Use of PREZISTA in Pediatric and Adolescent Patients

SUMMARY

• The DIONE (TMC114-C230) study was a phase 2, open-label, 48-week trial assessing the efficacy, safety, tolerability, and pharmacokinetics (PK) of PREZISTA/ritonavir (r) 800/100 mg once daily (QD) plus zidovudine (AZT)/lamivudine (3TC) or abacavir (ABC)/3TC in 12 treatment-naïve, HIV-1-infected adolescents aged 12 to <18 years.¹
  • At week 48, 83.3% (intent-to-treat population, time-to-loss of virologic response [ITT-TLOVR]) and 92% (FDA snapshot) of patients had achieved viral load (VL) <50 copies/mL.
• The ARIEL study (TMC114-C228) assessed the short-term safety and efficacy of PREZISTA/r plus an optimized background regimen (OBR) in HIV-1 infected, treatment-experienced children aged 3 to <6 years (N=21).²
  • At week 48, 81% (ITT-TLOVR) and 71.4% (FDA snapshot) of patients achieved VL <50 copies/mL, while the mean CD4+ cell count increased by 187 cells/mm.
• The DELPHI study (TMC114-C212) evaluated the efficacy, safety, and tolerability of PREZISTA/r plus an OBR in treatment-experienced, HIV-1-infected children aged 6-17 years.³
  • Virologic response to PREZISTA at week 48 was reduced in those patients with ≥3 darunavir (DRV) resistance-associated mutations (RAMs) at baseline.
  • At week 48, the proportion of patients that achieved VL <50 copies/mL and <400 copies/mL was 48% and 59%, respectively.
• The DIANA study (TMC114-TiDP29-C232) was an open-label, single arm study that evaluated long-term safety in patients receiving continued access to PREZISTA/r plus an OBR in patients aged 3 to <18 years who participated in the DELPHI, DIONE, or ARIEL studies.⁴
  • The overall median duration of PREZISTA/r intake was 4.2 years (0.1 – 7.1), with majority of patients aged ≥12 to <18 (54%, 25/46).
  • The most common AEs, any grade in ≥2 patients, were pneumonia (7%, 3/46), asthma (4%, 2/46), gastroenteritis (4%, 2/46), and lipoatrophy (4%, 2/46).
  • No deaths were reported and none of the serious adverse events (SAEs) were considered related to PREZISTA/r treatment or led to study discontinuation.

CLINICAL studies

TREATMENT-NAIVE PEDIATRIC PATIENTS

DIONE Study

The DIONE Study (TMC114-C230) was a phase 2, open-label, 48-week trial assessing the efficacy, safety, tolerability, and PK of PREZISTA/r 800/100 mg QD plus AZT/3TC or ABC/3TC in treatment-naïve, HIV-1-infected adolescents aged 12 to <18 years.¹

Study Design/Methods

• Treatment-naïve adolescents weighing ≥40 kg with VL levels ≥1,000 copies/mL were admitted to the study.
• Primary efficacy parameter: proportion of patients with VL <50 copies/ml at week 24 (IIT-TLOVR).
• Secondary outcome measures included VL <50 copies/mL at week 48 (ITT-TLOVR, noncompleter=failure [NC=F]), virologic response at weeks 24 and 48 via FDA snapshot analysis, VL <400 copies/mL, ≥1 log₁₀ decrease in VL compared to baseline (NC=F), and change in CD4+ count.
• Phenotypic and genotypic analyses were performed at baseline, week 24, week 48, or at time of study withdrawal for samples with VL ≥1000 copies/ML.
• DRV PK concentrations were determined using rich sampling (6 samples) over a 24-hour period after 2 weeks and sparse sampling (2 samples) after 4, 24, and 48 weeks of treatment.
• Safety was evaluated in the ITT population.

