Transcript Title

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 (ddI)
Zerit®
stavudine (D4T)
DDI and D4T safety update
Topics
• Peripheral neuropathy
• CV risk
• Hepatotoxicity
Peripheral neuropathy
% Patients with HIV-1 RNA < 50 c/mL
Study 903
% Patients < 50 Copies/mL
Intent to Treat (Missing=Failure)
100
80
73%
69%
60
40
TDF+3TC+EFV
20
d4T+3TC+EFV
0
0
24
48
72
Weeks
Adapted from Gallant et al JAMA July 14 2004 vol 202 191-201
96
120
144
Study 903 Selected Toxicities Associated with
Mitochondrial Dysfunction through Week 144
d4T+3TC+EFV
(n=301)
TDF+3TC+EFV
(n=299)
(All Grades)
Week 48
Week 144
Week 48
9 (3%)*
17 (6%)*
30 (10%)* 82 (27%)*
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
Patients (%) with Events
Week 144
Peripheral Neuritis/
+ 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 ?
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 THAB0301
Youle 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
1.9
1.5
1.2
RR
yes/no
95% CI
**
1.0
0.8
0.6
ZDV
#PYFU:
#MI:
ddI
138,109 74,407
523
331
ddC
d4T
3TC
29,676
148
95,320 152,009
405
554
* recent use = current or within the last 6 months
** not shown (low number of patients currently on ddC)
ABC
TDF
53,300
221
39,157
139
Lundgren JD, et al CROI Oral Abstract 44LB
• 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 2009:49 626-635
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 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
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
• “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 that EFV should be considered first line in all
patients. This is Based upon its efficacy, durability, toxicity profile, convenience
and cost”
A
NNRTI
EFVa
B
+
NNRTI PI
NVP*
ATV/r ~
fAPV/r
LPV/r
SQV/r
NRTI
TDF+
ABC&
C
+
NRTI
AZT>
ddI
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®
NRTI
FTC
3TC
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
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)
40
30
0
0
24
Number of Patients
EFV + 2 NRTIs
LPV/r + 2 NRTIs
EFV + LPV/r
48
72
96
120
144
Weeks After Randomization
250
253
250
210
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
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
n = 86
3 Years
(144 Weeks)
Study 903
d4t
BID
EFV
QD
3TC
BID
TDF placebo
QD
Study 903E
TDF
QD
EFV
QD
3TC
QD
(OPEN-LABEL)
Adapted from Madruga JVR, et al , ICDT 2008, Poster P4
7 Years
(336 Weeks)
903E Study: HIV-1 RNA, CD4, and Resistance
Proportion with HIV-1 RNA
<400 copies/mL through 7 Years (M=F)
Proportion with HIV-1 RNA
<50 copies/mL through 7 Years (M=F)
100
81%
80
n=86
60
40
20
% with HIV RNA <50 copies/mL
% with HIV RNA <400 copies/mL
100
80%
80
n=86
60
40
20
0
0
0
1
2
3
4
5
6
7
0
1
Years
3
4
5
6
7
Years
Mean Change from Baseline
in CD4 through 7 Years
500
+459
450
Mean Change in cells/mm3
2
400
350
300
250
200
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
150
100
50
0
0
1
2
3
4
5
6
7
82
77
73
71
Years
n= 86
85
85
84
Adapted from Madruga JVR, et al , ICDT 2008, Poster P4
903E Study: Median Total Limb Fat (IQR)
Years 2-7
12
Median Limb Fat in kg
10
8.0a
8
6.7
P<0.001a
6
4
2
0
0
1
2
3
4
5
6
7
65
61
59
58
Year
TDF + 3TC + EFV
n=
aP-value
69
69
for change from Year 2 using Wilcoxon Signed Rank test
Adapted from Madruga JVR, et al , ICDT 2008, Poster P4
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
Efficacy of boosted Reyataz ®
Atazanavir (ATV/r)
in naïve patients
26
CASTLE study design
Screening/enrolment
HIV RNA 5000 c/mL, no CD4 cell count restriction
Randomization (n=883)
Stratified: HIV RNA <100 000 c/mL vs 100 000 c/mL; 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
TDF/FTC 300/200 mg QD
Primary endpoint:
Proportion of subjects with HIV RNA <50 c/mL 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-1250d
27
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/mL: 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/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)
28
Adapted from Molina J-M, et al. Lancet 2008;372:646−655
Week 96 Results
HIV RNA <50 c/mL (CVR NC=F)
ATV/r (n=440)
LPV/r (n=443)
Responders (%)
100
80
60
* p<0.05
40
HIV RNA < 50 c/mL: 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/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)
29
Adapted from Molina J-M, et al. Poster presented at the joint ICAAC / IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d
As randomised: Week 96 CD4 mean
change from baseline
CD4 mean change (cells/mm3)
300
250
ATV/r (n=440)
LPV/r (n=443)
200
