| |
Early antiretroviral therapy decreases progression of perinatal HIV
|
| |
| |
By Karla Gale
NEW YORK (Reuters Health) - Very early treatment of perinatal HIV infection -- before age 3 months -- is associated with better outcomes than when treatment is delayed, making early diagnosis critical in these patients, investigators report in the May 11th issue of the Journal of the American Medical Association.
The risk of switching therapy, suggestive of treatment failure, is far greater among children treated with antiretroviral therapy (ART) that does not contain a protease inhibitor and those who begin ART after becoming severely immunosuppressed, a second paper in the Journal reports.
Dr. Yvonne A. Maldonado, at Stanford University School of Medicine, and members of the California Pediatric HIV Study Group studied temporal trends in early progression of perinatal HIV infection among 205 children born between 1988 and 2001, using records of clinic visits through age 3.
ART or prophylaxis against Pneumocystis carinii pneumonia (PCP) or both was initiated in 134 (65%).
By age 3 years, 81 had progressed to a category C diagnosis, 41 of whom died. Absence of treatment with ART was associated with increased risk of progression to a category C diagnosis (62% versus 28%, p < 0.001).
Among the 23 patients who received triple antiretroviral therapy, including either a protease inhibitor or a nonnucleoside reverse transcriptase inhibitor, none progressed to category C illness, a significant difference when compared with children receiving mono or dual ART or PCP (p < 0.001).
The authors note that even ART with one or two drugs, if initiated by age 2 months versus 3 to 4 months, was associated with delayed and decreased progression to category C by age 3 years (3 of 10 versus 11 of 16, p = 0.02).
"Because there are potential drawbacks of very early therapy...large, prospective clinical trials defining the differences between very early versus delayed institution of therapy are needed," Dr. Maldonado's group writes.
These findings emphasize the need to test pregnant women for HIV to detect HIV-infected infants as soon as possible to maximize the benefits of early HAART and PCP prophylaxis, they add.
In the second study, Dr. Susan Brogly, at Harvard School of Public Health in Boston, and her team examined changes in the treatment of pediatric HIV infection in the US from 1987 to 2003. Included were 766 children ages 1.2 months to 21.9 years at enrollment.
"After the pediatric guidelines were published, nobody had looked at whether they are being followed in clinical practice," Dr. Brogly told Reuters Health. Drug prescribing could be quite different compared with adult guidelines, she added, because of unique needs of pediatric patients.
The researchers observed that since the pediatric guidelines were released in 1998, 22% of patients initiated therapy with a regimen not recommended by the guidelines. Of 753 patients who were treated with any ART, 606 children were switched to a second regimen.
"Once our results were adjusted for age and year of calendar start, we found that older regimens -- those including one and two nucleoside reverse transcriptase inhibitors -- were associated with shorter time to first regimen switch," the researcher noted.
"We also identified that children who start therapy when they are severely immunosuppressed (CD4 < 15) also had a shorter time to regimen switch," she continued.
This is important, she added, because "more exposure to more drug classes and specific drugs, the more it can lead to drug resistance if not taken properly. Switching could also result in a reduction of future treatment options."
In a related editorial, Dr. Ram Yogev, at Children's Memorial Hospital in Chicago, points out that "while it is possible to celebrate the tremendous change in the outcomes of HIV-infected children treated with HAART, it is even more important to continue to prioritize research for the survivors who are now living with a chronic disease."
JAMA 2005;293:2213-2231,2272-2274.
Two JAMA Articles are below.
Temporal Trends in Early Clinical Manifestations of Perinatal HIV Infection in a Population-Based Cohort
David R. Berk, MD; Meira S. Falkovitz-Halpern, PhD; David W. Hill, MPH; Catherine Albin, MD, PhD; Antonio Arrieta, MD; Jane M. Bork, MD; Deborah Cohan, MD, MPH; Bjorn Nilson, MD; Ann Petru, MD; Juan Ruiz, MD, MPH; Peggy Sue Weintrub, MD; Wanda Wenman, MD; Yvonne A. Maldonado, MD; for the California Pediatric HIV Study Group
JAMA. 2005;293:2221-2231.
ABSTRACT
Context: The effect of early antiretroviral therapy (ART) on the early progression of perinatal human immunodeficiency virus (HIV) infection is not well defined.
Objective; To examine early disease progression and survival in a population-based cohort with perinatal HIV infection in relation to year of birth and use of ART.
Design, Setting, and Patients; Retrospective study of temporal trends in early progression of perinatal HIV infection among 205 HIV-infected children in Northern California born between January 1, 1988, and December 31, 2001, and followed up through age 3 years.
Main Outcome Measures: Prevalence of and age at progression to a first US Centers for Disease Control and Prevention category C diagnosis relative to year of birth, type of ART, and age at initiation of therapy.
Results; Of 205 children, 134 (65%) received ART and/or Pneumocystis jiroveci pneumonia prophylaxis. By age 3 years, 81 (40%) progressed to a category C diagnosis, 41 (51%) of whom died. Untreated children were significantly more likely to progress to a category C diagnosis (62% [44/71] untreated vs 28% [37/134] treated children, P<.001); none of 23 infants who received triple ART progressed to category C. However, even without triple ART, very early mono/dual ART (by age 2 months vs 3-4 months) was associated with delayed and decreased progression to category C (P = .02). Of 33 children born between January 1, 1996, and December 31, 2001, only 7 (21%) progressed to category C (P = .02 compared with 1988-1995), 6 of 7 of whom received no therapy. More recent year of birth and more advanced therapy were associated with improved survival.
