Transcript pag.ias2011.org

Defining the benefits of
NNRTI treatment
New data, new parameters
Defining the benefits of
NNRTI treatment
New data, new parameters
Jürgen Rockstroh, MD
Professor of Medicine
University of Bonn, Germany
Agenda
Time
Title
Speaker
10.15–10.20
Welcome and introduction
Jürgen Rockstroh
10.20–10.45
Nevirapine today:
what do we know?
Laura Waters
10.45–11.15
Nevirapine tomorrow
Joe Gathe
11.15–11.45
Defining success in HIV treatment:
should we broaden the
parameters?
Vicente Soriano
11.45–12.15
Discussion and debate session
All
Housekeeping
 Please ensure all mobile phones are set to
silent mode
 Please use the question cards available and hand
these to the hostesses for the discussion sessions
This symposium contains information that is in the
public domain but may not be in the labels of the
agents discussed. Inclusion of this material does not
represent recommendations for usage but is provided
for educational purposes only.
The views expressed in these presentations are
those of the presenters and do not necessarily
reflect the views of
Boehringer Ingelheim GmbH.
Please refer to your local label before
use of any agents discussed.
Nevirapine Today:
What Do We Know?
Dr Laura Waters
Brighton & Sussex University NHS Trust,
Brighton, UK
Disclosures
 Received funding and/or honoraria from all major
pharmaceutical companies working in virology
Overview
 First-line treatment
 Current 1st line recommendations
 What is the latest evidence for nevirapine first-line?
 Switching
 Reasons for switch
 Switch recommendations and options
 Benefits of switching to nevirapine
Brighton cohort, ART uptake, and
virological failure (VF)
2000
Patient number
1800
Cohort
1600
ART
VF
1400
1200
1000
800
600
400
200
Year
0
% with VF
2000
11%
2001
5%
2002
4%
2003
2004
2005
6%
3%
2%
Personal Communication. Dr Martin Fisher, June 2011
2006
2%
2007
2%
2008
2%
2009
1%
Current guidelines for initiating treatment:
preferred and alternative regimens
BHIVA (2008)1
EACS
V5.4 (2011)2
IAS-USA (2010)3
DHHS (2011)4‡
NRTI
preferred
TDF/FTC
ABC/3TC
TDF/FTC
ABC/3TC
TDF/FTC
TDF/FTC
NRTI
alternative
ddI
ZDV
ZDV/3TC
ddI/3TC or FTC
ABC/3TC
ABC/3TC
ZDV/3TC
3rd drug
preferred
EFV
EFV, NVP*
ATV/r, LPV/r,
DRV/r, SQV/r, RAL
EFV
ATV/r, DRV/r
RAL
EFV
ATV/r, DRV/r
RAL
LPV/r†
3rd drug
alternative
LPV/r, FPV/r,
ATZ/r, SQV/r,
NVP*, ATZ **
SQV/r, FPV/r
LPV/r, FPV/r,
MVC
NVP*, FPV/r,
LPV/r
*Only when CD4<250 cells/µL in females and <400 cells/µL in males
**Where there are established CV disease risk factors and a PI is required
†Preferred for pregnant women only (combined with ZDV/3TC)
‡Note that specific combinations are recommended
1. Gazzard et al. HIV Medicine 2008;9:563–608; 2. http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines
_FullVersion.pdf ; 3. Thompson et al. JAMA 2010;304:321-333; 4. http://www.aidsinfo.nih.gov/contentfiles/adultandadolescentgl.pdf
ATV/r vs EFV
Primary virologic endpoint
A5202: Overall
ATV/r versus EFV with
ABC/3TC: HR 1.13 (95% CI 0.82, 1.56)
Prob. VF free at wk 96: 83.4 vs. 85.3%, diff -1.9% (95% CI -6.8, 2.6)
TDF/FTC: HR 1.01 (95% CI 0.70, 1.46)
Prob. VF free at wk 96: 89.0 vs. 89.8%, diff -0.8% (95% CI -4.9, 3.3)
EFV + TDF/FTC
EFV + ABC/3TC
ATV/r + TDF/FTC
ATV/r + ABC/3TC
ARTEN involved a relatively advanced
ARV-naïve population
Baseline demographics
NVP qd
(n=188)
NVP bid
(n=188)
ATZ/r
(n=193)
Mean age (years)
38.4
40.0
37.6
Male gender (%)
80.9
86.7
83.9
Caucasian (%)
78.2
81.9
79.8
Western Europe (%)
72.3
71.8
68.4
Hepatitis B or C at screening (%)
11.2
10.6
11.9
50.5/5.9
54.8/5.9
52.8/6.7
pHIV-RNA >105 log copies/mL (%)
62.8
62.8
65.8
Mean CD4+ count (cells/L)
176.8
187.4
187.8
CD4+ count <50 cells/L (%)
7.4
9.0
6.2
MSM/IDU (%)
Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07;
Soriano et al; Antivir Ther 2011;16:333-348
Nevirapine is not currently indicated for qd dosing in Europe
ARTEN: treatment response
(ITT analyses; Week 48)
Treatment response by primary
endpoint (ITT) (two visits prior Wk 48)
95% CI= -5.9% to 9.8%;
p=0.63
80
67
65
60
40
20
0
Combined
NVP
100
Patients achieving
treatment response (%)
Patients achieving
treatment response (%)
100
Treatment response by sensitivity
analysis: TLOVR algorithm (ITT)
ATZ/r
80
95% CI= -10.4% to 4.5%;
p=0.44
70
74
60
40
20
0
Combined
NVP
ATZ/r
TLOVR; time to loss of virological response
Soriano et al. IAS 2009, Cape Town, South Africa. Poster LBPE07;
Soriano et al; Antivir Ther 2011;16:333-348
Nevirapine is not currently indicated for qd dosing in Europe
ARTEN: grade 3−4 events of interest
Combined NVP
ATZ/r
DAIDS
Grade (% patients)
G3
G4
G3
G4
ALT
3.7
3.5
1.6
0.0
AST
4.0
2.1
2.1
0.5
Total bilirubin
1.6