150
100
Increase in mean CD4 cells/mm3: 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-1250d
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
aThrough
bExcluding
96 weeks
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-1250d
31
Grade 2−4 diarrhoea through 96 weeks
14
12
Patients (%)
12
10
8
6
4
2
2
0
ATV/r (n=441)
LPV/r (n=437)
Molina J-M, et al. Poster presented at the joint ICAAC/IDSA, Washington, USA, 25−28 October 2008. Poster H-1250d
32
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)
Total: HDL cholesterol ratio >5
Baseline
Week 96
Baseline
Week 96
23%
17%
27%
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-1250d
33
Findings from CASTLE sub-analyses
Boosted Reyataz was
efficacious & generally well-tolerated
irrespective of race
Mc Grath et al, IAC 2008
August 2008, Poster # TUPE0058
Boosted Reyataz was efficacious
& generally well-tolerated
irrespective of gender
Absalon J, et al. XVII IAC, Mexico City, 3−8
August 2008, Poster # TUPE0062
Boosted Reyataz was efficacious &
generally well-tolerated irrespective
of HBV/HCV status
Perez-Elias MJ, et al. IAS 2005 Poster
TuPe1.1C25
Absalon J, et al. ICDT, Glasgow, UK, 9−13
November 2008, Poster 136
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
Su et al, IAC 2008
August 2008, POSTER # TUPE0060
Adapted from Molina JM, et al. 48th ICAAC,
Washington, DC, USA, 25−26 October 2008.
34
Poster H-1250d
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 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
Mean CD4 cell count
Mean absolute CD4 cell
(CVR NC=F) at Week 48:
change from baseline
count at Week 48
Responder/evaluable (%)
(SE), cells/mm3
(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
36
Boosted Reyataz was efficacious & generally
well-tolerated irrespective of HBV/HCV status
CASTLE: ATV/r Liver Function and Bilirubin
Bilirubin and ALT levels
Coinfected
Median total bilirubin
2.0
1.6
1.2
0.8
0.4
5
1.9 md/dL
1.8 mg/dL
Subjects with
moderate-to-severe
ALT elevation (%)
Total bilirubin (mg/dL)
2.4
Not coinfected
0.6 mg/dL
0.4 mg/dL
n=176 n=116
n=107
4
*†p=NS
3
1.90 %*
2
1.10 %*
1
n=75
0
ALT >200 UI/mL or ALT
>3.5 x baseline abnormal levels
0%†
n=176
n=116
0%†
n=107
n=75
0
Baseline
Month 6
Baseline
Month 6
n=subjects with measurements
37
Perez-Elias MJ, et al. IAS 2005 Poster TuPe1.1C25
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/mL
Mean CD4 cell count
(CVR NC=F) at Week 48:
change from baseline
n/N (%)
(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
38
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+
HBV/HCV−
HBV/HCV+
(n=380)
(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
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 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
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
40
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 CD4 count
at start of
treatment
suggests that
many patients
have advanced
disease
Egger M, 14th 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 Week 96
by qualifying HIV viral load
Responders (%) <50 c/mL
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/mL
HIV RNA
≥100 000 copies/mL
Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008, Poster H-1250d
42
CASTLE: 96-Week Efficacy by Baseline CD4
Cell Count
100
p=ns
p=ns
Responders (%) <50 c/mL
90
80
78
76
71
71
69
70
70
≥200
cells/mm3
100–<200 cells/mm3
69
58
60
50–<100 cells/mm3
<50 cells/mm3
50
40
30
20
10
0
ATV/r
n= 222 106 45
58
LPV/r
228 134 29 48
Adapted from Molina JM, et al. 48th ICAAC, Washington, DC, USA, 25−26 October 2008. Poster H-1250d
43
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 VL1,2
– 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
Efavirenz (Sustiva®)
ATRIPLA®
Emtricitabine
(Emtriva®)
Truvada®
Tenofovir DF
(Viread®)
The pills shown are not the actual size
Sustiva SmPC, September 2008
Viread SmPC, September 2008
Emtriva SmPC, September 2008
Truvada SmPC, December 2008
ATRIPLA SmPC, December 2008
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/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
ATRIPLA SmPC
Efficacy of ATRIPLA®
Study AI266073 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/mL
EFV/FTC/TDF Once Daily
Randomisation
2:1
Stratify by
PI or NNRTI
• No History of
Virologic Failure
Stayed on Baseline Regimen*
Week
0
24
48
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
*SBR: stayed on baseline regimen
**Time to loss of Virologic Response Algorithm
Adapted from Young B, et al., Glasgow 2008; Poster #P061
