Introduction

Globally, 1.8 million children are living with HIV, and 110,000 die annually due to AIDS-related illnesses [1]. For HIV-infected children, greatest survival outcomes can be achieved only with optimal, uninterrupted treatment on effective antiretroviral therapy (ART). Treatment disruptions, defined as any interruption or alteration of initial ART, may result from patient-level factors (e.g., poor adherence, drug intolerance), provider-level factors (e.g., prescription stops, changes, or errors), or systems-level factors (e.g., stock outs, interruptions in drug delivery). Unfortunately, treatment disruptions may result in treatment failure, acquisition of resistance mutations, and loss of future treatment options—which are particularly consequential in children. Compared with adults, children have greater pharmacokinetic variability and fewer available licensed drugs [2, 3]. Due to longer lifetime antiretroviral exposure, children have more potential for long-term toxicity [4, 5]. Children have greater social vulnerability related to their dependence on others for medical care and medication administration [6, 7]. If inadequately treated, children progress much faster to AIDS and death [8–10]. As children’s initial ART regimens are often their best opportunity for effective, tolerable treatment, optimizing the time on a successful initial regimen may result in greater long-term effectiveness of ART and more lifetime treatment options [11]. Analyzing longitudinal relationships between pediatric ART regimens and time to treatment disruption allows identification of initial ART regimens that pose greater challenges to maintaining optimal, continuous ART.

When deciding which regimen to prescribe to optimize clinical outcomes, clinicians must consider both drug pharmacology and potential adherence to ART regimens [12]. Boosted protease-inhibitor (PI)-based regimens appear more forgiving of treatment disruptions than do non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens [13–17]. However, certain PI characteristics decrease adherence and tolerability, particularly in children: poor taste; gastrointestinal toxicity; and regimen complexity, such as pill burden, storage requirements, and dosing frequency [7, 17–22]. Prior pediatric studies that have assessed the ability of children to maintain continuous therapy did not do so in settings in which use of PI- vs. NNRTI-based ART regimens was randomly allocated, nor have prior studies measured treatment disruptions longitudinally. As a result, these previously conducted studies have potential for residual confounding from unmeasured covariates. Furthermore, most studies have isolated analyses of prescription patterns, adherence, and tolerability, rather than evaluating the total effect of the regimen on maintaining optimal, continuous therapy. In the PENPACT-1 study, 266 HIV-1-infected, treatment-naïve children from Europe, North America, and South America were randomized to ART with either a PI or NNRTI and followed longitudinally for at least 4 years [23]. We aimed to assess PENPACT-1 participants for differences in time to treatment disruption across randomized PI vs. NNRTI treatment arms at 4 years and end of study.

Methods

Results

PENPACT-1 enrolled 266 HIV-1 infected children from 68 centers in 13 countries in Europe, North America, and South America. The mITT analysis was restricted to 263 participants who initiated ART. Participants were a median age of 6.5 years at enrollment (IQR [interquartile range], 1.8–12.9), 52% male, 49% black, and 79% exposed to HIV via vertical transmission (Table 1). Fifty-one percent had moderate to severe clinical symptoms (CDC stage B or C). Median growth parameters were below average (weight-for-age Z score -0.6; height-for-age Z score -0.9). Median CD4 Z-score was -3.5, consistent with predominance of moderate to severe immunosuppression, and median viral load was 5.0 log₁₀ copies/mL. Whereas 15% of children had ART exposure for prevention of mother-to-child transmission, 4% had at least one major resistance mutation at baseline. Although treatment groups had differences in racial distribution, baseline characteristics relating to mode of HIV-1 acquisition, clinical and immunological status, and ART resistance were generally balanced across ART regimens, consistent with the randomized design.

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Table 1. Baseline characteristics of study participants according to initial ART regimen.

https://doi.org/10.1371/journal.pone.0242405.t001

Median follow-up time was 261 weeks (IQR, 217–313). Two participants in each arm were started on a PI or NNRTI contrary to randomization; two underwent planned treatment interruption; five withdrew from study after ART initiation; 37 were lost to follow-up; and one patient died, due to HIV-related complications (Fig 1). Two hundred forty-nine participants ever completed an adherence questionnaire, totaling 2,112 questionnaires over the duration of the study for a mean of 8.5 questionnaires per participant.

