A randomized controlled trial of single-class maintenance therapy with abacavir/lamivudine/zidovudine after standard triple antiretroviral induction therapy: final 96-week results from the FREE study.

OBJECTIVES: The aim of the study was to test the antiviral efficacy of a triple nucleoside reverse transcriptase inhibitor (NRTI) regimen, with potential beneficial metabolic effects, as maintenance therapy after induction with dual NRTIs and a boosted protease inhibitor (PI). METHODS: An open-label, noninferiority study was carried out. Antiretroviral therapy (ART)-naïve patients with CD4 count ≤ 350 cells/µL and HIV-1 RNA >30000 copies/mL (n=207) were treated with zidovudine/lamivudine and lopinavir/ritonavir. After achieving HIV-1 RNA <50 copies/mL on two consecutive occasions between weeks 12 and 24 after baseline, 120 patients (baseline: median HIV-1 RNA 5.19 log10 copies/mL; median CD4 count 180 cells/µL) were randomized to receive abacavir/lamivudine/zidovudine (ABC/3TC/ZDV) (n=61) or to continue the PI-based ART (n=59). RESULTS: For the proportions of patients (intention-to-treat; missing=failure) with HIV-1 RNA <400 copies/mL (PI group, 66%; ABC/3TC/ZDV group, 71%) and <50 copies/mL (PI group, 63%; ABC/3TC/ZDV group, 62%) at 96 weeks, switching to ABC/3TC/ZDV was noninferior compared with continuing the PI regimen; the difference in failure rate (ABC/3TC/ZDV minus PI) was -4.4 percentage points [95% confidence interval (CI) -21.0 to +12.3 percentage points] and +0.4 percentage points (95% CI -16.9 to +17.7 percentage points), respectively. In the per protocol analysis, the difference in virological failure for HIV-1 RNA >400 copies/mL (0 of 39 patients in the PI group and two of 45 patients in the NRTI group) and for HIV-1 RNA >50 copies/mL (two of 39 and three of 45 patients, respectively) was +4.4 percentage points (95% CI -2.1 to +11.0 percentage points) and +1.5 percentage points (95% CI -8.6 to +11.7 percentage points), respectively, also showing noninferiority. Serum lipids significantly improved in the NRTI group, but not in the PI arm. CONCLUSIONS: A single-class NRTI regimen after successful induction with standard ART had similar antiviral efficacy compared to continuation of a PI-based regimen at 96 weeks after baseline, with improved serum lipids.

Psychometric properties of the TACQOL-asthma, a disease-specific measure of health related quality-of-life for children with asthma and their parents.

The disease-specific-TACQOL-asthma questionnaire measures health-status and appraisal of health-status. The TACQOL-asthma evaluates the personal feelings about problems in the domains, 'complaints, situations, emotions, treatment and medication'. The TACQOL-asthma can be used alone or in combination with the generic TACQOL. Our objective was to study the psychometric properties of the TACQOL-asthma-questionnaire. Responses of 298 parents and children with asthma (age eight to 16 years) in four paediatric practices in the northern part of The Netherlands were studied. The factor-analysis and item-domain correlation analysis show a moderate to strong correlation between the different items and their hypothesised domains. For all items, the correlation of the separate item with the hypothesized domain is stronger than with any other domain. The internal consistency (Cronbach's alpha) of the domains is moderate to good. Concurrent correlation with the Paediatric-Asthma-Quality-of-Life-Questionnaire-(PAQLQ) was significant. Effect sizes of differences between asthma-severity classes in TACQOL-asthma and PAQLQ-scores were similar and of clinical importance. This study validates the TACQOL-asthma as a new disease-specific questionnaire. The TACQOL-asthma ensures a measurement of health status as well as appraisal of health problems. The TACQOL-asthma has good reliability and validity properties to serve as an evaluative and discriminate disease-specific health-related-quality-of-life questionnaire.

Trimetrexate as biochemical modulator of 5-fluorouracil/leucovorin in advanced colorectal cancer: final results of a randomised European study.

