PEDIATRICS Vol. 119 No. 3 March 2007, pp. e705-e715 (doi:10.1542/peds.2006-1367)
ARTICLE |
Once-Daily Highly Active Antiretroviral Therapy for HIV-Infected Children: Safety and Efficacy of an Efavirenz-Containing Regimen
a Emma Children's Hospital
b Department of Human Retrovirology
c Center for Poverty-Related Communicable Diseases
d Department of Internal Medicine, Academic Medical Center, Amsterdam, Netherlands
e International Antiviral Therapy Evaluation Center, Amsterdam, Netherlands
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ABSTRACT |
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 TOP ABSTRACT METHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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OBJECTIVE. To improve adherence and virologic suppression, we assessed the feasibility and effectiveness of a once-daily regimen of efavirenz with 3 nucleoside reverse transcriptase inhibitors as first-line or second-line highly active antiretroviral therapy in a cohort of HIV-1–infected children.
METHODS. HIV-1–infected children naive to efavirenz were treated with a combination of efavirenz, abacavir, didanosine, and lamivudine in an observational, prospective, single-center study. Virologic failure-free survival was assessed with Kaplan-Meier analysis. The CD4+ T-cell increase was estimated by using a generalized linear model incorporating repeated measurements.
RESULTS. Thirty-six children received the study medication for a median of 69 weeks. Virologic failure-free survival rates were 76% and 67% after 48 weeks and 96 weeks, respectively. No significant difference was found in efficacy between first-line and second-line highly active antiretroviral therapy. All children receiving highly active antiretroviral therapy showed a sustained CD4+ T-cell increase, irrespective of virologic suppression. Growth rates improved with highly active antiretroviral therapy. Study medication administration was stopped for 14 children, mostly because of nonadherence (4 cases) or virologic rebound (5 cases) and because of adverse events (unrelated death and grade 2 liver toxicity) in 2 cases. Lipid abnormalities and abacavir-related hypersensitivity were not observed.
CONCLUSIONS. For the first time, once-daily highly active antiretroviral therapy is demonstrated to be a safe, convenient, and potent antiretroviral regimen for HIV-1–infected children.
Key Words: pediatric HIV • once-daily highly active antiretroviral therapy • efficacy • efavirenz • growth
Abbreviations: ART—antiretroviral therapy • HAART—highly active antiretroviral therapy • IQR—interquartile range • LLQ—lower limit of quantification • NNRTI—nonnucleoside reverse transcriptase inhibitor • NRTI—nucleoside reverse transcriptase inhibitor • PI—protease inhibitor • pVL—plasma viral load • RT—reverse transcriptase
Since highly active antiretroviral therapy (HAART) became the standard of treatment for HIV-1–infected children, morbidity and mortality rates have declined significantly.1–3 With the long-term use of HAART, however, the limitations are becoming apparent.
Recommended as initial therapy is the combination of 2 nucleoside reverse transcriptase inhibitors (NRTI) with 1 protease inhibitor (PI) or 1 nonnucleoside reverse transcriptase inhibitor (NNRTI).4,5 Regarding effectiveness, any PI-containing first-line HAART for children seems efficacious after 2 years for 42% to 87% of children.6–8
A PI-containing regimen may have the potential for development of blood lipid disturbances and lipodystrophy, as we and others have observed.9–11 The disfiguring appearance of lipodystrophy can influence negatively patients' adherence to HAART. Also, other antiretroviral agents, such as didehydrodeoxythymidine, are known to have effects on blood lipid levels. Alternatively, PI-sparing regimens in adults, using efavirenz combined with 2 NRTIs, showed virologic responses of 70% of treated individuals having HIV RNA levels of <400 copies per mL at 48 weeks.12 For HIV-1 infected children, it was shown that substitution of a PI by efavirenz resulted in the maintenance of virologic control for 17 children in whom HIV-1 was well suppressed.13 Positive effects on the lipid profile were seen in this patient population. In another study of 10 children, a success rate of 80% was reported.14 Therefore, efavirenz seems to be a suitable alternative to PIs. However, data regarding its use in once-daily regimens for children have not been reported.
A meta-analysis of virologic outcome data from clinical trials of various HAART regimens found a significant correlation between lower pill burden and treatment efficacy in adult patients.15 In a pediatric population, adherence can be additionally compromised because of the patients' young age, poor palatability of the medications, and dependence on the patients' caregivers. A once-daily regimen is therefore preferred.
