Transcript PowerPoint

The Safety of Tenofovir DF for the
Treatment of HIV Infection:
The First 4 Years
M Nelson,1 D Cooper,2 R Schooley,3 C Katlama,4 J Montaner,5
S Curtis,6 L Hsu,6 B Lu,6 S Smith,6 J Rooney,6 and
the Viread Global Expanded Access Program
1Chelsea
and Westminster Hospital, London, UK; 2University of New South Wales, Sydney,
Australia; 3University of California, San Diego, CA, USA;
4Pitié-Salpêtrière, Paris, France; 5University of British Columbia, Vancouver, Canada;
6Gilead Sciences, Inc., Foster City, CA, USA and Cambridge, UK
13th Conference on Retroviruses and Opportunistic Infections
February 5-9, 2006
Denver, Colorado
Poster No. 781
Introduction
•
Tenofovir disoproxil fumarate (TDF; Viread) is a once daily nucleotide reverse
transcriptase inhibitor indicated in combination with other antiretroviral agents
for the treatment of HIV-1 infection. TDF was approved in the US in 2001 and
in Europe in 2002. Cumulative patient exposure to TDF since first marketing
approval is estimated to be 455,392 patient-years of treatment. TDF is
administered as a single 300 mg tablet (Viread).
•
The most common adverse events that occurred in patients receiving TDF
with other antiretroviral agents in clinical trials were mild to moderate
gastrointestinal events, such as diarrhea, vomiting, and nausea. Laboratory
abnormalities observed in these studies occurred with similar frequency in the
TDF and placebo treated groups.
•
The safety of TDF for the treatment of HIV infection in clinical practice has not
been fully characterized. Nephrotoxicity, including renal insufficiency and
Fanconi’s syndrome, have been reported to occur infrequently but the
incidence, risk factors, and time to resolution remain uncertain.
Nelson M, et al. 13th CROI, 2006; #781.
Objective
• Evaluate the safety profile of TDF for the treatment of HIV
infection, as observed in the Viread Global EAP and via
spontaneous safety reports submitted to Gilead Drug
Safety and Public Health Department through the first 4
years following commercial availability.
Nelson M, et al. 13th CROI, 2006; #781.
Methods
• Viread EAP: Prior to commercial availability, a global expanded access
program (EAP) was initiated in March 2001 for HIV-1 infected patients
who failed prior HAART and had limited treatment options. To be
eligible to participate, patients must have met the following criteria prior
to dosing: age ≥ 18 years, confirmed laboratory diagnosis of HIV-1
infection, unable to construct a viable treatment regimen without
Viread, had no hematologic, renal, or hepatic dysfunction, not pregnant
or breast feeding and agreed to use effective barrier contraceptive
method while receiving Viread. Initial study entry criteria included
limitations on CD4 counts or HIV RNA at study entry. These specific
criteria (CD4 and HIV RNA) were removed shortly after the start of
enrollment in all countries.
Nelson M, et al. 13th CROI, 2006; #781.
Methods (cont’d)
– At total of 10,343 patients were enrolled in the EAP: 654 (Australia), 348
(Belgium), 1,761 (Canada), 1857 (France), 411 (Germany), 12 (Ireland), 553 (Italy),
256 (Netherlands), 58 (Portugal), 576 (Spain), 819 (United Kingdom), and 3,038
(United States).
– Data is available on all patients in the Viread EAP for serious adverse events
(SAEs). SAEs were tabulated, and SAEs of clinical importance were characterized.
Serum creatinines were collected in over 1,600 patients in the Viread EAP. Risk
factors for development of graded creatinine abnormalities were determined using
mulitvariate logistic regression models.
•
Post marketing safety data: Adverse drug reactions (ADRs), both serious and
non-serious received through spontaneous reporting up to April 30, 2005 have
been collected and analyzed. Reporting rates for individual serious ADRs
(SADRs) have been calculated. Based upon an estimated 455,392
patient-years of exposure to TDF (estimated from sales data).
Nelson M, et al. 13th CROI, 2006; #781.
Methods (cont’d)
•
Although reporting rates do not represent the true incidence of SADRs (as
post marketing SADRs tend to be underreported and are subject to various
reporting biases), the pattern of SADRs reporting in the post-marketing
database was compared with the pattern of SAEs reported in the EAP. For
patients with renal ADRs the renal events were grouped into relevant
categories (renal failure, renal tubulopathy, etc.), and the time to event onset
and resolution were calculated.
Concomitant risk factors for renal disease were tabulated. For patients with
renal ADRs where serum creatinine values were provided, time to onset,
median maximal serum creatinine, and time to resolution of serum creatinine
were determined.
Nelson M, et al. 13th CROI, 2006; #781.