…..Earlier ART was associated with delayed and decreased progression by age 3 years (P = .02). Of the 10 children who started mono or dual ART by age 2 months, 1 progressed to category C by age 12 months and a total of 3 progressed to category C by age 3 years. In contrast, of 16 children who started mono or dual ART by age 3 to 4 months, 8 progressed to category C by age 12 months, and by age 3 years a total of 11 had progressed to category C…..
Conclusions: This population-based cohort demonstrated decreased early HIV progression and improved survival at age 3 years, associated with more advanced therapy. Although limited by small sample size, the findings suggest that very early treatment, even without triple ART, was associated with improved outcome.
RESULTS
Study Population
The Northern California PSD surveillance system identified 223 children with perinatal HIV infection born between January 1, 1988, through December 31, 2001. Of these children, 2 (1%) were excluded because they died prior to age 3 years from causes unrelated to HIV (Werdnig-Hoffman disease, child abuse/head injury). In addition, 16 (7%) were excluded because they were lost to follow-up before age 3 years (median age, 15 months; range, 2-28 months). Of those lost to follow-up, 3 (19%) had progressed to a category C diagnosis (at ages 2, 4, and 7 months) before their last recorded clinic visit. Of all 18 excluded children, 14 (78%) had received PCP prophylaxis, ART, or both. After exclusions, the study population comprised 205 children born between January 1, 1988, and December 31, 2001, who were followed up through age 3 years or who died of HIV-related causes before age 3 years. Overall, 43 children died in the first 3 years of life (41 were included in the analysis). Two died of HIV-related causes but did not have category C disease at the time of death; the other 39 children died of category C disease.
The annual number of children identified through PSD with perinatal HIV infection was 16 to 25 between 1988-1996 but 6 or fewer after 1996. To determine whether this represented a true decline in perinatal transmission or decrease in ability to capture data on infants through surveillance, we compared the rates of identification of HIV-exposed infants in the 12-county surveillance area with the SCBW database. Based on a match of SCBW and PSD data, HIV-exposed infants born to 52.1% (548/1053) of HIV-infected women were identified by PSD surveillance in the 12 counties. The ratio of observed/expected infants of infected women increased from 29.6% in 1988 to 67.5% in 1998.47 The 52.1% value is not a direct calculation of data capture for HIV-infected children, but assessment of data capture for HIV-exposed infants can provide a means of assessing whether data for most HIV-infected infants were captured by the surveillance system. For example, if it is assumed that the transmission rate was as high as 25% overall among the 1053 HIV-infected women giving birth in 1988-1995 and 1998 in the 12-county surveillance area, then 263 infected infants would be expected to be born during those years. Since 52.1% of potentially HIV-exposed infants identified in the SCBW matched with the number of HIV-exposed infants identified in the PSD, this would suggest that many of the HIV-infected infants were identified by the PSD. Most HIV-exposed infants do not become infected.3-5
Progression to Category C and Survival in Relation to Prior Treatment
Of the 205 children, 134 (65%) received ART, PCP prophylaxis, or both by age 3 years. Of these, only 37 (28%) progressed to a category C diagnosis, compared with 44 of 71 (62%) untreated children (P<.001). Treatment was associated with delayed progression to the first category C diagnosis (median age at first category C diagnosis for treated vs untreated children, 14 months vs 4 months; IQR, 9-19 months vs 3-8 months; P<.001). Overall survival was 80% (164/205), and treatment was associated with improved survival (P = .02) as a result of decreased category C diagnoses. However, once children progressed to category C, survival and age at death were not associated with prior treatment. Similarly, age at progression was not associated with survival at age 3 years: the children who survived were diagnosed with a category C condition at median age 10 months (IQR, 4-16 months), while the children who died were diagnosed with a category C condition at median age 6 months (IQR, 4-11 months) (P = .23).
Among the 134 treated children, 99 (74%) received ART and PCP prophylaxis, 20 (15%) only PCP prophylaxis, and 15 (11%) only ART. Of the 114 children treated with ART, 59 (52%) received mono, 32 (28%) dual, and 23 (20%) triple ART as their most advanced ART. All children who received triple ART received a regimen that contained a PI or a nonnucleoside reverse transcriptase inhibitor. Children not receiving ART were more likely to progress to category C, compared with those receiving mono and dual ART with or without PCP prophylaxis. None of the 23 children who ever received triple ART before age 3 years progressed to category C; this association was highly significant compared with mono or dual ART or PCP prophylaxis (P<.001). The difference in progression to category C between mono ART (37% [22/59]) and dual ART (28% [9/32]) was not statistically significant, nor was it statistically different from the proportion of children receiving PCP prophylaxis without ART (30% [6/20]) who progressed to category C. However, any use of ART was associated with a delayed onset of category C symptoms. The median age at initial category C diagnosis was 4 months without any treatment, 8 months with only PCP prophylaxis, and 16 months with mono or dual ART with or without PCP prophylaxis (P<.001).