According to the history of antiretroviral therapy (ART), some children in our cohort had been treated initially with zidovudine, followed by zidovudine combined with didanosine or zalcitabine, until the introduction of nelfinavir as the first PI available for children. Considering the high plasma HIV-1 RNA load (plasma viral load [pVL]) observed in young children, compared with that in adults,16–18 a robust regimen was assumed to be required to avoid the early occurrence of new mutations in the viral reverse transcriptase (RT) gene associated with resistance to antiretroviral drugs.19 A 2-class regimen with 4 drugs, including abacavir, was reported to be successful.20,21 Therefore, to increase adherence and virologic success rates, we commenced a once-daily HAART regimen containing efavirenz and 3 NRTIs (ie, abacavir, didanosine, and lamivudine), and we describe its safety, tolerability, and effectiveness in HIV-1–infected children for up to 2 years.
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METHODS |
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Patients
Between January 2002 and August 2005, a prospective observational study was performed at the Academic Medical Centre (Amsterdam, Netherlands). HIV-1–infected children were eligible when they were 3 months to 18 years of age and had CD4+ T-cell counts of <1750 cells per µL (for those <1 year of age), <1000 cells per µL (for those between 1 and 2 years of age), <750 cells per µL (for those between 3 and 6 years of age), or <500 cells per µL (for those >6 years of age). Previous exposure to ART regimens was allowed. Exclusion criteria consisted of the presence of mutations associated with resistance to efavirenz or to
2 of the NRTI study drugs used at the commencement of the once-daily treatment regimen, pregnancy, and HLA typing results unfavorable with respect to abacavir use.22 All children in our cohort were naive to all NNRTIs before enrollment. No restrictions were made with respect to ethnicity, gender, route of HIV acquisition, or disease stage. The medical ethics committee of our institute approved the protocol. Parents or caregivers provided written informed consent.
Medications
Patients received efavirenz (starting dose according to manufacturer's instructions) (Table 1), abacavir (16 mg/kg; maximum: 600 mg/day), didanosine (200–240 mg/m2), and lamivudine (4 mg/kg [<6 weeks] or 8 mg/kg [6 weeks]; maximum: 300 mg/day). Dosage adjustments were performed according to the weight of the children. Because efavirenz is not registered for children <3 years of age, pharmacokinetics over 24 hours were tested at day 0, day 14, and 6 weeks for all patients starting efavirenz treatment, followed by consecutive plasma measurements to monitor drug levels for underdosing or overdosing (and to establish a trough level of >1 mg/L, which is considered a target value for virologic success in adults23 and children [Kristel Crommentuijn, H.J.S., Alwin Huitema, T.W.K., and Jos Beijnen, manuscript in preparation]).
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It was recommended that the children take their regimen with food. When taken as a solution for the optimal treatment of small children in our cohort, didanosine was prepared with acid-binding magnesium hydroxide, according to the instructions of the manufacturer. The didanosine solution was taken either 1 hour before or 1 hour after food was eaten. Otherwise, the extended-release form didanosine-EC was used, without food restriction.
Adherence
The children's guardians were counseled regarding the importance of treatment adherence. Where appropriate, the children were also counseled accordingly. Members of the treatment team monitored adherence by telephoning the guardians soon after the regimen was started and at each follow-up clinic visit.
Procedures
At each visit, a physical examination was performed, including weight, length, and head circumference measurements. Blood was drawn before and 1 and 2 weeks and 1, 2, and 3 months after initiation of HAART and every 3 to 4 months thereafter. Lymphocyte subsets were analyzed with a FACScan system (Becton Dickinson, San Jose, CA). The pVL was measured with a Versant HIV-1 bDNA 3.0 assay (Bayer, Mijdrecht, Netherlands), with a lower limit of quantification (LLQ) of 50 copies per mL (input: 1 mL of plasma). Virologic failure was defined as 2 consecutive pVL values of >50 copies per mL. Patients who never reached a pVL of <50 copies per mL were failing at the first measurement after the nadir pVL in the initial decline.