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Fig 1. Study profile.

ART, antiretroviral therapy; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

https://doi.org/10.1371/journal.pone.0242405.g001

Overall, 191 of 263 participants had at least one treatment disruption event during the study, with 66% (95% confidence interval [CI] 61–72%) treatment disruption probability at 4 years (primary follow-up period) and 83% (95% CI 76–91%) treatment disruption probability at study end (6.5 years). At 4 years, probabilities of treatment disruption were 70% (95% CI 62–78%) vs. 63% (95% CI 55–72%) in the PI and NNRTI arms, respectively (Fig 2). Hazards for treatment disruption, however, were similar for PI vs. NNRTI-based regimens (unadjusted hazard ratio [HR] 1.19, 95% CI 0.88–1.61), even after adjustment for stratification factors of age, receipt of perinatal ART, and research network/region (adjusted HR 1.24, 95% CI 0.91–1.68).

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Fig 2. Proportion of children experiencing treatment disruption from initial ART regimen by study week.

The vertical line delineates 4 years on study. ART, antiretroviral therapy; n, subsample size; NNRTI, non-nucleoside reverse transcriptase inhibitor; PI, protease inhibitor.

https://doi.org/10.1371/journal.pone.0242405.g002

After 4 years, treatment disruption probabilities converged, such that treatment disruption probabilities at study end were 81% (95% CI 72–90%) for PI vs. 84% (95% CI 73–94%) for NNRTI arms, but changes over time in the hazard ratio of treatment disruption by treatment arms were non-significant (unadjusted P for interaction = 0.33, adjusted P = 0.21). Hazards for treatment disruption over the entire study period were similar for PI vs. NNRTI-based regimens, unadjusted (HR 1.11, 95% CI 0.84–1.48) and adjusted (HR 1.13, 95% CI 0.84–1.50).

Of 191 treatment disruption events, 126 events were based on ART regimen stoppages or changes in the treatment record, and 67 events were reported missing doses on adherence questionnaires, with two participants experiencing both event types simultaneously. Of the treatment stops or changes, 25% of events were substitutions of at least one first-line ART drug (PI 32%, NNRTI 16%), 53% were stoppage or suspension of the entire first-line ART regimen (PI 48%, NNRTI 59%), and 22% were switches to a second-line ART regimen (PI 20%, NNRTI 25%). Most frequent reasons documented for ART stops or changes were adverse events (34%), viral failure (22%), caregiver request (18%), non-adherence (7%), and temporary break (6%), with the greatest difference between PIs over NNRTIs for adverse events (Table 2).

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Table 2. Reasons listed for treatment disruption events.

https://doi.org/10.1371/journal.pone.0242405.t002

Reports of missed doses on adherence questionnaires were balanced between PI and NNRTI arms, as 35% of non-adherence events in each arm were from patient or caregiver reports. The most common questionnaire-reported barriers to adherence, forgetting/lacking support (30%) or running out of medications (25%), were balanced between PI and NNRTI regimens. Other common questionnaire-reported adherence problems—including difficulties with administration, such as those attributed to intolerance, taste, patient refusal (24%); fear of disclosure to others (22%); patient refusal (21%); difficulties with scheduling or lifestyle (18%); and concerns about drug toxicity (16%)—were more frequently reported in participants in the PI arm (Table 2).

In sensitivity analyses, modifications of the outcome definition did not result in substantial hazard ratio changes. Point estimates at 4 years remained similar to the primary analysis when restricting events on the treatment record (or any event on questionnaire) to only ART regimen stops or changes lasting >3 days (unadjusted HR 1.16, 95% CI 0.85–1.57; adjusted HR 1.19, 95% CI 0.88–1.63), only ART regimen stops or changes lasting >14 days (unadjusted HR 1.27, 95% CI 0.93–1.74; adjusted HR 1.32, 95% CI 0.96–1.81), or only stops or changes including the PI or NNRTI drug (unadjusted HR 1.14, 95% CI 0.84–1.55; adjusted HR 1.18, 95% CI 0.87–1.61).

