Pharmacokinetics of lopinavir in HIV type-1-infected children taking the new tablet formulation once daily.

BACKGROUND: Recently, a new tablet formulation of the widely used HIV protease inhibitor lopinavir/ritonavir was licensed. Here, we present a pilot study of the pharmacokinetics of the new adult tablet formulation taken once daily in children. METHODS: Lopinavir pharmacokinetics of the new adult tablet formulation were evaluated in 15 HIV type-1-infected children between 4 and 15 years of age. A target dose of 460/115 mg/m2 was administered once daily. Plasma concentrations of lopinavir over the course of 24 h were determined with a validated HPLC method. RESULTS: The median lopinavir dose was 498 mg/m2 (range 424-548). The mean +/- SD for lopinavir area under the 24 h curve was 217.9 +/- 44.9 mg/l x h, the maximum concentration was 14.8 +/- 2.4 mg/l and the concentration 24 h after intake was 3.1 +/- 2.6 mg/l. The half-life of lopinavir was 5.8 +/- 4.5 h and the median time to maximum concentration was 5.8 h (range 1.8-12.2). Overall, the tablet formulation resulted in greater exposure to lopinavir with less variability compared with the soft-gel capsule formulation. All children treated with the new adult tablet formulation had undetectable viral loads (< 50 copies/ml) during 24 weeks follow-up. CONCLUSIONS: The tablet formulation could probably result in improved lopinavir dosing and increases the feasibility of once-daily lopinavir/ritonavir-based regimens in children.

Plasma concentrations of the HIV-protease inhibitor lopinavir are suboptimal in children aged 2 years and below.

BACKGROUND: Lopinavir/ritonavir (LPV/r) has been licensed for the treatment of HIV-infected children >6 months in the US and >2 years in the EU. Limited LPV paediatric pharmacokinetic data are available. We studied LPV pharmacokinetics to determine whether the recommended dose (230/57.5 mg/m2 twice daily) results in optimal LPV exposure in all age groups. Virological efficacy was a secondary objective. METHODS: HIV-1-infected children who started treatment with LPV/r and two nucleoside reverse transcriptase inhibitors underwent a 12-h pharmacokinetic curve. LPV plasma concentrations were determined with a validated HPLC method with UV detection. If Cmin was <1.0 mg/l LPV/r dose was increased by 33%. Plasma trough levels were drawn subsequently. HIV-1 RNA was followed-up until week 48. RESULTS: A total of 23 children were included (seven girls; 16 boys), with a median (range) age of 5.6 (0.4-13.2) years. Mean (+/-SD) AUC0-12h, Cmax and Cmin of LPV were 75.3 (+/-33.7) mg/l.h, 9.33 (+/-3.27) mg/l and 3.68 (+/-2.48) mg/l, respectively, which is similar to previously published data. Interindividual variability was large. Cmin was inadequate in 7/23 children. Significantly more children <2 years had inadequate Cmin compared with children >2 years. Dose increase to +/-300/75 mg/m2 LPV/r led to Cmin >1.0 mg/l. The studied regimen provided excellent viral suppression for naive and pretreated patients. CONCLUSIONS: Mean LPV pharmacokinetic parameters in these HIV-infected children are similar to published data, but exposure is significantly reduced in children <2 years. Prospective pharmacokinetic studies using 300/75 mg/m2 LPV/r in this age population are urgently warranted.

Pharmacokinetics of a once-daily regimen of lopinavir/ritonavir in HIV-1-infected children.

INTRODUCTION: Lopinavir is an HIV protease inhibitor that is co-formulated with ritonavir. The approved paediatric dose is 230/57.5 mg/m2 twice daily. Once-daily dosing may offer an advantage to adherence. We studied the pharmacokinetics of lopinavir/ritonavir in a once-daily regimen in HIV-1-infected children. METHODS: HIV-1-infected children on stable antiretroviral therapy with a viral load <50 copies/ml for at least 6 months received lopinavir/ritonavir 460/115mg/m2 once daily with zidovudine and lamivudine. Blood samples were collected at 0, 2, 4, 6, 8, 12, 18 and 24 h after observed intake during steady state. Target level for lopinavir Cmin was 1.0 mg/l, based on in vitro IC50 data. RESULTS: Nineteen HIV-1-infected children with a median (range) age of 4.5 (1.4-12.9) years were enrolled. The median (interquartile range) dose of lopinavir was 456 (444-477) mg/m2. The mean (standard deviation) AUC0-24, Cmax and Cmin of lopinavir were 149.8 +/- 58.8 h*mg/l, 10.77 +/- 2.90 mg/l and 2.88 +/- 3.74 mg/l respectively. These values are comparable to data observed in adults using lopinavir/ritonavir 800/200 mg once daily. In 10/19 (53%) children Cmin was considered to be too low (<1.0 mg/l). Younger children more often experienced subtherapeutic trough levels. CONCLUSION: Our findings indicate that 460/115 mg/m2 lopinavir/ritonavir once daily leads to mean pharmacokinetic parameters comparable to data of 800/200 mg lopinavir/ritonavir once daily in adults, although the variability observed in the trough levels is much higher in children. Further research, especially in young children, is necessary to determine whether a higher dosage of lopinavir/ritonavir once daily must be given to reach the target level for Cmin.

