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Keywords:

  • darunavir;
  • efficacy;
  • HIV;
  • once daily;
  • treatment-experienced

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Background

ODIN (once-daily darunavir in treatment-experienced patients) was a 48-week, phase III, randomized, open-label trial comparing once-daily (qd) darunavir/ritonavir (DRV/r) 800/100 mg with twice-daily (bid) DRV/r 600/100 mg, both with an optimized background regimen [OBR; at least two nucleoside reverse transcriptase inhibitors (NRTIs)], in treatment-experienced, HIV-1-infected adults with no DRV resistance-associated mutations (RAMs) at screening. Week 48 analyses of virological response by subgroups are reported.

Methods

A total of 590 patients were randomized to receive qd (n = 294) or bid (n = 296) DRV/r. Virological response (HIV-1 RNA < 50 copies/mL) was assessed according to: screening HIV-1 RNA (≥ or < 50 000 copies/mL), CD4 cell count, prior protease inhibitor (PI) use, number of active NRTIs in the OBR, presence of mutations (primary PI mutations, PI RAMs or M184V/I), gender, age, race, HIV-1 clade and adherence.

Results

Baseline characteristics were well balanced between arms and across subgroups. Response rates were comparable between qd and bid DRV/r treatments for all subgroups examined. Response rates were 78.4 and 76.8% in the qd and bid treatment arms, respectively, in patients with baseline HIV-1 RNA ≤ 50 000 copies/mL and 52.8% in both arms in those with > 50 000 copies/mL. Response rates for the qd and bid treatment arms by baseline CD4 cell count were also similar (69.6 vs. 65.2% for <200 cells/μL; 72.2 vs. 74.8% for 200− < 350 cells/μL; 77.0 vs. 74.3% for ≥ 350 cells/μL).

Conclusions

DRV/r administered either qd or bid provided effective treatment for antiretroviral treatment-experienced patients with no DRV RAMs, with comparable response rates across all subgroups studied. Low patient numbers in specific subgroups may limit interpretation of these specific subgroup results.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

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)] [9]. 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.

Methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patient population and study design

ODIN was a phase III, 48-week, randomized, open-label study comparing the efficacy, safety and tolerability of once-daily DRV/r 800/100 mg vs. twice-daily DRV/r 600/100 mg, with an optimized background regimen (OBR), in treatment-experienced, HIV-1-infected adult patients with no DRV RAMs at screening. Detailed methodology, including inclusion and exclusion criteria, has been reported previously [9].

Patients recruited to ODIN were treatment-experienced, HIV-1-infected adults with HIV-1 RNA > 1000 copies/mL and a CD4 cell count of > 50 cells/μL, receiving a stable highly active antiretroviral therapy regimen for ≥12 weeks and with none of the 11 DRV RAMs (V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V and L89V) [10, 11] detected at screening/baseline. Patients were stratified by screening HIV-1 RNA (≤ or > 50 000 copies/mL) and randomized in a 1 : 1 ratio to receive DRV/r 800/100 mg once daily or DRV/r 600/100 mg twice daily plus an investigator-selected OBR [at least two nucleoside reverse transcriptase inhibitors (NRTIs)].

Efficacy assessments

Plasma HIV-1 RNA was measured at screening, baseline and each study visit (weeks 4, 8, 12, 24, 36 and 48 or withdrawal). Efficacy assessments were performed using the ITT population, which included all randomized patients who took at least one dose of trial medication, irrespective of compliance to trial medication. Virological response was defined as a confirmed HIV-1 RNA < 50 copies/mL at two consecutive visits, with the TLOVR algorithm. In the present analysis, virological response was assessed at week 48 according to the following subgroup parameters:

  • screening HIV-1 RNA≤ or > 50 000 copies/mL
  • baseline CD4 cell count
  • number of International AIDS Society-USA (IAS-USA) major (primary) PI mutations at baseline [12]
  • number of International IAS-USA PI RAMs at baseline
  • presence of the reverse transcriptase (RT) M184V or I mutation at baseline
  • number of previously used PIs
  • number of active NRTIs in the OBR
  • gender
  • age
  • race
  • HIV-1 clade
  • patient-reported adherence

The NRTI (emtricitabine/lamivudine) RAM M184V/I was included as a parameter for subgroup analysis as this is the most prevalent NRTI mutation, and has previously been shown to be a predictor of virological response in patients receiving lopinavir/r (LPV/r) [13].