Discussion

In PENPACT-1, our estimates were not compatible with large differences in time to treatment disruption between participants randomized to PIs versus NNRTIs. Point estimates were mildly in the direction of more treatment disruptions in PI-based regimens, particularly in the primary end point of 4 years, but differences were small, possibly due to chance, and appeared to decrease by study end. Exploration of reasons for treatment disruptions suggested that PI-based regimens may be less tolerable, both due to adverse events leading to treatment stoppages or substitutions and to regimen-specific adherence barriers reported on the adherence questionnaire. However, these PI-associated difficulties did not interrupt continuous therapy to the initial PI-based regimens more than they did to NNRTI-based regimens.

Although we did not find a meaningful difference in treatment disruptions in PI vs. NNRTI-based regimens, the secondary analyses exploring reasons for treatment disruptions suggested that administration of a PI-based regimen to a child may be a struggle, even if not resulting in actual missed doses. The treatment record suggested that participants experienced more adverse events to PIs over NNRTIs, but adherence questionnaire responses formed a pattern of difficulties with PI tolerability, whether attributed to taste, medication volume or pill burden, toxicity, or simply patient refusal. This pattern would be consistent with existing literature on PI vs. NNRTI regimens. PIs have higher drug toxicity, especially gastrointestinal side effects, and intolerance, particularly regarding their noxious taste [7, 18–20, 25–27]. Even if children are able to swallow pills, certain PIs are available only as large pills [28, 29]. At the time of PENPACT-1, no PIs were available as complete-regimen combinations for children, whereas single-tablet NNRTI regimens could facilitate adherence through administration of fewer pills [2, 30–34]. More recently, a novel four-in-one fixed-dose combination of abacavir, lamivudine, and LPV/r granule-filled capsules has been under study and submitted to the FDA for approval [35]. Participants reported more barriers to adherence in PIs related to scheduling or lifestyle interference, which may relate to dosing frequency. We hypothesize that increased fear of disclosure to others, as noted in the PI arm, may relate to difficulties concealing drug administration when given more frequently. Higher dosing frequency has been associated with more frequent treatment disruptions [20, 30, 33, 34, 36–39]. Some NNRTIs, most notably efavirenz, have more suitable pharmacokinetics for once daily administration. In our study, most PI-based regimens were administered at least twice daily, whereas some commonly used NNRTI-based regimens allowed once-daily dosing.

Most children in PENPACT-1 experienced a treatment disruption event during the study. Only about one-third of participants remained continuously on their initial ART at 4 years; only one-sixth remained continuously on initial ART at study end. These results are consistent with other pediatric data on the durability of first-line treatment regimens [40]. Maintaining continuous therapy on ART is critical to sustained HIV-related outcomes, as suppressing viral load decreases the probability of HIV sub-populations acquiring antiretroviral resistance mutations and chances of forward infection [41–49]. Although optimal adherence targets vary by PI vs. NNRTI class, adherence has been modest across ART studies, especially patients failing to achieve viral suppression [12, 16, 17, 30, 50–56]. Notably, ART appears to be less successful in producing viral suppression in children, who are more prone to viral failure and resistance due to higher plasma viral loads, less robust antiviral immune responses, greater pharmacokinetic variability, and social dependency [44, 57]. Adolescents have particularly worse viral and immunological outcomes, due to poor ART adherence [48, 49, 58–60]. The large proportion of children in PENPACT-1 with disruptions of their initial ART raises concerns regarding long-term durability, especially as these patients were receiving adherence support on a clinical trial protocol at specialty pediatric HIV centers.

Based on our data, choice of an initial PI- vs. NNRTI-based regimen may not have a major impact on ART treatment disruption. Despite differences in reported regimen-related adherence barriers, participants in both treatment arms persevered in taking their regimens similarly. Moreover, the most common questionnaire-reported barriers were not regimen-specific: forgetting/lack of support and running out of drug. Novel interventions may still be able to improve the experience of drug administration. Pediatric pellets are heat-stable and generally more acceptable than syrups, but palatability and administration problems persist and may increase over time [61–63]. Pediatric granules, especially in the four-in-one combination, may improve palatability and decrease pill burden [35, 64]. Precision medicine related to taste-sensing genotypes may hold promise for prescribing according to individualized palatability [65]. In adult data, integrase strand transferase inhibitors (INSTIs) have been at least as tolerable as PIs or NNRTIs, if not more so, and INSTIs are increasingly preferred drugs in children [66–69]. Nevertheless, a primary goal of optimizing continuous therapy to ART is durable viral suppression, which was comparable across PI vs. NNRTI arms in this study’s parent trial, although similar trials had variable results [23, 70–74]. In this study population, choice of either PI- or NNRTI-based initial ART appears acceptable.