Detection of lipoatrophy in human immunodeficiency virus-1-infected children treated with highly active antiretroviral therapy.

BACKGROUND: Highly active antiretroviral therapy has been associated with lipodystrophy in adults. Much is unknown about its characteristics, especially in children. OBJECTIVE: To obtain an objective case definition of the lipodystrophy syndrome. METHODS: This was a cross-sectional study. One investigator rated clinical lipodystrophy. Body composition was measured using body mass index, skin fold thickness and circumference of arm, leg, waist and hip. Samples for human immunodeficiency virus (HIV)-1 RNA, CD4 cell count, fasting lipids and glucose variables were drawn. HIV-infected children with lipodystrophy were compared with HIV-infected children without lipodystrophy (controls). RESULTS: Thirty-four children were included: 28 controls, 2 nonassigned, and 4 with the lipoatrophic phenotype. Lipohypertrophy or mixed syndrome were not observed. All children with lipoatrophy were pubertal; they had used stavudine and didanosine longer. Children with lipoatrophy had significantly smaller arm and leg circumference, and their skin folds were thinner. The torso-to-arm ratio was 3 times higher in lipoatrophic children, but the difference did not reach significance. The waist-to-hip ratio was higher (P = 0.005). None of the laboratory values differed significantly between the two groups, but all children with lipoatrophy had an increased C-peptide level above the upper limit of normal. All children with lipoatrophy could be distinguised from controls by an increased C-peptide level, a waist-to-hip ratio z score of 1 standard deviation or higher and a sum of skin folds z score below -1 standard deviation. CONCLUSIONS: All children with lipoatrophy can be distinguished by using anthropometric measurements and C-peptide measurement in serum. This method is simple, readily available and inexpensive.

Initiating highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children in Europe and the United States: comparing clinical practice to guidelines and literature evidence.

Several guidelines are available to guide the initiation of highly active antiretroviral therapy (HAART) in human immunodeficiency virus (HIV)-infected children. The recommendations in these guidelines show significant variability. Because there is no well-established evidence on when to start HAART, it is left to the discretion of the pediatrician which guidelines to follow. We conducted a survey concerning the indications for starting antiretroviral therapy among pediatricians involved in the treatment of HIV-infected patients in Europe and the United States. We compared the results of this survey with the guidelines available at the time, the recently adapted guidelines and literature evidence. Our results indicate that in clinical practice HAART was initiated at higher viral loads and lower CD4 counts than recommended by the guidelines. American guidelines recommended and still recommend more aggressive treatment than the European guidelines, and this is reflected in clinical practice. Until recently all guidelines were based on long term risk analyses of progression to acquired immunodeficiency syndrome (AIDS) and death performed in cohort data. A recent short term risk analysis makes it possible to calculate the 6 or 12-month risk for progression to AIDS or death for an individual child. Because viral load and CD4 count are typically measured every 3 months, one can argue that it is clinically more relevant to base the decision of when to start HAART on the short term probability of disease progression. Guidelines in Europe are now based on this type of analysis. The American guidelines only adopted the thresholds for CD4 and viral load. The short term risk analysis also shows that the risk for developing AIDS varies markedly with age. This should be reflected in all guidelines. Determining the acceptable risk of disease progression is difficult and influenced by patient-, doctor- and culture-related factors. The controversy over whether or not to treat asymptomatic infants is unresolved as well. All infants have a very high risk of disease progression regardless of their viral load or CD4 count, but lifelong treatment with a potential for significant toxicities and risk of developing resistance is also not an appealing option. We recommend an attempt to achieve a consensus among the different working groups to reduce the number of different guidelines, which should be based on the literature evidence. Because all risk analyses are based on information from the pre-HAART era, a head-to-head trial comparing early versus deferred HAART would be useful. This may be difficult to accomplish. The first step could be an analysis of retrospective data from collaborative cohort data.

