Abstract
Introduction
Changes in combination antiretroviral therapy (cART) throughout childhood challenge the continuity of paediatric HIV treatment. This study aimed to evaluate the prevalence of treatment interruption (TI), including lamivudine (3TC) monotherapy, and the relationship of TI to virologic and immunologic parameters in HIV-infected paediatric patients.
Methods
Nested within a prospective observational study of a city-wide cohort of HIV-infected persons in the District of Columbia, this sub-study collected retrospective data on antiretroviral therapy, enrolment (endpoint) and historic (lifelong) CD4 counts and HIV RNA viral load (VL) of the paediatric cohort. TI was defined as interruption of cART ≥4 consecutive weeks. Data on TI, including 3TC monotherapy TI (MTI), were collected. Descriptive statistics and univariate testing were used to compare children with TI and MTI to children on continuous treatment (CT).
Results
Thirty-eight (28%) out of 136 enrolled children (median age=12.9 years) experienced TI, with 14 (37%) of those placed on 3TC MTI. Significantly lower endpoint median CD4 counts (598 cells/mm3 vs. 815 cells/mm3; p=0.003) and CD4% (27.5% vs. 33%; p=0.006) were observed in the TI cohort as compared to the CT cohort. The median endpoint VL in the overall TI cohort was ~4 times higher than among the CT cohort (1427 copies/mL vs. 5581 copies/mL; p<0.0001). After a median TI duration of one year, a majority (n=31; 82%) of patients with TI restarted cART, including 100% of those with total TI and 53% of those on MTI, respectively.
Conclusions
In our study, we observed high frequency of the TI in HIV in paediatric HIV clinical practice. All TIs, including 3TC MTI, were associated with significantly lower endpoint median CD4 counts and higher median VLs, as compared to CT in paediatric patients. The high frequency of TI and associated poor outcomes suggest a need for a better strategy in managing the course of the paediatric and adolescent cART.
Keywords: HIV, children, treatment interruption, antiretroviral therapy, lamivudine monotherapy
Introduction
Combination antiretroviral therapy (cART) has dramatically improved the outcome of paediatric HIV infection. Supported by the evidence from the START trial, the 2015 World Health Organization HIV treatment guidelines recommend a universal start of cART in all HIV-infected individuals including children and adolescents [1,2]. The USA and European guidelines support universal paediatric cART in infants and young children and recommend strong consideration for cART at older age [3,4].
With changes in the child's age and maturity, paediatric cART evolves from the administering liquid and powdered/granulated antiretroviral drugs (ARVs) to swallowing fixed-dose combinations tablets. This transition requires frequent adjustment of ARV dosing based on the child's age and weight and close monitoring for cART tolerability and toxicity. Adherence barriers also continue to evolve from acceptability of paediatric ARVs in infancy to increased peer pressure and disclosure challenges during puberty [5–7]. Moreover, in the areas of highest paediatric HIV epidemic (e.g. sub-Saharan Africa), continuity of paediatric cART is frequently challenged by comorbidities, limited availability of paediatric ARVs and suboptimal paediatric HIV healthcare capacity [8–10].
Together, these challenges create multiple settings for treatment interruptions (TI) of cART from infancy into adolescence. Paediatric and adolescent HIV providers have considered structured TI guided by CD4 count and clinical staging of the disease [11–13]. TI alternatives such as monotherapy with lamivudine (3TC) and lopinavir/ritonavir (LPV/r) have been also considered in children [14–17].
While existing data support the feasibility of structured TI in children, data on the long-term effects of TI in paediatric HIV-infected patients are limited [11,12]. In this study, we evaluated the prevalence and duration of TI, including placement on ARV monotherapy, and compared the virologic and immunologic outcomes between paediatric patients with TI and those on continuous treatment (CT) from a perinatal HIV cohort in Washington, DC, USA.
Methods
Data source
This analysis was conducted as part of a larger city-wide longitudinal cohort study of HIV-infected persons receiving care in the District of Columbia (DC), which is aimed to describe clinical outcomes and improve the quality of care for patients in Washington, DC, USA [18]. The paediatric Special Immunology Services (SIS) program at the Children's National Health System (CNHS) is 1 of 13 sites participating in the DC cohort. SIS provides care to ~200 children and adolescents with primarily perinatally acquired HIV. The majority of patients in care are Black (95%) and female (55%).
