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Altered white matter microstructure has been reported repeatedly using diffusion tensor imaging (DTI) in HIV-associated neurocognitive disorders. However, the associations between neurocognitive deficits and impaired white matter remains obscure due to frequent physical and psychiatric comorbidities in the patients. Severe immune suppression, reflected by low nadir CD4 T-cell counts, is reported to be associated with the neurocognitive deficits in the patients. In the present study, we examined white matter integrity using DTI and tract-based spatial statistics (TBSS), and neurocognitive functions using a battery of tests, in 15 HIV-infected patients with low nadir CD4, 16 HIV-infected patients with high nadir CD4, and 33 age- and sex-matched healthy controls. As DTI measures, we analyzed fractional anisotropy (FA) and mean diffusivity (MD). In addition, we investigated the correlation between white matter impairments and neurocognitive deficits. Among the three participant groups, the patients with low nadir CD4 showed significantly lower performance in processing speed and motor skills, and had significantly increased MD in widespread regions of white matter in both hemispheres. In the patients with low nadir CD4, there was a significant negative correlation between motor skills and MD in the right motor tracts, as well as in the corpus callosum. In summary, this study may provide white matter correlates of neurocognitive deficits in HIV-infected patients with past severe immune suppression as legacy effects.

Background Lenacapavir (LEN), a potent first-in-class inhibitor of HIV-1 capsid function, is in development as a long-acting agent for treatment and prevention of HIV-1. Methods CAPELLA is an ongoing, phase 2/3 study in heavily treatment-experienced (HTE) people with HIV-1 (PWH) with multidrug-resistance. 36 participants were randomized (2:1) to add oral LEN or placebo to their failing regimen. At D15, those on oral LEN received subcutaneous (SC) LEN 927 mg (Q6M); those on placebo started the oral LEN lead-in, followed by SC Q6M. All randomized participants initiated an investigator-selected, optimized background regimen (OBR) at D15. An additional 36 participants started OBR concurrent with LEN (oral lead-in → SC) in a non-randomized cohort. We report the Week (W) 52 efficacy and safety results from both cohorts. Results Of 72 participants enrolled, 25% were female, 38% Black, median age 52 years, 64% had CD4 < 200 cells/µL, 46% had HIV-1 resistant to all 4 major classes (NRTI, NNRTI, PI, INSTI), and 53% had OBR with 1 or no fully active agents. At W52, 78% (56/72) achieved VL< 50 c/mL and 82% (59/72) achieved VL< 200 c/mL via FDA Snapshot algorithm. CD4 count increased by a median 84 cells/µL (Q1 to Q3: 21 to 153) and the proportion of participants with CD4 count ≥200 cells/ul increased from 36% at baseline to 68% at W52. Ten participants had emergent LEN resistance (8 previously reported); 4 of 10 subsequently suppressed. The median (range) duration of follow up on LEN was 71 (13–111) weeks. One participant discontinued due to injection site nodule (Grade 1). The most common injection site reaction (ISR) was swelling (28% [20/72] and 17% [12/70] after the 1st and 2nd SC doses, respectively). Most ISRs were mild or moderate. The most common AEs (excluding injection site reactions) were nausea and diarrhea (14% each). Conclusion In HTE PWH, subcutaneous LEN was well tolerated and in combination with OBR led to high and sustained rate of virologic suppression at W52. These results support the potential role for LEN for treatment of multi-drug resistant HIV-1 infection. Disclosures Sorana Segal-Maurer, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Grant/Research Support|Gilead Sciences: Honoraria|JANSSEN THERAPEUTICS: Honoraria|ViiV: Honoraria Benoit Trottier, MD, Gilead Sciences: Advisor/Consultant|Gilead Sciences: Honoraria|Merck: Advisor/Consultant|Merck: Honoraria|ViiV Healthcare: Advisor/Consultant|ViiV Healthcare: Honoraria Jason Brunetta, M.D., Gilead Canada: Advisor/Consultant|Gilead Canada: Honoraria|Gilead Canada: Conference Attendance Sponsorship|Viiv Canada: Advisor/Consultant Hui Wang, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Nicolas A. Margot, MA, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Hadas Dvory-Sobol, PhD, Gilead Sciences: Employment|Gilead Sciences: Stocks/Bonds Martin S Rhee, MD, Gilead Sciences: Stocks/Bonds Jared Baeten, MD, PhD, Gilead Sciences: Employee|Gilead Sciences: Stocks/Bonds Jean-Michel Molina, MD; PhD, GIlead: Board Member|GIlead: Grant/Research Support|Merck: Board Member|Merck: Expert Testimony|ViiV: Board Member.