BACKGROUND: Trimetrexate (TMTX) is a biochemical modulator of 5-fluorouracil (5-FU) and leucovorin (LV). Phase II trials have shown promising activity of 5-FU/LV/TMTX in patients with advanced colorectal cancer (ACC). This trial evaluated the effect of TMTX in combination with 5-FU/LV as first-line treatment in ACC. PATIENTS AND METHODS: Patients with ACC were randomised to receive either intravenous LV 200 mg/m2/5-FU 600 mg/m2 or TMTX 110 mg/m2 followed 24 h later by LV 200 mg/m2/5-FU 500 mg/m2 plus oral LV rescue. Both schedules were given weekly for 6 weeks every 8 weeks. Patients were evaluated for progression-free survival (PFS), overall survival (OS), tumour response, quality of life (QoL) and toxicity. RESULTS: A total of 365 patients were randomised. A statistically significant prolongation of median PFS was seen in patients treated with TMTX/5-FU/LV compared with 5-FU/LV (5.4 months versus 4.1 months, respectively; P = 0.03), and a trend towards a significant benefit for OS (13.4 months versus 10.5 months, respectively; P = 0.08). Tumour response, QoL and toxicity were comparable between the two arms. Diarrhoea was the most frequently occurring grade 3 or 4 toxicity (22% and 30%, respectively). CONCLUSIONS: The addition of TMTX to a weekly regimen of 5-FU/LV results in a small but significant improvement in PFS without adding toxicity or worsening QoL in patients with ACC.

Immune restoration does not invariably occur following long-term HIV-1 suppression during antiretroviral therapy. INCAS Study Group.

BACKGROUND: Current antiretroviral treatment can induce significant and sustained virological and immunological responses in HIV-1-infected persons over at least the short- to mid-term. OBJECTIVES: In this study, long-term immune reconstitution was investigated during highly active antiretroviral therapy. METHODS: Patients enrolled in the INCAS study in The Netherlands were treated for 102 weeks (range 52-144 weeks) with nevirapine (NVP) + zidovudine (ZDV) (n = 9), didanosine (ddl) + ZDV (n = 10), or NVP + ddl + ZDV (n = 10). Memory and naïve CD4+ and CD8+ T cells were measured using CD45RA and CD27 monoclonal antibodies (mAb), T-cell function was assayed by CD3 + CD28 mAb stimulation, and plasma HIV-1 RNA load was measured by ultra-direct assay (cut-off < 20 copies/ml). RESULTS: Compared to both double combination regimens the triple combination regimen resulted in the most sustained increase in CD4+ T cells (change in CD4+, + 253 x 10(6) cells/l; standard error, 79 x 10(6) cells/l) and reduction of plasma HIV-1 RNA. In nine patients (31%) (ddl + ZDV, n = 2; NVP + ddl + ZDV, n = 7) plasma HIV-1 RNA levels remained below cut-off for at least 2 years. On average, these long-term virological responders demonstrated a significantly higher increase of naïve and memory CD4+ T cells (P = 0.01 and 0.02, respectively) as compared with patients with a virological failure, and showed improved T-cell function and normalization of the naïve; memory CD8+ T-cell ratio. However, individual virological success or failure did not predict the degree of immunological response. T-cell patterns were independent of baseline CD4+ T-cell count, T-cell function, HIV-1 RNA load or age. Low numbers of naïve CD4+ T cells at baseline resulted in modest long-term naïve T-cell recovery. CONCLUSIONS: Patients with prolonged undetectable plasma HIV-1 RNA levels during antiretroviral therapy do not invariably show immune restoration. Naïve T-cell recovery in the setting of complete viral suppression is a gradual process, similar to that reported for immune recovery in adults after chemotherapy and bone marrow transplantation.

Tolerability and activity of a new recombinant interferon-alpha B/D hybrid in patients with HIV-1 infection.

The maximum tolerated dose (MTD) and toxicity profile of a new recombinant interferon-alpha B/D hybrid (IFN-alpha B/D) in HlV-1-infected patients were determined in an outpatient, dose-escalating study with dose groups of three patients: 16, 32, 48, 64, 96 and 112 million international units (MIU) three times weekly subcutaneously during 12 weeks. The MTD was the last dose level just below the dose level at which more than one patient experienced > or = grade 3 toxicity. The study also searched for preliminary evidence of efficacy of IFN-alpha B/D. Sixteen HIV-1-infected patients with CD4 cell counts > or = 200/mm3 were enrolled: eight were asymptomatic and eight had symptomatic disease. Two patients were excluded as a result of protocol violations. Five patients (36 per cent; one at each tested dose level) discontinued prematurely due to side effects. One patient was lost to follow-up. Twelve patients (87 per cent) experienced > or = grade 2 toxicity. Toxicity > or = grade 3 occurred in none of three patients assigned to 16 MIU, one of five assigned to 32 MIU (fatigue), one of three assigned to 48 MIU (haemorrhagic colitis) and two of three assigned to 64 MIU (fatigue). One patient (48 MIU) had reversible cardiomegaly. Progressive weight loss was experienced by 12 of 14 participants. Serum HIV-1 p24 antigen declined in nine of 11 antigenaemic patients (seven persistently > 50 per cent) without a clear dose-response relationship. CD4 percentages showed no consistent pattern and T cell reactivity diminished. The tolerability and toxicity profile of IFN-alpha B/D appear to be fairly similar to that of other types of IFN-alpha.