To determine the association between very early initiation of ART with or without PCP prophylaxis and disease progression, we compared mono or dual ART with or without PCP prophylaxis started before age 2 months vs between 3 to 4 months. Children who received triple ART in the first 3 years of life were not included in this analysis because none progressed to category C. The age cutoffs were chosen because 4 months was the median age at which untreated children progressed to category C, whereas only 3 untreated children progressed prior to age 2 months. Earlier ART was associated with delayed and decreased progression by age 3 years (P = .02). Of the 10 children who started mono or dual ART by age 2 months, 1 progressed to category C by age 12 months and a total of 3 progressed to category C by age 3 years. In contrast, of 16 children who started mono or dual ART by age 3 to 4 months, 8 progressed to category C by age 12 months, and by age 3 years a total of 11 had progressed to category C. Administration of PCP prophylaxis did not differ significantly between these 2 early treatment groups, with only 1 of 26 children not receiving PCP prophylaxis. That child progressed to category C but did not develop PCP. Among all 26 children, only 2 developed PCP by age 3 years. Both started ART at age 3 to 4 months and PCP prophylaxis by 3 months and were diagnosed with PCP at approximately 1 year.
Temporal Trends in Progression to Category C
The rate of progression to a category C diagnosis declined over time (P = .048 for trend). Moreover, all 7 children who progressed to category C in the late cohort survived, compared with less than 50% in the earlier cohorts (P = .005). In addition, while 25% (22/89) and 23% (19/83) of the 2 earlier cohorts died by age 3 years, all 33 children in the late cohort survived. The decline in disease progression in later cohorts was associated with earlier median age at initial diagnosis of HIV infection: 6 months in the earliest cohort vs 14 days in the latest (P<.001). For all birth cohorts, treatment was associated with decreased progression to category C.
Temporal Trends in Use of ART
Later birth years were associated with increased proportion of treated children, treatment with dual or triple ART, and earlier institution of ART. First, the proportion treated with ART with or without PCP prophylaxis increased with time (P = .01 for trend) (Table 4). This trend was driven by the increasing proportion of children receiving ART. In contrast, administration of PCP prophylaxis did not change significantly over time. The type of ART administered changed with time, with all but 1 treated child in the early cohort receiving only mono ART and all treated children in the late cohort receiving dual or triple ART. Finally, the median age of starting either PCP prophylaxis or ART decreased with time. This trend was for initiating both ART and PCP prophylaxis.
While children in the late cohort (n = 33) had the best outcomes, 7 (21%) still progressed to category C. Of these, 6 had no treatment. Only 1 of 26 treated children progressed to category C. This includes 7 children who did not receive triple ART but who started ART before age 2 months. The child who progressed started treatment at age 6 months with dual ART and PCP prophylaxis.
Category C Diagnoses
Table 5 outlines the age at diagnosis and types of category C diagnoses in the first 3 years of life relative to treatment. We excluded the 2 children who died of HIV complications without a clear category C diagnosis in this analysis. Initial category C diagnoses included HIV encephalopathy (n = 33), PCP (n = 28), candidal infections (n = 8), cytomegalovirus infections (n = 7), Mycobacterium avium infection (n = 1) , and recurrent bacterial infections (n = 6). Among 35 treated children who developed category C diagnoses, 24 (69%) demonstrated encephalopathy and 3 (9%) PCP at the time of initial category C diagnosis, compared with 9 (20%) and 25 (57%), respectively, of 44 untreated children (P<.001). However, the proportion of all HIV-infected children who developed encephalopathy as their initial category C diagnosis or at any time by age 3 years did not differ significantly between untreated and treated children. Moreover, the age at encephalopathy diagnosis was not associated with treatment. This confirms that encephalopathy did not occur more often among treated compared with untreated children. Untreated children who progressed were more likely than treated children to demonstrate cytomegalovirus infections as their initial category C diagnosis (16% [7/44] vs 0%, P<.02).
AUTHOR COMMENTS
There are few data to guide time to initiation and selection of therapy among young children with perinatal HIV infection.21, 27 Our novel finding of improved outcomes even with mono/dual ART begun by age 2 months vs 3 to 4 months, though limited by the small sample size, suggests the importance of very early diagnosis and treatment and is consistent with small clinical trials demonstrating a short-term protective effect of early vs delayed ART among perinatally infected infants.24, 31 Initiating ART within the first 2 months offers the potential to begin therapy during or near the time of primary infection.50 Others have observed that ART begun by age 2 to 2.5 months is associated with reduction of viral replication and serum proviral DNA levels, seroreversion, and prevention of clinical and immunological symptoms.24, 31 Similarly, early combination ART begun prior to age 3 months has been associated with long-term suppression of viral replication, seroreversion, and preserved immune status,22, 51 independent of viral load at initiation of therapy.26 However, because there are potential drawbacks of very early therapy (particularly in asymptomatic infants), including concerns regarding compliance, risk of viral drug resistance, adverse effects, and long-term toxicity, large, prospective clinical trials defining the differences between very early vs delayed institution of therapy are needed.27-28
Analysis of our population-based cohort confirms that for children with perinatal HIV infection, outcomes by age 3 years improved with time, as children were evaluated for HIV infection earlier and were treated earlier, more often, and with more advanced ART. Over time, there was a delay and a decrease in progression to a category C diagnosis, associated with greater survival. Among all birth cohorts, any treatment and particularly more advanced ART were associated with improved outcomes at 3 years: reduced disease progression, older age at category C diagnosis, and improved survival. Outcomes with triple ART were especially favorable; none of 23 children in this analysis who ever received triple ART in the first 3 years of life progressed to category C diagnosis.
