d 4 T+3 TC+EFV (n=301) TDF+3 TC+EFV (n=299) (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%) Pancreatitis 0 0 + Investigator Defined * p value < 0. 001; ** p = 0. 013 Adapted from Gallant et al JAMA July 14 2004 vol 202 191 -201

Do treatments for HIV drug induced peripheral neuropathy work ? Pregabalin 1 Improved pain Do treatments for HIV drug induced peripheral neuropathy work ? Pregabalin 1 Improved pain but no better than placebo Acetyl L Carnitine 2 After 14 days no difference to placebo by ITT, but significant difference by EE analysis Simpson D IAC Aug 2008 abstract THAB 0301 Youle et al HIV Medicine (2007), 8, 241 -250

Morphological changes Morphological changes

What do BHIVA Guidelines recommend ? Lipoatrophy • Replace D 4 T or AZT What do BHIVA Guidelines recommend ? Lipoatrophy • Replace D 4 T 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 CV risk

NRTIs and Risk of MI: Recent* Exposure to Each Drug 1. 9 1. 5 NRTIs and Risk of MI: Recent* Exposure to Each Drug 1. 9 1. 5 RR yes/no 95% CI 1. 2 ** 1. 0 0. 8 0. 6 ZDV dd. I dd. C d 4 T 3 TC ABC TDF #PYFU: 138, 109 74, 407 29, 676 95, 320 152, 009 53, 300 39, 157 #MI: 523 331 148 405 554 221 139 * recent use = current or within the last 6 months ** not shown (low number of patients currently on dd. C) Lundgren JD, et al CROI Oral Abstract 44 LB

 • Newly described • Unknown cause in HIV infected Patients • Postulated to • 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 Kovari et al Clinical infectious diseases 2009: 49 Literature review of noncirrhotic portal hypertension Kovari et al Clinical infectious diseases 2009: 49 626 -635

Study design • Nested case control study • 15 patients with NCPH and 75 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 Kovari et al Clinical infectious diseases 2009: 49 626 -635

Definition of NCPH in this study • Endoscopically confirmed varices • Presenting symptoms include Definition of NCPH in this study • Endoscopically confirmed varices • Presenting symptoms include increased liver enzymes, heamatamesis or ascites Kovari et al Clinical infectious diseases 2009: 49 626 -635

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

Bivariable odds ratios for the effect of DDI on NCPH and ORs for the Bivariable odds ratios for the effect of DDI on NCPH and ORs for the covariables before and after adjustment for DDI Kovari et al Clinical infectious diseases 2009: 49 626 -635

Study Conclusions • Strong association between prolonged DDI exposure and development of NCPH • Study Conclusions • Strong association between prolonged DDI exposure and development of NCPH • “An important finding of this study is that longterm 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 drugrelated adverse events” Kovari et al Clinical infectious diseases 2009: 49 626 -635

Naïve patients: BHIVA 2008: What to start with? “It is the Writing Group’s view Naïve patients: BHIVA 2008: What to start with? “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 and cost” A d ferre pre ve ti erna alt NNRTI EFVa NNRTI PI NVP* ATV/r ~ f. APV/r LPV/r SQV/r + B NRTI TDF+ ABC& + NRTI AZT> dd. I aexcept in women who may wish to become pregnant *Only when CD 4 <250 cells/mm 3 in females, <400 cells/mm 3 in males ~ Where established cardiovascular disease risk factors and a PI required > Co-formulated as Combivir® & Co-formulated as Kivexa® + Co-formulated as Truvada® C NRTI FTC 3 TC

ACTG 5142 Study: Co-Primary Endpoint: Time to Virologic Failure (VF) EFV + 2 NRTIs ACTG 5142 Study: Co-Primary Endpoint: Time to Virologic Failure (VF) EFV + 2 NRTIs arm had a statistically significantly longer time to virologic failure than the LPV/r + 2 NRTIs arm Probability of no Virologic Failure (%) 100 EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r 90 80 70 60 50 40 30 0 24 Number of Patients EFV + 2 NRTIs LPV/r + 2 NRTIs EFV + LPV/r 48 72 96 ║ ║ 0 EFV + 2 NRTIs vs LPV/r + 2 NRTIs : P=0. 006 EFV + 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) 120 144 Weeks After Randomization 250 253 250 210 215 186 185 189 173 168 181 142 140 149 Adapted from: Riddler SA, et al. N Engl J Med. 2008; 358: 2095 -2106. 73 74 73 19 14 17