Our estimates of treatment disruption may have had measurement error. First, we had no direct measures of drug exposure, such as therapeutic drug monitoring. Treatment records captured only prescribing events and documented ART disruptions, and the adherence questionnaires relied on accurate reporting by either the child or the caregiver, if present and willing to answer. Although we relied on a questionnaire that has previously been validated [24], reporting biases and unanswered questionnaires may have affected our measures of missed doses. Our combining treatment records and adherence questionnaires into a composite outcome should have decreased measurement error from either instrument individually. Second, adherence questionnaires in this study focused on ART adherence over the 3 days prior to the most recent visit and inquired about adherence barriers encountered over the prior 2 weeks, rather than a daily measure of adherence throughout the study. The time-varying nature of treatment disruption means that patients may have experienced an initial or temporary period of treatment disruption that was subsequently corrected [75, 76], but our analysis presents only data on time to first event of treatment disruption. Third, limited participant report of individual drugs missed on the adherence questionnaire precluded definitive identification of treatment disruptions of individual drugs. Instead, we assessed treatment disruption to any component of the ART regimen. Fourth, heterogeneity of adherence questionnaires across networks, ages, and respondents regarding barriers to therapy should caution against rigorous interpretation of reasons for treatment disruptions. Finally, this study size was not sufficient to distinguish differences on the order of 7%, as was seen at 4 years.

Conclusions

In conclusion, children in PENPACT-1 had similar time to treatment disruption for initial PI-based regimens and NNRTI-based regimens. Although secondary analyses suggest that PI-based regimens may be more difficult to tolerate and may be less convenient to administer, these difficulties did not result in a large difference in children stopping, changing, or missing doses at 4 years (PI 70%, NNRTI 63%), and any suggested differences diminished by study end (PI 81%, NNRTI 84%). Initial ART with either a PI or NNRTI may be acceptable for maintaining continuous therapy on ART in children.

Supporting information

Acknowledgments

The PENPACT-1 (PENTA 9 / PACTG 390) study team

PENPACT-1 protocol team. PACTG/IMPAACT/NICHD: P Brouwers, D Costello, E Ferguson, S Fiscus, J Hodge, M Hughes, C Jennings, A Melvin (Co-Chair), R McKinney (Co-Chair), L Mofenson, M Warshaw, ME Smith, S Spector, E Stiehm, M Toye, R Yogev.

PENTA: JP Aboulker, A Babiker, H Castro, A Compagnucci, A De Rossi, C Giaquinto, J Darbyshire, M Debré, DM Gibb, L Harper, L Harrison, N Klein, D Pillay, Y Saidi, G Tudor-Williams (Co-Chair), AS Walker.

Data and Safety Monitoring Board: B Brody, C Hill, P Lepage, J Modlin, A Poziak, M Rein (Chair 2002–2003), M Robb (Chair 2004–2009), T Fleming, S Vella, KM Kim.

Clinical sites (L = lab, P = pharmacy). Argentina: Hospital de Pediatria Dr JP Garrahan, Buenos Aires: R Bologna, D Mecikovsky, N Pineda, L Sen (L), A Mangano (L), S Marino (L), C Galvez (L); Laboratorio Fundai: G Deluchi (L).

Austria: Universitätsklinik für Kinder und Jugendheilkunde, Graz: B Zöhrer, W Zenz, E Daghofer, K Pfurtscheller, B Pabst (L).

Bahamas: Princess Margaret Hospital: MP Gomez, P McNeil, M Jervis, I Whyms, D Kwolfe, S Scott (P).