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.

In patients infected with human immunodeficiency virus (HIV)-1 at our hospital, we observed increases in skin and soft-tissue infections (SSTIs) by community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA). Therefore, we analyzed factors related to CA-MRSA infection and performed a molecular epidemiological investigation.HIV-1-infected patients were diagnosed with SSTIs related to S. aureus between 2007 and 2017, and MRSA was classified into community and hospital-acquired types according to published criteria. Information was collected retrospectively from clinical records, and multivariate analysis by logistic regression was performed concerning factors related to CA-MRSA infection. We evaluated the staphylococcal cassette chromosome mec (SCCmec) type, multilocus sequence type, and the presence of genes encoding Panton-Valentine leucocidin (PVL) in 27 MRSA samples isolated during and after 2015.We found 218 episodes of SSTIs in 169 patients, and among initial episodes of SSTIs, the MRSA ratio was higher from 2015 to 2017 relative to that from 2007 to 2014 (88% vs. 44%; p 0.0001). Multivariate analysis showed that in men having sex with men [MSM; odds ratio (OR): 13] and exhibiting onset during and after 2015 (OR: 5.4), CD4These data describe an increased prevalence of SSTIs due to PVL-positive ST8-MRSA-IV, not previously considered epidemic in Japan, in MSM infected with HIV-1 in Osaka, Japan.

Although neuropsychological studies of human immunodeficiency virus (HIV)-infected patients have demonstrated heterogeneity in neurocognitive impairment and neuroimaging studies have reported diverse brain regions affected by HIV, it remains unclear whether individual differences in neurocognitive impairment are underpinned by their neural bases. Here, we investigated spatial distribution patterns of correlation between neurocognitive function and regional gray matter (GM) volume across patients with HIV. Thirty-one combination antiretroviral therapy-treated HIV-infected Japanese male patients and 33 age- and sex-matched healthy controls were included in the analysis after strict exclusion criteria, especially for substance use. Fifteen neurocognitive tests were used, and volumetric magnetic resonance imaging was performed. We used voxel-based morphometry to compare GM volume between groups and identify regional GM volumes that correlated with neurocognitive tests across patients. Using the Frascati criteria, 10 patients were diagnosed with asymptomatic neurocognitive impairment, while the others were not diagnosed with HIV-associated neurocognitive disorders. Patients showed a significantly lower performance in five neurocognitive tests as well as significantly reduced GM volume relative to controls, with volume-reduced regions spread diffusely across the whole brain. Different aspects of neurocognitive impairment (i.e., figural copy, finger tapping, and Pegboard) were associated with different GM regions. Our findings suggest a biological background constituting heterogeneity of neurocognitive impairment in HIV infection and support the clinical importance of considering individual differences for tailor-made medicine for people living with HIV.

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.

Background 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. Methods 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. Results 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. Conclusion 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. Electronic supplementary material The online version of this article (10.1186/s12879-018-3643-2) contains supplementary material, which is available to authorized users.

