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Background: This randomized controlled trial provided LC16m8 pre-exposure prophylaxis to high-risk individuals to assess its efficacy for mpox prevention, safety, and immunogenicity., Methods: This multicenter, randomized, open-label trial enrolled men and women aged ≥18 years at high risk of mpox. Participants were randomly assigned 1:1 to early- or late-vaccination groups. The primary endpoint was vaccine efficacy (VE) against mpox. Secondary endpoints included VE against severe mpox, symptoms, "take" incidence, adverse events (AEs), and immunogenicity in participants with human immunodeficiency virus (HIV)., Results: In total, 570 and 565 participants were assigned to early- and late-vaccination groups, respectively, with 530 and 476 vaccinated. The median age was 41 years; 99.7% were male, 89.7% were Japanese, and 34.4% had HIV. No mpox cases occurred, precluding VE calculations. The take rates were 89.5% (with HIV) and 93.9% (without HIV). AEs occurred in 97.2% and 98.2% of participants with and without HIV, respectively. No fatal AEs were observed. Serious adverse events (SAEs) were observed in 2/352 (0.6%) and 3/654 (0.5%) of participants with and without HIV, respectively, of which one SAE causally related to vaccination occurred in a participant without HIV. Seroconversion rates for LC16m8 and MPXV were 96.2% and 69.2%, respectively, in participants with HIV, and 92.0% and 52.0%, respectively, in individuals without HIV., Conclusions: LC16m8 efficacy in mpox remains inconclusive. However, in individuals with well-controlled HIV, it was immunogenic and raised no significant safety concerns, suggesting its suitability for targeted vaccination of at-risk groups. (Japan Registry of Clinical Trials number, jRCT1031230137)., (© The Author(s) 2025. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Background: The two-drug regimen of dolutegravir/lamivudine (DTG/3TC) is currently an optional antiretroviral therapy (ART). Despite its reported advantages on body weight and lipid profile, the same effects have not yet been reported for Asian population., Methods: We conducted a single-center retrospective study involving Japanese people living with HIV (PLWH). They were divided into four groups: those who had received abacavir/lamivudine/dolutegravir (ABC/3TC/DTG) and continued the same (ABC-ON group) or switched to DTG/3TC (ABC-OFF group), those who had received tenofovir alafenamide fumarate/emtricitabine/dolutegravir (TAF/FTC/DTG) and continued the same (TAF-ON group) or switched to DTG/3TC (TAF-OFF group). We compared changes in viral load, CD4⁺ cell count, CD4⁺/CD8⁺ ratio, body weight, BMI, lipid profiles, estimated glomerular filtration rate (eGFR), and fibrosis index based on four factors (FIB4-index) between the pre-switch and post-switch period., Results: Of the 541 PLWH on DTG-based ART, 165, 94, 264 and 18 constituted the ABC-ON, ABC-OFF, TAF-ON, and TAF-OFF groups, respectively. Neither viral rebound nor CD4 + decline was observed in the post-switch period in all groups. Multivariate analysis showed significant reduction in total cholesterol, LDL-C and HDL-C in the ABC-OFF group (-6.280, -6.957 and -2.268, p = 0.040, 0.012 and 0.022, respectively), but not in the TAF-OFF group (-3.000, 6.708 and 0.046, p = 0.607, 0.276 and 0.983, respectively). No significant changes were observed in body weight, eGFR, or FIB4-index at 72 weeks after the discontinuation of ABC or TAF., Conclusions: Switching from ABC/3TC/DTG to DTG/3TC lowered lipids significantly, but not with TAF/FTC/DTG. Neither switch affected body weight or other markers., (Copyright © 2024 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Non-acquired immunodeficiency syndrome-defining malignancies (NADMs) are the crucial cause of mortality in people living with haemophilia and human immunodeficiency virus (PLWHH). We aimed to analyse the types and characters of NADMs in PLWHH after approval of direct-acting antivirals (DAA), considering that most PLWHH are infected with hepatitis C virus (HCV). We conducted a nationwide questionnaire mail survey across 395 HIV core facilities in Japan between May 2022 and February 2023. Eight-year data from 64 respondent hospitals ( n = 328 PLWHH; 2015-2022) were collected; 35 NADM cases were identified and analysed. Standardised cancer incidence ratios (SCIRs) were calculated. The median age of PLWHH with NADMs was 51 years (interquartile range: 47-62 years); the SCIR was 2.08 (95% confidence interval [CI]: 1.48-2.90) for all malignancies (including carcinoma in situ ). Liver cancer accounted for most NADMs (43% [15/35]). The SCIRs of liver cancer (23.09 [95% CI: 13.92- 38.30]) and papillary thyroid cancer (9.38 [2.35-37.50]) significantly increased after adjusting for general Japanese male sex and age. Among PLWHH with liver cancers, 73% (11/15) achieved HCV-sustained virological response. Notably, for patients aged ≤ 50 years, 47% (7/15) were affected by liver cancers, and 27% (4/15) succumbed to NADMs. This study presents the largest survey of NADMs in PLWHH after DAA approval. Our findings emphasised the elevated risk of malignancies in PLWHH, underscoring the need for early cancer screening and preventive measures, particularly against liver cancers, even in younger PLWHH., Competing Interests: K.T. has received financial support for lectures from Shionogi Pharma Co, Ltd, ViiV Healthcare. R.M. has received financial support for lectures from ViiV Healthcare, Gilead Sciences, Inc. T.F. has received consulting fees from Gilead Sciences, Inc. and ViiV Healthcare and speakers bureaus from ViiV Healthcare and Gilead Sciences, Inc. D.W. has received grants for clinical trials from Gilead Sciences, ViiV Healthcare, GlaxoSmithKline, MSD, and Cmic out of this work, and honoraria from Gilead Science, ViiV Healthcare, MSD, and Janssen Pharmaceutical out of this work. All other authors declare no conflicts of interest., (2024, National Center for Global Health and Medicine.)

People living with human immunodeficiency virus (HIV) are at high risk of mental health problems. However, little is known about this risk in HIV-infected patients with hemophilia (HPH) who contracted the virus through blood products. This cross-sectional, observational study assessed patients' mood states and the factors associated with them among Japanese HPH to evaluate the need for psychosocial support. HPH completed self-administered questionnaires (Profile of Mood States [POMS] and General Health Questionnaire-28), neuropsychological tests, and brain magnetic resonance imaging (MRI) and fluorodeoxyglucose positron emission tomography/computerized tomography scans. HIV-infected patients with no hemophilia (HPnH) completed POMS and neuropsychological tests. Socio-demographic characteristics and HIV- and hemophilia-related data were obtained from participants' medical records and interviews. A Mann-Whitney U test and chi-squared analyses were conducted. Fifty-six HPH and 388 HPnH completed the questionnaires and neuropsychological tests. HPH had a significantly lower prevalence of tension-anxiety (HPH, 7%; HPnH, 18%; p = 0.049) and a significantly higher prevalence of low vigor (HPH, 63%; HPnH, 32%; p < 0.001). Low vigor in HPH was significantly associated with impaired executive function (low vigor, 66%; high vigor, 33%; p = 0.019) and a social dysfunction score ≥ 3 (moderate; low vigor, 26%; high vigor, 5%; p = 0.047). Our results highlight the high prevalence of low vigor among HPH, leading to impairments in executive and social functions. Therefore, healthcare workers need to pay attention to the vigor, executive function, and social function of HPH., Competing Interests: Ei Kinai received research grants from Chugai Pharmaceutical and CSL Behring and honoraria from Gilead Sciences, ViiV Healthcare, MSD, Chugai Pharmaceutical, Sanofi, Bayer, Takeda Pharmaceutical, Novo Nordisk, Fujimoto Pharmaceutical Corporation, and CSL Behring. Shinichi Oka received research grants from ViiV Healthcare and Gilead Sciences and honoraria from Gilead Sciences and ViiV Healthcare. The remaining authors have no conflicts of interest to disclose., (2024, National Center for Global Health and Medicine.)

