Published online February 29, 2008
PEDIATRICS Vol. 121 No. 3 March 2008, pp. e513-e521 (doi:10.1542/peds.2007-1086)
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ARTICLE

Clinical Outcomes After an Unstructured Treatment Interruption in Children and Adolescents With Perinatally Acquired HIV Infection

Akihiko Saitoh, MDa, Marc Foca, MDb, Rolando M. Viani, MDa, Susan Heffernan-Vacca, NPb, Florin Vaida, PhDc, Jorge Lujan-Zilbermann, MDd, Patricia J. Emmanuel, MDd, Jaime G. Deville, MDe and Stephen A. Spector, MDa

a Division of Infectious Diseases, Department of Pediatrics
c Division of Biostatistics and Bioinformatics, Department of Family and Preventive Medicine, University of California San Diego, La Jolla, California
b Division of Infectious Disease, Department of Pediatrics, Columbia University, New York, New York
d Division of Infectious Diseases, Department of Pediatrics, University of South Florida College of Medicine, Tampa, Florida
e Division of Infectious diseases, Department of Pediatrics, School of Medicine, University of California, Los Angeles, California


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
OBJECTIVE. An unstructured treatment interruption in children with perinatally acquired HIV infection is an issue with unresolved significance. The objective of this study was to investigate the actual prevalence and clinical outcomes of a treatment interruption in children and adolescents with perinatally acquired HIV-1 infection.

METHODS. Clinical data were analyzed for 72 children and adolescents who had HIV-1 infection and stopped their medications at 4 academic centers in the United States between January 2000 and September 2004.

RESULTS. Among 405 patients with perinatal HIV-1 infection, 72 (17.8%) experienced a treatment interruption during the observation period. The mean age of patients at the time of the treatment interruption was 12.8 years, and the mean length of the treatment interruption was 14 months. Medication fatigue was the most common reason for a treatment interruption. The CD4+ T-cell percentage nadir before the treatment interruption did not predict CD4+ T-cell percentage declines during the treatment interruption; however, the CD4+ T-cell percentage gain from nadir to the time of the treatment interruption predicted CD4+ T-cell percentage declines during the treatment interruption. During the median follow-up of 19 months (range: 6–48 months), 48 (67%) patients resumed antiretroviral medications. As expected, there was a continuous CD4+ T-cell percentage decrease and plasma HIV-1 RNA increase during the observation period. Overall, 7 (10%) patients were admitted to the hospital; 2 (3%) patients experienced an AIDS-defining illness.

CONCLUSIONS. An unstructured treatment interruption seems to be a major issue for youth with perinatally acquired HIV-1 infection. Patients who experienced the greatest rise in CD4+ T-cell percentage on treatment had the largest CD4+ T-cell percentage decline after the treatment interruption. Close monitoring is required when a treatment interruption occurs in children and adolescents with HIV infection.

Key Words: treatment interruption • HIV-1 • children • adolescent • nadir CD4+ T-cell percentage • medication fatigue

Abbreviations: HAART—highly active antiretroviral therapy • TI—treatment interruption • CD4%—CD4+ T-cell percentage • NRTI—nucleoside reverse transcriptase inhibitor • NNRTI—non–nucleoside reverse transcriptase inhibitor • PI—protease inhibitor • PCP—Pneumocystis jiroveci pneumonia • CI—confidence interval

Mother-to-child transmission of HIV-1 infection has decreased dramatically since the introduction of zidovudine prophylaxis for mothers with HIV-1 infection and their infants.1 Children who acquired HIV infection before the introduction of zidovudine prophylaxis predominate in the population of pediatric and adolescent HIV clinics, with greater numbers surviving into adulthood during the potent highly active antiretroviral therapy (HAART) era; however, important issues associated with long-term antiretroviral therapy have been recognized in these patients, including adverse effects, pill burden, development of drug resistance, and, most notably, decreased adherence to medications.2,3 Achieving full adherence to antiretroviral therapy in children with HIV infection requires not only the child's cooperation but also devoted and adherent parents or caregivers. Adolescents with HIV infection create significant medication challenges, given their unique developmental, psychosocial, and lifestyle issues.4

An unstructured treatment interruption (TI) is an issue in the adolescent population, because the potential alternative of suboptimal adherence can lead to antiretroviral resistance and diminished treatment options in the future; however, there is little information on the clinical, virologic, and immunologic outcomes of TI in pediatric and adolescent populations.5–7 We conducted a retrospective study at 4 academic centers in the United States to investigate the impact of unstructured TI on HIV-1–related disease progression in youth with perinatally acquired HIV-1 infection.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Patients
Among 405 children and adolescents with perinatally acquired HIV-1 infection at 4 academic centers in the United States between January 2000 and September 2004, 72 underwent an unstructured TI. We included the children who had been followed at the clinics during the period without age limitation. These 4 institutions were selected because they are located in areas with high rates of pediatric HIV infection. Children were analyzed because they satisfied the following criteria: (1) antiretroviral therapy had been taken for ≥6 months before TI; (2) antiretroviral medications were discontinued for ≥3 months; and (3) clinical data were available before and during the TI. When a patient had >1 TI during the observation period, only the first episode was included.

