INDICATIONS AND USAGE
PREZISTA, co-administered with 100 mg ritonavir (PREZISTA/rtv), and with other antiretroviral agents, is indicated for the treatment of human immunodeficiency virus (HIV) infection in antiretroviral treatment-experienced adult patients, such as those with HIV-1 strains resistant to more than one protease inhibitor.
This indication is based on Week 24 analyses of plasma HIV RNA levels and CD4+ cell counts from 2 controlled trials of PREZISTA/rtv in combination with other antiretroviral drugs. Both studies were conducted in clinically advanced, treatment-experienced (NRTIs, NNRTIs, and PIs) adult patients with evidence of HIV-1 replication despite ongoing antiretroviral therapy.
The following points should be considered when initiating therapy with PREZISTA/rtv:
- Treatment history and, when available, genotypic or phenotypic testing, should guide the use of PREZISTA/rtv (see MICROBIOLOGY).
- The use of other active agents with PREZISTA/rtv is associated with a greater likelihood of treatment response (see MICROBIOLOGY and INDICATIONS AND USAGE, Description of Clinical Studies).
- The risks and benefits of PREZISTA/rtv have not been established in treatment-naïve adult patients or pediatric patients.
Description of Clinical Studies
The evidence of efficacy of PREZISTA/rtv is based on the analyses of 24-week data from 2 ongoing, randomized, controlled trials, TMC114-C213 and TMC114-C202, in antiretroviral treatment-experienced HIV-1 infected adult subjects. These efficacy results were supported by the 24-week pooled analysis of the open label trials TMC114-C215 and TMC114-C208 of subjects who initiated PREZISTA/rtv at the recommended dose.
Treatment-Experienced Subjects
Studies TMC114-C213 and TMC114-C202
These are ongoing randomized, controlled, Phase 2b trials consisting of 2 parts: an initial partially-blinded, dose-finding part and a second long-term part in which all subjects randomized to PREZISTA/rtv received the recommended dose of 600/100 mg b.i.d.
HIV-1 infected subjects who were eligible for these trials had plasma HIV-1 RNA > 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. Analyses included 318 subjects in Study TMC114-C213 and 319 subjects in Study TMC114-C202 who had completed 24 weeks of treatment or discontinued earlier.
At 24 weeks, the virologic response rate was evaluated in subjects receiving PREZISTA/rtv plus an optimized background regimen (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 1.0 log10 versus baseline.
In the pooled analysis for TMC114-C213 and TMC114-C202, demographics and baseline characteristics were balanced between the PREZISTA/rtv arm and the comparator PI arm. Table 6 compares the demographic characteristics between subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and subjects in the comparator PI arm.
Table 6: Demographic Characteristics of Subjects in the Studies TMC114-C213 and TMC114-C202 (Pooled Analysis) | Randomized Studies TMC114-C213 and TMC114-C202 |
|---|
| PREZISTA/rtv
600/100 mg b.i.d. + OBR
N = 131 | Comparator PI(s) + OBR
N = 124 |
|---|
| Demographic Characteristics | | |
Age (years)
(range, years) | 43.0
(27-73) | 44.0
(25-65) |
| Sex | | |
| Male | 89% | 88% |
| Female | 11% | 12% |
| Race | | |
| White | 81% | 73% |
| Black | 10% | 15% |
| Hispanic | 7% | 8% |
Median Baseline Plasma HIV-1 RNA (log10 copies/mL)
(range, log10 copies/mL) | 4.52
(3.0-6.4) | 4.56
(2.2-6.1) |
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 | 24.4% | 29.0% |
| Percentage of Patients with Baseline CD4+ Cell Count < 200 cells/mm3 | 67% | 58% |
| Median Darunavir FC | 4.3 | 3.3 |
Table 7 compares the baseline characteristics between subjects in the PREZISTA/rtv 600/100 mg b.i.d. arm and subjects in the comparator PI arm.
Table 7: Baseline Characteristics of Subjects in the Studies TMC114-C213 and TMC114-C202 (Pooled Analysis) | Randomized Studies TMC114-C213 and TMC114-C202 |
|---|
| PREZISTA/rtv
600/100 mg b.i.d. + OBR
N = 131 | Comparator PI(s) + OBR
N = 124 |
|---|
| ^ L10F/I/R/V, K20I/L/M/R/T, L24I, D30N, V32I, L33F/I, M36I/L/V, M46I/L, I47A/V, G48V, I50L/V, F53L, I54A/L/M/S/T/V, A71V/T, G73A/C/S/T, V77I, V82A/F/L/S/T, I84A/C/V, N88D/S, L90M |
| † Based on the IAS-USA list of mutations (March 2005): D30N, L33F/I, M46I/L, G48V, I50L/V, V82A/F/L/S/T, I84A/C/V, L90M |
| ‡ Only counting ARVs, excluding low-dose ritonavir, taken for at least 2 months, and for which start and stop dates were available |
| § Based on phenotype (Antivirogram™) |
| ¶ Commercially available PIs at the time of study enrollment |
| Baseline Characteristics | | |
| Median Number of Resistance-Associated: | | |
| PI mutations^ | 8 | 8 |
| NNRTI mutations | 1 | 1 |
| NRTI mutations | 6 | 5 |
| Percentage of Subjects with the following Baseline IAS Primary Protease Mutations†: | | |
| ≤ 1 | 8% | 13% |
| 2 | 37% | 25% |
| ≥ 3 | 54% | 62% |
| 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 | 64% | 61% |
| Percentage of Subjects with Prior Use of Enfuvirtide | 19% | 16% |
Week 24 outcomes for subjects on the recommended dose PREZISTA/rtv 600/100 mg b.i.d. from the pooled Studies TMC114-C213 and TMC114-C202 are shown in Table 8.
