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The protease inhibitor (PI) darunavir (DRV), in combination with low-dose ritonavir (/r), has demonstrated sustained efficacy and favourable safety and tolerability in both treatment-experienced and treatment-naϊve HIV-1-infected adult patients [1-6]. Based on these findings, DRV/r, as part of combination therapy, is approved for use in treatment-experienced patients at a dose of 600/100 mg twice daily, and in treatment-naϊve patients at a dose of 800/100 mg once daily [7, 8].
For the treatment-experienced HIV-1-infected population, new therapeutic strategies are needed that facilitate patient convenience and long-term adherence. In the phase III ODIN (once-daily darunavir in treatment-experienced patients) trial (TMC114-C229, NCT00524368), once-daily DRV/r 800/100 mg was compared with twice-daily DRV/r 600/100 mg in treatment-experienced patients with no DRV resistance-associated mutations (RAMs) at screening. In the primary 48-week analysis, noninferiority in virological response of once-daily DRV/r 800/100 mg to twice-daily DRV/r 600/100 mg was established [intent to treat-time to loss of virological response (ITT-TLOVR)] . Once-daily DRV/r was associated with similar rates of virological failure and emergence of resistance as twice-daily DRV/r. DRV/r was well tolerated with a low rate of discontinuations because of adverse events (AEs). In addition, once-daily DRV/r was associated with a more favourable lipid profile than twice-daily DRV/r.
In an effort to understand the efficacy of DRV/r treatment among patients with diverse demographics and disease characteristics, the current analysis reports the 48-week virological response rates with once- vs. twice-daily DRV/r treatment for various baseline subgroups in the ODIN trial.
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Once-daily DRV/r was an effective treatment for ARV treatment-experienced patients with no DRV RAMs at screening and, in the primary analysis of ODIN data, once-daily DRV/r 800/100 mg was noninferior to twice-daily 600/100 mg in terms of virological response over 48 weeks of treatment . In the current analysis, comparable virological response rates were found in the once- and twice-daily DRV/r treatment arms across subgroups of baseline disease characteristics and demographics.
The population enrolled in ODIN was heterogeneous in terms of baseline viral load and had a wide range of prior treatment experience. The relatively low incidence of DRV RAMs at screening (13.7% of patients had at least one DRV RAM) is consistent with that observed in the general treatment-experienced population. A recent analysis of approximately 232 000 samples submitted for routine resistance testing reported that, in 2009, 93.9% of routine clinical HIV isolates and 86.3% (US FDA mutation list) or 82.6% (Virco®TYPE HIV-1 lower clinical cut-off) of those with evidence of PI resistance were found to harbour no DRV RAMs . Furthermore, this analysis found that, despite widespread DRV use, the prevalence of DRV RAMs has decreased since 2003 .
Univariate analyses showed that virological response rates were similar between treatment arms for each of the baseline viral load categories. For example, virological response rates were comparable between the two treatment arms in patients with baseline HIV-1 RNA < 100 000 copies/mL (77.6% of once-daily and 73.2% of twice-daily-treated patients achieving the target HIV-1 RNA < 50 copies/mL). There were too few patients with baseline HIV-1 RNA ≥ 100 000 copies/mL to provide a meaningful comparison. The pattern of response between the subgroups is not unexpected, as baseline HIV-1 RNA is established as the most important indicator of response to ARV therapy [15-17], and HIV-1 RNA has previously been reported as a predictor of response in patients receiving DRV/r . Furthermore, the response rates in the present study (Table 2) are similar to those reported with DRV/r 600/100 mg twice-daily in the treatment-experienced (LPV-naïve) TITAN (TMC114/r in treatment-experienced patients naïve to LPV) study, which showed a 74% response rate (HIV RNA < 50 copies/mL) among patients with a baseline viral load < 100 000 copies/mL and a 55% response rate among those with a viral load ≥ 100 000 copies/mL .
Virological response rates were also similar between the once- and twice-daily treatment arms stratified by baseline CD4 cell count, and also for gender, age and race subgroups. With regard to race, in both treatment arms, the highest response rates were seen in Asian patients and the lowest in Black patients. These findings are consistent with earlier data (n > 1300 patients) showing that African-Americans were significantly less likely to achieve viral suppression compared with patients of European origin .
Response rates were broadly comparable between the once- and twice-daily treatment arms among patients infected with HIV-1 clade B and clade non-B virus. In the subgroups harbouring the most prevalent non-B clades, C and CRF01_AE, the virological response rate was comparable between the treatment arms: 72.7% with once-daily dosing vs. 78.8% with twice-daily dosing (n = 44 and n = 33), and 90.5 vs. 91.2% (n = 42 and n = 34), respectively. The difference in efficacy observed between the once- and twice-daily DRV/r treatment arms in the clade non-B-infected patients appeared to be primarily driven by smaller groups of patients infected with clades CRF12_BF (66.7 vs. 100.0%, n = 12 and n = 10, in the once- and twice-daily arms, respectively) and F1 (46.2 vs. 80.0%, n = 13 and n = 15, respectively); however, conclusions regarding response in these non-B clades are limited by the low numbers of patients in each group. These data, indicating that clade (B vs. non-B) did not significantly affect the response to DRV/r therapy, are in accordance with the findings of the phase III ARTEMIS (antiretroviral therapy with TMC114 examined in naïve subjects) trial in treatment-naïve, HIV-1-infected patients, which found that in vitro susceptibility and virological response to DRV/r once-daily treatment were independent of HIV-1 clade .