Withdrawal of Pneumocystis jirovecii prophylaxis in HIV-infected children under highly active antiretroviral therapy.

OBJECTIVE: In HIV-infected adults Pneumocystis jirovecii pneumonia (PCP) prophylaxis can be safely withdrawn after immune reconstitution due to the introduction of highly active antiretroviral therapy (HAART). With regard to children only a small amount of data has been published. The present study investigated whether the withdrawal of PCP prophylaxis after immune reconstitution is safe in HIV-infected children. METHODS: A retrospective analysis at 10 European centers belonging to the Pediatric European Network on the treatment of AIDS (PENTA) using a standardized questionnaire. RESULTS: A total of 113 questionnaires were received. In 82 children the indication for PCP prophylaxis was provided following Centers for Disease Control (CDC) guidelines (72 primary and 10 secondary). Prophylaxis was withdrawn after the CD4 cell count increased above the age-related CDC thresholds. The observation period off prophylaxis was 335 years (300 years for primary and 35 years for secondary prophylaxis) and the median time per patient off prophylaxis was 4.1 years (range, 0.3-7.7 years). No episode of PCP occurred during the study period. In comparison with the incidence rate from historical data before the introduction of PCP prophylaxis and HAART, this was a significant reduction (P < 0.05). CONCLUSIONS: The increase in CD4 cell count provides functional reconstitution of the immune system in children. Our data suggests that the risk of developing a PCP after immune reconstitution is sufficiently low to withdraw PCP prophylaxis.

Sustained viral suppression and immune recovery in HIV type 1-infected children after 4 years of highly active antiretroviral therapy.

We report the data from a long-term study of 31 human immunodeficiency virus type 1 (HIV-1)-infected children who were treated with highly active antiretroviral therapy. A high proportion of the children had undetectable HIV-1 RNA levels. CD4+ T cell counts recovered and remained stable. Adverse events were observed frequently but were mostly mild.

Nevirapine use in HIV-1-infected children.

OBJECTIVES: To evaluate the safety, efficacy, and clinical, virological, and immunological responses in HIV-1-infected children receiving nevirapine as part of combination antiretroviral therapy (ART). METHODS: A review of case notes of all HIV-1-infected children 96 weeks after starting nevirapine, under a national compassionate access scheme between August 1997 and March 1999 in the UK. Nevirapine was dosed according to the manufacturer's guidelines. RESULTS: Seventy-four children (36 boys, 28 naive to ART) were enrolled, with a median age of 5.2 years, viral load of 5.1 log copies/ml and CD4 lymphocyte count of 13.5%. The liquid formulation and tablets of nevirapine were well tolerated. The proportions of patients achieving undetectable viral load levels at weeks 12, 24, 48 and 96 were 30, 40, 36 and 33%, respectively (intention-to-treat analysis). Of children not on a protease inhibitor who received more than 300 mg/m2/day of nevirapine, 60% had undetectable viral loads at week 96, compared with 17% on recommended doses. Outcomes were similar for patients receiving nevirapine once or twice daily. CD4 cell count percentages increased significantly, with median values sustained above 25% by week 48 onwards. Z-scores for weight and height increased significantly during 96 weeks of treatment. Rash occurred in 20%, of which four (5%) were severe. There were no cases of Stevens-Johnson syndrome. CONCLUSION: Nevirapine was mostly well tolerated, and was associated with encouraging clinical and immunological responses. Virological responses in this cohort support the use of nevirapine doses greater than 300 mg/m2/day, which is higher than currently recommended by the manufacturers.

Immunologic changes during unplanned treatment interruptions of highly active antiretroviral therapy in children with human immunodeficiency virus type 1 infection.

