PREZISTA (Page 9 of 12)

14.3 Treatment-Experienced Adult Subjects

TMC114-C229

TMC114-C229 is a randomized, open-label trial comparing PREZISTA/ritonavir 800/100 mg once daily to PREZISTA/ritonavir 600/100 mg twice daily in treatment-experienced HIV-1-infected patients with screening genotype resistance test showing no darunavir resistance associated substitutions (i.e. V11I, V32I, L33F, I47V, I50V, I54L, I54M, T74P, L76V, I84V, L89V) and a screening viral load of greater than 1,000 HIV-1 RNA copies/mL. Both arms used an optimized background regimen consisting of greater than or equal to 2 NRTIs selected by the investigator.

HIV-1-infected subjects who were eligible for this trial were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 50 copies/mL. Analyses included 590 subjects who had completed 48 weeks of treatment or discontinued earlier.

Table 21 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 800/100 mg once daily arm and subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm in trial TMC114-C229. No imbalances between the 2 arms were noted.

Table 21: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C229
PREZISTA/ritonavir 800/100 mg once daily + OBRN=294 PREZISTA/ritonavir 600/100 mg twice daily + OBRN=296
OBR=optimized background regimen
*
Based on phenotype (Antivirogram®)
Johnson VA, Brun-Vézinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: December 2008. Top HIV Med 2008; 16(5): 138–145
Only counting ARVs, excluding low-dose ritonavir
Demographic characteristics
Median age (years) (range, years) 40 (18–70) 40 (18–77)
Sex
Male 61% 67%
Female 39% 33%
Race
White 35% 37%
Black 28% 24%
Hispanic 16% 20%
Asian 16% 14%
Baseline characteristics
Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.19 4.13
Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 219 (24–1306) 236 (44–864)
Percentage of patients with baseline viral load ≥100,000 copies/mL 13% 11%
Percentage of patients with baseline CD4+ cell count <200 cells/mm3 43% 39%
Median darunavir fold change (range)* 0.50 (0.1–1.8) 0.50 (0.1–1.9)
Median number of resistance-associated :
PI mutations 3 4
NNRTI mutations 2 1
NRTI mutations 1 1
Percentage of subjects susceptible to all available PIs at baseline 88% 86%
Percentage of subjects with number of baseline primary protease inhibitor mutations :
0 84% 84%
1 8% 9%
2 5% 4%
≥3 3% 2%
Median number of ARVs previously used :
NRTIs 3 3
NNRTIs 1 1
PIs (excluding low-dose ritonavir) 1 1

Week 48 outcomes for subjects on PREZISTA/ritonavir 800/100 mg once daily from trial TMC114-C229 are shown in Table 22.

Table 22: Virologic Outcome of Randomized Treatment of Trial TMC114-C229 at 48 Weeks
PREZISTA/ritonavir 800/100 mg once daily + OBRN=294 PREZISTA/ritonavir 600/100 mg twice daily + OBRN=296
N = total number of subjects with data; OBR=optimized background regimen
*
Includes patients who discontinued prior to Week 48 for lack or loss of efficacy, patients who are ≥50 copies in the 48-week window, patients who had a change in their background regimen that was not permitted in the protocol (provided the switch occurred before the earliest onset of an AE leading to permanent stop of trial medication) and patients who discontinued for reasons other than AEs/death and lack or loss of efficacy (provided their last available viral load was detectable (HIV RNA ≥50 copies/mL).
Window 42–54 Weeks
Patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
§
Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL.
Virologic success HIV-1 RNA <50 copies/mL 69% 69%
Virologic failure * 26% 23%
No virologic data at Week 48 window
Reasons
Discontinued trial due to adverse event or death 3% 4%
Discontinued trial for other reasons § 2% 3%
Missing data during window but on trial 0% <1%

The mean increase from baseline in CD4+ cell counts was comparable for both treatment arms (108 cells/mm3 and 112 cells/mm3 in the PREZISTA/ritonavir 800/100 mg once daily arm and the PREZISTA/ritonavir 600/100 mg twice daily arm, respectively).

TMC114-C214

TMC114-C214 is a randomized, controlled, open-label Phase 3 trial comparing PREZISTA/ritonavir 600/100 mg twice daily versus lopinavir/ritonavir 400/100 mg twice daily in antiretroviral treatment-experienced, lopinavir/ritonavir-naïve HIV-1-infected adult subjects. Both arms used an optimized background regimen consisting of at least 2 antiretrovirals (NRTIs with or without NNRTIs).