Previously, we demonstrated that PCP prophylaxis and zidovudine monotherapy altered early disease progression in part by preventing PCP but not encephalopathy.18 Similarly, in the current study, we found that treatment with other regimens besides triple ART altered early disease progression to category C diagnoses but did not have an impact on the development of encephalopathy. However, triple ART protected against development of all category C diagnoses, including encephalopathy. Our analysis is consistent with other observational studies demonstrating that triple ART, administered both before and after a category C diagnosis, is more strongly associated with less disease progression and death than mono/dual ART.8-9,11 However, only a few other studies have analyzed the effect of any early ART on the progression to category C diagnosis.8, 13 In a study by Abrams et al,8 the investigators demonstrated a short-term effect of early mono/dual ART on progression and a long-term effect of triple ART among HIV-infected infants for up to 24 months of age. Our results demonstrate a protective effect of triple ART up to age 3 years.
The scope of our 16-year population-based observational study makes it unique in its ability to describe associations between advances in disease management and the natural history of perinatal HIV infection through at least age 3 years. Only a limited number of non-US studies10-11 have conducted longitudinal assessment of HIV-infected children identified from birth or through registries; a few US studies8, 52 have enrolled pregnant HIV-infected women and their infants in long-term follow-up.
There are limitations to this study. First, the observational nature of the study limits the ability to collect a broader array of variables and may provide variable information based on the documentation and practice customs of each treating physician. However, the collected variables were complete for all 205 infants included in the analysis and only 16 additional infants were excluded because they were lost to follow-up, reflecting the relatively consistent practices and follow-up among the physicians at each of the sites, which are all major pediatric specialty hospitals. Incomplete capture of data for all HIV-exposed infants in the surveillance area could have biased the study outcomes. However, the capture rate was based on identification of all HIV-exposed infants, including those not HIV-infected. Since most infants born to HIV-infected women will be uninfected, it is likely that most infants not identified through surveillance were uninfected. Also, hospital-based active surveillance such as that described herein may enhance the likelihood of identifying HIV-infected children. Temporal changes in the standard of care could also have accounted for some improvement in clinical outcome noted in this study, although the most significant of these temporal changes include increasing use of ART and PCP prophylaxis. Finally, the analysis of early vs delayed therapy was based on only a subset of the total study population. Clearly, these results are not sufficient to make recommendations about very early therapy, but this is one of the first observational studies to identify this correlation with results of clinical trials that have found short-term virological and immunological responses to early ART.22-26 A recent French study made a similar observation of positive effect of early vs delayed therapy but followed up a small number of infants only through age 2 years.13
In our study, 61% of children, and all of those receiving triple ART, remained free of category C diagnoses at age 3 years. Moreover, 50% of those who progressed were still alive at age 3 years. Analysis beyond age 3 years is needed to understand the long-term effect of treatment on progression and survival of HIV-infected children. Such studies should be feasible because PIs have been used for at least 8 years.
Despite advances in early identification and treatment, even in the most recent birth cohort, there were children who were not identified as HIV-infected until progression to category C occurred. In addition, only 1 of 26 treated children in the most recent cohort progressed to category C, and this child did not start treatment until age 6 months. This finding emphasizes that aggressive testing of pregnant women and early detection of HIV-infected infants must continue in order to maximize the benefits of early HAART and PCP prophylaxis. In addition, the effect of very early therapy among HIV-infected infants must be determined in efforts to improve the outcome of perinatal HIV infection.
Antiretroviral Treatment in Pediatric HIV Infection in the United States
From Clinical Trials to Clinical Practice
JAMA May 11, 2005
Susan Brogly, PhD; Paige Williams, PhD; George R. Seage III, ScD; James M. Oleske, MD, MPH; Russell Van Dyke, MD; Kenneth McIntosh, MD; for the PACTG 219C Team
JAMA. 2005;293:2213-2220.
ABSTRACT
Context: Antiretroviral therapy (ART) for pediatric human immunodeficiency virus (HIV) infection has evolved from simple nucleoside reverse transcriptase inhibitor (NRTI) regimens to complex combination therapies based largely on evidence from clinical trials. However, the integration of novel ART into the clinical care of pediatric HIV infection has not been examined.
Objectives: To describe changes in the treatment of pediatric HIV infection in the United States from 1987-2003, to assess concordance of initial regimens with US pediatric guidelines, and to identify predictors of the first regimen switch.
Design, Setting, and Participants: The study population included 766 perinatally HIV-infected children in the Pediatric AIDS Clinical Trials Group 219C cohort born before January 1, 2004, who had not participated in an ART clinical trial at 219C enrollment or during follow-up.