Eligibility criteria
HIV-infected children and adolescents (aged 0–24 years) treated at SIS were eligible to participate. Informed consent (parents and participants ≥18 years of age) and assent (7–17 years of age) were required. The study protocol was approved by the Institutional Review Boards (IRBs) at the George Washington University (GWU) and CNHS.
Study design
Demographic data (age, race and place of birth) and retrospective immunologic (CD4 count and CD4%, lifetime CD4 nadir), virologic (HIV RNA viral load (VL)) and antiretroviral therapy (age at initiations of ARVs and ARVs prescribed) data were collected from the medical records (MR) of patients enrolled into DC cohort during 2011 to 2013. Immunologic and virologic data collected at the time of enrolment through 2013 were used as endpoints across the overall study cohort.
TI was defined as a period of at least four consecutive weeks of discontinuation of cART, including placement on monotherapy TI (MTI), approved/prescribed by a clinical provider and documented in the MR. Within the TI cohort, the patients who underwent a TI with no ARVs prescribed were classified as having total TI (TTI). Patients who interrupted cART but were instead prescribed a single ARV 3TC or LPV/r were classified as MTI cohort. A patient with multiple TIs was analyzed as one unit using the data associated with the longest TI period. Patients on cART who did not have TI were classified as the CT cohort. TI data included age at the start and end of TI, reasons for TI, CD4 count and VL closest to the time of starting TI and after the restart of cART, maximal CD4 count prior and after TI and time to reaching maximal CD4 count after restarting cART.
Data analysis
Frequency distributions and summary statistics, including median and interquartile range (IQR), were used to describe the demographic, clinical and treatment characteristics in general and between those on CT compared to those with TI. Comparisons between groups (CT vs. TI and TTI vs. MTI) were performed using chi-squared and Wilcoxon rank sum tests as appropriate. Among those in the TTI cohort who restarted treatment, maximum CD4 count and VL before and after TI were compared using Wilcoxon sign rank test. Data were analyzed using SAS 9.3 (Cary, NC).
Results and discussion
Results
From October 2011 through December 2013, 136 patients were enrolled (Table 1). The majority (97.8%) were perinatally infected. At enrolment, the median CD4 count and CD4% within the overall patient cohort were 726 cells/mm3 and 31%, respectively. Approximately half of the study cohort had undetectable or very low VLs with 60 (44%) and 15 (9.4%) patients with HIV RNA VL <48 copies/mL and >48 to <200 copies/mL, respectively (data not shown). Among those with detectable VL, the median HIV RNA VL at enrolment was 3397 copies/mL.
Table 1.
Characteristics of CT and TI cohorts at enrolment after TI (univariate analysis of associations with demographic and clinical factors)
| Overall cohort (N=136) | Continuous treatment (CT) (N=98) | Treatment interruption (TI) (N=38) | P-value (CT and TI) | |
|---|---|---|---|---|
| Demographic parameters | ||||
| Age (years) | 12.9 (8.3–17.1)a | 12.4 (8.0–17.1)a | 14.6 (10.7–16.9)a | 0.24 |
| Age of ARVs initiation (years)b | 0.64 (0.3–2.8)a | 1 (0.3–3.7)a | 0.5 (0.33–1.5)a | 0.14 |
| Gender | 0.36 | |||
| Male | 63 (46%) | 43 (44%) | 20 (53%) | |
| Female | 73 (54%) | 55 (56%) | 18 (47%) | |
| Race | 0.43 | |||
| Black | 117 (86%) | 81 (83%) | 36 (95%) | |
| Hispanic/Latino | 5 (4%) | 4 (4%) | 1 (3%) | |
| Non-Hispanic | 9 (7%) | 9 (9%) | 0 (0%) | |
| White | 5 (4%) | 4 (4%) | 1 (3%) | |
| Other/unknown | ||||
| Birthplace | 0.42 | |||
| USA | 92 (68%) | 64 (65%) | 28 (74%) | |
| Africa | 17 (13%) | 15 (15%) | 2 (5%) | |
| Otherc | 27 (20%) | 19 (19%) | 8 (21%) | |
| Immunologic and virologic parameters | ||||
| CD4 count (cells/mm3) | 726 (490–1143)a | 815 (545–1240)a | 598 (271–897)a | 0.003* |
| CD4% | 31 (22–37)a | 33 (24–37.2)a | 27.5 (16–33)a | 0.006* |
| Nadir CD4 count (cells/mm3) | 400 (116–608)a | 429 (134–784)a | 282 (88–505)a | 0.04* |
| HIV RNA VL (copies/mL) | 3397 (202–24,928)a | 1427 (97–9132)a | 5581 (885–77,484)a | <0.0001* |
ARVs, antiretroviral drugs; VL, viral load.