The importance of genetic diagnosis for patients with hemophilia has been recently demonstrated. However, the pathological variant cannot be identified in some patients. Here, we aimed to identify the pathogenic intronic variant causing hemophilia A using induced pluripotent stem cells (iPSCs) from patients and genome editing. We analyzed siblings with moderate hemophilia A and without abnormalities in the F8 exon. Next-generation sequencing of the entire F8 revealed 23 common intron variants. Variant effect predictor software indicated that the deep intronic variant at c.5220-8563A>G (intron 14) might act as a splicing acceptor. We developed iPSCs from patients and used genome editing to insert the elongation factor 1α promoter to express F8 messenger RNA (mRNA). Then, we confirmed the existence of abnormal F8 mRNA derived from aberrant splicing, resulting in a premature terminal codon as well as a significant reduction in F8 mRNA in iPSCs due to nonsense-mediated RNA decay. Gene repair by genome editing recovered whole F8 mRNA expression. Introduction of the intron variant into human B-domain-deleted F8 complementary DNA suppressed factor VIII (FVIII) activity and produced abnormal FVIII lacking the light chain in HEK293 cells. Furthermore, genome editing of the intron variant restored FVIII production. In summary, we have directly proven that the deep intronic variant in F8 results in aberrant splicing, leading to abnormal mRNA and nonsense-mediated RNA decay. Additionally, genome editing targeting the variant restored F8 mRNA and FVIII production. Our approach could be useful not only for identifying causal variants but also for verifying the therapeutic effect of personalized genome editing., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

There is no established method for differentiating acquired hemophilia A (AHA) from lupus anticoagulant (LA) positivity because both present with prolonged activated partial thromboplastin time. We compared various parameters of rotational thromboelastometry (ROTEM), thrombin generation assay (TGA), and clot waveform analysis (CWA) in patients with AHA (n = 10) and LA (n = 44). Compared with AHA, possible (n = 12) and definite (n = 32) LA showed significantly shorter clotting time (CT) in NATEM mode of ROTEM (> 3600 vs. 501/533). In TGA, peak height was significantly lower in AHA (16 vs. 242/174 nM). In CWA, CT was significantly longer (81 vs. 36/41 s) and Ad|min1| was lower (2.1 vs. 8.7/6.7) in AHA. Notably, CT by NATEM and peak height in TGA completely discriminated between AHA and LA, whereas Ad|min1| did not discriminate between them in 4 cases of AHA and 1 of LA. Comparison of 3 patients with both AHA and LA against a patient with only LA and markedly low FVIII activity (3.5%) showed that both CT by NATEM and peak height of TGA precisely classified the former 3 cases as AHA and the latter 1 case as LA, whereas Ad|min1| classified all 4 cases as AHA. ROTEM and TGA can comparably distinguish between AHA and LA., (© 2023. Japanese Society of Hematology.)

Background: Hemophilia carriers occasionally present with bleeding tendency due to skewed inactivation of normal F8 carrying X chromosome., Key Clinical Question: Can extreme skewing of X-chromosome inactivation (XCI) with trisomy X cause low factor (F) VIII activity and bleeding in a hemophilia carrier?., Clinical Approach: A young female with low FVIII activity (2 IU/dL), who presented with history of frequent bleeding and F8 variant, NP&#95;000123.1:p.(Arg1800His), was identified. The mother was also confirmed genetically as hemophilia carrier. Karyotype was 47, XXX, multiplex ligation-dependent probe amplification for aneuploidy in the family identified trisomy X only in the index case. Digital polymerase chain reaction using leucocytes, urine, and oral mucosa identified one maternal F8 variant carrying and 2 wild-type F8 carrying X chromosomes, but it detected no somatic mosaicisms. Methylation-sensitive- Hpa II-polymerase chain reaction assay showed predominantly activated maternal and 2 fully inactivated paternal X chromosomes. The XCI patterns using tissues of different developmental origins showed extremely skewed XCI., Conclusion: Extreme skewing of XCI can occur even in hemophilia carriers with trisomy X, conferring frequent bleeding and low FVIII activity., (© 2023 The Author(s).)

Rapid initiation of antiretroviral therapy (ART) in HIV infection is recommended because it increases care retention rate and reduces the time to viral suppression. In Japan, although ART initiation is delayed, there is little information on the latency to ART initiation (time from HIV diagnosis to ART initiation). The present study was designed to obtain information on the latency to ART initiation in individuals with 1) acute or recent HIV infection (ARH), and with 2) advanced HIV diseases. Questionnaires were sent to 379 regional AIDS facilities requesting information on the people living with HIV (PLWH) who visited their facilities during 2020. Among 1098 new PLWH visitors, 706 were treatment-naïve patients, including 111 (15.7%) with ARH and 304 (43.1%) with advanced HIV diseases. Among those with ARH, only 8.2% received rapid ART initiation (latency to ART <2 weeks) and the time from diagnosis to virological suppression was longer than 14 weeks in 40.4%. Among those with advanced HIV diseases, 36.2% received late ART initiation (latency to ART ≧6 weeks). Our data showed that only a small proportion of PLWH with ARH in Japan received rapid ART. Furthermore, in PLWH with advanced HIV diseases in Japan, current latency to ART seems too long, though the timing of ART commencement should be tailored according to the presence/lack of opportunistic infections and accessibility to medical care. Further investigation is required to identify barriers to rapid ART initiation in Japan., Competing Interests: Declaration of competing interest EK received honoraria from Gilead Sciences, Inc., ViiV Healthcare, and MSD. DW received honoraria from Gilead Sciences Inc., ViiV Healthcare, and Janssen Pharmaceutical, and TS received honoraria from Gilead Sciences Inc., ViiV Healthcare, and Janssen Pharmaceutical. HW and MY declare no conflicts of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Reports describing symptoms and treatment of patients with congenital factor VII (FVII) deficiency frequently relate to patients in Europe, while only a small number describe data from Asian countries.This multicenter, prospective observational study (NCT01312636) collected data from 30 sites for 55% of patients registered in 2011 in Japan with congenital FVII deficiency treated with activated recombinant FVII (rFVIIa) for bleeding episodes and/or during surgery.The mean follow-up in 20 eligible patients was 11 months (range 1-49 months). Of 348 bleeding episodes in seven patients, 170 (48.9%) were intra-articular bleeding and 62 (17.8%) were menorrhagia, of which 92.9% (158/170) and 100% (62/62) were in patients with baseline factor VII activity 20 IU/dl or less, respectively. The hemostatic effect after rFVIIa treatment was rated as excellent, effective or partially effective for 45.7, 33.6 and 18.4% of 348 bleeding episodes. Overall, hemostasis for bleeding events and surgery was achieved in nearly 2 days, with the majority of patients receiving two doses or less. The hemostatic effect after the recommended dose (15-30 μg/kg) of rFVIIa was rapid and effective treatment for all categories of bleeding and surgical procedure.On the basis of data from routine clinical practice, no new safety signals were identified., Trial Registration: NCT01312636., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc.)