Resistance assessments

Genotypic (population sequencing) and phenotypic (Antivirogram®, Janssen Diagnostics BVBA, Beerse, Belgium) determinations were performed by Janssen Diagnostics BVBA. HIV-1 isolates were considered susceptible to a drug if the fold-change (determined by Antivirogram®) was below or equal to the low clinical or biological cut-off.

Adherence assessments

Adherence to trial medication was assessed by the Modified Medication Adherence Self-Report Inventory (M-MASRI) questionnaire, in which self-reported mean week 4–48 adherence was converted to a binary variable to determine adherence (> 95%) or suboptimal adherence (≤ 95%).

Statistical analysis

These analyses were exploratory in nature; the trial was not powered for treatment comparisons between subgroups for which stratification had not been performed.

As the subgroup analyses revealed some unexpected associations between subgroups and virological response in both treatment arms, factors predictive of virological response were investigated by means of a multivariate logistic regression analysis. This model assessed factors predictive of virological response in the overall population, not by individual treatment group. However, the difference between arms was accounted for by keeping treatment in the model for all analyses, regardless of the level of statistical significance. A P-value of > 0.05 was used to select variables for removal from the model. The aforementioned subgroup parameters were examined as candidate predictors of response in the model. Baseline CD4 cell count and baseline viral load were modelled as continuous predictors.

Associations between predictors of virological response were examined using contingency table analysis (χ2 tests).

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

Patient disposition and baseline characteristics

A total of 590 treatment-experienced patients were randomized and treated with once-daily DRV/r 800/100 mg (n = 294) or twice-daily DRV/r 600/100 mg (n = 296). Baseline demographics and disease characteristics were generally well balanced between treatment arms (Table 1). There were small numbers of patients in some specific subgroups; this may explain the apparent differences in response rates between some subgroups, which may be caused by random variation.

Table 1. Baseline characteristics
 Once-daily DRV/r 800/100 mg (n = 294)Twice-daily DRV/r 600/100 mg (n = 296)
  1. ARV, antiretroviral; DRV/r, darunavir/ritonavir; IAS-USA, International AIDS Society-USA; NNRTI, nonnucleoside reverse transcriptase inhibitor; NRTI, nucleoside reverse transcriptase inhibitor; PI, protease inhibitor; RAM, resistance-associated mutation; SE, standard error.

  2. *All eight currently available PIs, excluding ritonavir: (fos)amprenavir, atazanavir, indinavir, lopinavir, nelfinavir, saquinavir, tipranavir and DRV.

  3. Phenotypes were determined by Antivirogram®.

  4. Data available for 290 patients in the once-daily DRV/r arm and 284 in the twice-daily DRV/r arm; an ARV was considered susceptible if the fold-change was below or equal to the clinical or biological cut-off.

Baseline demographics  
Female [n (%)]115 (39.1)98 (33.1)
Age (years) [mean (SE)]40.2 (0.53)40.7 (0.55)
Race [n (%)]  
Caucasian102 (34.7)110 (37.2)
Black83 (28.2)72 (24.3)
Hispanic47 (16.0)59 (19.9)
Asian48 (16.3)41 (13.9)
Other14 (4.8)14 (4.7)
Baseline disease characteristics  
HIV-1 RNA (log10 copies/mL) [mean (SE)]4.19 (0.05)4.13 (0.05)
CD4 count (cells/μL) [median (range)]219 (24–1306)236 (44–864)
Stratification factor at screening  
HIV-1 RNA ≤ 50 000 copies/mL [n (%)]222 (75.5)224 (75.7)
Previous ARV experience [n (%)]  
Pls: 0135 (45.9)137 (46.3)
Pls: 174 (25.2)77 (26.0)
Pls: ≥ 285 (28.9)82 (27.7)
NRTIs: ≥ 3174 (59.1)164 (55.4)
NNRTIs: ≥ 1258 (87.8)258 (87.2)
DRV fold-change at baseline [median (range)]0.5 (0.1–1.8)0.5 (0.1–1.9)
Sensitivity to Pls* at baseline [n (%)]248 (85.2)247 (86.1)
OBR [n (%)]  
Number of active NRTIs used  
019 (6.6)15 (5.3)
153 (18.3)75 (26.4)
≥ 2218 (75.2)194 (68.3)
IAS-USA mutations at baseline12 [median (range)]  
PI RAMs3 (0–13)4 (0–14)
Major (primary) PI mutations0 (0–5)0 (0–4)
NRTI RAMs1 (0–7)1 (0–8)
NNRTI RAMs2 (0–5)1 (0–5)
Number of mutations at baseline [n (%)]  
PI RAMs  
0–2100 (34.0)85 (28.7)
3–4114 (38.8)120 (40.5)
≥580 (27.2)91 (30.7)
Major (primary) PI mutations  
0247 (84.0)250 (84.5)
≥147 (16.0)46 (15.5)
HIV-1 clade [n (%)]  
B179 (60.9)199 (67.2)
Non-B115 (39.1)97 (32.8)

