Fujiko Mitsumoto

Diagnostic workup for fever of unknown origin: a multicenter collaborative retrospective study.

Objective Fever of unknown origin (FUO) can be caused by many diseases, and varies depending on region and time period. Research on FUO in Japan has been limited to single medical institution or region, and no nationwide study has been conducted. We identified diseases that should be considered and useful diagnostic testing in patients with FUO. Design A nationwide retrospective study. Setting 17 hospitals affiliated with the Japanese Society of Hospital General Medicine. Participants This study included patients ≥18 years diagnosed with ‘classical fever of unknown origin’ (axillary temperature ≥38°C at least twice over a ≥3-week period without elucidation of a cause at three outpatient visits or during 3 days of hospitalisation) between January and December 2011. Results A total of 121 patients with FUO were enrolled. The median age was 59 years (range 19–94 years). Causative diseases were infectious disease in 28 patients (23.1%), non-infectious inflammatory disease in 37 (30.6%), malignancy in 13 (10.7%), other in 15 (12.4%) and unknown in 28 (23.1%). The median interval from fever onset to evaluation at each hospital was 28 days. The longest time required for diagnosis involved a case of familial Mediterranean fever. Tests performed included blood cultures in 86.8%, serum procalcitonin in 43.8% and positron emission tomography in 29.8% of patients. Conclusions With the widespread use of CT, FUO due to deep-seated abscess or solid tumour is decreasing markedly. Owing to the influence of the ageing population, polymyalgia rheumatica was the most frequent cause (9 patients). Four patients had FUO associated with HIV/AIDS, an important cause of FUO in Japan. In a relatively small number of cases, cause remained unclear. This may have been due to bias inherent in a retrospective study. This study identified diseases that should be considered in the differential diagnosis of FUO.

Early phase viral kinetics of chronic hepatitis C patients receiving telaprevir-based triple therapy: A comparison of two real-time PCR assays

Monitoring hepatitis C virus (HCV) kinetics during antiviral treatment is recommended for determining the best form of treatment management. We compared the measurement of HCV RNA by two Real-time PCR assays during the first 12weeks phase of telaprevir in combination with pegylated interferon α2b and ribavirin treatment for chronic hepatitis C patients. The viral kinetics of 65 patients with HCV genotype 1b was assessed. HCV RNA was tested at baseline, on day 3, and every week from 1 to 12 by both the first-generation Roche COBAS® AmpliPrep/COBAS® TaqMan® HCV (CAP/CTM) assay and the Abbott RealTime HCV (ART) assay. A total of 910 serum samples were obtained from the 65 patients. Of these, 168 (28.5%) of the 590 samples HCV RNA negative by CAP/CTM were positive by ART. In contrast, 17 (3.9%) of the 439 samples HCV RNA negative by ART were positive by CAP/CTM. The rates of HCV RNA negativity by ART at weeks 3, 4, and 5 were significantly lower than those by CAP/CTM (21.5% vs. 50.8%, 36.9% vs. 70.8% and 44.6% vs. 81.5%; P<0.001, P<0.0001 and P<0.05, respectively). Although the ART is superior for the determination of HCV RNA negativity, the predictive value of detectable HCV RNA for non-sustained virological response (non-SVR) by CAP/CTM is higher than by ART at weeks 4, 6, and 8. We also found that 16 (24.6%) by CAP/CTM and 28 (43.1%) by ART had a reappearance of residual HCV RNA during the telaprevir treatment period. However, the reappearance of residual HCV RNA was not associated with non-SVR. In conclusion, a significant difference was found between the two real-time PCR assays for the assessment of virological response based on undetectable HCV RNA.

