HIV Reports
Once-daily Antiretroviral Therapy in a Cohort of HIV-Infected Children and Adolescents Beatriz Jiménez-Montero, MD,* José Beceiro, MD,† M. Isabel de José-Gómez, MD,‡ M. Isabel González-Tomé, MD,§ Dolores Gurbindo-Gutierrez, MD,¶ Jorge Martínez-Pérez, MD,‖ M. José Mellado-Peña, MD,** M. Luisa Navarro-Gómez, MD,†† Miguel A. Roa-Francia, MD,‡‡ Pablo Rojo-Conejo, MD,§ Jesús Saavedra-Lozano, MD,†† Santiago Jiménez de Ory, MSc,§§ and José T. Ramos-Amador, MD,¶¶ on behalf of Madrid Cohort of HIV-Infected Children and from the working groups of CoRISpe Abstract: We evaluated the evolution over time of once-daily antiretroviral therapy in HIV-infected children and its relationship with adherence. An increase on the prevalence of once-daily antiretroviral therapy was observed over time (from 0.9% in 2002 to 44.2% in 2011). There was no difference in adherence regarding once-daily or BID regimens in 2011. Adherence was related to age and pill burden. Key Words: once-daily antiretroviral drugs, simplification, fixed-dose combination, adherence, HIV (Pediatr Infect Dis J 2014;33:1052–1054)
P
oor adherence to antiretroviral therapy (ART) is the most common cause of treatment failure in HIV-infected pediatric patients, particularly in adolescents.1 To achieve prolonged virological control, simplification of ART may be needed, which includes the use of once-daily (QD) dosing regimens, better tolerated and less toxic drugs and fixed-dose coformulations.2 QD therapy may enhance adherence and improve treatment acceptability and quality of life while maintaining the same virological and immunological efficacy. Previously published studies have assessed pharmacokinetics and safety of QD regimens of various antiretroviral drugs and their impact on adherence.2–6 Nevertheless, data on QD regimens in children are scarce and there is a lack of data regarding the trend in the use of QD over time in children and adolescents. The aim of this study was to evaluate the evolution over time of QD therapy in a large cohort of HIV-infected children, to Accepted for publication March 11, 2014. From the *Pediatrics Department, Hospital Infanta Sofía, San Sebastián de los Reyes; †Pediatrics Department, Hospital Principe de Asturias, Alcalá de Henares; ‡Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Universitario La Paz; §Division of Pediatric Infectious Diseases, Hospital Universitario 12 de Octubre; ¶Pediatric Immunology Department, Hospital General Universitario Gregorio Marañón; ‖Pediatrics Department, Hospital Universitario Niño Jesús; **Pediatric Infectious Diseases Department, Hospital Carlos III; ††Division of Pediatric Infectious Diseases, Hospital Universitario Gregorio Marañón; ‡‡Pediatrics Department, Hospital de Móstoles, Madrid; §§Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), and ¶¶Pediatrics Department, Hospital Universitario de Getafe, Madrid, Spain. This work was supported in part by grants from Fundación para la Investigación y Prevención de SIDA en España (FIPSE; grants no. 360829/09 and 361910/10) and Red Temática de Investigación Cooperativa Sanitaria ISCIII (RED RIS; RD06/0006/0035 and RD06/0006/0021). The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Beatriz Jiménez-Montero, C/Violeta 15, 28760 Tres Cantos, Madrid, Spain. E-mail address: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3310-1052 DOI: 10.1097/INF.0000000000000367
1052 | www.pidj.com
describe the characteristics and adherence to ART of the patients on these QD regimens in 2011 and compare them with those children on twice-daily regimens from the same period.
METHODS Population and Study Design A multicenter, retrospective, observational study was carried out in a cohort of HIV-infected children followed at the outpatient clinics of 8 public hospitals in Madrid since 2002, within the Madrid cohort of HIV-infected children and Spanish cohort of HIV-infected children (CoRISpe). Data were obtained from the Madrid cohort database and the review of the clinical charts and pharmacy dispensing records. Three of the patients were participating in PENTA18 trial, a study of twice-daily (BID) versus QD lopinavir/ritonavir in HIV-1–infected children.
