Darunavir once-daily is non-inferior to lopinavir/r in treatment-naive patients at 48 weeks (Artemis study)

2 December 2007. Related: Conference reports, Antiretrovirals, EACS 11 Madrid 2007.

Simon Collins, HIV i-Base

In an oral late breaker presentation, Nathan Clumeck presented results from a randomised, multinational (26 country) study, comparing darunavir once-daily to lopinavir/r (once- or twice-daily) in almost 700 treatment-naive patients. Use of lopinavir/r once-daily by some US patients was a patient/doctor choice and not subject to randomisation.

Darunavir is approved as a twice-daily protease inhibitor at 600mg/100mg twice daily, for use in combination with other active drugs as a treatment for PI-experienced patients. In this study, darunavir was dosed at 800mg with 100mg ritonavir once-daily (n=343) and lopinavir/r was dosed at 400/100mg twice-daily or 800/200mg once-daily (n=346). Truvada (tenofovir+FTC) once-daily was included as background nucleosides in both arms. Viral load needed to be >5,000 copies/mL at screening but there were no CD4 entry restrictions.

The study was designed as a non-inferiority study based on the primary endpoint of the percentage of patients with viral suppression <50 copies/mL at week 48. Secondary endpoints include safety, efficacy and tolerability results over 192 weeks.

All demographics were balanced at baseline: 70% of patients were men and 30% women, mean age 35 (SD+9), and just over 40% of patients were Caucasian. While the group as a whole was not advanced – with a median CD4 of around 220 cells/mm³ and viral load of 60,000 copies/mL – the ranges for these characteristics were broad: CD4 ranged from 2 to 750 cells/mm³ and viral load from 600 – 5.5 million copies/mL. It is unclear why some of these patients were entered into the study; some patients had CD4 counts far higher than guidelines recommend starting treatment and others had such advanced HIV, that they, arguably, should not be relying on an unproven treatment.

Approximately 14% patients were coinfected with hepatitis C and 10% were CDC class C.

Stratification at screening showed 40% patients had CD4 count <200 cells/mm³ and 36% had viral load >100,000 copies/mL.

At week 48, by Intent-To-Treat TLOVR (Time to Loss of Virologic Response) analysis, 84% of patients using DRV/r vs 78% of LPV/r patients reached <50 copies/mL. The estimated difference in response compared to LPV/r for non-inferiority per-protocol analysis was 5.6% (95% CI -0.1;11.3) p<0.001; and for superiority by ITT was 5.5% (95% CI -0.3;11.2) p=0.062. Assessed by primary endpont, darunavir once-daily was found to be non-inferior to lopinavir/r, and results showed a trend towards superiority.

71% of the subset of 52 mainly US patients who used lopinavir/r once daily (who as a group had similar baseline characteristics to the DRV/r and LPV/r BID groups) achieved suppression to <50 copies/mL. This 13% difference showed darunavir/r to be superior to once-daily lopinavir/r (95% CI 1; 24; p<0.05). Differences between the LPV/r once- vs twice daily [9%* (95% CI -3; 21)] and DRV/r once-daily vs LPV/r twice daily [(3% (95% CI -3; 9)] were not significant.

Results in patients with baseline viral load >100,000 copies/mL saw an even greater difference between DRV/r and once-daily LPV/r with 79% vs 56% achieving <50 copies/mL (P<0.05). The significance remained when comparing DRV/r to the overall LPV/r group (67%, p<0.05) but not when comparing to LPV/r twice-daily (71%).

Grade 2-4 side effects, summarised in Table 1, showed a higher rate of diarrhoea in the LPV/r arm overall (4% vs 10%). These rates were 8% in the LPV/r twice daily and 17% in the LPV/r once-daily groups. Nausea was similar at 2-3% in both arms and rash was slightly higher in the DRV/r (3% vs 1% LPV/r overall).

The majority of LPV/r QD use was in the US. The proportion of US patients who used LPV/r QD was 66% (45 of 68 patients). Only 7 patients outside of the US used LPV/r QD. 27 (8%) patient used both once- and twice-daily LPV/r dosing during the study, and were excluded from the QD vs BID LPV/r analyses.

Table 1: Grade 2-4 side effects and lipid changes (seen in >2% patients)

Comment

This study supports the use of darunavir/r as a once-daily option in naive patients, especially when viral load is >100,000 copies/mL, although it would be interesting to know whether twice-daily darunavir/r would improve on these rates or suppression in this group.

The results of the LPV/r once-daily analysis should be interpreted cautiously as this is a small non-randomised subset of US patients.

Several studies have previously shown lopinavir/r once daily to be inferior to twice-daily, with poorer trough concentrations, and although licensed as a once-daily option in the US for naive patients, Abbott no longer appear to be actively pursuing once-daily registration in Europe.

Reference:

Clumeck N et al. ARTEMIS: Efficacy and safety of lopinavir (BID vs QD) and darunavir (QD) in antiretroviral-naive patients. Late breaker abstract LBPS7/5. http://www.multiwebcast.com/eacs/2007/11th