Brazil: University of Sao Paulo at Ribeirao Preto: MM Mussi-Pinhata, ML Issac, MC Cervi, BVM Negrini, TC Matsubara, C BSS de Souza (L), JC Gabaldi (P); Institute of Pediatrics (IPPMG), Federal University of Rio de Janeiro: RH Oliveira, MC Sapia, T Abreu, L Evangelista, A Pala, I Fernandes, I Farias, M de F Melo (L), H Carreira (P), LM Lira (P); Instituto de Infectologia Emilio Ribas, Sao Paolo: M della Negra, W Queiroz, YC Lian; DP Pacola; Fleury Laboratories; Federal University of Minas Gerais, Belo Horizonte: J Pinto, F Ferreira, F Kakehasi, L Martins, A Diniz, V Lobato, M Diniz, C Hill (L), S Cleto (L), S Costa (P), J Romeiro (P).

France: Hôpital d’enfants Armand Trousseau, Paris: C Dollfus, MD Tabone, MF Courcoux, G Vaudre A Dehée (L), A Schnuriger (L), N Le Gueyades (P), C De Bortoli (P); CHU Hôtel Dieu, Nantes: F Méchinaud, V Reliquet, J Arias (L), A Rodallec (L), E André (L), I Falconi (P), A Le Pelletier (P); Hôpital de l’Archet II, Nice, F Monpoux, J Cottalorda (L), S Mellul (L); Hôpital Jean Verdier, Bondy: E Lachassinne; Laboratoire de virologie-Hôpital Necker Enfants Malades, Paris: J Galimand (L), C Rouzioux (L), ML Chaix (L), Z Benabadji (P), M Pourrat (P); Hôpital Cochin Port-Royal- Saint Vincent de Paul, Paris: G Firtion, D Rivaux, M Denon, N Boudjoudi, F Nganzali, A Krivine (L), JF Méritet (L), G Delommois (L), C Norgeux (L), C Guérin (P); Hôpital Louis Mourier, Colombes: C Floch, L Marty, H Hichou (L), V Tournier (P); Hôpital Robert Debré, Paris: A Faye, I Le Moal, M Sellier (P), L Dehache (P); Laboratoire de virologie-Hôpital Bichat Claude Bernard-Paris: F Damond (L), J Leleu (L), D Beniken (L), G Alexandre-Castor (L).

Germany: Universitäts-Kinderklinik Düsseldorf: J Neubert, T Niehues, HJ Laws, K Huck, S Gudowius, K Siepermann, H Loeffler, S Bellert (L), A Ortwin (L); Universitäts-Kinderkliniken, Munich: G Notheis, U Wintergerst, F Hoffman, A Werthmann, S Seyboldt, L Schneider, B Bucholz; Charité-Medizische Fakultät der Humboldt-Universität zu Berlin: C Feiterna-Sperling, C Peiser, R Nickel, T Schmitz, T Piening, C Müller (L); Kinder und Jugendklinik, Universität Rostock: G Warncke, M Wigger, R Neubauer.

Ireland: Our Lady’s Children’s Hospital Crumlin, Dublin: K Butler, AL Chong, T Boulger, A Menon, M O’Connell, L Barrett, A Rochford, M Goode, E Hayes, S McDonagh, A Walsh, A Doyle, J Fanning (P), M O’Connor (P), M Byrne (L), N O’Sullivan (L), E Hyland (L).

Italy: Clinica Pediatrica, Ospedale L Sacco, Milan: V Giacomet, A Viganò, I Colombo, D Trabattoni (L), A Berzi (L); Clinica Pediatrica, Università di Brescia: R Badolato, F Schumacher, V Bennato, M Brusati, A Sorlini, E Spinelli, M Filisetti, C Bertulli; Clinica Pediatrica, Università di Padova: O Rampon, C Giaquinto, M Zanchetta (L); Ospedale S. Chiara, Trento: A Mazza, G Stringari, G Rossetti (L); Ospedale del Bambino Gesù, Rome: S Bernardi, A Martino, G Castelli Gattinara, P Palma, G Pontrelli, H Tchidjou, A Furcas, C Frillici, A Mazzei, A Zoccano (P), C Concato (L).

Romania: Spitalul Clinic de Boli Infectioase Victor Babes, Bucharest: D Duiculescu, C Oprea, G Tardei (L), F Abaab (P); Institutul de Boli Infectioase Matei Bals, Bucharest: M Mardarescu, R Draghicenoiu, D Otelea (L), L Alecsandru (P); Clinic Municipal, Constanta: R Matusa, S Rugina, M Ilie, Silvia Netescu (P). Clinical monitors: C Florea, E Voicu, D Poalelungi, C Belmega, L Vladau, A Chiriac.

