Current international treatment guidelines recommend initiating antiretroviral (ARV) therapy for all HIV-infected children, regardless of clinical, virologic or CD4 criteria.1 , 2 Preferred first-line regimens if <3 years include 2 nucleos(t)ide reverse transcriptase inhibitors (NRTIs) with ritonavir-boosted lopinavir (LPV + RTV)1 , 2 or raltegravir,2 and for those between 3 and 10 years, abacavir + lamivudine + efavirenz1 or 2 NRTIs with ritonavir-boosted atazanavir (ATV + RTV), ritonavir-boosted darunavir, efavirenz, LPV+RTV or raltegravir.2
Fewer clinical trials evaluating efficacy, safety, pharmacokinetics (PK), and optimal dosage of ARV formulations have been conducted in young children than in adults.
Atazanavir (ATV), a HIV-1 protease inhibitor (PI) given once daily, is indicated for adults and children. ATV is available in capsule (150, 200 and 300 mg) formulations globally.3–5 More recently, an oral powder formulation (50 mg ATV per gram of powder) was developed for infants and young children,3 where LPV + RTV may be poorly tolerated. Other PIs currently available as liquid formulations/reconstituted oral suspensions for children include darunavir (for children 3 to ≤18 years of age; oral suspension approved in the United States and European Union [EU]),6 fosamprenavir (for children 2–18 years; oral suspension approved in the United States),7 co-formulated LPV + RTV (for infants and children ≥14 days; licensed worldwide via the Medicines Patent Pool)8 , 9 and LPV+RTV 40/10 mg oral pellets (tentative approval restricted to the President’s Emergency Plan for AIDS Relief in resource-limited countries).10
MATERIALS AND METHODS
This ongoing phase 3b, prospective, international, multicenter, nonrandomized, single-arm, 2-stage study is conducted at 24 centers in Argentina, Brazil, Chile, Mexico, Poland, Romania, Russia, South Africa, Spain and the United States. HIV-1-infected participants ≥3 months to <11 years and weighing ≥5 kg and <35 kg were enrolled. PRINCE-2 commenced in November 2011; Stage 1 was completed in September 2014, comprising a maximum of 48 weeks on ATV powder, and reported here. Stage 2 data collection, for long-term safety of ATV powder up to 18 years of age, is ongoing.
The study was conducted according to Good Clinical Practice, as per the International Conference on Harmonisation, and the ethical principles underlying EU Directive 2001/20/EC and US Code of Federal Regulations, Title 21, Part 50 (21CFR50). The study was approved by institutional review boards and independent ethics committees for participating centers. Informed consent was obtained from all parents/legal guardians and from minors able to assent. An independent data monitoring committee oversaw study progress.
Inclusion criteria were as follows: ARV-naive or -experienced patients with a screening plasma HIV-1 RNA level ≥1000 copies/mL. Treatment experience was defined as having previous exposure to ARVs, either as prior treatment for HIV-1 or as post-exposure prophylaxis with ≥1 ARV to prevent vertical transmission. ARV-naïve patients had to show genotypic sensitivity to ATV at screening and to both components of a locally approved NRTI backbone. ARV-experienced patients had to show both genotypic and phenotypic sensitivity to ATV and the 2 NRTIs at screening.
Exclusion criteria included previous exposure to ATV or prior history of ≥2 failures during PI treatment; documented cardiac conduction abnormality or significant cardiac dysfunction or a history of syncope; or either hepatitis B or C virus co-infection.