Treatment of the Budd-Chiari syndrome by insertion of a wall-stent in the hepatic vein after percutaneous transluminal angioplasty: the necessity of follow-up.

Budd-Chiari syndrome is a rare disease and, with or without treatment, the prognosis is usually poor. Percutaneous transluminal angioplasty of the hepatic vein in Budd-Chiari syndrome is a safe method, although recurrent stenosis makes it necessary to repeat it several times in most cases. Insertion of a wall-stent in the hepatic vein seems to be a more long-lasting treatment. Monitoring the blood flow through the wall-stent every 6 months is important because of the apparent obliteration of the wall-stent by intimal fibrosis of the hepatic vein. Further follow-up investigations of this method are necessary.

Substitution of didanosine sachets by chewable tablets: a pharmacokinetic study in patients with AIDS.

We have conducted a pharmacokinetic study of didanosine (ddI), formulated in sachets and in tablets, in patients with acquired immune deficiency syndrome (AIDS). Fifteen subjects received 250 or 167 mg of ddI twice daily as the sachet formulation and used this for at least 1 month. Subsequently, the patients were converted to receive ddI chewable/dispersible tablets (250-mg sachets to 200-mg tablets; 167-mg sachets to 125-mg tablets). Four subjects withdrew because of clinical deterioration or adverse effects. Serial blood samples were collected for pharmacokinetic monitoring during the use of the sachets and after 1 month of use of the tablets. No statistically significant differences were found in the maximum plasma concentration (Cmax), the time to reach Cmax (tmax), the area under the plasma concentration-time curve (AUC), or the terminal elimination half-life (t1/2) between the two formulations. Patients who received low-dose ddI (sachets, 167 mg; tablets, 125 mg) displayed lower plasma concentrations than did the patients receiving high-dose ddI (sachets, 250 mg; tablets, 200 mg), despite an equal weight-normalized dose of ddI in these two groups.

Treatment of poor prognosis epidemic Kaposi's sarcoma with doxorubicin, bleomycin, vindesine and recombinant human granulocyte-monocyte colony stimulating factor (rh GM-CSF).

The efficacy and toxicity of doxorubicin, bleomycin and vindesine in epidemic Kaposi's sarcoma, and the role of rh GM-CSF in chemotherapy-induced neutropenia were evaluated in this Phase II study. Patients with progressive Kaposi's sarcoma were eligible, and were staged according to ACTG criteria. Treatment consisted of 20 mg/m2 doxorubicin, and a fixed dose of 15 mg bleomycin and 4 mg vindesine every 2 weeks. All patients continued antiretroviral medication with severe myelosuppression, patients received subcutaneous 5 micrograms/kg rh GM-CSF (Leucomax) from days 2-12. Response and toxicity were measured according to ACTG and WHO criteria. 27 patients were evaluable, 25 patients classified as having a poor prognosis. The response rate was 70% (3 CR, 16 PR), the duration of response was 18 weeks (range 8-25) and the median survival 30 weeks (range 4-63+). The cause of death was mostly opportunistic infection. 4 patients died of pulmonary Kaposi's sarcoma. The toxicity of this regimen was mainly myelosuppression and 13 patients were treated with rh GM-CSF. Complete recovery of the white blood cells occurred in seven of the 27 courses of rh GM-CSF (26%). No bacterial infections were recorded, but 5 patients (19%) developed an opportunistic infection during treatment. Peripheral neuropathy occurred in 16% of patients. Combination chemotherapy is effective in poor prognosis Kaposi's sarcoma but has a shortlasting effect. The main toxicity of this treatment is severe myelosuppression which can be ameliorated by rh GM-CSF. It remains to be established whether rh GM-CSF is also able to reduce the incidence of opportunistic infections.