Spain: Hospital Materno-Infantil 12 de Octubre, Madrid: JT Ramos Amador, MI Gonzalez Tomé, P Rojo Conejo, M Fernandez, R Delgado Garcia (L), JM Ferrari (P); Institute de Salud Carlos III, Madrid: M Garcia Lopez, MJ Mellado Peña, P Martin Fontelos, I Jimenez Nacher (P); Biobanco Gregorio Marañon, Madrid: MA Muñoz Fernandez (L), JL Jimenez (L), A García Torre (L); clinical monitors: M Penin, R Pineiro Perez, I Garcia Mellado.

UK: Bristol Royal Children’s Hospital: A Finn, M LaJeunesse, E Hutchison, J Usher (L), L Ball (P), M Dunn (P); St. George’s Healthcare NHS Trust, London: M Sharland, K Doerholt, S Storey, S Donaghy, R Chakraborty, C Wells (P), K Buckberry (P), P Rice (P); University Hospital of North Staffordshire: P McMaster, P Butler, C Farmer (L), J Shenton (P), H Haley (P), J Orendi (L), University Hospital Lewisham: J Stroobant, L Navarante, P Archer, C Mazhude, D Scott, R O’Connell, J Wong (L), G Boddy (P); Sheffield Children’s Hospital: F Shackley, R Lakshman, J Hobbs, G Ball (L), G Kudesia (L), J Bane (P), D Painter (P); Ealing Hospital NHS Trust: K Sloper, V Shah, A Cheng (P), A Aali (L); King’s College Hospital, London: C Ball, S Hawkins, D Nayagam, A Waters, S Doshi (P); Newham University Hospital: S Liebeschuetz, B Sodiende, D Shingadia, S Wong, J Swan (P), Z Shah (P); Royal Devon and Exeter Hospital: A Collinson, C Hayes, J King (L), K O’Connor (L); Imperial College Healthcare NHS Trust, London: G Tudor-Williams, H Lyall, K Fidler, S Walters, C Foster, D Hamadache, C Newbould, C Monrose, S Campbell, S Yeung, J Cohen, N Martinez-Allier, D Melvin, J Dodge, S Welch, G Tatum, A Gordon, S Kaye (L), D Muir (L), D Patel (P); Great Ormond Street Hospital: V Novelli, D Gibb, D Shingadia, K Moshal, J Lambert, N Klein, J Flynn, L Farrelly, M Clapson, L Spencer, M Depala (P); Institute of Child Health, London: M Jacobsen (L); John Radcliffe Hospital, Oxford: S Segal, A Pollard, D Kelly, S Yeadon, B Ohene-Kena Y Peng (L), T Dong (L), Y Peng (L), K Jeffries (L), M Snelling (P), Nottingham University Hospitals: A Smyth, J Smith; Chelsea and Westminster Hospital, London: B Ward; Mortimer Market Centre, London: E Jungmann; Doncaster Royal Infirmary: C Ryan, K Swaby; Health Protection Agency, London: A Buckton (L); Health Protection Agency, Birmingham: E Smit (L).

