Treatment-experienced Children Research Articles

Once- versus twice-daily lopinavir/ritonavir tablets in virologically suppressed, HIV-infected, treatment-experienced children: comparative pharmacokinetics and virological outcome after switching to once-daily lopinavir/ritonavir

Data on lopinavir/ritonavir tablets administered once daily in children are limited. We compared the pharmacokinetics (PK) of lopinavir/ritonavir twice daily versus once daily in virologically suppressed, HIV-infected children, and assessed the virological outcome, at 48 weeks, in children receiving the regimen of lopinavir/ritonavir once daily. HIV-infected children receiving a twice-daily lopinavir/ritonavir-based regimen and with an HIV-1 RNA viral load (VL) <40 copies/mL for at least 3 months were enrolled. Intensive steady-state 12 h blood sampling for PK assessment was performed at enrolment. Immediately afterwards, the lopinavir/ritonavir dose was changed to once daily with the equivalent daily dose, and intensive steady-state 24 h blood sampling was repeated 2 weeks later. If the lopinavir C(trough) was <1.0 μg/mL, the lopinavir/ritonavir dose was increased by 20%-30% and C(trough) measurement repeated. CD4 cell counts and VL were determined at baseline and at 12, 24 and 48 weeks. Twelve children were enrolled. The median age was 13.1 years. Lopinavir AUC(0-24) following twice-daily and once-daily dosing was 169.7 (124.0-200.8) and 167.1 (95.1-228.1) μg · h/mL, respectively. Seven children, including all six concomitantly receiving efavirenz, had a C(trough) <1.0 μg/mL with once-daily lopinavir/ritonavir dosing, and four of seven children had a C(trough) <1.0 μg/mL after dose adjustment. All children maintained virological suppression throughout the 48 week period. Lopinavir/ritonavir-based once-daily regimens could simplify therapy in children/adolescents with virological control, but a lower lopinavir C(trough) was evident. Further efficacy studies of lopinavir/ritonavir once daily in children are necessary before routinely recommending this dosing strategy.

Treatment adherence with the easypod™ growth hormone electronic auto-injector and patient acceptance: survey results from 824 children and their parents

BackgroundAccurately monitoring adherence to treatment with recombinant human growth hormone (r-hGH) enables appropriate intervention in cases of poor adherence. The electronic r-hGH auto-injector, easypod™, automatically records the patient's adherence to treatment. This study evaluated adherence to treatment of children who started using the auto-injector and assessed opinions about the device.MethodsA multicentre, multinational, observational 3-month survey in which children received r-hGH as part of their normal care. Physicians reviewed the recorded dose history and children (with or without parental assistance) completed a questionnaire-based survey. Children missing ≤2 injections per month (92% of injections given) were considered adherent to treatment. Adherence was compared between GH treatment-naïve and treatment-experienced children.ResultsOf 834 recruited participants, 824 were evaluated. The median (range) age was 11 (1-18) years. From the recorded dose history, 87.5% of children were adherent to treatment over the 3-month period. Recorded adherence was higher in treatment-naïve (89.7%, n = 445/496) than in treatment-experienced children (81.7%, n = 152/186) [Fisher's exact test FI(X) = 7.577; p = 0.0062]. According to self-reported data, 90.2% (607/673) of children were adherent over 3 months; 51.5% (421/817) missed ≥1 injection over this period (mainly due to forgetfulness). Concordance between reported and recorded adherence was 84.3%, with a trend towards self-reported adherence being higher than recorded adherence. Most children liked the auto-injector: over 80% gave the top two responses from five options for ease of use (720/779), speed (684/805) and comfort (716/804). Although 38.5% (300/780) of children reported pain on injection, over half of children (210/363) considered the pain to be less or much less than expected. Given the choice, 91.8% (732/797) of children/parents would continue using the device.Conclusionseasypod™ provides an accurate method of monitoring adherence to treatment with r-hGH. In children who received treatment with r-hGH using easypod™, short-term adherence is good, and significantly higher in treatment-naïve children compared with experienced children. Children/parents rate the device highly. The high level of acceptability of the device is reflected by a desire to continue using it by over 90% of the children in the survey.