Results

Patient Characteristics

• All 12 patients enrolled in the study completed 48 weeks of treatment (median age [range]: 14.4 years [12.6 - 17.3]; 67% female; 58% Caucasian).
  • PREZISTA /r plus AZT/3TC (n=6)
  • PREZISTA/r plus ABC/3TC (n=6)
• Mean (SE) baseline VL was 4.72 (0.172) copies/mL; median CD4+ cell count was 282 cells/mm³ (range 204-515).

Efficacy

• In the primary analysis at week 24, 11/12 (92%) patients achieved VL <50 copies/mL (ITT-TLOVR).
• At week 48, 10/12 patients (83%; ITT-TLOVR) and 11/12 (92%; FDA snapshot) had VL <50 copies/mL.
• Eleven patients (ITT-TLOVR) had VL <400 copies/mL at week 48.
• All 12 patients achieved ≥1 log₁₀ decrease in VL by week 24, which was maintained at week 48.
• Mean CD4+ count increased by 221 cells/mm³ from baseline.

Resistance

• One patient was considered a VF.
  • The patient had an unconfirmed VL <50 copies/mL at week 24, but subsequent VL measurements were >50 copies/mL.
  • The primary PI mutation M46I had emerged, but the patient’s virus remained susceptible to all PIs and NRTIs.
  • This patient was nonadherent from week 24 onward according to both the Study Adherence Questionnaire and pill count.
• One patient experienced rebound at week 40 but was resuppressed at week 48.
  • The patient had a treatment-emergent NRTI RAM (K219Q) but remained susceptible to the background regimen of AZT/3TC and all PIs.
• The only patient with a baseline DRV RAM (V11I) achieved virologic response at week 16, which was maintained through week 48 (ITT-TLOVR).

PK

• At week 2, the median (range) DRV area under the plasma concentration-time curve over the 24-hour dosing interval (AUC_T) and trough concentrations (C_0h) were 87.9 μg•h/mL (34.6-128) and 2196 ng/mL (510-3975), respectively.⁵
• At week 48, the mean (SD) DRV AUC_24h and C_0h were 80.7 (23.6) μg•h/mL and 1.93 (0.87) μg•h/mL, respectively.¹
• Overall DRV exposure was comparable to that observed in HIV-1-infected, treatment-naïve adults receiving PREZISTA/r 800/100 mg QD in the ARTEMIS study (mean AUC_24h 89.7 μg•h/mL).¹
• No relevant relationships were observed between DRV PK and virologic response, change in VL from baseline, or AEs of clinical interest.

Safety

• AEs were reported in 11/12 patients (Table: Incidence of AEs at Week 48).

• AEs (regardless of causality or severity) reported in ≥2 patients included vomiting (n=4), anemia (n=3), nausea (n=3), cough (n=2), diarrhea (n=2), furuncle (n=2), pyrexia (n=2), and sinusitis (n=2).
• Five SAEs were reported in 4 patients; 4 were considered unrelated to PREZISTA and 1 (anemia) was considered doubtfully related to PREZISTA.
• No patients discontinued treatment due to an AE.
• Grade 2-4 treatment-emergent lipid- and glucose-related laboratory-related abnormalities are presented in Table: Lipid and Glucose-Related Laboratory Abnormalities at Week 48.

TREATMENT-EXPERIENCED PEDIATRIC PATIENTS

ARIEL Study

The ARIEL study (TMC114-C228) assessed the short-term safety and efficacy of PREZISTA/r plus an OBR in HIV-1 infected, treatment-experienced children aged 3 to <6 years (N=21) to support PREZISTA/r bodyweight dosage recommendations.²