903 E Study: The Safety and Efficacy of Tenofovir DF (TDF) in Combination with 903 E Study: The Safety and Efficacy of Tenofovir DF (TDF) in Combination with Lamivudine (3 TC) 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 (903 E) • Data obtained from patients originally randomized to TDF and participating in 903 E were analyzed Study Design TDF OD EFV OD 3 TC BID d 4 t placebo BID n = 86 TDF 3 Years (144 Weeks) Study 903 d 4 t BID EFV QD 3 TC QD (OPEN-LABEL) BID TDF placebo QD QD 3 TC Study 903 E QD Adapted from Madruga JVR, et al , ICDT 2008, Poster P 4 7 Years (336 Weeks)

903 E Study: HIV-1 RNA, CD 4, and Resistance Proportion with HIV-1 RNA <400 903 E Study: HIV-1 RNA, CD 4, and Resistance Proportion with HIV-1 RNA <400 copies/m. L through 7 Years (M=F) <50 copies/m. L through 7 Years (M=F) 100 81% 80 n=86 60 40 20 % with HIV RNA <50 copies/m. L % with HIV RNA <400 copies/m. L 100 n=86 60 40 20 0 0 1 2 3 4 5 6 80% 80 0 7 0 1 Years 3 4 5 6 7 Years Mean Change from Baseline in CD 4 through 7 Years 500 +459 450 Mean Change in cells/mm 3 2 400 350 300 250 200 150 Resistance • 4 patients discontinued due to virologic failure – 2 Wild type genotypes – 1 T 69 N, M 184 V, K 103 N at Week 240 – 1 M 184 M/V, K 103 K/N, V 108 V/I, P 225 P/H, T 69 A/T, K 219 K/R, K 70 K/E/G/R at Week 336 – No K 65 R 100 50 0 0 1 2 3 4 5 6 82 77 73 7 Years n= 86 85 85 84 71 Adapted from Madruga JVR, et al , ICDT 2008, Poster P 4

903 E Study: Median Total Limb Fat (IQR) Years 2 -7 12 Median Limb 903 E Study: Median Total Limb Fat (IQR) Years 2 -7 12 Median Limb Fat in kg 10 8. 0 a 8 6. 7 6 P<0. 001 a 4 2 0 0 1 2 3 4 5 65 61 6 7 59 58 Year TDF + 3 TC + EFV n = 69 a. P-value for change from Year 2 using Wilcoxon Signed Rank test Adapted from Madruga JVR, et al , ICDT 2008, Poster P 4

903 E Study: Investigators’ Conclusions Through 7 years of therapy in antiretroviral-naïve patients, TDF 903 E Study: Investigators’ Conclusions Through 7 years of therapy in antiretroviral-naïve patients, TDF + 3 TC+ EFV demonstrated the following: • Sustained, durable antiretroviral efficacy • Continued CD 4 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 P 4

Efficacy of boosted Reyataz ® Atazanavir (ATV/r) in naïve patients 26 Efficacy of boosted Reyataz ® Atazanavir (ATV/r) in naïve patients 26

CASTLE study design Screening/enrolment HIV RNA 5000 c/m. L, no CD 4 cell count CASTLE study design Screening/enrolment HIV RNA 5000 c/m. L, no CD 4 cell count restriction Randomization (n=883) Stratified: HIV RNA <100 000 c/m. L vs 100 000 c/m. L; geographic region (1: 1) ATV/r 300/100 mg QD (n=440) LPV/r 400/100 mg BID (n=443) TDF/FTC 300/200 mg QD Primary endpoint: Proportion of subjects with HIV RNA <50 c/m. L at Week 48 Principal analysis: ITT-confirmed virological response (CVR) – (NC=F) 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-1250 d 27

