Comparison of 48 week efficacy and safety of 400mg QD
nevirapine (NVP) extended release formulation (Viramune XR)
versus 200mg BID nevirapine immediate release formulation
(Viramune IR) in combination with emtricitabine/tenofovir in
antiretroviral (ARV) naïve HIV-1 infected patients (VERxVE)
J. Gathe, JR. Bogner, S. Santiago, A. Horban, M. Nelson, P.
Cahn, J. Andrade, D. Spencer, C. Yong, T. Nguyen, W. Zhang, M.
Drulak and A. Quinson*
*Boehringer Ingelheim Pharmaceuticals Inc, Ridgefield, CT, USA
VERX VE: Rationale for Viramune Extended Release (XR)
Formulation
 Viramune 200mg immediate release (IR) is a well established component of effective antiretroviral therapy in
HIV-1 infected patients
 Viramune 200mg IR plus emtricitabine/tenofovir (FTC/TDF) recently demonstrated similar efficacy to
atazanavir/ritonavir plus FTC/TDF, with a more favourable lipid profile1
 Viramune extended release formulation (Viramune XR) may increase therapeutic benefit by improving
compliance through once-daily
(QD) dosing
1. Soriano V. et al. 2010 Manuscript submitted
VERX VE: Objectives and Study Design
Objective:
 To evaluate the efficacy of Viramune XR 400 mg QD vs Viramune IR 200 mg BID, in ARV treatmentnaïve, HIV–1-infected patients after 48 weeks of treatment
Study design:
• Double-blind, double-dummy, non-inferiority study
• 1:1 randomization to Viramune XR or Viramune IR after 14-day Viramune IR lead-in 200 mg QD dose
(given to all patients)
• Emtricitabine/tenofovir (FTC/TDF) fixed-dose background
ARV treatment
• Baseline viral load (VL) stratification
(≤100,000 vs >100,000 copies/mL)
VERX VE: 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
 Genotypic resistance associated with virologic failure
 AEs, SAEs, AEs leading to discontinuation; laboratory parameters
VERX VE: Demographic Data
Parameter
Viramune IR
Viramune XR
508
505
Male, n
433
431
Female, n
75
74
38.0
38.3
North America/Australia
150
141
Europe
252
257
Latin America
49
58
Africa
57
49
Baseline HIV-1 viral load, median log10 copies/mL
4.7
4.7
CD4+ cell count, mean cells/mm3
227
229
History of AIDS (%)
26
30
Number of patients, N
Gender
Age, mean
Region
Note: Total randomized=1068, 1011=randomized & treated (full analysis set, FAS), 2 randomized not
treated, 55 DC during lead-in
VERX VE: Disposition of Randomized Patients Through Week
48
Parameter
Viramune IR
Viramune XR
Total
508
505
1013
Treated with blinded dose, n (%)
506 (100.0)
505 (100.0)
1011 (100)
Completed Week 48 visit, n (%)
409 (80.1)
421 (83.4)
830 (82.1)
Prematurely discont. prior to Week 48 visit, n (%)
97 (19.2)
84 (16.6)
181 (17.9)
Death/events leading to death*
3 (0.6)
1 (0.2)
4 (0.4)
Adverse events
42 (8.3)
32 (6.3)
74 (7.3)
Lost to follow-up
7 (1.4)
8 (1.6)
15 (1.5)
Consent withdrawn
9 (1.8)
4 (0.8)
13 (1.3)
Non-adherence
9 (1.8)
6 (1.2)
15 (1.5)
Lack of efficacy
26 (5.1)
24 (4.8)
50 (4.9)
Pregnancy
0 (0.0)
6 (1.2)
6 (0.6)
Other
1 (0.2)
3 (0.6)
4 (0.4)
Randomized, N
Reasons for discont., n (%)
*None of the deaths/events were related to study medication, as judged by the investigators
VERX VE: Sustained Virologic Response at Week 48 (VL <50 copies/mL, FAS)
Proportion of patients with Virologic Response Week 48
Viramune IR
100
90
80
70
60
50
40
30
20
10
0
Viramune XR
80.99
75.89
Viramune IR: 75.89% (384/506)
Viramune XR: 80.99% (409/505)
Adjusted difference
4.92% in favour of Viramune XR, with 95% CI of (−0.11, 9.96)