Main Outcome Measures: Proportion of children receiving specific ART regimens, proportion of children initiating ART according to pediatric guidelines, and time to first regimen switch (risk of switching).
Results: Single and dual NRTI regimens were used most frequently through 1997. In 1998, 2 years after protease inhibitors were approved for adult HIV infection and at the time pediatric guidelines were issued, regimens of highly active antiretroviral therapy including a protease inhibitor became most frequently used. From 1998-2003, 22% of children initiated ART with a regimen not recommended by pediatric guidelines. In multivariate regression, the risk of switching decreased with age at ART initiation (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.94-0.99) and increased with year of initiation (HR, 1.28; 95% CI, 1.23-1.33). The risk of switching was higher in children who started with 1 NRTI (HR, 8.05; 95% CI, 5.80-11.18), 2 NRTIs (HR, 4.08; 95% CI, 3.08-5.40), or an unconventional regimen (HR, 6.23; 95% CI, 3.36-11.54) vs children who started with a protease inhibitor–containing regimen; and in children who initiated ART at CD4 T lymphocyte percentages less than 15 vs 15 or greater (HR, 2.90; 95% CI, 1.03-8.13).
Conclusions: There was a short lag between the identification of novel ART and its adoption in the pediatric community. A variety of regimens were used, including some unorthodox therapies. Important predictors of first regimen switch were identified.
INTRODUCTION
Antiretroviral therapy (ART) for pediatric human immunodeficiency virus (HIV) infection has evolved from the single or dual nucleoside reverse transcriptase inhibitor (NRTI) regimens of the 1980s and early 1990s to today’s complex regimens of NRTI in combination with protease inhibitors (PIs) and/or nonnucleoside reverse transcriptase inhibitors (NNRTIs). Changes in the treatment of pediatric HIV infection were driven by evidence from randomized controlled trials in HIV-infected adults,1-6 a small number of pediatric trials,7-10 and nonexperimental pediatric studies.11-14 No studies have examined how novel therapies have been integrated into the clinical care of pediatric HIV infection.
Since 1998, the US Working Group on Antiretroviral Therapy and the Medical Management of HIV-Infected Children has published guidelines for the use of combination ART for pediatric HIV infection.15 Current pediatric guidelines recommend a regimen of 2 NRTIs in combination with a PI or an NNRTI.16 These guidelines exist to aid the practicing physician and are not meant to supplant clinical decision-making. To date, concordance between the US pediatric guidelines and treatment in clinical practice has not been assessed.
As HIV becomes a treatable disease, it is becoming increasingly important to take a long-term strategic approach to initial and subsequent ART. Quantifying the frequency of treatment switches provides an estimate of the rate at which regimens are failing or not tolerated.17 We identified only 1 study of ART use in HIV-infected children from 6 US sites that reported increases in use of highly active antiretroviral therapy (HAART) and frequent regimen changes from 1998 through 2000.18
The objectives of this study were to describe changes in the treatment of pediatric HIV in the United States from 1987 to 2003; to determine initial treatment choices, including the concordance between the US pediatric ART guidelines and clinical practice; and to identify predictors of first regimen switch.
This study describes changes in the treatment of pediatric HIV infection in the United States from 1987 through 2003. There was a short lag between the identification of novel ART—including new drugs and drug combinations—and its adoption in the pediatric community; both ritonavir and nelfinavir were approved for children in 1997 and were in widespread use the following year. Pediatricians involved in ART clinical trials treated the children in our study population, which probably enhanced the transfer of research to clinical practice. Some children who initiated dual NRTI before the HAART era continued to have good immunological and clinical profiles, which thwarted the need to switch to a more potent regimen.10 Further, the uptake of PIs in 1998 corresponded to the publication of the pediatric guidelines for combination ART.15 Thus, the clinicians, patients, and caregivers may have been reluctant to use novel treatment in the absence of recommendations for use in children.
To our knowledge, this is the first study to examine concordance between the US pediatric ART guidelines16 and clinical practice. We found that most clinicians of the collaborating institutions—of which the majority were university affiliated HIV clinics—followed pediatric guidelines. However, since publication of the pediatric guidelines in 1998, 22% of children initiated therapy with a regimen not recommended by the guidelines, and a small proportion was receiving unorthodox treatment at any time in therapy. Children who initiated therapy with these unorthodox regimens had a shorter time to switch than did those who initiated therapy with HAART plus a PI. A shorter time to switch might affect prognosis because of the increased exposure to multiple drugs and drug classes, the consequent development of resistance, and the reduction of future therapy options.16 The relatively common use of nonstandard regimens may reflect some children’s intolerance of standard therapy or the willingness of this group of physicians to try unorthodox regimens.
Because a key objective of this study was to describe and assess the treatment of pediatric HIV infection in clinical practice, the study population was restricted to children in the PACTG 219C cohort who were not participants in ART clinical trials. Although there was no difference in the virological status of the 2 groups, the study population was younger, more likely to be black and less likely to be Hispanic, and less likely to have CD4 lymphocyte percentages in the lower range than were children who participated in ART clinical trials. Furthermore, the clinical sites were university-affiliated institutions, which may differ from other HIV clinics. As a result, our findings may not be generalizable to all HIV-infected children. Nonetheless, 766 children from 79 institutions in 25 states across the United States constituted our study population, and therefore their ART experience should validly characterize clinical practice in these university settings.