Median (IQR)
any initial ARVs, including dual and unboosted ARV regimens in older participants
other included Kazakhstan, Philippines, Trinidad, Ukraine and unknown (not recorded in MR).
p<0.05 are given in bold.
Thirty-eight (28%) participants experienced at least one TI since initiating ARVs. There were six patients with more than one episode of TI lasting at least four weeks. There were no statistically significant differences in demographic characteristics between the TI and CT cohorts (Table 1).
The median CD4 count, CD4% and nadir CD4 count were significantly lower in those who experienced TI as compared to patients in the CT cohort (p=0.003, 0.006 and 0.04, respectively; Table 1). There was no difference between the two cohorts in the highest ever CD4 cell count and CD4% after HIV diagnosis (data not shown). The median VL in the TI cohort was almost four times higher than that among children in the CT cohort (1427 vs. 5581 copies/mL; p<0.0001).
Among the 38 participants who experienced TI, the median duration of the last cART regimen before TI was 3.97 years and the median age at the time of TI was 10.8 years (Table 2).
Table 2.
Characteristics of the TI cohort and reasons for TI
| TI cohort | N=38 |
|---|---|
| Age at TI (years) | 10.8 (7.5–15.7)a |
| Duration of last cART regimen prior to TI (years) | 3.97 (2.5–7.6)a |
| Maximum CD4 count ever prior to TI (cells/mm3) | 1509 (1111–1800)a |
| Maximum CD4% ever prior to TI (%) | 37 (31–43)a |
| Maximum VL ever prior to TI (copies/mL) | 5199 (381–81,758)a |
| CD4 count prior to TIb (cells/mm3) | 789 (475–1058)a |
| CD4% priorb to TI | 27 (22–34)a |
| HIV RNA VL priorb to TI (copies/mL) | 2362 (309–65,577)a |
| Reason for TI | |
| Non-adherence | 11 (29%)c |
| ART toxicity | 2 (5%)c |
| Viral resistanced | 4 (11%)c |
| Othere | 10 (26%)c |
| Unknownf | 11 (29%)c |
TI, treatment interruption; VL, viral load; ART, antiretroviral therapy; cART, combination antiretroviral therapy.
Median (IQR)
the most recent value before the TI (median=2.3 months (IQR 1.1–8.8 months))
N (%)
viral resistance to cART with no other treatment options available
other reasons included difficulties with dose/formulation, high pill burden and ART holiday
not documented in the MR.
More than half of the patients with TI (n=23; 61%) had experienced TTI of cART. Among the remaining 15 (36.8%) children with TI, 14 (93%) patients with known resistance to 3TC were placed on 3TC MTI, and one patient was switched to LPV/ritonavir MTI (data not shown). In the overall TI cohort, the median CD4 count prior to TI was 789 cells/mm3 and the median VL was 2362 copies/mL. The most common reason for TI was non-adherence (29%), followed by viral resistance with limited options for alternative cART (11%) and ARV-related toxicity (5%) (Table 2). In 29% of the patients with TI, the reason for stopping cART was not documented. Among 38 patients with TI, 31 (82%) restarted cART after a median TI duration of one year (Table 3).
Table 3.