Aim: Many women with inherited bleeding disorders are not diagnosed because of a lack of appropriate indicators. This study aimed to assess the predictability of the pictorial blood loss assessment chart (PBAC) as an indicator of menorrhagia and identify an easy indicator of menorrhagia resulting from bleeding disorders., Methods: A multicenter study enrolled 9 patients with von Willebrand disease (VWD), 23 hemophilia carriers, and 71 controls aged 20-45 years who completed PBACs for two menstrual cycles as well as questionnaires., Results: The PBAC scores of the VWD were significantly higher than those of other groups, even in multivariate analysis with age and sanitary item factors (p = 0.014). A PBAC score of 100 was not an appropriate cutoff because of its low specificity (VWD: sensitivity, 100; specificity, 29.5; hemophilia carriers: 74 and 29.5, respectively). In the ROC analysis, the cutoff of optimal PBAC for VWD was 171 (sensitivity, 66.7; specificity, 72.3; AUC, 0.7296). As the pad length increased, the total length of the pads used during one menstrual period could be a new and easy indicator. However, the cutoff for VWD was 735 cm (sensitivity, 42.9; specificity, 94.3; AUC 0.6837). A threshold could not be established for the hemophilia carrier. Therefore, we multiplied the coefficient by the length of thick pads, which caused a lower PBAC. For the VWD, the sensitivity increased to 85.7 (specificity, 77.1). For the hemophilia carrier, sensitivity (66.7) and specificity (88.6) could be separated from the control., Conclusions: The total length of the pads with a thick-pad adjustment can be a simple method to identify bleeding disorders., (© 2023 Japan Society of Obstetrics and Gynecology.)

Background: Supporting people living with HIV using anti-retroviral therapy (ART) is important due to the requirement for strict medication adherence. To date, no data from longitudinal studies evaluating adherence by treatment-naïve people living with HIV are currently available. We investigated the adherence of treatment-naïve people living with HIV over time and examined the relationships among decisional conflicts, adherence, and health-related quality of life (HRQL)., Methods: The survey items included adherence (visual analogue scale [VAS]), decisional conflict (decisional conflict scale [DCS]), and HRQL (Medical Outcomes Study HIV Health Survey [MOS-HIV]). The DCS and MOS-HIV scores and the VAS and MOS scores were collected electronically at the ART initiation time point and at 4-, 24-, and 48-week post-treatment time points., Results: A total of 215 participants were enrolled. The mean DCS score was 27.3 (SD, 0.9); 23.3% of participants were in the high-score and 36.7% in the low-score groups. The mean adherence rates at 4, 24, and 48 weeks were 99.2% (standard error [SE], 0.2), 98.4% (SE, 0.4), and 96.0% (SE, 1.2), respectively. The least-square means of the MOS-HIV for the DCS (high vs. low scores) were 64.4 vs. 69.2 for general health perceptions and 57.7 vs. 64.0 for HRQL, respectively., Conclusion: Adherence among treatment-naïve people living with HIV was maintained at a higher level, and HRQL tended to improve with ART. People with high levels of decisional conflict tended to have lower HRQL scores. Support for people living with HIV during ART initiation may be related to HRQL., (© 2023. The Author(s).)

[Introduction] Emicizumab, a bispecific antibody mimicking activated factor VIII (FVIII), is increasingly used in prophylaxis against bleeding in hemophilia A. Human factor-based chromogenic substrate assay (hCSA) shows concentration-dependency between emicizumab and reported FVIII activity. However, the assay measurement settings have not been optimized for emicizumab, and the reported FVIII activity cannot be directly referred as surrogate FVIII activity. [Materials and Methods] For in vitro validation of hCSA-reported surrogate FVIII activity, we compared the equation curves for emicizumab concentration with surrogate FVIII activity using spiked plasma in the thrombin generation assay (TGA), hCSA, and clot waveform analysis (CWA). Then, we generated conversion equations for hCSA-reported surrogate FVIII value to that of TGA. We also assessed the additive effect of rFVIII onto 340 nM (i.e., 50 μg/mL) emicizumab using the same assays. [Results] With 1:20 diluted plasma, halving hCSA-reported surrogate FVIII activity can be approximated to that in TGA triggered by the extrinsic pathway reagent (27.3 IU/dL vs. 13.9 IU/dL) under therapeutic emicizumab concentration. Both in TGA and hCSA, the additive effect of added FVIII on therapeutic emicizumab concentration (340 nM) was maintained at low levels of FVIII but gradually decreased at higher levels. [Conclusions] Surrogate FVIII activity can be estimated simply by halving hCSA-reported FVIII value, and the additive effect of FVIII on emicizumab diminishes at high concentrations. Based on our in vitro study, a clinical study is currently being conducted to compare individual variation of surrogate FVIII activity in hCSA and TGA., Competing Interests: Declaration of competing interest HI received research grant from Sysmex, consulting fee from CSL-Behring and speaker honoraria from Sanofi, Bayer and CSL-Behring. KS was an endowed Assistant Professor funded by Baxter/Baxalta/Shire and CSL-Behring (until March 2020). KA received research grant from KM Biologics, consulting fee from Chugai Pharmaceutical, and honoraria from Chugai Pharmaceutical, Sanofi, Bayer, Takeda Pharmaceutical, Novo Nordisk, CSL Behring, KM Biologics, Pfizer, Fujimoto Pharmaceutical Corporation and Japan Blood Products Organization. EK received research grants from Chugai Pharmaceutical and CSL-Behring, and honoraria from Chugai Pharmaceutical, Sanofi, Bayer, Takeda Pharmaceutical, Novo Nordisk, Fujimoto Pharmaceutical Corporation and CSL Behring. All other authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Treatment with tenofovir alafenamide fumarate (TAF) is associated with body weight gain. However, little or no information is available on this issue in Asian populations., Methods: This single-center retrospective study included Japanese people living with HIV (PLWH) who satisfied the following criteria; 1) switching from TDF to TAF after HIV-suppression, 2) follow-up for ≥2 years while on TDF and TAF, and 3) no switching of the third antiretroviral agent. Changes in annual body weight and lipid profiles were compared between the TDF and TAF periods., Results: Of 328 patients, dolutegravir (DTG) was used in 118 PLWH. Overall, no significant difference in weight gain was observed between TDF and TAF (0.76 vs. 0.9 kg/year, p = 0.331). In TAF-period, younger (<50 years of age) group showed significantly greater weight gain than older group (1.03 vs. 0.12 kg/year, p = 0.037). In DTG group, weight gain was larger in TAF-period (0.74 vs. 1.31 kg/year, p = 0.046), especially in younger subgroup (1.43 kg/year) compared with older one (-0.12 kg/year). Multivariate regression analysis showed that TAF was not associated with weight gain (estimates 0.201, p = 0.170) except for DTG group, whereas young age was associated with weight gain in all subjects (estimates -0.033/1 year older, p < 0.001), DTG, RAL, and EFV groups., Conclusion: In Japanese PLWH, annual body weight change was comparable in TDF- and TAF-period, while TAF plus DTG correlated with weight gain. Since young age was a key determinant of weight change, careful interpretation is needed for TAF-associated weight gain., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 Japanese Society of Chemotherapy, Japanese Association for Infectious Diseases, and Japanese Society for Infection Prevention and Control. Published by Elsevier Ltd. All rights reserved.)