Nucleotide sequence analyses of the HIV-1 protease and RT genes were performed at baseline and after virologic failure. Sequence analyses were performed with the Viroseq HIV-1 genotyping kit (version 2; Abbott Laboratories, Abbott Park, IL). Resistance-conferring mutations were screened as described by the International AIDS Society-USA.24
Adverse events were recorded during the study period and were defined as any clinical sign or symptom or meaningful laboratory test abnormality possibly or probably related to the study medication, excluding HIV-related disorders. The National Institute of Allergy and Infectious Diseases toxicity tables were used to grade the severity of pediatric adverse experiences.25 Parents were asked about the presence of adverse effects at every visit.
Statistical Analyses
The primary outcome was virologic failure-free survival, which was assessed by using Kaplan-Meier analysis. Censoring was applied if the last patient visit or a switch to another regimen occurred before virologic failure. The secondary outcomes were factors associated with virologic failure, changes in CD4+ and CD8+ T-cell counts over time, changes in growth parameters (weight and height) over time, reported adverse events, and the occurrence of resistance mutations. Age-adjusted CD4+ and CD8+ T-cell ratios were calculated by dividing the counts by the mean for an age-matched healthy control group.26 Growth of the children was analyzed by means of the z scores (normal SD) of height and length. These scores were calculated with the use of Growth Analyser 2.0 software (Dutch Growth Foundation, Rotterdam, Netherlands), with Dutch reference values. Age-adjusted CD4+ and CD8+ T-cell ratios and height and weight z scores were modeled by using a mixed model incorporating repeated measurements. This model handles missing data adequately by estimating the outcome given a specific covariate structure. The estimates of a specific level of the fixed effects were modeled by using the "first-order autoregressive" approach. Differences in these estimates between different levels of the variable were tested for significance by using the t statistic. When subgroups of patients were compared, the differences between groups were evaluated by using Fisher's exact test for categorical data and the Kruskal-Wallis test for continuous data. All statistical analyses were performed with SPSS for Windows (SPSS, Chicago, IL). A 2-sided P value of <.05 was considered statistically significant.
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RESULTS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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Patients
All 36 HIV-1–infected children who started a once-daily ART regimen with efavirenz between January 2002 and August 2005 were included in the present analyses. ART-naive and pretreated HIV-1–infected children were included. Twenty-two children (61%) had been receiving HAART for a median 259 weeks before enrollment (interquartile range [IQR]: 104–310 weeks). Of these children, 10 were also pretreated with single/dual NRTI therapy for a median of 134 weeks before the start of HAART. One child used 2 different HAART regimens before enrollment; all others used 1 HAART regimen before enrollment.
Baseline characteristics are shown in Table 2. The median age of the children at baseline was 6.6 years (IQR: 3.3–10.7 years). One of the children was <1 year of age, 6 were between 1 and 2 years of age, 12 were between 3 and 6 years of age, and 17 were >6 years of age. Children who were naive to ART were younger at baseline than were children who received second-line HAART (median: 3.3 years [IQR: 1.7–9.9 years] vs 8.8 years [IQR: 5.2–11.5 years]; P = .04). Thirty-four children (94%) acquired HIV infection perinatally from their HIV-1–infected mothers; 15 children (42%) presented with Centers for Disease Control and Prevention category C-classified AIDS-defining symptoms. The majority of the children were black (African or Surinamese). The children received study medication for a median duration of 69 weeks (IQR: 39–122 weeks).
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Virologic Findings
At baseline, the median pVL for the whole group was 3.6 log copies per mL (IQR: 2.4–4.7 log copies per mL). Children who started the once-daily regimen as second-line HAART had a significantly lower pVL than did children who started ART naive to the regimen (median: 2.5 vs 5.4 log copies per mL; P < .001). Twelve (55%) of 22 children who started second-line HAART had undetectable levels at the switch of therapy. The virologic failure-free survival rates were 76% and 67% after 48 and 96 weeks, respectively (Fig 1A). Twelve children completed a follow-up period of 96 weeks with study medication. Of the patients who experienced failure of therapy or discontinued study medication at any time during the follow-up period, 6 never had a pVL below the LLQ. Of the remaining 30 children in this observational cohort, 4 showed a rebound of their pVL after having experienced a period of viral suppression below the LLQ after the initiation of study medication. The effect of previous HAART on virologic effectiveness was analyzed with a log-rank test; there was no difference between virologic responders and nonresponders (P = .7) (Fig 1B).
