Tolerability of four-drug antiretroviral combination therapy in primary HIV-1 infection.

OBJECTIVES: Rapid initiation of antiretroviral therapy (ART) is important for individuals with high baseline viral loads, such as in primary HIV-1 infection (PHI). Four-drug regimens are sometimes considered; however, data are lacking on tolerability. We aimed to evaluate the tolerability of four-drug regimens used in the Research in Viral Eradication of HIV-1 Reservoirs (RIVER) study. METHODS: At enrolment, ART-naïve adult participants or those newly commenced on ART were initiated or intensified to four-drug regimens within 4 weeks of PHI. Rapid start was defined as pre-confirmation or ≤ 7 days of confirmed diagnosis. Primary and secondary outcomes were patient-reported adherence measured by 7-day recall and regimen switches between enrolment and randomization, respectively. RESULTS: Overall, 54 men were included: 72.2% were of white ethnicity, with a median age of 32 years old, 42.6% had a viral load of ≥ 100 000 HIV-1 RNA copies/mL, and in 92.6% sex with men was the mode of acquisition of HIV-1. Twenty (37%) started a four-drug regimen and 34 (63%) were intensified. Rapid ART initiation occurred in 28%, 100% started in ≤ 4 weeks. By weeks 4, 12, and 24, 37.0%, 69.0%, and 94.0% were undetectable (viral load < 50 copies/mL), respectively. Adherence rates of 100% at weeks 4, 12, 22 and 24 were reported in 88.9%, 87.0%, 82.4% and 94.1% of participants, respectively. Five individuals switched to three drugs, four changed their regimen constituents, and two switched post-randomization. CONCLUSIONS: Overall, four-drug regimens were well tolerated and had high levels of adherence. Whilst their benefit over three-drug regimens is lacking, our findings should provide reassurance if a temporarily intensified regimen is clinically indicated to help facilitate treatment.

Host and disease factors are associated with cognitive function in European HIV-infected adults prior to initiation of antiretroviral therapy.

OBJECTIVES: Deficits in cognitive function remain prevalent in HIV-infected individuals. The aim of this European multicentre study was to assess factors associated with cognitive function in antiretroviral therapy (ART)-naïve HIV-infected subjects at the time of enrolment in the NEAT 001/Agence Nationale de Recherche sur le SIDA (ANRS) 143 study. METHODS: Prior to starting ART, seven cognitive tests exploring domains including episodic memory, verbal fluency, executive function and psychomotor speed were administered with scores standardized to z-score using the study population sample mean and standard deviation. The primary measure was overall z-score average (NPZ). We assessed associations between baseline factors and test results using multivariable regression models. RESULTS: Of 283 subjects with baseline cognitive assessments, 90% were male and 12% of black ethnicity. Median (interquartile range) age, years of education, years of known HIV infection, baseline CD4 count and baseline HIV RNA were 39 (31, 47) years, 13 (11, 17) years, 1 (0, 4) years, 344 (279, 410) cells/µL and 4.74 (4.28, 5.14) log10 HIV-1 RNA copies/mL, respectively. Forty per cent were current smokers. Factors significantly associated with poorer overall cognitive performance in multivariable models included older age, shorter duration of education, black ethnicity, lower height, and lower plasma HIV RNA. CONCLUSIONS: In this large, European-wide, ART-naïve population with relatively preserved immunity and early HIV infection, cognitive function scores at the time of ART initiation were associated with demographic and HIV-disease factors.

CD4 cell count and initiation of antiretroviral therapy: trends in seven UK centres, 1997-2003.

OBJECTIVES: We examined whether the timing of initiation of antiretroviral therapy (ART) in routine clinical practice reflected treatment guidelines, which have evolved towards recommending starting therapy at lower CD4 cell counts. METHODS: We analysed longitudinal data on 10,820 patients enrolled in the UK Collaborative HIV Cohort (UK CHIC) Study, which includes seven large clinical centres in south-east England. CD4 cell and viral load measurements performed in the period between 1 January 1997 and 31 December 2003 were classified according to whether ART was subsequently initiated or deferred, to estimate the probability of ART initiation by CD4 count and viral load over time. The effect of nonclinical factors (age, sex, ethnicity, and exposure category) was analysed by logistic regression. Kaplan-Meier analysis was used to estimate the proportion of patients who had initiated ART by a particular CD4 count among 'early' presenters (initial CD4 cell count >500 cells/microL). RESULTS: There was a tendency to initiate ART at lower CD4 cell counts over time in the years 1997-2000, especially in the range 200-500 cells/microL, with little change thereafter. An estimated 34% of HIV-infected individuals having presented early initiated ART at a CD4 count <200 cells/microL. We also found an independent influence of viral load, which was particularly pronounced for CD4 <350 cells/microL. Use of injection drugs was the only nonclinical factor associated with initiation of ART at lower CD4 cell counts. CONCLUSIONS: The initiation of ART in the clinics included in this analysis reflected evolving treatment guidelines. However, an unexpectedly high proportion of patients started ART at lower CD4 counts than recommended, which is only partly explained by late presentation.

