Summary of antiretroviral studies at Glasgow
Simon Collins, HIV i-Base
The following short summaries cover some of the new research presented on current and pipeline antiretrovirals.
Please see abstract links for further details of each study.
Unboosted atazanavir as maintenance treatment in naïve patients
JF Delfraissy presented results from a 48-week study that randomised 252 treatment-naïve patients after a 26-30 week induction phase of boosted atazanaivr/r 300/100mg plus 2 RTIs, to either continue or switch to once-daily unboosted atazanavir (400mg) plus continued RTIs. Only patients suppressed to <50 copies/mL were randomised to switch. Tenofovir was not allowed as an RTI because of the negative drug interaction with atazanavir.
Of 252 patients at baseline (median CD4 245 cells/mm3; median HIV-RNA 4.95 logs), 30 discontinued (nine for side effects) and 50 failed to reach undetectable viral load and continued on boosted ATV/r. This left 172 patients who were randomised 1:1 to either ATV or ATV/r.
At week 48, the ATV arm demonstrated similar (non-inferior, margin 15%) efficacy with 78% and 86% of patients suppressed to < 50 and <400 copies/mL respectively, compared to 75% and 81% of patients who remained on boosted ATV.
CD4 responses were similar. Although there were more discontinuations prior to week 48 with boosted atazanavir (14% vs 8%), fewer patients on ATV/r experienced virological rebound (7 vs 11). None had emergence of PI resistance.
As expected, side effects favoured unboosted ATV: grade 3–4 total bilirubin in 47% vs 14% and mean percent triglyceride
change from the switch to week 48 was +9.8 vs. -27.0, both for ATV/r & ATV, respectively.
The balance between maintaining suppression and improved tolerability may make maintenance treatment without ritonavir an option for some naîve patients who have tolerability difficulties, but this will also reduce the safety buffer zone for adherence times.
Confirming individual drug levels using therapeutic drug monitoring (TDM) would be a safer approach.
Delfraissy JF et al. Efficacy and safety of 48-week maintenance with QD ATV vs ATV/r (both + 2NRTIs) in patients with VL <50 copies/mL after induction with ATV/r + 2NRTIs: study AI424136. 9th International Congress on Drug Therapy in HIV Infection. 9-13 November 2008, Glasgow. Abstract O415.
Darunavir/r vs lopinavir/r: 96 week resistance results from TITAN study
The Phase 3 TITAN study has previously reported superiority of darunavir/r (DRV/r) compared to lopinavir/r (LPV/r), with 67.5% vs. 59.5% patients achieving <400 copies/mL (difference 8%, 95% CI 0.1–15.8, p=0.03), in almost 600 treatment-naïve patients.
Virological failure was higher in the LPV/r arm (25.6%, n = 76) was higher than in the DRV/r arm (13.8%, n = 41).
Primary PI mutations were found in 25/72 of LPV/r and 7/ 39 for DRV/r patients with matched resistance results (with darunavir/r V32I occured in three patients, I47V and L76V in two patients and M46I, I54L, I54M and L90M in one patient).
NRTI mutations occured in 20/72 the LPV/r arm compared to 4/39 in the DRV/r, with similar proportions of patients loosing phenotypic sensitivity to the study protease inhibitor. The majority of patients failing darunavir/r retained susceptibility to other PIs: amprenavir (31/31), atazanavir (29/30), indinavir (31/32), LPV (33/33), nelfinavir (24/26), saquinavir (31/31) and tipranavir (34/35). Susceptibility to the background NRTIs (20/55 vs. 4/35) or any NRTI (27/66 vs. 7/38) was also reduced in significantly more lopinavir/r patients.
The differences between darunavir/r and lopinavir/r suggest a greater role for darunavir/r in first-line therapy, and as we went to press once-daily darunavir/r was approved in Europe. The retained phenotypic sensitivity to second-line protease options is encouraging, but this will need confirmation with clinical results.
De Meyer S et al. Resistance development in virological failures with DRV/r or LPV/r: 96-week analysis of the Phase III TITAN trial in treatment-experienced patients. 9th International Congress on Drug Therapy in HIV Infection. 9-13 November 2008, Glasgow. Abstract O424.
Apricitabine 48 week results
Final 48 week results from a Phase 2b study of apricitabine (ATC), a new cytidine analogue similar to 3TC, in approximately 40 treatment-experienced patients with resistance to 3TC (at baseline, 52% of patients had ≥3 thymidine mutations and 76% had ≥1 non-NRTI mutation). At week 24 all patients switched to the higher dose 800mg ATC.
By week 48, around 90% patients achieved viral suppression <50 copies/mL in all arms. CD4 increases were ~ +260 cells/mm3 in the ATC arms vs +200 cells/mm3 in the 3TC arm. No significant ATC-related SAEs were reported.
Cahn P et al. 48-week data from Study AVX-201 – A randomised phase IIb study of apricitabine in treatment-experienced patients with M184V and NRTI resistance. Abstract O414.