Summary of Demographic and Baseline Disease
Characteristics for the Viread EAP
EU &
Australia
(n = 5,544)
Canada
(n = 1,761)
US
(n = 3,038)
All EAP
(n = 10,343)
n = 5,395
n = 1,734
n = 2,846
n = 9,975
Median
41
44
43
42
Sex (%)
n = 5,452
n = 1,744
n = 2,855
n = 10,051
Male
80
89
90
85
Female
20
11
10
15
n = 5,269
n = 1,469
n = 707a
n = 6,738
Median
4.32
4.38
4.99
4.34
Range
1.69, 7.60
1.69, 6.68
0.90, 6.92
1.69, 7.60
n = 5,345
n = 1,611
n = 846a
n = 6,956
Median
234
210
90
230
Range
0, 1,850
0, 2,060
0, 1,016
0, 2,060
n = 1,311
n = 296
n = 1,631
N = 3,238
22.6
22.0
12.0
16.1
Age (available data)
Baseline HIV RNA (log10copies/mL)
Baseline CD4 Count (cells/mm3)
Time on Tenofovir DF (weeks)
Median
Nelson M, et al. 13th CROI, 2006; #781.
Summary of Demographic and Baseline Disease
Characteristics for the Viread EAP (cont’d)
EU &
Australia
(n = 5,544)
Canada
(n = 1,761)
US
(n = 3,038)
All EAP
(n = 10,343)
2,505
972
748
3,700
n = 4,713
n = 1,761
n = 3,035
n = 9,509
PI
92
72
84
86
NNRTI
82
60
77
76
NRTI
99
81
86
92
PI + NNRTI + NRTI
76
53
75
72
n = 5,385
n = 1,511
n = 2,633
n = 9,529
Lopinavir/ritonavir
54
47
46
51
Lamivudine
47
56
45
48
Didanosine
34
32
28
32
Abacavir
31
27
30
30
Stavudine
15
21
31
21
Person-years of Exposure to TDF
Prior ART (%)
ART at Baseline (%)
a. The collection of Baseline HIV RNA and CD4 were no longer required by the protocol shortly after the initiation of the
EAP in the US.
Nelson M, et al. 13th CROI, 2006; #781.
SAEs from EAPa,b and Most Common SARDs from
Post Marketing Safety Databasec
(Excluding SAEs listed in Specific SAE Categories of Interest
and Serious Renal Adverse Event Categories)
EAP (n = 10,343)
(3,700 person years)
PM Safety Database
(455,392 person years)
# of
patients
(%)
Incidence Per
100,000 person years
Reporting Rate
Per 100,000 person yearsd
Anemia
22
0.2
594
0.9
Asthenia
10
< 0.1
270
1.3
Diarrhea
20
0.2
541
0.9
Drug Interaction
0
0
0
2.0
Fever
42
0.4
1,135
2.4
Infection Bacterial
26
0.3
703
0.6
Lymphoma like Reaction
26
0.3
703
0.2
Multi-organ Failure
4
< 0.1
108
1.3
Nelson M, et al. 13th CROI, 2006; #781.
SAEs from EAPa,b and Most Common SARDs from
Post Marketing Safety Databasec
(Excluding SAEs listed in Specific SAE Categories of Interest
and Serious Renal Adverse Event Categories) (cont’d)
EAP (n = 10,343)
(3,700 person years)
PM Safety Database
(455,392 person years)
# of
patients
(%)
Incidence Per
100,000 person years
Reporting Rate
Per 100,000 person yearsd
Nausea
11
0.1
297
1.8
Rash
10
< 0.1
270
1.8
mL
g/
Pneumonia
h
Weight Decrease
C
(
U
A
20
0.2
541
1.3
66
0.6
1,784
0.6
5
< 0.1
135
22
Vomiting
a.
b.
c.
d.
Repeated by  0.1% of patients.
SAEs were reported by 631 patients (6%) in the EAP, and 211 patients (2%) had related SAEs.
1.3 per 100,000 person years.
Reporting rates do not represent the true incidence of SADRs as PM events tend to be underreported and are subject
to various reporting biases.
Nelson M, et al. 13th CROI, 2006; #781.
Specific SAE Categories of Interesta
EAP (n = 10,343)
(3,700 person years)
PM Safety Database
(455,392 person years)
# of patients
(%)
Incidence per
100,000 person years
Reporting Rate per
100,000 person yearsc
12
0.1
324
1.1
Lactic Acidosis
13
0.1
351
4.2
Mitochondrial Toxicity
1
< 0.1
27
1.5
Neuropathy
6
< 0.1
162
0.7
0.5b
1,297
5.5
Bone Abnormalities
)
CL/F (mL/min
48
Pancreatitis
a.
b.
c.
