The new protease inhibitor darunavir (Prezista), boosted by ritonavir, is more likely to suppress viral load below detectable levels in treatment-experienced patients than Kaletra (lopinavir/ritonavir), according to results of an international study published this week in The Lancet.
In particular the study showed that for individuals who already had at least one protease inhibitor-related resistance mutation, darunavir was significantly more likely than lopinavir to control viral load, suggesting that in future patients with any signs of protease inhibitor resistance will be more likely to be offered darunavir than lopinavir.
The study, called TITAN, recruited 595 patients, 31% of whom had never taken a protease inhibitor, in Europe, Australia, Thailand, Brazil, South Africa, Central and North America.
TITAN compared twice daily darunavir/ritonavir (600/100mg) with twice daily lopinavir/ritonavir capsules (the old formulation) (400/100mg), plus a background regimen selected by resistance testing. The predominant nucleoside reverse transcriptase inhibitors used in the background regimen were tenofovir (56%), 3TC (46%) and AZT (40%). Nine per cent included a non-nucleoside reverse transcriptase inhibitor in the background regimen.
Patients participating in the study represented a cross-section of treatment-experienced individuals, with almost half having experience of at least one drug from each class (47%), but the vast majority of participants were still susceptible to at least four licensed protease inhibitors (82%) and at least two nucleoside analogues (92%) as measured by the Antivirogram assay.
The pattern of drug exposure among study participants suggests that around half of patients had taken a protease inhibitor-containing regimen and then switched on failure to an NNRTI-containing regimen, with a median 61 months of NRTI exposure, 41 months of PI exposure and 28 months of NNRTI exposure recorded in study participants. Around 30% had no previous experience of protease inhibitor treatment.
The median baseline viral load was 4.3 log10 copies/ml (approximately 20,000 copies/ml) and the median CD4 cell count was 232 cells/mm3. Study participants were predominantly male (79%).
Two hundred and ninety-eight patients received darunavir/ritonavir and 297 received lopinavir/ritonavir. Participants were not allowed to take enfuvirtide or any other unlicensed drug as part of the background regimen.
After 48 weeks of treatment, intent to treat analysis showed that 77% of those randomised to receive darunavir had viral load below 400 copies/ml, compared with 68% of those randomised to lopinavir/ritonavir (p
A similar difference emerged when the proportion of patients with viral load below 50 copies/ml at week 48 was compared. Seventy-one per cent of the darunavir/ritonavir group had viral load below 50 copies/ml, compared with 60% of the lopinavir/ritonavir group (p=0.005), and this difference was apparent by week 24.
Darunavir/ritonavir-treated patients also had a greater mean reduction in viral load at week 48 (-1.95 log10 copies/ml vs 1.72 log10 copies/ml).
More patients stopped lopinavir/ritonavir treatment than darunavir treatment due to virologic failure (11% vs 1%), but the rate of discontinuation due to adverse events was similar between the two arms (7%). Diarrhoea of grades 2-4 severity was more frequent in the lopinavir/ritonavir group (15% vs 8%), although Professor Bernard Hirschel of the University of Geneva points out in an accompanying editorial that the adverse event profile might have been different had participants received the new Kaletra tablet, which has been observed to cause less diarrhoea. Rash was seen more frequently in darunavir-treated patients (16% vs 7%).
Elevation of total cholesterol occurred with similar frequency in both study arms (darunavir 32%, lopinavir 29%), but grade 2-4 triglyceride elevations were more common in the lopinavir-treated group (25% vs 19%). Total cholesterol elevations were modest in both arms (0.44mmol/L in the darunavir group, 0.66mmol/L in the lopinavir group), as were other lipid changes.
The investigators say the superior virologic performance of darunavir cannot be explained by poorer susceptibility to lopinavir at baseline, since only 2% had a reduction in lopinavir susceptibility of greater than 40-fold at baseline, and only 10% had a reduction in lopinavir susceptibility of greater than tenfold.
They point to the trend towards an inferior virologic response seen in the lopinavir recipients who had a reduction in lopinavir susceptibility at baseline of less than tenfold (i.e. patients who would not be considered to have clinically relevant phenotypic resistance to lopinavir by current standards). Sixty-three per cent of the lopinavir-treated patients with a reduction in lopinavir susceptibility of less than tenfold achieved a viral load below 50 copies/ml at week 48, compared to 70% of the darunavir-treated patients.
This trend suggests that darunavir is intrinsically more potent, due to its greater barrrier to developing resistance mutations. Fewer patients in the darunavir/ritonavir arm developed new primary protease inhibitor mutations whilst they remained on treatment after virologic failure (21% vs 36% in the lopinavir group), although the median time on treatment after viral rebound is not stated and fewer patients in the darunavir arm developed new NRTI-associated resistance mutations (14% vs 27%).
Madruga JV et al. Efficacy and safety of darunavir-ritonavir compared with that of lopinavir-ritonavir at 48 weeks in treatment-experienced, HIV-infected patients in TITAN: a randomised controlled phase III trial. The Lancet 370: 49-58, 2007.
Herschel B, Perneger T. No patient left behind – better treatments for resistant HIV infection. The Lancet 370: 3-5, 2007.