Characteristics of patients with TI who restarted cART
| Restarted cART | N=31a |
|---|---|
| Age at cART restart (years) | 12.6 (8.5–16.2)b |
| Duration of TI (years) | 0.98 (0.4–2.4)b |
| CD4 count (cells/mm3) priorc to restarting cART | 493 (270–740)b |
| CD4% priorc to restarting cART | 22 (16–30)b |
| HIV RNA VL priorc to restarting cART (copies/mL) | 52,002 (3967–129,410)b |
| CD4 count (cells/mm3) afterd restarting ART | 613 (420–1116)b |
| CD4% afterd restarting cART (%) | 26 (19–35)b |
| HIV RNA VL afterd restarting cART (copies/mL) | 2510 (129–40,500)b |
| Maximum CD4 count afterd restarting cART (cells/mm3) | 706 (534–1116)b |
| Time to maximum CD4 count afterd restarting cART (years) | 0.56 (0.2–1.1)b |
cART, combination antiretroviral therapy; TI, treatment interruption VL, viral load; ART, antiretroviral therapy.
Patients who restarted cART include 23 patients in TTI cohort and eight patients in MTI cohort
median (IQR)
the most recent value before restarting cART while on TI (median=2.3 months; IQR=1.1–8.8 months)
the most recent value after restarting cART (median=1.8 months; IQR=2 days–4.8 months).
All patients with TTI restarted cART (n=23; 100%), while only 8 out of 15 patients (53%) on MTI restarted cART. The highest CD4 count ever reached prior to TI (1509 cells/mm3 (IQR 1137–1820)) was significantly higher than the maximal CD4 count ever reached after TI (706 cells/mm3 (IQR 531–1140); p=0.0005), most likely due to the increased age. TTI and MTI groups did not demonstrate any significant differences in demographic, immunologic or virologic characteristics (data not shown). The only finding in this sub-analysis was the shorter time required by patients in the MTI cohort (two months (IQR 1.4–3.5)) to reach their highest CD4 count after restarting cART as compared to the patients in the TTI cohort (7.9 months (IQR 4.2–22).
Discussion
Convincing evidence of the detrimental effect of TI on the outcome of HIV disease from adult trials has led to the abandonment of the structured TI as a therapeutic cART approach [19,20]. The TI data from paediatric clinical trials, however, have been more complex [11,12,21]. In resource-limited settings, structured TI of cART has been evaluated as a feasible strategic approach to address limited coverage with paediatric cART [21–23]. CHER trial results have demonstrated that immediate initiation of cART with planned TI resulted in better long-term outcomes compared to the deferred cART [22,23]. Most recently, structured TI of efavirenz-based cART, defined as short-cycle therapy, showed non-inferiority in viral suppression compared to the CT arm in HIV-infected adolescents and young adults [13]. These data advocate for the potential consideration of structured TI in paediatric cART.
The prevalence of TI in our study (28%) was similar to that reported across the observational studies of unstructured TI from developed countries reporting TI in up to 40% of paediatric populations [24–28]. Many of these studies presented data from the early 2000s with limited options for alternative paediatric cART and higher ARV-associated toxicity. Our retrospective cohort included patients up to 17 years of age, some with a history of dual and unboosted cART, which might have resulted in limited choices for replacement regimens. Similar to findings from adult and paediatric studies from the USA and Europe, the most common reason for TI in our study was non-adherence to cART [24,26–29].
Several studies have suggested higher immunologic resilience and rebound following prolonged TI in children due to the inherent differences in immune system maturation compared to adults [11,12,21,23]. Despite the apparent tolerability of TI, concern for the delayed formation of drug resistance and long-term immunologic effect in children remained [11]. In a recent analysis of the three-year follow-up of the ARROW trial, every month of TI was associated with a 2% (1–3%, p=0.001) decrease in CD4% among children and the history of any TI was associated with a trend to increased mortality (hazard ratio: 2.6 (95% CI 0.7–10.4)) [21]. In the CHER study, the majority (80%) of children in the TI arm reached immunologic and clinical criteria requiring restarting cART after 4.8 years [23]. Consistent with these studies, in our paediatric cohort, the endpoint immunologic parameters in the patients with TI were significantly lower as compared to those on CT.