Outcome, Clinical Data and Definitions Among the patients on ART since 2002, the proportion on QD-ART over the past 9 years was assessed at 4 time points: December 2002, December 2005, December 2008 and December 2011. QD-ART was defined as a regimen in which all of the antiretroviral drugs were given QD. Among the patients on QD-ART in 2011, data regarding demographic characteristics, coinfections, HIV status, current QD regimen and adherence were collected. Undetectable viral load (VL) was defined as plasma HIV-RNA levels 90% of the prescribed antiretroviral medication, intermediate as taking between 70% and 90% and poor as taking 90%) and intermediate/poor adherence (14 years, n (%) Female gender, n (%) Caucasian ethnic group, n (%) Vertical transmission, n (%) CDC-clinical category, n (%) A (ref) B C (AIDS) CDC-immunological category, n (%) 1 (ref) 2 3 HBV coinfection, n (%) HCV coinfection, n (%) HIV-infection markers VL 90%) (ref) Intermediate (70–90%) Poor (12 years of age, 2002), abacavir (>12 years of age, 2004), didanosine (>6 years of age, 2000), emtricitabine (>4 months of age, 2004), tenofovir (≥2 years of age, 2013), efavirenz (>3 years of age, 1999), atazanavir (≥6 years of age, 2010) and darunavir (treatment-naive ≥12 years of age, 2013). Most of these drugs have been prescribed for QD dosing in an off-label way based on evidence or their FDA approval or adult use. We found good adherence in almost 77% of the patients on QD therapy in 2011. However, there were patients with suboptimal adherence, regardless of QD or BID therapy. These findings can be explained because adherence is influenced by a number of factors such as those related to ART, patient characteristics, caregiver/family characteristics, culture and society.8 There is a little data about adherence on QD regimen in children. LePrevost et al6 demonstrated good adherence to lamivudine/abacavir QD, but only 29% were receiving the whole regimen QD. Good adherence to combination lamivudine/didanosine/ efavirenz QD was reported in a cohort from Africa.5 Several studies in adults have demonstrated better adherence in QD compared with BID regimens,3,9 but there are no published studies in children. A possible explanation for the lack of observed associations in our study might have been the older age in the QD regimen. Older age was an independent risk factor for nonadherence, as also shown in other studies.8 HIV-infected adolescents are dealing with this complex chronic disease besides facing the normal challenges of adolescence. However, after adjustment for this confounding effect of age in multivariate analysis, pill burden, but not QD regimen, was associated with level of adherence. We found that patients with lower pill burden were more likely to reach good adherence, in keeping with published studies.10 Furthermore, since QD dosing, coformulations and pill burden are often correlated, it may be difficult to assess each factor independently. This study has some limitations. First, it is a retrospective study. Second, we analyzed adherence at one-time point and adherence can vary over time. Third, self and/or caregiver report may overestimate adherence. Fourth, evaluations have not included social and behavioral assessments, factors known to be involved in adherence. In addition, our study cannot completely rule out other potential unknown factors implicated in adherence. A larger sample size might demonstrate the better adherence in QD regimens. In conclusion, the use of QD therapy has increased over time in HIV-infected children in our setting. Reduction in pill burden
1054 | www.pidj.com
and more availability of fixed-dose combinations of antiretroviral drugs may improve adherence in children and adolescents.