Pharmacokinetic variability of zidovudine in HIV-infected individuals: subgroup analysis and drug interactions.

OBJECTIVE: To investigate determinants of inter- and intraindividual variability of zidovudine (ZDV) pharmacokinetics in HIV-infected patients. DESIGN: A prospective study in a general 525-bed hospital with special funding for treatment and research of HIV-infected patients. METHODS: Serial blood samples were collected from 68 HIV-infected individuals providing a total of 95 pharmacokinetic curves. ZDV was measured with high-performance liquid chromatography and radioimmunoassay. Pharmacokinetic parameters were calculated by non-compartmental analysis. Patient characteristics were investigated by multivariate analysis for an influence on ZDV pharmacokinetics. RESULTS: Apparent ZDV clearance was significantly lower in patients with a lower body weight, in women, and in patients with a more advanced stage of HIV disease. Co-administration of methadone with ZDV resulted in higher plasma concentrations of ZDV, while rifampin and ganciclovir increased apparent ZDV clearance. Age, the duration of ZDV use, CD4+ cell count, creatinine clearance, elevated serum liver enzyme levels, and the use of 11 other co-administered medications were not independently related to apparent ZDV clearance. CONCLUSIONS: The pharmacokinetic profile of ZDV in several subpopulations has been evaluated, as well as the observation of possible drug-drug interactions between ZDV and 14 different drugs or groups of drugs. These data suggest that patient-individualized antiretroviral therapy may be appropriate once pharmacokinetic-pharmacodynamic relationships have been established.

Application of a radioimmunoassay for determination of levels of zalcitabine (ddC) in human plasma, urine, and cerebrospinal fluid.

A specific and sensitive radioimmunoassay for the determination of levels of zalcitabine in human plasma, urine, and cerebrospinal fluid has been developed. Commercially available radiolabel and antiserum (Sigma Chemicals) were used after dilution in assay buffer. Prior to the immunoassay, standard and patient samples were subjected to solid-phase extraction on silica columns in order to obtain purified samples. The lower limit of quantitation was determined to be 1 ng/ml. Intra- and interassay variations were less than 11% for a number of quality control samples of drug in plasma and urine. Results from parallelism studies with plasma and urine demonstrated that samples outside the standard range (1 to 30 ng/ml) could be diluted by blank plasma or assay buffer, respectively. A large number of related compounds and potentially coadministered drugs were tested for cross-reactivity. Stability tests showed that heat treatment for 30 min at 60 degrees C or storage for 1 month at -30 degrees C did not affect zalcitabine concentrations in plasma or urine. The radioimmunoassay with solid-phase extraction for sample cleanup discussed here has been successfully applied in a pharmacokinetic study of a single patient, demonstrating its applicability for clinical pharmacokinetic research with zalcitabine.

Zidovudine and interferon-alpha combination therapy versus zidovudine monotherapy in subjects with symptomatic human immunodeficiency virus type 1 infection.

Forty-five subjects with symptomatic human immunodeficiency virus type 1 (HIV-1) infection, CD4+ lymphocyte counts of > or = 150 x 10(6)/L, and Karnofsky scores > or = 60 were enrolled in a multicenter, randomized, controlled trial that compared zidovudine monotherapy and combination therapy for 48 weeks with zidovudine and interferon-alpha (IFN-alpha). Zidovudine with IFN-alpha (n = 25) had a favorable effect on CD4+ cell counts compared with zidovudine alone (n = 20). At all time points analyzed, the mean change from baseline was higher, reaching significance at week 24 (+10% versus -21%; P = .029). At week 48 the difference was -12% versus -45% (P = .07). Anti-CD3 monoclonal antibody-induced T cell reactivity improved temporarily in both groups. Serum HIV p24 antigen levels decreased maximally during the first 12 weeks of treatment. At weeks 0 and 48, polymerase chain reaction analysis for mutations at codons 67 and 215 of the HIV-1 reverse transcriptase gene conferring zidovudine resistance was conducted in 10 subjects receiving zidovudine and in 8 subjects receiving combination therapy. At week 48, 1 of 8 and 4 of 6 samples from the groups receiving zidovudine only or combination therapy, respectively, contained wild type virus at codon 215. Grade 3 or 4 toxicity was uncommon. Drug-related malaise and anorexia were observed more frequently in patients receiving both zidovudine and IFN-alpha.