Thyroid function in paediatric and young adult patients after sarcoma therapy: a report from the Late Effects Surveillance System.

OBJECTIVE: The role of chemotherapy in thyroid sequelae after cancer treatment has not been studied systematically, especially in sarcoma patients. The aim of this study was to determine the incidence of post-therapeutic thyroid disorders and their contributing factors in a cohort of paediatric sarcoma patients. DESIGN: Late effects of sarcoma treatment have been collected prospectively within the Late Effects Surveillance System (LESS) in Germany, Austria and Switzerland since 1998. PATIENTS: We studied 340 relapse-free paediatric patients (median age at diagnosis 12.2 [interquartile range (IQR) = 7.3-15.6 years] treated for osteosarcoma, soft tissue sarcoma or Ewing's sarcoma within the COSS-96, CWS-96/CWS-2002P or EICESS-92/EURO-E.W.I.N.G.-99 therapy trials. In addition to polychemotherapy, 127 patients were irradiated (mean cumulative dose 47 +/- 9.7 Gy), including 51 patients with irradiation to the head/neck region. Median follow-up was 24.6 (IQR = 11.9-44.9) months. MEASUREMENTS: We reviewed the results of yearly examinations of serum TSH and fT4 levels and thyroid ultrasound examinations. RESULTS: The incidence of thyroid disorders was 37% (19/51, 95% CI 24-52%) in patients with head/neck irradiation, and 11% (32/289, 95% CI 8-15%) in patients without irradiation to the head/neck. Thyroid disorders were more frequent in patients treated with idarubicin (P = 0.027) and trofosfamide (P = 0.016). We also found a significant association between raised TSH levels and treatment with trofosfamide (P = 0.008) or idarubicin (P = 0.037) (n = 250). CONCLUSIONS: The incidence of thyroid disorders in the head/neck-irradiated group was high. Even without head/neck irradiation, we found an increased proportion of patients with thyroid disorders, possibly as a result of chemotherapy.

Ifosfamide-induced nephrotoxicity in 593 sarcoma patients: a report from the Late Effects Surveillance System.

BACKGROUND: Ifosfamide is widely used in paediatric oncology, but its use is limited by nephrotoxic side effects. The aim of this study was to evaluate the incidence and risk factors of tubulopathy, with special emphasis on the influence of age, where different findings have been published so far. PROCEDURE: Five hundred ninety three children and adolescents treated for Ewing, osteo- or soft-tissue sarcoma (median age at diagnosis: 11.7 years) were prospectively investigated for nephrotoxicity in the Late Effects Surveillance System (LESS) study. Tubulopathy was diagnosed in case of continuing hypophosphatemia and proteinuria. RESULTS: After a median follow up of 19 months, 27 patients (4.6%; 95% CI: 3.0-6.6%) had newly developed tubulopathy. This incidence was 0.4% (95% CI: 0-2.4%) in patients treated with a cumulative ifosfamide dose of < or =24 g/m2, 6.5% (95% CI: 3.6-10.7%) after 24-60 g/m2, and 8.0% (95% CI: 4.2-13.6%) after > or = 60 g/m2. In multivariate analysis, children younger than 4 years at time of diagnosis had an 8.7-fold (95% CI: 3.5-21.8) higher risk for tubulopathy than older patients. Neither carboplatin treatment nor abdominal irradiation showed any significant influence. CONCLUSION: Ifosfamide-induced nephrotoxicity was found in 4.6% of patients. Risk factors were the cumulative ifosfamide dose and young age at treatment.

Nephrotoxicity of cisplatin and carboplatin in sarcoma patients: a report from the late effects surveillance system.

