Published online March 10, 2008
PEDIATRICS Vol. 121 No. 4 April 2008, pp. e827-e835 (doi:10.1542/peds.2006-3078)
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ARTICLE

Long-term Safety and Efficacy Results of Once-Daily Emtricitabine-Based Highly Active Antiretroviral Therapy Regimens in Human Immunodeficiency Virus-Infected Pediatric Subjects

Xavier Saez-Llorens, MDa, Avy Violari, MDb, Dalubuhle Ndiweni, MDc, Ram Yogev, MDd, Miguel Cashat, MDe, Andrew Wiznia, MDf, Greg Chittick, BScg, Jeanette Harris, BSg, John Hinkle, PhDg, M. Robert Blum, PhDg, Nathalie Adda, MDg, Franck Rousseau, MDg for the FTC-203 Study Team

a Infectious Disease Department, Hospital del Nino, Panama City, Panama
b Perinatal HIV Research Unit, Baragwanath Hospital, Soweto, South Africa
c Pediatric HIV Clinic, Helen Joseph Hospital, Johannesburg, South Africa
d Section of Pediatric and Maternal HIV Infection, Children's Memorial Hospital, Chicago, Illinois
e Department of Infectious Diseases, Hospital Infantil de Mexico Federico Gomez, Mexico City, Mexico
f Division of Pediatric Allergy and Immunology, Jacobi Medical Center, Albert Einstein College of Medicine, Bronx, New York
g Gilead Sciences, Inc, Durham, North Carolina


   ABSTRACT
TOP
 ABSTRACT
METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
OBJECTIVES. The purpose of this work was to obtain long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects and confirm that a pediatric dose of 6 mg/kg once daily would provide steady-state emtricitabine concentrations comparable to those observed in adults given 200 mg of emtricitabine once daily.

PATIENTS AND METHODS. HIV-infected subjects between 3 months and 16 years of age were enrolled, including 71 antiretroviral-naïve subjects and 45 antiretroviral-experienced subjects. Naive subjects received emtricitabine plus stavudine plus lopinavir or ritonavir. Experienced subjects replaced the lamivudine in their existing regimens with emtricitabine. Tolerance, safety, disease progression, and virologic and immunologic responses were evaluated.

RESULTS. The Kaplan-Meier probability of persistent virologic response in the intent-to-treat population through week 164 at ≤400 copies per mL and ≤50 copies per mL was 74% and 62%, respectively. Three subjects (3%) discontinued the study for adverse events, 8 (7%) for virologic failure, and 1 died through a median follow-up of 164 weeks. The annualized incidence rate of grade 3 to 4 adverse events and grade 3 to 4 laboratory abnormalities was 6% and 3%, respectively. The annualized incidence rate of serious adverse events was 9%, with 1% attributed as related to emtricitabine. Genotypic analysis showed the emergence of the M184V mutation in 4 of the 15 subjects who experienced virologic failure through week 164. Pharmacokinetic evaluation demonstrated plasma drug exposures in these children comparable to adults receiving the approved dose of 200 mg once daily.

CONCLUSIONS. These results demonstrate the safety and efficacy of emtricitabine in pediatric patients. They also support that the safety and efficacy profile of emtricitabine in children is similar to that demonstrated in adults.

Key Words: emtricitabine • FTC • pediatric • HIV • pharmacokinetics

Abbreviations: QD—once daily • ART—antiretroviral therapy • PCR—polymerase chain reaction • AUC{tau}—area under the plasma concentration-time curve over the 24 hour dosing interval • BID—twice daily • TLOVR—time to loss of virologic response • AIR—annualized incidence rate • SAE—serious adverse event

Although the treatment of HIV disease in pediatric patients shares many characteristics with the adult population,1 there are considerations of particular importance to children and adolescents. Treatment options for adolescents and adults have become fairly broad; however, fewer therapies are available for children who cannot swallow pills or who require a liquid formulation to allow for incremental dose adjustments as the child matures.2,3 Poor tolerability and inadequate adherence are major determinants of the failure of highly active antiretroviral therapy regimens, and suboptimal adherence is a particularly acute problem among children.4 Thus, whereas potent regimens can initially reduce viral load to below assay quantitation limits in the majority of HIV-infected children, published data indicate that 30% to 80% of children5–10 will experience regimen failure and the return of detectable plasma virus within 12 months of initiating therapy.