This was a retrospective study, and the following data were collected from the patients before TI: age, demographic information, reasons for TI, antiretroviral regimens, immunologic and virologic data including CD4+ T-cell counts and CD4+ T-cell percentages (CD4%), plasma HIV-1 RNA, and nadir CD4+ T-cell counts and CD4% (the lowest CD4+ T-cell counts and CD4% before TI). During the TI, immunologic and virologic data including CD4+ T-cell counts and CD4%, plasma HIV-1 RNA, clinical events during TI including hospitalization, AIDS-defining illness, and post-TI antiretroviral regimens were collected from the closest time points at 3, 6, 9, 12, 18, and 24 months after TI. These time points were chosen to evaluate the short- and long-term outcomes after a TI.

The reasons for the TI were defined as follows: (1) medication fatigue: patients who were unable to take antiretroviral medications because of pill burden and/or nonadherence; (2) social issues: family interactions that made it difficult for patients to continue to take their medications; (3) toxicity: abnormal laboratory findings including hepatitis, pancreatitis, abnormal lipid panels, and other laboratory abnormalities associated with the use of antiretroviral medications; (4) adverse effects: patient-driven complaints such as diarrhea, vomiting, nausea, abdominal pain, body characteristic changes, or other symptoms associated with the use of antiretroviral medications; (5) behavior issues: developmental issues such as refusal to swallow pills or resistance to commands by parents or caregivers; and (6) psychiatric diseases: psychiatric and other associated disorders including depression, anxiety disorders, or personality disorders. The reasons for a TI were selected by the primary care doctors, and >1 reason was allowed to be recorded.

The decision to resume antiretroviral therapy was made on a case-by-case basis by the primary care doctor. The decisions to resume antiretroviral therapy were categorized as follows: (1) immunologic and/or virologic deterioration; (2) improvement of patients’ self-motivation to resume antiretroviral medications; (3) resolution of the adverse effects associated with antiretroviral medications; (4) change in patient's environment (eg, new caregiver available, patient was removed from caregivers into other services); (5) availability of alternative regimens (eg, simplified regimens, once-a-day regimen); (6) pregnancy; (7) required hospitalization; and (8) others (eg, hematologic disorders related to acute viral replication). This study followed the human experimentation guidelines of the US Department of Health and Human Services and the review board of each institution.

Statistical Analysis
The Wilcoxon rank-sum test was used to analyze the group comparisons between baseline continuous variables, and the Wilcoxon signed-rank test was used to analyze 2 related parameters in different time points. The Kruskal-Wallis test was used to determine whether (1) the reasons for TI were similar among the treatment groups and (2) the numeric variables were similar among institutions. The {chi}2 and Fisher's exact tests were used to evaluate whether the categorical variables were similar among institutions. The Spearman correlation test was used to evaluate the correlation between 2 numeric variables. Binomial regression analysis was performed to compare the proportions of patients who started TI or continued TI in each year in each institution. For longitudinal analyses of the CD4% and CD8%, CD4+ T-cell counts, and log10 HIV-1 RNA, mixed-effects model with random intercepts and normal errors were used.8 This model adjusts for progressive dropout. In addition, HIV-1 RNA was adjusted for censoring below the limit of detection.9 To analyze the impact of nadir CD4% on CD4% during treatment interruption, we fitted a linear mixed-effects model with random intercept for patient, unconstrained time effect, a group effect for nadir CD4% ≥25%, and an interaction term between CD4% ≥25% and linear time. The last term measures the difference in rates of CD4% decay between the groups with nadir CD4% ≥25% and <25%. Similar models were fit with baseline CD4% instead of nadir CD4% and for log viral load response instead of CD4% response.

For the longitudinal analyses, the P values were calculated from Wald-type t tests of the model coefficients and were corrected for multiple comparisons using Bonferroni correction within each analysis. All P values calculated were 2-sided. A P value of <.05 was considered to be statistically significant. The analyses were performed by using statistical software R10 and SPSS (SPSS Inc, Chicago, IL).