Study Design/Methods

• Forty-eight week, open-label, single-arm, phase 2 trial.
• Inclusion criteria: HIV-1 infected children (3 to <6 years) receiving highly active antiretroviral therapy (HAART) for > 12 weeks; weight 10 to <20 kg; VL >1000 copies/mL; <2 DRV RAMs at screening.
• The initial dose of PREZISTA/r was 20 mg/kg (oral suspension 100 mg/mL) and 3.0 mg/kg, respectively, administered BID.
  • Following PK analysis at week 2, the PREZISTA dose was amended to 25 mg/kg twice daily for patients weighing 10 to <15 kg and 375 mg twice daily (fixed) for patients weighing 15 to <20 kg.
  • The RTV dose remained the same for the lower weight group but was changed to 50 mg (fixed) for the upper weight group.
• Patients also received an investigator-selected OBR consisting of ≥2 ARVs.
• The primary efficacy analysis occurred at week 24, with final analysis at week 48.
• Primary efficacy endpoint: proportion of patients achieving VL <50 copies/mL (ITT-TLOVR).
• Secondary analyses included VL <50 copies/mL via FDA snapshot, VL <400 copies/mL, ≥1 log₁₀ decrease in VL compared to baseline, change in CD4+ cell count and CD4+ percentage from baseline.
• Resistance was evaluated at screening (genotyping only), and at baseline, week 24, week 48, and in the event of early withdrawal (both genotyping and phenotyping) in patients with VL ≥1000 copies/mL.
• Resistance determinations were attempted on samples from VFs if VL >50 copies/mL.

Results

Patient Characteristics

• Twenty-one patients were treated with PREZISTA/r plus an OBR.
  • Demographics: male 10/21 (47.6%), median age 4.4 years, black (12/21), white (6/21), Asian (1/21), multiple races (2/21).
  • Mean (SE) baseline VL was 4.34 (0.18) copies/mL, with a median CD4+ count of 927 (range 209-2429) and median CD4+ percentage of 27.7.
  • Sixteen patients (76%) had previously received lopinavir (LPV)/r.
• Nineteen patients (90%) received 2 NRTIs while 2 patients (10%) received 3 NRTIs in the OBR.
  • 3TC and AZT (62% each) were the most commonly used NRTIs.
• Baseline resistance data are provided in Table: Baseline Resistance Data for Patients Enrolled in ARIEL.

Efficacy

• In the primary analysis at week 24, 12/21 (57.1%) patients achieved VL <50 copies/mL (ITT-TLOVR).
• At week 48, VL <50 copies was achieved in 17/21 (81%) and 15/21 (71.4%) patients via ITT-TLOVR and snapshot analysis, respectively.
  • Secondary endpoints, VL <400 copies/mL and ≥1 log₁₀ reduction in VL from baseline, were achieved by 85.7% and 90.5% of patients, respectively.
• Mean increase in CD4+ cell count was 187 cells/mm³, and CD4+ percentage increased by 4% from baseline to week 48.

Safety

• Twenty patients (95%) experienced ≥1 AE (Table: Frequency of AEs at Week 48).

• The most common AEs were upper respiratory tract infection (n=6), cough (n=5), diarrhea (n=5), tinea capitis (n=5), nasopharyngitis (n=4), vomiting (n=4), impetigo (n=3), nasal congestion (n=3), pyrexia (n=3), rash (n=3), rhinitis (n=3), and rhinorrhea (n=3).
• There were no clinically relevant changes in laboratory parameters from baseline to endpoint.
• All laboratory abnormalities were grade 1-2 except one case of grade 3 neutropenia, which was present since baseline and not considered treatment-related.
• Baseline median age-adjusted z-scores for height, weight and body mass index (BMI) revealed that patients were below normal population values with respect to height and weight, but not BMI.
  • At week 48, mean increases from baseline in height (5 cm), weight (1.7 kg), and BMI (0.1 kg/m²) were observed.

Resistance

• The 2 patients with DRV RAMs (L33F + L76V, n=1; L76V, n=1) at baseline were virologically suppressed at weeks 24 and 48.
• At week 48, 3 patients were considered VFs (2 never suppressed, 1 rebounder).
• Of 2 VF patients with paired baseline/endpoint genotypes, none developed new PI or NRTI RAMs.
  • Both patients remained susceptible to DRV and NRTIs in the OBR.