Structured TI has been linked to holding or bridging regimen using 3TC or emtricitabine (FTC) monotherapy in the presence of the M184V HIV resistance mutation to reduce viral fitness and prevent formation of additional resistance mutations [14,15]. IMPAACT P1094 study compared the immunologic outcome of continuing failing cART versus switching to 3TC/FTC MTI in perinatally infected non-adherent adolescents [14]. Participants (n=17) randomized to 3TC MTI were more likely than those maintained on failing cART (n=16) to sustain a ≥30% decline in CD4 count [14]. Recent observational data from 71 South African children on 3TC MTI as an alternative to failing cART reported that a majority of children (67.5%) on 3TC MTI had a >25% decline in CD4 count; however, only 23% were switched to second- or third-line cART [15]. In our study, all patients in the TTI group were restarted on cART, whereas less than half (46%) in the 3TC MTI cohort restarted cART. We did not observe significant immunologic or virologic differences between those on TTI and on 3TC MTI, although a shorter time was required by patients on 3TC holding regimen to reach their highest CD4 count after restarting cART. The single site and small sample size limits our ability to generalize these findings.
Conclusions
Due to the developmental changes throughout childhood and adolescence, TI represents an ongoing challenge to the continuum of paediatric cART. Prolonged TI can have potentially detrimental effects on the long-term outcomes in HIV-infected children. In our study, significantly lower median CD4 count and higher median VL were observed in children with a history of TI, including patients on 3TC MTI, as compared to those on continued cART. A sub-group analysis suggests a trend for a shorter time for 3TC MTI cohort to reach their highest CD4 count after restarting cART, which warrants further evaluation. Finally, the high frequency of TIs reported in our and other paediatric studies suggests a need for a better strategy in maintaining the continuity of the paediatric and adolescent cART.
Acknowledgements
The authors acknowledge the DC cohort investigators and research staff including Alan E. Greenberg, MD, MPH, Naji Younes, PhD, James Peterson, EdD, Maria Jaurretche, MS, and Lindsey Powers Happ, MPH, George Washington University Milken Institute School of Public Health; Debra Benator, MD, Veterans Affairs Medical Center; Princy Kumar, MD, Georgetown University; David Parenti, MD, George Washington Medical Faculty Associates; Richard Elion, MD, Whitman-Walker Health; Maria Elena Ruiz, MD, Washington Hospital Center; Angela Wood, MSW, Family and Medical Counseling Service; Lawrence D'Angelo, MD, MPH, Burgess Adolescent Clinic, Children's National Health System; Sohail Rana, MD, Pediatric Clinic, Howard University Hospital; Maya Bryant, MD, Saumil Doshi, MD, Adult Infectious Disease Clinic Howard University Hospital; Annick Hebou, MD, MetroHealth; Ricardo Fernandez, MD, La Clinica Del Pueblo; Stephen Abbott, MD, Unity Health Care; Jeffrey Binkley, PhD, Harlen Hays, MS, Thilakavathy Subramanian, MS, Dana Franklin, MPH, and Rachel Hart, MS, Cerner Corporation; Michael Kharfen, BA, HIV/AIDS, Hepatitis, Sexually Transmitted Diseases, Tuberculosis Administration, DC Department of Health; Henry Masur, MD, National Institutes of Health. The authors also like to acknowledge Dr. Mary Young, Dr. Carl Dieffenbach and Dr. Deborah Goldstein for their assistance with the DC cohort study as well as the research assistants at all of the participating sites and the DC cohort Community Advisory Board.
Competing interests
The authors have no competing interests to declare.
Authors' contributions
All authors listed on submitted manuscripts have read and agreed to its content, and meet the authorship requirements as detailed below. Specific contributions of each author are as follows:
NR developed the conception and design, served as a site principal investigator, led acquisition of data, analysis and interpretation of data, and drafted and critically revised the manuscript.
KSL made substantial contributions to conception and design, collected the data, participated in the analysis and interpretation of data, and has been involved in drafting the manuscript and revising it critically.
JH has made substantial contributions to study design, collected the data, participated in the analysis and interpretation of data, and has been involved in drafting the manuscript and revising it critically.
HAY has analyzed and interpreted the data and has been involved in drafting the manuscript and revising it critically for data analysis and interpretation.