Patients had a broad range of prior antiretroviral (ARV) treatment experience: overall, 46.1% of patients were PI-naïve and 28.3% had previously used at least two PIs (Table 1). Treatment arms were similar with respect to the number of active NRTIs in the OBR, with the majority of patients (71.7%) using at least two active NRTIs (Table 1). Overall, 15.8% of all patients had at least one major PI mutation at baseline (Table 1). The M184V/I mutation was present in 64.6% of patients at screening or baseline.

In total, 15.1% of patients (13.9% in the once-daily arm and 16.2% in the twice-daily arm) discontinued the trial prematurely. Most discontinuations were because of AEs (3.4 and 4.1% with once- and twice-daily DRV/r, respectively) and loss to follow-up (3.1 and 4.4%, respectively).

Univariate analyses

Virological response rates by disease and demographic characteristics

Response rates were similar between treatment arms for patients with screening HIV-1 RNA ≤ 50 000 copies/mL, with 78.4% of once-daily and 76.8% of twice-daily DRV/r patients achieving HIV-1 RNA < 50 copies/mL (Table 2). For patients with screening HIV-1 RNA > 50 000 copies/mL the response was identical in each arm (Table 2). Thus, in both treatment arms, a numerically higher response rate overall was seen in patients who had screening HIV-1 RNA ≤ 50 000 copies/mL than in those with > 50 000 copies/mL. Response rates were also similar between treatment arms for patients with baseline HIV-1 RNA < 100 000 copies/mL (Table 2). In patients with > 100 000 copies/mL at baseline there were too few patients to make a meaningful comparison (Table 2).

Table 2. Virological response rates (HIV-1 RNA < 50 copies/mL; ITT-TLOVR) at week 48 by subgroup (univariate analyses)
FactorOnce-daily DRV/r 800/100 mg (n = 294)Twice-daily DRV/r 600/100 mg (n = 296)Difference in response [% (95% Cl)]
n*Response [n (%)]n*Response [n (%)]
  1. CI, confidence interval; DRV/r, darunavir/ritonavir; IAS-USA, International AIDS Society-USA; ITT-TLOVR, intent to treat-time to loss of virological response; M-MASRI, Modified Medication Adherence Self-Report Inventory; NRTI, nucleoside reverse transcriptase inhibitor; OBR, optimized background regimen; PI, protease inhibitor.

  2. *Total subgroup.