Primary efficacy endpoint: ITT-confirmed virological response (NC=F) ATV/r (n=440) LPV/r (n=443) Responders, % (SE) Primary efficacy endpoint: ITT-confirmed virological response (NC=F) ATV/r (n=440) LPV/r (n=443) Responders, % (SE) 100 80 60 40 HIV RNA <50 c/m. L: 78% ATV/r vs 76% LPV/r Difference estimate: 1. 7 (95% CI, -3. 8%, 7. 1%) 20 0 BL 4 12 24 Time (weeks) 36 48 ATV/r has noninferior antiviral efficacy compared with LPV/r Supporting analyses: ITT–TLOVR: HIV RNA <50 c/m. L: ATV/r 78%, LPV/r 76%; 1. 9 (-3. 6, 7. 4) OT–VROC: HIV RNA <50 c/m. L: ATV/r 84%, LPV/r 87%; -3. 5 (-8. 7, 1. 8) 28 Adapted from Molina J-M, et al. Lancet 2008; 372: 646− 655

Week 96 Results HIV RNA <50 c/m. L (CVR NC=F) ATV/r (n=440) LPV/r (n=443) Week 96 Results HIV RNA <50 c/m. L (CVR NC=F) ATV/r (n=440) LPV/r (n=443) Responders (%) 100 80 60 * p<0. 05 40 HIV RNA < 50 c/m. L: 74% ATV/r vs 68% LPV/r Difference estimate: 6. 1 (95% CI, 0. 3%– 12. 0%)* 20 0 BL 4 12 24 36 48 60 Time (weeks) 72 84 96 ATV/r has noninferior antiviral efficacy compared with LPV/r Supporting analyses: ITT–TLOVR: HIV RNA <50 c/m. L: ATV/r 70%, LPV/r 63%; 6. 6 (0. 4, 12. 7) OT–VROC: HIV RNA <50 c/m. L: ATV/r 89%, LPV/r 88%; 1. 6 (-3. 1, 6. 2) 29 Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25− 28 October 2008. Poster H-1250 d

As randomised: Week 96 CD 4 mean change from baseline CD 4 mean change As randomised: Week 96 CD 4 mean change from baseline CD 4 mean change (cells/mm 3) 300 250 ATV/r (n=440) LPV/r (n=443) 200 150 100 Increase in mean CD 4 cells/mm 3: 268 ATV/r vs 290 LPV/r 50 Estimated difference: -21. 2 (95% CI: -43. 3, 0. 9) 0 BL 4 12 24 36 48 60 Time (weeks) 72 84 96 30 Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25− 28 October 2008. Poster H-1250 d

Adverse events: Summary ATV/r (n=441) n (%) LPV/r (n=437) n (%) Serious adverse events Adverse 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) Jaundice 18 (4) 0 Nausea 18 (4) 33 (8) Diarrhoea 11 (2) 54 (12) Grade 2– 4 treatmentrelated AEs 3%a, b • 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 a. Through 96 weeks b. Excluding laboratory abnormalities reported as AEs Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25− 28 October 2008. Poster H-1250 d 31

Patients (%) Grade 2− 4 diarrhoea through 96 weeks Molina J-M, et al. Poster Patients (%) Grade 2− 4 diarrhoea through 96 weeks Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25− 28 October 2008. Poster H-1250 d 32

Fasting lipids: NCEP and ratios ATV/r (n=441) LPV/r (n=437) Total cholesterol 16% 29% LDL Fasting lipids: NCEP and ratios ATV/r (n=441) LPV/r (n=437) Total cholesterol 16% 29% LDL cholesterol 32% 40% Triglycerides 23% 49% NCEP shifts up (≥ 1 category) Baseline Total: HDL cholesterol ratio >5 Week 96 Baseline Week 96 23% 17% 27% 2% of subjects on ATV/r versus 9% of subjects on LPV/r initiated lipid-lowering drugs on study Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25− 28 October 2008. Poster H-1250 d 33