AW contributed to study design, collected the data and participated in the interpretation of data, and has been involved in revising manuscript critically.
ADC has made substantial contributions to study design, analysis and interpretation of data, served as overall DC cohort study principal investigator and has been involved in drafting the manuscript and revising it critically.
All authors have given final approval of the version to be published.
Funding sources
The DC cohort is sponsored by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health (UO1 AI69503-03S2). Additionally, this publication resulted (in part) from research supported by the District of Columbia Center for AIDS Research, an NIH funded program (P30AI117970), which is supported by the following NIH co-funding and participating institutes and centres: NIAID, NCI, NICHD, NHLBI, NIDA, NIMH, NIA, FIC, NIGMS, NIDDK and OAR. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
References
- 1.The INSIGHT START Study Group. Initiation of antiretroviral therapy in early asymptomatic HIV infection. N Engl J Med. 2015;373:795–807. doi: 10.1056/NEJMoa1506816. doi: http://dx.doi.org/10.1056/NEJMoa1506816. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2.Guideline on when to start antiretroviral therapy and on pre-exposure prophylaxis for HIV. WHO; 2015. [cited 2016 Aug 11]. Available from: http://apps.who.int/iris/bitstream/10665/186275/1/9789241509565_eng.pdf?ua=1. [PubMed] [Google Scholar]
- 3.Guidelines for the use of antiretroviral agents in pediatric HIV infection [Internet] [cited 2016 Aug 11]. Available from: http://aidsinfo.nih.gov/guidelines.
- 4.Bamford A, Turkova A, Lyall H, Foster C, Klein N, Bastiaans D, et al. (PENTA Steering Committee). Paediatric European Network for Treatment of AIDS (PENTA) guidelines for treatment of paediatric HIV-1 infection 2015: optimizing health in preparation for adult life. HIV Med. 2015 doi: 10.1111/hiv.12217. doi: http://dx.doi.org/10.1111/hiv.12217. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Bernheimer JM, Patten G, Makeleni T, Mantangana N, Dumile N, Goemaere E, et al. Paediatric HIV treatment failure: a silent epidemic. J Int AIDS Soc. 2015;18(1):20090. doi: 10.7448/IAS.18.1.20090. doi: http://dx.doi.org/10.7448/IAS.18.1.20090. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Costenaro P, Penazzato M, Lundin R, Rossi G, Massavon W, Patel D, et al. Predictors of treatment failure in HIV-positive children receiving combination antiretroviral therapy: cohort data from Mozambique and Uganda. J Pediatric Infect Dis Soc. 2015;4(1):39–48. doi: 10.1093/jpids/piu032. doi: http://dx.doi.org/10.1093/jpids/piu032. [DOI] [PubMed] [Google Scholar]
- 7.Coetzee B, Kagee A, Bland R. Barriers and facilitators to paediatric adherence to antiretroviral therapy in rural South Africa: a multi-stakeholder perspective. AIDS Care. 2015;27(3):315–21. doi: 10.1080/09540121.2014.967658. doi: http://dx.doi.org/10.1080/09540121.2014.967658. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Towards an AIDS free generation: children and AIDS. Sixth Stocktaking Report 2013. UNAIDS Programme Coordinating Board. UNAIDS/PCB (35)/14.23.2014. Available from: http://www.unaids.org/sites/default/files/media_asset/20131129_stocktaking_report_children_aids_en_0.pdf.
- 9.Gap analysis on paediatric HIV treatment, care and support. UNAIDS. 2014. UNAIDS Programme Coordinating Board. UNAIDS/PCB (35)/14.23. [cited 2014 Nov 12]. Available from: http://www.unaids.org/sites/default/files/media_asset/20141117_Gap_Analysis_on_paediatric_ARVs.pdf.