Type 3 von Willebrand disease (VWD), a rare and severe subtype, can produce inhibitors in roughly 5% to 10% of cases. We present a case of type 3 VWD with inhibitors in late pregnancy, which was successfully managed with a combination of neutralization and factor (F)VIII replacement during cesarean delivery. The patient, a 30-year-old woman, had no history of inhibitors despite over 100 exposures to VWF/FVIII. She developed inhibitors after 28 weeks of weekly pd VWF/FVIII prophylaxis for recurrent urolithiasis-associated hematuria during pregnancy. Genetic analysis detected two novel frameshift mutations: VWF Exon7 c.777&#95;784dup and Exon14 c.1625&#95;1646del. Titers of inhibitors to factors VIII and VWF using the Bethesda assay were 1.2 and 1.1 BU/mL, respectively. Pharmacokinetics revealed significantly low in vivo recovery of FVIII:C and VWF:Rcof and shortened half-life. During cesarean delivery, a combination of bolus pd VWF/FVIII once daily for neutralizing inhibitors plus continuous infusion of recombinant FVIII Fc fusion protein resulted in minimal bleeding without allergic reactions. Both VWF:Rcof and FVIII:C levels increased transiently during the 7-h of combination therapy without thrombotic events. In conclusion, combination therapy with neutralization and continuous FVIII replacement was effective for hemostasis with a low VWD inhibitor titer, though further optimization is required., (© 2022. Japanese Society of Hematology.)

In hemophilia A, bleeding mostly correlates with factor VIII activity (FVIII:C), although some patients show discrepancy in bleeding severity and FVIII:C. We report a novel procoagulant mechanism associated with F8 p.H118R (c.353A > G) in a young Japanese man with few bleeding episodes despite low levels of FVIII:C (< 1 IU/dL). Plasma FVIII:C was < 1 IU/dL measured by one-stage clotting assay (OSA) and chromogenic substrate assay (CSA), whereas FVIII antigen (FVIII:Ag) was 9.7%. The global coagulation assay showed higher max speed in clot waveform analysis (CWA), shorter clotting time in rotation thromboelastometry (ROTEM) (1605 vs. > 5000 s), shorter lag time (4.87 vs. 12.47 min) and larger ETP (207.9 vs. 53.3 nM*min) in thrombin generation assay, compared with FVIII-deficient control. Expressed recombinant H118R mutant in culture media showed low FVIII:C (1-5 IU/dL) by OSA, with non-hemophilia level of FVIII:Ag. Western blot analysis using recombinant H118R showed longer persistence of heavy-chain of H118R after incubation with α-thrombin, compared with wild-type. Incubation of H118R with activated protein C (APC) also showed longer persistence of A1-A2 domain. In conclusion, H118R showed prolonged activation by α-thrombin and delayed APC-related FVIII degradation. These properties may confer the procoagulant activity and few bleeding episodes despite low FVIII:C., (© 2022. Japanese Society of Hematology.)

Patients with non-severe hemophilia A often show discrepancies in factor VIII (FVIII) activity. However, information on variant-specific coagulation assay characteristics in Japanese patients is limited. Pathogenic variants were classified into three groups, thrombin-cleavage site (TC), A1-A2-A3 interface (IF), and non-discrepant, with reference to previous studies. Cutoff values for the one-stage assay (OSA)/chromogenic substrate assay (CSA) ratio, which is suitable for distinguishing discrepancies, were determined for all five aPTT reagents. TGA and CWA parameters and bleeding scores were compared between groups. Two of the 39 patients with non-severe hemophilia A (5%) were classified as TC, 10 (26%) as IF, and 27 (69%) as non-discrepant. The OSA/CSA cutoff values between the groups varied widely by aPTT reagent and tended to be relatively low compared to previous studies. As an indicator of bleeding tendency, TGA had a low correlation coefficient for the IF variant, but this was not significant and was comparable to FVIII activity and CWA. Moreover, various parameters and bleeding tendency differed among patients with the same variants. Thus, our findings suggest that it is difficult to adequately assess the bleeding tendency of individual patients, even with the various assessments currently available., (© 2021. Japanese Society of Hematology.)

Background and Aims: In many developed countries, hemophilia care is provided by specialized centers which can offer standardized high-quality care for patients and collect data for patient registries. However, in countries with less centralized provision of hemophilia care, registry data lacks accuracy and medical care is inconsistent among providers. Claims databases can be an alternative for obtaining nationwide data on hemophilia care, and we applied this approach to evaluate inequalities in hemophilia care in Japan., Methods: Medical records of hemophilia A patients were collected by a combination of ICD-10 code (D66) and prescribed coagulation factors from two major Japanese claims databases (JMDC and Medical Data Vision [MDV]). Patient records with an anti-inhibitor coagulant complex were excluded.Based on the annual number of hemophilia A patients, medical facilities were categorized into specialized facilities (SP, ≥5 patients) and nonspecialized facilities (N-SP, <5 patients). Patient age, comorbidities, diagnostic testing, prescribed drugs and their dosages were compared between facility types., Results: The JMDC and MDV databases included 274 and 1266 hemophilia A patients, respectively. In the MDV database, SP facilities prescribed extended half-life factor VIII (FVIII) products for more patients (31.8% vs 24.3%) than N-SP. The mean annual FVIII consumption per patient was higher in SP facilities (240 333 IU [international units] vs 210 334 IU), and the mean FVIII dosage was higher in SP facilities for all types of FVIII products. The proportion of patients who received diagnostic blood tests was higher in SP (75.7% vs 56.2%)., Conclusion: The MDV database revealed disparities in hemophilia A care between SP and N-SP facilities in types of FVIII products prescribed, FVIII consumption, and frequency of the relevant management such as blood tests. Claims databases can be an alternative for the assessment of nationwide hemophilia care patterns in countries without a well-established registry., Competing Interests: Ei Kinai has no conflicts of interest to declare. Midori Ono, Akinori Oh, Mihoko Ota, Yasuo Myaguchi, and Hitoshi Ueda are employees of Takeda Pharmaceutical Company Limited. Midori Ono, Akinori Oh, Mihoko Ota, and Hitoshi Ueda own shares in Takeda Pharmaceutical Company Limited., (© 2022 The Authors. Health Science Reports published by Wiley Periodicals LLC.)