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Reasons for Treatment Discontinuation
Study medication needed to be discontinued for 14 children (39%) during the follow-up period, for the following reasons: 5 virologic failures with several new mutations, 4 reported cases of nonadherence, 2 cases of aversion to the taste of the medication, 1 pregnancy, 1 serious adverse event (death), and 1 adverse event (grade 2 elevation in liver transaminase levels). The fatality involved a patient who experienced a severe electrolyte disturbance and lactate acidosis because of persistent diarrhea, despite a rapid virologic response to undetectable levels. In the opinion of the treating physicians, this was not attributable to the study drugs. Hypersensitivity to abacavir was not seen.
Resistance Mutations
The RT gene from HIV-1 in plasma samples was sequenced for all 36 children. The HIV-1 strains in children who experienced failure of the study medication were scrutinized for the occurrence of additional critical mutations in the RT gene associated with NNRTI resistance, for efavirenz in particular (ie, 100I, 103N, 106A/M, 108I, 181C/I, 190A/S, 225H, or 230L). One HAART-experienced boy had a 181C mutation at the start of the study regimen. His pVL became undetectable with the study medication. For one ART-naive child, a 69N mutation in the RT gene was found at baseline. Mutations associated with resistance to 1 NRTI were detected in the group of children who had shown viral blips previously or had experienced complete failure with their first-line, PI-containing, HAART regimen (Table 3). In a survival analysis, there was no significant difference in the time to virologic failure for patients with existing mutations at baseline, compared with children without mutations at baseline (P = .5).
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Immunologic Findings
At baseline, the median CD4+ T-cell count for the total study population was 730 cells per µL (IQR: 400–1050 cells per µL), the age-adjusted CD4+ T-cell ratio was 0.5 (IQR: 0.3–0.9), and the CD4+ T-cell percentage was 26% (IQR: 16%–37%). The baseline age-adjusted CD4+ T-cell ratio and the absolute number and percentage of CD4+ T cells were statistically significantly higher in children who started the regimen as second-line HAART, compared with children who had not received previous ART (P = .003, P = .03, and P < .001, respectively) (Table 2). The median CD8+ T-cell count for the total study population was 1270 cells per µL (IQR: 800–1910 cells per µL), and the age-adjusted CD8+ T-cell ratio was 1.5 (1.1–1.8).
The median age-adjusted CD4+ T-cell ratio demonstrated an increase during the 96 weeks of treatment (Fig 2A). Children who started naive to ART had a more-profound increase, compared with children receiving second-line HAART (Fig 2B). This was attributable to a lower baseline CD4+ T-cell count. The age-adjusted CD8+ T-cell ratios demonstrated slight but nonsignificant decreases in the total study population (Fig 2C) and in both subgroups, based on pretreatment (Fig 2D).
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Lipids
Although there was a significantly lower total cholesterol level for patients who started naive to ART, compared with patients who started second-line HAART (median: 3.4 vs 4.3 mmol/L; P < .001), all children were below the cutoff value of 6.5 mmol/L (upper limit of the reference range). The same applied to triglyceride levels at baseline (median: 1.1 vs 0.7 mmol/L; P = .04; normal levels: <5.0 mmol/L).
During the treatment with HAART, total cholesterol levels increased. However, for children with second-line HAART, total cholesterol levels remained stable. Children who started naive to ART showed an increase toward the values of the group with second-line HAART within the first weeks. Triglyceride levels did not change over time during treatment with the once-daily regimen.
Growth and Development
Growth parameters are shown in Fig 3. The median height-for-age z score at baseline for the total study population was –1.2, and the median weight-for-height z score was 0.6. Children naive to ART had a significantly lower height-for-age z score, compared with children receiving second-line HAART (median z score: –1.9 vs –0.5; P = .001). The ART-naive group showed a distinct increase in the first 48 weeks, but values did not reach the level of the second-line HAART group (Fig 3B). An increase in weight-for-age z scores was seen during 96 weeks of treatment, almost to normal values (Fig 3C). Children with second-line HAART showed a different pattern over time, compared with children who started naive to ART (Fig 3D). The children who started naive to ART showed an increase, in contrast to the children receiving second-line HAART, who showed a higher baseline level that remained stable. Weight-for-height z scores remained stable in both treatment groups (Fig 3, E and F).