BACKGROUND: There are few data on the decline of CD4 cells or percentage during unplanned treatment interruptions in HIV-infected children. METHODS: Data were analyzed on children undergoing interruptions of three or four drug antiretroviral therapy (HAART) in the United Kingdom and Irish Collaborative HIV Paediatric Study and from Sophia Children's Hospital, Rotterdam. Children were included if they had taken HAART continuously for 3 months or longer before interruption and stopped for at least 4 weeks. The effects of CD4 at treatment initiation and of age, CD4, HIV RNA and disease stage at interruption on the CD4 decline during interruption were explored with linear mixed models. RESULTS: Seventy-one children (median age, 7.0 years) had experienced 82 unplanned interruptions of median duration 4.1 (interquartile range, 2.3 to 7.6) months. HAART was restarted after 59 (72%) interruptions (17 with the same and 42 with a new regimen). In children restarting HAART, median CD4% increased toward preinterruption levels by 6 months, when 46% had HIV RNA <400 copies/ml (vs. 15% at interruption). The rate of CD4% decline in 51 children with a median of 3 (range, 2 to 10) CD4 measurements was 0.52% per month (6.2% annually); it was independent of age, CD4 at HAART, preinterruption CD4 or HIV RNA or previous AIDS. CONCLUSIONS: Although the average CD4 decline after stopping HAART appears similar to that in adults, large variability suggests that when designing pediatric trials of planned treatment interruptions, interruption length could be determined by time taken for CD4 to decline below a threshold, rather than by imposing interruptions of fixed duration.

Increased dose of lopinavir/ritonavir compensates for efavirenz-induced drug-drug interaction in HIV-1-infected children.

BACKGROUND: Nucleoside reverse transcriptase inhibitor-sparing regimens have not yet been systematically evaluated in children. The nonnucleoside reverse transcriptase inhibitors nevirapine and efavirenz lower plasma levels of protease inhibitors in adults and children. Therefore, coadministration of lopinavir/ritonavir with nevirapine and efavirenz necessitates a 30% increase in the dose of lopinavir/ritonavir in adults. In children, the extent of the pharmacokinetic interaction between efavirenz and lopinavir/ritonavir has not yet been studied. OBJECTIVE: To investigate the pharmacokinetics of increased-dose (300/75 mg/m2 twice-daily) lopinavir/ritonavir with normal-dose (14 mg/kg once-daily) efavirenz in HIV-1-infected children. METHODS: Steady-state pharmacokinetics of lopinavir and efavirenz were determined and compared with historical data. RESULTS: Fifteen children of median age 11.8 (range, 5.7-16.3) years were included. Area under the plasma concentration-time curve (AUC0-12), peak levels (Cmax), and trough levels (Cmin) of lopinavir were similar to historical data in adults and children. Medians (interquartile range) were 92.3 (43.5-138.5) mg/L.h, 12.5 (6.9-16.7) mg/L, and 5.7 (1.3-8.0) mg/L, respectively. Efavirenz pharmacokinetics approximated previous data in adults and children. CONCLUSION: The increased dose of 300/75 mg/m2 twice-daily lopinavir/ritonavir compensates for the enzyme-inducing effect of efavirenz in HIV-infected children.

Plasma levels of zidovudine twice daily compared with three times daily in six HIV-1-infected children.

OBJECTIVES: Zidovudine is often administered every 12 h in HIV-infected children, but so far no pharmacokinetic data are available for the administration of this agent every 12 h. We have evaluated the plasma pharmacokinetics of zidovudine administered every 8 h versus every 12 h in HIV-1-infected children. METHODS: In HIV-1-infected children who switched from zidovudine every 8 h to every 12 h, a pharmacokinetic curve was recorded both before and after the switch. Zidovudine plasma levels were measured by HPLC. Pharmacokinetic parameters were calculated by non-compartmental methods. RESULTS: Six HIV-1-infected children [median age (range) 7.8 (2.5-13.4) years] were included. In these patients, geometric mean ratios of AUC(0-24) and C(max) for zidovudine every 12 h versus every 8 h were not significantly different from 1.0. CONCLUSIONS: The plasma pharmacokinetic parameters of zidovudine taken every 8 h and every 12 h were not significantly different and therefore suggest bioequivalence of these two dose frequencies.

Treatment with highly active antiretroviral therapy in human immunodeficiency virus type 1-infected children is associated with a sustained effect on growth.