USA: Harlem Hospital Center: EJ Abrams, S Champion, AD Fernandez, D Calo, L Garrovillo, K Swaminathan, T Alford, M Frere, Columbia University Laboratories, J Navarra (P, Town Total Health); NYU School of Medicine: W Borkowsky, S Deygoo, T Hastings, S Akleh, T Ilmet (L); Seattle Children’s Hospital: A Melvin, K Mohan, G Bowen (Additional support by NIH Grant UL1 RR025014); University of South Florida: PJ Emmanuel, J Lujan-Zimmerman, C Rodriguez, S Johnson, A Marion, C Graisbery, D Casey, G Lewis; All Children’s Hospital Laboratories; Oregon Health and Science University: J Guzman-Cottrill, R Croteau; San Juan City Hospital: M Acevedo-Flores, M Gonzalez, L Angeli; L Fabregas, Lab 053, P Valentin (P); SUNY-Upstate Medical University-Syracuse: L Weiner, KA Contello, W Holz, M Butler; SUNY, Health Science Center at Stonybrook: S Nachman, MA Kelly, DM Ferraro, UNC Retrovirology Lab; Howard University Hospital: S Rana, C Reed, E Yeagley, A Malheiro, J Roa; LAC and USC Medical Center: M Neely, A Kovacs, L Spencer, J Homans, Y Rodriguez Lozano, Maternal Child Virology Research Laboratory, Investigational Drug Service; South Florida Children’s Diagnostic & Treatment Center: A Puga, G Talero, R Sellers; Broward General Medical Center, University of Miami (L); University College of Florida College of Medicine-Gainesville: R Lawrence; University of Rochester Pediatrics: GA. Weinberg, B Murante, S Laverty; Miller Children’s Hospital Long Beach: A Deveikis, J Batra, T Chen, D Michalik, J Deville, K Elkins, S Marks, J Jackson Alvarez, J Palm, I Fineanganofo (L), M Keuth (L), L Deveikis (L), W Tomosada (P); Tulane University New Orleans: R Van Dyke, T Alchediak, M Silio, C Borne, S Bradford, S Eloby-Childress (L), K Nguyen (P); University of Florida/Jacksonville: MH Rathore, A Alvarez; A Mirza, S Mahmoudi, M Burke; University of Puerto Rico: IL Febo, L Lugo, R Santos; Children’s Hospital Los Angeles: JA Church, T Dunaway, C Rodier; St. Jude/UTHSC: P Flynn, N Patel, S DiScenza, M Donohoe; WNE Maternal Pediatric Adolescent AIDS: K Luzuriaga, D Picard; Texas Children’s Hospital: M Kline, ME Paul, WT Shearer, C McMullen-Jackson; Children’s Memorial Hospital, Chicago: R Yogev, E Chadwick, E Cagwin, K Kabat; New Jersey Medical School: A Dieudonne, P Palumbo, J Johnson; Robert Wood Johnson Medical School, New Brunswick: S Gaur, L Cerracchio; Columbia IMPAACT: M Foca, A Jurgrau, S Vasquez Bonilla, G Silva; Babies’ Hospital, Columbia/Presbyterian Medical Center, New York: A Gershon; University of Massachusetts Medical Center, Worcester: J Sullivan; UCLA Medical Center, Los Angeles: Y Bryson; Children’s Hospital, Seattle: L Frenkel; UNC-Chapel Hill Virology Lab: S Fiscus (L), J Nelson (L).

Trials units/support. INSERM SC10 Paris: JP Aboulker, A Compagnucci, G Hadjou, S Léonardo, Y Riault, Y Saïdi.

MRC Clinical Trials Unit, UK: A Babiker, L Buck, JH Darbyshire, L Farrelly, S Forcat, DM Gibb, H Castro, L Harper, L Harrison, J Horton, D Johnson, S Moore, C Taylor, AS Walker.

Westat/NICHD: D Collins, S Buskirk, P Kamara, C Nesel, M Johnson, A Ferreira.

Frontier Science: J Hodge, J Tutko, H Sprenger.

IMPAACT: M Hughes, M Warshaw, P Britto, C Powell.

NIAID: R DerSimonian, E Handelsman (deceased).

PENTA Steering Committee: JP Aboulker, J Ananworanich, A Babiker, E Belfrage, S Bernardi, S Blanche, AB Bohlin, R Bologna, D Burger, K Butler, G Castelli-Gattinara, H Castro, P Clayden, A Compagnucci, JH Darbyshire, M Debré, R De Groot, M Della Negra, A De Rossi, A Di Biagio, D Duiculescu, A Faye, V Giacomet, C Giaquinto (Chair), DM Gibb, I Grosch-Wörner, M Hainault, L Harper, N Klein, M Lallemant, J Levy, H Lyall, M Marczynska, M Mardarescu, MJ Mellado Pena, D Nadal, L Naver, T Niehues, C Peckham, D Pillay, J Popieska, JT Ramos Amador, L Rosado, R Rosso (deceased), C Rudin, Y Saïdi, H Scherpbier, M Sharland, M Stevanovic, C Thorne, PA Tovo, G Tudor-Williams, AS Walker, S Welch, U Wintergerst, N Valerius.

Participants, families, and staff

We thank all the children, families, and staff from the centers participating in the PENPACT-1 trial. We thank the Children’s Mercy Medical Writing Center for copyediting this document.