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 CONCLUSIONS
 REFERENCES
 
Baseline Characteristics
Among 405 children and adolescents who had perinatally acquired HIV-1 infection and were followed at 4 academic centers in the United States between January 2000 and September 2004, 72 (17.8%) underwent an unstructured TI. The proportion of patients who started a TI in each year increased from 2.4% in 2000 to 5.7% in 2003 (P = .02). There were differences in the proportions of patients who started a TI and continued a TI among the 4 institutions (P = .001 and P < .001, respectively). One center (University of South Florida) had constant rates of patients who started a TI (1.7%–3.0%) and continued a TI (2.3%–3.9%) from 2000 to 2003, whereas increased rates were observed at the other centers: University of California, Los Angeles (0%–7.5% and 0%–10%, respectively), Columbia University (3.9%–10.5% and 1.3%–9.2%, respectively), and University of California San Diego (0%–13.8% and 0%–22.4%, respectively).

Baseline characteristics of the 72 patients who underwent a TI are summarized in Table 1. Sixty percent (43 of 72) of patients remained off antiretroviral therapy for >12 months. Twenty-four percent (17 of 72) of patients had HIV-1 RNA <400 copies per mL, and the remaining 55 (76%) patients had detectable HIV-1 RNA ≥400 copies per mL at the time of the TI. Before the TI, 60 (80%) patients received HAART and 12 (20%) patients received nucleoside reverse transcriptase inhibitors (NRTIs) alone. The mean length of the TI was 15.9 months (range: 3–56 months). Among the 4 institutions, significant differences in baseline characteristics were observed, including age (P = .006), race/ethnicity (P = .004), antiretroviral regimens (P = .002), baseline CD4+ T-cell counts (P = .03), and CD4% (P = .05), except log HIV-1 RNA (P = .06).


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  		TABLE 1 Baseline Characteristics of Children and Adolescents Who Had HIV-1 Infection and Underwent an Unstructured TI

 
Reasons for TI
Among 72 patients, a total of 87 reasons for starting the TI were recorded: 59 (82%) patients had 1 reason, 11 (15%) patients had 2 reasons, and 2 (3%) patients had 3 reasons for the TI. Medication fatigue was the most common reason for a TI (50 of 72 [69%]; Table 2). Among the 50 (69.4%) patients who discontinued antiretroviral therapy because of medication fatigue, 11 (15.3%) had additional reasons for the TI, including social issues, adverse effects, toxicities, and behavior issues. Among the 22 (30.6%) patients who discontinued antiretroviral therapy with other reasons, toxicities were the most common reason for a TI, followed by social issues, behavior issues, adverse effects, and psychiatric diseases. No significant difference was observed in overall antiretroviral regimens between patients who discontinued antiretroviral therapy with medication fatigue and those who discontinued antiretroviral therapy for other reasons (P = .29); however, the patients who underwent a TI for medication fatigue were older than those who underwent a TI for other reasons (13.8 vs 10.6 years; P = .01). In addition, among patients who received a protease inhibitor (PI)-based regimen (n = 48), those who underwent a TI for medication fatigue were older than those who underwent a TI for other reasons (14.7 vs 10.2 years; P = .003). Of note, no significant age difference was observed between patients who received PI-based regimens and those who received non–PI-based regimens (13.3 vs 11.7 years; P = .19).


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  		TABLE 2 Reasons for TI in 72 Children and Adolescents With Perinatally Acquired HIV-1 Infection

 
Clinical Outcome During TI
Overall, 7 (9%) patients required hospitalization during their TI. Among them, 2 (3%) patients experienced an AIDS-defining illness; pulmonary tuberculosis, and Pneumocystis jiroveci pneumonia (PCP). A 9-year-old boy discontinued zidovudine, lamivudine, abacavir, and lopinavir + ritonavir because of medication fatigue (nonadherence). His CD4+ T-cell count (CD4%) was 1219/µL (28%) and HIV-1 RNA level was 147000 copies per mL at time of his TI. He received a diagnosis of pulmonary tuberculosis 6 months later with a CD4+ T-cell count (CD4%) of 636/µL (24%) and HIV-1 RNA of 267000 copies per mL. The other patient was a 16-year-old girl who discontinued tenofovir and saquinavir + ritonavir because of a behavior issue (developmental issue). Her CD4+ T-cell count (CD4%) was 108 (19%) and HIV-1 RNA level was 9419 copies per mL at time of the TI. After 1 year without medication, she received a diagnosis of PCP with a CD4+ T-cell count (CD4%) of 3/µL (1%) and plasma HIV-1 RNA level of 246343 copies per mL. Both patients resumed antiretroviral therapy after treatment for their AIDS-defining illnesses. The remaining patients were hospitalized with cytomegalovirus hepatitis (n = 1), empyema (n = 1), bacterial pneumonia (n = 1), pyelonephritis (n = 1), and sinusitis (n = 1). No patient died during a TI.