In addition to palatability, toxicity, antiviral potency, and the pattern of resistance that will develop with regimen failure, considerations on ease of use will factor into the choice of an antiretroviral treatment regimen. Entirely once daily (QD) regimens have shown superior efficacy, in part because of the individual potency of each agent but also because of enhanced adherence.11–15 Of the 12 drugs currently approved in the United States for the treatment of HIV infection in children, 2 are approved for QD dosing, efavirenz (Sustiva) and, more recently, emtricitabine (Emtriva), a deoxycytidine nucleoside analog that was shown to be safe and effective during the adult clinical program.14,16 Of the nucleoside reverse transcriptase inhibitors commercially available as liquid formulation, Emtriva is the only 1 administered QD.

A phase 1, single-dose, dose escalation study of the safety and pharmacokinetics of emtricitabine (Study FTC-105) in pediatric subjects showed that the overall pharmacokinetic properties of emtricitabine were similar across all of the ages studied (22 months to 17 years).17 Based on the results from this study, a dose of 6 mg/kg QD up to a maximum of 240 mg per day was predicted to produce plasma drug exposure comparable to adults receiving the approved dose of 200 mg QD. Having identified a pediatric dose, this phase 2 trial was conducted in HIV-infected children to obtain long-term safety and efficacy data for regimens containing emtricitabine in HIV-1 infected pediatric subjects <18 years old and to confirm the recommended pediatric dose of 6 mg/kg QD.


   METHODS
TOP
 ABSTRACT
 METHODS
RESULTS
 DISCUSSION
 REFERENCES
 
Study Population
Prospective subjects had to be 3 months to 17 years of age with a documented HIV-1 infection and CD4+ cell count ≥200 cell per mm3. Plasma HIV-1 RNA criteria for study entry was between 5000 and 600000 copies per mL in antiretroviral therapy (ART)-naïve subjects and ≤400 copies per mL in ART-experienced subjects. Naïve patients were allowed to have received ≤56 days of previous antiviral therapy for perinatal HIV prophylaxis, whereas experienced subjects had to have been stable on a lamivudine-containing regimen for ≥3 months before screening. Subjects were excluded from the study if they had a life expectancy of <12 months, had experienced a new Centers for Disease Control and Prevention clinical category C diagnosis in the 12 months before study entry, or had an acute and serious medical event within 30 days before enrollment.

This study was conducted at 12 study centers in Mexico (n = 1), Panama (n = 1), South Africa (n = 2), and the United States (n = 8). The institutional review board or ethics committee at each center approved the study protocol and the written informed consent form before initiation of the study at that center. Before any study-related procedures were performed, the informed consent form was reviewed, signed, and dated by the subject's parent(s) or legal guardian(s) and, if age appropriate, the subject themselves, as well as the person who administered the consent process.

Study Design
This was a phase 2, open-label, nonrandomized, multicenter clinical study designed to evaluate the safety, pharmacokinetics, and efficacy of emtricitabine in combination with other antiretroviral agents in ART-naïve and ART-experienced pediatric HIV-infected subjects. Subjects were enrolled by age groups as follows: age group 1 (3–24 months), age group 2 (25 months to 6 years), age group 3 (7–12 years), and age group 4 (13–17 years).