Children 3 months to <11 years of age were dosed with ATV powder and RTV liquid, capsules or tablets according to baseline weight bands. Four weight-band ATV + RTV dosing groups were planned: 5 to <10 kg = 150/80 mg; 10 to <15 kg = 200/80 mg; 15 to <25 kg = 250/80 mg and 25 to <35 kg = 300/100 mg. After an interim PK analysis in PRINCE-1, an additional group (5 to <10 kg = 200/80 mg) was added to determine if ATV exposure could be enhanced by an increased dose in this weight band. The site investigator selected the 2 NRTIs based on availability, viral resistance and treatment history. Tenofovir disoproxil fumarate, which decreases ATV through concentration by 23%, was excluded.3
Stage 1 comprised a maximum of 48 weeks on ATV powder. Children reaching 35 kg before 48 weeks required transitioning onto ATV capsules and entered stage 2. Children not reaching 35 kg during stage 1 continued ATV powder during stage 2. It was originally planned to assess ATV powder safety and efficacy when all children had completed the 48-week stage 1 period; however, the study protocol was amended to conduct the primary outcome evaluation at week 24 instead of week 48, based upon guidelines from EU regulatory authorities.16 Consequently, 13 children did not reach week 48 when the last treated child had reached week 24. In this report, the analysis of safety and acceptability/palatability through a maximum of 48 weeks was based upon data collected during this amended definition of stage 1. An additional efficacy analysis was later performed using updated data for all children reaching week 48.
The primary outcome was the safety of RTV-boosted ATV powder through a maximum of 48 weeks. Safety outcomes included the frequency of adverse events (AEs), serious AEs (as judged by the investigator), AEs leading to discontinuation, Centers for Disease Control and Prevention Class C AIDS events, other significant AEs and laboratory abnormalities.
The efficacy of ATV powder was measured by the proportion of patients with HIV-1 RNA <50 or <400 copies/mL at week 24 (primary efficacy analysis) and at week 48 using the Roche Amplicor HIV-RNA Assay (version 1.5; Roche Diagnostic Systems, Inc., Branchburg, NJ) or the Abbott RealTime HIV-1 assay (Abbott Molecular Inc., Des Plaines, IL) after the Roche assay was discontinued in August 2014. Efficacy outcomes were summarized by the 5 ATV + RTV dosing categories and by prior ARV experience. Other efficacy assessments included CD4+ cell counts and percentages. For resistance testing methods, see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C888.
Acceptability and palatability of ATV powder and RTV through a maximum of 48 weeks were assessed through a caregiver questionnaire at each study visit. Caregivers were asked if their child had trouble completing the dose of ATV powder or RTV (acceptability). Reasons for having trouble completing the dose included general dislike of taking medicines, specific dislike of the study medication’s taste (palatability) and regurgitation of the dose.
PK results of ATV powder administered with RTV were evaluated with the recently completed PRINCE-1 study and are presented in an accompanying publication.
No statistical comparisons were conducted. The week 24/week 48 ATV powder cohort was defined as treated patients not switching to ATV capsules before or within the week 24/week 48 efficacy analysis window (week 18 to <week 30/week 42 to <week 54) or before their HIV-1 RNA week 24/week 48 assessment. Response rates through week 24 (or week 48) for the ATV powder cohort used a snapshot algorithm employing the last HIV-1 RNA in the predefined efficacy window to determine response. In a modified intent-to-treat analysis, the numerator was based on patients meeting the response criteria (ie, on-treatment HIV-1 RNA <50 or <400 copies/mL at the analysis week, with discontinuation considered as virologic failure). The denominator was all patients in the cohort. Observed value analysis was also reported, where the denominator was patients with available HIV-1 RNA values at the analysis week. For the percentages of patients with virologic suppression, exact binomial 95% confidence intervals were calculated. All analyses were conducted using the statistical software SAS version 9 (SAS Institute, Inc., Cary, NC).
Of 160 screened patients from 24 centers, 99 (62%) were enrolled and treated, of whom 83 (83.8%) and 59 (59.6%) remained on ATV powder for up to 24 and 48 weeks, respectively (Table 1). Over 48 weeks, the most common reasons for discontinuing ATV powder were lack of efficacy (11 patients, 2 of whom had resistance to the assigned NRTI lamivudine at baseline), AEs, and withdrawal of consent (Table 1). Eight children transitioned to capsules and entered stage 2. Excluding these patients, the proportion discontinuing was highest in the 5 to <10 kg = 200/80 mg group in the first 24 weeks (5/12; 41.7%). The reasons for discontinuations included AEs (pulmonary tuberculosis and abnormal amylase; both considered unrelated to study therapy by the investigator), withdrawal of consent owing to geographical relocation, lost to follow-up and no longer meeting study criteria (patient discontinued study therapy at week 4 after confirming elevated transaminases before starting ATV + RTV).