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DISCUSSION |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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We demonstrated for the first time the virologic effectiveness, tolerability, and safety of a once-daily HAART regimen in an HIV-1–infected pediatric cohort. Virologic failure-free survival rates were 76% and 67% after 48 and 96 weeks, respectively, for all children, with equal effectiveness of the study regimen when used as first-line or second-line HAART (77% and 75%, respectively, after 48 weeks). The only pediatric report on efavirenz-containing HAART to date involved 17 children with persistently suppressed pVL switching to efavirenz-containing HAART for reasons of convenience and simplification.13 Our treatment regimen contained efavirenz and 3 NRTIs as the backbone and was administered to 36 children. A limited number of studies on once-daily regimens for ART-naive adults have been reported up to 48 weeks, with virologic failure-free survival rates ranging from 50% to 78%.27–32 The combination of tenofovir and didanosine as the NRTI backbone seemed the least effective,30,31 despite good adherence as defined with the medication event monitoring system and plasma efavirenz concentration monitoring.31 Our results in children demonstrate favorably the strong antiretroviral activity of the chosen once-daily regimen (irrespective of previous treatment experience).
Our efavirenz-containing once-daily regimen was well tolerated. Regarding safety and tolerability, we observed medication-related grade 2 toxicity in only 1 child, consisting of an increase in blood liver enzyme levels. This concurs with other reports on children.13,17,33 The nonfasting lipid levels remained within reference ranges, although total cholesterol levels showed an increase during the first weeks in the ART-naive group, compared with children who started second-line HAART. In the 2NN study, it was shown that the efavirenz-associated increase in total cholesterol levels was mainly attributable to high-density lipoprotein cholesterol.34 One patient with AIDS-related severe cachexia died as a result of persisting electrolyte disturbances despite very successful HIV-1 suppression. For 14 children, the regimen was stopped despite good tolerability and simplification of intake, compared with most of the previous regimens for children. Discontinuation was for several reasons but mostly for reasons of virologic rebound attributable to assumed or self-reported nonadherence.
A latent viral reservoir may harbor viruses that are generated at various times throughout the life of perinatally infected children, including wild-type, drugsensitive viruses transmitted from the mother and any drug-resistant viruses that arise during nonsuppressive HAART therapy.19 Seventeen of the 22 patients who received second-line HAART showed extensive RT mutations. For one child naive to ART, a 69N mutation in RT was found at baseline. This mutation is associated with resistance to zidovudine, stavudine, and didanosine. Most probably the virus was acquired from the mother, although the predominant virus population in the mother seemed to contain a 69S mutation in RT. The amino acid difference at this position can be explained by viral evolution, because the baseline sequences of the mother and child were obtained 3.5 years after birth. One HAART-experienced boy had an 181C mutation at the start of the study regimen. Although this mutation is associated with resistance to efavirenz, it has a greater impact on the sensitivity to nevirapine.35 With the addition of lopinavir/ritonavir to the study regimen, a lasting virologic response was achieved.
Apart from preexisting mutations, the impact of adherence on the effectiveness of HAART must be considered seriously. Of the virologic failures, 2 patients treated previously with HAART, without mutations, reported nonadherence to the regimen by themselves. In most of the other virologic failures, including that of the pregnant girl, efavirenz was repeatedly below the trough level of 1 mg/L even after dose adjustments, which suggests nonadherence. Critical NNRTI-associated resistance mutations were found for 7 of those 8 patients. Similar to the findings of Luzuriaga et al,36 we did not observe an association between preexisting NRTI (or PI) resistance mutations and success or failure of virologic control (P = .5), which suggests that adherence may indeed be the most important factor for lasting virologic suppression in our cohort.
Increases in CD4+ T-cell counts were observed in both groups, although the increase in cell number was more profound in the group that started naive to ART, because of the lower baseline counts. As expected, the baseline age-adjusted CD4+ T-cell ratio and absolute and relative CD4+ T-cell counts were statistically significantly higher for children who started the regimen as second-line HAART. No severe clinical infections occurred during the study period in either group, irrespective of virologic failure.
With respect to general growth and development, ART-naive children showed an increase in height-for-age z scores but did not reach the level of the second-line HAART group at 96 weeks. In our cohort, the children receiving first-line HAART showed normalization of weight-for-age z scores, whereas the second-line HAART group already had almost-normal z scores at the start. Nachman et al37 described similar findings for 192 children in clinically stable condition, of whom 50% had been pretreated with NRTIs but were naive to the new HAART regimens. Most of the second-line HAART group in our study had used stavudine, lamivudine, and nelfinavir as first-line HAART, for a median of 259 weeks. Almost 30% had developed clinically evident lipodystrophy.11
The follow-up period in the present once-daily study was too short for any effect on fat distribution to be expected. Moreover, the number of ART-naive children was small, and the total treatment follow-up period was relatively short for judging any alteration in this respect.