Glycated albumin as a diagnostic tool for diabetes in a general Japanese population

OBJECTIVE Diabetes mellitus is a major cause of cardiovascular, kidney, neurologic, and eye diseases, and may be preventable in some cases by lifestyle modification. Screening tests for diabetes mellitus include fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Our objective was to evaluate the utility of plasma glycated albumin (GA) in the diagnosis of diabetes mellitus. DESIGN AND METHODS A cross-sectional, community-based population study of 908 non-diabetic Japanese residents was conducted. Of these subjects, 176 with FPG value between 5.5 and 6.9mmol/l, and an HbA1c level of <6.5% received an oral glucose tolerance test (OGTT). RESULTS The OGTT results were used for the diagnosis of diabetes mellitus using World Health Organization criteria. Receiver operating characteristic (ROC) analyses demonstrated that optimal threshold values for the diagnosis of diabetes in this population were 15.2% for GA and 5.9% for HbA1c, respectively. Using these cutoff levels, the sensitivity of GA at 62.1% for detecting diabetes was the same as that of HbA1c. However the specificity for GA for detecting diabetes was 61.9%, while for HbA1c it was higher at 66.7%. CONCLUSIONS Our results indicate that the measurement of glycated albumin may serve as a useful screening test for diabetes in a general Japanese population.

Therapeutic drug monitoring of telaprevir in chronic hepatitis C patients receiving telaprevir-based triple therapy is useful for predicting virological response

OBJECTIVES This prospective, pharmacokinetic study was done to investigate the impact of telaprevir plasma trough concentration (Ctrough) in the early stage of treatment on the response to telaprevir-based triple therapy for chronic hepatitis C patients. METHODS Participants were 70 chronic hepatitis C patients infected with genotype 1. All patients received 12 week triple therapy that included telaprevir (2250 mg/day), pegylated interferon-α2b (pegylated-IFNα2b) (60-150 μg/week) and ribavirin (600-1000 mg/day) followed by a 12 week dual therapy that included pegylated-IFNα2b and ribavirin. Plasma telaprevir Ctrough was determined by a validated assay using HPLC at days 3, 7 and 14. The study was registered as a clinical trial on the University Hospital Medical Information Network (ID 000009656). RESULTS The rates of undetectable hepatitis C virus RNA at week 4 [rapid virological response (RVR)] and at 24 weeks after therapy [sustained virological response (SVR)] were 71.4% and 82.9%, respectively. Of the patients with RVR, 90% achieved SVR. The mean telaprevir Ctrough levels at days 3, 7 and 14 of SVR patients (2.748, 2.733 and 2.999 μg/mL, respectively) were significantly higher than those of non-SVR patients (1.616, 1.788 and 2.314 μg/mL, respectively) (all P < 0.05). Multiple logistic regression analysis of possible predictors of SVR extracted higher telaprevir Ctrough at day 3 (OR 1.012 by 0.001 μg/mL, P < 0.0001) and interleukin 28B (rs8099917) TT allele (OR 6.16 versus non-TT alleles, P < 0.0001). CONCLUSIONS Therapeutic drug monitoring of telaprevir in the early stage of treatment is useful in clinical practice for predicting the virological response of patients receiving telaprevir-based triple therapy.

A case of successful treatment with telaprevir-based triple therapy for hepatitis C infection after treatment failure with vaniprevir-based triple therapy

Recently direct-acting antiviral agents, such as hepatitis C virus (HCV) non-structural 3/4A (NS3/4A) protease inhibitors (PI), have been introduced, and triple therapy regimens that include PI with conventional pegylated interferon α and ribavirin have significantly improved the sustained virological response (SVR) rate, up to 80% for both treatment-naïve and treatment-experienced patients with HCV genotype 1. We here report for the first time a case of the successful treatment of HCV genotype 1 infection with a first generation PI drug (telaprevir) based triple therapy after treatment failure with a second generation PI drug (vaniprevir) based triple therapy. A 67-year-old treatment-naïve Japanese man with HCV genotype 1b infection took part in a phase III clinical trial of vaniprevir-based triple therapy. His serum HCV RNA had become undetectable at week 2 and SVR was highly expected, but HCV RNA reappeared at week 4 after vaniprevir treatment. Polymerase chain reaction direct sequence of the HCV NS3/4A gene at week 8 after vaniprevir treatment showed the emergence of a vaniprevir-resistance mutation (D168V), the probable reason for the treatment failure. Six months later, retreatment with telaprevir-based triple therapy was started. Although the dosages of telaprevir and ribavirin had to be reduced due to severe anemia, the patient achieved an SVR. This case shows the value of repeating PI-based triple therapy with a different drug, a process that would reduce the chance of drug resistant mutation.

A case of successful hepatitis C virus eradication by 24 weeks of telaprevir-based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon-α and ribavirin therapy

In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-α (PegIFN-α) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN-α and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-α2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-α2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen.