Overall, 51 patients (51.5%) were female, 64 patients (64.6%) were from Africa and 62 patients (62.6%) were ARV experienced. Baseline viral load and the proportion of ARV-experienced patients were highest in the 5 to <10 kg = 200/80 mg group (Table 2).
General Adverse Events
No deaths or unexpected safety events were reported. Through week 48, most patients receiving ATV powder (85.9%) had AEs; the most common being upper respiratory tract infections, gastroenteritis and vomiting (Table 3). Hyperbilirubinemia occurred in 18.2% (none led to discontinuation) and rash in 11.1% (3.0% considered related to study therapy). One child in the 15 to <25 kg = 250/80 mg group had treatment-related first-degree atrioventricular block not requiring specific intervention or ATV + RTV interruption.
Serious AEs occurred in 20.2% of patients; serious AEs reported in at least 2 patients in any group were alanine aminotransferase increase in 3.0%, overdose in 2.0% and hyperbilirubinemia related in 2.0% (“hyperbilirubinemia” and “blood bilirubin increased”). For a detailed summary, see Table, Supplemental Digital Content 1, http://links.lww.com/INF/C888.
Adverse Events Leading to Discontinuation
AEs led to discontinuation in 7 children. AEs considered related to study therapy by the investigator included acute pancreatitis with increased amylase and lipase in the 5 to <10 kg = 150/80 mg group (n = 1); vomiting in the 10 to <15 kg = 200/80 mg group (n = 1) and in the 25 to <35 kg = 300/100 mg group (n = 1; also reported a bad taste with increased pancreatic amylase). AEs considered unrelated to study therapy by the investigator included abnormal pancreatic amylase without pancreatitis in the 5 to <10 kg = 200/80 mg group (n = 1); raised alanine/aspartate aminotransferases in the 10 to <15 kg = 200/80 mg group (n = 1); pulmonary tuberculosis in the 5 to <10 kg = 200/80 mg group (n = 1) and lymph node tuberculosis in the 15 to <25 kg = 250/80 mg group (n = 1). Both tuberculosis cases required co-treatment with rifampicin, which reduces ATV exposure through CYP3A4 induction.17
Laboratory Abnormalities Through Week 48
Overall, the most common grade 3–4 laboratory abnormality was elevated amylase (Table 3) in 33/98 patients (33.7%), in whom 30 (90.9%) had normal pancreatic amylase. Grade 3–4 total bilirubin elevations occurred in 9/98 patients (9.2%) and elevations of any grade in 44/98 (44.9%).
Virologic and Immunologic Efficacy
Two patients in the highest baseline weight group had transitioned to capsules by the primary week 24 efficacy analysis. Using a modified intent-to-treat approach based on the week 24 ATV powder cohort (ie, patients who did not switch to ATV capsules before or within the week 24 window), 46/99 patients (46.5%) had HIV-1 RNA levels <50 copies/mL and 65/99 (65.7%) had HIV-1 RNA levels <400 copies/mL. At week 24, the proportion achieving virologic suppression trended higher as baseline weight increased but was lowest in the 5 to <10 kg baseline weight band receiving ATV + RTV 200/80 mg (Figs. 1 and 2: overall bars).
At week 24, median changes from baseline in HIV-1 RNA were −2.17, −3.68, −3.17, −2.80 and −2.08 log10 copies/mL in the 5 ATV + RTV groups, respectively. Corresponding median changes from baseline in CD4 cell count (percent) were 104 (5.0%), 34 (4.5%), 257 (8.5%), 297 (6.0%) and 70 (0.5%), respectively.
Interpretation of virologic suppression by baseline weight bands for the week 48 ATV powder cohort was complicated as 6 patients (3 in the 15 to <25 kg baseline weight band and 3 in the 25 to <35 kg baseline weight band) had transitioned to ATV capsules by the week 48 efficacy analysis (Fig. 1). However, the overall proportions of patients achieving virologic suppression to HIV-1 RNA levels of <50 and <400 copies/mL at week 48 (43.0% and 60.2%, respectively) were similar to those at week 24 (46.5% and 65.7%, respectively; Fig. 2).