After study entry, visits were scheduled at weeks 2 and 4 and then every 4 weeks through week 48 and every 12 weeks thereafter until the last enrolled subject completed 96 weeks of treatment. Laboratory analysis (hematology, chemistry, and urinalysis panels) was obtained at baseline, every 4 weeks through week 24, every 8 weeks through week 48, and every 12 weeks thereafter. Blood samples for the determination of plasma HIV RNA levels were obtained at baseline, every 4 weeks through week 48, and every 12 weeks thereafter. CD4+ lymphocyte counts were obtained at baseline and every 12 weeks thereafter. Aliquots of plasma for possible determination of viral genotype/phenotype were obtained from all of the subjects at each visit and archived.

For subjects enrolled in Mexico, Panama, and the United States, plasma HIV-1 RNA levels were measured by using the standard (limit of quantitation of 400 copies per mL) and ultrasensitive (limit of quantitation of 50 copies per mL) reverse-transcriptase polymerase chain reaction (PCR) assay Amplicor HIV-1 Monitor test 1.0 (Roche Molecular Systems, Branchburg, NJ). For subjects enrolled in South Africa, screening viral load was measured using both the 1.0 and 1.5 versions of the Amplicor HIV-1 Monitor test assay. If the difference in results between the 2 assay versions was ≥0.7 log10 copies per mL, the subject was followed throughout the study using the version 1.5 assay; otherwise the version 1.0 assay was used.

A full pharmacokinetic evaluation was obtained for the first 6 to 8 subjects enrolled in each age group. After 2 weeks of dosing, blood samples were collected over a 24-hour interval (predose and 1, 2, 8, 12, and 24 hours postdose). Plasma concentrations of emtricitabine were determined by a validated liquid chromatography-tandem mass spectroscopy method with a lower limit of sensitivity of 5 ng/mL.18 Pharmacokinetic analysis was conducted by noncompartmental pharmacokinetic methods using WinNonlin (Professional version 3.3, Pharsight Corporation, Mountain View, CA).

Each subject was closely monitored for the development of clinical and/or laboratory abnormalities, including HIV-related clinical events, throughout the study. Clinical and laboratory abnormalities were evaluated using the Division of AIDS toxicity tables for grading the severity of adverse events in children and adolescents (April 1994).

Study Regimen
Emtricitabine was supplied as a cotton candy-flavored, sweetened, alcohol-free oral solution (10 mg/mL) and/or as 200-mg hard gelatin capsules and administered at a dose of 6 mg/kg QD (up to a maximum of 240 mg QD using the oral solution formulation or as one 200-mg capsule for children >33 kg and able to swallow solid medicine). The oral solution dose was selected to produce plasma levels similar to those in adults receiving the recommended 200-mg QD dose with a minimum area under the plasma concentration-time curve over the 24-hour dosing interval (AUC{tau}) of ≥6 h*µg/mL (10th percentile of the adult area under the plasma concentration-time curve given 200 mg QD) regardless of the age group.18 Adherence was measured by pill count or by weighing individual bottles of oral solution at each clinic visit.

In addition to emtricitabine, ART-naïve subjects received stavudine plus lopinavir or ritonavir. Stavudine (Zerit, Bristol-Myers Squibb, Princeton, NJ) was supplied as a 1.0-mg/mL oral solution or as 30- and 40-mg capsules and was administered at a dose of 1 mg/mL twice daily (BID) if <30 kg, 30 mg BID if 30 to 59 kg, or 40 mg BID if ≥60 kg. Lopinavir/ritonavir (Kaletra, Abbott Laboratories, Abbott Park, IL) was supplied as either as a coformulated oral solution (80/20 mg/mL) or as coformulated capsules (133.3/33.3 mg) and was administered at a dose of 12/3 mg/kg BID if ≥7 to <15 kg, 10/2.5 mg/kg BID if ≥15 to ≤40 kg, or 400/100 mg BID if >40 kg. ART-experienced subjects replaced the lamivudine in their existing antiretroviral regimens with emtricitabine. At the investigator's discretion, ≥1 of the subject's background antiretroviral medication(s) could be replaced by different drug(s) at the same time the lamivudine was replaced with emtricitabine. All of the antiretroviral drugs were administered in dosages recommended by the respective manufacturer's package insert.