Findings from CASTLE sub-analyses Boosted Reyataz was efficacious & generally well-tolerated irrespective of race Findings from CASTLE sub-analyses Boosted Reyataz was efficacious & generally well-tolerated irrespective of race Boosted Reyataz was efficacious & generally well-tolerated irrespective of gender Boosted Reyataz was efficacious & generally well-tolerated irrespective of HBV/HCV status Boosted Reyataz resulted in improvements in patients’ quality of life Boosted Reyataz was an effective and well-tolerated in advanced HIV-infected treatment-naïve patients Mc Grath et al, IAC 2008 August 2008, Poster # TUPE 0058 Absalon J, et al. XVII IAC, Mexico City, 3− 8 August 2008, Poster # TUPE 0062 Perez-Elias MJ, et al. IAS 2005 Poster Tu. Pe 1. 1 C 25 Absalon J, et al. ICDT, Glasgow, UK, 9− 13 November 2008, Poster 136 Su et al, IAC 2008 August 2008, POSTER # TUPE 0060 Adapted from Molina JM, et al. 48 th ICAAC, Washington, DC, USA, 25− 26 October 2008. 34 Poster H-1250 d

Boosted Reyataz was efficacious & generally well-tolerated irrespective of race 35 Mc Grath et Boosted Reyataz was efficacious & generally well-tolerated irrespective of race 35 Mc Grath et al, IAC 2008

Boosted Reyataz was efficacious & generally well-tolerated irrespective of gender Efficacy • ATV/r QD Boosted Reyataz was efficacious & generally well-tolerated irrespective of gender 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 CD 4 cell count regardless of gender HIV RNA <50 copies/m. L Mean absolute CD 4 cell (CVR NC=F) at Week 48: change from baseline count at Week 48 Responder/evaluable (%) Gender Mean CD 4 cell count (SE), cells/mm 3 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 # TUPE 0062 36

Boosted Reyataz was efficacious & generally well-tolerated irrespective of HBV/HCV status CASTLE: ATV/r Liver Boosted Reyataz was efficacious & generally well-tolerated irrespective of HBV/HCV status CASTLE: ATV/r Liver Function and Bilirubin and ALT levels Coinfected Median total bilirubin 2. 0 1. 6 1. 2 0. 8 0. 4 0 5 1. 9 md/d. L 1. 8 mg/d. L Subjects with moderate-to-severe ALT elevation (%) Total bilirubin (mg/d. L) 2. 4 Not coinfected 0. 6 mg/d. L 0. 4 mg/d. L n=176 n=116 Baseline n=107 n=75 Month 6 ALT >200 UI/m. L or ALT >3. 5 x baseline abnormal levels 4 *†p=NS 3 2 1. 90 %* 1. 10 %* 1 0 0%† n=176 n=116 Baseline 0%† n=107 n=75 Month 6 n=subjects with measurements 37 Perez-Elias MJ, et al. IAS 2005 Poster Tu. Pe 1. 1 C 25

CASTLE: Efficacy by Hepatitis B/C coinfection • Virological and immunological responses at Week 48 CASTLE: 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/m. L Mean CD 4 cell count (CVR NC=F) at Week 48: change from baseline n/N (%) (SE), cells/mm 3 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 38

CASTLE: Adverse Events by Hepatitis B/C Coinfection Grade 2– 4 treatment-related AEs through Week CASTLE: Adverse Events by Hepatitis B/C Coinfection Grade 2– 4 treatment-related AEs through Week 48: As-treated patients, n (%) ATV/r LPV/r HBV/HCV− HBV/HCV+ (n=60) (n=385) (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 • HBV/HCV− (n=380) • HBV/HCV+ 16 (4) 2 (3) 0 0 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 39 Absalon J, et al. ICDT, Glasgow, UK, 9− 13 November 2008, Poster 136