Although not statistically significant, time to first regimen switch was shorter in male vs female participants. Studies in HIV-infected adults have found that women have lower HIV RNA levels than men with comparable CD4 cell counts,22-23 and this was observed in a study of HIV-infected infants.24 If this phenomenon is in fact true of the pediatric population and clinicians primarily are basing treatment initiation and switches on HIV RNA levels, then this could explain our observed association. Levels of HIV RNA at ART initiation were unavailable for most of the study population, and therefore we were unable to examine this association. The role of sex, HIV RNA, and ART should be studied further; the adult guidelines propose considering lower HIV RNA thresholds when initiating therapy in women with CD4 cell counts greater than 350 cells/µL.25
Others have reported that poor ART adherence is associated with an increased likelihood of virological failure26-27 and disease progression,27 which could warrant a change in therapy. In our study, we found no association between switching and ART adherence. Our adherence data concerned missed doses in the past 3 days and was measured at cohort enrollment, which was after ART initiation for many children and may have misclassified ART adherence prior to switching.
Time to first regimen switch decreased with calendar year of ART initiation. Children who initiated ART in the era of viral load monitoring, a larger selection of treatments, and more potent therapies had a shorter time to first regimen switch. Unfortunately, the 219C protocol did not record reasons for treatment switch. While we have speculated that most switches were due to virological, immunological, or clinical failure, other reasons such as drug toxicity and palatability, age appropriateness of formulations, number of pills or volume of liquid, frequency of dosing, and availability of new ART also may have prompted a regimen switch.
A European survey conducted in 1998 found that most pediatric HIV physicians delayed therapy until disease progression—evident through symptoms, low CD4 cell counts, or high viral load—was apparent.28 In our study, children who began ART when severely immunosuppressed (CD4 percentages <15) had a significantly shorter time to first regimen switch than children who were immunocompetent or moderately immunosuppressed at initiation. Studies conducted in adults also have found that lower CD4 cell counts and higher viral load have been associated with switching.17, 29-30 Although our analysis included children from all birth cohorts and who initiated ART at varying ages, our findings on CD4 percentages were based on a small number of children and may not be generalizable to the larger pediatric population.
In sum, this study describes changes in the treatment of pediatric HIV infection in US children from 1987 through 2003. We identified demographic differences in children who were participating in ART clinical trials and in those who were not, as well as a short lag in the uptake of novel therapies in this latter group of children. The use of unorthodox regimens not recommended by the US pediatric guidelines was relatively common, and was related to a shorter time to first regimen switch. Younger age at ART initiation, recent ART initiation, immunosuppression at ART initiation, and initial therapy of 1 or 2 NRTIs were significantly associated with a shorter time to first regimen switch. Monitoring and documenting ART use in HIV-infected children can provide important insight regarding the clinical care of this population.
RESULTS
Of 2399 perinatally HIV-infected children enrolled in PACTG 219C between September 2000 and April 2004, 1633 (68.1%) participated in an ART clinical trial and thus were excluded. The remaining 766 children in the study population were recruited from 79 institutions in 25 states across the United States. The study population was significantly younger, more likely to be non-Hispanic black and less likely to be Hispanic, and less likely to have CD4 lymphocyte percentages in the lower range than ART trial participants. At 219C enrollment, the participants’ ages ranged from 1.2 months to 21.9 years, with a mean age of 8.1 years.
Dual NRTI regimens began to be used in 1993 and became the most frequently used regimens in 1996-1997. In 1998—2 years after the implementation of PIs for adult HIV infection—regimens of HAART including a PI became the most frequently used. In 2003, 51.3% of children were receiving HAART including a PI; 12.3% were receiving HAART including an NNRTI; 16.3% were receiving HAART including a PI plus an NNRTI; 12.5% were receiving single, dual, and triple NRTIs; and 3.3% were receiving unconventional regimens (ie, 1 NRTI plus 1 PI, 1 NRTI plus 1 NNRTI, PI only). After 2000, the most frequently used regimen was either combination lamivudine, stavudine, and nelfinavir or combination lamivudine, zidovudine, and nelfinavir, with 18.7% and 13.6% of children taking one of these regimens in 2000 and 2003, respectively. The increased proportion of children receiving HAART was accompanied by increases in CD4 percentages (<15: 20.0%, 20.0%, 18.3%, 9.7%, and 7.4% in 1997, 1998, 1999, 2000, and 2003, respectively) and by decreases in HIV viral load (>10 000 copies/mL: 75.0%, 60.0%, 77.8%, 32.1%, and 23.2%).
Zidovudine was the most frequently used NRTI in the early years of the epidemic, reaching a peak of 90.4% in 1991 and decreasing to around 35% in 1999 as other NRTIs became available. The use of didanosine also decreased after its peak of 51.3% in 1996. Stavudine and lamivudine were the most frequently used NRTIs (approximately 55%) from 1998 onward. The use of both nevirapine and efavirenz steadily increased following FDA approval in 1996 and 1998, respectively, with efavirenz becoming the most frequently used NNRTI in 2002. However, less than 20% of children were receiving either drug. The uptake of PIs was steady; nelfinavir was the most frequently used PI from 1998-2002 but declined after its peak of 38.4% in 1999. In 2003, boosted lopinavir was the most frequently used PI (28.4%), followed in frequency by nelfinavir (27.3%).