Background: Genetic characteristics and genetic carrier diagnosis in Japanese hemophilia female carriers have not been evaluated., Objectives: To provide genetic information on Japanese hemophilia female carriers and demonstrate the advantages of genetic testing in carrier diagnosis., Methods: DNA sequencing combined with long polymerase chain reaction for inversion and multiplex ligation-dependent probe amplification for large mutations., Results: Genetic analysis was performed in 69 male hemophiliac patients (48 hemophilia A [HA] and 21 hemophilia B [HB]) and 112 female family members (FFM) (80 from 50 families with HA and 32 from 22 families with HB). In 72 hemophiliac families, the identified F8 mutations were inversion (42%), missense (26%), and other variations (32%), while 74% of F9 mutations were point mutations. Among the 112 FFM, 53/80 (66%) with HA and 21/32 (66%) with HB were diagnosed genetically as carriers based on detection of heterozygous mutations. Low factor VIII activity (FVIII:C) levels (<50 IU/dL) were detected in only 10% of gene-confirmed carriers, suggesting that FVIII:C is not suitable for HA carrier prediction. Low FVIII/von Willebrand factor ratio (<0.9) was observed in 67% of gene-confirmed carriers. Half of the gene-confirmed HB carriers had low FIX:C (<60 IU/dL). Importantly, 32 mothers of 37 sporadic cases (86%) (24/27 [89%] HA and 8/10 [80%] HB) showed the relevant mutations, suggesting low incidence of de novo mutations in males., Conclusions: This study is the first to provide genetic information on Japanese hemophilia female carriers. Gene analysis is the gold standard for carrier diagnosis as it well identifies undetected female carriers based on pedigree information and hemostatic measurements., (© 2021 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Tenofovir disoproxil fumarate (TDF) is still widely prescribed for human immunodeficiency virus (HIV)-infected pregnant women, despite its renal and bone toxicity. Although TDF-exposed infants often show transient growth impairment, it is not clear whether maternal TDF causes infantile rickets via maternal/fetal renal dysfunction in Asian populations. This prospective observational study was conducted in Vietnam and involved pregnant HIV-infected women treated with TDF-based regimen (TDF group) or zidovudine-based regimen (AZT-group). At birth, 3, 12, and 18 months of age, and included body length, weight, head circumference, serum alkaline phosphatase (ALP), creatinine, calcium, phosphorus, urine-β2-microglobulin (U-BMG), percentage of tubular reabsorption of phosphate (%TRP), and radiographic wrist score for rickets. Age-adjusted multivariate linear regression analysis evaluated the association of TDF/AZT use during pregnancy with fetal renal function and bone health. The study included 63 mother-infant pairs (TDF group = 53, AZT group = 10). In the mothers, detectable U-BMG (>252 μg/L) was observed more frequently in the TDF- than AZT group (89 vs 50%, p<0.001), but other renal/bone parameters were similar. In infants, maternal TDF use was not associated with growth impairment, renal dysfunction, or abnormal bone findings, but with a slightly higher ALP levels (p = 0.019). However, shorter length was associated with maternal AZT (p = 0.021), and worse radiographic scores were associated with LPV/r (p = 0.024). In Vietnamese population, TDF usage during pregnancy was not associated with infant transient rickets, growth impairment, or renal dysfunction, despite mild maternal tubular impairment. Maternal AZT and LPV/r influenced infant growth and bone health, though further studies are needed to confirm this finding., Competing Interests: E.K. has received honoraria from Gilead Sciences, ViiV Healthcare, and MSD. S.O. received honoraria from MSD, Janssen Pharmaceutical and Gilead Sciences, and research grants from MSD, ViiV Healthcare, Gilead Sciences. The remaining authors declare no conflict of interest. This research was supported by the Japan Initiative for Global Research Network on Infectious Diseases from the Japan Agency for Medical Research and development, AMED. During the study period, antiretrovirals for Vietnamese patients were provided under the financial support of the U.S. President’s Emergency Plan for AIDS Relief (PEPFAR). This does not alter our adherence to PLOS ONE policies on sharing data and materials.

This single-institution cross-sectional study aimed to grasp the prevalence and features of neurocognitive dysfunction in HIV-infected hemophilia patients in Japan. We conducted neuropsychological tests and medical examinations in 56 HIV-infected hemophilia patients who received outpatient treatment at the AIDS Clinical Center, National Center for Global Health and Medicine. A total of 388 HIV-infected non-hemophilia patients who received outpatient treatment at the same institution were included as a control group. To investigate sites responsible for neurocognitive dysfunction in HIV-infected hemophilia patients using brain FDG-PET/CT scans, the accumulation of FDG in each brain region was compared. Approximately 50% of HIV-infected hemophilia patients had neurocognitive dysfunction. The prevalence of asymptomatic neurocognitive impairment was high (34%). Neurocognitive dysfunction was associated with educational level in HIV-infected hemophilia patients. In the symptomatic group, hemophilic arthropathy and history of cerebrovascular disorders were associated with neurocognitive dysfunction. Left temporal lobe function was reduced in the symptomatic group., Competing Interests: The authors have declared that no competing interests exist.

Detailed information of the effects of age and long-term HIV infection on various neurocognitive function have not been fully evaluated yet. In a prospective Japanese nationwide multicenter study of 17 facilities (J-HAND study), 728 HIV-infected individuals completed 14 neuropsychological (NP) tests; Verbal Fluency (VF; category and letter), Digit Span (DS; forward and backward), Trail Making Test (TMT) A-B, Rey-Osterrieth Complex Figure Test (ROCFT; copy, immediate and delayed recall), Story Memory Test (SMT; immediate and delayed recall), Digit Symbol Subset (DSS), and the Grooved Pegboard (GP; dominant and non-dominant). Multivariate analysis identified older age (≥ 50 years) to be associated with lower scores in all three ROCFT and GP dominant [odds ratio (OR) [95% confidence interval (CI)] 1.801 (1.217-2.664), 2402 (1.366-3.055), 2.691 (1.720-4.211), and 2.302 (1.145-4.628), respectively], whereas longer time since diagnosis was associated with a lower score in ROCFT (delayed recall) (OR 1.224, 95%CI 1.045-1.434). In VF letter, older age and longer time since diagnosis were associated with a better score [OR (95%CI) 0.449 (0.234-0.861) and 0.831 (0.692-0.997)]. In DSS and TMT-A, longer time since diagnosis was associated with a better score [OR (95%CI): 0.808 (0.670-0.973) and 0.795 (0.665-0.949), respectively]. Older patients in later years since diagnosis are at higher risk of visuospatial and motor impairments despite ART, whereas they are less likely to develop verbal impairment, suggesting that verbal function is relatively resistant to aging and long history of HIV infection under ART. These findings suggest that customtailored supports should be established based on the individual background.

There is no detailed information on the association between age, time of disease, and HIV-associated neurocognitive disorders (HAND). In this prospective study involving 17 medical facilities across Japan, we recruited HIV-infected patients to complete a 14-test neuropsychological battery that assess eight neurocognitive domains. HAND were diagnosed by the Frascati criteria. Of 1399 recruited patients, 728 were enrolled. The prevalence of HAND was 25.3% [13.5% asymptomatic neurocognitive impairment, 10.6% mild neurocognitive disorder (MND), and 1.2% HIV-associated dementia (HAD)]. Tests that assess executive and visuospatial functions showed better diagnostic accuracy than other tests for HAND. Multivariate analysis identified age (≥ 50 years) and incomplete virological suppression as risk factors for MND and HAD and current ART as a protective factor. The prevalence of MND and HAD was low in the early stage of infection (6.3% in ≥ 2 to < 6 years), then increased in the later stage [17.3% in ≥ 11 years, p = 0.001 (vs. ≥ 2 to < 6 years)], independent of age or treatment. Older patients were more likely to show MND or HAD in the early stage of HIV infection (26.7 vs. 8.7% for < 2 years and 17.4 vs. 3.1% for ≥ 2 to < 6 years, p = 0.040 and 0.004, respectively) compared to younger ones. In conclusion, MND and HAD were more commonly found in later years since diagnosis of HIV infection and older patients are at risk of neurocognitive impairment at the early stage of HIV infection. Tests for executive and visuospatial functions seem more sensitive than other tests for diagnosing HAND.