Epstein-Barr virus (EBV) reactivation causes serious diseases in immunocompromised hosts, such as acquired immunodeficiency syndrome (AIDS). We report on a case of plasmablastic lymphoma (PBL) with hemophagocytic lymphohistiocytosis (HLH).A-53-year-old Japanese man was diagnosed with PBL and AIDS. In addition to combined antiretroviral therapy, HyperCVAD (cyclophosphamide, doxorubicin, vincristine, prednisone)/high-dose methotrexate + cytarabine was initiated immediately. Partial remission was attained with chemotherapy. However, the patient developed HLH and died despite intensive therapy. Autopsy findings suggested that PBL was controlled, and immunosuppression appeared to cause fatal infection. The patient showed high titers of EBV viral-capsid antigen (VCA)-IgG (1:2560) on PBL diagnosis and high EBV-DNA levels throughout the clinical course. Moreover, EBV-DNA was detected in the fraction of CD8-positive cells, which strongly supports the pathogenesis of EBV-associated HLH.Our report highlights the importance of EBV control in patients with EBV-positive AIDS lymphoma. EBV not only behaves as the etiologic pathogen of PBL but also can be a trigger of HLH, the fatal complication. Careful follow-up of the EBV status should be performed, and if needed, preemptive anti-EBV therapy should also be considered to prevent EBV-associated complications such as HLH.

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.

Objective: This study aimed to determine improvement in HIV RNA levels and the CD4 cell count by switching to an antiretroviral regimen with an integrase strand transfer inhibitor (INSTI) in patients with HIV. Method: This study was conducted on Japanese patients with HIV who were infected by blood products in the 1980s. Data were collected between 2007 and 2014. Data of 564 male hemophiliac patients with HIV from the Japan Cohort Study of HIV Patients Infected through Blood Products were available. Changes in antiretroviral regimen use, HIV RNA levels, and the CD4 cell count between 2007 and 2014 were examined. Results: From 2007 to 2014, the proportion of use of a regimen with an INSTI increased from 0.0% to 41.0%. For patients with HIV who used a regimen, including an INSTI, the proportion of HIV RNA levels Conclusion: There is a large effect of switching to an antiretroviral regimen with an INSTI for Japanese patients with HIV who are infected by blood products. This suggests that performing this switch in clinical practice will lead to favorable effects.

Aim To investigate the efficacy and safety of all-oral direct-acting antiviral treatments in patients coinfected with hepatitis C virus (HCV) and HIV. Methods In all, 35 patients with HCV/HIV coinfection (22 patients with HCV genotype 1 infection, 6 with genotype 2, and 7 with genotype 3) were treated with sofosbuvir and ledipasvir (for genotype 1 patients) or sofosbuvir and ribavirin (for genotypes 2 and 3). Sustained virological response (SVR) at 24 weeks after end of treatment and adverse events were assessed. Results The overall SVR rate was 91.4% (32/35). One patient with genotype 1 infection discontinued treatment on day 2 due to severe headache, which subsided after the cessation of medication; all other patients completed their treatment without severe adverse events. Two patients who had a relapse of HCV were infected with a genotype 3 strain. We observed hyperbilirubinemia in a patient with genotype 3, who was under antiretroviral therapy including atazanavir. He completed the treatment and achieved SVR. Conclusion Direct-acting antiviral treatment for patients coinfected with HCV/HIV is as effective as in patients infected only with HCV. It was generally well tolerated, except in one patient who discontinued the treatment due to severe headache.

BACKGROUND Simulation studies were performed to predict the future supply and demand for blood donations, and future shortfalls. STUDY DESIGN AND METHODS Using data from all donations in 2006 to 2009, the Markov model was applied to estimate future blood donations until 2050. Based on data concerning the actual use of blood products, the number of blood products needed was estimated based on future population projections. RESULTS We estimated that the number of blood donations increased from 5,020,000 in 2008 to 5,260,000 in 2012, but will decrease to 4,770,000 units by 2025. In particular, the number of donors in their 20s and 30s decreased every year. Moreover, the number of donations required to supply blood products would have been increased from 5,390,000 in 2012 to 5,660,000 units in 2025. Thus, the estimated shortfall of blood donations is expected to increase each year from 140,000 in 2012 to 890,000 in 2025 and then more than double to 1,670,000 in 2050. CONCLUSION If the current blood donation behaviors continue, a shortfall of blood availability is likely to occur in Japan. Insufficient blood donations are mainly related to a projected reduction in population of 20 to 30 year olds, a significant group of donors. Thus, it is crucial to recruit and retain new donors and to develop recommendations for proper use of blood products to minimize unnecessary use. This study provides useful information that can be used by governments to help ensure the adequacy of the blood supply through promoting donations and conserving blood resources.