In 2000, 20% of children initiated ART with combination lamivudine, zidovudine, and nelfinavir, and 20% initiated ART with combination lamivudine, stavudine, and nelfinavir. The proportion who initiated ART with combination lamivudine, zidovudine, and boosted lopinavir has increased since 2001 (5.3%) to become the most frequent initial regimen (30.0%) in 2003.
Concordance between the first regimens of the study population and pediatric guidelines was assessed in 261 children who started therapy after the guidelines were published. These 261 children initiated therapy with the following pediatric guideline–classified regimens: "strongly recommended" (49.0%), "alternative" (14.6%), "secondary alternative" (8.8%), "special circumstance" (5.4%), "not recommended" (7.3%), and "other" (14.9%). The regimens of the 19 children who initiated a "not recommended" regimen included 1 NRTI (84.2%), 1 NNRTI (5.3%), 3 NRTIs (including both zidovudine and stavudine) (5.2%), and 1 PI (5.3%). The regimens of the 39 children who initiated a regimen classified as "other" included HAART with a PI plus an NNRTI (66.7%), HAART with an NNRTI but not the recommended one (10.3%), HAART with a PI but not the recommended one (7.7%), 1 NRTI and 1 PI (5.1%), 3 NRTIs but not the recommended combination (5.1%), 1 NRTI and 1 NNRTI (2.6%), and 1 NNRTI and 1 PI (2.6%).
Among the 4 birth cohorts, 0.5% of cohort 1980-1990, 7.3% of cohort 1991-1995, 27.7% of cohort 1996-1999, and 50.0% of cohort 2000-2003 used zidovudine prophylaxis in the first 6 weeks of life. The first, second, and third regimens of each birth cohort were examined, and key findings are summarized in Figure 3. Most of birth cohort 1980-1990 initiated therapy with 1 NRTI (66.1%), mainly zidovudine, which gradually decreased to 11.5% in birth cohort 2000-2003 (Figure 3A). HAART including a PI became the most frequently used first regimen in birth cohort 1996-1999 (37.4%), increasing to 61.5% of birth cohort 2000-2003. In the earlier birth cohorts, children frequently switched between single and/or dual NRTI regimens, with a small number returning to single or dual NRTI regimens after HAART. In contrast, none of birth cohort 2000-2003 switched to single or dual NRTIs after HAART. Forty-one percent of birth cohort 1980-1990 used HAART including a PI by their third regimen, which increased to almost 90% of birth cohort 2000-2003. The median age at the initiation of ART decreased from 5.8 years in the 1980-1990 birth cohort to 2.4 months in the 2000-2003 cohort, as did the median age at initiation of HAART including a PI. Age at ART initiation decreased irrespective of the availability of ART, but the decrease in age at first PI use was affected by the availability of PIs. The median number of regimens used was 4 (10th, 90th percentiles: 1, 9) in birth cohort 1980-1990, 4 (10th, 90th: 1, 10) in birth cohort 1991-1995, 2 (10th, 90th: 1, 6) in birth cohort 1996-1999, and 2 (10th, 90th: 1, 3) in birth cohort 2000-2003. Five children (2.2%) of birth cohort 1980-1990, 5 children (1.8%) of birth cohort 1991-1995, 1 child (0.5%) of birth cohort 1996-1999, and 2 children (2.5%) of birth cohort 2000-2003 never initiated ART.
Eleven children died from HIV infection or a related diagnosis, 10 from birth cohort 1980-1990 and 1 from birth cohort 1991-1995. The median age of death was 14.6 years (10th, 90th percentiles: 11.9, 19.2). All 11 children were ART experienced, with a median age of ART initiation of 7.1 years (10th, 90th: 0.5, 14.0).
Six hundred six (80.5%) of the 753 children receiving ART switched from a first to a second regimen. The median time to first regimen switch decreased from 31.3 months in the 1980-1990 birth cohort to 13.8 months in the 2000-2003 cohort. The unadjusted hazard ratio (HR) for a first regimen of 1 NRTI, 2 NRTIs, or other ART dramatically increased when adjusted for other covariates in the multivariate model, primarily because of confounding by year of ART initiation. Thus, we focus on the multivariate results. As shown, male participants had a higher risk of switching—or shorter time to switch—than female participants (HR, 1.17; 95% confidence interval [CI], 1.00-1.38). Risk of switching significantly decreased (ie, a significantly longer time to switch) with age (years) at ART initiation (HR, 0.96; 95% CI, 0.94-0.99) and significantly increased (ie, a significantly shorter time to switch) with calendar year of ART initiation (HR, 1.28; 95% CI, 1.23-1.33). The first regimen was associated with the likelihood of switching: children who initiated therapy with 1 or 2 NRTIs or an unconventional regimen had a significantly higher risk of switching (ie, shorter time to switch) than those who initiated therapy with HAART including a PI. There was no significant difference in the risk of switching among children who initiated ART with 3 or more NRTIs or HAART including an NNRTI or a PI plus an NNRTI vs those who initiated therapy with HAART including a PI. Adherence to ART and living in a state with an AIDS Drug Assistance Program were not associated with switching, did not change the other parameter estimates, and therefore were not retained in the model.