- 10.Ebonyi AO, Ejeliogu EU, Okpe SE, Shwe DD, Yiltok ES, Ochoga MO, et al. Factors associated with antiretroviral treatment interruption in human immunodeficiency virus (HIV)-1-infected children attending the Jos University Teaching Hospital, Jos, Nigeria. Niger Med J. 2015;56(1):43–7. doi: 10.4103/0300-1652.149170. doi: http://dx.doi.org/10.4103/0300-1652.149170. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Borkowsky W, Yogev R, Muresan P, McFarland E, Frenkel L, Fenton T, et al. Planned multiple exposures to autologous virus in HIV type 1-infected pediatric populations increases HIV-specific immunity and reduces HIV viremia. AIDS Res Hum Retroviruses. 2008;24(3):401–11. doi: 10.1089/aid.2007.0110. doi: http://dx.doi.org/10.1089/aid.2007.0110. [DOI] [PubMed] [Google Scholar]
- 12.Paediatric European Network for Treatment of AIDS (PENTA) Response to planned treatment interruptions in HIV infection varies across childhood. AIDS. 2010;24(2):231–41. doi: 10.1097/QAD.0b013e328333d343. doi: http://dx.doi.org/10.1097/QAD.0b013e328333d343. [DOI] [PubMed] [Google Scholar]
- 13.Butler K, Inshaw J, Ford D, Bernays S, Scott K, Kenny J, et al. BREATHER (PENTA 16) short-cycle therapy (SCT) (5 days on/2 days off) in young people with chronic human immunodeficiency virus infection: an open, randomised, parallel-group Phase II/III trial. Health Technol Assess. 2016;20(49):1–108. doi: 10.3310/hta20490. doi: http://dx.doi.org/10.3310/hta20490. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Agwu A, Warshaw M, Siberry GK, Melvin A, McFarland E, Wiznia A, et al. 6th Pediatric HIV Workshop. Melbourne, Australia: 3TC/FTC monotherapy vs. continuing failing cART as a bridging ART strategy in persistently non-adherent HIV-infected youth with M184V resistance: results of IMPAACT P1094. [Abstract O-11] [Google Scholar]
- 15.Linder V, Goldswain C, Boon G, Carty C, Jackson V, Harper K, et al. Lamivudine monotherapy as a safe option for HIV-infected paediatric clients with adherence challenges: new evidence from a large South African cohort. J Int AIDS Soc. 2014;17(4):19763. doi: 10.7448/IAS.17.4.19763. doi: http://dx.doi.org/10.7448/ias.17.4.19763. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Bunupuradah T, Panthong A, Kosalaraksa P, Wongsabut J, Puthanakit T, Lumbiganon P, et al. Simplifying antiretroviral therapy to lopinavir/ritonavir monotherapy did not improve quality of life and therapy adherence in pretreated HIV-infected children. AIDS Res Hum Retroviruses. 2014;30(3):260–5. doi: 10.1089/AID.2013.0204. doi: http://dx.doi.org/10.1089/aid.2013.0204. [DOI] [PubMed] [Google Scholar]
- 17.Schenone E, Di Biagio A, Parisini A, Bruzzone B, Sticchi L, Calzi A, et al. Simplification to monotherapy with lopinavir/ritonavir in adolescents with vertically acquired HIV-1 infection. J Chemother. 2012;24(1):56–8. doi: 10.1179/1120009X12Z.00000000011. doi: http://dx.doi.org/10.1179/1120009X12Z.00000000011. [DOI] [PubMed] [Google Scholar]
- 18.Greenberg AE, Hays H, Castel AD, Subramanian T, Powers-Happ L, Binkley J, et al. Development of a large urban HIV/AIDS longitudinal cohort using a web-based platform to merge electronically and manually abstracted data from disparate medical record systems: technical challenges, innovative solutions. J Am Med Inform Assoc. 2016;23(3):635–43. doi: 10.1093/jamia/ocv176. doi: http://dx.doi.org/10.1093/jamia/ocv176. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19.Guidelines for the use of antiretroviral agents in HIV-1-infected adults and adolescents [Internet] [cited 2016 July 07]. Available from: https://aidsinfo.nih.gov/guidelines.