1.6
44.6*
8.8
*Leading to discontinuation in one patient
Grade 3−4
%
Rash
Combined NVP
ATZ/r
1.6
0.0
 No Grade 4 rashes
 No cases of SJS, TEN, or deaths due to liver or skin toxicity
Soriano et al; Antivir Ther 2011;16:333-348
Nevirapine is not currently indicated for qd dosing in Europe
Swiss HIV Cohort: 2005–2008
Treatment
modification
41.5 per 100PY
Change for
drug toxicity
22.4 per 100 PY
Reasons for
toxicity change:
•
•
•
•
GI
HSR
CNS
Hepatic
28.9%
18.3%
17.3%
11.5%
Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65
Virological safety
(12 month
VL <50 c/mL):
• 85% switchers
• 87% non-switchers
Time to treatment modification (all reasons)
according to the cART regimen
Probability of treatment change
n=1318
AZT/3TC + LPV/r
TDF/FTC + LPV/r
TDF/FTC + ATZ/r
TDF/FTC + NVP
ZDV/3TC + EFV
TDF/FTC + EFV
ABC/3TC + EFV
1.00
0.75
0.50
p<0.001
0.25
0.00
0
3
6
Months
9
12
NVP initial toxicity, but limited long-term treatment modification
Elzi L et al and the Swiss HIV Cohort Study. Arch Intern Med 2010;170:57-65
Toxicity management
Earlier ART
Longer life
expectancy
Better
understanding
of toxicity
Ageing &
impact of HIV?
Toxicity management
will form more
and more of
our workload!
Switching: EACS Guidelines
“Intra-class switch preferable if drug-specific
related adverse event”
“PI/r to NNRTI switch for simplification,
prevention or improvement of metabolic
abnormalities, adherence facilitation.
NVP has the advantage of its metabolic profile.
EFV has the advantage of possible FDC”
http://www.europeanaidsclinicalsociety.org/guidelinespdf/EACS-EuroGuidelines_FullVersion.pdf
ARTEN: impact on lipid levels
Mean change from baseline
to Week 48 (LOCF)
in TC and TG
30
25
20
p=0.0382
ATZ/r
p=0.0001 27.8
0.15
24.4
Mean change in ratio
Mean change (LOCF; mg/dL)
Combined NVP
Mean change from
baseline to Week 48
(LOCF) in TC:HDL-c ratio
19.6
15
10
5
0.02
0
Combined NVP
ATZ/r
p=0.0001
0.13
0.1
0.05
0
-0.05
-0.1
-0.15
-0.2
-0.25
-0.24
-0.3
Total cholesterol
Triglycerides
Adapted from Podzamczer et al. HIV Med 2011;12:374-382
Nevirapine is not currently indicated for qd dosing in Europe
Many studies support virological &
immunological efficacy of switching
 Backbone
 RAVE
 SWEET
 BICOMBO
 3rd agent
 ATARITMO
 SSAT0029
 Several T20 to RAL studies
Recent label change for switching to
nevirapine
 August 2010 update to Summary of Product Characteristics:
‒ “VIRAMUNE should not be initiated in adult females with CD4 cell
counts greater than 250 cells/mm3 or in adult males with CD4 cell
counts greater than 400 cells/mm3, who have a detectable
plasma HIV-1 RNA unless the benefit outweighs the risk.” 1
 Therefore
‒ It is now possible to switch patients with
undetectable viral loads (<50 copies/ml) to
NVP irrespective of their CD4 cell counts
Viramune SPC, August 2010.
Switch to NVP: relative risks of NVP
treatment-limiting toxicities – 7 cohorts
Hazard ratios for discontinuation due to toxicity or HSRs for ARV
naïve and experienced patients stratified by CD4 count and VL
Toxicities or patient/physician choice = TOXPC
TOXPC, 2610/10186 discontinued
TOXPC 18 wks, 1088/10186 discontinued
HSR with detailed reasons for discontinuation, 458/6547 discontinued
Kesselring et al. AIDS 2009;23:1-11
Long-term CNS effects with efavirenz vs
raltegravir and vs rilpivirine (TMC278)
100
90
80
70
60
50
40
30
20
10
0
58
34
RAL (n=160)
Neuropsychiatric symptoms
by 96 weeks: Study C2042
% patients
% patients
Neuropsychiatric AEs
by 96 weeks: Protocol 0041
100
90
80
70
60
50
40
30
20
10
0
EFV (n=38)
TMC278* (n=93)
EFV (n=89)
60
33
17
Neurological AEs
of interest
21
Psychiatric
AEs
*25 mg once daily dose – dose taken into Phase III trials
Rilpivirine is not currently licensed for use in Europe
1. Markowitz et al. J Acquir Immune Defic Syndr 2009;52:350-356;
2. Pozniak et al. AIDS 2010;24:55–65
Switching from efavirenz to nevirapine:
impact on CNS toxicity
 Retrospective review of switch from EFV to NVP 1998-2007 (n=67)




Mean EFV exposure: 25.6 months (range: 1-96 months)
Other regimen components unchanged
Median CD4 cell count at switch: 576 cells/mm3
All 62 patients with VL <50 copies/mL pre-switch maintained virological
suppression post-switch (median 42.6 months [range: 3 months to 10
years])
 0/67 patients who switched from EFV to NVP developed rash
On EFV before
switch
After switch from
EFV to NVP
Neuropsychiatric side effects (n)
43
13
Sleep disturbance (n)
34
9
Ward et al. HIV 9, 2008. Glasgow UK. Poster P057
Switching from EFV to NVP in ACTG A5095:
switches due to CNS toxicity
Patients switched to NVP due to
CNS symptoms (n=47)
Resolved CNS symptoms (n=46)
Persistent CNS symptoms (n=1)
No recurrent CNS