Summary: Role of ATV in Coinfected Patients • ATV hyperbilirubinaemia is common in clinical Summary: Role of ATV in Coinfected Patients • ATV hyperbilirubinaemia is common in clinical practice, particularly when ATV is used with RTV (boosting) and among patients with altered bilirubin levels at baseline 1 • Pre-existing Gilbert’s syndrome predisposes patients to higher bilirubin levels with ATV 2 • Severe hyperbilirubinaemia occurs in only a minority of patients 1 • 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 transaminases 1 • Results confirm that hyperbilirubinaemia is manageable in clinical practice and an ‘innocent’ phenomenon in most cases as far as liver tolerability is concerned 1 • 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 impairment 3 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. htm 40

Boosted Reyataz was an effective and well-tolerated in advanced HIV-infected treatment-naïve patients 2003– 2005 Boosted Reyataz was an effective and well-tolerated in advanced HIV-infected treatment-naïve patients 2003– 2005 • 42 countries, 176 sites, 33 008 patients • Low CD 4 count at start of treatment suggests that many patients have advanced disease Egger M, 14 th CROI, 2007, Abstract 62. ART Cohort Collaboration http: //www. art-cohort-collaboration. org 41

CASTLE: 96 -Week Efficacy According to Baseline Viral Load ITT-confirmed virological response (NC=F) at CASTLE: 96 -Week Efficacy According to Baseline Viral Load ITT-confirmed virological response (NC=F) at Week 96 by qualifying HIV viral load Responders (%) <50 c/m. L 100 90 80 75 70 70 60 74 66 ATV/r LPV/r 50 40 30 20 10 0 n=217 n=218 n=223 n=225 HIV RNA <100 000 copies/m. L HIV RNA ≥ 100 000 copies/m. L Adapted from Molina JM, et al. 48 th ICAAC, Washington, DC, USA, 25− 26 October 2008, Poster H-1250 d 42

CASTLE: 96 -Week Efficacy by Baseline CD 4 Cell Count 100 p=ns Responders (%) CASTLE: 96 -Week Efficacy by Baseline CD 4 Cell Count 100 p=ns Responders (%) <50 c/m. L 90 80 70 60 76 78 71 71 69 70 ≥ 200 cells/mm 3 100–<200 cells/mm 3 69 58 50–<100 cells/mm 3 <50 cells/mm 3 50 40 30 20 10 0 ATV/r LPV/r n= 222 106 45 58 228 134 29 48 Adapted from Molina JM, et al. 48 th ICAAC, Washington, DC, USA, 25− 26 October 2008. Poster H-1250 d 43

Treatment Experienced patients Evolving goal of antiretroviral therapy for all HIV-positive patients regardless of 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 VL 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/file 1030835. 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 Efavirenz (Sustiva®) ATRIPLA® Emtricitabine (Emtriva®) Truvada® Tenofovir DF (Viread®) Evolution of Once-daily ATRIPLA® Dosing Efavirenz (Sustiva®) ATRIPLA® Emtricitabine (Emtriva®) Truvada® Tenofovir DF (Viread®) The pills shown are not the actual size Sustiva Sm. PC, September 2008 Viread Sm. PC, September 2008 Emtriva Sm. PC, September 2008 Truvada Sm. PC, December 2008 ATRIPLA Sm. PC, December 2008

The ATRIPLA® Indication in Europe • ATRIPLA® is a fixed‑dose combination of efavirenz, emtricitabine The ATRIPLA® Indication in Europe • 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/m. L 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 ATRIPLA Sm. PC

Efficacy of ATRIPLA® Study AI 266073 Design Phase IV, multicentre (55 US sites), open-label Efficacy of ATRIPLA® Study AI 266073 Design Phase IV, multicentre (55 US sites), open-label study (N = 300) • Stable ARV Regimen (PI or NNRTI + 2 NRTIs) for ≥ 3 months • VL <200 copies/m. L Randomisation 2: 1 Stratify by PI or NNRTI • No History of Virologic Failure EFV/FTC/TDF Once Daily h tc wi S Co n tin ue Week Stayed on Baseline Regimen* 0 24 48 Primary Endpoint: assess non-inferiority of EFV/FTC/TDF vs. SBR in terms of maintenance of HIV-1 RNA <200 copies/m. L through Week 48 by TLOVR**analyses *SBR: stayed on baseline regimen **Time to loss of Virologic Response Algorithm Adapted from Young B, et al. , Glasgow 2008; Poster #P 061 ATRIPLA® is not indicated for treatment-naïve patients in the EU