Frequency of Resuming Antiretroviral Therapy
The proportion of patients who resumed antiretroviral therapy is shown using a Kaplan-Meier curve (Fig 1). The median time to restarting treatment was 14 months (25th and 75th percentiles: 8–27 months; range: 3 to >57 months, censored observation). The estimated proportion (95% confidence interval [CI]) of patients who were still off therapy at 6, 12, and 24 months after TI were 84% (76%–93%), 56% (46%–69%), and 30% (20%–46%), respectively. Nine (13%) patients resumed antiretroviral therapy after 24 months of TI.


Figure 1
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  		FIGURE 1 The Kaplan-Meier curve of time to resume antiretroviral therapy. Subjects who were still on the TI at the end of 2004 were censored at that time point. The dotted lines indicate 95% CIs, and the vertical bars indicate the time points at which each subject resumed antiretroviral therapy.

 
Reasons for Resuming Antiretroviral Therapy
During the observational period, 48 (67%) patients resumed antiretroviral therapy, and their reasons to resume antiretroviral therapy are summarized in Table 3. Fifty-six percent of patients (27 of 48) resumed antiretroviral therapy because of immunologic and/or virologic deterioration, and the other 44% (21 of 48) resumed antiretroviral therapy with other reasons, including patient request, environmental change, and pregnancy. Among 4 institutions, the reasons for resuming antiretroviral therapy were significantly different (P < .001). Eighty-four percent (16 of 19) of patients resumed antiretroviral therapy because of immunologic or/and virologic deterioration in 1 center (University of South Florida), whereas only 16% (3 of 19) did at another center (Columbia University).


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  		TABLE 3 Reasons for Resuming Antiretroviral Therapy for 48 Children and Adolescents With Perinatally Acquired HIV-1 Infection

 
The new antiretroviral regimens were different from those previously prescribed, except for 2 patients (3% [2 of 48]), who resumed the same regimens used before their TI. The regimens included NRTIs alone (1 patient [2%]), NRTIs + Pis (31 patients [65%]), NRTIs + non–nucleoside reverse transcriptase inhibitor (NNRTI) (6 patients [12%]), and NRTIs + PIs + NNRTI (10 patients [21%]).

Immunologic and Virologic Outcomes During TI
There was a significant CD4% decrease from baseline to 3 months (P < .001) and the rest of the observation time points (P < .001). We also analyzed the data on the basis of CD4+ T-cell counts, and the same significant decline in CD4+ T-cell counts was observed from 684/µL (95% CI: 601–766/µL; n = 71) at baseline to 534/µL (95% CI: 449–619/µL; n = 60) at 3 months (P < .001) and 471 (95% CI: 376–566/µL) at 12 months (P < .001). In contrast, there was a significant CD8+ T-cell percentage increase from baseline to 3 months (P = .003) and the rest of the observation period up to 24 months (P < .001; Fig 2A). Similarly, HIV-1 RNA increased significantly from baseline to 3 months (P < .001) and the rest of the observation period (P < .001; Fig 2B). The decline of CD4% and counts and the increase in plasma HIV-1 RNA was sustained throughout the observation period.


Figure 2
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  		FIGURE 2 CD4+ and CD8+ T-cell percentages (A) and log plasma HIV-1 RNA (B) in perinatally acquired HIV-infected children and adolescents during TI. The bars indicate the 95% CIs. The plots were adjusted for dropout and for HIV-1 RNA below the limit of detection. The changes in CD4+ and CD8+ T-cell percentage and log plasma HIV-1 RNA were significant overall (P < .001).

 
Patients With Undetectable Plasma HIV-1 RNA Before TI
Seventeen (24%) patients had HIV-1 RNA <400 copies per mL before their TI. Baseline characteristics of these patients compared with the 55 patients with detectable plasma RNA at their TI are listed in Table 1. As expected, the mean CD4% was higher in those with an undetectable RNA (36%; 95% CI: 31%–41%) than in those whose RNA value was >400 (24%; 95% CI: 21%–27%; P < .001). In addition, this group included more female patients (82% vs 53%; P = .05), and these patients received more triple-class regimens (59% vs 26%; P = .05). The mean duration of virologic control before the TI was 31 months (range: 3–77 months). The majority of patients (88% [15 of 17]) experienced a rapid increase in HIV-1 RNA after 3 months of interrupting therapy, and in only 1 patient (6% [1 of 17]) did HIV-1 RNA remain undetectable after 12 months off therapy.

