Original Article
Combination Therapy with Efavirenz, Nelfinavir, and Nucleoside Reverse-Transcriptase Inhibitors in Children Infected with Human Immunodeficiency Virus Type 1
N Engl J Med 1999; 341:1874-1881December 16, 1999
- Abstract
Background
Consistent long-term viral suppression has been difficult to achieve in children with human immunodeficiency virus type 1 (HIV-1) infection. We tested the safety and antiviral efficacy of a novel combination consisting of efavirenz, nelfinavir, and one or more nucleoside reverse-transcriptase inhibitors in 57 children previously treated with only nucleoside reverse-transcriptase inhibitors.
Methods
The children were monitored for 48 weeks after the initiation of therapy. We assessed plasma concentrations of efavirenz and nelfinavir, plasma HIV-1 RNA levels, and lymphocyte subpopulations.
Results
At base line, the 57 HIV-1–infected children (age range, 3.8 to 16.8 years) had a median of 699 CD4 cells per cubic millimeter and 10,000 copies of HIV-1 RNA per milliliter of plasma. The most common treatment-related effects of at least moderate severity were rash (in 30 percent of children), diarrhea (in 18 percent), neutropenia (in 12 percent), and biochemical abnormalities (in 12 percent). Serious side effects were uncommon. The mean values for the area under the curve for efavirenz and nelfinavir corresponded to expected values. In an intention-to-treat analysis, 76 percent of children had plasma HIV-1 RNA levels of less than 400 copies per milliliter after 48 weeks of therapy and 63 percent had levels of less than 50 copies per milliliter. A high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma levels of HIV-1 RNA would become undetectable during treatment.
Conclusions
In HIV-1–infected children who were previously treated with nucleoside reverse-transcriptase inhibitors, the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was generally well tolerated and had a potent and sustained antiviral effect.
Media in This Article
Figure 2
Percentage of Children with Plasma HIV-1 RNA Levels of Less Than 50 Copies per Milliliter, According to an Analysis in Which Only the HIV-1 RNA Levels of Children Who Were Receiving Treatment Were Included (Analysis of Actual Treatment), an Intention-to-Treat Analysis, and an Analysis in Which HIV-1 RNA Levels Were Assigned a Value of More Than 50 Copies per Milliliter for All Visits after the Discontinuation of Treatment (Conservative Analysis).Figure 3
Median Absolute Changes from Base Line in the Percentage of CD4 Cells and Plasma HIV-1 RNA Levels, According to an Analysis in Which Only the Values in Children Who Were Receiving Treatment Were Included.Article Activity
- Article
A major objective of antiretroviral therapy is to reduce the amount of human immunodeficiency virus type 1 (HIV-1) RNA in plasma to undetectable levels, because these levels appear to reflect the degree of viral replication in the body. Even low levels of replication may contribute to the emergence of resistant strains of HIV-1. Studies of highly active antiretroviral therapy have generally yielded less impressive results in HIV-infected children than in infected adults. In small studies of combinations that included a protease inhibitor in children who had previously been treated with nucleoside reverse-transcriptase inhibitors, plasma HIV-1 RNA levels decreased to undetectable levels (less than 400 copies per milliliter) in 39 to 78 percent, but subsequently rebounded in 20 to 44 percent.1-5 In another study, only two of eight HIV-1–infected infants had undetectable plasma HIV-1 RNA levels after combination therapy with zidovudine, didanosine, and nevirapine.6 Clearly, other promising antiretroviral combinations need to be tested in children.
Efavirenz, a new nonnucleoside reverse-transcriptase inhibitor, has good oral bioavailability and a long terminal half-life, permitting once-daily dosing.7,8 We tested efavirenz in combination with a protease inhibitor in children, the majority of whom were receiving one or more nucleoside reverse-transcriptase inhibitors, in accordance with recommendations that at least two new antiretroviral drugs be added to an existing regimen.9 Nelfinavir was selected as the protease inhibitor because it is available in a pediatric formulation, has approved dosing recommendations for children older than two years of age, and has no pharmacokinetic interactions with efavirenz.10
Methods
Study Design
This open-label study was conducted at 18 Pediatric AIDS Clinical Trials Group (PACTG) sites. Eligibility criteria included an age of less than 16 years, a plasma HIV-1 RNA level of more than 400 copies per milliliter on measurement with a quantitative RNA reverse-transcriptase–polymerase chain reaction assay (Amplicor HIV-1 Monitor assay, Roche Diagnostic Systems, Branchburg, N.J.), no previous treatment with nonnucleoside reverse-transcriptase inhibitors or protease inhibitors, concomitant treatment with at least one nucleoside reverse-transcriptase inhibitor, and the ability to swallow capsules. The children were enrolled between October 27, 1997, and February 12, 1998.
Efavirenz (Sustiva, Dupont Pharmaceuticals, Wilmington, Del.) was provided by the manufacturer in 50-mg, 75-mg, and 100-mg capsules. Nelfinavir (Viracept, Agouron Pharmaceuticals, La Jolla, Calif.) was provided by the manufacturer in tablet (250 mg) and powder (50 mg per gram) form. The initial doses of efavirenz were allometrically scaled to body size according to the following formula: the dose (in milligrams per day)=(the weight of the child in kilograms ÷ 70)0.7 × 600. The doses were rounded to the nearest 25-mg increment. Efavirenz was given daily in the morning. The initial dose of nelfinavir was the recommended pediatric dose of 20 to 30 mg per kilogram of body weight thrice daily. At entry, the children continued to take the same nucleoside reverse-transcriptase inhibitors or were switched to new ones, at the discretion of the site investigators.
The doses of efavirenz and nelfinavir were adjusted if the area under the curve was too small. The target value for the area under the curve from 0 to 24 hours was 190 to 380 μmol per liter · hour for efavirenz, representing the range from the 50th percentile to twice the 50th percentile of such values in adults receiving 600 mg per day of efavirenz. This target value was selected to help ensure that therapeutic levels would be achieved in this pediatric study. For nelfinavir, the target value for the area under the curve from zero to eight hours was 10 mg per liter · hour, the 10th percentile for adults receiving 750 mg of nelfinavir thrice daily. The areas under the curve for efavirenz and nelfinavir were determined at weeks 2 and 6 and again at week 10, if necessary. Blood samples were obtained before a dose and 2, 5, 6, 8, 12, and 24 hours after a dose. If target values for the area under the curve were not achieved, the doses of efavirenz, nelfinavir, or both were adjusted proportionally.