Statistical Analysis
The primary population for analysis was all of the confirmed HIV-1-infected subjects who received ≥1 dose of emtricitabine (intent to treat). No prestudy minimum sample size calculation was performed. Sixty to 120 subjects were planned for enrollment to provide sufficient data to characterize the safety, efficacy, and pharmacokinetic profile of emtricitabine in a pediatric population based on US Food and Drug Administration guidance.1

Persistent virologic response, defined as achieving and/or maintaining plasma HIV-1 RNA levels at or below the limit of assay quantitation (calculated through week 96 and week 164 [the latter was the median duration of follow-up when the last subject completed week 96]), was the primary efficacy end point. This end point followed the US Food and Drug Administration time to loss of virologic response (TLOVR) algorithm,19 which considered a subject to be a nonresponder at the earliest time point of the following events: death (all reasons), permanent discontinuation of emtricitabine, loss to follow-up, having 2 consecutive viral load values above the limit of assay quantitation after having achieved the limit of assay quantitation (loss of response), or never achieving suppression of viral load at the lower limit of assay quantitation (lack of response). Subjects who never achieved confirmed viral loads below the limit of assay quantitation before any of the above events were considered nonresponders at study day 1. All of the visits with an observed viral load while receiving emtricitabine, including off-schedule visits and visits after week 96, were used in the algorithm. Viral load was not interpolated for visits or time points with missing data. No data were collected on subjects after the termination of emtricitabine, and missing data at isolated time points were censored from all of the analyses. In this manner, all of the subjects enrolled were classified as either responders or nonresponders. For the TLOVR analysis, subjects missing data as a result of discontinuation of emtricitabine were considered nonresponders at the time of discontinuation, and any single missing value for subjects continuing in the study was ignored. Persistent virologic response was analyzed at each of the viral load assay thresholds, that is, 400 copies per mL and 50 copies per mL. Persistent virologic response at the median duration of follow-up was estimated by using Kaplan-Meier methods.

Secondary end points included virologic failure, change from baseline in median plasma HIV-1 RNA, and change from baseline in absolute and relative CD4+ cell count, genotypic resistance, clinical disease progression, treatment-limiting adverse events, and treatment-emergent grade 3 or 4 laboratory abnormalities. Virologic failure was defined as the lack or loss of response as classified by the TLOVR algorithm using the 400 copies per mL limit of assay quantitation. Similarly, in the analysis of treatment-limiting adverse events, only subjects who were classified as having an adverse event resulting in the permanent discontinuation of emtricitabine by the TLOVR algorithm were counted. The analysis of change from baseline in CD4+ cell count used observed data; thus, missing data were ignored. A sensitivity analysis was also performed using an intent-to-treat analysis with the last CD4+ cell count observation carried forward to week 96. To correct for the effect of the natural decline of CD4+ cells as a child develops, an age-adjusted analysis of the change from baseline in absolute CD4+ cell count and percentage of CD4+ measurements was performed by using the reference ranges for a healthy normal pediatric population (Quest Diagnostics, Inc, Van Nuys, CA). Clinical disease progression was defined as a development of a new clinical event included in category C of the 1993 classification of the Centers for Disease Control and Prevention20 or death because of any cause. In addition, the analyses of safety data are presented as annualized incidence rates (AIRs). The AIR is calculated based on the total person-years of exposure and presented as the number of new events per 100 subjects. Gilead Sciences performed all of the statistical analyses by using SAS software 8.2 (SAS Institute, Inc, Cary, NC).

Genotypic Analysis
Genotypic analysis was performed on paired plasma samples (baseline and time of failure) from subjects who experienced virologic failure during treatment. HIV-1 RNA extracted from plasma served as the template for amplification of the protease and reverse transcriptase genes. Viral RNA was extracted, reverse transcribed, and the complementary DNA amplified by nested PCR.