DELPHI Study

The DELPHI study (TMC114-C212) evaluated the efficacy, safety, and tolerability of PREZISTA/r plus an OBR through 48 weeks in treatment-experienced, HIV-1-infected children aged 6-17 years.³

Study Design/Methods

• Randomized, 2-part, open-label, phase 2, 48-week study.
  • Part 1: dose-finding study based on body weight (n=44).⁶
    • Patients received 1 of 2 PREZISTA/r weight-based dosing regimens (group A: PREZISTA 9-15 mg/kg and RTV 1.5–2.5 mg/kg BID or group B: PREZISTA 11–19 mg/kg and RTV 1.5-2.5 mg/kg BID) in combination with ≥2 antiretrovirals (ARVs) for 14 days.
      • Group A: PREZISTA/r PK parameters (C_0h, AUC_24h, C_max) were 9%, 19%, and 12% lower than the reference adult exposure (PREZISTA/r 600/100 mg dose).
      • Group B: PREZISTA/r PK parameters in group B were 14%, 2%, and 12% greater than the reference adult exposure.
  • Part 2 of the study included all 44 patients from part 1, 24 additional patients with body weight 20-50 kg, plus 12 patients with body weight ≥50 kg (who received the adult dosage).³
  • Based on PK, safety, and efficacy data from part 1, PREZISTA 11–19 mg/kg and RTV 1.5–2.5 mg/kg BID was selected as an appropriate dose for administration in part 2 of the DELPHI study.^3,6

• Inclusion criteria: 6-17 years; body weight ≥20 kg; VL ≥1,000 copies/mL; stable CD4+ percentage; on HAART ≥12 weeks; able to swallow the PREZISTA 75 mg or 300 mg tablets.^3,7
• PK and pharmacodynamic (PD) analyses:
  • Steady-state DRV AUC_12h and C_0h at week 48.
  • Effect of DRV PK on efficacy or safety at week 24.⁶

Results

Patient Characteristics

• Previous ARV exposure: ≥1 NRTI (100%); ≥1 PI (96%); ≥1 NNRTI (79%); enfuvirtide (ENF; 10%).³
• ARVs in the OBR: NRTIs (98%); NNRTIs (6%); ENF (30%).³
  • NRTIs in the OBR: 3TC (48%), tenofovir disoproxil fumarate (TDF; 45%), AZT (40%), didanosine (DDI; 30%).
• Median (range) number of IAS-USA mutations at baseline: PI RAMs 11 (0–19); primary PI RAMS 3 (0-6); NNRTI RAMs 2 (0–4); NRTI RAMs 4 (0–8).⁷

Pharmacokinetics

• DRV exposure in pediatric patients was comparable to that of treatment-experienced, HIV-infected adults from a 24-week analysis of POWER 1 and 2 studies (Table: DRV PK Comparison Between Pediatric and Adult Patients).³
• Trough concentrations (C_0h) were well above the protein-binding corrected EC₅₀ value (550 ng/mL) for PI-resistant virus.³

• No relationship was observed between PREZISTA/r AUC_12h or C_0h and virologic response or AEs.⁶

Efficacy

• Fifty-eight patients (73%) were adherent to treatment (had not missed any doses of PREZISTA/r) based on responses to an adherence questionnaire. In the 6 to less than 12 years age group, 16 patients (67%) were adherent, whereas in the 12-17 years age group, there were 42 adherent patients (75%).

Factors associated with virologic success³

• A logistic regression model on virologic response (<50 copies/mL) at week 48 was performed and included the covariates: baseline VL, sex, age, number of DRV mutations, number of sensitive NRTIs in the OBR, ENF use and treatment compliance.
• Compliance and the number of DRV mutations were found to significantly affect response (P<0.0001); no other factors were significant.