BACKGROUND: Cisplatin and carboplatin are both nephrotoxic and can induce, to a different degree, impairment in glomerular function and hypomagnesemia. Prospective longitudinal studies on these renal impairments are rare in children and adolescents. PROCEDURE: Six hundred and fifty one sarcoma patients were investigated prospectively for nephrotoxicity in the Late Effects Surveillance System (LESS) network (median follow-up 2 years). Median cumulative dose was 360 mg/m(2) for cisplatin, and 1,500 mg/m(2) for carboplatin. Patients not treated with any platinum derivative were used as controls. Most patients (including controls) also received ifosfamide. Renal function was tested by serum magnesium, serum creatinine, and the GFR as estimated by the Schwartz formula. We evaluated incidence, dependencies, and the course of impairments. RESULTS: There was no observed platinum-induced reduction of glomerular function over time. After cessation of antineoplastic therapy, hypomagnesemia (<0.7 mmol/L) occurred in 12.1% (95% CI: 6.8%-19.4%) of patients after cisplatin therapy, and in 15.6% (95% CI: 5.3%-32.8%) after carboplatin therapy, in comparison with 4.5% (95% CI: 2.0%-8.7%) in patients without any treatment with platinum derivatives (P = 0.008). In all groups, the frequency of hypomagnesemia decreased with ongoing follow-up, but serum magnesium remained lower in platinum treated patients throughout the study period. CONCLUSION: Nephrotoxicity after treatment with cisplatin and carboplatin was mild in our study. Further studies have to show if serum magnesium is permanently decreased in platinum treated patients and if this will result in any clinically relevant impairment.

Comparison of epirubicin and doxorubicin cardiotoxicity in children and adolescents treated within the German Cooperative Soft Tissue Sarcoma Study (CWS).

PURPOSE: Up to now, cardiotoxicity of epirubicin has been studied almost exclusively in adult cancer patients. The aim of this study was to investigate epirubicin in children and adolescents, in comparison with doxorubicin. METHODS: About 172 soft tissue sarcoma patients (mean age at diagnosis: 8.3 years), treated with epirubicin (median cumulative dose: 450 mg/m2) or doxorubicin (median cumulative dose: 240 mg/m2) within the high-risk group of the CWS-96 study, were examined in a prospective multicentre study. Heart function was analysed by echocardiography, measuring left-ventricular fractional shortening (FS). The median follow up was 27.7 months. RESULTS: Incidence of clinically manifest cardiomyopathy was 0% (0/60; 95% CI: 0-6.0%) in patients treated with epirubicin, and 0.9% (1/108; 95% CI: 0-5.1%) in patients treated with doxorubicin. A further three patients showed subclinical cardiomyopathy. There was no difference in FS between the two treatment arms. CONCLUSIONS: Cardiotoxicity was low in our study. For the short term, cardiotoxicity seems to be only a minor problem in patients treated with epirubicin as applied in this cohort.

Prospective longitudinal evaluation of doxorubicin-induced cardiomyopathy in sarcoma patients: a report of the late effects surveillance system (LESS).

BACKGROUND: Prospective longitudinal examinations of anthracycline-induced cardiomyopathy in a homogeneous cohort are rare in pediatric oncology. We herein report the results of observations on the frequency of cardiomyopathy in doxorubicin-treated sarcoma patients in Germany, Austria, and Switzerland. PROCEDURE: The Late Effects Surveillance System (LESS) prospectively collects longitudinal data on late sequelae of antineoplastic therapy in Ewing-, soft tissue-, and osteosarcoma patients treated within the therapy trial protocols of the German Society of Pediatric Oncology and Hematology. Two hundred sixty-five relapse-free patients who had received doxorubicin for the treatment within the EICESS-92/EURO-E.W.I.N.G.-99, COSS-96, and CWS-96 therapy trials were serially examined by echocardiography. The analyzed population consisted of 142 males and 123 females. Their mean age at the end of therapy was 13 +/- 5 years. The mean follow-up time was 34 +/- 12 months. The mean cumulative doxorubicin dose was 290 +/- 91 mg/m(2). RESULTS: In this cohort, the total cumulative incidence of doxorubicin-induced cardiomyopathy was 7.5%. Four patients (1.5%) suffered from a symptomatic cardiomyopathy and 16 (6%) from a subclinical cardiomyopathy. Cardiomyopathy manifested in 11 cases already under antineoplastic therapy and in the remaining nine cases at a median of 26 days (range: 17-174 days) after stopping antineoplastic therapy. Univariate and multivariable analysis did not confirm any of the known risk factors for developing anthracycline-induced cardiomyopathy in our patient group within the described time interval. CONCLUSIONS: After a mean follow-up of 34 +/- 12 months, cumulative incidence of doxorubicin-induced cardiomyopathy in our pediatric sarcoma patients was at the lower end of that reported by other groups.