Introduction: Almost 30 years ago, about 30% of Japanese hemophiliacs became infected with HIV-1 and hepatitis C virus (HCV) after receiving contaminated blood products. While several studies have reported the high efficacy and safety of direct acting antivirals (DAA) in HIV-1 co-infected patients, such data are limited in hemophiliacs., Methods: We conducted a single-center, open-label study involving 27 Japanese patients (median age; 45 years) with inherited bleeding disorders who were co-infected with HCV/HIV-1. Patients with HCV genotype 1 (GT1) and GT4 received ledipasvir (90 mg) plus sofosbuvir (400 mg), those with HCV GT2 received sofosbuvir plus weight-based ribavirin, and those with HCV GT3 received daclatasvir (60 mg) plus sofosbuvir. Treatment was continued for 12 weeks in all patients. The primary endpoints were rate of sustained virologic response at 12 weeks after end of therapy (SVR12) and occurrence of adverse events during DAA therapy., Results: Eighteen (67%) patients had had received interferon-based therapy, and 11 (41%) had compensated cirrhosis. HCV genotypes were GT1a 4 (15%), GT1b 16 (59%), GT1 undetermined 2 (7%), GT2a 1 (4%), GT3a 3 (11%) and GT4a 1 (4%). All patients were on combination antiretroviral therapy (cART) and had undetectable HIV-1 viral load (<20 copies/μL) at baseline. All patients achieved SVR12. Serious adverse events were observed in 3 patients: arteritis of the leg, which resolved after completion of DAA therapy, asymptomatic QT prolongation and gastrointestinal hemorrhage. cART failure was noted in one patient due to emergence of raltegravir resistance during ledipasvir/sofosbuvir treatment. Although α-fetoprotein, Mac-2 binding protein glycosylation isomer (M2BPGi), and Fibro Scan (FS) scores decreased in most patients during DAA therapy, M2BPGi (>2.0 cutoff index) and FS scores (>15.0 kPa) were still high in 6 patients at week 36., Conclusions: DAA therapy is effective in all patients. However, adverse events and efficacy of cART should be monitored closely.

Background: Clinical and experiments evidence indicate that protease inhibitors (PI) can cause bone mineral density (BMD) loss. However, the mechanism of such loss remains obscure., Methods: This single-center, cross-sectional study included 184 HIV-infected patients treated with PI who underwent dual-energy X-ray absorptiometry scan. Serum phosphorus, percentage of tubular reabsorption of phosphate (%TRP), thyroid and parathyroid function (iPTH), vitamin D, osteocalcin (OC), urinary deoxypyridinoline (DPD), and urinary cross-linked N-telopeptide of type I collagen (u-NTx) were measured., Results: The rate of hypothyroidism in PI-users [32/117 (27%)] was double that in non-PI users [8/67 (12%), p = 0.016] and was significantly associated with PI use in multivariate analysis [odds ratio (OR) 11.37, 95% confidence interval (CI) 1.358-95.17, p = 0.025]. Spine BMD was significantly lower in hypothyroid patients than euthyroid, for both total population (-1.37 vs. -1.00, p = 0.041) and PI users (-1.56 vs. -1.13, p = 0.029). Multivariate regression analysis identified inverse correlation between hypothyroidism and spine BMD [estimate -0.437, 95% CI -0.858 to -0.024, p = 0.042]. OC, DPD and u-NTx were significantly higher in PI users than in non-PI users (p = 0.01, 0.05, and 0.01, respectively)., Conclusions: PI use is associated with hypothyroidism as well as bone turnover acceleration, which worsens PI-associated BMD loss. In PI-treated patients, thyroid function tests are warranted to prevent further progression of PI-associated BMD loss., (Copyright © 2016 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: The epidemiology of incident syphilis infection among HIV-1-infected men who have sex with men (MSM) largely remains unknown., Methods: The incidence and risk factors for incident syphilis (positive TPHA and RPR> = 1:8) among HIV-1-infected MSM who visited a large HIV clinic in Tokyo for the first time between 2008 and 2013 were determined, using clinical data and stored blood samples taken every three months for screening and determination of the date of incident syphilis. Poisson regression compared the incidence of syphilis at different observation periods., Results: Of 885 HIV-1-infected MSM with baseline data, 34% either presented with active syphilis at baseline (21%) or became infected with syphilis during follow-up (13%). After excluding 214 patients (MSM with syphilis at baseline (n = 190) and no follow-up syphilis test (n = 24)), of 671 men, 112 (17%) developed incident syphilis with an incidence of 43.7/1,000 person-years [95% CI, 36.5-52.3]. The incidence decreased slightly during observation period although the trend was not significant (2008-2009: 48.2/1,000 person-years, 2010-2011: 51.1/1,000 person-years, 2012-2013: 42.6/1,000 person-years, 2014 to 2015: 37.9/1,000 person-years, p = 0.315). Multivariable analysis identified young age (<33 years versus >40, HR 4.0, 95%CI 2.22-7.18, p<0.001), history of syphilis at baseline (HR 3.0, 95%CI 2.03-4.47, p<0.001), positive anti-amoeba antibody (HR 1.8, 95%CI 1.17-2.68, p = 0.006), and high baseline CD4 count (CD4 ≥350 /μL versus CD4 <200, HR 1.6, 95%CI 1.00-2.53, p = 0.050) as risk factors for incident syphilis. Incidence of syphilis was particularly high among young patients (age <33 years: 60.1/1,000 person-years). Interestingly, 37% of patients with incident syphilis were asymptomatic., Conclusions: Although incidence of syphilis did not increase during the observation period, it was high among HIV-1-infected MSM, especially among young HIV-1-infected MSM and those with history of syphilis, in Tokyo. Regular screening for syphilis needs to be strictly applied to this population., Competing Interests: The authors have declared that no competing interests exist.

Objectives: Zidovudine (AZT) is mainly used to prevent mother-to-child HIV-1 transmission (PMTCT). Despite serious concerns on AZT-associated toxicity, there is little information on pharmacokinetics of intracellular AZT metabolites in infants., Methods: We conducted a prospective study in 31 HIV-uninfected infants who received AZT for PMTCT. Blood samples were obtained from 14 infants on postdelivery days (PDD) 1, 7, 14, and 28 and from 17 infants at 0 and 4 hours after dosing on PDD-1. Plasma AZT concentrations (pAZT) and intracellular concentrations of AZT-monophosphate (icAZT-MP), diphosphate (icAZT-DP), and triphosphate (icAZT-TP) were determined., Results: Plasma AZT and icAZT-MP concentrations were 2713 nmol/L and 79 fmol/10 cells in PDD-1, but decreased to 1437 nmol/L and 31 fmol/10 cells by PDD-28 (P = 0.02 and P = 0.07 for all PDDs, respectively), whereas those of icAZT-DP and icAZT-TP remained low throughout the sampling period (P = 0.29 and P = 0.61 for all PDDs, respectively) There were no differences in icAZT-TP between infants of the 2 mg/kg 4 times a day dose and 4 mg/kg twice daily dose (P = 0.25), whereas pAZT and icAZT-MP levels were higher in the latter (P < 0.01 and <0.01, respectively). The pAZT and icAZT-MP significantly increased from 0 to 4 hours after dosing (P < 0.001 and <0.001, respectively), whereas icAZT-DP, icAZT-TP levels were not changed (P = 0.41 and 0.33, respectively)., Conclusions: The level of icAZT-TP did not change with age, time, or a single dose despite the wide range of pAZT concentration. A safer dosage needs to be determined because high pAZT levels do not parallel those of icAZT-TP.