Sex-Based Outcomes of Darunavir–Ritonavir Therapy: The GRACE (Gender, Race, and Clinical Experience) Study

In 2006, an estimated 1 106 400 adults and adolescents in the United States were living with HIV or AIDS (1). Of the new cases of HIV reported in 2006, 27% were women, and 45% were black (2). Since the beginning of the epidemic, women have accounted for an increasing proportion of persons with the disease (3). Furthermore, women of color are disproportionately affected: 64% and 15% of women living with HIV/AIDS in the United States in 2005 were black and Hispanic, respectively, yet these groups collectively represent only approximately 25% of the U.S. female population (3, 4). Women, and particularly women of color, have been underrepresented in antiretroviral clinical trials for treatment-experienced patients (5). This may reflect challenges in both recruiting and retaining women in clinical trials as a whole and highlights barriers to continuous medical care for this population, such as family commitments, job-related time constraints, or other socioeconomic factors. These observations have been noted in clinical trials of several other therapeutic areas (6–9), including cardiovascular, lung, and cancer research, suggesting that the challenges of recruiting women and persons or color are not specific to trials of antiretroviral therapy. An analysis (6) of the enrollment of women in cardiovascular clinical trials funded by the National Heart, Lung, and Blood Institute showed that studies of congestive heart failure enrolled only 26% women, although women account for 43% of patients with congestive heart failure. Likewise, examination of high-impact cancer studies published in 2006 (10) showed that women were underrepresented in studies of non–sex-specific types of cancer, averaging only 38.8% of enrolled participants. This has resulted in a paucity of clinical data for diverse populations. Although sex-based analyses are required for registration trials (11), studies with less than 25% female enrollment generally have limited statistical power to assess sex differences, thereby limiting sex-based conclusions in most trials (12). The recruitment and retention of women in clinical trials are essential to provide accurate information on the efficacy and safety of therapeutic agents in all patients and, ultimately, to guide treatment decisions for women (13, 14). Darunavir, a protease inhibitor, combined with a low dose of ritonavir, was initially introduced as a therapeutic option (600/100 mg twice daily) for treatment-experienced patients with HIV (15). Subsequently, darunavir–ritonavir was approved for use in treatment-naive adults (800/100 mg once daily) and treatment-experienced children (aged 6 to 17 years; weight-dependent twice-daily dosing) (15). In the POWER (Performance Of TMC114/r When evaluated in treatment-Experienced patients with PI [protease inhibitor] Resistance) and TITAN (TMC114/r In Treatment-experienced pAtients Naive to Lopinavir) trials, which assessed the efficacy and safety of darunavir–ritonavir, the number of women enrolled was approximately 10% to 21% of the overall population (16, 17). In the ARTEMIS (AntiRetroviral Therapy with TMC114 ExaMined In naive Subjects) trial, treatment-naive women accounted for 30% of patients in the darunavir–ritonavir group, with results showing similar safety and efficacy between the sexes at week 96 and no differences in discontinuation rates due to adverse events (18). To expand the clinical data available for darunavir–ritonavir in treatment-experienced women, the GRACE (Gender, Race, And Clinical Experience) trial, conducted from 6 October 2006 to 19 December 2008, was specifically designed and powered to assess sex-based differences in efficacy and to evaluate the incidence of adverse events (5). The study was also designed to enroll a high proportion of treatment-experienced North American women to reflect the distribution and demographic characteristics of women with HIV in the United States. We report the efficacy outcomes and incidence of adverse events in women and men who received darunavir–ritonavir-based therapy over 48 weeks during the GRACE study; data on outcomes by race and ethnicity will be presented elsewhere.

Pharmacokinetics, safety and efficacy of darunavir/ritonavir in treatment-experienced children and adolescents

To assess pharmacokinetics, safety and efficacy of darunavir/ritonavir (DRV/r) and optimized background regimen in treatment-experienced patients (6-17 years). Forty-eight-week, open-label, two-part, phase II study. In part I, 44 patients were randomized (1: 1 ratio) to receive a body weight-adjusted, adult-equivalent dose (group A) or a 20-33% higher DRV/r twice daily (b.i.d.) dose (group B). Pharmacokinetics, safety and efficacy were assessed following 2-week dosing (part I), which determined dosing for part II (evaluated 48-week safety and efficacy). In part I, both groups met the protocol-specified criteria for pharmacokinetics and showed favorable tolerability and efficacy. The following body-weight doses were selected: DRV/r 375/50 mg b.i.d. (20-<30 kg), 450/60 mg b.i.d. (30-<40 kg) and 600/100 mg b.i.d. (> or =40 kg); these gave an AUC24h, C0h and Cmax of 102, 114 and 112%, respectively, versus the corresponding mean adult pharmacokinetic parameter. In part II, 80 patients received DRV/r (median age: 14 years, mean baseline HIV-1 RNA: 4.64 log(10)copies/ml). One patient (1%) discontinued (treatment-unrelated grade 3 anxiety). An abnormal mean baseline triglyceride level was normalized at 48 weeks (P < 0.01). At week 48, 65% had at least 1.0 log(10)HIV-1 RNA reduction; 59 and 48% achieved HIV-1 RNA less than 400 and less than 50 copies/ml, respectively (time-to-loss-of-virologic response). Mean age-adjusted weight z-score increased by 0.2 (P = 0.003). In treatment-experienced children and adolescents, DRV/r showed comparable exposure to adults with appropriate dose selection, favorable safety and tolerability, improved body weight and significant virologic response. DRV/r is a valuable therapeutic option for this population.

