The ARTEN study: 48 week efficacy data stratified by
screening viral load and CD4+ cell count
Reported by Jules Levin
EACS Nov 13 2009 Cologne Germany
Vicente Soriano1, Siegfried Koppe2, Horacio Mingrone3, Thomas Lutz4, Milos Opravil5, Jaime Andrade-Villanueva6, Francisco Antunes7,
Giovanni Di Perri8, Daniel Podzamczer9, Stephen Taylor10, Andrzej Horban11, Dan Duiculescu12, Holger Gellermann13 and Lothar de Rossi14
1Department of Infectious Diseases, Hospital Carlos III, Madrid, Spain; 2Epimed GmbH, Berlin, Germany; 3Infectología de Asistencia Ambulatoria, Ciudad de Buenos Aires, Argentina; 4Infektiologicum Frankfurt, Frankfurt, Germany; 5Division of Infectious Diseases, University
Hospital Zurich, Zurich, Switzerland; 6Antiguo Hospital Civil de Guadalajara, Guadalajara, Mexico; 7Servico de Doenças Infecciosas, Hospital de Santa Maria, Lisbon, Portugal; 8Clinical Department of Infectious Diseases, University Hospital Amedeo di Savoia, Turin, Italy;
9Infectious Disease Service, Hospital Universitario de Bellvitge, Barcelona, Spain; 10HIV Service, Directorate of Infection, Birmingham Heartlands Hospital, Birmingham, UK; 11AIDS Diagnosis and Therapy Centre, Hospital for Infectious Diseases,Warsaw, Poland; 12Hospital for
Tropical and Infectious Diseases, Bucharest, Romania; 13Boehringer Ingelheim, Medical Affairs Virology, Ingelheim, Germany; 14Boehringer Ingelheim, Clinical Research Department Virology, Biberach, Germany
Objectives: In the ARTEN trial, nevirapine (NVP) showed a similar efficacy to ritonavirboosted
atazanavir (ATZ/r), with a more favourable lipid profile in drug-naïve, HIVinfected
patients after 48 weeks of therapy. The subanalysis presented here examines
the efficacy and safety stratified by screening viral load (VL) and CD4+ cell count.
Methods: Randomised, prospective study of once-daily ATV/r vs NVP (once-daily or twicedaily), both with co-formulated tenofovir/emtricitabine in 569 treatment-naive patients. Confirmed virological response (TLOVR-algorithm) at Week 48, stratified by screening VL (≤100,000 or >100,000 copies/mL) and screening CD4+ count (<50 or ≥50 cells/mm3), was determined.
Rash was themost frequent AE leading to NVP discontinuation. Overall, 19/376 patients in the NVP arms discontinued prematurely due to rash compared to no patients receiving ATZ/r.
Conclusions: In patients with HIV-RNA >100,000 copies/mL and in those with CD4+ counts ≥50 cells/mm3, NVP and ATZ/r display comparable efficacy. However, the number of subjects with CD4+ counts <50 cells/mm3 is too small to draw any conclusion. The lower response to NVP vs ATZ/r seen in patients with VL ≤100,000 copies/mL was mainly driven by discontinuations due to AEs.
The ARTEN trial compared the virologic efficacy and safety of nevirapine (NVP) and ritonavir-boosted atazanavir (ATZ/r) both in combination with tenofovir DF and emtricitabine (TDF/FTC); NVP showed a similar efficacy to ATZ/r with a more favourable lipid profile after 48 weeks1
This subanalysis presents efficacy and safety of NVP, compared with ATZ/r stratified by screening VL (≤100,000 or >100,000 copies/mL) and CD4+ cell count (<50 or ≥50 cells/mm3)
ARTEN is an open-label, randomised, international, non-inferiority clinical trial comparing the efficacy and safety of NVP versus ATZ/r in a total of 569 ARV-naïve patients with HIV-1-infection. It is the first prospective clinical trial to apply the CD4+ cell count thresholds, of ≤250 cells/mm3 in women and ≤400 cells/mm3 in men, to the administration of NVP.2-5
The ARTEN study included one arm with patients treated with NVP once-daily dosing.
However, NVP is not indicated for once-daily dosing and the efficacy and safety of NVP
once-daily have not yet been established.
The primary efficacy data and results of the sensitivity analysis of the ARTEN study on
confirmed virological response (TLOVR algorithmand primary endpoint) atWeek 48, stratified by screening VL (≤100,000 or >100,000 copies/mL) and screening CD4+ count (<50 or ≥50 cells/mm3) are reported here.
Key inclusion criteria:
· HIV-1-infected patients aged ≥18 years
· Adequate renal function (creatinine clearance ≥50 mL/min)
· Not previously treated with ARVs for >7 days
· CD4+ cell counts <400 cells/mm3 or <250 cells/mm3 for male and female patients,
Key exclusion criteria:
· Hepatic cirrhosis stage Child-Pugh B or C
· DAIDS grade >2 laboratory parameters (DAIDS grade >3 triglycerides)
· Active hepatitis B or C, defined as HBsAg-positive or HCV-RNA positive
with AST/ALT >2.5x ULN (DAIDS grade 1)
Patients were randomised (1:1:1) to receive i) NVP 200 mg BID, ii) NVP 400 mg QD or iii) ATZ 300mg QD plus RTV 100mg QD (ATZ/r), in combination with fixed-dose FTC 200mg QD/TDF 300 mg QD. Randomisation was stratified according to high (>100,000 copies/mL) or low (≤100,000 copies/mL) HIV-1 RNA and high (≥50 cells/mm3) or low (<50 cells/mm3) CD4+ cell count at screening. During the first 14 days of the study both NVP BID and NVP QD dose groups started out with a lead-in dose of NVP 200 mg QD according to the product label.