Although zidovudine (AZT) is not the preferred antiretroviral drug for adult HIV-infected patients, it is still widely used in infants for both prevention of mother-to-infant HIV-1 transmission and treatment of HIV-infected children. However, it is difficult to measure intracellular concentrations of AZT metabolites in small blood samples due to their extremely low concentrations in peripheral blood mononuclear cells and interference by endogenous nucleotide triphosphates, residual plasma phosphates and electrolytes. We developed an ultrasensitive assay using liquid chromatography-tandem mass spectrometry (LC-MS/MS) for measurement of intracellular concentrations of zidovudine (AZT)-monophosphate (AZT-MP), -diphosphate (AZT-DP) and -triphosphate (AZT-TP). The high sensitivity was due to the improvement of peripheral blood mononuclear cells extraction for complete removal of plasma and electrolytes, alkalization of LC buffer and use of alkaline-stable high performance liquid chromatography column and tetrabutylammonium hydroxide as the ion pair. Using this method, the lower limits of quantification of AZT, AZT-MP, -DP and -TP were 6, 6, 10 and 10 fmol per sample, respectively. Accuracy ranged 89-115% and precision was lower than 15% in the quantification range of 6-6000 fmol/sample for plasma AZT and intracellular AZT-MP and 10-10 000 fmol/sample for AZT-DP and -TP. The validation parameters met the international requirements. Among nine AZT-treated HIV-infected adult patients, five had low AZT-TP levels (<10 fmol/10(6) cells). Our assay has high sensitivity and is advantageous for evaluation of AZT phosphates in children and infants based on minimum blood sampling requirement., (Copyright © 2015 John Wiley & Sons, Ltd.)

Objectives: To investigate the effect of long-term tenofovir disoproxil fumarate (TDF) use on renal function, especially in patients with low body weight who are vulnerable to TDF nephrotoxicity., Design: A single-center, observational study in Tokyo, Japan., Methods: We performed a 10 years cohort study of 792 HIV-1-infected patients. The effect of long-term TDF use on estimated glomerular filtration rate (eGFR) was investigated on treatment-naive patients who started TDF-containing antiretroviral therapy (n = 422) and those who started abacavir-containing antiretroviral therapy as control (n = 370). Three renal endpoints were examined by the logistic regression model: decrement in eGFR of higher than 10 ml/min per 1.73 m relative to the baseline, more than 25% decrement in eGFR, and eGFR lower than 60 ml/min per 1.73 m at least 3 months apart. The loss in eGFR was estimated using linear mixed models for repeated measures., Results: The median weight at baseline was 63 kg. TDF use increased the risk of all three renal outcomes compared with the control group: higher than 10 ml/min per 1.73 m decrement in eGFR [adjusted odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.45-3.14, P < 0.001], more than 25% decrement (adjusted OR = 2.1, 95% CI 1.50-2.90, P < 0.001), and eGFR lower than 60 ml/min per 1.73 m at least 3 months apart (adjusted OR = 3.9, 95% CI 1.62-9.36, P = 0.002). The cumulative mean loss relative to the control after 1, 2, 3, 4, and 5 years of TDF exposure was -3.8, -3.6, -5.5, -6.6, and -10.3 ml/min per 1.73 m, respectively, indicating that the loss in eGFR increased over time (P < 0.001)., Conclusion: In this cohort of patients with low body weight, TDF exposure increased the risk of renal dysfunction. Furthermore, the loss in eGFR relative to the control increased continuously up to 5 years.

HIV-infected patients are at high risk for bone mineral density (BMD) loss. The present study was designed to provide information on characteristics of BMD abnormalities in Japanese HIV-1-infected patients and risk factors involved in worsening of BMD. A total of 184 Japanese HIV-1-infected men were studied with a dual-energy X-ray absorptiometry scan (DXA) at the lumbar spine and femoral neck. Multivariate logistic regression models were used for comparison of the impact of risk factors on BMD loss. Osteopenia and osteoporosis were diagnosed in 46% and 10% of the patients at lumbar spine, and 54% and 12% at femoral neck, respectively. In logistic analysis, factors associated with low BMD at both lumbar spine and femoral neck were long-term treatment with a protease inhibitor (PI) [odds ratio (OR) 1.100 and 1.187 per 1 year increase of PI use; 95% confidence interval (CI) 1.003-1.207 and 1.043-1.351; p=0.042 and 0.009, respectively] and a low body mass index [OR: 0.938 and 0.852, CI 0.892-0.992 and 0.783-0.927; p=0.024 and <0.001, respectively]. Patients who discontinued PI had a significantly higher BMD than those who currently use PI at lumbar spine (t score -0.8 vs. -1.3, p=0.04) but not at femoral neck (-1.3 vs. -1.5, p=0.38). In HIV-infected Japanese patients, the duration of treatment with PI correlated significantly with BMD loss. Discontinuation of PI is a promising option in the treatment of BMD loss since it allows recovery of BMD, especially in the lumbar spine.

Ritonavir-boosted darunavir (DRV/r) is a protease inhibitor widely used in the treatment of HIV-1 infection. However, skin rash is a well-known adverse event of DRV, and limited data are available from observational settings. This observational study examined the characteristics of DRV-induced skin rash in treatment-naïve patients who commenced once-daily DRV/r-containing antiretroviral therapy (ART). Of the 292 study patients, DRV rashes developed in 31 (11%) patients with a median latency of 10 days (developing from 7 to 14 days in 93%) from initiation of ART. DRV skin rash was generally mild, as only one patient (3%) had grade 3 rash whereas 24 (77%) patients had grade 2 and 6 (19%) patients had grade 1. Only two patients (7%) discontinued DRV/r due to skin rash, and the other continued DRV/r and their rashes disappeared completely without any complications. Interestingly, DRV rash occurred more frequently to patients with less advanced HIV-1 infection than those with advanced infection. The incidence of DRV rash was not significantly different between patients with and without history of sulfonamide allergy (p = 0.201). Furthermore, when we exclude patients without history of sulfonamide use and only examine patients with sulfonamide use (n = 145), the result was similar (p = 0.548). In conclusion, DRV rashes were frequently observed but the prognosis was benign. Most patients tolerated DRV rashes with use of oral steroid or antihistamine without discontinuation of DRV. To date, there is no clear clinical evidence to suggest that DRV should be avoided in patients with history of sulfonamide allergy., (Copyright © 2014 Japanese Society of Chemotherapy and The Japanese Association for Infectious Diseases. Published by Elsevier Ltd. All rights reserved.)