ARV Baseline Regimen PIs (53%) NNRTIs (47%) FPV (3%) IDV (2%) ATV/r 15% NFV ARV Baseline Regimen PIs (53%) NNRTIs (47%) FPV (3%) IDV (2%) ATV/r 15% NFV (7%) NVP 11% SQV/r (2%) FPV/r (9%) LPV/r 13% EFV 36% a. Most frequent NNRTI regimens were: EFV+AZT/3 TC (16%), EFV+ABC/3 TC (6%), EFV+TDF+3 TC (5%) b. Most frequent PI regimens were: ATV/r + FTC/TDF (13%), LPV/r + FTC/TDF (6%), FPV/r+ABC/3 TC (4%) Adapted from De. Jesus 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/m. L Through 48 Primary Endpoint Analysis: Percentage of Patients with HIV-1 RNA <200 copies/m. L Through 48 Weeks (TLOVR) Percent with Virologic Response Treatment Difference (EFV/FTC/TDF – SBR) and 95% CI: 1. 1% (– 6. 7%, 8. 8%) 89% 88% • The primary endpoint of non-inferiority of EFV/FTC/TDF to SBR was demonstrated Adapted from Young B, et al. , Glasgow 2008; Poster #P 061 ATRIPLA® is not indicated for treatment-naïve patients in the EU

Efficacy Analysis by Prior Treatment Stratum: Week 48 Stratum at Baseline Prior NNRTI Patients Efficacy Analysis by Prior Treatment Stratum: Week 48 Stratum at Baseline Prior NNRTI Patients Below HIV-1 RNA Threshold (%) Prior PI EFV/FTC/TDF (N = 95) SBR (N = 45) EFV/FTC/TDF (N = 108) SBR (N = 52) TLOVRa 92% 84% 87% 90% M=Eb 100% TLOVR 92% 83% 87% M=E 100% 97% 98% <200 copies/m. L <50 copies/m. L a. Time to loss of virologic response algorithm (NC=F) b. Missing data (for any reason) was excluded in this analysis P=NS for all comparisons in both strata Adapted from Young B, et al. , Glasgow 2008; Poster #P 061 ATRIPLA® is not indicated for treatment-naïve patients in the EU

Discontinuations Due to Adverse Events EFV/FTC/TDF (N=203) SBR (N=97) Any Adverse Event 10 (5%) Discontinuations Due to Adverse Events 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 0 1 (1%) N (%) Gastritis 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/d. L and discontinued at Week 6 with Scr = 2. 3 mg/d. L; 1 patient had baseline Scr = 1. 4 mg/d. L and discontinued at Week 21 with Scr = 1. 3 mg/d. L. Neither patient experienced a Scr elevation while on study in excess of their baseline value Adapted from Young B, et al. , Glasgow 2008; Poster #P 061 ATRIPLA® is not indicated for treatment-naïve patients in the EU

Patient Preference Studies Study AI 266073 ADONE ATRIPLA® is not indicated for treatment-naïve patients Patient Preference Studies Study AI 266073 ADONE ATRIPLA® is not indicated for treatment-naïve patients in the EU

Study AI 266073 Methods • The following patient reported outcomes were collected in both Study AI 266073 Methods • The following patient reported outcomes were collected in both treatment arms: – Adherence by Visual Analog Scale – Quality of Life (QOL) by SF-36 (v 2) 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