History taking and physical examinations were performed at base line; at weeks 2, 4, 6, and 8; and every four weeks thereafter. A complete blood count and differential count were obtained and blood chemical analysis and urinalysis were performed at base line and at weeks 2, 4, 8, 12, 16, 20, 24, 32, 40, and 48. Specimens for the determination of plasma HIV-1 RNA levels and lymphocyte subpopulations were obtained at base line and at weeks 2, 4, 8, 12, 20, 32, 40, and 48.
We used the Division of AIDS Toxicity Table to grade the severity of adverse effects. A grade of 0 indicates the absence of adverse effects; a grade of 1 indicates mild adverse effects, a grade of 2 moderate effects, a grade of 3 severe effects, and a grade of 4 life-threatening effects. Treatment was discontinued if a child had grade 4 effects, repeated grade 3 effects, or poor compliance, defined as consumption of less than 80 percent of the doses of efavirenz or nelfinavir over a one-month period. Virologic failure was defined as a reduction in plasma HIV-1 RNA levels of less than 1 log (on a logarithmic [base 10] scale) by week 12, HIV-1 RNA levels of more than 1000 copies per milliliter on two successive measurements in children whose levels had been less than 400 copies per milliliter, or HIV-1 RNA levels that were more than 0.75 log copies above the nadir value on two successive occasions in children whose plasma HIV-1 RNA levels had remained detectable.
The institutional review boards at each site approved the study. Written informed consent was obtained from the parents or guardians of all children.
Measurement of Plasma Efavirenz and Nelfinavir Concentrations
Concentrations of efavirenz and nelfinavir in plasma were measured by high-performance liquid chromatography. The total variability (expressed as a composite of within-day and day-to-day variability) of the efavirenz and nelfinavir assays was 1 to 4.5 percent and 1.7 to 10.3 percent, respectively.
Determination of Lymphocyte Subpopulations and Quantitation of Plasma HIV-1 RNA
The percentages and absolute numbers of CD4 cells were determined in PACTG-certified laboratories according to the PACTG consensus protocol for flow cytometry.11 Plasma was stored at –70°C, and HIV-1 RNA was measured with a quantitative assay (Amplicor, Roche Diagnostic) with a lower limit of quantitation of 400 copies per milliliter. Samples containing less than 400 copies per milliliter were tested with an ultrasensitive assay with a lower limit of quantitation of 50 copies per milliliter. All RNA assays were performed in a single PACTG-certified laboratory.
Statistical Analysis
Primary efficacy was assessed on the basis of plasma HIV-1 RNA levels. For each child, a series of composite HIV-1 RNA measures was constructed as follows: the result of the quantitative assay was used, unless it was less than 400 copies per milliliter or was not available, in which case the result of the ultrasensitive assay was used. Log-transformed values were used for analyses.
Three types of analysis were used to evaluate primary efficacy: an analysis according to the intention to treat, in which all HIV-1 RNA levels were included, regardless of whether a child was still receiving drugs; an analysis in which only the HIV-1 RNA levels of children who were receiving treatment were included; and an analysis in which HIV-1 RNA levels were assigned a value of more than 400 copies per milliliter for all visits after the discontinuation of treatment (or a value of more than 50 copies per milliliter with the use of the ultrasensitive assay). Missing HIV-1 RNA values were assigned as a value of more than 400 copies per milliliter (or more than 50 copies per milliliter) if the first value preceding or following the missing value exceeded 400 (or 50) copies per milliliter. No value was imputed for a missing result if preceding and succeeding values were both less than 400 or less than 50 copies per milliliter.
We calculated exact 95 percent confidence intervals for the percentage of children with a virologic response at each visit, assuming a binomial distribution. We determined the median change in plasma HIV-1 RNA levels from base line and corresponding 95 percent confidence intervals according to the method of Brookmeyer and Crowley, in which HIV-1 RNA levels below the limit of detection were treated as censored observations.12
All other analyses used an intention-to-treat approach unless otherwise noted. The times to various outcomes were estimated according to the Kaplan–Meier method.13 We used the Cox proportional-hazards regression model to estimate relative risks and corresponding 95 percent confidence intervals.14 We used a stepwise proportional-hazards model to assess the relative importance of risk factors in predicting the likelihood that plasma HIV-1 RNA levels would become undetectable. Weight measurements were converted to z scores after adjustment for age and sex.15 The effect of treatment on CD4 measures was examined with use of the Wilcoxon signed-rank test (pairwise comparison), and the one-sample application of the Wei–Johnson test, in which components of the global test statistic were weighted by reciprocals of variances of the test statistic at each time.16 The 95 percent confidence intervals for the median changes in the absolute numbers and percentages of CD4 cells were based on order statistics.17 The Wilcoxon rank-sum test was used to compare the duration of rash between children.18 All reported P values are two-sided.
Results
Base-Line Characteristics
The base-line characteristics of the 57 children who were enrolled in the study are shown in Table 1Table 1
Base-Line Characteristics of the 57 Children in the Study.. Before enrollment, 55 children were receiving one or more nucleoside reverse-transcriptase inhibitors. Thirty-four children (60 percent), including 2 who were not already receiving nucleoside reverse-transcriptase inhibitors, began to receive at least one new nucleoside reverse-transcriptase inhibitor within two weeks after study entry, 21 (37 percent) had no change in their regimen of nucleoside reverse-transcriptase inhibitors, and 2 (4 percent) had one nucleoside reverse-transcriptase inhibitor dropped from their regimen.Adverse Effects
Twenty-six children (46 percent) had either no adverse effects or no more than mild effects, 25 (44 percent) had no more than moderate effects, 5 (9 percent) had severe effects, and 1 (2 percent) had a life-threatening adverse effect. The most common adverse effects of at least moderate severity were rash (17 children; 30 percent), diarrhea (10 children; 18 percent), neutropenia (7 children; 12 percent), and biochemical abnormalities (7 children; 12 percent). Most rashes (88 percent) appeared within 14 days after the initiation of study treatment (median, 9; range, 6 to 205) and lasted for a median of 6 days (range, 2 to 37). Most rashes were maculopapular and pruritic. One child had target lesions juxtaposed with a maculopapular rash, and two children had urticarial lesions. None of the children with a moderate rash were febrile at the time of the rash, and none had mucous-membrane involvement. Severe adverse effects consisted of neutropenia in two children and hepatic toxicity, diarrhea and neutropenia, and rash with fever (temperature, >39°C) in one child each. The only life-threatening adverse effect was neutropenia in a child with concurrent varicella. Central nervous system toxicity was uncommon. Eight children had mild dizziness or lightheadedness that resolved once efavirenz was given at bedtime rather than in the morning.