Changes in Height and Weight

• Patients that received PREZISTA/r experienced statistically significant increases in height (+4.1 cm; P<0.001) and weight (+4.3 kg, P<0.003) from baseline at week 48.³

Resistance

• Thirty percent of patients (24/80) experienced VF: 21% (17/80) were rebounders, and 9% (7/80) were never suppressed.³
• Virologic response to PREZISTA at week 48 was reduced in those patients with ≥3 DRV RAMs at baseline (Table: Effect of DRV RAMs on Virologic Response).⁷
• PI mutations developing in at least 10% of rebounders (n ≥2) were 154L (n=5), V32I (n=4), I50V (n=3), I13V (n=2), M36L (n=2), V77I (n=2), and L89M (n=2). V32I, I50V, and I54L are DRV RAMs.³

Safety

• Incidence of both grade 2-4 treatment-related diarrhea and rash was 1%.
• The most common grade 2-4 lipid laboratory abnormalities at week 48 were increased total cholesterol (TC) and increased LDL (Table: Selected Grade 2-4 Laboratory Abnormalities through Week 48).

• No significant increases were noted in mean blood glucose levels in patients who received PREZISTA/r through week 48 (P=0.77).

LONG-TERM SAFETY DATA

DIANA STUDY

The DIANA study (TMC114-TiDP29-C232) was an open-label, single arm study that evaluated long-term safety in patients receiving continued access to PREZISTA/r plus an OBR in patients aged 3 to <18 years who participated in the DELPHI, DIONE, or ARIEL studies.⁴

Study Design/Methods

• Treatment-experienced pediatric patients aged ≥3 years who completed the phase 2, open-label DELPHI, ARIEL, or DIONE studies and, per investigators, benefitted from PREZISTA use in countries where PREZISTA was unavailable or not accessible free of charge, were included in the study.
  • Safety was evaluated in the ITT population.
  • The patients continued to receive the same PREZISTA/r dosage regimen based on the original study protocols that they participated in (or on a body weight adjusted dose for patients from the DELPHI or ARIEL studies). Patients also received an OBR that was composed by the investigators.
  • Treatment with PREZISTA/r would be discontinued if the following criteria was met, whichever occurred first: virologic failure; treatment-limiting toxicity; loss to follow-up; withdrawal of consent/assent by the patient or withdrawal of consent by the parent(s)/legal representative(s); pregnancy; or termination of the study by the sponsor.
  • Treatment was also discontinued if PREZISTA became commercially available or could be accessed through another source.

Results

Patient Characteristics

• Forty-six patients were enrolled and received at least 1 dose of PREZISTA (ITT population).
• Median age (range) and number of patients from each study:
  • DELPHI: 15.0 years (11–17); n=16
  • ARIEL: 5.0 years (4–6); n=20
  • DIONE: 14.5 years (13–17); n=10
• The overall median (range) duration of PREZISTA/r intake was 4.2 years (0.1–7.1).
• Lamivudine was the most frequently used NRTI in the ITT population (74%; 34/46).

Safety

• AEs were reported in 33% (15/46) of patients (Table: Incidence of AEs).
• SAEs were reported in 26% (12/46) of patients.
• The most common AEs, any grade in ≥2 patients, were pneumonia (7%, 3/46), asthma (4%, 2/46), gastroenteritis (4%, 2/46), and lipoatrophy (4%, 2/46).

• No deaths were reported, and none of the grade 3 or 4 AEs or SAEs were considered related to PREZISTA/r treatment or led to study discontinuation.
• Only one AE was considered related to PREZISTA/r treatment (grade 1 lipoatrophy).
• There were 3 pregnancies amongst the patients and 2 of them were reported as an AE. All the pregnancies that were reported led to study discontinuation.
  • Follow-up data was available for 2 patients; one patient gave birth to an infant with no abnormalities and the other patient reported grade 3 SAEs (blighted ovum and spontaneous abortion).

Literature Search

A literature search of MEDLINE^®, EMBASE^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 03 January 2025.