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CONCLUSIONS |
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TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
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This is the first study of a once-daily, efavirenz-containing, HAART regimen in a pediatric cohort. Our study demonstrated virologic and immunologic effectiveness, even for children who were HAART experienced. We can conclude that the once-daily regimen used is a convenient, safe, and robust regimen for children. Most children were ART experienced but demonstrated equal effectiveness of the once-daily regimen, compared with children receiving first-line HAART. Because of the high pVL in young children,16–18 a robust regimen is required. A 2-class regimen with 4 drugs containing abacavir was considered more successful.20,21 Simplification of the study regimen by stopping one of the NRTIs when the pVL is below the LLQ may be a possibility with similar outcomes and efficacy. A considerable number of patients who stopped the treatment regimen admitted nonadherence or were suspected of nonadherence because of low drug levels in consecutive blood samples, irrespective of the dose adjustments made. Additional improvement of the effectiveness of treatment can be reached in the future, because once-daily regimens allow for various measures to support adherence (such as the medication event monitoring system or directly observed therapy), in larger, well-designed studies on virologic outcomes.
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ACKNOWLEDGMENTS |
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Dr Bekker was supported in part by grant 7006 from the Dutch AIDS Foundation. Bristol-Myers Squibb provided the study medication (didanosine) and Maalox to prepare the didanosine solution for the children in our cohort.
We thank our patients, their parents, and their caretakers for their participation; our HIV nurses, Atie van der Plas and Eugenie le Poole, for their enthusiasm and care of our pediatric cohort; and the home care teams for their support. We thank Kristel Crommentuyn, Rob ter Heine, Alwin Huitima, and Jos Beijnen for their collaboration on the pharmacodynamic population studies and for providing the efavirenz levels. We also thank Michael Kangas for critical reading of and comments on the manuscript.
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FOOTNOTES |
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Accepted Sep 15, 2006.
Address correspondence to Taco W. Kuijpers, MD, PhD, Emma Children's Hospital, Academic Medical Center, G8-205, Meibergdreef 9, 1105 AZ Amsterdam, Netherlands. E-mail: t.w.kuijpers{at}amc.uva.nl
Drs Scherpbier and Bekker contributed equally to the work presented.
Dr Bekker’s current affiliation is Section on Genomic Variation, Pediatric Oncology Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
The authors have indicated they have no financial relationships relevant to this article to disclose.
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REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONCONCLUSIONSREFERENCES |
|---|
- Gortmaker SL, Hughes M, Cervia J, et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1.
N Engl J Med. 2001;345
:1522
–1528
[Abstract/Free Full Text] - Gibb DM, Duong T, Tookey PA, et al. Decline in mortality, AIDS, and hospital admissions in perinatally HIV-1 infected children in the United Kingdom and Ireland.
BMJ. 2003;327
:1019
[Abstract/Free Full Text] - Viani RM, Araneta MR, Deville JG, Spector SA. Decrease in hospitalization and mortality rates among children with perinatally acquired HIV type 1 infection receiving highly active antiretroviral therapy. Clin Infect Dis. 2004;39 :725 –731[CrossRef][Web of Science][Medline]
- National Institutes of Health. Guidelines for the use of antiretroviral agents in pediatric HIV infection. Available at: http://aidsinfo.nih.gov/contentfiles/PediatricGuidelines.pdf. Accessed April 1, 2006
- Sharland M, Blanche S, Castelli G, Ramos J, Gibb DM. PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Med. 2004;5(suppl 2) :61 –86
- van Rossum AM, Fraaij PL, de Groot R. Efficacy of highly active antiretroviral therapy in HIV-1 infected children. Lancet Infect Dis. 2002;2 :93 –102[CrossRef][Web of Science][Medline]
- King JR, Nachman S, Yogev R, et al. Efficacy, tolerability and pharmacokinetics of two nelfinavir-based regimens in human immunodeficiency virus-infected children and adolescents: Pediatric AIDS Clinical Trials Group protocol 403. Pediatr Infect Dis J. 2005;24 :880 –885[CrossRef][Web of Science][Medline]