ACKNOWLEDGMENTS We thank José María Bellón (Biomedical Research Foundation, Hospital Gregorio Marañón, Madrid) for his support with the statistical analysis. REFERENCES 1. Watson DC, Farley JJ. Efficacy of and adherence to highly active antiretroviral therapy in children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J. 1999;18:682–689. 2. Nachega JB, Mugavero MJ, Zeier M, et al. Treatment simplification in HIVinfected adults as a strategy to prevent toxicity, improve adherence, quality of life and decrease healthcare costs. Patient Prefer Adherence. 2011;5:357– 367. 3. Parienti JJ, Bangsberg DR, Verdon R, et al. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infect Dis. 2009;48:484–488. 4. McKinney RE Jr, Rodman J, Hu C, et al.; Pediatric AIDS Clinical Trials Group Protocol P1021 Study Team. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIVinfected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics. 2007;120:e416–e423. 5. Barro M, Some J, Foulongne V, et al. Short-term virological efficacy, immune reconstitution, tolerance, and adherence of once-daily dosing of didanosine, lamivudine, and efavirenz in HIV-1-infected African children: ANRS 12103 Burkiname. J Acquir Immune Defic Syndr. 2011;57 (suppl 1):S44–S49. 6. LePrevost M, Green H, Flynn J, et al.; Pediatric European Network for the Treatment of AIDS 13 Study Group. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. 2006;25:533–537. 7. Panel on Antiretroviral Therapy and Medical Management of HIVInfected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. August 11, 2011. Available at: http://aidsinfo. nih.gov/ContentFiles/lvguidelines/PediatricGuidelines.pdf. Accessed August 24, 2012. 8. Williams PL, Storm D, Montepiedra G, et al.; PACTG 219C Team. Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics. 2006;118:e1745–e1757. 9. Viciana P, Rubio R, Ribera E, et al.; Investigadores del Estudio CUVA. [Longitudinal study on adherence, treatment satisfaction, and effectiveness of once-daily versus twice-daily antiretroviral therapy in a Spanish cohort of HIV-infected patients (CUVA study)]. Enferm Infecc Microbiol Clin. 2008;26:127–134. 10. Juday T, Gupta S, Grimm K, et al. Factors associated with complete adherence to HIV combination antiretroviral therapy. HIV Clin Trials. 2011;12:71–78.
© 2014 Lippincott Williams & Wilkins
Once-daily Antiretroviral Therapy in a Cohort of HIV-Infected Children and Adolescents Beatriz Jiménez-Montero, MD,* José Beceiro, MD,† M. Isabel de José-Gómez, MD,‡ M. Isabel González-Tomé, MD,§ Dolores Gurbindo-Gutierrez, MD,¶ Jorge Martínez-Pérez, MD,‖ M. José Mellado-Peña, MD,** M. Luisa Navarro-Gómez, MD,†† Miguel A. Roa-Francia, MD,‡‡ Pablo Rojo-Conejo, MD,§ Jesús Saavedra-Lozano, MD,†† Santiago Jiménez de Ory, MSc,§§ and José T. Ramos-Amador, MD,¶¶ on behalf of Madrid Cohort of HIV-Infected Children and from the working groups of CoRISpe Abstract: We evaluated the evolution over time of once-daily antiretroviral therapy in HIV-infected children and its relationship with adherence. An increase on the prevalence of once-daily antiretroviral therapy was observed over time (from 0.9% in 2002 to 44.2% in 2011). There was no difference in adherence regarding once-daily or BID regimens in 2011. Adherence was related to age and pill burden. Key Words: once-daily antiretroviral drugs, simplification, fixed-dose combination, adherence, HIV (Pediatr Infect Dis J 2014;33:1052–1054)
P
oor adherence to antiretroviral therapy (ART) is the most common cause of treatment failure in HIV-infected pediatric patients, particularly in adolescents.1 To achieve prolonged virological control, simplification of ART may be needed, which includes the use of once-daily (QD) dosing regimens, better tolerated and less toxic drugs and fixed-dose coformulations.2 QD therapy may enhance adherence and improve treatment acceptability and quality of life while maintaining the same virological and immunological efficacy. Previously published studies have assessed pharmacokinetics and safety of QD regimens of various antiretroviral drugs and their impact on adherence.2–6 Nevertheless, data on QD regimens in children are scarce and there is a lack of data regarding the trend in the use of QD over time in children and adolescents. The aim of this study was to evaluate the evolution over time of QD therapy in a large cohort of HIV-infected children, to Accepted for publication March 11, 2014. From the *Pediatrics Department, Hospital Infanta Sofía, San Sebastián de los Reyes; †Pediatrics Department, Hospital Principe de Asturias, Alcalá de Henares; ‡Pediatric Infectious Diseases Unit, Pediatrics Department, Hospital Universitario La Paz; §Division of Pediatric Infectious Diseases, Hospital Universitario 12 de Octubre; ¶Pediatric Immunology Department, Hospital General Universitario Gregorio Marañón; ‖Pediatrics Department, Hospital Universitario Niño Jesús; **Pediatric Infectious Diseases Department, Hospital Carlos III; ††Division of Pediatric Infectious Diseases, Hospital Universitario Gregorio Marañón; ‡‡Pediatrics Department, Hospital de Móstoles, Madrid; §§Laboratorio InmunoBiología Molecular, Hospital General Universitario Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón and Networking Research Center on Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN), and ¶¶Pediatrics Department, Hospital Universitario de Getafe, Madrid, Spain. This work was supported in part by grants from Fundación para la Investigación y Prevención de SIDA en España (FIPSE; grants no. 360829/09 and 361910/10) and Red Temática de Investigación Cooperativa Sanitaria ISCIII (RED RIS; RD06/0006/0035 and RD06/0006/0021). The authors have no other funding or conflicts of interest to disclose. Address for correspondence: Beatriz Jiménez-Montero, C/Violeta 15, 28760 Tres Cantos, Madrid, Spain. E-mail address: [email protected]. Copyright © 2014 by Lippincott Williams & Wilkins ISSN: 0891-3668/14/3310-1052 DOI: 10.1097/INF.0000000000000367
