With the advent of antiretroviral therapy (ART), the prognosis of people infected with human immunodeficiency virus (HIV) has improved, and the frequency of HIV-related central nervous system (CNS) ...diseases has decreased. Nevertheless, mortality from HIV-related CNS diseases, including those associated with ART (e.g., immune reconstitution inflammatory syndrome) remains significant. Magnetic resonance imaging (MRI) can improve the outlook for people with HIV through early diagnosis and prompt treatment. For example, HIV encephalopathy shows a diffuse bilateral pattern, whereas progressive multifocal leukoencephalopathy, HIV-related primary CNS lymphoma, and CNS toxoplasmosis show focal patterns on MRI. Among the other diseases caused by opportunistic infections, CNS cryptococcosis and CNS tuberculosis have extremely poor prognoses unless diagnosed early. Immune reconstitution inflammatory syndrome shows distinct MRI findings from the offending opportunistic infections. Although distinguishing between HIV-related CNS diseases based on imaging alone is difficult, in this review, we discuss how pattern recognition approaches can contribute to their early differentiation.
A multispecies outbreak of IMP-6 carbapenemase-producing Enterobacterales (IMP-6-CPE) occurred at an acute care hospital in Japan. This study was conducted to understand the mechanisms of IMP-6-CPE ...transmission by pulsed-field gel electrophoresis (PFGE), multilocus sequence typing and whole-genome sequencing (WGS), and identify risk factors for IMP-6-CPE acquisition in patients who underwent abdominal surgery. Between July 2013 and March 2014, 22 hospitalized patients infected or colonized with IMP-6-CPE (Escherichia coli n = 8, Klebsiella oxytoca n = 5, Enterobacter cloacae n = 5, Klebsiella pneumoniae n = 3 and Klebsiella aerogenes n = 1) were identified. There were diverse PFGE profiles and sequence types (STs) in most of the species except for K. oxytoca. All isolates of K. oxytoca belonged to ST29 with similar PFGE profiles, suggesting their clonal transmission. Plasmid analysis by WGS revealed that all 22 isolates but one shared a ca. 50-kb IncN plasmid backbone with bla
suggesting interspecies gene transmission, and typing of plasmids explained epidemiological links among cases. A case-control study showed pancreatoduodenectomy, changing drains in fluoroscopy room, continuous peritoneal lavage and enteric fistula were associated with IMP-6-CPE acquisition among the patients. Plasmid analysis of isolates in an outbreak of IMP-6-CPE suggested interspecies gene transmission and helped to clarify hidden epidemiological links between cases.
The outcome of relapsed/refractory HIV-associated lymphoma remains poor, even in the era of combined antiretroviral therapy. However, recent reports showed the efficacy of autologous stem cell ...transplantation (ASCT). We conducted a single-arm, multicenter phase II study in patients with relapsed/refractory HIV-associated lymphoma to assess the safety and efficacy of ASCT. The study included 14 patients with relapsed/refractory HIV-associated lymphoma. Five patients who achieved partial remission or better after the standard salvage regimen proceeded to ASCT. Conditioning treatment involved ranimustine (300 mg/m2) on day − 6, etoposide (200 mg/m2) on days − 5 to − 3, cytarabine (200 mg/m2) on days − 5 to − 3, and L-PAM (140 mg/m2) on day − 2. All patients achieved engraftment and were alive on day 100 of ASCT. One-year and 2-year overall survival rates were both 40% and 1-year and 2-year progression-free survival rates were both 40%. Grade 2 or 3 diarrhea and oral mucositis were observed in 43% of patients. Cytomegalovirus antigenemia, retinitis, and bacterial infections were noted in 43%, 29%, and 29% of patients, respectively. Therapy-related death was not observed. Although the number of enrolled patients was insufficient for statistical analysis. ASCT was feasible and safe for relapsed/refractory HIV-associated lymphoma.
Registration: This study is registered in UMIN-CTR (UMIN000003159).
Dolutegravir (DTG) is metabolized mainly by uridine diphosphate (UDP)-glucuronosyltransferase 1A1 (UGT1A1), and partly by cytochrome P450 3A (CYP3A). Therefore, we focused on UGT1A1 gene ...polymorphisms (*6 and *28) in Japanese individuals infected with human immunodeficiency virus (HIV)-1 to examine the relationship between their plasma trough concentration of DTG and gene polymorphisms. Recently, neuropsychiatric adverse events (NP-AEs) after the use of DTG have become a concern, so the association between UGT1A1 gene polymorphisms and selected NP-AEs was also investigated.
The study subjects were 107 Japanese patients with HIV-1 infections who were receiving DTG. Five symptoms (dizziness, headache, insomnia, restlessness, and anxiety) were selected as NP-AEs. The subjects were classified by their UGT1A1 gene polymorphisms for the group comparison of DTG trough concentration and the presence or absence of NP-AEs.