Treatment was discontinued in 14 children. One child was found to be ineligible owing to prior use of nevirapine. Another was unable to take efavirenz capsules. Treatment was discontinued at the request of the parent, guardian, or investigator in four children in whom a moderate rash developed and, as specified by the protocol, in one child who had a severe rash. None of these children resumed treatment after the rash resolved. The median duration of rash in the children who discontinued treatment was six days, as compared with nine days in those who continued treatment (P=0.14). Other reasons for discontinuation were virologic failure (six children) and noncompliance (one child).
Pharmacokinetic Evaluations
Pharmacokinetic evaluations of efavirenz and nelfinavir were performed on 50 children at weeks 2 and 6. At week 2, the mean dose of efavirenz was 310 mg per day (11.7 mg per kilogram per day), and the mean value for the area under the curve from 0 to 24 hours was 218 μmol per liter · hour. One child was excluded from the analysis because of apparently reduced clearance (a value of 1313 μmol per liter · hour for the 24-hour area under the curve). On the basis of the evaluations at week 2, increased doses of efavirenz were recommended for 22 children and decreased doses were recommended for 3 children. The average dose of efavirenz was 369 mg per day (14.2 mg per kilogram per day), and the average value for the 24-hour area under the curve was 244 μmol per liter · hour at week 6. On the basis of the evaluations at week 6, increased doses of efavirenz were recommended for nine children, and decreased doses were recommended for six children. An intention-to-treat analysis showed that values for the 24-hour area under the curve were within the target range in 44 percent of children (22 of 50) at week 2 and 56 percent (28 of 50) at week 6.
The average doses of nelfinavir were 606 mg given three times a day (23.6 mg per kilogram) at week 2 and 631 mg given three times a day (24.6 mg per kilogram) at week 6. The corresponding mean values for the area under the curve from zero to eight hours were 21.6 mg per liter · hour at week 2 and 19.9 mg per liter · hour at week 6. On the basis of the evaluations at week 2 and week 6, the doses of nelfinavir were increased in two children and one child, respectively. Seventy-four percent of children (37 of 50) had values for the eight-hour area under the curve above the target range at week 2, and 80 percent (40 of 50) had such values at week 6. On the basis of evaluations performed at week 10 in 15 children, the doses of efavirenz were increased in 5 children and decreased in 1, and the dose of nelfinavir was increased in 1 child.
Effect of Treatment on Plasma HIV-1 RNA Levels
The percentage of children with plasma HIV-1 RNA levels of less than 400 copies per milliliter rose rapidly after the initiation of treatment and remained stable from week 8 to week 48 in the intention-to-treat analysis, the analysis in which only the HIV-1 RNA levels of children who were receiving treatment were included, and the analysis in which HIV-1 RNA levels were assigned a value of more than 400 copies per milliliter for all visits after the discontinuation of treatment (Figure 1Figure 1
Percentage of Children with Plasma HIV-1 RNA Levels of Less Than 400 Copies per Milliliter, According to an Analysis in Which Only the HIV-1 RNA Levels of Children Who Were Receiving Treatment Were Included (Analysis of Actual Treatment), an Intention-to-Treat Analysis, and an Analysis in Which HIV-1 RNA Levels Were Assigned a Value of More Than 400 Copies per Milliliter for All Visits after the Discontinuation of Treatment (Conservative Analysis).). After the exclusion of 2 children who discontinued treatment shortly after entry, we found that 50 of 55 children (91 percent) had decreases in plasma HIV-1 RNA levels to less than 400 copies per milliliter. Eight of these 50 children (16 percent) subsequently fulfilled the criteria for virologic failure. At week 48, the percentage of children with plasma HIV-1 RNA levels of less than 400 copies per milliliter was 81 percent in the analysis in which only the HIV-1 RNA levels of children who were receiving treatment were included, 76 percent in the intention-to-treat analysis, and 61 percent in the analysis in which HIV-1 RNA levels were assigned a value of more than 400 copies per milliliter for all visits after the discontinuation of treatment.The proportion of children with plasma HIV-1 RNA levels of less than 50 copies per milliliter rose rapidly during the first 12 weeks of therapy and then more slowly (Figure 2Figure 2
Percentage of Children with Plasma HIV-1 RNA Levels of Less Than 50 Copies per Milliliter, According to an Analysis in Which Only the HIV-1 RNA Levels of Children Who Were Receiving Treatment Were Included (Analysis of Actual Treatment), an Intention-to-Treat Analysis, and an Analysis in Which HIV-1 RNA Levels Were Assigned a Value of More Than 50 Copies per Milliliter for All Visits after the Discontinuation of Treatment (Conservative Analysis).). At week 48, the percentage of children with plasma HIV-1 RNA levels of less than 50 copies per milliliter was 70 percent in the analysis in which only the HIV-1 RNA levels of children who were receiving treatment were included, 63 percent in the intention-to-treat analysis, and 53 percent in the analysis in which HIV-1 RNA levels were assigned a value of more than 50 copies per milliliter for all visits after the discontinuation of treatment.Plasma HIV-1 RNA levels fell dramatically during the first 20 weeks of therapy (Figure 3Figure 3
Median Absolute Changes from Base Line in the Percentage of CD4 Cells and Plasma HIV-1 RNA Levels, According to an Analysis in Which Only the Values in Children Who Were Receiving Treatment Were Included.). At both weeks 32 and 48, the upper 95 percent confidence bound for the median change was –2.7 log copies per milliliter; thus, there is a 95 percent probability that the median decrease was at least this amount at these points.Predictors of a Decrease in Plasma HIV-1 RNA to Undetectable Levels
We used Cox proportional-hazards regression models to examine the effect of base-line characteristics on the likelihood that plasma HIV-1 RNA levels would decrease to less than 400 copies per milliliter and 50 copies per milliliter during treatment (Table 2Table 2
Effects of Base-Line Characteristics on the Likelihood That Plasma HIV-1 RNA Levels Would Become Undetectable on the Quantitative Assay and the Ultrasensitive Assay.). In univariate analysis, a higher percentage of CD4 cells at base line and a higher age- and sex-adjusted z score for weight significantly increased the likelihood that plasma HIV-1 RNA levels would drop below 400 copies per milliliter, whereas only the latter variable was associated with the likelihood of a drop in HIV-1 RNA levels to less than 50 copies per milliliter. Higher plasma HIV-1 RNA levels at base line significantly decreased the likelihood that plasma HIV-1 RNA levels would become undetectable, whereas changing the regimen of nucleoside reverse-transcriptase inhibitors within two weeks after entry into the study did not have a significant effect.In models with multiple covariates, a high plasma HIV-1 RNA level at base line significantly decreased the likelihood that plasma HIV-1 RNA levels would drop below 400 copies per milliliter or 50 copies per milliliter, whereas the age- and sex-adjusted z score for weight was a significant risk factor for the failure of levels to drop below 400 copies per milliliter but not 50 copies per milliliter.