The kinetics of the hepatitis B surface antigen level after the initiation of antiretroviral therapy for hepatitis B virus and human immunodeficiency virus coinfected patients

BACKGROUND Hepatic flares (HF), which reflect hepatitis B virus (HBV)-related immune reconstitution inflammatory syndrome (IRIS), frequently occur in patients with HBV and human immunodeficiency virus (HIV) coinfection after the start of antiretoroviral therapy (ART). The rate of hepatitis B envelope antigen (HBeAg) and hepatitis B surface antigen (HBsAg) loss is higher for patients with HF after the initiation of ART. METHODS We retrospectively examined the kinetics of the HBsAg and HBeAg levels of six HBV/HIV coinfected patients after the commencement of ART that included tenofovir. All were male and HBeAg positive. RESULTS Three patients developed HF after the initiation of ART. All subsequently lost HBeAg and one of them lost HBsAg after HF. None who did not experience HF lost HBeAg. The HBsAg and HBeAg levels remarkably decreased when HF occurred, but the decline of HBsAg was very slow in the periods before and after HF. The median decline of the HBsAg level at 48 weeks was 2.20 Log IU/mL for patients with HF, but only 1.00 Log IU/ml for patients without HF. Little decline was seen for either group in the median decline of the HBsAg level from 48 weeks to 96 weeks, 0.28 Log IU/mL in the HF group and 0.06 Log IU/mL in the non-HF group. CONCLUSION The immune reconstitution of a HBV/HIV coinfected patient plays an important role in the clearance of HBV. If HBsAg and HBeAg levels decrease rapidly when HF occurs, the hepatic flare would be due to HBV-related IRIS.

Efficacy and Tolerance of Interferon β Plus Ribavirin Treatment for Chronic Hepatitis C Patients with Depression or ThrombocytopeniaComparison with Pegylated Interferon α Plus Ribavirin Treatment

Objective: Limited data has been reported comparing natural human interferon β (nIFNβ) and pegylated IFN-α (PEG-IFNα) when Ribavirin (RBV) is combined. This case-control study was done to compare the efficacy and adverse effects of a combination treatment of nIFNβ or PEG-IFNα plus RBV for chronic hepatitis C patients. Methods: Sixty patients with chronic hepatitis C, 42 infected with hepatitis C virus (HCV) genotype 1 and 18 infected with genotype 2, were treated with nIFNβ plus RBV. Of them, 23 (38.3%) suffered pre-treatment severe depression. Their data was compared with 60 undepressed patients treated with a combination of PEG-IFNα plus RBV. nIFNβ was given intravenously and PEG-IFNα was injected subcutaneously. Results: Sustained virological response (undetectable HCV RNA at 24 weeks after the end of treatment) did not significantly differ between the nIFNβ and PEG-IFNα treated patients (genotype 1, 21.4% vs. 33.3%, P=0.328; genotype 2, 72.2% vs. 88.9%, respectively, P=0.402). None of the nIFNβ treated patients showed exacerbation of depression, while 7 (11.7%) of 60 PEG-IFNα treated patients developed severe depression or malaise. The platelet count of nIFNβ treated patients increased to higher than baseline after week 8, but the platelet count of PEG-IFNα treated patients decreased throughout the treatment. There were significant differences of the changes of platelet counts between the both groups throughout the treatment (all P<0.001). Conclusion: nIFNβ plus RBV treatment was well tolerated by chronic hepatitis C patients with depression or thrombpcytopenia.

A case report of human immunodeficiency virus-associated anaplastic lymphoma kinase protein-negative anaplastic large cell lymphoma

Human immunodeficiency virus (HIV)-associated anaplastic large cell lymphoma (ALCL) is not so common, and anaplastic lymphoma kinase protein (ALK)-negative ALCL is rare and has a low survival rate. We report a case of a 31-year-old Japanese man diagnosed with HIV-associated ALK-negative ALCL who presented with long-lasting fever of unknown origin. The diagnosis was based on a full work-up that included inguinal lymph-node biopsy. Eight-cycle chemotherapy that included cyclophosphamide, doxorubicin, vincristine, and prednisone in addition to antiretroviral therapy for HIV infection provided a complete remission of his ALCL and over 5-year survival for him.