The prepared PCR product was used as the template in a fluorescence-based cycle-sequencing reaction. Dideoxy sequencing was performed by using the ABI 377/3100 sequencing system using labeled dye terminators following standard techniques (Applied Biosystems Inc, Foster City, CA). Analysis of the sequence fragments was performed with the Sequencher DNA sequencing program (Genes Codes Corp, Inc, Ann Arbor, MI), and the resulting HIV amino acid sequence was compared with a clade B consensus to determine amino acid changes. HIV-1 reverse transcriptase mutations associated with drug resistance were defined according to the Resistance Collaborative Group definition.21 Resistance to protease inhibitors was defined as any change at codon positions: D30, V32, M36, M46, I47, G48, I50, I54, A71, G73, V77, V82, I84, N88, and L90. Resistance to stavudine was defined as the presence of V75 T/M/A mutations or the presence of thymidine analog mutations, defined as amino acid changes at positions M41, D67, K70, L210, T215, or K219. Resistance to emtricitabine was defined as the presence of the M184V/I mutations.


   RESULTS
TOP
 ABSTRACT
 METHODS
 RESULTS
DISCUSSION
 REFERENCES
 
Subjects were recruited from 12 clinical sites in 4 countries: United States, Panama, Mexico, and South Africa. Of the 211 subjects screened for participation in the study, 117 subjects were eligible and enrolled between February 7, 2001, and June 3, 2003 (Fig 1). Data for 1 subject who was not HIV infected and enrolled in error was censored and are not included in the analysis. Therefore, the intent-to-treat population included 116 subjects enrolled into 4 age groups as follows: 16 subjects in age group 1 (3–24 months), 68 subjects in age group 2 (25 months to 6 years), 29 subjects in age group 3 (7–12 years), and 3 subjects in age group 4 (13–17 years).


Figure 1
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  		FIGURE 1 Flow of subjects through the FTC-203 study (median follow-up of 164 weeks).

 
Demographic and baseline characteristics are presented in Table 1. Eighty-seven percent of the subjects completed 96 weeks of therapy, corresponding with a discontinuation rate of 13%. The median duration of follow-up was 164 weeks (ie, >3 years) at the time the last subject completed the week 96 visit with a cumulative exposure of 344 person-years. Reflecting the age of the study population at study enrollment, the majority of subjects (104 of 116 [89%]) received the oral solution formulation of emtricitabine.


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  		TABLE 1 Demographic and Other Baseline Characteristics by Antiretroviral Therapy Stratum and Overall

 
Efficacy
At week 96, the proportion of subjects with persistent virologic response of ≤400 copies per mL was 84% (89% for the ART-naïve group and 76% for the ART-experienced group). Similarly, 72% of subjects also achieved or maintained suppression of plasma HIV-1 RNA to ≤50 copies per mL (75% for the ART-naïve group and 67% for the ART-experienced group; Table 2).


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  		TABLE 2 Summary of Time to Loss of Virologic Response-Defined Outcome Through Week 96 by Antiretroviral Therapy Stratum and Overall

 
At the median follow-up of 164 weeks, the Kaplan-Meier probability of persistent virologic response ≤400 copies per mL was 74% (Fig 2). The probability of persistent virologic response ≤50 copies per mL was 62% overall (71% for the ART-naïve group and 50% for the ART-experienced group; Fig 2). There were no differences or trends in efficacy response related to age group.


Figure 2
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  		FIGURE 2 Kaplan-Meier probability of persistent virologic response at 400 and 50 copies per mL (all available data). The percentages presented in the curves include those subjects who have not yet reached the lower limit of assay detection, as well as those who have achieved it and are maintaining it, until the point of failure. If subjects did not achieve the lower limit of assay detection and did not discontinue therapy for some other reason, they were classified as nonresponders having virologic failure at day 1, which accounts for the curves dropping to <100% at day 1. The median duration of follow-up at the time the last subject completed the week-96 visit was 164 weeks.