Effect of Treatment on CD4 Cells
At week 48, the CD4 cell count had increased by a median of 74 per cubic millimeter from base line (data not shown), and the absolute percentage of CD4 cells had increased by a median of 3 percent (Figure 3). When all CD4 measurements during the 48-week period were combined, the increases in median percentage and number of CD4 cells were statistically significant (global P values, 0.01 and <0.001, respectively).
Discussion
Combination therapy with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors was well tolerated by most HIV-infected children in this study. The most common treatment-related adverse effect of at least moderate severity was rash, which occurred in 30 percent of the children (17 of 57), an incidence similar to that with efavirenz therapy in HIV-infected adults.19 Only five children (9 percent), all of whom had a rash, discontinued treatment permanently because of adverse effects. One child had severe rash with a fever (temperature, >39°C) and thus fulfilled the criteria for the discontinuation of treatment. The other four children had moderate rashes and might have been able to continue treatment. Most cases of diarrhea were probably caused by nelfinavir, because diarrhea is a common side effect of nelfinavir therapy. Central nervous system symptoms were reported in 51.9 percent of adults receiving efavirenz,19 but they occurred much less frequently and were milder in the children in our study.
The mean values for the 24-hour area under the curve for efavirenz at week 2 (218 μmol per liter · hour) and week 6 (244 μmol per liter · hour) compared favorably with the mean value of 184 μmol per liter · hour in adults receiving 600 mg of efavirenz per day.19 Similarly, the mean values for the eight-hour area under the curve for nelfinavir at week 2 (21.6 mg per liter · hour) and week 6 (19.9 mg per liter · hour) were similar to the median value of 19 mg per liter · hour in children who were receiving a mean dose of 23 mg per kilogram.20
We observed potent and sustained antiviral effects in HIV-1–infected children who were treated with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors. Even in the conservative analysis in which HIV-1 RNA levels were assigned a value of more than 400 copies per milliliter for all visits after the discontinuation of treatment, 53 percent of the children had plasma HIV-1 RNA levels of less than 50 copies per milliliter at week 48. Long-term follow-up will provide important information on the durability of this antiviral effect. There was also a significant but moderate increase in the number and percentage of CD4 cells, despite the fact that most of the children had values within the normal range for age at base line.
A high viral load at base line significantly reduced the likelihood that plasma levels of HIV-1 RNA would become undetectable with treatment. The mechanisms responsible for this effect remain to be determined. A low age- and sex-adjusted z score for weight at base line, indicating poor growth, was a significant, albeit weaker, risk factor for the failure of plasma HIV-1 RNA levels to become undetectable. Previously, this marker was reported to be predictive of clinical outcome in HIV-infected children.21-23 Our analysis also showed that changing the regimen of nucleoside reverse-transcriptase inhibitors within two weeks after entry into the study did not affect the likelihood that plasma HIV-1 RNA levels would become undetectable. The plasma HIV-1 RNA levels and age- and sex-adjusted z scores for weight were similar at base line among the children whose nucleoside reverse-transcriptase inhibitors were changed and those whose nucleoside reverse-transcriptase inhibitors were not changed (data not shown). Nevertheless, these results should be interpreted with caution, since the sample may not have been large enough to demonstrate an effect.
The sustained antiviral effect observed in HIV-1–infected children who were treated with efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors appears to be similar or superior to that reported with other regimens containing a protease inhibitor.1-5 These results may be attributable, at least in part, to the fact that we studied children who were 3.8 years old or older and who had mostly normal numbers and percentages of CD4 cells and relatively low viral loads at base line. Although controlled trials will be necessary to establish the relative potency of the combination of efavirenz, nelfinavir, and nucleoside reverse-transcriptase inhibitors, it is an important addition to the antiretroviral armamentarium for HIV-1–infected children.
Presented in part at the 38th Interscience Conference on Antimicrobial Agents and Chemotherapy, San Diego, Calif., September 24–27, 1998.
Supported by the Pediatric AIDS Clinical Trials Group, by grants from the National Institute of Allergy and Infectious Diseases (AI33835, to Dr. Fletcher, and AI41110, to Ms. Yong and Dr. Fenton), by General Clinical Research Center grants from the National Center for Research Resources, by Dupont Pharmaceuticals Company, and by Agouron Pharmaceuticals.
We are indebted to the study patients and their parents and guardians for their participation; to Necia Smith and Amy Kinney for their help with protocol development and study management; to Karen Hsia for the virologic assays; and to Lane R. Bushman and Dennis Weller for performing the measurements of efavirenz and nelfinavir.
Source Information
From Children's Hospital of Philadelphia, Philadelphia (S.E.S.); the University of Minnesota, Minneapolis (C.V.F., R.C.B.); the University of California at San Diego, San Diego (S.A.S.); Harvard School of Public Health, Boston (F.H.Y.); Frontier Science and Technology Research Foundation, Brookline, Mass. (T.F.); Dupont Pharmaceuticals Company, Wilmington, Del. (D.M., N.M.R.); Agouron Pharmaceuticals, La Jolla, Calif. (M.G., M.B.); the National Institute of Allergy and Infectious Diseases, Rockville, Md. (J.M.); and the National Institute of Child Health and Human Development, Rockville, Md. (L.M.M.).
Address reprint requests to Dr. Starr at the Division of Immunologic and Infectious Diseases, Children's Hospital of Philadelphia, 34th St. and Civic Center Blvd., Philadelphia, PA 19104, or at starr@email.chop.edu.
Other participants in the study are listed in the Appendix.
Other authors were Lynette Purdue, Pharm.D., National Institute of Allergy and Infectious Diseases, Rockville, Md.; Suzanne Siminski, M.S., and Bobbie Graham, B.S., Frontier Science and Technology Research Foundation, Amherst, N.Y.; David M. Kornhauser, M.D., and William Fiske, Ph.D., Dupont Pharmaceuticals Company, Wilmington, Del.; Carol Vincent, C.R.N.P., Children's Hospital of Philadelphia, Philadelphia; Harold W. Lischner, M.D., St. Christopher's Hospital for Children, Philadelphia; Wayne M. Dankner, M.D., University of California at San Diego, San Diego; and Patricia M. Flynn, M.D., St. Jude Hospital for Children, Memphis, Tenn.