When we analyzed the immunologic and virologic outcomes of patients who started their TI with an undetectable HIV-1 RNA and those who started their TI with a detectable HIV-1 RNA (Fig 3), a rapid CD4% decline (–6.6% [95% CI: –9.5% to –3.6%; P < .001; n = 15] vs –1.4% [95% CI: –3.1% to 0.3%; P = .70; n = 44]) and a HIV-1 RNA increase (2.6 log copies per mL [95% CI: 2.2 to 3.0 log copies per mL; P < .001; n = 15] vs 0.2 log copies per mL [95% CI: 0.004–0.40 log copies per mL; P = .29; n = 43]) were observed at 3 months. The initial CD4% decline and plasma HIV-1 RNA increase were maintained throughout the observation period among patients who started with an undetectable HIV-1 RNA (P < .001).


Figure 3
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  		FIGURE 3 CD4+ T-cell percentage (A) and log plasma HIV-1 RNA (B) in perinatally acquired HIV-infected children and adolescents whose plasma HIV-1 RNA was undetectable (<400 copies per mL; dotted line) and detectable (≥400 copies per mL; solid line) at the time of treatment interruption. A, The plots were adjusted for dropout, and the difference in CD4+ T-cell percentage between 2 groups was significant overall (P < .05) except 3, 6, and 18 months (P = .10–0.19). B, The plots were adjusted for dropout and log plasma HIV-1 RNA below the limit of detection. The differences between groups were significant overall (P < .05). The bars indicate the 95% CIs. a P < .01; b P < .05.

 
No correlation was observed between the duration of undetectable HIV-1 RNA before the TI and the increase in HIV-1 RNA at 3 months (r = 0.10, P = .76). During the observation period, a total of 9 (53%) patients resumed antiretroviral therapy, and no patient was hospitalized or received a diagnosis as having an AIDS-defining illness. Sixty-six percent (6 of 9) of patients resumed antiretroviral therapy because of immunologic and/or virologic deterioration.

Impact of Nadir and Baseline CD4% on Changes in CD4% and HIV-1 RNA During TI
To investigate the impact of nadir CD4% on immunologic and virologic outcomes during the TI, we compared the longitudinal CD4% and HIV-1 RNA between patients with nadir CD4% <25% and those with nadir CD4% ≥25% (n = 33 and 38, respectively). As expected, mean baseline CD4% were statistically different between the 2 groups (22% and 37%; P < .001); however, the CD4% decline was not significantly different between the 2 groups during the follow-up period (P = .45). Similarly, the mean log HIV-1 RNA differed between the 2 groups at baseline (3.87 log copies per mL and 3.05 log copies per mL; P = .001); there was no difference in log HIV-1 RNA rate of increase during follow-up between the 2 groups (P = .74).

In addition, we conducted a similar analysis to analyze the impact of baseline CD4% (<25% and ≥25%; n = 27 and n = 43, respectively) on immunologic and virologic outcomes during TI. The 2 groups differed in mean baseline CD4% (16% and 33%; P < .001) but not in rate of decline of CD4% during TI (P = .55). The mean baseline log HIV-1 RNA was different between the 2 groups at baseline (4.12 copies per mL and 3.27 log copies per mL; P < .001), but the rate of increase was not different between the 2 groups (P = .19).

Association Between Changes in CD4% Gain From Nadir to Time of TI and Change in CD4% During TI
We also evaluated the relationship between CD4% gain from nadir before the TI and changes in CD4% during the TI. There were consistent negative correlations between CD4% gain while receiving antiretroviral therapy and changes in CD4% at 3 months (r = –0.41, P = .002; n = 54), 6 months (r = –0.51, P < .001; n = 54; Fig 4A), 9 months (r = –0.30, P = .07; n = 39), and 12 months of TI (r = –0.68, P < .001; n = 30; Fig 4B).


Figure 4
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  		FIGURE 4 The correlations between CD4+ T-cell percentage gain from nadir to time of TI and changes in CD4+ T-cell percentage from TI to 6 months after TI (A) and changes in CD4+ T-cell percentage from TI to 12 months after TI (B) in HIV-1 infected children and adolescents who experienced TI.

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
CONCLUSIONS
 REFERENCES
 
We have shown that an unstructured TI is a major issue among children and adolescents with perinatally acquired HIV-1 infection. TI was associated with HIV disease progression including a rapid HIV-1 RNA increase during the first several months and a precipitous CD4% decline. Thus, close monitoring is required when a TI is undertaken by children and adolescents.