Raltegravir (RAL), an HIV integrase inhibitor, is metabolized mainly by UDP-glucuronosyltransferase 1A1 (UGT1A1). Polymorphisms in UGT1A1 may cause alterations in the pharmacodynamics of RAL, which is taken twice daily with no dietary restrictions. We compared the effect of two polymorphic alleles in this gene, UGT1A1*6 and UGT1A1*28 on plasma RAL concentrations in Japanese HIV-1-infected patients. Of 114 Japanese HIV-1-infected patients who received RAL, the frequencies of UGT1A1*6 and UGT1A1*28 were 18% and 13%, respectively. The percentage of homozygotes for UGT1A1*6 and UGT1A1*28 was 6% and 4%, respectively, the percentage of compound heterozygotes for UGT1A1*6 and UGT1A1*28 was 2%, and that of heterozygotes for UGT1A1*6 and UGT1A1*28 was 22% and 17%, respectively. RAL plasma trough concentrations were compared for each polymorphism. Significantly higher levels of RAL were observed with patients who were homozygous for UGT1A1*6 (median: 1.0 μg/mL) than for the normal allele (median: 0.11 μg/mL; p = 0.021). Multivariate logistic regression analysis showed that the presence of one or two alleles of UGT1A1*6 or two alleles of UGT1A1*28 were independent factors associated with high RAL plasma trough concentrations (≥ 0.17 μg/mL). These results indicated that UGT1A1*6 and UGT1A1*28 are both factors influencing the RAL plasma trough concentrations in Japanese HIV-1-infected patients.

Background 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. Methods 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. Results 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

The diagnosis of non-cirrhotic portal hypertension (NCPH), a rare but potentially life-threatening complication in human immunodeficiency virus (HIV)-positive individuals, often occurs only after the emergence of fatal manifestations such as bleeding of esophageal varices. We herein report a female Japanese HIV patient who developed NCPH approximately 4 years after discontinuation of 65 months of didanosine (ddI) administration. The patient presented with severe ascites, bloody bowel discharge, extreme abdominal swelling, and symptoms of portal hypertension but no sign of liver cirrhosis. Examination revealed esophageal varices, oozing-like bleeding from a wide part of the colon, significant atrophy of the right lobe of the liver, and arterio-portal shunting and recanalization from the left medial segment branch of the portal vein to a paraumbilical vein, but no visible obstruction of the main trunk of the portal vein. Treatment for esophageal varices consisted of coagulation therapy with argon plasma after enforcement by endoscopic sclerotherapy and oral administration of β-blockers for elevated portal blood pressure. The patient has not experienced gastrointestinal bleeding in the approximately 5 years since the diagnosis of NCPH. Reviewing this case suggests the importance of suspecting NCPH in HIV patients with liver dysfunction of unknown etiology with a history of ddI and other purine analogs use, as well as the importance of controlling portal hypertension and esophageal varices in the treatment of NCPH.

The development of herpes zoster is associated with reduced varicella zoster virus (VZV)-specific cell-mediated immune (CMI) reactions. In this study, VZV-specific CMI reactions in 42 anti-VZV-IgG antibody-positive adults infected with HIV-1 were evaluated by measuring the IFN-γ production levels in whole blood in response to stimulation with ultraviolet light-inactivated live attenuated VZV vaccine. The median VZV-specific IFN-γ production level in all patients was 63 pg/ml. Antiretroviral therapy (ART)-naive patients with an AIDS-defining illness (HIV classification category C) had significantly lower IFN-γ production than ART-naive patients in categories A and B and patients receiving ART (P=0.0194 and P=0.0046, respectively). IFN-γ production increased significantly in patients within 1 month of the onset of recurrent VZV disease and at more than 1 year from onset, compared with patients who had never had recurrent VZV disease (P=0.0396 and P=0.0484, respectively). In multivariate analyses, category C and history of recurrent VZV disease were significant factors affecting IFN-γ production. Levels of IFN-γ were measured before and after ART in seven ART-naive patients with no history of recurrent VZV disease, and no significant changes were observed. The results indicate that VZV-specific CMI reactions were reduced in patients with an AIDS-defining illness and enhanced in patients with a history of recurrent VZV disease, but not enhanced by ART alone. Vaccination may be necessary to inhibit the development of herpes zoster in patients receiving ART; this IFN-γ releasing assay is one useful method for evaluating VZV-specific CMI reactions in clinical settings.