HIV-1-infected subjects who were eligible for this trial had plasma HIV-1 RNA greater than 1000 copies/mL and were on a highly active antiretroviral therapy regimen (HAART) for at least 12 weeks. Virologic response was defined as a confirmed plasma HIV-1 RNA viral load less than 400 copies/mL. Analyses included 595 subjects in trial TMC114-C214 who had completed 96 weeks of treatment or discontinued earlier.

Demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the lopinavir/ritonavir arm (see Table 23). Table 23 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the lopinavir/ritonavir 400/100 mg twice daily arm in trial TMC114-C214.

Table 23: Demographic and Baseline Characteristics of Subjects in Trial TMC114-C214
PREZISTA/ritonavir 600/100 mg twice daily + OBRN=298 lopinavir/ritonavir 400/100 mg twice daily + OBRN=297
OBR=optimized background regimen
*
Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125–130
Only counting ARVs, excluding low-dose ritonavir
Based on phenotype (Antivirogram®)
§
Commercially available PIs at the time of trial enrollment
Demographic characteristics
Median age (years) (range, years) 40 (18–68) 41 (22–76)
Sex
Male 77% 81%
Female 23% 19%
Race
White 54% 57%
Black 18% 17%
Hispanic 15% 15%
Asian 9% 9%
Baseline characteristics
Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.33 4.28
Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 235 (3–831) 230 (2–1096)
Percentage of patients with baseline viral load ≥100,000 copies/mL 19% 17%
Percentage of patients with baseline CD4+ cell count <200 cells/mm3 40% 40%
Median darunavir fold change (range) 0.60 (0.10–37.40) 0.60 (0.1–43.8)
Median lopinavir fold change (range) 0.70 (0.40–74.40) 0.80 (0.30–74.50)
Median number of resistance-associated *:
PI mutations 4 4
NNRTI mutations 1 1
NRTI mutations 2 2
Percentage of subjects with number of baseline primary protease inhibitor mutations *:
≤1 78% 80%
2 8% 9%
≥3 13% 11%
Median number of ARVs previously used :
NRTIs 4 4
NNRTIs 1 1
PIs (excluding low-dose ritonavir) 1 1
Percentage of subjects resistant to all available § PIs at baseline, excluding darunavir 2% 3%

Week 96 outcomes for subjects on PREZISTA/ritonavir 600/100 mg twice daily from trial TMC114-C214 are shown in Table 24.

Table 24: Virologic Outcome of Randomized Treatment of Trial TMC114-C214 at 96 Weeks
PREZISTA/ritonavir 600/100 mg twice daily + OBRN=298 lopinavir/ritonavir 400/100 mg twice daily + OBRN=297
N = total number of subjects with data; OBR=optimized background regimen
*
Includes patients who discontinued prior to Week 96 for lack or loss of efficacy and patients who are ≥50 copies in the 96-week window and patients who had a change in their OBR that was not permitted by the protocol.
Window 90–102 Weeks
Includes patients who discontinued due to adverse event or death at any time point from Day 1 through the time window if this resulted in no virologic data on treatment during the specified window.
§
Other includes: withdrew consent, loss to follow-up, etc., if the viral load at the time of discontinuation was <50 copies/mL.
Virologic success HIV-1 RNA <50 copies/mL 58% 52%
Virologic failure * 26% 33%
No virologic data at Week 96 window
Reasons
Discontinued trial due to adverse event or death 7% 8%
Discontinued trial for other reasons § 8% 7%
Missing data during window but on trial 1% <1%

In trial TMC114-C214 at 96 weeks of treatment, the median increase from baseline in CD4+ cell counts was 81 cells/mm3 in the PREZISTA/ritonavir 600/100 mg twice daily arm and 93 cells/mm3 in the lopinavir/ritonavir 400/100 mg twice daily arm.

TMC114-C213 and TMC114-C202

TMC114-C213 and TMC114-C202 are randomized, controlled, Phase 2b trials in adult subjects with a high level of PI resistance consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to PREZISTA/ritonavir received the recommended dose of 600/100 mg twice daily.

HIV-1-infected subjects who were eligible for these trials had plasma HIV-1 RNA greater than 1000 copies/mL, had prior treatment with PI(s), NNRTI(s) and NRTI(s), had at least one primary PI mutation (D30N, M46I/L, G48V, I50L/V, V82A/F/S/T, I84V, L90M) at screening, and were on a stable PI-containing regimen at screening for at least 8 weeks. Randomization was stratified by the number of PI mutations, screening viral load, and the use of enfuvirtide.