symptoms (n=41)
New CNS
symptoms (n=5)
No NVP discontinuations for CNS symptoms
Schouten et al. Clin Infect Dis 2010;50:787–791
Comparison of CV risk factors and ultrasonography
among patients treated for >5 years with NVP or EFV
CV risk factor
(median value)
Nevirapine (n=156)
Efavirenz (n=120)
Baseline
Follow up
P
Baseline
Follow up
P
TC (mg/dL)
199
189
0.0081
177
194
0.0001
HDLc (mg/dL)
44.7
47.1
0.0076
43.2
44.8
0.3938
LDLc (mg/dL)
126
118
0.0054
108
116
0.01
TG (mg/dL)
184
136
0.0001
144
230
0.0001
BMI (kg/m2)
24.1
23.8
0.097
23.6
24.2
0.002
Glucose (mg/dL)
94
93
0.4694
94
101
0.0025
Statistically significant changes in a favourable direction
Statistically significant changes in an unfavourable direction
Subclinical carotid lesions detected by colour-Doppler ultrasonograph
Ultrasonography
(% patients)
Baseline
Follow up
P
Baseline
Follow up
P
Normal
69
64
0.8029
77
26
0.0001
Pathological
31
36
23
74
Maggi et al. J Antimicrob Chemother 2011;66:896–900
SIROCCO: LDLc levels with continued EFV
or switch from EFV to NPV
NVP (n=18)
EFV (n=17)
Mean change from
baseline (mmol/L)
0.0
-0.1
-0.09
-0.2
-0.3
-0.4
-0.43
-0.5
At 52 weeks, the data indicated a 20% decrease in
10 year relative risk for major CV events
(based on the Framingham equation)
Parienti et al. Clin Infect Dis 2007;45:263-266
Other within class options
 Etravirine
 Unlicensed indication to use as a 3rd agent (ie without a PI)
 Twice daily dose
Etravirine SPC , Janssen-Cilag, April 2010: http://www.medicines.org.uk/emc/medicine/21185/SPC/
Median number of Grade 2–4 CNS AE
following a switch from EFV to ETR
Median number G2–4 CNS AE
3.5
p<0.001
3
Baseline (n=38)
Week 12 (n=32)
2.5
2
1.5
1
0.5
0
Combined Analysis
Waters et al. AIDS 2011;25:65-71
Change in lipids 12 weeks after switching
from EFV to ETR
Mean Baseline
mmol/L
(IS arm)
Mean Baseline
mmol/L
(DS arm)
Mean change
mmol/L (SD)
(both arms)
Total
cholesterol
5.33
5.26
-0.64
(1.02)
<0.001
HDLcholesterol
1.34
1.09
-0.04
(0.21)
ns
LDLcholesterol
3.58
3.41
-0.58
(1.09)
0.021
Triglycerides
1.45
1.73
-0.19
(0.62)
0.092
IS: immediate switch; DS: delayed switch
Waters et al. AIDS 2011;25:65-71
p-value
12-year experience of NVP-containing
regimens in routine clinical practice
Patients receiving NVP from 1996–2008
N=592 followed up
61% (N=361) still on NVP
Median duration: 176 weeks
(range: 0.3–600)
N=231 discontinued
Reasons for discontinuation:
• 42% failure
• 28% side effects
• 30% other causes
N
CD4 (cells/µL)
Day 0, median
CD4 (cells/µL)
Latest value,
median
VL <200 c/mL
Day 0, %
VL <200 c/mL
Latest value (%)
Naïve
67
271
551
0
97
Failure
54
289
565
0
96
Switch
240
461
547
100
100
 Comparative 5-year persistence from April 2003–April 2008 for most frequently
prescribed 3rd agent: NVP 61%; EFV 41%; LPV/r 23% (p<0.0001)
Reliquet et al. HIV Clin Trials 2010;11:110–117
Summary
 NVP combined with TDF/FTC is an effective treatment
option in ARV-naïve patients when used within CD4+ cell
count thresholds
 NVP provides an established switch option and now can be
used without CD4 restrictions in virally suppressed patients
 NVP has a favourable lipid profile which may be important given
that long-term morbidities include CV disease
Nevirapine Tomorrow
Joseph C Gathe, Jr, MD, FACP, FIDSA
Therapeutic Concepts, PA
Houston, TX, USA
[email protected]
Disclosures
 Received funding and/or honoraria from all major
pharmaceutical companies working in virology
Nevirapine Tomorrow
 Can twice daily nevirapine be improved?
 Historical perspective
 Available data
 Basic science
 Clinical science
 Conclusions
Adherence To HAART
 Adherence correlated with viral suppression,
reduced rates of resistance, increased survival,
and improved QoL
 Predictors of poor adherence:
Low levels of literacy
Treatment fatigue
Psychosocial issues
(eg depression,
inadequate social
support)
Complex regimens
(eg pill burden, dosing
frequency,
food requirements)
Adverse drug effects
Stigma
Difficulty taking
medication (eg trouble
swallowing pills)
Active substance
abuse
Age-related
challenges (eg vision
loss, cognitive
impairment)
Panel on Antiretroviral Guidelines for Adults and Adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and
adolescents. Department of Health and Human Services. January 10, 2011; 1–166
Adherence With QD vs More Frequent Dosing
% patients
Correct adherence following switch to a qd regimen
(EFV/3TC/D4T XR) vs continued use of a bid or more
frequent ARV regimen
Correct adherence = % days with the correct number of doses taken, evaluated with Medication Event Monitoring
System (MEMS) caps
Boyle et al. HIV Clin Trials 2008;9:164–176
Nevirapine Tomorrow
 Can twice daily viramune be improved?