Appendix
The following institutions and persons participated in the study: Baylor–Texas Children's Hospital — C.G. Hanson, M.E. Paul, C. Owen; Bellevue Hospital; Children's Hospital of Boston — S.K. Burchett, R. Galvin, M. Chaliki; Children's Hospital of Brooklyn — H. Mendez, H. Moallem, D.M. Swindell; Children's Hospital of Philadelphia — A.L. Kamrin, D.H. Conway, D.H. Schaible; Children's Hospital and Medical Center, Seattle — K.M. Mohan, A.J. Melvin, P.F. Lewis; Howard University Hospital — S. Rana, H. Finke, P. Houston; Los Angeles County Medical Center — M. Khoury, J. Homans, A. Kovacs; Moffitt Hospital–University of California at San Francisco; San Juan City Hospital — E. Jiménez, M. Acevedo, C. Clemente; St. Jude Children's Research Hospital; Tulane University — R. Van Dyke, T. Maupin, M. Glazer; University of California at Los Angeles Medical Center; University of California at San Diego — K. Hsia, L. Stangl, M. Caffery; University of Florida Health Science Center — M.H. Rathore, E. Buckley, S. Mahmoudi; University of Massachusetts Medical School; University of Mississippi Medical Center — H. Gay, S. Naylor, S. Sadler; University of Puerto Rico.
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Citing Articles
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Ingrid A Beck, Minyoung Jang, Jennifer McKernan, Marta Bull, Thor A Wagner, Sharon Huang, Lin-Ye Song, Sharon Nachman, Paul Krogstad, Susan Eshleman, Andrew Wiznia, Lisa Marie Frenkel. (2011) Monitoring of HIV-1 DNA Load and Drug Resistance in Peripheral Blood Mononuclear Cells during Suppressive Antiretroviral Therapy does not Predict Virologic Failure. AIDS Research and Human Retroviruses111115031133002
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Ingrid A Beck, Minyoung Jang, Jennifer McKernan, Marta Bull, Thor A Wagner, Sharon Huang, Lin-Ye Song, Sharon Nachman, Paul Krogstad, Susan Eshleman, Andrew Wiznia, Lisa Marie Frenkel. (2011) Monitoring of HIV-1 DNA Load and Drug Resistance in Peripheral Blood Mononuclear Cells during Suppressive Antiretroviral Therapy does not Predict Virologic Failure. AIDS Research and Human Retroviruses111115031133002
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Martina Penazzato, Carlo Giaquinto. (2011) Role of Non-Nucleoside Reverse Transcriptase Inhibitors in Treating HIV-Infected Children. Drugs 71:16, 2131-2149
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Namandjé N. Bumpus. (2011) Efavirenz and 8-hydroxyefavirenz induce cell death via a JNK- and BimEL-dependent mechanism in primary human hepatocytes. Toxicology and Applied Pharmacology
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Laurence Ahoua, Gunar Guenther, Christine Rouzioux, Loretxu Pinoges, Paul Anguzu, Anne-Marie Taburet, Suna Balkan, David M Olson, Charles Olaro, Mar Pujades-Rodríguez. (2011) Immunovirological response to combined antiretroviral therapy and drug resistance patterns in children: 1- and 2-year outcomes in rural Uganda. BMC Pediatrics 11:1, 67
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S Ghosh, J Neubert, T Niehues, O Adams, N Morali-Karzei, A Borkhardt, HJ Laws. (2011) Induction maintenance concept for HAART as initial treatment in HIV infected infants. European Journal of Medical Research 16:6, 243
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Camille E. Introcaso, Janet M. Hines, Carrie L. Kovarik. (2010) Cutaneous toxicities of antiretroviral therapy for HIV. Journal of the American Academy of Dermatology 63:4, 563-569
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Ana Blas-García, Nadezda Apostolova, Daniel Ballesteros, Daniel Monleón, Jose M. Morales, Milagros Rocha, Victor M. Victor, Juan V. Esplugues. (2010) Inhibition of mitochondrial function by efavirenz increases lipid content in hepatic cells. Hepatology 52:1, 115-125
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Michelle Viljoen, Hermien Gous, Herculina S. Kruger, Alison Riddick, Tammy M. Meyers, Malie Rheeders. (2010) Efavirenz Plasma Concentrations at 1, 3, and 6 Months Post-Antiretroviral Therapy Initiation in HIV Type 1-Infected South African Children. AIDS Research and Human Retroviruses 26:6, 613-619
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Amandine Rubio, Fabrice Monpoux, Emilie Huguon, Régine Truchi, Valérie Triolo, Maria-Alessandra Rosenthal-Allieri, Anne Deville, Eric Rosenthal, Patrick Boutté, Albert Tran. (2009) Noninvasive Procedures to Evaluate Liver Involvement in HIV-1 Vertically Infected Children. Journal of Pediatric Gastroenterology and Nutrition 49:5, 599-606
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Jean B Nachega, Michael Hislop, Hoang Nguyen, David W Dowdy, Richard E Chaisson, Leon Regensberg, Mark Cotton, Gary Maartens. (2009) Antiretroviral Therapy Adherence, Virologic and Immunologic Outcomes in Adolescents Compared With Adults in Southern Africa. JAIDS Journal of Acquired Immune Deficiency Syndromes 51:1, 65-71
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Jennifer R. King, Edward P. Acosta, Ram Yogev, Andrew Wiznia, Joyce Kraimer, Bobbie Graham, Vincent Carey, Paula Britto, Patrick Jean-Philippe, John Moye, Douglas Watson. (2009) STEADY-STATE PHARMACOKINETICS OF LOPINAVIR/RITONAVIR IN COMBINATION WITH EFAVIRENZ IN HUMAN IMMUNODEFICIENCY VIRUS-INFECTED PEDIATRIC PATIENTS. The Pediatric Infectious Disease Journal 28:2, 159-161
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Keswadee Lapphra, Nirun Vanprapar, Sanay Chearskul, Wanatpreeya Phongsamart, Pimpanada Chearskul, Wasana Prasitsuebsai, Kulkanya Chokephaibulkit. (2008) Efficacy and tolerability of nevirapine- versus efavirenz-containing regimens in HIV-infected Thai children. International Journal of Infectious Diseases 12:6, e33-e38
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Serge Schneider, Alexandra Peltier, Alain Gras, Vic Arendt, Christine Karasi-Omes, Anastasie Mujawamariwa, Patrick C Ndimubanzi, Gilles Ndayisaba, Robert Wennig. (2008) Efavirenz in Human Breast Milk, Mothersʼ, and Newbornsʼ Plasma. JAIDS Journal of Acquired Immune Deficiency Syndromes 48:4, 450-454