ATRIPLA® is not indicated for treatment-naïve patients in the EU
ARV Baseline Regimen
PIs (53%)
NNRTIs (47%)
FPV (3%) IDV (2%)
ATV (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/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%)
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)
Percent with Virologic Response
Treatment Difference (EFV/FTC/TDF – SBR) and 95% CI:
1.1% (–6.7%, 8.8%)
100
89%
88%
80
60
EFV/FTC/TDF
SBR
40
20
0
% <200 copies/mL
• The primary endpoint of non-inferiority of EFV/FTC/TDF to SBR was demonstrated
Adapted from Young B, et al., Glasgow 2008; Poster #P061
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 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%
100%
100%
100%
TLOVR
92%
82%
83%
87%
M=E
100%
97%
98%
98%
<200 copies/mL
<50 copies/mL
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 #P061
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%)
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/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
Adapted from Young B, et al., Glasgow 2008; Poster #P061
ATRIPLA® is not indicated for treatment-naïve patients in the EU
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
Percent experiencing HIV-related symptom
60
PRIOR PI STRATUM
OVERALL
52 *
Baseline
50
42*
37 *
40
32
Week 48
41*
33
31
30
24
20
10
0
Diarrhea or loose bowel movements Bloating, pain, or gas in the stomach
(p = 0.002)
(p = 0.002)
Changes in the way their body
looked
(p = 0.002)
HIV Symptom Indices
Problems having sex
(p = 0.032)
*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
50
Percent Experiencing Symptoms of
Dizziness or Lightheadedness
45
40
35
30
46 *%
39 %
**
32 %
25 %
25
35 %
30 %
27 %
24 %
20
15
30 %
28 %
26%
24 %
EFV/FTC/TDF Overall
5
26 %
23 %
32 %
28 %
24 %
16 %
EFV/FTC/TDF (prior NNRTI)
10
30 %
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)
How Easy Did Patients Consider their Regimen?
% of patients who considered their regimen
"very easy" to take
100
90
92
*
94
*
*
*
94
95
*
97
SBR
80
75
70
78
77
79
68
60
EFV/FTC/TDF
81
75
50
40
30
20
10
0
Baseline
n=
202 96
Week 4
199 93
Week 12
Week 24
Week 36
Week 48
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 "much
better" than their previous regimen
Preference of Medication (POM) Questionnaire
in Patients Randomised to EFV/FTC/TDF
100
90
85 %
80
70
60
79 %
80 %
Week 24
Week 36
74 %
64 %
50
40
30
20
10
0
Week 4
Week 12
n = 116
139
n = total number of patients taking the questionnaire
Adapted from Hodder S et al, P 063, HIV 9, Glasgow 2008
146
143
Week 48
146
ATRIPLA® is not indicated for treatment-naïve patients in the EU
ADONE study
Self reported adherence
P = 0.042
P = 0.042
100
99
Baseline
adherence % and 95%CI
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
Doses
consumed
right time
last week
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
REYATAZ® HARD CAPSULES PRESCRIBING INFORMATION
See summary of product characteristics prior to prescribing
PRESENTATION: Hard capsules: 150mg, 200mg, 300mg atazanavir.
INDICATION: Antiretroviral combination treatment of HIV-1 infected, adults.
DOSAGE AND ADMINISTRATION: Oral. 300mg with ritonavir 100mg 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 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 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 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
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 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. 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 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
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]
ZERIT® PRESCRIBING INFORMATION
Summary 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 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]
VIDEX® EC PRESCRIBING INFORMATION
Please 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 HIV1 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 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: 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
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]
ATRIPLA PRESCRIBING INFORMATION
ATRIPLA® PRESCRIBING INFORMATION
Presentation: 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 reevaluated 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. Coadministration 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]
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 [email protected]