Adverse events sometimes associated with ARV use. Each category includes multiple related SAE terms
Incidence of pancreatitis was 0.7% in patients taking didanosine and 0.3% in patients not taking didanoise (p <0.001)
See footnote d, SAEs from EAPa,b and Most Common SADRs from Post Marketing Safety Databasec.
Nelson M, et al. 13th CROI, 2006; #781.
Serious Renal Adverse Event Categoriesa
EAP (n = 10,343)
(3,700 person years)
PM Safety Database
(455,392 person years)
# of
patients
(%)
Incidence per
100,000 person years
Reporting Rate per
100,000 person yearsd
Any Renal SAEb
56
0.5
1,514
43.3c
Renal Failure
32
0.3
865
24.2
Renal Other
11
0.1
297
4.0
Serum Creatinine Inc. /
Inc BUN
10
< 0.1
270
5.1
Fanconi / Tubular /
Hypophos / Glyco
7
< 0.1
189
22.4
Nephrogenic DI
1
< 0.1
27
2.2
Nephritis
0
0
0
2.4
Proteinuria
0
0
0
2.2
a.
b.
c.
d.
Each category includes multiple related SAE terms.
Patients can have > 1 event.
Reporting rate for non-serious renal events was 61.5 events per 100,000 person years.
See footnote d, SAEs from EAPa,b and Most Common SADRs from Post Marketing Safety Databasec.
Nelson M, et al. 13th CROI, 2006; #781.
Viread EAP: Abnormalities in Serum Creatininea
Patients with elevation in Serum Creatinine
Baseline (n = 2,821)
On Study (n = 1,699)
Serum Creatinine Grade
n (%)
n (%)
Grade 1 ( 0.5 mg/dL from BL)
0 (0)
32 (1.9)
Grade 2 (2.0 – 3.0 mg/dL)
2 (0.1)
5 (0.3)
Grade 3 (3.1 – 6.0 mg/dL)
0 (0)
3 (0.2)
3 (0.1)
2 (0.1)
Grade 4 (> 6.0 mg/dL)
a.
Patients in Viread EAP with available serum creatinine data.
Nelson M, et al. 13th CROI, 2006; #781.
Viread EAP: Risk Factors for Unconfirmed ≥ Grade 1
Serum Creatinine Increase – Multivariant Analysis
Odds Ratio (95% CI)
p-value
Age
1.05 (1.01, 1.09)
0.021
Baseline CD4 – Ordinal Categories
0.46 (0.30, 0.73)
< 0.001
Baseline Weight
0.94 (0.90, 0.97)
< 0.001
Nephrotoxic Medications Taken at Baseline
2.40 (1.08, 5.34)
0.032
•
•
All patients with a baseline and followup serum creatinine, and relevant information on risk factors available (n = 911).
Other risk factors evaluated in the model but did not reach significance were:
– Abacavir taken at baseline, didanosine taken at baseline, LPV/r taken at baseline, lamivudine taken at baseline,
stavudine taken at baseline, baseline creatinine, baseline HIV RNA - ordinal categories, CDC classification,
coinfection with HBV, days since HIV diagnosis, diabetes at baseline, gender, hypertension at baseline, ACE
inhibitors at baseline, and nephrotoxic antibiotics at baseline.
Nelson M, et al. 13th CROI, 2006; #781.
Viread EAP: Risk Factors for Unconfirmed ≥ Grade 2
Serum Creatinine Increase – Multivariant Analysis
•
•
Odds Ratio (95% CI)
p-value
Baseline Creatinine
17.4 (1.64, 184.1)
< 0.018
Baseline Weight
0.88 (0.82, 0.95)
0.001
All patients with a baseline and followup serum creatinine, and relevant information on risk factors available (n = 911).
Other risk factors evaluated in the model but did not reach significance were:
– Abacavir taken at baseline, didanosine taken at baseline, LPV/r taken at baseline, lamivudine taken at baseline,
stavudine taken at baseline, age, baseline CD4-ordinal categories, baseline HIV RNA ordinal categories, CDC
classification, coinfection with HBV, days since HIV diagnosis, diabetes at baseline, gender, hypertension at
baseline, nephrotoxic medications taken at baseline, ACE inhibitors at baseline, and nephrotoxic antibiotics at
baseline.
Nelson M, et al. 13th CROI, 2006; #781.
Post Marketing Safety Database:
• For all post marketing renal events with creatinine data,
the median maximum serum creatinine was 2.3 mg/dL
(IQR 4.1).
• For post marketing serious renal events with creatinine
data, the median maximum serum creatinine was
2.7 mg/dL (IQR 4.4).
Nelson M, et al. 13th CROI, 2006; #781.
Post Marketing Serious Renal Events – Time to Onseta
Time to Onset
Percent of Total
Missing
32
Available
68
Percent of Available
≤ 30 days
17
1 – 3 months
11
> 3 to 6 months
15
> 6 to 12 months
17
> 1 to 12 months
27
> 2 to 3 years
11
> 3 to 4 years
2
TOTAL
a.