The likelihood of switching was examined in 39 children for whom CD4 percentages were available at ART initiation. In this multivariate model (adjusted for a first regimen of 1 NRTI, 2 NRTIs vs other, and ART initiation at 3 years or younger vs other), children who initiated ART at CD4 percentages less than 15 had a significantly higher risk of switching (ie, a shorter time to switch) than did children who initiated ART with CD4 percentages of 15 or greater (HR, 2.90; 95% CI, 1.03-8.13).
METHODS
The source population for this study was the Pediatric AIDS Clinical Trials Group (PACTG) 219C cohort. All children born to an HIV-positive mother, whether infected or uninfected, younger than 24 years, and receiving care at a PACTG site were eligible. The PACTG 219C cohort has been enrolling and following up children since September 2000. PACTG 219C was a revised version of PACTG 219—a protocol initiated in 1993 to study the long-term effects of in utero ART exposure and complications of HIV infection in children.19 Children eligible for the present study must have been perinatally HIV infected, born before January 1, 2004, and must not have participated in an ART clinical trial at 219C enrollment or during follow-up. Although the latter criterion excluded roughly two thirds of perinatally infected children, it was essential to allow investigation of trends in the treatment of pediatric HIV infection in clinical practice. The institutions obtained approval from their respective review boards for human research, and each child’s parent or guardian provided written informed consent.
At 219C enrollment, medical and clinical histories and lifetime ART use including start and stop dates were abstracted from clinical records, CD4 T lymphocyte percentages and HIV viral loads were measured, and sociodemographic information was obtained. Information on race/ethnicity was volunteered by each child and/or guardian. Use of ART, HIV immunological and virological parameters, and clinical diagnoses were recorded at follow-up visits every 3 months. CD4 percentages and HIV viral load at ART initiation and by calendar year also were obtained from PACTG 219 when available; most children initiated ART before 219C enrollment and the 219C protocol did not collect information on CD4 percentages or viral load prior to enrollment. Thus, measures at ART initiation were unavailable for many children.
We used the following ART regimen classification: 1 NRTI, 2 NRTIs, 3 or more NRTIs, HAART (3 or more drugs from at least 2 classes) including a PI, HAART including an NNRTI, HAART including a PI plus an NNRTI, and other. Zidovudine prophylaxis taken in the first 6 weeks of life to prevent HIV infection was not counted as a regimen. The duration of use of each regimen was constructed from the start and stop dates of lifetime ART use. When examining the number of unique drug regimens, individual drugs rather than drug classes were considered. To examine trends in ART use by calendar time, the proportion of children receiving each of the above regimens from 1987 (the earliest date of ART use in the study population) through 2003 was determined. If a child used more than 1 regimen in a given year, 1 regimen was randomly selected. The use of specific drugs, CD4 percentages, and viral load by calendar year also were identified.
Concordance between first regimens and US pediatric guidelines was assessed in children who initiated ART at 11 years or younger and on or after April 17, 1998—the date on which the pediatric guidelines for HIV infection in the HAART era were published.15 The upper age limit was used to ensure children were treated according to pediatric, not adult and adolescent, guidelines. The first regimen was classified according to the pediatric guidelines in effect at the time each child started therapy. The guidelines classified initial regimens as "strongly recommended," "alternative," "secondary alternative," "special circumstance," and "not recommended." The proportion of children who initiated therapy in each regimen category was reported. Children who started with a regimen that did not correspond to one of the pediatric guideline categories were classified as "other."
To identify trends in the first, second, and third ART regimens and to account for the temporal availability of ART, children were classified into 4 birth cohorts. Birth cohort 1980-1990 was the period during which zidovudine was the only US Food and Drug Administration (FDA)–approved ART for HIV or AIDS; birth cohort 1991-1995 was the period during which additional NRTIs became available; birth cohort 1996-1999 reflected the advent of HAART, when PIs and NNRTIs were approved and began to be used; and birth cohort 2000-2003 reflected widespread use of PIs and NNRTIs. Dates of FDA approval of initial drugs in each class are provided in Table 1. The first, second, and third regimens and duration of use of each regimen by birth cohort were determined.
Multivariate Cox proportional hazards regression was used to identify predictors of time to first regimen switch. Variables considered included sex, race/ethnicity, age at ART initiation, calendar year of ART initiation, the first ART regimen, ART adherence at cohort enrollment, and whether the child lived in a state with an AIDS Drug Assistance Program. Additional models were constructed including CD4 percentages at the time of ART initiation for children for whom these data were available. There were too few children with HIV viral load measured at ART initiation to include this variable. The validity of the proportional hazards assumption was assessed, and no marked violations were identified. Analyses were performed using SAS version 8.2 (SAS Institute Inc, Cary, NC); P<.05 was used to determine statistical significance.
|
|
| |
| |
|
|
|