Importantly, nadir CD4+ T-cell counts were reported to predict a CD4+ T-cell decline11–14 as well as the duration of TI15–18 in adults who had HIV-1 infection and underwent scheduled or structured TI. Although no report has shown the impact of nadir CD4% on immunologic outcomes during a TI, we used nadir CD4% for the analysis because CD4+ T-cell counts are significantly influenced by age, especially in younger children. Our results showed that nadir CD4% were not predictive of a CD4% decline. In addition, no correlation was observed between nadir CD4% and change in CD4% from baseline to each observation time point. These differences between children and adults may be attributable to their different viral dynamics during TI, because all of our patients had long-term HIV-1 infection from birth. It is also possible that this may be attributable to different immunologic kinetics secondary to functional thymic activity in children.19–21 In addition, in this study, youth with higher nadir CD4% had higher CD4% before TI, which could be a confounding factor determining the decline in CD4% after TI. Additional studies are necessary to elucidate the impact of nadir CD4% on immunologic recovery in children and adolescents with HIV-1 infection.

Because immune reconstitution of children during HAART is believed to result from the continued presence of a functional thymus,19–21 CD4+ T-cell dynamics after a TI may also be different from that of adults; however, our data showed that a CD4+ T-cell count decline in 72 patients was 10.8 cells per week, which was similar to findings in adult studies.22–25 Similar declines in CD4+ T-cell count during a TI were reported in other pediatric studies.6,7 Because the majority of our patients were adolescents (mean age: 12.8 years), the effect of the thymus may be limited in this study population.

Medication fatigue was the most common reason for a TI in this study. Although our data did not demonstrate the actual pill counts from each individual, adolescent patients who were receiving PI-based regimens (at the time a greater pill burden) were more likely to interrupt antiretroviral therapy because of medication fatigue. This may indicate that regimens with lower pill burden and decreased frequency of administration may be preferable for an adolescent population to prevent nonadherence and subsequent discontinuation of medications.

Although several studies have shown the clinical outcomes of adults who had HIV-1 infection and whose HIV-1 RNA was undetectable at TI,26–31 no data are available regarding the clinical outcomes in youth who have HIV-1 infection and whose HIV-1 RNA was undetectable at TI. We had a total of 17 patients who satisfied these criteria and compared their data with those of patients with detectable HIV-1 RNA at TI. Children with undetectable HIV-1 RNA had a more rapid decrease in CD4% and an increase in HIV-1 RNA during the first 3 months. Of note, this may reflect that patients with undetectable HIV-1 RNA before TI had better compliance to medications compared with those with detectable HIV-1 RNA before TI. These finding suggest that patients with undetectable HIV-1 RNA at the time of TI should be monitored closely during the first several months after TI.

We have also shown that there is a persistent negative correlation between CD4% gains from nadir to the time of TI and changes in CD4% during a TI. Patients who gained the greatest CD4% while receiving antiretroviral therapy experienced the greatest CD4% decline during the first year of a TI. A similar finding was reported for adults who had long-term HIV infection and discontinued antiretroviral therapy.32 This may be used as a marker for change in CD4% during the early stage of a TI.

Our study has some limitations. There were significant differences in the proportions of patients who started and continued a TI among the 4 institutions and baseline characteristics because the decision to stop and to resume antiretroviral therapy was determined by the patients and their treating physicians, not by definitive virologic or immunologic criteria; therefore, we were not able to demonstrate the long-term immunologic or virologic outcome in the whole study population because >40% of patients resumed antiretroviral therapy during the first year of TI. Second, we did not investigate the long-term consequences of TI when antiretroviral medications were reinstituted. The clinical responses after reinitiation of antiretroviral medications need to be evaluated, especially focusing on the development of resistant virus against antiretroviral regimens that patients received before their TI. Last, our study was a retrospective study, which contains some confounding factors when analyzing the data, including difficulty in distinguishing periods of nonadherence from a TI, significant differences in baseline characteristics among 4 institutions, limited number of patients, and different reasons for resuming antiretroviral therapy.


   CONCLUSIONS
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
REFERENCES
 
We have documented significant use of an unstructured TI among youth with HIV-1 infection. A TI was associated with HIV disease progression, including a significant decrease in CD4% and an increase in HIV-1 RNA levels and hospitalizations as a result of AIDS-defining illnesses. These data suggest that youth and their families should be counseled regarding the possible serious consequences that can be associated with TI. A larger, prospective study is necessary to elucidate the long-term virologic and immunologic outcomes of youth who have HIV-1 infection and undergo TI.


   ACKNOWLEDGMENTS
 
This work was supported by the Pediatric AIDS Clinical Trials Group and the International Maternal Perinatal Adolescent AIDS Clinical Trials Group and by grants from the National Institute of Allergy and Infectious Diseases (5K23AI-56931 to Dr Saitoh, and AI27563, AI41089, and AI-36214 [Virology Core-University of California San Diego Center for AIDS Research]); by Bristol-Myers Squibb and Pfizer Pharmaceuticals Inc; by the San Diego EXPORT Center, National Center of Minority Health and Health Disparities, National Institutes of Health grant P60 MD00220 to Dr Viani and by grants MH22005, AI43638, AI51164 to Dr Vaida.