The subjects consisted of eight (7%) *6 homozygotes, three (3%) *28 homozygotes, four (4%) for *6/*28 compound heterozygotes, 23 (21%) *6 heterozygotes, 18 (17%) *28 heterozygotes, and 51 (48%) patients carrying the normal allele. The plasma DTG trough concentration of the *6 homozygous patients was significantly higher than that of the patients carrying the normal allele (median, 1.43 and 0.82 μg/mL, respectively, p = 0.0054). The *6 and *28 heterozygous patients also showed significantly higher values than those shown by patients with the normal allele. Multivariate analysis revealed that carrying one or two UGT1A1*6 gene polymorphisms, one UGT1A1*28 polymorphism, and age of < 40 years were independent factors associated with high DTG trough concentrations. The median DTG trough concentration was significantly higher in the patients with NP-AEs (1.31 μg/mL) than in those without NP-AEs (1.01 μg/mL). Consistent with these results, subjects carrying UGT1A1*6, UGT1A1*28, or both alleles showed a higher cumulative incidence of having selected NP-AEs than those carrying the normal alleles (p = 0.0454).
In addition to younger age, carrying UGT1A1*6 and/or UGT1A1*28 was demonstrated to be a factor associated with high DTG trough concentrations. Our results also suggest a relationship between plasma DTG trough concentrations and NP-AEs, and that carrying UGT1A1*6 and/or UGT1A1*28 alleles might be a risk factor for NP-AEs.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Aim
Ongoing hepatitis A outbreaks among men who have sex with men (MSM) have been reported worldwide, mainly in Europe, since 2016. In Japan, there has been an increase in the number of notified ...hepatitis A cases since January 2018, most of which were suspected to have been transmitted through homosexual contact. In this paper, we describe the current outbreak situation of hepatitis A among MSM.
Methods
Between March and July 2018, 13 cases of hepatitis A were identified in our hospital. All cases were identified as MSM. Data on clinical and laboratory findings and therapies were collected from medical records. Serum or stool samples were obtained from 13 patients and subjected to sequence analysis.
Results
Of all patients, 12 reported to have male‐to‐male homosexual contact within 7 weeks prior to symptom onset, and 6 visited sex‐on‐premises venues in the same area. Furthermore, 12 patients were infected with HIV and consequently received antiretroviral therapy with sustained viral suppression. Ten patients received pulsed methylprednisolone therapy. Plasma exchange was additionally carried out in one patient. All patients received inpatient hospital care and were discharged alive. Sequence information, which was available in all cases, showed that the hepatitis A virus strain was identical to the EuroPride strain (RIVM‐HAV16–090).
Conclusions
Results of sequence analysis suggest that the ongoing hepatitis A outbreak among MSM in Japan is linked to the 2016 European outbreaks. A vaccination program is urgently required for high‐risk populations to control this ongoing outbreak.
HIV/HCV co‐infection from blood products for hemophilia has been a social problem in Japan. Liver transplantation (LT) is an important treatment option for hepatic failure and cirrhosis of the liver ...in co‐infected patients, and appropriate indications for LT, especially organ form deceased donors, are required by society. The aim is to propose priority status for the waiting list for deceased donor (DD) LT in HIV/HCV co‐infected patients in Japan based on medical and scientific considerations. Since 2009, we have been working on the subject in research projects under grants‐in‐aid for health and labour sciences research on AIDS measures provided by the Ministry of Health, Labour and Welfare (the Kanematsu project and Eguchi project). Our research showed that hepatic fibrosis is advanced in HIV/HCV co‐infected Japanese patients, especially those with hemophilia who became infected from blood products at a faster rate than HCV mono‐infected patients. In addition, those patients who developed portal hypertension had a poor prognosis at a young age. The results of our research contributed to increasing the priority score of those patients on the deceased donor liver transplantation (DDLT) waiting list in 2013 and to establishing a scoring system for DDLT corresponding to the Model for End‐stage Liver disease (MELD) score in 2019. This paper introduces changes in priority and the current state of priority of the DDLT waiting list for HIV/HCV co‐infected patients in Japan.
Dolutegravir may inhibit creatinine transporters in renal tubules and elevate serum creatinine levels. We investigated the usefulness of glomerular filtration rate (GFR) measured using inulin ...clearance (Cin), creatinine clearance (Ccr), and estimated GFR based on both serum creatinine (eGFRcre) and serum cystatin C (eGFRcys).
HIV-1-infected Japanese patients with suppressed viremia and whose antiretroviral drug was switched to dolutegravir from other drugs were included (n = 108, Study 1). We compared eGFRcre and eGFRcys at the start and after 48 weeks of dolutegravir administration. For the patients providing consent, we measured Cin and Ccr (n = 15, Study 2). We assessed biases and accuracy and compared Cin with eGFRcre, eGFRcys, and Ccr.