Managing treatment-experienced pediatric and adolescent HIV patients: role of darunavir

Darunavir is currently the most recently approved HIV-1 protease inhibitor. It is approved for twice-daily dosing with ritonavir in treatment-experienced patients as young as 6 years of age and is available in numerous pill strengths. Emergence of darunavir-specific mutations is generally slow; therefore it can retain activity against viral strains that are resistant to other protease inhibitors, including tipranavir. Darunavir pharmacokinetics, clinical efficacy, resistance mutations and pharmacodynamics, and adverse effects are reviewed here. Substantial data support its use as a potent, well-tolerated option for salvage therapy in highly treatment-experienced children and adolescents.

HIV drug resistance in HIV-infected children

Almeida et al. report, in this issue of the journal, a retrospective studyon theprevalence and patterns of antiretroviral drug resistance in 24 treatment-naive and 23 treatment-experienced children failing therapy between 2000 and 2004 attending a clinic in Sao Paulo. All children were vertically infected, and the median age of the naiveand treatment-experienced children was 22 months and 102 months, respectively. In the children failing ART, the median duration of ART exposure was 60 months (range3-120months), and the log viral load at treatment failure was 5.04 log copies/mL. The overall distribution of subtypes among both groups of children was 78.3% subtype B, 13% subtype F, 4.4%BFmosaics and 4.3% subtype C, which reflects thedistinctivemolecular epidemiologyofHIV-1 inBrazil, with the low-level but rising prevalence of subtypeC infection in the south of the country.

Treatment-experienced children with HIV-1 infection may achieve long-term immune recovery with lopinavir/ritonavir treatment,

Treatment-experienced children with HIV-1 infection may achieve long-term immune recovery with lopinavir/ritonavir treatment,

The combination of darunavir and ritonavir appears to be effective for treatment-experienced children and adolescents with HIV-1 infections,

The combination of darunavir and ritonavir appears to be effective for treatment-experienced children and adolescents with HIV-1 infections,

Safety, efficacy, and pharmacokinetics of adefovir dipivoxil in children and adolescents (age 2 to &lt;18 years) with chronic hepatitis B

This study investigated the efficacy, safety, and pharmacokinetics of adefovir dipivoxil (ADV) in children and adolescents with chronic hepatitis B (CHB). A total of 173 treatment-naive and treatment-experienced children with hepatitis B e antigen (HBeAg)+ CHB were randomized to ADV or placebo. Randomization was stratified by age (2 to <7 years; >7 to <12 years; >12 to <18 years) and prior treatment. Significantly more ADV-treated subjects aged 12 to <18 years achieved the primary efficacy endpoint (serum hepatitis B virus [HBV] DNA <1,000 copies/mL and normal alanine aminotransferase) compared to placebo-treated subjects (23% versus 0%; P = 0.007). In the younger groups, differences between ADV and placebo at the end of blinded treatment were not statistically significant. More ADV-treated subjects had HBeAg seroconversion: 18 of 113 (15.9%) versus three of 57 (5.3%) (but P = 0.051), and more met the combined endpoint of HBeAg seroconversion, HBV DNA <1,000 copies/mL and normal alanine aminotransferase (12/113 versus 0/57; P = 0.009). No subject developed an ADV-associated mutation that has been linked to HBV DNA rebound (that is, mutations rtN236T or rtA181V). ADV plasma concentrations were comparable across groups and within the target range. ADV treatment was well tolerated; no new safety issues were identified. Treatment-related adverse events were reported for 12% of ADV-treated and 10% of placebo-treated subjects. After 48 weeks of ADV treatment, antiviral efficacy in subjects ages 12 to <18 years with HBeAg+ CHB was similar to that observed in a study in adult treatment-naive subjects with HBeAg+ CHB. ADV was not different from placebo in subjects aged 2 to 11 years despite adequate plasma ADV exposure in all three age groups. ADV showed significant antiviral efficacy in subjects aged 12 to 17 years with HBeAg+ CHB, but was not different from placebo in subjects aged 2 to 11 years.