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Kunjal Patel, Miguel A. Hernán, Paige L. Williams, John D. Seeger, Kenneth McIntosh, Russell B. Van Dyke, George R. Seage III, . (2008) Long‐Term Effects of Highly Active Antiretroviral Therapy on CD4 + Cell Evolution among Children and Adolescents Infected with HIV: 5 Years and Counting. Clinical Infectious Diseases 46:11, 1751-1760
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CV Fletcher, RC Brundage, T Fenton, CG Alvero, C Powell, LM Mofenson, SA Spector. (2008) Pharmacokinetics and Pharmacodynamics of Efavirenz and Nelfinavir in HIV-infected Children Participating in an Area-under-the-curve Controlled Trial. Clinical Pharmacology & Therapeutics 83:2, 300-306
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Carlo Giaquinto, Erika Morelli, Federica Fregonese, Osvalda Rampon, Martina Penazzato, Anita de Rossi, Ruggero D’Elia. (2008) Current and Future Antiretroviral Treatment Options in Paediatric HIV Infection. Clinical Drug Investigation 28:6, 375-397
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Pablo Rojo, Maria Isabel Gonzalez-Tome, Jose Tomas Ramos. (2007) Initial Antiretroviral Drugs. The Pediatric Infectious Disease Journal 26:12, 1167
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Patricia M. Flynn, Bret J. Rudy, Jane C. Lindsey, Steven D. Douglas, Janet Lathey, Stephen A. Spector, Jaime Martinez, Margarita Silio, Marvin Belzer, Lawrence Friedman, Lawrence D'Angelo, Elizabeth Smith, Janice Hodge, Michael D. Hughes. (2007) Long-Term Observation of Adolescents Initiating HAART Therapy: Three-Year Follow-Up. AIDS Research and Human Retroviruses 23:10, 1208-1214
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Masaaki Takahashi, Shiro Ibe, Yuichi Kudaka, Naoya Okumura, Atsushi Hirano, Tatsuo Suzuki, Naoto Mamiya, Motohiro Hamaguchi, Tsuguhiro Kaneda. (2007) No Observable Correlation between Central Nervous System Side Effects and EFV Plasma Concentrations in Japanese HIV Type 1-Infected Patients Treated with EFV Containing HAART. AIDS Research and Human Retroviruses 23:8, 983-987
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Yuan Ren, James J C Nuttall, Claire Egbers, Brian S Eley, Tammy M Meyers, Peter J Smith, Gary Maartens, Helen M McIlleron. (2007) High Prevalence of Subtherapeutic Plasma Concentrations of Efavirenz in Children. JAIDS Journal of Acquired Immune Deficiency Syndromes 45:2, 133-136
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P. Myung, D. Pugatch, M. F. Brady, P. Many, J. I. Harwell, M. Lurie, J. Tucker. (2007) Directly Observed Highly Active Antiretroviral Therapy for HIV-Infected Children in Cambodia. American Journal of Public Health 97:6, 974-977
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Akihiko Saitoh, Courtney V Fletcher, Richard Brundage, Carmelita Alvero, Terrence Fenton, Karen Hsia, Stephen A Spector. (2007) Efavirenz Pharmacokinetics in HIV-1???Infected Children Are Associated With CYP2B6-G516T Polymorphism. JAIDS Journal of Acquired Immune Deficiency Syndromes PAP,
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Miguel Goicoechea, Brookie Best. (2007) Efavirenz/emtricitabine/tenofovir disoproxil fumarate fixed-dose combination: first-line therapy for all?. Expert Opinion on Pharmacotherapy 8:3, 371-382
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Carlos Alberto Zaccarelli-Filho, Erika Ono, Daisy Maria Machado, Milena Brunialti, Regina Célia de Menezes Succi, Reinaldo Salomão, Esper Georges Kallás, Maria Isabel de Moraes-Pinto. (2007) HIV-1-infected children on HAART: Immunologic features of three different levels of viral suppression. Cytometry Part B: Clinical Cytometry 72B:1, 14-21
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Salvador Resino, Rosa Resino, Jose Ma Bellon, Dariela Micheloud, Ma Dolores Gurbindo Gutierrez, Ma Isabel de Jose, Jose Tomas Ramos, Pablo Martin Fontelos, Luis Ciria, Ma Angeles Munoz‐Fernandez, . (2006) Clinical Outcomes Improve with Highly Active Antiretroviral Therapy in Vertically HIV Type‐1–Infected Children. Clinical Infectious Diseases 43:2, 243-252
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Kristel M. L. Crommentuyn, Henri??tte J. Scherpbier, Taco W. Kuijpers, Ron A. A. Math??t, Alwin D. R. Huitema, Jos H. Beijnen. (2006) Population Pharmacokinetics and Pharmacodynamics of Nelfinavir and Its Active Metabolite M8 in HIV-1-Infected Children. The Pediatric Infectious Disease Journal 25:6, 538-543
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Tim Niehues, Ulrich Baumann, Bernd Buchholz, Dominik Dunsch, Markus Funk, Christoph Königs, Martin Edelhäuser, Jennifer Neubert, Gundula Notheis, Uwe Wintergerst. (2006) Empfehlungen zur antiretroviralen Therapie bei HIV-infizierten Kindern. Monatsschrift Kinderheilkunde 154:6, 565-577
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Bret J. Rudy, Jane C. Lindsey, Patricia M. Flynn, Ronald J. Bosch, Craig M. Wilson, Michael E. Hughes, Steven D. Douglas. (2006) Immune Reconstitution and Predictors of Virologic Failure in Adolescents Infected through Risk Behaviors and Initiating HAART: Week 60 Results from the PACTG 381 Cohort. AIDS Research and Human Retroviruses 22:3, 213-221
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Vincent Bekker, Henriëtte J Scherpbier, Radjin Steingrover, Suzanne Jurriaans, Joep MA Lange, Katja C Wolthers, Taco W Kuijpers. (2006) Viral dynamics after starting first-line HAART in HIV-1-infected children. AIDS 20:4, 517-523
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MP Rhoads, CJ Smith, G Tudor-Williams, P Kyd, S Walters, CA Sabin, EGH Lyall. (2006) Effects of highly active antiretroviral therapy on paediatric metabolite levels. HIV Medicine 7:1, 16-24
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Jennifer R. King, Sharon Nachman, Ram Yogev, Janice Hodge, Grace Aldrovandi, Michael D. Hughes, Jie Chen, Andrew Wiznia, Bharat Damle, Edward P. Acosta. (2005) Efficacy, Tolerability and Pharmacokinetics of Two Nelfinavir-Based Regimens in Human Immunodeficiency Virus-Infected Children and Adolescents. The Pediatric Infectious Disease Journal 24:10, 880-885