1052 | www.pidj.com
describe the characteristics and adherence to ART of the patients on these QD regimens in 2011 and compare them with those children on twice-daily regimens from the same period.
METHODS Population and Study Design A multicenter, retrospective, observational study was carried out in a cohort of HIV-infected children followed at the outpatient clinics of 8 public hospitals in Madrid since 2002, within the Madrid cohort of HIV-infected children and Spanish cohort of HIV-infected children (CoRISpe). Data were obtained from the Madrid cohort database and the review of the clinical charts and pharmacy dispensing records. Three of the patients were participating in PENTA18 trial, a study of twice-daily (BID) versus QD lopinavir/ritonavir in HIV-1–infected children.
Outcome, Clinical Data and Definitions Among the patients on ART since 2002, the proportion on QD-ART over the past 9 years was assessed at 4 time points: December 2002, December 2005, December 2008 and December 2011. QD-ART was defined as a regimen in which all of the antiretroviral drugs were given QD. Among the patients on QD-ART in 2011, data regarding demographic characteristics, coinfections, HIV status, current QD regimen and adherence were collected. Undetectable viral load (VL) was defined as plasma HIV-RNA levels 90% of the prescribed antiretroviral medication, intermediate as taking between 70% and 90% and poor as taking 90%) and intermediate/poor adherence (14 years, n (%) Female gender, n (%) Caucasian ethnic group, n (%) Vertical transmission, n (%) CDC-clinical category, n (%) A (ref) B C (AIDS) CDC-immunological category, n (%) 1 (ref) 2 3 HBV coinfection, n (%) HCV coinfection, n (%) HIV-infection markers VL 90%) (ref) Intermediate (70–90%) Poor (12 years of age, 2002), abacavir (>12 years of age, 2004), didanosine (>6 years of age, 2000), emtricitabine (>4 months of age, 2004), tenofovir (≥2 years of age, 2013), efavirenz (>3 years of age, 1999), atazanavir (≥6 years of age, 2010) and darunavir (treatment-naive ≥12 years of age, 2013). Most of these drugs have been prescribed for QD dosing in an off-label way based on evidence or their FDA approval or adult use. We found good adherence in almost 77% of the patients on QD therapy in 2011. However, there were patients with suboptimal adherence, regardless of QD or BID therapy. These findings can be explained because adherence is influenced by a number of factors such as those related to ART, patient characteristics, caregiver/family characteristics, culture and society.8 There is a little data about adherence on QD regimen in children. LePrevost et al6 demonstrated good adherence to lamivudine/abacavir QD, but only 29% were receiving the whole regimen QD. Good adherence to combination lamivudine/didanosine/ efavirenz QD was reported in a cohort from Africa.5 Several studies in adults have demonstrated better adherence in QD compared with BID regimens,3,9 but there are no published studies in children. A possible explanation for the lack of observed associations in our study might have been the older age in the QD regimen. Older age was an independent risk factor for nonadherence, as also shown in other studies.8 HIV-infected adolescents are dealing with this complex chronic disease besides facing the normal challenges of adolescence. However, after adjustment for this confounding effect of age in multivariate analysis, pill burden, but not QD regimen, was associated with level of adherence. We found that patients with lower pill burden were more likely to reach good adherence, in keeping with published studies.10 Furthermore, since QD dosing, coformulations and pill burden are often correlated, it may be difficult to assess each factor independently. This study has some limitations. First, it is a retrospective study. Second, we analyzed adherence at one-time point and adherence can vary over time. Third, self and/or caregiver report may overestimate adherence. Fourth, evaluations have not included social and behavioral assessments, factors known to be involved in adherence. In addition, our study cannot completely rule out other potential unknown factors implicated in adherence. A larger sample size might demonstrate the better adherence in QD regimens. In conclusion, the use of QD therapy has increased over time in HIV-infected children in our setting. Reduction in pill burden
1054 | www.pidj.com
and more availability of fixed-dose combinations of antiretroviral drugs may improve adherence in children and adolescents.