There were no differences in serum cystatin C and eGFRcys between baseline and at 48 weeks. Moreover, eGFRcre was significantly less accurate (within 30% of measured GFR) than both eGFRcys and Ccr (40% accuracy compared to 93% and 93%, respectively). eGFRcys was significantly less biased than eGFRcre and Ccr (p < 0.0001, p = 0.00036, respectively). No significant difference between Cin and eGFRcys was observed. eGFRcys was significantly correlated with Cin (γ = 0.85, p < 0.0001).
eGFRcys provided the most precise estimate and most closely approximate Cin in HIV-1-infected Japanese patients with suppressed viremia treated with dolutegravir. We demonstrated clinical benefits of inulin clearance and eGFRcys. This is the first study performing inulin clearance for HIV-1-infected individuals and to show data for eGFRcys from a large cohort following a switch to dolutegravir from other antiretroviral agents.
Circulating interferon-γ (IFN-γ) concentration may be sustained at a high level regardless of the initiation of antiretroviral therapy (ART) in some patients with HIV-1 infection. In the present ...study, we examined the clinical characteristics of HIV-1-infected patients with high levels of plasma IFN-γ.
The study subjects were patients infected with HIV-1 who were either naïve to ART with CD4
cell count > 200 cells/μL (n = 12), or had achieved viral suppression after ART for over a year (n = 188). The levels of plasma IFN-γ and interleukin-6 (IL-6) were measured by the enzyme-linked immunosorbent assay. Patients were divided into high IFN-γ and low IFN-γ groups based on a cutoff level of 5 pg/mL.
The high IFN-γ group included 41 patients (21%). Compared to the patients on ART with low IFN-γ levels, those on ART in the high IFN-γ group were more likely to be younger than 50 years of age (P = 0.0051) and less likely to have dyslipidemia (P = 0.0476) or to be on a protease inhibitor (P = 0.0449). There was no significant difference between groups in the median increase of CD4
cell counts from the initiation of ART for up to 3 years. However, after 4 years, the increase in CD4
cell counts was significantly lower in the high IFN-γ group compared with that in the low IFN-γ group. There were no such significant differences between patients with low and high (> 2 pg/mL) levels of plasma IL-6.
We concluded that HIV-1-infected patients with high levels of circulating IFN-γ did not have a higher rate of comorbidities related to immune activation. However, they exhibited lower CD4
cell count recovery after 4 years of being on ART. This deficit could be a consequence of persistent immune activation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The relationship between plasma tenofovir (TFV) concentration at the beginning of tenofovir disoproxil fumarate (TDF) administration and the development of renal dysfunction during long-term ...administration of TDF has not been demonstrated yet. The objective of the present study was to determine whether plasma TFV trough concentrations during early TDF administration could serve as an indicator of renal dysfunction when TDF is administered for long periods.
We included 149 HIV-1 infected Japanese patients who were prescribed TDF. We investigated the relationship between plasma TFV trough concentrations and the rate of discontinuation due to the development of renal dysfunction for up to five years after the start of TDF administration. We also examined how the decrease in renal function over time due to TDF administration was related to factors associated with high TFV levels and plasma TFV trough concentrations.
The median TFV trough concentration in the TDF discontinuation group was 88 ng/mL, which was significantly higher (p = 0.0041), than that in the continuation group (72 ng/mL). Further, using an ROC curve, the cut-off value for TFV trough concentration at which TDF discontinuation was significantly high was found to be 98 ng/mL. Logistic multivariate analysis of factors associated with discontinuation of TDF due to renal function-related adverse events showed that being ≥ 50 years old (OR = 2.96; 95% CI, 1.01-8.64), having eGFR < 80 mL/min/1.73m
at the start of TDF administration (OR = 5.51; 95% CI, 1.83-17.5), and TFV trough concentration ≥ 98 ng/mL (OR = 2.96; 95% CI, 1.16-7.60) were independent factors.
The results suggested that the importance of measuring TFV concentrations to evaluate the risk of developing renal function-related adverse events during long-term TDF administration.
Plasmablastic lymphoma (PBL) is a rare AIDS-related malignancy with a poor prognosis. Little is known about this entity, and no standard treatment regimen has been defined. To establish an adequate ...treatment strategy, we investigated 24 cases of PBL arising in human immunodeficiency virus-positive individuals. Most of the patients were in the AIDS stage, with a median CD4 count of 67.5/µL. Lymph nodes (58 %), gastrointestinal tract (42 %), bone marrow (39 %), oral cavity (38 %), and CNS (18 %) were the most commonly involved sites. Histology findings for the following were positive at varying rates, as follows: CD10 (56 %); CD30 (39 %); CD38 (87 %); MUM-1 (91 %); CD138 (79 %); EBER (91 %); and LMP-1 (18 %). There was a marked increase in patients in 2011–12, and the cases found in that period appeared to be more aggressive, showing a higher rate of advanced-stage PBL. Fourteen cases were treated with CHOP, while the others were treated with more intensive regimens, including bortezomib and hematopoietic stem cell transplantation. The overall median survival time was 15 months. A CD4 count of >100/µL at diagnosis and attaining complete remission in the first-line chemotherapy were associated with better outcomes (
P
= 0.027 and 0.0016, respectively). Host immune status and chemosensitivity are associated with improved prognosis in PBL.
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