An elderly woman with human immunodeficiency virus-1 infection developed short bowel syndrome as a result of extensive intestinal resection. Considering the possibility of poor absorption of antiretroviral drugs (ARVs), therapeutic drug monitoring (TDM) was performed. A single-dose test of 6 ARVs (darunavir, ritonavir, lopinavir, etravirine, maraviroc, and raltegravir) did not provide information on the appropriate ARV, and repeated TDM under continuous antiretroviral therapy resulted in viral suppression below 50 copies/mL, which was considered to be treatment success. These assessments suggest the importance of TDM in the steady state for the successful treatment of individuals with impaired gastrointestinal function using ARVs.

High human herpesvirus 8 (HHV-8) seroprevalence has been reported in men who have sex with men (MSM) and are infected with HIV-1. However, it is unclear when they become infected with HHV-8. Thus, we conducted cross-sectional and longitudinal investigations of HHV-8 seroprevalence in HIV-1-infected individuals in Osaka, Japan.Plasma was collected from 121 individuals infected with HIV-1 and the anti-HHV-8 antibody titer was measured using an enzyme-linked immunosorbent assay with whole virus lysate. Subjects were classified into those with and without a past medical history of HHV-8-associated disease; the latter group was then classified into 3 subgroups based on the assumed route of HIV-1 infection: blood products, homosexual contact, and other routes. HHV-8 seroprevalence was compared among the groups and measured again approximately 3 years after the baseline measurement. The relationship between HHV-8 seropositivity and possible associated factors was also investigated.All 15 subjects with HHV-8-associated disease were seropositive, and all 11 subjects in the blood product group were seronegative. In the MSM group, 25 (30%) of 79 subjects were HHV-8 seropositive and, in the non-MSM group, 1 (6%) of 16 subjects was (p 0.0001). In the longitudinal investigation, seroconversion was observed in 10 (19%) of 52 subjects in the MSM group who were seronegative at baseline. A correlation was observed between seroconversion and symptomatic syphilis (p = 0.0432).HHV-8 seropositivity and seroconversion rates were high in HIV-1-infected MSM, suggesting that, currently, HHV-8 is an epidemic pathogen in this population.

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.

A 44-year-old male, who was HIV seropositive, developped weight loss, high grade fever, and multiple lymphadenopathies. Bone marrow biopsy revealed a granuloma lesion, and at the same part of the specimen, Ziehl Neelsen staining showed multiple mycobacterium diffusely arranged in the histocytes. The culture did not show positive after 6 to 8 weeks. Finally we diagnosed disseminated Mycobacterium genavense using a house-keeping gene analysis including 16S rRNA sequencing of lymph punctate with fine needle aspiration and the specimen from the biopsy of the lymph node. If a specimen tests positive for Ziehl Neelsen staining smear positive, culture negative, and PCR negative for tuberculosis and Mycobacterium avium complex, we should consider M. genavense infection as one of the differential diagnoses.

Simulation studies were performed to predict the future supply and demand for blood donations, and future shortfalls.Using data from all donations in 2006 to 2009, the Markov model was applied to estimate future blood donations until 2050. Based on data concerning the actual use of blood products, the number of blood products needed was estimated based on future population projections.We estimated that the number of blood donations increased from 5,020,000 in 2008 to 5,260,000 in 2012, but will decrease to 4,770,000 units by 2025. In particular, the number of donors in their 20s and 30s decreased every year. Moreover, the number of donations required to supply blood products would have been increased from 5,390,000 in 2012 to 5,660,000 units in 2025. Thus, the estimated shortfall of blood donations is expected to increase each year from 140,000 in 2012 to 890,000 in 2025 and then more than double to 1,670,000 in 2050.If the current blood donation behaviors continue, a shortfall of blood availability is likely to occur in Japan. Insufficient blood donations are mainly related to a projected reduction in population of 20 to 30 year olds, a significant group of donors. Thus, it is crucial to recruit and retain new donors and to develop recommendations for proper use of blood products to minimize unnecessary use. This study provides useful information that can be used by governments to help ensure the adequacy of the blood supply through promoting donations and conserving blood resources.