 
The median change from baseline to last visit in absolute CD4+ cell count and CD4+ percent were +123 cells per mm3 (range: –206 to 408 cells per mm3) and +7.5% (range: 1.2%–13.0%), respectively. Analyses of T-cell repopulation in groups of children with different ages are confounded by the fact that CD4+ T-cell counts are highly dependent on the age of the patients and significantly decrease with age.22,23 The results of the age-adjusted analysis showed an increase or no change in CD4+ cell count and percentage in 95% and 94% of the subjects, respectively (data not shown). Because lymphocyte subpopulation counts in children are age dependent, the median change in percentage of CD4+ T cells is more appropriate to assess the therapeutic effect.24 Median change in the percentage of CD4+ was +7.5% in the overall population, showing the preservation of CD4+ cells. This immunologic benefit was confirmed clinically by the lack of HIV clinical progression with 98% (114 of 116) of the subjects not developing any category C HIV-related events during the course of the study.

Genotypic Analysis
Genotypic analysis was performed on 15 subjects (13%) who met the TLOVR criteria of virologic failure (6 in the ART-naïve group and 9 in the ART-experienced group; Table 3). Among the 6 ART-naive subjects, the samples collected at baseline were all found to contain wild-type virus. At the time of virologic failure, 4 of the subjects developed the M184V mutation alone, which confers resistance to emtricitabine.


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  		TABLE 3 Genotypic Analysis of Viral Samples From Subjects Who Were Time to Loss of Virologic Response-Defined Virologic Failures by Antiretroviral Therapy Stratum

 
Among the 9 ART-experienced subjects, 3 subjects harbored the M184V mutation with the other nucleoside reverse transcriptase inhibitor, nonnucleoside reverse transcriptase inhibitor, and/or protease inhibitor-specific mutations at baseline. At the time of virologic failure, the M184V mutation was present in the samples collected from 5 of the 9 subjects. In 3 of the 5 subjects, the mutation was present at baseline, whereas genotypic data were not available for the 2 remaining subjects at baseline.

Safety and Tolerability
The AIR of the most frequent (≥10%) adverse events is summarized in Table 4. Skin discoloration, which typically presented as small, asymptomatic maculae on the palms or soles, was reported in 45 subjects, giving an AIR of 13%. With 1 exception, assessed as moderate (grade 2) in severity, all of the skin discoloration cases were assessed as mild (grade 1) in severity; no pathologic skin condition or other systemic condition was associated with the skin discoloration, and it did not require interruption or discontinuation of study treatment. Median time to onset was 113 days, ranging from 20 to 307 days. There was no apparent contribution of concomitant medications to the development of skin discoloration, although 2 of the children were also taking zidovudine, which has also been associated with skin discoloration.25–32


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  		TABLE 4 Annual Incidence Rates (%) of the Most Frequent (≥10%) Adverse Events by Antiretroviral Therapy Stratum and Overall

 
A multivariable logistic regression model was used to evaluate the association of several possible factors (demographic factors: gender, race, and age, and baseline characteristics: weight, height, CD4+, and HIV-1 RNA) with the incidence of skin discoloration in children enrolled in this study and 1 other emtricitabine pediatric study (FTC-211; data on file). Living in South Africa was found to be the only factor significantly associated with the development of skin discoloration.

The AIR of grade 3 or 4 (severe or life-threatening) adverse events was 5.5%, with 1.5% attributed as related to emtricitabine. The most frequent grade 3 or 4 adverse events regardless of the causality were pneumonia (AIR: 1.5%) and leukopenia (AIR: 1%). Overall, there were few adverse events assessed as grade 3 or 4 and of probable or possible relationship to emtricitabine: leukopenia (AIR: <1%), anemia (AIR: <1%), gastroenteritis (AIR: <1%), and pancreatitis (AIR: <1%).