We acknowledge the physicians, nurses, and co-workers who take care of children and adolescents who have HIV-1 infection and were involved in this study. We also acknowledge Drs Lawrence Friedman, Karen Loper, and Jennifer Blanchard at University of California San Diego, Dr Philip LaRussa at Columbia University Medical Center, and Carolyn Graisbery and Cindy Brown at University of South Florida College of Medicine for help in conducting this study.


   FOOTNOTES
 
Accepted Jul 19, 2007.

Address correspondence to Akihiko Saitoh, MD, Division of Infectious Diseases, Department of Pediatrics, University of California San Diego, 9500 Gilman Dr, La Jolla, CA 92093-0672. E-mail: asaitoh{at}ucsd.edu

The authors have indicated they have no financial relationships relevant to this article to disclose.

This work was presented in part as posters 771 and 772 at the 12th Conference on Retroviruses and Opportunistic Infections; February 22–25, 2005; Boston, MA.


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 CONCLUSIONS
 REFERENCES
 

  1. Wiznia AA, Crane M, Lambert G, Sansary J, Harris A, Solomon L. Zidovudine use to reduce perinatal HIV type 1 transmission in an urban medical center. JAMA.1996; 275 (19):1504 –1506[Abstract]
  2. Murphy DA, Belzer M, Durako SJ, Sarr M, Wilson CM, Muenz LR. Longitudinal antiretroviral adherence among adolescents infected with human immunodeficiency virus. Arch Pediatr Adolesc Med.2005; 159 (8):764 –770[Abstract/Free Full Text]
  3. Steele RG, Grauer D. Adherence to antiretroviral therapy for pediatric HIV infection: review of the literature and recommendations for research. Clin Child Fam Psychol Rev.2003; 6 (1):17 –30[CrossRef][ISI][Medline]
  4. Osterberg L, Blaschke T. Adherence to medication. N Engl J Med.2005; 353 (5):487 –497[Free Full Text]
  5. Pai NP, Tulsky JP, Lawrence J, Colford JM Jr, Reingold AL. Structured treatment interruptions (STI) in chronic suppressed HIV infection in adults. Cochrane Database Syst Rev.2005; (4):CD005482
  6. Gibb DM, Duong T, Leclezio VA, Walker AS, Verweel G, Dunn DT. 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 –450[CrossRef][ISI][Medline]
  7. Monpoux F, Tricoire J, Lalande M, Reliquet V, Bebin B, Thuret I. Treatment interruption for virological failure or as sparing regimen in children with chronic HIV-1 infection. AIDS.2004; 18 (18):2401 –2409[Medline]
  8. Pinheiro JC, Bates DM. Mixed-Effects Models in S and S-PLUS. New York, NY: Springer;2000
  9. Vaida F, Fitzgerald A, DeGruttola V. Efficient hybrid EM for linear and nonlinear mixed effects models with censored response. Comput Stat Data Anal.2008 , in press
  10. R Development Core Team: A Language and Environment for Statistical Computing. R Foundation for Statistical Computing, Vienna, Austria;2006 . Available at: www.R-project.org. Accessed July 6, 2007
  11. Maggiolo F, Ripamonti D, Gregis G, Quinzan G, Callegaro A, Suter F. Effect of prolonged discontinuation of successful antiretroviral therapy on CD4 T cells: a controlled, prospective trial. AIDS.2004; 18 (3):439 –446[CrossRef][ISI][Medline]
  12. Thiébaut R, Pellegrin I, Chene G, et al. Immunological markers after long-term treatment interruption in chronically HIV-1 infected patients with CD4 cell count above 400 x 106 cells/L. AIDS.2005; 19 (1):53 –61[Medline]
  13. Pellegrin I, Thiebaut R, Blanco P, et al. Can highly active antiretroviral therapy be interrupted in patients with sustained moderate HIV RNA and > 400 CD4+ cells/microl? Impact on immunovirological parameters. J Med Virol.2005; 77 (2):164 –172[CrossRef][ISI][Medline]
  14. Touloumi G, Pantazis N, Antoniou A, Stirnadel HA, Walker SA, Porter K. Highly active antiretroviral therapy interruption: predictors and virological and immunologic consequences. J Acquir Immune Defic Syndr.2006; 42 (5):554 –561[CrossRef][ISI][Medline]
  15. Boschi A, Tinelli C, Ortolani P, Moscatelli G, Morigi G, Arlotti M. CD4+ cell-count-guided treatment interruptions in chronic HIV-infected patients with good response to highly active antiretroviral therapy. AIDS.2004; 18 (18):2381 –2389[Medline]