The virologic response rate was evaluated in subjects receiving PREZISTA/ritonavir plus an OBR versus a control group receiving an investigator-selected PI(s) regimen plus an OBR. Prior to randomization, PI(s) and OBR were selected by the investigator based on genotypic resistance testing and prior ARV history. The OBR consisted of at least 2 NRTIs with or without enfuvirtide. Selected PI(s) in the control arm included: lopinavir in 36%, (fos)amprenavir in 34%, saquinavir in 35% and atazanavir in 17%; 98% of control subjects received a ritonavir boosted PI regimen out of which 23% of control subjects used dual-boosted PIs. Approximately 47% of all subjects used enfuvirtide, and 35% of the use was in subjects who were ENF-naïve. Virologic response was defined as a decrease in plasma HIV-1 RNA viral load of at least 1 log10 versus baseline.

In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/ritonavir arm and the comparator PI arm (see Table 25). Table 25 compares the demographic and baseline characteristics between subjects in the PREZISTA/ritonavir 600/100 mg twice daily arm and subjects in the comparator PI arm in the pooled analysis of trials TMC114-C213 and TMC114-C202.

Table 25: Demographic and Baseline Characteristics of Subjects in the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis)
PREZISTA/ritonavir 600/100 mg twice daily + OBR Comparator PI(s) + OBR
N=131 N=124
OBR=optimized background regimen
*
Johnson VA, Brun-Vezinet F, Clotet B, et al. Update of the drug resistance mutations in HIV-1: Fall 2006. Top HIV Med 2006; 14(3): 125–130
Based on phenotype (Antivirogram®)
Commercially available PIs at the time of trial enrollment
Demographic characteristics
Median age (years) (range, years) 43 (27–73) 44 (25–65)
Sex
Male 89% 88%
Female 11% 12%
Race
White 81% 73%
Black 10% 15%
Hispanic 7% 8%
Baseline characteristics
Mean baseline plasma HIV-1 RNA (log10 copies/mL) 4.61 4.49
Median baseline CD4+ cell count (cells/mm3) (range, cells/mm3) 153 (3–776) 163 (3–1274)
Percentage of patients with baseline viral load >100,000 copies/mL 24% 29%
Percentage of patients with baseline CD4+ cell count <200 cells/mm3 67% 58%
Median darunavir fold change 4.3 3.3
Median number of resistance-associated *:
PI mutations 12 12
NNRTI mutations 1 1
NRTI mutations 5 5
Percentage of subjects with number of baseline primary protease inhibitor mutations *:
≤1 8% 9%
2 22% 21%
≥3 70% 70%
Median number of ARVs previously used :
NRTIs 6 6
NNRTIs 1 1
PIs (excluding low-dose ritonavir) 5 5
Percentage of subjects resistant to all available PIs at baseline, excluding tipranavir and darunavir 63% 61%
Percentage of subjects with prior use of enfuvirtide 20% 17%

Week 96 outcomes for subjects on the recommended dose PREZISTA/ritonavir 600/100 mg twice daily from the pooled trials TMC114-C213 and TMC114-C202 are shown in Table 26.

Table 26: Outcomes of Randomized Treatment Through Week 96 of the Trials TMC114-C213 and TMC114-C202 (Pooled Analysis)
Randomized trialsTMC114-C213 and TMC114-C202
PREZISTA/ritonavir 600/100 mg twice daily + OBR Comparator PI(s) + OBR
N=131 N=124
OBR=optimized background regimen
*
Subjects who did not achieve at least a confirmed 0.5 log10 HIV-1 RNA drop from baseline at Week 12
Subjects with an initial response (confirmed 1 log10 drop in viral load), but without a confirmed 1 log10 drop in viral load at Week 96
Subjects who never reached a confirmed 1 log10 drop in viral load before Week 96
Virologic responders confirmed at least 1 log10 HIV-1 RNA below baseline through Week 96 (<50 copies/mL at Week 96) 57% (39%) 10% (9%)
Virologic failures 29% 80%
Lack of initial response * 8% 53%
Rebounder 17% 19%
Never suppressed 4% 8%
Death or discontinuation due to adverse events 9% 3%
Discontinuation due to other reasons 5% 7%

In the pooled trials TMC114-C213 and TMC114-C202 through 48 weeks of treatment, the proportion of subjects with HIV-1 RNA less than 400 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily compared to the comparator PI arm was 55.0% and 14.5%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were –1.69 log10 copies/mL in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily and –0.37 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving PREZISTA/ritonavir 600/100 mg twice daily (103 cells/mm3) than in the comparator PI arm (17 cells/mm3).

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