The proportions achieving virologic suppression were similar between the ARV-naïve/experienced patients at either week 24 or at week 48 (Fig. 2). At week 24, the median changes from baseline in HIV RNA were −3.10 and −2.56 log10 copies/mL in ARV-naive/experienced patients, respectively.
By week 48, 36 patients met criteria for resistance testing: 11 (30.6%) were previously ARV naïve and 25 (69.4%) were ARV experienced. Baseline genotypic and phenotypic results were available for 35 and 26 patients, respectively. One treatment-experienced patient in the 10 to <15 kg = 200/80 mg group developed an emergent minor PI resistance mutation by 24 weeks (V82VAIT; IAS-USA 2013 classification) without phenotypic resistance to ATV and thereafter a major PI resistance mutation (I84V), also without phenotypic resistance to ATV. Three patients developed M184V mutation (one of whom also had I84V described above). All 3 exhibited phenotypic resistance to emtricitabine and lamivudine plus decreased susceptibility to didanosine. Two subjects with pretreatment M184V mutations and phenotypic resistance to emtricitabine and lamivudine developed decreased susceptibility to didanosine.
At week 24, most caregivers mixed ATV powder with water (48.2%) or milk (27.7%). Corresponding values over 48 weeks were 53.7% and 22.2%, respectively. At week 24, 86.7% and 80.7% of caregivers reported no trouble giving ATV powder and RTV, respectively. Corresponding values over 48 weeks were 83.3% and 74.1%, respectively. At week 24, 10.8% and 15.7% of caregivers reported that their children disliked the taste of ATV powder and RTV, respectively. Corresponding values over 48 weeks were 13.0% and 22.2%, respectively.
This study has limitations. Only small numbers of HIV-1-infected children were enrolled in each ATV + RTV dosing category (particularly the 5 to <10 kg = 200/80 mg and 25 to <35 kg = 300/100 mg groups). Further data on using RTV-boosted ATV powder, especially in infants weighing <10 kg, is required (see accompanying publication). This study was nonrandomized with no statistical comparisons between baseline weight bands or by prior ATV experience. At week 48, 22.2% of children were reported by their caregivers to dislike the taste of RTV liquid. This contrasts with a recent retrospective review of 119 HIV-infected children and a cross-sectional survey of physicians’ views on ARV palatability in which 50% disliked the taste of RTV liquid.26 Our palatability survey was based exclusively upon caregiver report and may have underestimated the proportion of children disliking the taste of RTV.
In conclusion, RTV-boosted ATV powder with optimized dual NRTI therapy in children ≥3 months to <11 years had an adequate overall rate of virologic suppression at week 24, which was maintained at week 48. The combination was highly acceptable to caregivers and was generally safe and well tolerated, regardless of prior ARV experience. No new safety concerns were identified, and no major PI substitutions associated with ATV phenotypic resistance were reported. Although LPV + RTV has established efficacy in young children, additional ARV formulations are needed for children requiring other options because of resistance, toxicity, tolerability (eg, taste) or adherence issues. ATV powder is an option for children unable to swallow pills, and for those who can, both powder and capsule ATV formulations facilitate a once-daily regimen when combined with solid NRTI formulations.2
These findings, along with those from the PRINCE-1 study, support using RTV-boosted ATV powder as a new treatment option for children aged ≥3 months to <11 years.
The authors thank Benjamin Dale and Julian Martins of inScience Communications, Springer Healthcare, who provided medical writing support funded by Bristol-Myers Squibb.
1. World Health Organization. Consolidated guidelines on the use of antiretroviral drugs for treating and preventing HIV infection: Recommendations for a public health approach. 2016. 2nd ed. Geneva, Switzerland: WHO Press, World Health Organization; Available at: http://www.who.int/hiv/pub/arv/arv-2016/en/
. Accessed September 1, 2016.