Overall, 30 subjects experienced ≥1 serious adverse event (SAE) through the median follow-up of 164 weeks. The AIR of SAEs was 8.7%, with 1.2% assessed by the investigators as related to emtricitabine. The most frequent SAEs regardless of the causality were pneumonia (AIR: 2.9%), hepatitis A (AIR: 1.5%), accidental injury (AIR: 0.9%), abscess (AIR: 0.9%), and pharyngitis (AIR: 0.9). The SAEs reported to be at least possibly related to emtricitabine were anemia (AIR: 0.3%), gastroenteritis (AIR: 0.3%), and pancreatitis (AIR: 0.6%). The AIR of grade 3 or 4 laboratory abnormalities was 2.9%, with the most frequent abnormalities being increased alanine aminotransferase (AIR: 0.9%), leukopenia (AIR: 0.6%), increased amylase (AIR: 0.6%), and increased bilirubin (AIR: 0.6%).

Treatment-Limiting Adverse Events
The AIR of adverse events that led to the permanent discontinuation of emtricitabine was 0.9%. Four adverse events in 3 subjects resulted in permanent discontinuation of emtricitabine: a grade 3 anemia and 2 episodes of pancreatitis that were each assessed as possibly related to emtricitabine and acute myeloid leukemia, which was considered remotely related to emtricitabine and resulted in the death of the subject.

Pharmacokinetic Results
Pharmacokinetic data were available from 35 children: 14 of 16 subjects in age group 1, 9 of 68 subjects in age group 2, 9 of 29 subjects in age group 3, and 3 of 3 subjects in age group 4 (Table 5). In general, drug exposure achieved in the children was comparable to that reported in various adult studies.18


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  		TABLE 5 Median (Range) if Emtricitabine Pharmacokinetic Parameters at Steady State by Age Group

 

   DISCUSSION
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
REFERENCES
 
Van Rossum et al,3 in an overview of HIV-1 pediatric clinical trials published in the scientific literature, concluded that the efficacy response rates in the majority of pediatric trials were inferior to those in adults. In this study, emtricitabine administered QD in combination with other antiretroviral drugs showed good tolerability and robust and durable antiviral efficacy in HIV-1–infected children. The proportions of children maintaining complete viral suppression (≤50 copies per mL) were 76%, 72%, and 64% at a median follow-up of 48, 96, and 164 weeks, respectively. The response rates for the children enrolled in this study were comparable with those observed in clinical trials of the same regimen (emtricitabine with lopinavir or ritonavir and stavudine) in adults,33,34 as well as in clinical trials of emtricitabine administered in combination with didanosine and efavirenz in a full QD regimen in adults.11–13,35 In addition, virologic response rates were consistent with those observed in 2 other pediatric trials using emtricitabine administered in combination with didanosine and efavirenz36 (Study FTC-211, data not shown). Through 204 weeks of therapy (median: 164 weeks), the incidence of virologic failure observed in this study was 13% (15 of 116), and the emergence of the M184V mutation was 3% (4 of 116), which is consistent with that seen in our adult program.14,35

Pharmacokinetic parameters (low or inadequate plasma blood levels) may be also associated with virologic failure in HIV-infected infants and children. In our study 17% (6 of 35) of children did not achieve the target AUC{tau} threshold of 6 µg/mL. However, only 1 subject (AUC{tau} = 5.99 h*µg/mL) was discontinued as a virologic failure, and retrospective analysis found this subject to have the M184V mutation at baseline. An association between virologic failure and plasma emtricitabine exposure was not seen in this study. This is not surprising, because intracellular emtricitabine triphosphate is the active antiviral form of the drug and has a considerably longer half-life compared with emtricitabine in plasma (39 hours vs 8–10 hours).18

In making a final recommendation for the dosing of emtricitabine in pediatric subjects, the 20% decreased bioavailability of the oral solution was taken into consideration.17 The pediatric dosage recommendation is that subjects should take emtricitabine solution at the recommended dose of 6 mg/kg QD up to a maximum of 240 mg and that subjects weighing >33 kg and able to swallow pills may take 1 emtricitabine 200-mg capsule QD. This recommendation allows subjects to switch to the capsule formulation as early as possible or to remain on oral solution if ingestion of the capsule is difficult for the child.