Response rates were comparable between the once- and twice-daily treatment arms among patients with no, or one or more primary (major) PI mutations. The response rates in both treatment arms were slightly higher in patients with one or more primary (major) PI mutations at baseline compared with those with no primary (major) PI mutations, while response rates between the two arms were comparable across patients with 0–2, 3–4 and ≥ 5 IAS-USA PI mutations. These findings are consistent with previous data showing that response rates with twice-daily DRV/r 600/100 mg are maintained in treatment-experienced patients with increasing baseline primary PI mutations [21, 22]. This supports DRV/r as an appropriate choice in treatment-experienced patients when primary PI mutations are present. It is important to note, however, that individuals with DRV RAMs were excluded from ODIN. These results address a diverse population of treatment-experienced patients harbouring a variable number of RAMs and suggest that once-daily DRV/r dosing is efficacious in this setting.
The presence of NRTI RAM M184V/I at baseline was significantly associated with higher virological response rates in both the once- and twice-daily DRV/r treatment arms compared with patients lacking the mutation. Other studies have also found similar associations between the presence of the M184V/I mutation at baseline and virological response [23, 24]. In study M06-802, M184V/I was associated with higher rates of adherence, and it was hypothesized that this may have accounted for the difference in virological response rates, rather than NRTI hypersensitivity . This was not the case in the ODIN trial, with the presence of the M184V/I mutation being a marker for fewer active NRTIs in the OBR and a lower number of previously used PIs. It should also be noted, however, that increased susceptibility to zidovudine, stavudine and tenofovir has been demonstrated in vitro in the presence of M184V/I . The NRTIs most frequently used in the ODIN trial were tenofovir (81%), zidovudine (53%) and lamivudine (53%). Further investigation on the effect of the M184V/I mutation is needed.
In both treatment arms, lower response rates were observed in the univariate analysis in patients who had previously used at least one PI than in those who had not previously received PIs. This trend was not accounted for by baseline PI resistance. A similar pattern was seen for the number of active NRTIs in the OBR with, contrary to what might be expected, higher response rates observed among patients with no or fewer active NRTIs in their OBR. It is possible that these findings may have been affected by the small patient numbers in some subgroups; however, another possibility relates to the M184V/I mutation. The presence of the M184V/I mutation was a marker for fewer active NRTIs in the OBR (P < 0.0001) and a lower number of previously used PIs (P < 0.0001). Thus, the presence of M184V/I may at least in part account for the unexpected finding that virological response was higher in patients with no active NRTIs in their OBR.
Factors that may be predictive for virological response were investigated by means of multivariate logistic regression analysis in the overall population. The multivariate analysis revealed that baseline HIV-1 RNA (P = 0.0014), the presence of M184V/I at baseline (P < 0.0001) and adherence (P < 0.0001) were independently associated with response in the overall population. Adherent patients having higher virological response rates than those who were suboptimally adherent is not an unexpected finding given that adherence has long been established as a predictor of virological response .
A limitation of these analyses is that they are exploratory in nature. These findings should be interpreted with caution as the trial was not powered for treatment comparisons between subgroups for which stratification had not been performed and, in addition, there were small numbers of patients in some subgroups. In some instances, the small sample sizes may explain the apparent differences in response rates between some subgroups, which may be caused by random variation.
In conclusion, treatment with once-daily DRV/r 800/100 mg was noninferior to twice-daily DRV/r 600/100 mg (in each case in combination with an OBR) in terms of virological response at 48 weeks . Both treatment arms were associated with high rates of virological suppression in this treatment-experienced population with no DRV RAMs at screening. There were no clinically relevant differences in virological response rates between once- and twice-daily DRV/r treatments across any subgroup analysed. The results of these exploratory subgroup analyses suggest that once-daily DRV/r 800/100 mg is a suitable treatment option in treatment-experienced patients with no DRV RAMs, regardless of their baseline disease and demographic characteristics.
Conflicts of interest: MS has received grants or research support from Tibotec, Gilead and Bristol-Myers Squibb. He has served as a consultant for Tibotec and Gilead and has also been a speaker for Tibotec, Gilead, Merck and Bristol-Myers Squibb. PC has been an advisory board member for Avexa, Gilead, GlaxoSmithKline, Myriad, Merck, Pfizer, Pharmasset, Schering Plough and Tibotec. He has been an investigator for Avexa, Boehringer Ingelheim, Gilead, GlaxoSmithKline, Roche, Merck Sharp & Dohme, Pfizer, Pharmasset, Schering Plough, Tibotec, Abbott and Bristol-Myers Squibb. He has been a speaker for Abbott, Bristol-Myers Squibb, Boehringer Ingelheim, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer and Tibotec. He has served as a scientific advisor for Merck Sharp & Dohme, Pfizer, GlaxoSmithKline, Avexa and Tibotec. PD has received honoraria or research funds from Tibotec, Janssen-Cilag, Boehringer Ingelheim, Merck Sharp & Dohme, Bristol-Myers Squibb, GlaxoSmithKline, ViiV Healthcare and Gilead Sciences. SH has received grants or research support from Bristol-Myers Squibb, GlaxoSmithKline and Tibotec Therapeutics. She has served as a consultant for Bristol-Myers Squibb, Boehringer Ingelheim, Gilead Sciences, Merck and Co. and Tibotec Therapeutics. EL, MO, TVdeC and FT are all full-time employees of Tibotec.