Primary endpoint at Week 48:
Treatment response (TR) was defined as the proportion of patients with HIV-1 RNA <50 copies/mL measured at two consecutive visits (e.g.Weeks 24 and 36) prior to Week 48 and without subsequent rebound or change of ARV therapy prior to or at Week 48
Secondary endpoints at Week 48 included:
A sensitivity analysis: a time to loss of virologic response (TLOVR) algorithm was applied, which defined TR as the proportion of patients with HIV-RNA <50 copies/mL at two consecutive visits (e.g.Weeks 36 and 48) up toWeek 48 and without subsequent rebound or change of ARV therapy prior to or at Week 48
Safety endpoints included the incidence of adverse events (AEs), serious adverse events
(SAEs) and discontinuations due to AEs.
The statistical analysis of efficacy and safety was performed on all randomised patients receiving at least one dose of study medication. For the primary efficacy analysis, an intention-to-treat, non-completers considered failures (ITT-NCF) analysis was performed. The primary analysis was the test of non-inferiority of the combined NVP arms compared to ATZ/r. The non-inferiority test was performed by calculating the two-sided 95% confidence interval (CI) for the difference in the proportions of responders between the combined NVP groups and ATZ/r. Non-inferiority of NVP was established if -12% was excluded from the CI.
A Cochran-Mantel-Haenszel test controlling for screening VL and CD4+ cell count categories was performed.
Demographic data and HIV baseline characteristics
A total of 576 patients were enrolled and randomised to treatment; 569 received study medication (70.8% inWestern Europe, 21.4% in Latin America and 7.7% in Eastern Europe). The proportion of patients with baseline HIV-1 RNA >100,000 copies/mL was >62% in all treatments groups.
By Week 48, 43/188 (22.9%) patients treated with NVP QD, 56/188 (29.8%) patients treated with NVP BID and 18/193 (9.3%) patients treated with ATZ/r discontinued their study medication. Patient disposition is presented in Figure 2.
Primary efficacy results
Non-inferiority of NVP vs. ATZ/r was established in the primary analysis (lower limit of the CI was above the pre-defined -12% non-inferiority margin at Week 48), and was confirmed by the sensitivity analysis (TLOVR algorithm) (Figure 3). Among the observed cases on-treatment atWeek 48, 92.7% of patients in the combined NVP armand 86.3% of patients in the ATZ/r group had a VL <50 copies/mL (95%CI for difference -0.0 to 11.6).
Efficacy results stratified by VL
When the primary endpoint data was stratified by viral load, TR was comparable between the combined NVP arm and the ATZ/r arm in patients with screening HIV-1 RNA ≤100,000 copies/mL and in those with screening HIV-1 RNA >100,000 copies/mL (Figure 4).
At Week 48, a comparable proportion of patients achieved and maintained a TR (TLOVR algorithm, ITT-NCF analysis) in the combined NVP group compared with the ATZ/r group (70.2% vs 73.6%). Patients with screening HIV-1 RNA >100,000 copies/mL generally had lower treatment response rates than patients with screening HIV-1 RNA ≤100,000 copies/mL (Figure 5). In patients with screening HIV-1 RNA >100,000 copies/mL, numerically higher TR rates were observed with NVP than ATZ/r. However, in patients with screening HIV-1
RNA ≤100,000 copies/mL, ATZ/r TR rates were numerically higher compared to NVP. The lower response to NVP (78.1%) compared with ATZ/r (91%) seen in patients with VL ≤100,000 copies/mL was mainly a result of the higher number of discontinuations up to Week 48 due to AEs in this group (13.7% vs 1.3%).
Efficacy results stratified by CD4+ cell count
At Week 48, a comparable proportion of patients with screening CD4+ cell counts
≥50 cells/mm3 had a TR in both the combined NVP group and ATZ/r group (73% and 74.9%, respectively). Among those patients with screening CD4+ cell counts of <50 cells/mm3, a TR was observed in 38.7% of patients in the combined NVP arm and 57.1% of patients in the ATZ/r group. However, the number of subjects with CD4+ counts <50 cells/mm3 was too small to draw any conclusions (Table 1).
Overall, AE rates were similar between groups (85.9% among NVP patients and 86.5% among ATZ/r patients) (Figure 6). However, despite similar AE rates, the incidence of AE-related treatment discontinuations was lower with ATZ/r than with combined NVP in both patients with screening VL ≤100 000 copies/mL and in patients with screening VL >100 000 copies/mL. The number of treatment-related AEs was lower in the combined NVP arm compared with the ATZ/r arm (Figure 6).
Rash was reported in 16.0% of combined NVP and 12.4% of ATZ/r patients. Grade 3 rash was reported in only 1.6% of combined NVP patients and 0% of ATZ/r patients and no Grade 4 rash was reported for either group. However, rash was the most frequent cause of treatment discontinuation among patients in the combined NVP arm. More NVP patients were discontinued due to rash compared with ATZ/r (5.1% vs. 0%).
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