Viramune XR shows non-inferiority to Viramune IR within
pre-specified margin of −10%
Virologic response was independent of age, gender, race or geographic region
FAS = Full analysis set
VERX VE: Proportion with Virologic Response by Visit (VL <50
copies/mL, FAS)
Proportion of Virologic Responders
100.00
80.00
60.00
40.00
Viramune IR
Viramune XR
20.00
0.00
0 2 4 6 8
FAS = Full analysis set
12
16
Weeks
24
32
40
48
VERX VE: PK Sub-study at Day 28
•
Designated trial centres participated in a pharmacokinetic sub-study, involving ~25 patients from each
treatment arm
•
Blood samples collected intensively for 24 hr following morning NVP administration in week 4 (visit 4): day
28
•
Plasma NVP levels measured by tandem mass spectrometry (LC-MS/MS)
•
Arithmetic mean (±SD) plasma concentration of NVP following 400mg QD and 200mg BID dosing
determined
VERX VE: PK Sub-study at Day 28: Results
200mg Viramune IR BID (N=25)
400mg Viramune XR QD (N=24)
Viramune Plasma (ng/mL)
7000
6000
5000
4000
3000
2000
0
4
8
12
Time [hours]
16
20
24
VERX VE: PK-PD Response Week 48 (FAS): Viramune XR Equivalent to Viramune IR at
≥1000ng/mL
Virologic response rates stratified by geometric mean steady state
(ss) trough plasma concentrations (ng/mL)
Parameter
Viramune IR
Viramune XR
Total number of patients, n/N
372/464 (80.2)
406/486 (83.5)
Geometric mean, trough ss (ng/mL),
<1000
No. Responders/Total within stratum (n/N)
3/5 (60.0)
3/9 (33.3)
1000–<2000
25/31 (80.6)
46/54 (85.2)
2000–<3000
50/66 (75.8)
116/144 (86.6)
3000–<4000
108/125 (86.4)
127/147 (86.4)
≥4000
186/237 (78.5)
114/142 (80.3)
LLOQ (lower limit of quantification) = 50 copies/mL
FAS = Full analysis set
VERX VE: Percentage Change in Lipid Profile Viramune IR vs Viramune XR at
Week 48
Change in median value from baseline at Week 48 (%)
Substrate
Viramune IR
Viramune XR
[mg/dL]
(N=406)
(N=419)
Triglycerides
-8 (–9%)
-6 (–7%)
Cholesterol
22 (13%)
19 (11%)
LDL-c
8 (9%)
7 (7%)
HDL-c
12 (32%)
10 (27%)
-14%
-12%
Total cholesterol/HDL-c
Viramune XR demonstrated a similar lipid profile to that of Viramune IR
VERX VE: AE Summary Randomized Phase, FAS
Parameter
Viramune IR
Viramune XR
506
505
452 (89.3)
443 (87.7)
AEs leading to discontinuation, n (%)
45 (8.9)
32 (6.3)
Serious AEs, n (%)
54 (10.7)
58 (11.5)
5 (1.0)
1 (0.2)
Drug-related* AEs
123 (24.3)
100 (19.8)
DAIDS Grade 3 or 4 AEs
91 (18.0)
73 (14.5)
DAIDS Grade 4 AEs
23 (4.5)
16 (3.2)
Number of patients (N)
Any AE, n (%)
Deaths
*Investigator defined. Please note: No drug-related fatalities. Atherosclerosis/hypertension; tuberculosis (meningitis); two sepsis, myocardial
infarction; respiratory alkalosis.
FAS = Full analysis set
VERX VE: Conclusions
 Pivotal Trial (VERXVE) demonstrated:
 Non-inferior efficacy for Viramune XR to Viramune IR
 Similar safety and tolerability profiles for both formulations
 The combination of Viramune IR or Viramune XR with FTC/TDF is an effective ARV treatment
 PK – PD:
 Similar efficacy noted across many PK strata indicating adequate trough drug exposure for Viramune XR
 Consistent relative trough exposure of Viramune XR to IR across gender, region, and baseline viral-load
strata
 Once-daily dosing with VIRAMUNE XR provides patients with a more convenient treatment regimen with
comparable efficacy and safety to VIRAMUNE IR
VERX VE: Acknowledgments
We would like to thank all the patients and investigators for their involvement
and
dedicated support in this trial