Immune reconstitution inflammatory syndrome (IRIS) is an unsolved problem in the treatment of human immunodeficiency virus (HIV)-1 infection. Despite the high seroprevalence of parvovirus B19 (PVB19) among HIV-1-positive patients, reports on PVB19-induced anemia, especially that associated with PVB19-related IRIS, in these patients are limited. We present the case of a man with acquired immunodeficiency syndrome who developed severe transfusion-dependent anemia and was seropositive and borderline positive for immunoglobulin-M and IgG antibodies against PVB19, respectively. PVB19-DNA was also detected in his serum. The patient was diagnosed with pure red cell anemia (PRCA) caused by a primary PVB19 infection and was treated with periodical blood transfusions. However, he subsequently tested negative for IgG antibodies and developed chronic severe anemia with high levels of PVB19 viremia. This indicated a transition from primary to persistent infection. After initiation of highly active antiretroviral therapy, the patient showed an inflammatory reaction with rapid deterioration of anemia and seroconversion of the IgG antibody to PVB19. Subsequently, PRCA was completely resolved, but the patient's serum still contained low levels of PVB19-DNA. Thus, this was a case of IRIS associated with PVB19 infection. Our report highlights the significance of seroconversion to PVB19 in the diagnosis of IRIS and re-emphasizes the finding that persistently high levels of PVB19 viremia after primary infection are probably because of the lack of protective antibodies.

Background As the survival of human immunodeficiency virus (HIV)-infected individuals has improved due to the widespread use of antiretroviral therapy, the mortality rate due to hepatitis C virus (HCV)-related liver disease has increased in HIV/HCV-coinfected patients. Aim The aims of this study were to establish the appropriate therapeutic strategy for HIV/HCV-coinfected patients by evaluating the liver function, including the hepatic functional reserve and portal hypertension, and to investigate the prognosis of HIV/HCV-coinfected patients in Japan. Patients and Methods In addition to regular liver function tests, the hepatic functional reserve of 41 patients with HIV/HCV coinfection was evaluated using the indocyanine green retention rate and liver galactosyl serum albumin-scintigraphy. The data for 146 patients with HIV/HCV coinfection through blood products were extracted from 4 major HIV centers in Japan. In addition to liver function tests, the platelet counts (PLT) were evaluated as a marker of portal hypertension. Results In spite of the relatively preserved general liver function test results, approximately 40% of the HIV/HCV-coinfected patients had an impaired hepatic functional reserve. In addition, while the albumin and bilirubin levels were normal, the PLT was, Transplantation Proceedings, 46(3), pp.736-738; 2014

The emergence and transmission of drug-resistant human immunodeficiency virus-1 (HIV-1) compromises antiretroviral treatment for HIV-1. Thus, testing for drug resistance is recommended at diagnosis and before initiating highly active antiretroviral treatment. We conducted an epidemiological study enrolling newly diagnosed patients between 2003 and 2008 in our nationwide surveillance network. In the 6-year study period, the prevalence of drug-resistant HIV-1 among 2573 patients, consisting mainly of Japanese men in their late-30s and infected through male-to-male sexual contacts, followed an increasing trend from 5.9% (16/273) in 2003 to 8.3% (50/605) in 2008. Nucleoside reverse transcriptase inhibitor-associated mutations predominated in each year, with T215 revertants being the most abundant. The predictive factor for drug-resistant HIV-1 transmission was subtype B (OR=2.36; p=0.004), and those for recent HIV-1 infection were male gender (OR=3.79; p=0.009), MSM behavior (OR=1.67; p=0.01), Japanese nationality (OR=2.31; p=0.008), and subtype B (OR=5.64; p