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Richard M. Rutstein, Kelly A. Gebo, Patricia M. Flynn, John A. Fleishman, Victoria L. Sharp, George K. Siberry, Stephen A. Spector. (2005) Immunologic Function and Virologic Suppression Among Children With Perinatally Acquired HIV Infection on Highly Active Antiretroviral Therapy. Medical Care 43:suppl, III-15-III-22
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T. Puthanakit, A. Oberdorfer, N. Akarathum, S. Kanjanavanit, P. Wannarit, T. Sirisanthana, V. Sirisanthana. (2005) Efficacy of Highly Active Antiretroviral Therapy in HIV-Infected Children Participating in Thailand's National Access to Antiretroviral Program. Clinical Infectious Diseases 41:1, 100-107
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Salvador Resino, Isabel Galán, Alicia Pérez, José Tomás Ramos, Jose M. Bellón, Pablo Martín Fontelos, M. Isabel De José, M. Dolores Gurbindo Gutiérrez, Esther Cabrero, M. Ángeles Muñoz-Fernández. (2005) Immunological Changes after Highly Active Antiretroviral Therapy with Lopinavir–Ritonavir in Heavily Pretreated HIV-Infected Children. AIDS Research and Human Retroviruses 21:5, 398-406
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Akihiko Saitoh, Kumud K Singh, Christine A Powell, Terrence Fenton, Courtney V Fletcher, Richard Brundage, Stuart Starr, Stephen A Spector. (2005) An MDR1-3435 variant is associated with higher plasma nelfinavir levels and more rapid virologic response in HIV-1 infected children. AIDS 19:4, 371-380
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P. L. A. Fraaij, G. Verweel, A. M. C. van Rossum, E. G. van Lochem, M. Schutten, C. M. R. Weemaes, N. G. Hartwig, D. M. Burger, R. de Groot. (2005) Sustained Viral Suppression and Immune Recovery in HIV Type 1--Infected Children after 4 Years of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 40:4, 604-608
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Pieter L A Fraaij, Jeroen J A van Kampen, David M Burger, Ronald de Groot. (2005) Pharmacokinetics of Antiretroviral Therapy in HIV-1-Infected Children. Clinical Pharmacokinetics 44:9, 935-956
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Caroline M Perry, James E Frampton, Paul L McCormack, M Asif A Siddiqui, Risto S Cvetkovi??. (2005) Nelfinavir. Drugs 65:15, 2209-2244
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Salvador Resino, José Maria Bellón, José Tomás Ramos, Maria Luisa Navarro, Pablo Martín-Fontelos, Esther Cabrero, Maria Ángeles Muñoz-Fernández. (2004) Salvage Lopinavir-Ritonavir Therapy in Human Immunodeficiency Virus-Infected Children. The Pediatric Infectious Disease Journal 23:10, 923-930
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M Sharland, S Blanche, G Castelli, J Ramos, DM Gibb, . (2004) PENTA guidelines for the use of antiretroviral therapy, 2004. HIV Medicine 5:s2, 61-86
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C Engelhorn, F Hoffmann, M Kurowski, H Stocker, G Kruse, G Notheis, B H Belohradsky, Uwe Wintergerst. (2004) Long-term pharmacokinetics of amprenavir in combination with delavirdine in HIV-infected children. AIDS 18:10, 1473-1475
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S. Resino, J. M. {a. } Bellon, R. Resino, M. {a. } L. Navarro, J. T. Ramos, M. {a. } I. de Jose, M. {a. } J. Mellado, M. {a. } a. Munoz-Fernaendez. (2004) Extensive Implementation of Highly Active Antiretroviral Therapy Shows Great Effect on Survival and Surrogate Markers in Vertically HIV-Infected Children. Clinical Infectious Diseases 38:11, 1605-1612
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Pieter L. A. Fraaij, Natella Rakhmanina, David M. Burger, Ronald de Groot. (2004) Therapeutic Drug Monitoring in Children with HIV/AIDS. Therapeutic Drug Monitoring 26:2, 122-126
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Lisa M. Frenkel, Nicole H. Tobin. (2004) Understanding HIV-1 Drug Resistance. Therapeutic Drug Monitoring 26:2, 116-121
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Courtney V Fletcher. (2004) Antiretroviral therapy for HIV-infected infants. AIDS 18:2, 325-326
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Jennifer Handforth, Mike Sharland. (2004) Triple Nucleoside Reverse Transcriptase Inhibitor Therapy in??Children. Pediatric Drugs 6:3, 147-159
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Michael Neely, Andrea Kovacs. (2003) Management of antiretroviral therapy in neonates, children, and adolescents. Current Infectious Disease Reports 5:6, 521-530
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S. Resino, J. M. Bellon, D. Gurbindo, J. T. Ramos, J. A. Leon, M. J. Mellado, M. A. Mu oz-Fernandez. (2003) Viral Load and CD4+ T Lymphocyte Response to Highly Active Antiretroviral Therapy in Human Immunodeficiency Virus Type 1-Infected Children: An Observational Study. Clinical Infectious Diseases 37:9, 1216-1225
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Gwenda Verweel, Mike Sharland, Hermione Lyall, Vas Novelli, Diane M Gibb, Gillian Dumont, Colin Ball, Ed Wilkins, Sam Walters, Gareth Tudor-Williams. (2003) Nevirapine use in HIV-1-infected children. AIDS 17:11, 1639-1647
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G. Gatti, G. C. Gattinara, M. Cruciani, S. Bernardi, C. R. De Pascalis, E. Pontali, L. Papa, F. Miletich, D. Bassetti. (2003) Pharmacokinetics and Pharmacodynamics of Nelfinavir Administered Twice or Thrice Daily to Human Immunodeficiency Virus Type 1-Infected Children. Clinical Infectious Diseases 36:11, 1476-1482
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JENNIFER R. KING, EDWARD P. ACOSTA, ELLEN CHADWICK, RAM YOGEV, MARILYN CRAIN, ROBERT PASS, DAVID W. KIMBERLIN, MARSHA S. STURDEVANT, GRACE M. ALDROVANDI. (2003) Evaluation of multiple drug therapy in human immunodeficiency virus-infected pediatric patients. The Pediatric Infectious Disease Journal 22:3, 239-244