100
100
All serious renal events with TDF start date and event onset data available. Reporting rate 29.2 events per 100,000
person-years. Median time to onset for all post marketing serious renal adverse events was 282 days
(IQR 443 days).
Nelson M, et al. 13th CROI, 2006; #781.
Post Marketing Renal Events: Median Time to
Resolution of Serum Creatininea
Days to Resolution (95% CI)
Resolution to Grade 0b
(≤ 2.0 mg/dL)
86
(67 – 145)
Resolution to ≤ Grade 1c
(≤ 2.0 mg/dL)
52
(29 – 95)
Resolution to ≤ Grade 2d
(≤ 3.0 mg/dL)
29
(24 – 45)
a.
b.
c.
d.
KM analysis of renal spontaneous reports with serum creatinine data available, time to resolution from TDF stop data.
Includes maximum grades 1, 2, 3, and 4.
Includes maximum grades, 2, 3, and 4.
Includes maximum grades 3 and 4.
Nelson M, et al. 13th CROI, 2006; #781.
Possible Concomitant Risk Factors for Renal/Urinary Events
Reported Between 1 November 2004 and 30 April 2005a
Concomitant Risk Factors for Renal Dysfunctionb
% of cases with
medical history
TOTAL Cases with information on medical historyc
100%
TOTAL Cases with one or more potential alternative cause of renal events
84%
a.
b.
c.
d.
e.
Sepsis / Serious infection
26%
History of renal disease / baseline renal impairment
24%
Late stage HIV
22%
Concurrent nephrotoxic drugd
19%
Hypertension
16%
Othere
16%
Dehydration (e.g. due to vomiting / diarrhea)
11%
Diabetes
9%
Intercurrent lactic acidosis / pancreatitis / liver failure
7%
Spontaneous and serious, related clinical trial adverse event reports.
Each case may involve more than one alternative cause.
Reporting rate of 86 per 100,000 person years.
Restricted to drugs well known for causing renal toxicity.
Rhabdomyolysis, drug / alcohol abuse, liver disease, chemotherapy, hx low phosphate.
Nelson M, et al. 13th CROI, 2006; #781.
Conclusions
•
The most common SAEs reported in the Viread EAP were pneumonia
(0.6%), pancreatitis (0.5%), fever (0.4%), bacterial infection (0.3%), and
lymphoma (0.3%). No individual SAE was reported in > 1% of patients.
•
The incidence of all serious renal SAEs was 0.5% amongst 10,343
patients in the Viread EAP.
•
The most common SADR categories reported in post-marketing safety
surveillance were renal, pancreatitis, lactic acidosis, and fever. The
pattern of renal events is similar in the post-marketing safety database
and the Viread EAP database.
•
Possible risk factors for renal events reported in the postmarketing
safety database include concomitant nephrotoxic medications, late
stage HIV, past history of renal disease, and sepsis.
•
For all post marketing renal events with creatinine data, the median
maximal serum creatinine was 2.3 mg/dL, and the median time to
resolution to ≤ Grade 2 serum creatinine was 29 days.
Nelson M, et al. 13th CROI, 2006; #781.
Conclusions (cont’d)
• In multivariate analysis of data from Viread EAP, risk factors for
increase in serum creatinine included low CD4 cell count, older
age, low baseline weight, higher baseline serum creatinine, and
concomitant nephrotoxic medications, but coadministration of
Kaletra was not a risk factor.
• Bone fractures, neuropathy, and mitochondrial toxicity were
reported infrequently in both the Viread EAP (≤ 0.1%) and in the
postmarketing safety database.
• The safety profile of tenofovir DF observed in the Viread EAP
confirms and extends the safety profile observed in the tenofovir
DF clinical trials program. No new major unexpected toxicities
have been observed in the post marketing safety surveillance
program through 4 years observation.
Nelson M, et al. 13th CROI, 2006; #781.
Acknowledgments
Gilead Sciences , Inc., would like to thank the large number of patients, physicians, and their
research personnel who have participated in the Viread EAP and the CROs that assisted in
the conduct of these studies: Parexel International; Ingenix Pharmaceutical Services, Inc.;
and Charles River Labaratories.
Additional members of the Viread Global Expanded Access Program include B Gazzard (UK),
H Gallais (France), A Lazzarin (Italy), A Adam (Germany), B Clotet (Spain), R Colebunders
(Belgium), J Lange (The Netherlands), MJ Aguas (Portugal), F Mulcahy (Ireland),
S Follansbee (USA), J Elder (Charles River Laboratories), M Wulfsohn, L Metzler, A Cheng,
and N Bischofberger (Gilead Sciences).
Nelson M, et al. 13th CROI, 2006; #781.