Cisplatin-induced ototoxicity in osteosarcoma patients: a report from the late effects surveillance system.

The aim of this study was to analyze cisplatin-induced ototoxicity in a recent study trial. Seventy-four patients who had received cisplatin for the treatment of osteosarcoma (median cumulative dose: 360 mg/m2) were investigated prospectively for ototoxicity in a multicenter trial. Hearing function was tested by audiometry. We evaluated the incidence and dependencies of hearing loss. After cessation of therapy, 51% of the patients showed a hearing loss of >20 dB in the frequency range of 4-8 kHz. Only in one patient a hearing loss was found at 2 kHz, and in none at 1 kHz. At a cumulative cisplatin dose of < or = 240 mg/m2, almost no ototoxicity was found. Incidence and magnitude of hearing loss increased significantly with a higher cumulative dose. Furthermore, hearing thresholds were significantly poorer in children <12 years. A further follow-up investigation showed only a marginal change in hearing function. We conclude that ototoxicity is moderate in our group of patients and probably irreversible.

Prospective multicenter registration of major late sequelae in sarcoma patients using the Late Effects Surveillance System (LESS).

BACKGROUND: Late effects become progressively more important for the evaluation of therapeutic success in paediatric oncology. Thus, in 1998, the Late Effects Surveillance System (LESS) started to register and assess multicentrally, prospectively and longitudinally late effects of treatment for the group of Ewing's, soft tissue- and osteosarcoma patients. PATIENTS AND METHODS: The yearly results of the follow-up examinations of 785 Ewing's, soft tissue- and osteosarcoma patients, who were treated from 1.1.1998 until 31.12.2001, were prompted and assessed conforming to the guidelines developed by the LESS-study. RESULTS: 136/181 (75 %) of follow-up institutions take part in the LESS-study. Only 8 % of patients eligible for the LESS-study were cared for in non-cooperating facilities. Questionnaire return could be raised to 73-78 % and data completeness could also be significantly improved in the course of the study. Departments of internal medicine had a lower questionnaire return percentage than departments of paediatrics. Data availability for the nephrologic after-care was not satisfactory. CONCLUSIONS: The LESS project has been well established. Thus, the basis has been set for the development of risk-oriented strategies for intervention and for the further improvement of the follow-up of major late effects in sarcoma patients.

[Early factors influencing body weight and prevalence of overweight in 4610 children prior to school entry in the Erlangen District (Northern Bavaria)]. / Frühe Einflussfaktoren auf das Körpergewicht und die Prävalenz von Ubergewicht zum Zeitpunkt der Schuleingangsuntersuchung bei 4610 Kindern im Raum Erlangen/Nordbayern.

OBJECTIVE: Childhood obesity is a growing health problem among German children. Birth weight is considered to have a major influence on the course of postnatal weight. The present study investigates the relation between birth weight and body weight at health examination prior to school entry. We tested other parameters influencing childhood obesity, and hypothesized that within a 5-year interval the prevalence of obesity in children has increased significantly. METHODS: Our study is based on the retrospective analysis of the school enrolment health examinations of 4610 children in North Bavaria, e. g. the town Erlangen and administrative district Erlangen-Hoechstadt in 1995/96 and 2000/01. RESULTS: A higher birth weight was associated with a higher weight and BMI at school entry examination (p < 0.0001). An increased birth weight is therefore a considerable risk factor for later overweight in childhood. Hypotrophic newborn, however, gain less weight and exhibit a lower BMI in our study group. In general, boys were significantly heavier than girls (p < 0.001). Children of foreign origin were heavier and had a higher BMI corrected for age than German pupils but they were also 0.07 years older. Our regional survey revealed local differences in the prevalence of obesity. Comparing the cohorts 1995/96 and 2000/01 at school entry, a significant increase of BMI in the latter was found (p < 0.0001). CONCLUSIONS: A highly significant increase in the prevalence of infantile overweight has to be faced. Early prevention of childhood obesity is therefore mandatory to avoid the complications and higher morbidity.

Hearing function in soft tissue sarcoma patients after treatment with carboplatin: a report from the Late Effects Surveillance System.

The aim of this study was to analyse carboplatin-induced ototoxicity in a recent study trial. Twenty patients who had received carboplatin for the treatment of soft tissue sarcoma were investigated prospectively for ototoxicity in a multi-centre trial. Hearing function was tested by audiometry. All patients but one were treated with a cumulative dose of 1500 mg/m(2), the remaining with 500 mg/m(2). We evaluated the incidence and dependencies of hearing loss, and compared hearing thresholds to those of an untreated control group (n=60). Hearing thresholds in the carboplatin treated group were only marginally poorer compared with those of the control group. After carboplatin therapy no patient (0%; 95%-KI: 0-17%) had a hearing loss >20 dB. Hearing thresholds were not dependent on age, sex or cranial irradiation. We conclude that ototoxicity after carboplatin was low in our group of patients.

