PRINCE‐1: safety and efficacy of atazanavir powder and ritonavir liquid in HIV‐1‐infected antiretroviral‐naïve and ‐experienced infants and children aged ≥3 months to <6 years

Abstract

IntroductionPRINCE-1 is an ongoing prospective, international, multicentre, nonrandomized, two-stage clinical trial assessing safety and efficacy of once-daily atazanavir (ATV) powder boosted with ritonavir (RTV) liquid plus optimized dual nucleoside reverse-transcriptase inhibitor (NRTI) background therapy in antiretroviral (ARV)-naïve and -experienced children with HIV-1 infection aged ≥3 months to <6 years.MethodsChildren with HIV-1 infection without prior ATV exposure and with a screening HIV-1 RNA ≥1000 copies/mL were enrolled. The dosing of ATV powder, boosted with 80 mg RTV liquid, was based on three baseline weight bands (5 to <10 kg=150 mg, 10 to <15 kg=200 mg and 15 to <25 kg=250 mg).ResultsOf the 56 treated patients, 46 completed 48 weeks of therapy, 67.9% were from Africa and 60.7% were ART-naïve. Median ages at baseline were 6, 35 and 55 months, and proportions with HIV-1 RNA >100,000 were 85.7, 52.6 and 25% in the three baseline weight bands, respectively. No unexpected safety events occurred and no deaths were reported. Over 48 weeks, upper respiratory tract infections, diarrhoea, vomiting and Grade 3 to 4 hyperbilirubinaemia occurred in 35.7, 35.7, 28.6, and 9.4% of patients, respectively; five patients (8.9%) discontinued due to adverse events (AEs); and 11 patients (19.6%) experienced serious adverse events. At Week 48, using a modified intent-to-treat analysis (two patients were excluded because they switched to ATV capsules before Week 48), 61.1 and 74.1% of patients overall had an HIV-1 RNA level <50 copies/mL and <400 copies/mL, respectively. Virologic suppression rates increased across the lowest to highest baseline weight bands (47.6, 68.4 and 71.4% had HIV-1 RNA <50 copies/mL, and 66.7, 73.7 and 85.7% had HIV-RNA <400 copies/mL, respectively) but did not differ meaningfully between ARV-naïve and -experienced patients. Overall, the median change from baseline in CD4 cell count was +363 cells/mm3, and the median change from baseline in CD4 percent was +7.5%.ConclusionsATV powder boosted with RTV liquid once daily plus optimized dual NRTI background therapy was effective and well tolerated in this ART-naïve or -experienced paediatric population aged ≥3 months to <6 years. No unexpected safety findings compared with those from previous ATV paediatric and adult studies were identified.

Optimizing Pediatric Dosing Recommendations and Treatment Management of Antiretroviral Drugs Using Therapeutic Drug Monitoring Data in Children Living With HIV

“…The PRINCE I and PRINCE II trials showed that ATV powder formulation in combination with RTV liquid in children 3 months to <11 years and weighing 5 to <35 kg dosed in weight bands reached the target drug exposure levels. 61,65,66 Results from the PRINCE I and II trials together with IMPAACT P1020 and the modeling study by Hong et al supported the FDA approval of ATV/r doses in children (see Table 3 , Supplemental Digital Content 2 , http://links.lww.com/TDM/A324).…”

Hepatic, Renal, Hematologic, and Inflammatory Markers in HIV-Infected Children on Long-term Suppressive Antiretroviral Therapy

“…In addition, many of the newer ARVs are better tolerated and provide additional options for treatment should modifying ART as a result of intolerance become necessary. Most studies of ART-associated toxicity in children have reported only grade 3 or higher adverse events or are limited to short-term follow-up [22][23][24] and include children on ART but with elevated HIV RNA levels. It can be difficult to sort the medication effects from the effects of active viral replication, which itself can lead to elevations in liver enzyme levels [25], neutropenia, thrombocytopenia, and anemia [26,27].…”

Effectiveness and Safety of Atazanavir Use for the Treatment of Children and Adolescents Living With HIV: A Systematic Review

“…Among the 1.085 records identified, 901 titles and abstracts were screened after duplicates removed. Overall, 23 full papers were assessed for eligibility, of which five were included in the narrative synthesis ( Figure 1 ) ( 22 – 26 ).…”

“…Those five studies contributed data for 975 children and adolescents, of whom 544 (56%) received atazanavir. Three were observational cohort studies ( 22 , 23 , 25 ) (two retrospective and one prospective comparative, based on a phase 3b clinical trial) and two were prospective non-randomized clinical trials ( 24 , 26 ). The single comparative cohort study ( 23 ) compared atazanavir-based with darunavir-based regimens, and was conducted in Europe and Thailand between 2011 and 2014.…”