 Historical perspective
 Available data
 Basic science
 Clinical science
 Conclusions
Can Twice Daily Nevirapine Be Improved?
YES!!!
 Nevirapine immediate release (NVP IR) 200 mg twice-daily
(bid) is a well established component of effective triple
HAART therapy1,2,3
 A nevirapine preparation given once daily (qd) would be
beneficial in providing dosing symmetry with the guideline
recommended qd combination nucleoside therapies3,4
 Is this possible?
Nevirapine is not currently indicated for qd dosing in Europe.
1. Gazzard et al. HIV Med 2008; 9:563–608
2. EACS Guidelines 2009 http://www.europeanaidsclinicalsociety.org/guidelinespdf/1_Treatment_of_HIV_Infected_Adults.pdf;
3. DHHS 2011 http://aidsinfo.nih.gov/contentfiles/AdultandAdolescentGL.pdf; 4.Thompson A et al. JAMA 2010; 304:321–333
Past Experience With Nevirapine
 Safety
 2004 2NN study (D4T/3TC) + NVP daily or NVP bid or EFV
daily or NVP/EFV
 Suggested some AEs may be related to extremes of NVP
pharmacokinetic (PK) parameters
 Lowering NVP Cmax may reduce common AEs
Nevirapine is not currently indicated for qd dosing in Europe.
van Leth et al. Lancet 2004;363:1253–63
Past Experience With Nevirapine
 Efficacy (2NN data)
 Efficacy not predicted by PK at NVP 400 mg/day dose
 Patients with lowest NVP trough plasma levels did as well as
patients with the highest levels
 Viral decay and 48-week data supported use of NVP 3 µg/mL
steady state equivalent plasma exposure as target
 Median NVP Cmin of 3 µg/mL should be target
van Leth et al. HIV Clin Trials 2005;6:254-261; Leth et al. AIDS Res Hum Retroviruses 2006:22:232–239
Nevirapine Tomorrow
 Can twice daily viramune be improved?
 Historical perspective
 Available data – once daily nevirapine
 Basic science
 Clinical science
 Conclusions
Nevirapine is not currently indicated for qd dosing in Europe.
The Basics Of Nevirapine eXtended Release
(XR)
 NVP XR should ideally show:
 qd dosing
 No specific dietary requirements
 Lower peak plasma levels without compromising efficacy
 Comparable/improved safety and maintained efficacy vs bid
dosing of NVP IR
 Formulation: hydrophilic polymer matrix system,
widely used in oral controlled release drug delivery
Nevirapine is not currently indicated for qd dosing in Europe.
The Basics Of Nevirapine XR: Target PK
NVP plasma concentration (µg/mL)
 Steady state Cmin 3 µg/mL (>30 fold higher than IC90 of
wild type virus*)
 Cmax/Cmin ratio <1.5
8
NVP IR (bid)
NVP XR (qd)
6
4
2
IC90
0
0
4
8
12
16
20
24
Hours
*IC90 for wild type virus = 100 ng/mL
Nevirapine is not currently indicated for qd dosing in Europe.
Nevirapine XR:
Overview Of Development
Colonic
absorption
Q2–Q4 2005
Phase Ia
(single dose)
~10 prototypes,
healthy
volunteers
Q1–Q3 2006
Phase Ib: ERVIR
multiple-dose PK (to
steady state), NVP IRpretreated HIV patients
switched to NVP XR
Q4 2006–Q2 2007
Phase III, VERXVE
48-wk final NVP XR formulation vs NVP IR (bid)
Q4 2007–Q3 2009
Phase III, TRANXITION
48-wk transition study from NVP IR to XR
Q4 2008–Q3 2010
Nevirapine is not currently indicated for qd dosing in Europe.
Nevirapine XR:
Overview Of Development
Colonic
absorption
Q2–Q4 2005
Phase Ia
(single dose)
~10 prototypes,
healthy
volunteers
Q1–Q3 2006
Phase Ib: ERVIR
multiple-dose PK (to
steady state), NVP IRpretreated HIV patients
switched to XR
Q4 2006–Q2 2007
Phase III, VERXVE
48-wk final NVP XR formulation vs NVP IR (bid)
Q4 2007–Q3 2009
Phase III, TRANXITION
48-wk transition study from NVP IR to XR
Q4 2008–Q3 2010
Nevirapine is not currently indicated for qd dosing in Europe.
The Basics Of Nevirapine XR
Phase Ib: ERVIR
 Objectives:
 To establish the steady state PK profile of 2 different NVP XR
formulations (formulation A and formulation B) under fasting
and fed conditions
 To compare the steady state bioavailability of the 2 different
NVP XR formulations with NVP IR (200 mg bid)
 Open-label, multiple-dose, parallel group study:
 4 countries: Germany, Switzerland, France, USA
 Enrolled HIV-infected patients (viral load <50 c/mL; n=92)
treated for >12 weeks with a stable regimen based on NVP IR
200 mg bid
 Plasma samples at steady-state after IR and XR collected
over 24h
Nevirapine is not currently indicated for qd dosing in Europe.