Background: Although ritonavir-boosted atazanavir (ATV/r) is known to be associated with nephrolithiasis, little is known about the incidence of nephrolithiasis in patients treated with ritonavir-boosted Darunavir (DRV/r), the other preferred protease inhibitor., Methods: In a single-center cohort, the incidence of nephrolithiasis was compared between HIV-infected patients who commenced DRV/r-containing antiretroviral therapy and those on ATV/r. The effects of ATV/r use over DRV/r were estimated by univariate and multivariate Cox hazards models., Results: Renal stones were diagnosed in only one patient (0.86 per 1000 person-years) of the DRV/r group (n=540) and 37 (20.2 per 1000 person-years) of the ATV/r group (n=517). The median [interquartile (IQR)] observation period in the DRV/r group was 27.1 months (IQR 18.1-38.4 months), and 40.6 months (IQR 17.5-42.7) for the ATV/r group. The total observation period was 1,163.6 person-years and 1,829.6 person-years for the DRV/r group and for the ATV/r group, respectively. In the 37 patients on ATV/r who developed nephrolithiasis, the median time from commencement of ATV/r to diagnosis was 28.1 months (IQR 18.4-42.7), whereas nephrolithiasis in the single patient of the DRV/r group occurred 11.2 month after the introduction of DRV/r. ATV/r use over DRV/r was significantly associated with nephrolithiasis by uni- and multivariate analyses (HR=26.01; 95% CI, 3.541-191.0; p=0.001) (adjusted HR=21.47; 95% CI, 2.879-160.2; p=0.003)., Conclusion: The incidence of nephrolithiasis was substantially lower in patients on DRV/r than those on ATV/r. The results suggest that DRV/r should be selected for treatment of HIV-infected patients at risk of chronic kidney disease.

Objective: To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection., Design: We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART., Methods: The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model., Results: The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152-2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339-3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494-5.139; p = 0.001) (61-68 kg: adjusted HR = 1.908; 95%CI, 0.764-4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318-3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003)., Conclusion: The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.

Background: Treatment with tenofovir is sometimes associated with renal dysfunction. Limited information is available on this side effect in patients with small body weight, although the use of tenofovir will spread rapidly in Asia and Africa, where patients are likely to be of smaller body weight., Methods: In a single-center cohort, Japanese patients with HIV infection who started tenofovir-containing antiretroviral therapy were retrospectively analyzed. The incidence of tenofovir-associated renal dysfunction, defined as more than 25% decrement of estimated glomerular filtration rate (eGFR) from the baseline, was determined. The effects of small body weight and body mass index (BMI) on tenofovir-associated renal dysfunction, respectively, were estimated in univariate and multivariate Cox hazards models as the primary exposure. Other possible risk factors were evaluated by univariate analysis and those found significant were entered into the multivariate analysis., Results: The median weight of 495 patients was 63 kg. Tenofovir-related renal dysfunction occurred in 97 (19.6%) patients (incidence: 10.5 per 100 person-years). Univariate analysis showed that the incidence of tenofovir-related renal dysfunction was significantly associated with smaller body weight and BMI, respectively (per 5 kg decrement, HR = 1.23; 95% CI, 1.10-1.37; p<0.001)(per 1 kg/m(2) decrement, HR = 1.14; 95% CI, 1.05-1.23; p = 0.001). Old age, high baseline eGFR, low serum creatinine, low CD4 count, high HIV viral load, concurrent nephrotoxic drugs, hepatitis C infection, and current smoking were also associated with tenofovir-related renal dysfunction. Multivariate analysis identified small body weight as a significant risk (adjusted HR = 1.13; 95% CI, 1.01-1.27; p = 0.039), while small BMI had marginal significance (adjusted HR = 1.07; 95% CI 1.00-1.16; p = 0.058)., Conclusion: The incidence of tenofovir-associated renal dysfunction in Japanese patients was high. Small body weight was identified as an independent risk factor for tenofovir-associated renal dysfunction. Close monitoring of renal function is advocated for patients with small body weight treated with tenofovir.

It became evident that tenofovir DF (TDF) causes a modest and gradual decline in GFR, however, the impact of long-term use of TDF on tubular function has not been fully evaluated. In 40 patients treated with TDF and 23 patients treated with other NRTIs, urine beta(2)-microglobulin (U-BMG), percentage tubular reabsorption of phosphate (%TRP), alkaline phosphatase (ALP), serum creatinine, and calculated GFR were prospectively measured for 96 weeks. In patients receiving TDF, median U-BMG rose from 188 microg/liter at baseline to 555 microg/liter at week 96 (p = 0.02), median %TRP declined from 94% at baseline to 90% at week 96 (p = 0.002), median ALP ratio compared with baseline persistently increased from 1 to 1.278 at week 96 (p = 0.001), and serum creatinine showed significant but minimal change from 0.64 mg/dl to 0.74 mg/dl at week 96 (p = 0.02). The GFR level declined minimally but significantly in TDF-receiving patients (-17 ml/min/1.73 m(2)), whereas it did not change in other NRTI-receiving patients [+ 3 ml/min/1.73 m(2); mixed models analysis of variance (MMANOVA) p = 0.03 for overall change from baseline to week 96]. U-BMG, %TRP, ALP, or serum creatinine did not change significantly in other NRTI-receiving patients during the observation period. In five patients with marked changes in U-BMG (>10,000 microg/liter) and %TRP (<80%), both U-BMG and %TRP immediately recovered in all patients after discontinuing TDF, whereas GFR levels did not fully recover for 6 months in three patients. Prolonged treatment with TDF caused progressive renal tubular dysfunction as well as a modest decline in GFR. If U-BMG levels >10,000 microg/liter and %TRP values <80% are observed, discontinuing TDF may be beneficial.

We describe a novel method for isolating plasma-free peripheral blood mononuclear cells retaining intracellular efavirenz. Quantification of efavirenz in 13 human immunodeficiency virus-infected patients by liquid chromatography-tandem mass spectrometry showed a higher correlation of intracellular levels with unbound plasma levels (accumulation ratio, 1,190) than with total plasma levels.

The efficacy of interferon therapy for hepatitis C virus (HCV) infection improved remarkably. However, virologic relapse occurs in a substantial proportion of patients with virologic response (defined as an HCV RNA level below 50 IU/ml at the end-of-treatment). A highly sensitive RT-nested PCR assay capable of detecting almost a single copy of HCV RNA and a real-time RT-PCR assay to quantify HCV RNA down to 120 copies per ml were developed. The RT-nested PCR assay showed that 1 IU of HCV RNA is equivalent to 12.2 copies. For 28 patients with virologic response (12 relapsers and 16 sustained virologic responders), week-4 and end-of-treatment plasma samples were retested. At week 4, HCV RNA was detected by the RT-nested PCR and qualitative COBAS Amplicor HCV version 2.0 in 8/9 (89%) and 6/9 (67%) samples from relapsers, and in 4/16 (25%) and 2/16 (13%) samples from sustained virologic responders, respectively. End-of-treatment samples with HCV-negative by the qualitative COBAS Amplicor were positive by the present assay in 4/12 (25%) of relapsing patients and 0/16 (0%) of sustained virologic responders. The viral levels detected by the present assay in the Amplicor-negative samples were 3.5-17.3 copies/ml, which is below the detection limit of COBAS Amplicor. In conclusion, the highly sensitive RT-nested PCR assay can predict sustained virologic response at week 4 and virologic relapse at the end-of-treatment more accurately than COBAS Amplicor, suggesting its usefulness in monitoring antiviral therapy for HCV infection.

Despite its wide use, the renal tubular toxicity of tenofovir has not been fully evaluated. Twelve weeks after initiating a tenofovir-containing HAART regimen, a high urine-beta 2 microglobulin level was observed in 12 out of 17 patients, the percentage of tubular reabsorption of phosphate decreased from 96.0 to 91.1% and alkaline phosphatase increased from 294 to 365 U/l, whereas serum creatinine and phosphorus remained largely unchanged. Patients with the above findings should be monitored carefully for renal tubular toxicity.