Percent experiencing HIV-related symptom HIV Symptoms Index: Statistically Significant Improvements in Patients Randomised to Percent experiencing HIV-related symptom HIV Symptoms Index: Statistically Significant Improvements in Patients Randomised to EFV/FTC/TDF PRIOR PI STRATUM * OVERALL * * * (p = 0. 002) (p = 0. 032) HIV Symptom Indices *p-values compare change from baseline to Week 48 in patients switched to EFV/FTC/TDF 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 Percent Experiencing Symptoms of HIV Symptoms Index: Proportion of Patients Reporting Dizziness & Lightheadedness Percent Experiencing Symptoms of Dizziness or Lightheadedness 50 45 40 35 30 46 % * 39 % ** 32 % 25 35 % 30 % 27 % 24 % 20 15 10 5 30 % 28 % 26% 24 % EFV/FTC/TDF Overall 30 % 26 % 23 % 32 % 28 % 24 % 16 % EFV/FTC/TDF (prior NNRTI) EFV/FTC/TDF (prior PI) SBR 0 Baseline Week 4 Week 12 Week 24 Week 36 Week 48 * = p < 0. 002 ** = p < 0. 0014 Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU

Perceived Ease of the Regimen for Condition (PERC) % of patients who considered their Perceived Ease of the Regimen for Condition (PERC) % of patients who considered their regimen "very 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. 001 p-values compare treatment arms at each timepoint Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU

% reporting that EFV/FTC/TDF was % reporting that EFV/FTC/TDF was "much better" than their previous regimen Preference of Medication (POM) Questionnaire in Patients Randomised to EFV/FTC/TDF n = 116 139 146 143 146 n = total number of patients taking the questionnaire Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008 ATRIPLA® is not indicated for treatment-naïve patients in the EU

ADONE study Self reported adherence 100 P = 0. 042 adherence % and 95%CI ADONE study Self reported adherence 100 P = 0. 042 adherence % and 95%CI 99 Baseline 98 1 month post switch 97 2 months post switch 96 95 94 93 92 Doses consumed last month Doses consumed right time last month Doses consumed last week Adapted from Maggiolo F et al. HIV 9, November 2008, Glasgow. Poster# P-167. Doses consumed right time last week ATRIPLA® is not indicated for treatment-naïve patients in the EU

ADONE study Conclusions • These preliminary data suggest that switching to a FDC of 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. HIV 9, November 2008, Glasgow. Poster# P-167. ATRIPLA® is not indicated for treatment-naïve patients in the EU

Thank you Questions Thank you Questions

REYATAZ® HARD CAPSULES PRESCRIBING INFORMATION See summary of product characteristics prior to prescribing PRESENTATION: REYATAZ® HARD CAPSULES PRESCRIBING INFORMATION See summary of product characteristics prior to prescribing PRESENTATION: Hard capsules: 150 mg, 200 mg, 300 mg atazanavir. INDICATION: Antiretroviral combination treatment of HIV-1 infected, adults. DOSAGE AND ADMINISTRATION: Oral. 300 mg with ritonavir 100 mg oncedaily 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 CYP 3 A 4 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 preexisting 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. 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 CYP 3 A 4. 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, 150 mg: £ 303. 38, 200 mg: £ 303. 38, carton of 30 capsules, 300 mg: £ 303. 38 MARKETING AUTHORISATION NUMBERS: EU/1/03/267/003 - 150 mg Bottle; EU/1/03/267/005 - 200 mg Bottle. EU/1/03/267/008 -300 mg Bottle MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG, BMS House, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex. UB 8 1 DH. Telephone: 0800 -731 -1736. DATE OF PI PREPARATION: January 2009 REY/0109/2630 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. [email protected] com

SUSTIVA® 600 mg FILM-COATED TABLETS PRESCRIBING INFORMATION See Summary of Product Characteristics prior to SUSTIVA® 600 mg FILM-COATED TABLETS PRESCRIBING INFORMATION See Summary of Product Characteristics prior to prescribing PRESENTATION: Film‑coated tablets: 600 mg 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 40 kg: 600 mg 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 CYP 3 A 4 See SPC for details. WARNINGS AND PRECAUTIONS: Not for sole use. Coadministration 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 CYP 3 A 4 and an inhibitor of some CYP isozymes including CYP 3 A 4. Other compounds that are substrates of CYP 3 A 4 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 CYP 3 A 4 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 H 1 -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. UB 8 1 DH Telephone: 0800 -731 -1736. DATE OF PI PREPARATION: February 2009 SUS/0209/2280 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. [email protected] com