Quinson et al. ICAAC 2009, Poster, Abstract A1-1310;
Battegay et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77
Mean NVP plasma conc. (ng/mL) ± SD
ERVIR Results: NVP XR vs NVP IR
400 mg Formulation A
IR 400 mg
XR 400 mg fed
XR 400 mg fasted
n=24
10000
8000
6000
4000
2000
IC90
0
-4
0
4
(day)
*IC90 for wild type virus = 100 ng/mL
Quinson et al. ICAAC 2009, Poster, Abstract A1-1310;
Battegay et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77
8
12
Time (h)
16
20
24
Nevirapine is not currently indicated for qd dosing in Europe.
Bioavailability (%)
Pharmacokinetic data:
relative bioavailability
100
90
80
70
60
50
40
30
20
10
0
100
100
94
Nevirapine IR
80
Fasted
Nevirapine XR
Fed
Relative to nevirapine (100%)
 The bioavailability for nevirapine XR under fasted conditions was 80%
 The bioavailability for nevirapine XR under fed conditions was 94%
Quinson A et al. ICAAC 2009, Poster, Abstract A1-1310;
Battegay, M et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77
The Basics Of Nevirapine XR
Can Nevirapine Be Given QD?
 Administration of NVP XR 400 mg qd resulted in extended
absorption and reductions in peak levels at steady state while
attaining similar troughs levels as NVP IR
 NVP 400 XR formulation A exhibited better bioavailability and lower
variability than other XR formulations
 NVP XR formulations demonstrated similar rates of AEs and
nearly all were mild
 No virologic failures were observed
 NVP XR 400 mg formulation A
selected for Phase III studies
Nevirapine is not currently indicated for qd dosing in Europe.
Quinson et al. ICAAC 2009, Poster, Abstract A1-1310;
Battegay et al. 12th EACS, Nov 2009; HIV Med 10, Suppl 2: 76-77
Nevirapine Tomorrow
 Can twice daily viramune be improved?
 Historical perspective
 Available data
 Basic science
 Clinical science
 Conclusions
Nevirapine XR:
overview of clinical development
Colonic
absorption
Q2–Q4 2005
Phase Ia
(single dose)
~10 prototypes,
healthy
volunteers
Q1–Q3 2006
Phase Ib: ERVIR
multiple dose PK (to
steady state), NVP IRpretreated HIV patients
switched to XR
Q4 2006–Q2 2007
Phase III, VERXVE
48-wk final NVP XR formulation vs NVP IR (bid)
Q4 2007–Q3 2009
Phase III, TRANXITION
48-wk transition study from NVP IR to XR
Q4 2008–Q3 2010
Nevirapine is not currently indicated for qd dosing in Europe.
Efficacy and safety of nevirapine
extended-release once daily versus
nevirapine immediate-release twice daily
in treatment-naïve HIV-1 infected patients
J Gathe, J Andrade-Villaneuva, S Santiago et al.
Antivir Ther 2011;16: in press
VERXVE: Objectives And Study Design
• Objective:
– To evaluate the efficacy and safety of NVP XR 400 mg qd
vs NVP IR 200 mg bid, in ARV treatment-naïve,
HIV–1-infected patients
• Study design:
– 48 week, double-blind, double-dummy, non-inferiority study
• Subjects:
– NVP eligible adult subjects with CD4/mm3 counts of 50–400 for
men and 50–250 for women
– Baseline viral load (VL) stratification (≤100,000 vs
>100,000 copies/mL)
Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)
Nevirapine is not currently indicated for qd dosing in Europe.
VERXVE Study Schema
Screening
Eligible patient
NVP IR 200 mg qd +
TDF/FTC for 14 days
Randomisation
Group A (n=505)
400 mg qd
NVP XR + TDF/FTC
Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)
Group B (n=506)
200 mg bid
NVP IR + TDF/FTC
Nevirapine is not currently indicated for qd dosing in Europe.
VERXVE: Study Endpoints
• Primary endpoint:
– Sustained virologic response at 48 weeks – defined as VL
<50 copies/mL prior to and at week 48, without virologic
rebound or change of ARV therapy
• Secondary endpoints:
– Time-to-loss of virologic response (TLOVR)
– Time to new AIDS or AIDS-related progression event or
death
– AEs, SAEs, AEs leading to discontinuation; laboratory
parameters
– PK parameters – NVP plasma trough concentrations
– Genotypic resistance associated with virologic failure
Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)
Nevirapine is not currently indicated for qd dosing in Europe.
VERXVE:
Virologic Response at Week 48
Proportion of Virologic Responders
(FAS; %)
100
AD 4.9%
95% CI: −0.1%, 10.0%
90
80
76
AD 2.3%
95% CI: −6.6%, 11.1%
AD 6.6%
95% CI: 0.7%, 12.6%
86
81
79
71
73
70
60
50
NVP IR
NVP XR
40
30
FAS: full analysis set
AD: adjusted difference
20
10
n=506 n=505
n=203 n=194
n=303 n=311
Total
Baseline HIV-RNA
>100,000 c/mL
Baseline HIV-RNA
<100,000 c/mL
0
Virologic response was independent of age, gender, race or geographic region
Mean CD4+ increase from baseline at Week 48: NVP IR 181 cells/mm3; NVP XR 192 cells/mm3
Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)
Nevirapine is not currently indicated for qd dosing in Europe.
VERXVE: Multiple Dose Trough Concentrations NVP
IR and NVP XR
Geometric Mean, µg/mL
Mean dose trough NVP (µg/mL)
6
NVP IR (4.11 µg/mL)
NVP XR (3.35 µg/mL)
5
(~38-fold
higher)
4
3
2
10th percentile trough concentration for Viramune XR
1
IC90 for wild type HIV-1 virus*
0
4
6
*IC90 for wild type virus = 100 ng/mL
Boehringer Ingelheim: Data on file
8
12
16
Weeks
24
32
40
48
Nevirapine is not currently indicated for qd dosing in Europe.