- 20.Strategies for Management of Antiretroviral Therapy (SMART) Study Group. El-Sadr WM, Lundgren JD, Neaton JD, Gordin F, Abrams D, et al. CD4+ count-guided interruption of antiretroviral treatment. N Engl J Med. 2006;355(22):2283–96. doi: 10.1056/NEJMoa062360. doi: http://dx.doi.org/10.1056/NEJMoa062360. [DOI] [PubMed] [Google Scholar]
- 21.Thompson LC, Ford D, Hakim J, Munderi P, Kekitiinva A, Musiime V, et al. Long term effects of treatment interruptions in adults and children; Conference on Retroviruses and Opportunistic Infections; 2014 Mar 3-6; Boston, MA. 2014[abstract 562] [Google Scholar]
- 22.Violari A, Cotton MF, Gibb DM, Babiker AG, Steyn J, Madhi SA, et al. Early antiretroviral therapy and mortality among HIV-infected infants. N Engl J Med. 2008;359(21):2233–44. doi: 10.1056/NEJMoa0800971. doi: http://dx.doi.org/10.1056/NEJMoa0800971. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Cotton MF, Violari A, Otwombe K, Panchia R, Dobbels E, Rabie H, et al. Early time-limited antiretroviral therapy versus deferred therapy in South African infants infected with HIV: results from the children with HIV early antiretroviral (CHER) randomized trial. Lancet. 2013;382(9904):1555–63. doi: 10.1016/S0140-6736(13)61409-9. doi: http://dx.doi.org/10.1016/S0140-6736(13)61409-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Gibb DM, Duong T, Leclezio VA, Walker AS, Verweel G, Dunn DT, et al. Immunologic changes during unplanned treatment interruptions of highly active antiretroviral therapy in children with human immunodeficiency virus type 1 infection. Pediatr Infect Dis J. 2004;23(5):446–50. doi: 10.1097/01.inf.0000122601.62358.74. doi: http://dx.doi.org/10.1097/01.inf.0000122601.62358.74. [DOI] [PubMed] [Google Scholar]
- 25.Saitoh A, Foca M, Viani RM, Heffernan-Vacca S, Vaida F, Lujan-Zilbermann J, et al. Clinical outcomes after an unstructured treatment interruption in children and adolescents with perinatally acquired HIV infection. Pediatrics. 2008;121(3):513–21. doi: 10.1542/peds.2007-1086. doi: http://dx.doi.org/10.1542/peds.2007-1086. [DOI] [PubMed] [Google Scholar]
- 26.Siberry GK, Patel K, Van Dyke RB, Hazra R, Burchett SK, Spector SA, et al. Pediatric HIV/AIDS Cohort Study (PHACS). CD4+ lymphocyte-based immunologic outcomes of perinatally HIV-infected children during antiretroviral therapy interruption. J Acquir Immune Defic Syndr. 2011;57(3):223–9. doi: 10.1097/QAI.0b013e318218e068. doi: http://dx.doi.org/10.1097/QAI.0b013e318218e068. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27.Aupiais C, Faye A, Le Chenadec J, Rouzioux C, Bouallag N, Laurent C, et al. ANRS EPF-CO10 French pediatric cohort. Interruption of cART in clinical practice is associated with an increase in the long-term risk of subsequent immunosuppression in HIV-1-infected children. Pediatr Infect Dis J. 2014;33(12):1237–45. doi: 10.1097/INF.0000000000000450. doi: http://dx.doi.org/10.1097/INF.0000000000000450. [DOI] [PubMed] [Google Scholar]
- 28.Kranzer K, Ford N. Unstructured treatment interruption of antiretroviral therapy in clinical practice: a systematic review. Trop Med Int Health. 2011;16(10):1297–313. doi: 10.1111/j.1365-3156.2011.02828.x. doi: http://dx.doi.org/10.1111/j.1365-3156.2011.02828.x. [DOI] [PubMed] [Google Scholar]
- 29.Fairlie L, Karalius B, Patel K, Van Dyke RB, Hazra R, Hernán MA, et al. Pediatric HIV AIDS Cohort Study (PHACS), The International Maternal Pediatric Adolescent AIDS Clinical Trials (IMPAACT) CD4+ and viral load outcomes of antiretroviral therapy switch strategies after virologic failure of combination antiretroviral therapy in perinatally HIV- infected youth in the United States. AIDS. 2015;29(16):2109–19. doi: 10.1097/QAD.0000000000000809. doi: http://dx.doi.org/10.1097/QAD.0000000000000809. [DOI] [PMC free article] [PubMed] [Google Scholar]