  3. Clades A1, D, F1, G, K, CRF02 AG, CRF12 BF and CRF06 cpx.

Screening HIV-1 RNA     
≤ 50 000 copies/mL222174 (78.4)224172 (76.8)1.6 (−6.2, 9.4)
>50 000 copies/mL7238 (52.8)7238 (52.8)0.0 (−16.4, 16.4)
Baseline HIV-1 RNA     
≤ 100 000 copies/mL255198 (77.6)265194 (73.2)4.4 (−3.0, 11.9)
>100 000 copies/mL3914 (35.9)3116 (51.6)−15.7 (−39.2, 7.7)
Baseline CD4 cell count     
<200 cells/μL12587 (69.6)11575 (65.2)4.4 (−7.5, 16.3)
200−<350 cells/μL10878 (72.2)10780 (74.8)−2.5 (−14.4, 9.3)
≥ 350 cells/μL6147 (77.0)7455 (74.3)2.7 (−12.0, 17.4)
HIV-1 clade     
B179126 (70.4)199128 (64.3)6.1 (−3.4, 15.6)
Non-B11586 (74.8)9782 (84.5)−9.8 (−20.7, 1.2)
Type CRF01_AE4238 (90.5)3431 (91.2)−0.7 (−14.0, 12.6)
Type C4432 (72.7)3326 (78.8)−6.1 (−2.6, 13.7)
Other2916 (55.2)3025 (83.3)−28.2 (−51.0, −5.3)
Gender     
Female11580 (69.6)9868 (69.4)0.2 (−12.3, 12.7)
Male179132 (73.7)198142 (71.7)2.0 (−7.0, 11.1)
Age     
≤ 30 years3525 (71.4)3521 (60.0)11.4 (−11.0, 33.9)
30−≤ 45 years180136 (75.6)169123 (72.8)2.8 (−6.4, 12.0)
45−≤ 55 years6439 (60.9)7252 (72.2)−11.3 (−27.2, 4.6)
55−≤ 65 years1411 (78.6)1812 (66.7)11.9 (−20.6, 44.4)
> 65 years11 (100)22 (100)0 (0, 0)
Race     
Black8352 (62.7)7247 (65.3)−2.6 (−17.9, 12.7)
Caucasian/White10273 (71.6)11076 (69.1)2.5 (−9.9, 14.9)
Hispanic4734 (72.3)5940 (67.8)4.5 (−13.2, 22.3)
Asian4843 (89.6)4136 (87.8)1.8 (−11.6, 15.1)
Other1410 (71.4)1411 (78.6)−7.1 (−40.7, 26.4)
Number of active NRTIs in the OBR     
01917 (89.5)1514 (93.3)−3.9 (−23.8, 16.1)
15342 (79.2)7559 (78.7)0.6 (−13.9, 15.1)
≥ 2218149 (68.3)194127 (65.5)2.9 (−6.2, 12.0)
Number of PIs previously used     
0135111 (82.2)137109 (79.6)2.7 (−6.7, 12.0)
17448 (64.9)7749 (63.6)1.2 (−14.2, 16.6)
≥ 28553 (62.4)8252 (63.4)−1.1 (−15.8, 13.7)
Adherence (M-MASRI)     
>95%166141 (84.9)149127 (85.2)−0.3 (−8.2, 7.6)
≤ 95%9755 (56.7)11974 (62.2)−5.5 (−18.7, 7.7)
Presence of primary PI mutations at baseline     
0247175 (70.9)250175 (70.0)0.9 (−7.2, 8.9)
≥ 14737 (78.7)4635 (76.1)2.6 (−14.6, 19.9)
Number of IAS-USA PI mutations12     
0–210064 (64.0)8558 (68.2)−4.2 (−18.0, 9.5)
3–411487 (76.3)12083 (69.2)7.1 (−4.3, 18.6)
≥ 58061 (76.3)9169 (75.8)0.4 (−12.5, 13.3)
M184V/I mutation at baseline     
Absent10463 (60.6)10558 (55.2)5.3 (−8.1, 18.8)
Present190149 (78.4)191152 (79.6)−1.2 (−9.4, 7.0)

Virological response rates were similar between treatment arms regardless of baseline CD4 cell count, ranging from 69.6 to 77.0% for once-daily and from 65.2 to 74.8% for twice-daily DRV/r (Table 2). Overall, higher response rates were seen with increasing baseline CD4 cell count, for both treatment arms.

The treatment arms showed comparable virological response rates for patients with viral clade B and for those with clade non-B (Table 2). Within each treatment arm, the response rate was slightly higher for the clade non-B than for the clade B subgroup; however, the clade non-B subgroup comprised 10 different clades, and the sample sizes for these clade subgroups were small. Across all gender, age and race subgroups, response rates were comparable for both once- and twice-daily DRV/r (Table 2). Some differences were seen across race subgroups, with the highest overall response rates seen in Asian patients (87.8%), whereas Black patients had slightly lower virological response rates (Table 2). However, once- and twice-daily DRV/r showed similar response rates in each of these subgroups.

Virological response rates by baseline resistance mutations

While response rates were similar between treatment arms by number of major (primary) PI mutations at baseline (Table 2), slightly higher overall response rates were seen in the patients with at least one major PI mutation at baseline. Comparable response rates were observed with both once- and twice-daily DRV/r across subgroups of patients with 0–2, 3–4 and ≥ 5 IAS-USA [12] PI RAMs (Table 2).

Comparable percentages of patients in the once- and twice-daily DRV/r treatment arms achieved HIV-1 RNA < 50 copies/mL at week 48 in the presence of M184V/I at baseline and in its absence (Table 2). Within each treatment arm, the response rate was higher in patients with the M184V/I mutation at baseline than in those without it.