Comparison of leptin gene expression in different adipose tissues in children and adults.

OBJECTIVE: Adipose tissue displays depot-specific metabolic properties and a predominant gene expression of leptin in subcutaneous tissue. The aim of the study was to evaluate leptin mRNA expression in various adipose tissues and to relate it to plasma leptin concentrations. Furthermore, developmental changes in leptin gene expression from childhood to adulthood were examined. DESIGN AND METHODS: Thoracic subcutaneous and intrathoracic adipose tissue specimens were obtained in 22 adults (51-81 years) and 23 children (0.1-17 years) undergoing cardiac surgery, and abdominal subcutaneous, omental and mesenterial fat specimens were collected from 21 adults (38-79 years) and 22 children (0.2-17 years) before abdominal surgery. Preoperative plasma leptin concentrations were measured by RIA. Leptin mRNA expression was quantified by TaqMan real-time PCR. RESULTS: In adults, there was no difference between leptin gene expression in subcutaneous and intrathoracic fat, whereas in children leptin mRNA expression was significantly higher in subcutaneous adipose tissue. In omental fat, leptin mRNA levels were significantly lower compared with subcutaneous and mesenterial sites in both children and adults. Adults revealed a significantly higher leptin gene expression in subcutaneous, omental and mesenterial adipose tissues than children. Subcutaneous and omental leptin gene expression are independent factors for plasma leptin concentrations in children and adults. CONCLUSION: Leptin is differentially expressed at different adipose tissue sites, a situation which is even more pronounced in children. There is a developmental increase in leptin mRNA expression in adipose tissue during childhood, reaching maximal capacity in adulthood.

Multicentre analysis of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH.

BACKGROUND: To study cardiac function and the incidence of anthracycline-induced cardiotoxicity in children following treatment according to the nephroblastoma studies SIOP No.9/GPOH and SIOP 93-01/GPOH. PROCEDURE: Analysis of clinical status, echocardiography, and ECG findings prior to administration of anthracyclines (median cumulative doxorubicin dose: 250 mg/m(2) [range: 90-411 mg/m(2)] and after a median posttherapeutic interval of 2.9 years [range: 0-10.2 years]. Data on cardiac function before and/or after therapy could be obtained of 186 patients. RESULTS: Posttherapy left ventricular fractional shortening was reduced in 4/157 (2.5%) patients. Out of the 4 children, 2 had clinically reduced tolerance to exercise and received anticongestive therapy. Abnormal ECG findings that were not detectable prior to therapy were found in 7/124 (5.6%) children. CONCLUSIONS: The incidence of abnormal findings is low in our study group in comparison to data from the literature and might be due to the comparably short posttherapeutic interval.

Longterm heartrate telemetry in small mammals: a comprehensive approach as a prerequisite for valid results.

This paper describes a miniature telemetry system which is capable of precise, reliable longterm registration of heartrate (HR) in animals as small as laboratory mice. The ECG-transmitters have a weight of 0.9-1.5 g and a respective lifetime of 3-6 months depending on battery size. With suitable receiving antennas, transmitting range is sufficient for continuous reception in 200 m2 enclosures. The radio signals are demodulated in a signal processor and the ECG is converted to HR on the base of single interbeat intervals. General technical problems of telemetry like miniaturization, performance control, HR acquisition and artifact distinction are discussed. The experimental approach emphasizes the necessity of continuous registration of HR as a reference for experimental responses. Longterm shifts of HR due to social and nonsocial influences as well as experimental feedback effects are demonstrated and discussed.

Diurnal patterns of scent-marking, serum testosterone concentration and heart rate in male Mongolian gerbils.

The diurnal rhythms of scent marking behavior in an open-field test as well as the diurnal rhythms of serum testosterone concentration and heart rate under home cage conditions were investigated in male Mongolian gerbils. The behavioral measures of scent marking activity, sniffing frequency and locomotor activity in the open field showed a clear rhythm during the 24 hour period with a significant maximum during the dark. In contrast to this, the mean testosterone concentration was lower during the dark as compared to the light phase. The heart rate was not different during light and dark phase of the diurnal cycle, instead, bursts of increased frequency occurred approximately once per hour, both during light and dark phase.