Selected AEs Of Interest During The
Randomisation Phase (Post-NVP IR Lead-In)
NVP IR, n (%)
NVP XR, n (%)
Treatment-related rash
(all grades)
25 (4.9)
29 (5.7)
Grade 3 rash
3 (0.6)
3 (0.6)
Stevens Johnson
Syndrome
3 (0.6)*
0 (0.0)
46 (9.1)
28 (5.5)
22 (4.3)
14 (2.8)
Any hepatic event
Symptomatic hepatic
events
*2 grade 3 and 1 grade 4 cases. No instances of SJS or grade 4 rash in the nevirapine XR group
Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)
Nevirapine is not currently indicated for qd dosing in Europe.
VERXVE: Conclusions
• The VERXVE pivotal trial demonstrated:
– Non-inferior efficacy for NVP XR compared with
NVP IR independent of baseline viral load, age, race,
gender, region, HIV-1 subtype or CDC class
– No new AEs identified, reflecting similar safety and
tolerability profiles for both formulations
Gathe et al. Antivir Ther 2011;16: in press (doi:10.3851/IMP1803)
Nevirapine is not currently indicated for qd dosing in Europe.
Nevirapine XR:
Overview Of Clinical Development
Colonic
absorption
Q2–Q4 2005
Phase Ia
(single dose)
~10 prototypes,
healthy
volunteers
Q1–Q3 2006
Phase Ib: ERVIR
multiple-dose PK (to
steady state), NVP IRpretreated HIV patients
switched to XR
Q4 2006–Q2 2007
Phase III, VERXVE
48-wk final XR formulation vs NVP IR (bid)
Q4 2007–Q3 2009
Phase III, TRANXITION
48-wk transition study from NVP IR to XR
Q4 2008–Q3 2010
Nevirapine is not currently indicated for qd dosing in Europe.
TRANXITION: Objectives And Study Design
 Objectives:
 To assess the efficacy, safety and tolerability of switching HIV-1
infected patients from NVP IR to XR vs continued NVP IR
 Study design:
 Open-label, randomised, parallel group study
 Subjects:
 Adults with HIV RNA <50 copies/mL
 Randomised 2:1 to NVP XR 400 mg qd vs NVP IR 200 mg bid
 n=200 vs 100 patients
 Stratified by background therapy and CD4+ count
 Patients remain on previous background therapy
 Treatment duration: 48 weeks
Nevirapine is not currently indicated for qd dosing in Europe.
Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster
TRANXITION Study Schema
NVP IR 200 mg bid
regimen ≥18 wks
HIV-RNA <50 copies/mL
Randomisation (2:1)
NVP XR 400 mg qd
+ background ARV
Continued
NVP IR 200 mg bid
+ background ARV
Nevirapine is not currently indicated for qd dosing in Europe.
Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster
TRANXITION: Endpoints
 Primary endpoint: sustained treatment response at
24 weeks
 Sustained treatment response: viral load <50 copies/mL for
two consecutive visits prior to Week 24
 Secondary endpoints:
 Virologic response after 48 weeks of treatment
 Proportion of patients with viral load <50 copies/mL
at each visit
 Change in CD4+ cell count from baseline at each visit
 Genotypic resistance associated with virologic failure
 Incidence of AIDS progression or death
Nevirapine is not currently indicated for qd dosing in Europe.
Arasteh et al. JIAS 2010;13(Suppl 1):abstract P45 and poster
Conclusions: Nevirapine Tomorrow
 It remains important for health care professionals to
have as many evidence-based treatment options for
the millions of HIV infected patients worldwide
 Once-daily regimens may make it easier for patients
to accept and adhere to therapy
 Nevirapine XR qd provides the potential for:
 Dosing symmetry with preferred combination
nucleoside analogues
 A more convenient treatment regimen for patients
compared with bid dosing
Nevirapine is not currently indicated for qd dosing in Europe.
Defining success in
HIV treatment:
should we broaden the
parameters?
Vicente Soriano
Infectious Diseases Department
Hospital Carlos III
Madrid, Spain
Disclosures
 Received funding and/or honoraria from most major
pharmaceutical companies working in virology
Background
 Although NNRTIs as a class have been available
for over 15 years, new data continue to emerge on
older (NVP and EFV) as well as newer agents (ETV)
 Although current ARV regimens allow suppression
of viral load (HIV-RNA <50 copies/mL) in most
adherent individuals, there is still room to
improve efficacy
– Consideration of new parameters may help in this task
New parameters of interest
 What is the potential significance of ultra-sensitive
viral load measurement?
 What is the clinical value of baseline tropism
assessment?
 What is the clinical relevance of Vitamin D levels in
HIV-infected patients?
New parameters of interest
 What is the potential significance of ultra-sensitive
viral load measurement?
 What is the clinical value of baseline tropism
assessment?
 What is the clinical relevance of Vitamin D levels in
HIV-infected patients?