Emtricitabine was well tolerated in this pediatric population, which ranged in age from 3 months to ~16 years of age. With the majority of the patients enrolled living in developing nations, most adverse events occurring during the study were consistent with the ailments and health issues that would be expected for this patient population.

Notwithstanding the above, the safety profile of emtricitabine was similar to that observed in other long-term clinical trials of emtricitabine capsules in adults.14,35 However, skin discoloration was reported more frequently in these children than has been observed in adults.37 Thirty-nine black subjects in South Africa and a few black subjects (n = 3) in the United States reported skin discoloration. Skin discoloration was a mild cosmetic finding, akin to the skin and nails pigmentation abnormalities observed in black subjects treated with zidovudine,25–32 and did not require discontinuation of study medication.

To our knowledge, we reported the first prospective study that presents long-term follow-up (ie, >3 years of treatment) of efficacy and safety results in HIV-infected children who received highly active ART. Furthermore, we have shown that emtricitabine-based regimens consistently demonstrated efficacy and good tolerance over these ≥3 years of therapy with a small rate of discontinuations and virologic failure.

As HIV becomes a treatable chronic disease, it is becoming important to take a long-term strategic approach to initial and subsequent ART. This study supports the use of emtricitabine as an initial and long-term treatment for pediatric HIV-infected subjects.


   ACKNOWLEDGMENTS
 
We thank of the investigators and their staff comprising the FTC-203 Study Group: Kenneth Boyer, Chicago, IL; Patricia Flynn, Memphis, TN; Andrea Kovacs, Los Angeles, CA; Sharon Nachman, Stony Brook, NY; Ana Puga, Fort Lauderdale, FL; Joseph Stavola, New York, NY; Andrew Wiznia, Bronx, NY; Ram Yogev, Chicago, IL; Miguel Cashat, Mexico City, Mexico; Xavier Saez-Llorens, Panama City, Panama; Maria Mercedes Castrejon, Panama City, Panama; Avy Violari, Soweto, South Africa; and Dalubuhle Ndiweni, Johannesburg, South Africa.

We thank the patients and their parents for agreeing to their participation in this study.


   FOOTNOTES
 
Accepted Aug 20, 2007.

Address correspondence to Franck Rousseau, MD, Gilead Sciences Inc, 4 University Place, 4611 University Dr, Durham, NC 27707. E-mail: maria.powell{at}gilead.com

Financial Disclosure: Dr Wiznia is a consultant to Gilead Sciences, Inc.


What's Known on This Subject

It is known that there is limited long-term follow-up of efficacy and safety results in HIV-infected children who received highly active antiretroviral therapy. The efficacy response rates in the majority of pediatric trials were inferior to those in adults.

 

What This Study Adds

The study provides long-term safety and efficacy data for antiretroviral regimens containing emtricitabine in HIV-infected pediatric subjects. These results demonstrate that emtricitabine has a safety and efficacy profile in children similar to that demonstrated in adults.

 


   REFERENCES
TOP
 ABSTRACT
 METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

  1. Food and Drug Administration. Regulations Requiring Manufacturers to Assess the Safety and Effectiveness of New Drugs and Biological Products in Pediatric Patients; pp66631 –66672[FR Doc. 98–31902] OC 98142, Docket No. 97N-0165. Available at: www.fda.gov/cder/guidance/pedrule.htm. Accessed February 6, 2008
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PEDIATRICS (ISSN 1098-4275). ©2008 by the American Academy of Pediatrics




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