ACKNOWLEDGMENTS We thank José María Bellón (Biomedical Research Foundation, Hospital Gregorio Marañón, Madrid) for his support with the statistical analysis. REFERENCES 1. Watson DC, Farley JJ. Efficacy of and adherence to highly active antiretroviral therapy in children infected with human immunodeficiency virus type 1. Pediatr Infect Dis J. 1999;18:682–689. 2. Nachega JB, Mugavero MJ, Zeier M, et al. Treatment simplification in HIVinfected adults as a strategy to prevent toxicity, improve adherence, quality of life and decrease healthcare costs. Patient Prefer Adherence. 2011;5:357– 367. 3. Parienti JJ, Bangsberg DR, Verdon R, et al. Better adherence with once-daily antiretroviral regimens: a meta-analysis. Clin Infect Dis. 2009;48:484–488. 4. McKinney RE Jr, Rodman J, Hu C, et al.; Pediatric AIDS Clinical Trials Group Protocol P1021 Study Team. Long-term safety and efficacy of a once-daily regimen of emtricitabine, didanosine, and efavirenz in HIVinfected, therapy-naive children and adolescents: Pediatric AIDS Clinical Trials Group Protocol P1021. Pediatrics. 2007;120:e416–e423. 5. Barro M, Some J, Foulongne V, et al. Short-term virological efficacy, immune reconstitution, tolerance, and adherence of once-daily dosing of didanosine, lamivudine, and efavirenz in HIV-1-infected African children: ANRS 12103 Burkiname. J Acquir Immune Defic Syndr. 2011;57 (suppl 1):S44–S49. 6. LePrevost M, Green H, Flynn J, et al.; Pediatric European Network for the Treatment of AIDS 13 Study Group. Adherence and acceptability of once daily Lamivudine and abacavir in human immunodeficiency virus type-1 infected children. Pediatr Infect Dis J. 2006;25:533–537. 7. Panel on Antiretroviral Therapy and Medical Management of HIVInfected Children. Guidelines for the Use of Antiretroviral Agents in Pediatric HIV Infection. August 11, 2011. Available at: http://aidsinfo. nih.gov/ContentFiles/lvguidelines/PediatricGuidelines.pdf. Accessed August 24, 2012. 8. Williams PL, Storm D, Montepiedra G, et al.; PACTG 219C Team. Predictors of adherence to antiretroviral medications in children and adolescents with HIV infection. Pediatrics. 2006;118:e1745–e1757. 9. Viciana P, Rubio R, Ribera E, et al.; Investigadores del Estudio CUVA. [Longitudinal study on adherence, treatment satisfaction, and effectiveness of once-daily versus twice-daily antiretroviral therapy in a Spanish cohort of HIV-infected patients (CUVA study)]. Enferm Infecc Microbiol Clin. 2008;26:127–134. 10. Juday T, Gupta S, Grimm K, et al. Factors associated with complete adherence to HIV combination antiretroviral therapy. HIV Clin Trials. 2011;12:71–78.
© 2014 Lippincott Williams & Wilkins