  16. Toulson AR, Harrigan R, Heath K, et al. Treatment interruption of highly active antiretroviral therapy in patients with nadir CD4 cell counts >200 cells/mm3. J Infect Dis.2005; 192 (10):1787 –1793[CrossRef][Medline]
  17. Mussini C, Bedini A, Borghi V, et al. CD4 cell-monitored treatment interruption in patients with a CD4 cell count > 500 x 106 cells/L. AIDS.2005; 19 (3):287 –294[ISI][Medline]
  18. Moltó J, Ruiz L, Romeu J, et al. Influence of prior structured treatment interruptions on the length of time without antiretroviral treatment in chronically HIV-infected subjects. AIDS Res Hum Retroviruses.2004; 20 (12):1283 –1288[CrossRef][Medline]
  19. Franco JM, Leon-Leal JA, Leal M, et al. CD4+ and CD8+ T lymphocyte regeneration after anti-retroviral therapy in HIV-1-infected children and adult patients. Clin Exp Immunol.2000; 119 (3):493 –498[CrossRef][ISI][Medline]
  20. Gibb DM, Newberry A, Klein N, de Rossi A, Grosch-Woerner I, Babiker A. Immune repopulation after HAART in previously untreated HIV-1-infected children. Paediatric European Network for Treatment of AIDS (PENTA) Steering Committee. Lancet.2000; 355 (9212):1331 –1332[CrossRef][ISI][Medline]
  21. Sharland M, Watkins AM, Dalgleish AG, Cammack N, Westby M. Immune reconstitution in HAART-treated children with AIDS. Highly Active Anti-Retroviral Therapy. Lancet.1998; 352 (9127):577 –578[CrossRef][ISI][Medline]
  22. García F, Plana M, Ortiz GM, et al. The virological and immunological consequences of structured treatment interruptions in chronic HIV-1 infection. AIDS.2001; 15 (9):F29 –F40[CrossRef][ISI][Medline]
  23. Poulton MB, Sabin CA, Fisher M. Immunological changes during treatment interruptions: risk factors and clinical sequelae. AIDS.2003; 17 (1):126 –128[CrossRef][ISI][Medline]
  24. Taffé P, Rickenbach M, Hirschel B, et al. Impact of occasional short interruptions of HAART on the progression of HIV infection: results from a cohort study. AIDS.2002; 16 (5):747 –755[CrossRef][ISI][Medline]
  25. Youle M, Janossy G, Turnbull W, et al. Changes in CD4 lymphocyte counts after interruption of therapy in patients with viral failure on protease inhibitor-containing regimens. Royal Free Centre for HIV Medicine. AIDS.2000; 14 (12):1717 –1720[CrossRef][ISI][Medline]
  26. Achenbach CJ, Till M, Palella FJ, et al. Extended antiretroviral treatment interruption in HIV-infected patients with long-term suppression of plasma HIV RNA. HIV Med.2005; 6 (1):7 –12[CrossRef][Medline]
  27. Bedimo R, Chen RY, Westfall AO, Raper JL, Allison JJ, Saag MS. Sustained HIV viral suppression following treatment interruption: an observational study. AIDS Res Hum Retroviruses.2006; 22 (1):40 –44[CrossRef][ISI][Medline]
  28. Cardiello PG, Hassink E, Ananworanich J, et al. A prospective, randomized trial of structured treatment interruption for patients with chronic HIV type 1 infection. Clin Infect Dis.2005; 40 (4):594 –600[CrossRef][ISI][Medline]
  29. Molina-Pinelo S, Vivancos J, De Felipe B, et al. Thymic volume predicts CD4 T-cell decline in HIV-infected adults under prolonged treatment interruption. J Acquir Immune Defic Syndr.2006; 42 (2):203 –206[CrossRef][Medline]
  30. Sanchez R, Portilla J, Gimeno A, et al. Immunovirologic consequences and safety of short, non-structured interruptions of successful antiretroviral treatment. J Infect.2007; 54 (2):159 –166[CrossRef][ISI][Medline]
  31. Wit FW, Blanckenberg DH, Brinkman K, et al. Safety of long-term interruption of successful antiretroviral therapy: the ATHENA cohort study. AIDS.2005; 19 (3):345 –348[Medline]
  32. Mata RC, Viciana P, de Alarcon A, et al. Discontinuation of antiretroviral therapy in patients with chronic HIV infection: clinical, virologic, and immunologic consequences. AIDS Patient Care STDS.2005; 19 (9):550 –562[CrossRef][Medline]
PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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