icon-folder.gif   Conference Reports for NATAP  
  50th ICAAC
Boston, MA
September 12-15, 2010
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24 Wk Efficacy and Safety of Transitioning Virologically Stable HIV-1 Patients from IR Nevirapine 200 mg BID to Nevirapine XR 400 mg QD (TRANxITION)
  Reported by Jules Levin
ICAAC Boston Sept 13 2010
K. ARASTEH1, D. WARD2, A. PLETTENBERG3, JM. LIVROZET4, A. WINSTON5, C. CORDES6, E. WANG7, A. QUINSON7 1 EPIMED c/o Vivantes Auguste-Viktoria-Klinikum, Berlin, GER; 2Dupont Circle Physicians Group, Washington DC, US; 3Asklepios Klinik St. Georg, Hamburg, GER; 4H˘pital Edouard Herriot, Lyon, FRA; 5St Mary's Hospital, London, UK; 6EPIMED c/o Private Practice, Berlin, GER; 7Boehringer Ingelheim Inc, US.
Background: Nevirapine extended release (NVP XR) may offer therapeutic benefit relative to NVP immediate release (NVP IR) by facilitating a once-daily (QD) regimen. Efficacy and safety of switching pts from chronic dosing with NVP IR 200 mg twice daily (BID) to NVP XR 400 mg QD was assessed.
Methods: Open-label, non-inferiority (12% margin), randomized (2:1 ratio) study. HIV-1 pts >18 years, receiving NVP IR plus one of three NRTI combination (3TC/ABC, FTC/TDF or 3TC/AZT) with undetectable (<50 copies/mL) viral load (VL) were enrolled. Primary endpoint was sustained virologic response (<50 copies/mL) through Wk 24 (time-to-loss of virologic response algorithm). Cochran's statistic, adjusted for background regimen, was used to test noninferiority of NVP XR to NVP IR.
Results: 443 Pts randomized and treated. Demographic/baseline characteristics were similar between groups.

Conclusions: Pts switched from NVP IR BID to NVP XR QD demonstrated non-inferior efficacy to patients continuing on NVP IR BID. AEs, primarily mild/moderate, were reported more frequently with NVP XR than NVP IR, likely due to the open-label design. No drug-related SAEs or Grade 3/4 LFT elevations or rashes were noted, no unexpected AEs were observed. These data support switching from NVP IR to NVP XR in patients virological stable on the former formulation.
· Compliance and adherence to therapeutic regimens are major factors in ensuring long term successful treatment, in addition to potency of antiviral agents [1-3]
· NVP (VIRAMUNE) plus tenofovir/emtricitabine (TDF/FTC) has been shown to have similar efficacy to a combination of atazanavir/ritonavir plus TDF/FTC, as well as a more favorable lipid profile [4]
· NVP is currently available as an immediate release (IR) formulation, to be administered as 200mg twice daily (BID). However, once-daily (QD) dosing provides the advantage of simple administration of NVP and the potential to improve compliance, which in turn should enhance long term efficacy
· NVP extended release (NVP XR, 400mg QD) has recently been found to have high and comparable efficacy to NVP immediate release (NVP IR, 200mg BID) in treatment-naïve individuals
· This study presents the efficacy and safety of switching patients from NVP IR 200mg BID to NVP XR 400mg QD, in terms of sustained virologic response, and safety.
TRANxITION is an open-label, randomized, parallel group study assessing the efficacy and safety of switching HIV-1-infected patients from NVP IR based regimen to NVP XR based regimen. After screening, patients were randomized with a 2:1 allocation ratio to NVP XR 400 mg QD or NVP IR 200 mg BID. Patients remained on their previous background therapy. The randomization at baseline was stratified by background therapy. This presentation summarizes the analysis at 24 week follow-up.
Inclusion/exclusion criteria
Key inclusion criteria:

· HIV-1-infected patients aged ≥18 years receiving NVP treatment for at least 18 weeks, with background therapy with fixed dose combinations (or their specific components) with lamivudine/abacavir (3TC/ABC), emtricitabine/ tenofovir (FTC/TDF) or lamivudine/zidovudine (3TC/AZT)
· An undetectable HIV-1 viral load in the preceding 1 - 4 months with a lower level of detection <100 copies/mL and HIV-1 viral load of <50 copies/mL at screening
Key exclusion criteria · Current treatment with an HIV protease inhibitor
· Participation in another trial or use of an investigational medicine within the preceding two months
· Females patients of child-bearing potential unwilling to use double-barrier methods for contraception
· Laboratory parameters >DAIDS Grade 2 (coagulation, haematology, biochemistry) or 3 (total triglycerides); hepatic cirrhosis stage Child-Pugh B or C
Study endpoints
Primary endpoint:

· Proportion of patients with sustained virologic response (viral load <50 copies/mL) through Week 24
Secondary endpoints included: · Proportion of sustained virologic resonse (viral load <400 copies/mL); time to loss of virologic response (TLOVR); and change in viral load and CD4+ cell counts, from baseline
· The incidence of adverse events (AEs), serious adverse events (SAEs), occurrences of rashes and hepatic events and laboratory measurement abnormalities
The primary endpoint (proportion with sustained virologic response at Week 24) and its 95% CI which was analyzed using the TLOVR algorithm using Cochran's statistic.
A non-inferiority test with a 12% margin was performed by constructing a two-sided 95% CI for the difference in proportions of virologic response for the two treatment arms (NVP XR vs. NVP IR) for the primary endpoint.
All safety data were analyzed using descriptive statistical methods.
Disposition of study population

· The disposition of patients throughout the trial is shown in Figure 1.

Demographic data
Disposition of subjects is displayed in Figure 1; 54 patients were excluded primarily due to not meeting eligibility criteria. Baseline characteristics are shown in Table 1. Of the 499 patients enrolled, 445 were randomized and 443 treated (148 with NVP IR and 295 with NVP XR).
By Week 24, 3/148 (2.0%) patients treated with NVP IR and 7/295 (2.4%) patients treated with NVP XR had discontinued their study medication.

Primary efficacy and safety results
Results of the primary endpoint are summarised in Table 2. Sustained virologic response at Week 24 was observed in 93.6% of NVP XR treated patients and 92.6% of NVP IR patients, with an adjusted difference of 1.0% (95% CI: -4.3, 6.0), using the TLOVR algorithm and Cochran statistic and adjusting for three strata of background treatment. For the primary endpoint, NVP XR was non-inferior to NVP IR, using either a -12% or -10% noninferiority margin.
Virologic responses by ARV treatment stratum were generally similar to that for the overall result (Table 2).

The results were consistent when different HIV viral load assays, different definitions of virologic response, different study populations and higher levels of viral load were used to define viral suppression (Table 3).

There was no significant difference in time-to-loss of virologic response between the two treatment groups using the Cox model adjusting for background ARV Therapy (Figure 2).

There was no difference between the two treatment groups in median change from baseline to Week 24 in CD4+ cell counts (NVP IR 32.5 cells/mm3 vs NVP XR 39.8 cells/mm3).
Adverse events
· AEs are reported in Table 4
· The frequency of DAIDS Grade 3 or 4 AEs was similar between the two treatment groups, whereas AEs of these grades considered to be drugrelated occurred in only one (0.3%) patient treated with NVP XR and two (1.4%) with NVP IR
· None of the SAEs were considered drug-related and there were no life-threatening or fatal events
· Three (1.0%) of the patients taking NVP XR discontinued due to gastrointestinal complaints, headache and dizzines, respectively

Adverse events summary
Rash and hepatic events were observed in four (1.3%) patients in the NVP XR group but none in the NVP IR group. Hepatic events related to study drug were recorded in either treatment group.
There were no differences between the two treatment groups in terms of changes in safety laboratory tests or vital signs
· Grade 2 and 3 AST and ALT elevations were infrequent in both treatment groups (<5.0% combined for each marker and each group) and there was only one occurrence of Grade 4 ALT enzyme elevation in the NVP XR group
· One patient in the NVP XR group, who also had HCV infection, developed acute hepatitis
AEs that occurred with greater frequency in the NVP XR group were mild in nature and were observed in six system organ classes (Table 5), with the most frequently reported term for each being diarrhea, fatigue, dizziness, insomnia and pruritis/eczema/dry skin, respectively.

1. Mannheimer S et al. Clin Infect Dis 2002; 34: 1115-21.
2. Garcia de Olalla P et al. J Acquir Immune Defic Syndr 2002; 30: 105-10.
3. Flandre P et al. Antivir Ther 2002; 7: 113-21.
4. Podzamczer D et al. Presented at 11th Workshop on Adverse Drug Reactions and Co-morbidities in HIV, Philadelphia, USA, 2009, Poster P29.