11. Kiser JJ, Rutstein RM, Samson P, et alAtazanavir and atazanavir/ritonavir
pharmacokinetics in HIV-infected infants, children, and adolescents. AIDS. 2011;25:1489–1496.
12. Rutstein RM, Samson P, Fenton T, et alPACTG 1020A Study Team. Long-term safety and efficacy of atazanavir-based therapy in HIV-infected infants, children and adolescents: the Pediatric AIDS Clinical Trials Group Protocol 1020A. Pediatr Infect Dis J. 2015;34:162–167.
13. Strehlau R, Donati AP, Arce PM, et alPRINCE-1: safety and efficacy of atazanavir powder
liquid in HIV-1-infected antiretroviral-naïve and -experienced infants and children aged ≥3 months to <6 years. J Int AIDS Soc. 2015;18:19467.
14. Hong Y, Kowalski KG, Zhang J, et alModel-based approach for optimization of atazanavir dose recommendations for HIV-infected pediatric patients. Antimicrob Agents Chemother. 2011;55:5746–5752.
17. Burger DM, Agarwala S, Child M, et alEffect of rifampin on steady-state pharmacokinetics of atazanavir with ritonavir
in healthy volunteers. Antimicrob Agents Chemother. 2006;50:3336–3342.
18. Johnson M, Grinsztejn B, Rodriguez C, et al96-week comparison of once-daily atazanavir/ritonavir
and twice-daily lopinavir/ritonavir
in patients with multiple virologic failures. AIDS. 2006;20:711–718.
19. Molina JM, Andrade-Villanueva J, Echevarria J, et alCASTLE Study Team. Once-daily atazanavir/ritonavir
compared with twice-daily lopinavir/ritonavir
, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 96-week efficacy and safety results of the CASTLE study. J Acquir Immune Defic Syndr. 2010;53:323–332.
20. Daar ES, Tierney C, Fischl MA, et alAIDS Clinical Trials Group Study A5202 Team. Atazanavir plus ritonavir
or efavirenz as part of a 3-drug regimen for initial treatment of HIV-1. Ann Intern Med. 2011;154:445–456.
21. Zhang D, Chando TJ, Everett DW, et alIn vitro
inhibition of UDP glucuronosyltransferases by atazanavir and other HIV protease inhibitors and the relationship of this property to in vivo
bilirubin glucuronidation. Drug Metab Dispos. 2005;33:1729–1739.
22. Molina JM, Andrade-Villanueva J, Echevarria J, et alCASTLE Study Team. Once-daily atazanavir/ritonavir
versus twice-daily lopinavir/ritonavir
, each in combination with tenofovir and emtricitabine, for management of antiretroviral-naive HIV-1-infected patients: 48 week efficacy and safety results of the CASTLE study. Lancet. 2008;372:646–655.
23. DeJesus E, Rockstroh JK, Henry K, et alGS-236-0103 Study Team. Co-formulated elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate versus ritonavir
-boosted atazanavir plus co-formulated emtricitabine and tenofovir disoproxil fumarate for initial treatment of HIV-1 infection: a randomised, double-blind, phase 3, non-inferiority trial. Lancet. 2012;379:2429–2438.
24. Lennox JL, Landovitz RJ, Ribaudo HJ, et alACTG A5257 Team. Efficacy and tolerability of 3 nonnucleoside reverse transcriptase inhibitor-sparing antiretroviral regimens for treatment-naive volunteers infected with HIV-1: a randomized, controlled equivalence trial. Ann Intern Med. 2014;161:461–471.
25. Musiime V, Fillekes Q, Kekitiinwa A, et alThe pharmacokinetics and acceptability of lopinavir/ritonavir
minitab sprinkles, tablets, and syrups in African HIV-infected children. J Acquir Immune Defic Syndr. 2014;66:148–154.
26. Lin D, Seabrook JA, Matsui DM, et alPalatability, adherence and prescribing patterns of antiretroviral drugs for children with human immunodeficiency virus infection in Canada. Pharmacoepidemiol Drug Saf. 2011;20:1246–1252.