Virological response rates by prior treatment history and activity of the OBR

No relevant differences in virological response were observed between once- and twice-daily DRV/r by number of active NRTIs in the OBR or by number of PIs previously used (Table 2). While response rates were unexpectedly higher in patients with no active NRTIs in the OBR than in those with one or at least two active NRTIs in the OBR (Table 2), the number of patients with no active NRTIs in the OBR was small (n = 19), limiting the interpretation of these results. A trend towards lower response rates was observed in patients who had previously used at least one PI than in those who had not previously received PIs (Table 2).

Virological response rates by adherence

Similar response rates were observed in the once- and twice-daily DRV/r arms for patients who were adherent (84.9 vs. 85.2%, respectively). For patients who were suboptimally adherent, the virological response was lower in the once-daily arm than in the twice-daily arm (56.7 vs. 62.2%, respectively; Table 2). Overall, adherent patients (> 95% adherence; based on self-report) had higher virological response rates than those suboptimally adherent (≤ 95%).

Multivariate analyses

Factors predictive of virological response

In view of the unexpected associations observed between certain subgroups and virological response in both treatment arms, a multivariate analysis of the entire study population (once- and twice-daily treatment arms) was performed. In this analysis, only baseline viral load, modelled as a continuous predictor (P = 0.0014), the presence of the M184V/I mutation at baseline (P < 0.0001) and adherence (P < 0.0001) were identified as significant predictors of virological response to DRV/r treatment.

The observed association between virological response and (a) previous PI use and (b) number of active NRTIs in the OBR appeared to be driven by the presence of the M184V/I mutation at baseline. In fact, 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).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

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 [9]. 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 [14]. Furthermore, this analysis found that, despite widespread DRV use, the prevalence of DRV RAMs has decreased since 2003 [14].

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 [18]. 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 [1].

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 [19].

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 [20].

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 [23]. 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 [25]. 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 [26].

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 [9]. 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.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References

The authors would like to thank the patients and their families for their participation and support during the study. In addition, the authors would like to acknowledge Catherine Elliott (Medical Writer, Gardiner-Caldwell Communications, Macclesfield, UK) for assistance in drafting the manuscript and collating author contributions. Financial assistance to support this service was provided by Janssen BVBA. The ODIN study was funded by Janssen BVBA.