Clinical, toxicological and pharmaceutical aspects of the antineoplastic drug taxol: a review.

Taxol, a diterpene alkaloid isolated from the bark of Taxus brevifolia, has a unique mechanism of action. The drug promotes the formation of microtubule polymers in a cell, by reversibly and specifically binding the beta-subunit of tubulin. Taxol is administered intravenously by a 3-24-hour infusion at 3-week intervals. Myelosuppression, especially neutropenia, appears to be the dose limiting toxicity in solid tumours at 200-250 mg/m2. Furthermore, side effects such as sensory neurotoxicity (with typical numbness, tingling and painful paraesthesiae in the extremities), diarrhoea and alopecia appear frequently. Mucositis appears to be the non-haematological dose limiting side effect at 390 mg/m2 that has been determined in patients with leukaemia. Hypersensitivity reactions, which have been fatal in individual cases, might be schedule dependent. Furthermore, antiallergic prophylaxis must be given, although this precaution might not be considered to be fully protective. Phase I studies performed with combinations of taxol and cisplatin, doxorubicin or cyclophosphamide have indicated the feasibility of these regimens and show promise for future investigations. Addition of granulocyte-colony stimulating factor (G-CSF), aimed at modulating myelosuppressive toxicity, showed in Phase I studies that the taxol dose could be increased to 250 mg/m2, with peripheral neuropathy as the dose limiting toxicity. In Phase II studies, taxol has been shown to be effective, including producing complete tumour remission, in advanced drug refractory ovarian carcinoma (19%-36% response rate), previously treated patients with metastatic breast carcinoma (27%-62% response rate), advanced non-small lung cancer (21%-24% response rate), advanced small cell lung cancer (37% response rate) and advanced head and neck cancer (34% response rate).(ABSTRACT TRUNCATED AT 250 WORDS)

[A man with spontaneous regression of non-Hodgkin lymphoma, hypergammaglobulinemia and infection caused by 2 herpesviruses; causality or coincidence?]. / Een man met spontane regressie van non-Hodgkin-lymfoom, hypergammaglobulinemie en infectie met twee herpes-virussen; causaliteit of coïncidentie?

A febrile illness with atypical peripheral blood lymphocytosis (polyclonal CD8+ suppressor/cytotoxic phenotype), complement activation and IgA/G class hypergammaglobulinaemia was found in a 76-year old male with clinical stage III follicular non-Hodgkin lymphoma (NHL). There was serological evidence of active cytomegalovirus (CMV) as well as reactivated chronic Epstein-Barr virus (EBV) infection. Spontaneous regression of NHL appeared, the signs of viral infection improved but hypergammaglobulinaemia persisted. In patients with malignant lymphoma, clinical signs and abnormalities of peripheral blood lymphocytes and serum immunoglobulins should not automatically be considered a consequence of the lymphoma.

Kikuchi's lymphadenitis: report of a Yersinia enterocolitica-associated case and an overview of aetiology and clinical outcome.

Kikuchi's lymphadenitis (KL; histiocytic necrotizing lymphadenitis without granulocytic infiltration) is a generally benign, febrile disorder of unknown aetiology with distinct histological features. To date, a minority of cases reported have been associated with infectious agents. A typical pathological case of KL is described where involvement of Yersinia enterocolitica was shown by an indirect immunofluorescent assay applied to lymphatic tissue. The case is discussed with emphasis on recent insight into the course and aetiology of KL.

[Doctor's delay in HIV infection caused by blood transfusion]. / 'Doctor's delay' bij infectie met HIV door bloedtransfusie.

Transfusion-associated symptomatic HIV infection in four patients led to death in two patients and to development of serious neurological sequelae in a third patient who also transmitted HIV infection to his spouse. The tardy diagnosis of HIV-associated disease in all cases can be ascribed to ignoring the earlier blood transfusion as a possible cause of HIV infection. This was due partly to advanced age of the patients and partly to lack of familiarity of the attending physicians with HIV-associated problems. This resulted in a substantial doctor's delay.

Common variable immunodeficiency in a family.

Common variable immunodeficiency (CVID) is mainly characterised by hypo- or agammaglobulinaemia of late onset, usually discovered in the second decade of life. In individuals CVID is associated with a variable impairment of cellular immunity and the susceptibility to microbial infection may vary as well. CVID is described in a mother and a son who suffered from serious bacterial infections. In addition, minor immunological test abnormalities of apparently healthy first degree relatives are described.