- Puthanakit T, Oberdorfer A, Akarathum N, et al. Efficacy of highly active antiretroviral therapy in HIV-infected children participating in Thailand's National Access to Antiretroviral Program. Clin Infect Dis. 2005;41 :100 –107[CrossRef][Web of Science][Medline]
- European Paediatric Lipodystrophy Group. Antiretroviral therapy, fat redistribution and hyperlipidaemia in HIV-infected children in Europe. AIDS. 2004;18 :1443 –1451[CrossRef][Web of Science][Medline]
- Sanchez Torres AM, Munoz MR, Madero R, Borque C, Garcia-Miguel MJ, De Jose Gomez MI. Prevalence of fat redistribution and metabolic disorders in human immunodeficiency virus-infected children. Eur J Pediatr. 2005;164 :271 –276[CrossRef][Web of Science][Medline]
- Scherpbier HJ, Bekker V, van Leth F, Jurriaans S, Lange JM, Kuijpers TW. Long-term experience with combination antiretroviral therapy that contains nelfinavir for up to 7 years in a pediatric cohort. Pediatrics. 2006;117(3) . Available at: www.pediatrics.org/cgi/content/full/117/3/e528
- Staszewski S, Morales-Ramirez J, Tashima KT, et al. Efavirenz plus zidovudine and lamivudine, efavirenz plus indinavir, and indinavir plus zidovudine and lamivudine in the treatment of HIV-1 infection in adults.
N Engl J Med. 1999;341
:1865
–1873
[Abstract/Free Full Text] - McComsey G, Bhumbra N, Ma JF, Rathore M, Alvarez A. Impact of protease inhibitor substitution with efavirenz in HIV-infected children: results of the First Pediatric Switch Study. Pediatrics. 2003;111(3) . Available at: www.pediatrics.org/cgi/content/full/111/3/e275
- Funk MB, Notheis G, Schuster T, et al. Effect of first line therapy including efavirenz and two nucleoside reverse transcriptase inhibitors in HIV-infected children. Eur J Med Res. 2005;10 :503 –508[Web of Science][Medline]
- Bartlett JA, DeMasi R, Quinn J, Moxham C, Rousseau F. Overview of the effectiveness of triple combination therapy in antiretroviral-naive HIV-1-infected adults. AIDS. 2001;15 :1369 –1377[CrossRef][Web of Science][Medline]
- Dickover RE, Dillon M, Leung KM, et al. Early prognostic indicators in primary perinatal human immunodeficiency virus type 1 infection: importance of viral RNA and the timing of transmission on long-term outcome. J Infect Dis. 1998;178 :375 –387[Web of Science][Medline]
- Palumbo PE, Raskino C, Fiscus S, et al. Predictive value of quantitative plasma HIV RNA and CD4+ lymphocyte count in HIV-infected infants and children.
JAMA. 1998;279
:756
–761
[Abstract/Free Full Text] - Rouet F, Sakarovitch C, Msellati P, et al. Pediatric viral human immunodeficiency virus type 1 RNA levels, timing of infection, and disease progression in African HIV-1-infected children. Pediatrics. 2003;112(4) . Available at: www.pediatrics.org/cgi/content/full/112/4/e289
- Ruff CT, Ray SC, Kwon P, et al. Persistence of wild-type virus and lack of temporal structure in the latent reservoir for human immunodeficiency virus type 1 in pediatric patients with extensive antiretroviral exposure.
J Virol. 2002;76
:9481
–9492
[Abstract/Free Full Text] - Williams I, Asboe D, Babiker A, Goodall R, Hooker M, FORTE Trial Steering Committee. A virological benefit from an induction/maintenance strategy compared with a standard 3-drug regimen in antiretroviral naive patients: the FORTE Trial. Presented at the 11th Conference on Retroviruses and Opportunistic Infections; February 8–11, 2004; San Francisco, CA
- Handforth J, Sharland M. Triple nucleoside reverse transcriptase inhibitor therapy in children. Paediatr Drugs. 2004;6 :147 –159[CrossRef][Medline]
- Mallal S, Nolan D, Witt C, et al. Association between presence of HLA-B*5701, HLA-DR7, and HLA-DQ3 and hypersensitivity to HIV-1 reverse-transcriptase inhibitor abacavir. Lancet. 2002;359 :727 –732[CrossRef][Web of Science][Medline]
- Kappelhoff BS, Huitema AD, Yalvac Z, et al. Population pharmacokinetics of efavirenz in an unselected cohort of HIV-1-infected individuals. Clin Pharmacokinet. 2005;44 :849 –861[CrossRef][Web of Science][Medline]
- International AIDS Society-USA. Update of the drug resistance mutations in HIV-1: fall 2006. Available at: www.iasusa.org/resistance_mutations/mutations_figures.pdf. Accessed April 1, 2006
- National Institute of Allergy and Infectious Diseases, Regulatory Compliance Center. Toxicity tables. Available at: http://rcc.tech-res.com/tox_tables.htm Accessed April 1, 2006
- Kuijpers TW, Vossen MT, Gent MR, et al. Frequencies of circulating cytolytic, CD45RA+CD27–, CD8+ T lymphocytes depend on infection with CMV.
