Introduction
TMC278 had a high virologic response rate, non-inferior to EFV, in two Phase III double-blind trials ECHO (TMC278-C209, NCT00540449) and THRIVE (TMC278-C215, NCT00543725) in treatment-naïve HIV-infected adult patients. As the use of NNRTIs, particularly nevirapine, has been associated with hepatic-related adverse events (AEs), especially in HIV/hepatitis B (HBV) and/or hepatitis C (HCV) co-infected patients, a subgroup analysis of these events was performed on the pooled Week 48 Phase III data.
Methods
Patients (N=1368) with alanine aminotransferase (ALT)/ aspartate aminotransferase (AST) ≤ 5x upper limit of normal received TMC278 25mg qd or EFV 600mg qd, plus TDF/FTC (ECHO) or TDF/FTC, AZT/3TC or ABC/3TC (THRIVE). HIV/HBV and/or HCV co-infection status was determined at baseline in 1335 patients by HBV surface antigen, HCV antibody and RNA testing.
Results
At baseline, 112/1335 patients (8.4%) had evidence of HIV/HBV and/or HCV co-infection (randomised to TMC278, n=49: 7.3%; EFV, n=63: 9.5%). Table 1 summarises the outcomes.
Table 1.
| HIV/HBV and/or HCV co-infected patients | HIV mono-infected patients | |||
|---|---|---|---|---|
| TMC278 25mg qd | EFV 600mg qd | TMC278 25mg qd | EFV 600mg qd | |
| Efficacy (Week 48 outcomes)* | N=49 | N=63 | N=621 | N=602 |
| % (95% CI) with viral load <50 copies/mL, ITT-TLOVR | 73.5 (60.7-86.3) | 79.4 (69.1-89.6) | 85.0 (82.2-87.8) | 82.6 (79.5-85.6) |
| Mean CD4 count (95% CI) | N=48 | N=63 | N=621 | N=602 |
| Baseline, cells/mm3 | 230 (198-263) | 246 (216-276) | 262 (251-273) | 274 (262-285) |
| Change from baseline, NC=F†, cells/mm3 | +137 (100-175) | +192 (147-238) | +197 (186-209) | +173 (161-185) |
| Change from baseline, NC=F†, % | +6.6 (5.0-8.3) | +7.7 (6.4-9.0) | +8.6 (8.1-9.0) | +8.4 (7.9-8.8) |
| Safety‡, § | ||||
| Treatment-emergent hepatic AEs of interest, n (%) | N=54 | N=66 | N=632 | N=616 |
| Any hepatic AE | 15 (27.8) | 17 (25.8) | 23 (3.6) | 28 (4.5) |
| Hepatobiliary disorders¶ | 3 (5.6) | 7 (10.6) | 6 (0.9) | 9 (1.5) |
| HBV or HCV reported as an AE | 3 (5.6) | 5 (7.6) | - | - |
| Hepatic laboratory abnormalities reported as an AE | 9 (16.7) | 8 (12.1) | 19 (3.0) | 21 (3.4) |
| Grade 3 to 4 hepatic laboratory abnormalities, n (%) | N=54 | N=66 | N=631 | N=604 |
| ALT increased | 9 (16.7) | 11 (16.7) | 1 (0.2) | 12 (2.0) |
| AST increased | 7 (13.0) | 5 (7.6) | 7 (1.1) | 14 (2.3) |
| Hyperbilirubinaemia | 0 | 0 | 4 (0.6) | 1 (0.2) |
ITT-TLOVR = intent-to-treat-time-to-loss of virologic response; CI=confidence interval; *Patients included in efficacy analysis were those with baseline HBV/HCV assessments; †NC=F = non completer = failure: missing values after discontinuation imputed with change = 0; Last observation carried forward otherwise; ‡Safety analyses performed using all available data, including beyond Week 48; §Patients who seroconverted for HBV/HCV during the study were included in the subgroup of HIV/HBV and/or HCV co-infected patients; ¶Selection of preferred terms from System Organ Class as defined by MedDRA. Compared with HIV mono-infected patients, co-infected patients had more hepatic AEs (clinical and laboratory) and lower virologic responses, which were similar across treatment groups. Hepatic AEs rarely led to treatment discontinuation (TMC278: n=3 vs. EFV: n=9 patients). There were no fatal hepatic AEs.
Compared with HIV mono-infected patients, co-infected patients had more hepatic AEs (clinical and laboratory) and lower virologic responses, which were similar across treatment groups. Hepatic AEs rarely led to treatment discontinuation (TMC278: n=3 vs. EFV: n=9 patients). There were no fatal hepatic AEs.
Conclusions
Overall, both TMC278 and EFV were well tolerated with no hepatic safety differences observed. Hepatic AEs were more common in co-infected than in HIV mono-infected patients (27% vs. 4%, respectively), but there were no differences between the two treatment groups. Virologic responses were similar for TMC278 and EFV within the co-infected and HIV mono-infected groups, and lower in co-infected than in HIV mono-infected patients.