A tipranavir/ritonavir oral solution demonstrates virological and immunological efficacy in treatment-experienced children with HIV,

A tipranavir/ritonavir oral solution demonstrates virological and immunological efficacy in treatment-experienced children with HIV,

Tenofovir Disoproxil Fumarate and an Optimized Background Regimen of Antiretroviral Agents as Salvage Therapy for Pediatric HIV Infection

Highly active antiretroviral therapy has altered the course of HIV infection among children, but new antiretroviral agents are needed for treatment-experienced children with drug-resistant virus. Tenofovir disoproxil fumarate (DF) is a promising agent for use in pediatric salvage therapy, because of its tolerability, efficacy, and resistance profile. We designed this study to provide preliminary pediatric safety and dosing information on tenofovir DF, while also providing potentially efficacious salvage therapy for heavily treatment-experienced, HIV-infected children. Tenofovir DF, alone and in combination with optimized background antiretroviral regimens, was studied among 18 HIV-infected children (age range: 8.3-16.2 years) who had progressive disease with > or = 2 prior antiretroviral regimens, in a single-center, open-label trial. Tenofovir DF monotherapy for 6 days was followed by the addition of individualized antiretroviral regimens. Subjects were monitored with HIV RNA reverse transcription-polymerase chain reaction, flow cytometry, and routine laboratory studies; monitoring for bone toxicity included measurement of lumbar spine bone mineral density (BMD) with dual-energy x-ray absorptiometry. Subjects were monitored through 48 weeks. Two subjects developed grade 3 elevated hepatic transaminase levels during monotherapy and were removed from the study. The remaining 16 subjects had a median of 4 antiretroviral agents (range: 3-5 agents) added to tenofovir DF. HIV plasma RNA levels decreased from a median pretreatment level of 5.4 log10 copies per mL (range: 4.1-5.9 log10 copies per mL) to 4.21 log10 copies per mL at week 48 (n = 15), with 6 subjects having < 400 copies per mL, including 4 with < 50 copies per mL. The overall median increases in CD4+ T cell counts were 58 cells per mm3 (range: -64 to 589 cells per mm3) at week 24 and 0 cells per mm3 (range: -274 to 768 cells per mm3) at week 48. The CD4+ cell responses among the virologic responders were high and sustained. The major toxicity attributed to tenofovir DF was a >6% decrease in BMD for 5 of 15 subjects evaluated at week 48, necessitating the discontinuation of tenofovir DF therapy for 2; all 5 subjects experienced >2 log10 copies per mL decreases in HIV plasma RNA levels. Tenofovir DF-containing, individualized, highly active antiretroviral therapy regimens were well tolerated and effective among heavily treatment-experienced, HIV-infected children. Loss of BMD may limit tenofovir DF use among prepubertal patients.

Pharmacokinetic and Pharmacodynamic Analysis of Amprenavir‐Containing Combination Therapy in HIV‐1—Infected Children

Several factors influence the antiviral response to antiretroviral therapy. In this pharmacokinetic and pharmacodynamic analysis, the relationship of drug exposure, demographics, and cotherapy measures to antiviral response in a cohort of largely treatment-experienced children treated with amprenavir and nucleoside reverse transcriptase inhibitors was examined. Multiple pharmacodynamic and demographic factors were examined, but only the minimum plasma concentration (C(min))/protein-binding-adjusted 50% inhibitory drug concentration (IC(50)) ratio and whether individuals received 2 versus fewer than 2 nucleosides to which their viral isolates were susceptible were associated with the magnitude of the time-weighted average change in HIV-1 RNA log(10) copies/mL from baseline (AAUCMB). In multivariate logistic regression analysis, only the C(min)/IC(50) ratio was independently associated with having a >or=1 log(10) AAUCMB decline. The probability in the study population of having a >or=1log(10) AAUCMB was 50% and 85% at C(min)/IC(50) ratios of approximately 1 and 4, respectively. Of the multiple factors examined, only the C(min)/IC(50) ratio was a significant predictor of antiviral response in the first 8 weeks on amprenavir-containing combination antiretroviral therapy.