Disseminated penicilliosis-an AIDS-indicator disease in Southeast Asian countries -but not Japan- is a systemic fungal infection caused by Penicillium marneffei. A 30-year-old HIV-positive Japanese man visiting Southeast Asia three months before admission and reporting fever, general fatigue, and enlarged lymph nodes lasting over one month was admitted for detailed tests. Blood culture and fine-needle aspiration lymph node biopsy a led to a diagnosis of disseminated penicillioisis, later cured by several anti-fungal agents. Caution is thus recommended regarding the possibility of this disease, given the large number of travelers visiting overseas, geographical proximity to Southeast Asia, and increasing numbers of HIV patients in Japan.

We treated three cases of fungemia in HIV-infected patients. These cases were caused by Candida albicans, Cryptococcus neoformans, and Penicillium marneffei, respectively, and all were diagnosed through the use of mycobacterial blood culture bottles. Although the detection of the etiologic agents of fungal infection is difficult, it has been shown that blood culture media for mycobacteria are more effective for the detection of fungemia than media for aerobes and anaerobes. Some reports have shown that Bactec Myco/F lytic bottles were useful for the diagnosis of fungemia in clinical samples. Here, we report the successful use of BacT MB bottles.

Suicide is a major social and health issue in Japan. We assessed prevalence of attempted suicide and explored individual, interpersonal, behavioral, and psychological risk factors associated with attempted suicide in a general community sample of youth in a metropolitan Japanese city. Survey of 2,095 participants age between 15 and 24 who were recruited using street-intercept techniques. Overall, 6% of males and 11% of females reported a prior suicide attempt. For males, attempted suicide was independently associated with experience of school bullying, being homosexual or bisexual, history of drug use, experience of unwanted sex, history of a diagnosed sexually transmitted infection, and low self-esteem. For females, attempted suicide was independently associated with being younger (ages 15–19 compared to 20–24), experience of school bullying, history of drug use, and history of smoking. Prevention intervention programs for youth in Japan are necessary to achieve national aims to reduce attempted suicides and suicide mortality.

It is speculated that HLA-A( *)26-restricted HIV-1-specific CTLs can control HIV-1, since HLA-A( *)26 is associated with a slow progression to AIDS. In three major HLA-A( *)26 subtypes, HLA-A( *)2601-restricted, and HLA-A( *)2603-restricted HIV-1 epitopes have been identified, but HLA-A( *)2602-restricted ones have not. We here identified HLA-A( *)2602-restricted HIV-1 epitopes by using reverse immunogenetics and compared the immunodominance of the epitopes among the three subtypes. Out of 110 HIV-1 peptides carrying HLA-A( *)26 anchor residues, only the Gag169-177 peptide, which had been previously identified as an HLA-A( *)2601- and HLA-A( *)2603-restricted immunodominant epitope, induced Gag169-177-specific CD8(+) T cells from only two of six HLA-A( *)2602(+) HIV-1-infected individuals. No difference in affinity of this epitope peptide was found among these three HLA-A( *)26 subtypes, indicating that Gag169-177 was effectively presented by HLA-A( *)2602 but recognized as a subdominant epitope in HIV-1-infected HLA-A( *)2602(+) individuals. These findings indicate different immunodominance of Gag169-177 epitope among 3 HLA-A( *)26 subtypes.