INTRODUCTION: Growth failure is a common feature of children with human immunodeficiency virus type 1 (HIV-1) infection. Children who are treated with mono or dual nucleoside analogue reverse transcriptase inhibitor (NRTI) therapy show a temporary increase in weight gain and linear growth rate. In adults, protease-inhibitor-containing antiretroviral therapy is associated with a sustained weight gain and increased body mass index (BMI). Experience with protease inhibitors and growth in children is still limited. The data mainly deal with short-term effects on growth. OBJECTIVE: To evaluate the effect of highly active antiretroviral therapy (HAART) on growth in children with HIV-1 infection. DESIGN AND METHODS: We analyzed selected growth parameters, clinical data, and laboratory results as part of a prospective, open, uncontrolled, multicenter study to evaluate the clinical, immunologic, and virologic response to HAART consisting of indinavir, zidovudine, and lamivudine in children with HIV-1 infection. Height and weight were measured at 0, 12, 24, 36, 48, 60, 72, 84, and 96 weeks after initiation of HAART. Information about the children's growth before enrollment in the study was retrieved from the hospital medical records and/or the school doctor or health center. BMI was calculated. z Scores were used to express the standard deviation (SD) in SD units from the Dutch reference curves for age and gender. Viral loads and CD4+ T-cell counts were examined prospectively and related to these growth parameters. z Scores were also calculated for CD4+ T-cell counts to correct for age-related differences. A z score of 0 represents the P50, which is exactly the age/sex-appropriate median. A height z score of -1 indicates that a child's height is 1 SD below the age- and gender-specific median height for the normal population. Virologic responders were defined as those who either reached an undetectable viral load (<500 copies/mL) or had a >1.5 log reduction in viral load compared with baseline at week 12 after the initiation of HAART, which was maintained during the follow-up period. RESULTS. PATIENTS: Twenty-four patients were included (age: 0.4-16.3 years at baseline), with a median HIV-1 RNA load of 105 925 copies/mL (5.03 log), a median CD4+ T-cell count of 0.586 x 10(9)/L (median z score: -2.28 SD), a median height z score of -1.22, a median weight z score of -0.74, and a median baseline BMI z score of -0.32. Eleven patients were naive to antiretroviral therapy, and 13 patients had received previous treatment with NRTI monotherapy. Twenty children used indinavir and 4 children used nelfinavir as part of HAART. VIROLOGIC AND IMMUNOLOGIC RESPONSES TO HAART: Seventeen children were virologic responders, and 7 children were virologic nonresponders. In patients naive to NRTIs, median baseline viral loads were significantly higher than in pretreated patients. However, at weeks 48 and 96, there was no significant difference between the viral loads of both groups. At baseline, there was no significant difference in CD4+a T-cell z scores between virologic responders and nonresponders or between naive and pretreated patients. During 96 weeks of HAART, the increase of CD4+ T-cell z score was significantly higher in responders than in nonresponders. The increase in CD4+ T-cell z score was not significantly different for naive and pretreated patients. HEIGHT, WEIGHT, AND BMI z SCORE CHANGES: We found that there was a trend toward a significantly increased z score change during 96 weeks of HAART compared with the z score change before HAART initiation for height and weight, but not for BMI. GROWTH AND VIROLOGIC RESPONSE TO HAART: When the data were analyzed separately for virologic responders and nonresponders, virologic responders showed significant increases in height and weight. The height and weight of virologic nonresponders did not change significantly. The BMI did not change significantly in responders or in nonresponders. GROWTH AND IMMUNOLOGIC RESPONSE TO HAART: The increase of weight and BMI z scores from baseline correlated positively with the CD4+ T-cell z score increase from baseline. It did not correlate with absolute CD4+ T-cell count increase. Height z score increase did not correlate with CD4+ T-cell z score or with absolute CD4+ T-cell counts. GROWTH AND PREVIOUS NRTI TREATMENT: The height z score decrease from week -48 to baseline was significantly larger in naive than in pretreated patients. The weight and BMI z score change from week -48 to baseline was not significantly different for pretreated and naive patients. From baseline to week 96, the height and weight z score change increased significantly in naive patients but not in pretreated patients compared with the change from week -48 to baseline. The BMI z score did not change significantly over 96 weeks of HAART for naive or pretreated patients. GROWTH AND CLINICAL STAGE OF INFECTION: The clinical stage of infection according to the Centers for Disease Control and Prevention classification correlated negatively with the BMI z score and the weight z score at baseline but not with the height z score. Thus, children with the most severe clinical disease had the lowest BMI and weight z scores at baseline. The BMI z score increased more in children with more advanced clinical infection at baseline, who had lower BMI at baseline. The clinical stage of infection did not correlate with the change in weight z score from baseline to week 96. CONCLUSIONS: HAART has a positive influence effect on the growth of HIV-1-infected children. This effect is sustained for at least 96 weeks. Height and weight are favorably influenced in children in whom HAART leads to a reduction of the viral load of at least 1.5 log or to <500 copies/mL and to an increase in the CD4+ T-cell z score. In contrast to the increase of the BMI in adults on HAART, BMI did not increase in all children effectively treated with HAART. BMI increased more in children with an advanced stage of infection and a poor nutritional status at baseline. Data from pretreated and naive patients were difficult to interpret, because the baseline characteristics of these 2 groups differed too much.