Ultra-sensitive VL measurement
 Residual HIV replication is a major obstacle for HIV eradication
using ARV drugs
 Low-level HIV replication may contribute to systemic
inflammation and drives organ dysfunction in the
long-term
 Selection of drug resistance has been described in patients with
undetectable plasma viremia but low-level replication in other
compartments
 Encephalitis and meningoencephalitis have been reported in
patients treated with ARVs with low CNS penetration
 NVP was the only independent
predictor of VL <2.5 copies/mL
 NVP shows a greater penetration
into extravascular compartments
% patients
 154 HIV-infected patients on
ARV therapy with plasma
HIV-RNA <50 copies/mL
(average: 29 months)
 Mean nadir CD4 count
270 cells/µL
Plasma HIV-RNA
<2.5 copies/mL
AIDS 2011; 25: 341-344

165 pts with plasma HIV-RNA
<50 c/mL for >6 months on
TDF/FTC + NVP or EFV
HIV-RNA 1–49 c/mL was
independently associated with:
– EFV vs NVP (OR 2.9; p=0.005)
– Shorter length of viral
suppression (OR 2.3; p=0.004)

Good penetration of NVP in
anatomic compartments could
explain greater control of viral
replication
Plasma HIV-RNA <1 cop/mL
% patients

p<0.001
Two patients with undetectable plasma viremia on atazanavir/r developed
encephalitis with detectable viremia in CSF and drug-resistant viruses
Three patients with undetectable plasma viremia using ARVs with
low CNS penetration (TDF, NFV, LPV/r) developed meningo-encephalitis
Sanctuary site
penetration-effectiveness ranks
CNS 1*
NRTIs
4
ZDV
3
ABC
FTC
2
ddI
3TC
d4T
NNRTIs
NVP
ETR
PIs
IDV/r
DLV
EFV
DRV/r
fAPV/r
IDV
LPV/r
Entry/
Fusion
inhibitors
MVC
Integrase
inhibitors
RAL
ATZ
ATZ/r
fAPV
1
TDF
Genital tract 2
1 (>50%)
0.5 (10–50%)
TDF
ZDV
ABC
FTC
3TC
ddI
NVP
NFV
RTV
SQV
SQV/r
TPV/r
IDV/r
T-20
MVC
APV/r
ATZ/r
DRV/r
RAL
*Rank: 4 (much above average) to 1 (below average)
1. Letendre et al. 17th CROI 2010; abstract 172; 2. Lambert-Niclot et al. J Med Virol 2011;83:1391–1394
0 (<10%)
EFV
ETR
NFV
RTV
LPV/r
T-20
New parameters of interest
 What is the potential significance of ultra-sensitive
viral load measurement?
 What is the clinical value of baseline tropism
assessment?
 What is the clinical relevance of Vitamin D levels in
HIV-infected patients?
The ARTEN study
Soriano et al. Antivir Ther 2011;16:339-48.
100
Patients achieving
treatment response (%)
Key data
 569 ARV-naive HIV individuals
 Non-inferiority of NVP vs ATV/r
 Similar CD4 gain with NVP
and ATV/r
 The combination of NVP +
TDF/FTC was effective
 Use of CD4 thresholds for NVP
initiation was associated with
manageable side effects
 Better lipid profile following
NVP than ATV/r
Treatment response by primary
endpoint (ITT)
(HIV-RNA <50 copies/mL at
2 visits prior Wk 48)
95% CI= -5.9% to 9.8%;
p=0.63
80
67
65
NVP
qd + bid
ATZ/r
60
40
20
0
Nevirapine is not currently indicated for qd dosing in Europe
Tropism sub-study in ARTEN
ARTEN
Main characteristics of the tropism sub-study
population
Treatment arm
HIV tropism
ATV/r
NVP
P
R5
X4
P
N
146
282
–
336
55
–
Male, %
84.2
87.6
>0.1
88.4
85.5
>0.1
Non-B subtypes, %
21.9
22.7
>0.1
20.8
10.9
0.099
HCV coinfection, %
11.0
10.3
>0.1
11.0
9.1
>0.1
5.19
(4.71–5.61)
5.17
(4.73–5.59)
>0.1
5.16
(4.67–5.59)
180
184
>0.1
188
Median baseline plasma
HIV RNA level,
log copies/mL (IQR)
Median baseline CD4,
cells/µL (IQR)
Seclen et al. J Infect Dis 2011;204:139–144
5.38
0.044
(5.03–5.69)
145
<0.001
ARTEN
Virologic and immunologic outcomes
HIV tropism
Endpoint, week
Treatment arm
R5
X4
P
ATV/r
NVP
P
24
116
(56–197)
117
(66–172)
>0.1
116
(72–204)
111
(45–189)
>0.1
48
156
(83–244)
180
(86–235)
>0.1
180
(99–251)
152
(78–230)
0.037
24
83.2
60.9
0.001
77.2
82.1
>0.1
48
91.6
76.9
0.009
88.5
92.0
>0.1
Median CD4,
cells/µL (IQR)
HIV RNA <50 copies/mL
(% patients)
Seclen et al. J Infect Dis 2011;204:139–144
ARTEN
Predictors of VL response and CD4 recovery
β Coefficient (95% CI)
P
-
>0.1
-14.73 (-27.50 to -1.96)
0.024
Baseline viral load
33.74 (14.44–53.04)
0.001
Viral tropism (R5)
-
>0.1
Treatment arm (ATV/r)
35.05 (7.82–62.27)
0.012
Baseline viral load
47.86 (27.14–68.58)
<0.001
End-point, covariable
CD4 count, cells/µL
Week 24
Viral tropism (R5)
Baseline CD4 cell count
Week 48
Viral load of <50 copies/mL
Week 24
Week 48
Seclen et al. J Infect Dis 2011;204:139–144
OR (95% CI)
Baseline CD4 cell count
1.40 (0.99–1.96)
0.055
Viral tropism (R5)
2.62 (1.24–5.52)
0.012
Baseline viral load
0.19 (0.10–0.36)
<0.001
Viral tropism (R5)
2.43 (0.96–6.16)
0.061
Viral subtype
(non-B subtypes)
0.43 (0.18–1.01)
0.054
Baseline CD4 cell count
1.68 (1.04–2.72)
0.035
Baseline viral load
0.41 (0.20–0.84)
0.014
ARTEN
Predictors of VL response and CD4 recovery in HIV
clade B viruses (n=315)
β Coefficient (95% CI)
P
-
>0.1
-18.34 (-32.14 to -4.53)
0.009
Baseline viral load
36.68 (14.54–58.83)
0.001
Viral tropism (R5)
-
>0.1
Treatment arm (ATV/r)
32.24 (1.33–63.15)
0.041
Baseline viral load
55.55 (31.30–79.81)
<0.001
End-point, covariable
CD4 cell count, cells/µL
Week 24
Viral tropism (R5)
Baseline CD4 cell count
Week 48
Viral load of <50 copies/mL
Week 24
Week 48
Seclen et al. J Infect Dis 2011;204:139–144
OR (95% CI)
Viral tropism (R5)
3.50 (1.61–7.64)
0.002
Baseline viral load
0.17 (0.08–0.34)
<0.001
Viral tropism (R5)
4.02 (1.48–10.96)
0.007
Baseline viral load
0.22 (0.09–0.56)
0.001
HIV tropism in ARTEN
Summary
 In ARV-naive patients beginning ART, baseline
HIV-1 tropism is an independent predictor of viral
load response
 Baseline tropism testing should be considered along
with viral load, CD4 count and resistance testing in
all newly diagnosed HIV individuals
 Potential implications for interpretation of clinical
trials comparing drug regimens
New parameters of interest
 What is the potential significance of ultra-sensitive
viral load measurement?