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XAVIER SÁEZ-LLORENS, AVYI VIOLARI, CARL O. DEETZ, RICHARD A. RODE, PERRY GOMEZ, EDWARD HANDELSMAN, STEPHEN PELTON, OCTAVIO RAMILO, PEDRO CAHN, ELLEN CHADWICK, UPTON ALLEN, STEPHEN ARPADI, MARIA MERCEDES CASTREJÓN, RENEE S. HEUSER, DALE J. KEMPF, RICHARD J. BERTZ, ANN F. HSU, BARRY BERNSTEIN, CHERYL L. RENZ, EUGENE SUN. (2003) Forty-eight-week evaluation of lopinavir/ritonavir, a new protease inhibitor, in human immunodeficiency virus-infected children. The Pediatric Infectious Disease Journal 22:3, 216-223
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Jeffrey L. Foti, Janice P. Piatt. (2003) Hypersensitivity to Efavirenz Treated With Corticosteroids in a 6-Year-Old Child. AIDS Patient Care and STDs 17:1, 1-3
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CATHERINE LITALIEN, ALBERT FAYE, ALEXANDRA COMPAGNUCCI, CARLO GIAQUINTO, LYNDA HARPER, DIANA M. GIBB, EVELYNE JACQZ-AIGRAIN. (2003) Pharmacokinetics of nelfinavir and its active metabolite, hydroxy-tert-butylamide, in infants perinatally infected with human immunodeficiency virus type 1. The Pediatric Infectious Disease Journal 22:1, 48-55
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M.C Re, P Monari, I Bon, M Borderi, D Gibellini, P Schiavone, F Vitone, G Furlini, M La Placa. (2002) Development of drug resistance in HIV-1 patients receiving a combination of stavudine, lamivudine and efavirenz. International Journal of Antimicrobial Agents 20:3, 223-226
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M Sharland, G Castelli Gattinara di Zub, J Tomas Ramos, S Blanche, DM Gibb. (2002) PENTA guidelines for the use of antiretroviral therapy in paediatric HIV infection. HIV Medicine 3:3, 215-226
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STUART E. STARR, COURTNEY V. FLETCHER, STEPHEN A. SPECTOR, RICHARD C. BRUNDAGE, FLORENCE H. YONG, STEVEN D. DOUGLAS, PATRICIA M. FLYNN, MARK W. KLINE. (2002) Efavirenz liquid formulation in human immunodeficiency virus-infected children. The Pediatric Infectious Disease Journal 21:7, 659-663
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Claudia A. Chiriboga. (2002) Human immunodeficiency virus (HIV) in children. Current Treatment Options in Neurology 4:3, 213-224
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Annemarie M. C. van Rossum, Sibyl P. M. Geelen, Nico G. Hartwig, Tom F. W. Wolfs, Corry M. R. Weemaes, Henriette J. Scherpbier, Ellen G. van Lochem, Wim C. J. Hop, Martin Schutten, Albert D. M. E. Osterhaus, David M. Burger, Ronald de Groot, . (2002) Results of 2 Years of Treatment with Protease‐Inhibitor–Containing Antiretroviral Therapy in Dutch Children Infected with Human Immunodeficiency Virus Type 1. Clinical Infectious Diseases 34:7, 1008-1016
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Paul Krogstad, Sophia Lee, George Johnson, Kenneth Stanley, James McNamara, John Moye, J. Brooks Jackson, Rosaura Aguayo, Arry Dieudonne, Margaret Khoury, Hermann Mendez, Sharon Nachman, Andrew Wiznia, . (2002) Nucleoside‐Analogue Reverse‐Transcriptase Inhibitors Plus Nevirapine, Nelfinavir, or Ritonavir for Pretreated Children Infected with Human Immunodeficiency Virus Type 1. Clinical Infectious Diseases 34:7, 991-1001
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(2002) Comparison of dual nucleoside-analogue reverse-transcriptase inhibitor regimens with and without nelfinavir in children with HIV-1 who have not previously been treated: the PENTA 5 randomised trial. The Lancet 359:9308, 733-740
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K. A. Rosenbach, R. Allison, J. P. Nadler. (2002) Daily Dosing of Highly Active Antiretroviral Therapy. Clinical Infectious Diseases 34:5, 686-692
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David Back, Giorgio Gatti, Courtney Fletcher, Rodolphe Garaffo, Richard Haubrich, Richard Hoetelmans, Michael Kurowski, Andrew Luber, Concepta Merry, Carlo-Federico Perno. (2002) Therapeutic drug monitoring in HIV infection: current status and future directions. AIDS 16, S5-S37
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Annemarie MC van Rossum, Pieter LA Fraaij, Ronald de Groot. (2002) Efficacy of highly active antiretroviral therapy in HIV-1 infected children. The Lancet Infectious Diseases 2:2, 93-102
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K Doerholt, M Sharland, C Ball, G DuMont. (2002) Paediatric antiretroviral therapy audit in South London. HIV Medicine 3:1, 44-48
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Jennifer R. King, David W. Kimberlin, Grace M. Aldrovandi, Edward P. Acosta. (2002) Antiretroviral Pharmacokinetics in the Paediatric Population. Clinical Pharmacokinetics 41:14, 1115-1133
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Daniel Avi Lemberg, Pamela Palasanthiran, Michele Goode, John B. Ziegler. (2002) Tolerabilities of Antiretrovirals in Paediatric HIV Infection. Drug Safety 25:14, 973-991
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Patrick J. Gavin, Ram Yogev. (2002) The Role of Protease Inhibitor Therapy in Children with HIV Infection. Pediatric Drugs 4:9, 581-607
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MARK W. KLINE, RICHARD C. BRUNDAGE, COURTNEY V. FLETCHER, HEIDI SCHWARZWALD, NANCY R. CALLES, NEIL E. BUSS, PAUL SNELL, PATRICIA DELORA, MONICA EASON, KARIN JORGA, CHARLES CRAIG, FRANK DUFF. (2001) Combination therapy with saquinavir soft gelatin capsules in children with human immunodeficiency virus infection. The Pediatric Infectious Disease Journal 20:7, 666-671
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MARGARET KHOURY, ANDREA KOVACS. (2001) Pediatric HIV Infection. Clinical Obstetrics and Gynecology 44:2, 243-275
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Regina Treudler, Ralf Husak, Monika Raisova, Constantin E. Orfanos, Beate Tebbe. (2001) Efavirenz-induced photoallergic dermatitis in HIV. AIDS 15:8, 1085-1087
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