J Immunol. 2003;170
:4342
–4348
[Abstract/Free Full Text] - Ena J, Pasquau F. Once-a-day highly active antiretroviral therapy: a systematic review. Clin Infect Dis. 2003;36 :1186 –1190[CrossRef][Web of Science][Medline]
- Saag MS, Cahn P, Raffi F, et al. Efficacy and safety of emtricitabine vs stavudine in combination therapy in antiretroviral-naive patients: a randomized trial.
JAMA. 2004;292
:180
–189
[Abstract/Free Full Text] - Moyle GJ, DeJesus E, Cahn P, et al. Abacavir once or twice daily combined with once-daily lamivudine and efavirenz for the treatment of antiretroviral-naive HIV-infected adults: results of the Ziagen Once Daily in Antiretroviral Combination Study. J Acquir Immune Defic Syndr. 2005;38 :417 –425[CrossRef][Web of Science][Medline]
- Leon A, Martinez E, Mallolas J, et al. Early virological failure in treatment-naive HIV-infected adults receiving didanosine and tenofovir plus efavirenz or nevirapine. AIDS. 2005;19 :213 –215[Web of Science][Medline]
- Maitland D, Moyle G, Hand J, et al. Early virologic failure in HIV-1 infected subjects on didanosine/tenofovir/efavirenz: 12-week results from a randomized trial. AIDS. 2005;19 :1183 –1188[Web of Science][Medline]
- Ribera E, Rodriguez-Pardo D, Rubio M, et al. Efficacy and safety of once-daily combination therapy with didanosine, lamivudine and nevirapine in antiretroviral-naive HIV-infected patients. Antivir Ther. 2005;10 :605 –614[Web of Science][Medline]
- Starr SE, Fletcher CV, Spector SA, et al. Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors in children infected with human immunodeficiency virus type 1: Pediatric AIDS Clinical Trials Group 382 Team.
N Engl J Med. 1999;341
:1874
–1881
[Abstract/Free Full Text] - van Leth F, Phanuphak P, Stroes E, et al. Nevirapine and efavirenz elicit different changes in lipid profiles in antiretroviral therapy-naive patients infected with HIV-1. PLoS Med. 2004;1 :e19[CrossRef][Medline]
- Harrigan PR, Salim M, Stammers DK, et al. A mutation in the 3' region of the human immunodeficiency virus type 1 reverse transcriptase (Y318F) associated with nonnucleoside reverse transcriptase inhibitor resistance.
J Virol. 2002;76
:6836
–6840
[Abstract/Free Full Text] - Luzuriaga K, McManus M, Mofenson L, Britto P, Graham B, Sullivan JL. A trial of three antiretroviral regimens in HIV-1-infected children.
N Engl J Med. 2004;350
:2471
–2480
[Abstract/Free Full Text] - Nachman SA, Lindsey JC, Moye J, et al. Growth of human immunodeficiency virus-infected children receiving highly active antiretroviral therapy. Pediatr Infect Dis J. 2005;24 :352 –357[CrossRef][Web of Science][Medline]
- Centers for Disease Control and Prevention. 1994 revised classification system for human immunodeficiency virus infection in children less than 13 years of age: official authorized addenda: human immunodeficiency virus infection codes and official guidelines for coding and reporting: ICD-9-CM. MMWR Recomm Rep. 1994;43(RR-12) :1 –19
- Fredriks AM, van Buuren S, Burgmeijer RJ, et al. Continuing positive secular growth change in The Netherlands 1955–1977. Pediatr Res. 2000;47 :316 –323[Web of Science][Medline]
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