 What is the clinical value of baseline tropism
assessment?
 What is the clinical relevance of Vitamin D levels in
HIV-infected patients?
Vitamin D metabolism
Vit D2 (ergocalciferol)
Vit D3 (cholecalciferol)
7-dehydro-D
Vit D
Vit D3
Skin
Small intestine
Liver
25(OH)D
(calcidiol)
1,25(OH)2D3
(calcitriol)
Kidney
 Screening for Vit D deficiency is recommended only in
patients at risk
 Measurement of serum 25(OH)D is the best parameter to
evaluate Vit D status
 Vit D deficiency definition:
– Serum 25(OH)D <20 ng/mL (50 nmol/L)
 Oral treatment with Vit D2 or D3 supplements (up to
10,000 IU/day) should be considered for individuals with
serum 25(OH)D deficiency
 Intake of 1500–2000 IU/day Vit D are required to keep
serum 25(OH)D >30 ng/mL
Diseases associated with Vitamin D
deficiency




Type 2 diabetes mellitus
Cardiovascular disease
Chronic hepatitis C
HIV infection
Vitamin D levels in HIV-infected adults
in NYC
80
69
70
60
% patients
 274 HIV-infected adults
 25(OH)D levels by RIA
 Multivariate analysis for
Vit D deficiency:
 Black race:
OR 4.1; p=0.007
 Detectable HIV-RNA:
OR 2.4, p=0.024
50
40
30
21
20
10
10
0
Deficiency
(<25)
Insufficiency Optimal (>75)
(25-74)
25(OH)D (nmol/L)
Kim et al. ARHR (in press)
Determinants of Vitamin D insufficiency




Reduced milk consumption
Decreased sun exposure (sunscreen use)
Obesity
Others: fat malabsorption syndromes, nephrotic
syndrome, primary hyperparathyroidism,
anticonvulsants, ARV drugs (efavirenz,
tenofovir, PI/r)
Holick M et al. J Clin Endocrin Metab 2011 (in press)
Gharakhanian & Kotler. AIDS 2011; 25: 531-3.
Exposure to EFV but not NVP associated
with severe Vitamin D deficiency
Risk factors for severe vitamin D deficiency
[25(OH)D <10µg/L; <25 nmol/L]
in 843 HIV-infected patients on cART
Risk factor
Univariate analysis
Multivariate analysis
OR (95% CI)
P
OR (95% CI)
P
Black ethnicity
2.7 (2.0–3.7)
<0.001
2.7 (2.0–3.7)
<0.001
Female sex
1.4 (1.04–1.8)
0.03
1.1 (0.8–1.5)
NS
Winter season
2.2 (1.6–2.9)
<0.001
2.1 (1.6–2.9)
<0.001
CD4 nadir <200 cells/µL
1.5 (1.1–2.0)
0.01
1.4 (1.0–1.9)
0.05
Current EFV use
1.9 (1.4–2.5)
<0.001
2.0 (1.5–2.7)
<0.001
Current NVP use
0.7 (0.6–1.0)
0.06
0.6 (2.3–4.1)
NS
Current PI use
0.7 (0.5–0.9)
0.01
0.9 (0.6–1.3)
NS
Current TDF use
0.8 (0.6–1.0)
<0.1
0.8 (0.6–1.1)
NS
2
Welz et al. AIDS 2010;24:1923–1928
SUN study
 70% prevalence of Vit D insufficiency/deficiency (<30 ng/ml) in
a cohort of 672 HIV+ patients in the US
 Comparison: 79% in US adults from the NHANES database
 Predictors of Vit D insufficiency/deficiency:
–
–
–
–
Non-Caucasian race
High BMI
Decreased UV exposure
Efavirenz
 Efavirenz reduces 5
̴ ng/mL 25(OH)D by inducing
24-hydroxylase, that catabolizes 25(OH)D and 1,25(OH)D
Dao et al. Clin Infect Dis2011; 52: 395-404
Vit D deficiency & HIV infection
Summary
 The prevalence of Vit D deficiency/insufficiency is
high in HIV+ subjects in the US and West Europe
( 7
̴ 0%)
 Besides classical predictors of low Vit D levels, as
reduced sun exposure, obesity and black race, the
use of efavirenz is a consistent risk factor for Vit D
deficiency
 The long-term consequences of low Vit D levels
must be assessed, including effects on the immune
system and skeletal fragility
Defining success in
HIV treatment:
should we broaden the parameters?
Discussion and debate
Defining the benefits of
NNRTI treatment
New data, new parameters