ZERIT® PRESCRIBING INFORMATION Summary of Product Characteristics prior to prescribing PRESENTATION: Capsules: 20 mg, ZERIT® PRESCRIBING INFORMATION Summary of Product Characteristics prior to prescribing PRESENTATION: Capsules: 20 mg, 30 mg, or 40 mg stavudine. Powder for Oral Solution 200 mg. 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: <60 kg - 30 mg twice daily, ≥ 60 kg - 40 mg 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 - 1 mg/kg twice daily; patients 30 kg - 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, 20 mg: £ 142. 28, 30 mg: £ 149. 20, 40 mg: £ 153. 70. Powder for Oral Solution 200 ml: £ 23. 40 per pack. MARKETING AUTHORISATION NUMBERS: EU/1/96/009/004(20 mg), EU/1/96/009/006 (30 mg), EU/1/96/009/008(40 mg), EU/1/96/009 (Powder for Oral Solution). MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharma EEIG, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB 8 1 DH. 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 UB 8 1 DH. Telephone: 0800 -731 -1736. HIV/0509/2893 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. [email protected] com

VIDEX® EC PRESCRIBING INFORMATION Please refer to Summary of Product Characteristics prior to prescribing VIDEX® EC PRESCRIBING INFORMATION Please refer to Summary of Product Characteristics prior to prescribing PRESENTATION: Gastro-resistant hard capsules: 125 mg, 200 mg, 250 mg or 400 mg 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 100 ml of water. Adults: Recommended daily dose: 400 mg for patients weighing 60 kg and 250 mg for patients weighing <60 kg. Children (over 6 years): recommended daily dose based on body surface area is 240 mg/m 2 (180 mg/m 2 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 inutero 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 4060% 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: 125 mg: £ 49. 16, 200 mg: £ 78. 65, 250 mg: £ 98. 31, 400 mg: £ 157. 30 MARKETING AUTHORISATION NUMBERS: 11184/0083 125 mg, 11184/0084 200 mg, 11184/0085 250 mg, 11184/0086 400 mg. MARKETING AUTHORISATION HOLDER: Bristol-Myers Squibb Pharmaceuticals Limited, Uxbridge Business Park, Sanderson Road, Uxbridge, Middlesex UB 8 1 DH. 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 UB 8 1 DH. Telephone: 0800 -731 -1736. HIV/0509/2892 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. [email protected] com

ATRIPLA PRESCRIBING INFORMATION ATRIPLA® PRESCRIBING INFORMATION Presentation: Atripla film-coated tablet. Each tablet contains 600 ATRIPLA PRESCRIBING INFORMATION ATRIPLA® PRESCRIBING INFORMATION Presentation: Atripla film-coated tablet. Each tablet contains 600 mg of efavirenz, 200 mg of emtricitabine and 245 mg 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 (Cr. Cl <50 ml/min). No dose modification necessary in patients with mild to moderate liver disease. Contraindications: Hypersensitivity to efavirenz, emtricitabine, 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 CYP 3 A 4 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 Cr. Cl 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 Cr. Cl is decreased to <50 ml/min or serum phosphate is decreased to <1. 5 mg/dl, renal function should be re-evaluated within one week. Treatment with Atripla should be interrupted if Cr. Cl is confirmed to be <50 ml/min or if serum phosphate is decreased to <1 mg/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. Coadministration of Atripla and didanosine is not recommended as exposure to didanosine is significantly increased. Avoid in antiretroviral experienced patients with strains harbouring K 65 R, M 184 V/I or K 103 N mutations. Contains sodium – consider in patients on sodium-restricted diet. Interactions: Efavirenz is an inducer of CYP 3 A 4 and an inhibitor of some CYP 450 isoenzymes including CYP 3 A 4. Other compounds that are substrates of CYP 3 A 4 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 CYP 3 A 4 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 i n 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, CB 21 6 GT. Telephone: 01223 897555. e-mail: [email protected] com CONSULT 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 medical. [email protected] com