Table 8: Outcomes of Randomized Treatment Through Week 24 of the Studies TMC114-C213 and TMC114-C202 (Pooled Analysis) | Randomized Studies TMC114-C213 and TMC114-C202 |
|---|
| PREZISTA/rtv 600 mg b.i.d. + OBR
N=131 | Comparator PI + OBR
N=124 |
|---|
| ^ 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 24 |
| ‡ Subjects who never reached a confirmed 1 log10 drop in viral load before Week 24 |
Virologic Responders
confirmed at least 1 log10 HIV-1 RNA below baseline
through Week 24
(< 50 copies/mL at Week 24) | 69.5%
(45.0%) | 21.0%
(12.1%) |
| Virologic failures | 26.0% | 71.0% |
| Lack of initial response^ | 9.9% | 57.3% |
| Rebound† | 9.2% | 9.7% |
| Never Suppressed‡ | 6.9% | 4.0% |
| Death or discontinuation due to adverse events | 3.9% | 1.6% |
| Discontinuation due to other reasons | 0.8% | 6.5% |
Through 24 weeks of treatment, the proportion of subjects with HIV-1 RNA < 400 copies/mL in the arm receiving PREZISTA/rtv 600/100 mg b.i.d. compared to the comparator PI arm was 63% and 19%, respectively. In addition, the mean changes in plasma HIV-1 RNA from baseline were -1.89 log10 copies/mL in the arm receiving PREZISTA/rtv 600/100 mg b.i.d. and -0.48 log10 copies/mL for the comparator PI arm. The mean increase from baseline in CD4+ cell counts was higher in the arm receiving PREZISTA/rtv 600/100 mg b.i.d. (92 cells/mm3) than in the comparator PI arm (17 cells/mm3).
The TMC114-C215/C208 analysis
Additional data on the efficacy of PREZISTA/rtv 600/100 mg b.i.d. have been obtained in treatment-experienced subjects participating in the non-randomized trials TMC114-C215 and TMC114-C208. The 246 subjects from these trials included in the TMC114-C215/C208 24-week efficacy analysis initiated therapy with PREZISTA/rtv with the recommended dose of 600/100 mg b.i.d. The OBR consisted of at least two NRTIs with or without enfuvirtide. Entry criteria for the TMC114-C215/C208 analysis were the same as those for Studies TMC114-C213 and TMC114-C202.
Baseline characteristics of the subjects included in the TMC114-C215/C208 analysis were comparable to those subjects in Studies TMC114-C213 and TMC114-C202.
The TMC114-C215/C208 24-week efficacy analysis supported the viral load reduction and CD4+ cell count increases observed in the Studies TMC114-C213 and TMC114-C202. Of the 246 subjects at Week 24, 65% had a virologic response defined as a decrease of at least 1.0 log10 in plasma viral load versus baseline and 40% of the subjects reached less than 50 HIV-1 RNA copies/mL. The mean increase in CD4+ cell count versus baseline was 80 cells/mm3 at Week 20. At Week 24, 57% of the subjects reached less than 400 HIV-1 RNA copies/mL, and the mean changes in plasma HIV-1 RNA from baseline were -1.65 log10 copies/mL.
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DOSAGE AND ADMINISTRATION
Adults
The recommended oral dose of PREZISTA tablets is 600 mg (two 300 mg tablets) twice daily taken with ritonavir 100 mg twice daily and with food. The type of food does not affect exposure to darunavir.
Pediatric Patients
The safety and efficacy of PREZISTA in pediatric patients has not been established (see CLINICAL PHARMACOLOGY, Special Populations, Pediatric Patients).
Hepatic Impairment
There are no data regarding the use of PREZISTA/rtv when co-administered to patients with varying degrees of hepatic impairment; therefore, specific dosage recommendations cannot be made. PREZISTA/rtv should be used with caution in patients with hepatic impairment (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Hepatic Impairment and PRECAUTIONS, Patients with co-existing conditions, Hepatic Impairment).
Renal Impairment
No dose adjustment is required in patients with moderate renal impairment. There are no pharmacokinetic data available in HIV-1 infected patients with severe renal impairment or end stage renal disease (see CLINICAL PHARMACOLOGY, Pharmacokinetics in Adults, Special Populations, Renal Impairment and PRECAUTIONS, Patients with co-existing conditions, Renal Impairment).
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