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.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. References
  • 1
    Madruga JV, Berger D, McMurchie Met 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. Lancet 2007; 370: 4958.
  • 2
    Arastéh K, Yeni P, Pozniak Aet al. Efficacy and safety of darunavir/ritonavir in treatment-experienced HIV type-1 patients in the POWER 1, 2 and 3 trials at week 96. Antivir Ther 2009; 14: 859864.
  • 3
    Haubrich R, Berger D, Chiliade Pet al. Week 24 efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients. AIDS 2007; 21: F11F18.
  • 4
    Katlama C, Esposito R, Gatell JMet al. Efficacy and safety of TMC114/ritonavir in treatment-experienced HIV patients: 24-week results of POWER 1. AIDS 2007; 21: 395402.
  • 5
    Mills AM, Nelson M, Jayaweera Det al. Once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive, HIV-1-infected patients: 96-week analysis. AIDS 2009; 23: 16791688.
  • 6
    Ortiz R, Dejesus E, Khanlou Het al. Efficacy and safety of once-daily darunavir/ritonavir versus lopinavir/ritonavir in treatment-naive HIV-1-infected patients at week 48. AIDS 2008; 22: 13891397.
  • 7
    PREZISTA® (darunavir). EPARs for authorised medicinal products for human use. Updated 22 January 2013. Available at www.emea.europa.eu/ema/index.jsp?curl=pages/medicines/human/medicines/000707/human_med_000988.jsp&mid=WC0b01ac058001d124 (accessed 27 February 2013).
  • 8
    PREZISTA® (darunavir). Full prescribing information. Tibotec Inc. Revised February 2013. Available at www.prezista.com/sites/default/files/pdf/us_package_insert.pdf (accessed 27 February 2013).
  • 9
    Cahn P, Fourie J, Grinsztejn Bet al. ODIN: 48-week analysis of once- versus twice-daily darunavir/ritonavir in treatment-experienced HIV-1-infected patients. AIDS 2011; 25: 929939.
  • 10
    De Meyer S, Dierynck I, Lathouwers Eet al. Phenotypic and genotypic determinants of resistance to darunavir: analysis of data from treatment-experienced patients in POWER 1, 2, 3 and DUET-1 and 2. 16th International HIV Drug Resistance Workshop. Sitges, Spain, June 2008 [Abstract 31].
  • 11
    Johnson VA, Brun-Vezinet F, Clotet Bet al. Update of the drug resistance mutations in HIV-1: December 2009. Top HIV Med 2009; 17: 138145.
  • 12
    Johnson VA, Brun-Vezinet F, Clotet Bet al. Update of the drug resistance mutations in HIV-1. Top HIV Med 2008; 16: 138145.
  • 13
    King MS, Lawal AA, Fredrick LMet al. Impact of baseline resistance on virologic outcome with once-daily (QD) or twice-daily (BID) lopinavir/ritonavir (LPV/r) through 48 weeks of combination antiretroviral therapy in treatment-experienced, HIV-1-infected subjects. 12th European AIDS Conference. Cologne, Germany, November 2009 [Abstract PE10.1/1].
  • 14
    De La Rosa G, Pattery T, Picchio Get al. Changing prevalence of darunavir resistance-associated mutations (DRV RAMs) in clinical samples received for routine resistance testing: 2003–2009. 10th International Congress on Drug Therapy in HIV Infection. Glasgow, UK, November 2010 [Abstract P132].
  • 15
    Department of Health and Human Services. Panel on antiretroviral guidelines for adults and adolescents. Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents. Updated 12 February 2013; 1166.
  • 16
    Powderly WG, Saag MS, Chapman Set al. Predictors of optimal virological response to potent antiretroviral therapy. AIDS 1999; 13: 18731880.
  • 17
    Vray M, Meynard JL, Dalban Cet al. Predictors of the virological response to a change in the antiretroviral treatment regimen in HIV-1-infected patients enrolled in a randomized trial comparing genotyping, phenotyping and standard of care (Narval trial, ANRS 088). Antivir Ther 2003; 8: 427434.
  • 18
    Berger DS, Northland R, Scribner Aet al. Effect of baseline factors on virological response to darunavir/r and lopinavir/r at Week 48 in TITAN. 11th European AIDS Conference. Madrid, Spain, October 2007 [Abstract P7.3/27].
  • 19
    Weintrob AC, Grandits GA, Agan BKet al. Virologic response differences between African Americans and European Americans initiating highly active antiretroviral therapy with equal access to care. J Acquir Immune Defic Syndr 2009; 52: 574580.
  • 20
    Dierynck I, De Meyer S, Lathouwers Eet al. Comparable in-vitro susceptibility and virologic outcome to darunavir in patients infected with subtype B and subtype non-B HIV isolates participating in the ARTEMIS Phase III trial. XVIIth International AIDS Conference. Mexico City, Mexico, August 2008 [Abstract TUPE0049].
  • 21
    De Meyer S, Hill A, Picchio Get al. Influence of baseline protease inhibitor resistance on the efficacy of darunavir/ritonavir or lopinavir/ritonavir in the TITAN trial. J Acquir Immune Defic Syndr 2008; 49: 563564.
  • 22
    Molina J-M, Cohen C, Katlama Cet al. Safety and Efficacy of Darunavir (TMC114) with low-dose Ritonavir in treatment-experienced patients: 24-week results of POWER 3. J Acquir Immune Defic Syndr 2007; 46: 2431.
  • 23
    Maroldo L, Lawal A, Rivero Ret al. Effect of the M184V/I mutation and other nucleoside reverse transcriptase inhibitor (NRTI)-associated mutations on virologic response to a lopinavir/ritonavir-based regimen. XVIII International AIDS Conference. Vienna, Austria, July 2010 [Abstract TUPE0119].
  • 24
    Miller V, Stark T, Loeliger AEet al. The impact of the M184V substitution in HIV-1 reverse transcriptase on treatment response. HIV Med 2002; 3: 135145.
  • 25
    Whitcomb JM, Parkin NT, Chappey Cet al. Broad nucleoside reverse-transcriptase inhibitor cross-resistance in human immunodeficiency virus type 1 clinical isolates. J Infect Dis 2003; 188: 9921000.
  • 26
    Paterson DL, Swindells S, Mohr Jet al. Adherence to protease inhibitor therapy and outcomes in patients with HIV infection. Ann Intern Med 2000; 133: 2130.