Background Efavirenz (EFV) is metabolized primarily by cytochrome P450 2B6 (CYP2B6), and high plasma concentrations of the drug are associated with a G-->T polymorphism at position 516 (516G-->T) of CYP2B6 and frequent central nervous system (CNS)-related side effects. Here, we tested the feasibility of genotype-based dose reduction of EFV. Methods CYP2B6 genotypes were determined in 456 human immunodeficiency virus type 1 (HIV-1)-infected patients who were receiving EFV treatment or were scheduled to receive EFV-containing treatment. EFV dose was reduced in CYP2B6 516G-->T carriers who had high plasma EFV concentrations while receiving the standard dosage (600 mg). EFV-naive homozygous CYP2B6 516G-->T carriers were treated with low-dose EFV. In both groups, the dose was further reduced when plasma EFV concentration remained high. Results CYP2B6 516G-->T was identified in the *6 allele (found in 17.9% of our subjects) and a novel allele, *26 (found in 1.3% of our patients). All EFV-treated CYP2B6 *6/*6 and *6/*26 carriers had extremely high plasma EFV concentrations (>6000 ng/mL) while receiving the standard dosage. EFV dose was reduced to 400 mg for 11 patients and to 200 mg for 7 patients with persistently suppressed HIV-1 loads. EFV-containing treatment was initiated at 400 mg in 4 CYP2B6 *6/*6 carriers and one *6/*26 carrier. Two of them still had a high plasma EFV concentration while receiving that dose, and the dose was further reduced to 200 mg, with successful HIV-1 suppression. CNS-related symptoms improved with dose reduction in 10 of the 14 patients, although some had not been aware of the symptoms at initial dosage. Conclusions Genotype-based EFV dose reduction is feasible in CYP2B6 *6/*6 and *6/*26 carriers, which can reduce EFV-associated CNS symptoms.

Reversible Posterior Leukoencephalopathy Syndrome (RPLS) is an uncommon neurological disorder which shows the diffuse edema in white matter of occipital lobe of brain. In this report, we describe a RPLS case with Human Immunodeficiency Virus (HIV) infection, whose lesion was improved with Highly Active Antiretroviral Therapy (HAART). A HIV-infected man, who was diagnosed as a mental deterioration with Central Pontine Myelinolysis (CPM) appearing high intensity pontine lesion in brain Magnetic Resonance Imaging (MRI), improved with HAART. No episode of hyponatremia or hypertension was observed in his clinical course. Evaluation of apparent diffusion coefficient (ADC) mapping in diffusion weight imaging (DWI) was performed in brain MRI at the onset and four months after commencement of HAART. ADC mapping enabled to interpret the pontine lesion as RPLS. HAART improved the mental deterioration within two weeks and the elevated ADC value at the onset was normalized at four-month clinical course.

Background Estimates of the interval from HIV-1 infection to disease progression may be affected by selection bias, and data concerning asymptomatic early seroconverters are limited. We examined the interval until disease progression in HIV-1 seroconverters in whom the timing of infection could be estimated within 1 year before diagnosis. Methods Subjects included newly diagnosed patients at Osaka National Hospital between 2003 and 2010 who had either (1) symptomatic acute HIV-1 infection with a negative or intermediate reaction on Western blotting and a positive reaction on an HIV RNA test (symptomatic acute group) or (2) a positive reaction on Western blotting at diagnosis and a

A 46-year-old man presented with a high-grade fever, multiple lymphadenopathies, hepatosplenomegaly and human immunodeficiency virus (HIV) seropositivity, without severe immunosuppression. We suspected human herpesvirus-8 (HHV-8)-associated multicentric Castleman's disease (MCD) based on the results of a physical examination and laboratory investigations, including bone marrow aspiration. However, the patient died eight days after admission due to multiorgan failure. An autopsy revealed MCD and lymphoma cell infiltration in multiple organs. The final diagnosis was large B-cell lymphoma (LBCL) arising in HHV-8-associated MCD. This case illustrates the potential for LBCL in HHV-8 MCD in HIV-infected patients with hepatosplenomegaly and lymphadenopathy without severe immunosuppression and highlights the clinical significance of bone marrow aspiration.

Objective To assess DNA polymorphisms in mycobacterial isolates obtained from human immunodeficiency virus (HIV)-seropositive patients with tuberculosis in Japan from 1996 to 2003. Methods Restriction fragment length polymorphisms (RFLP) from Mycobacterium tuberculosis and Mycobacterium avium isolates obtained from individual seropositive patients with tuberculosis ( n =78) were analysed with the use of IS 6110 and (CGG) 5 or IS 1245 and IS 1311 , respectively, as markers. As a control, the same procedures were applied to isolates from HIV-seronegative tuberculosis patients ( n =87). Results Of 86 mycobacterial strains, M. tuberculosis , M. avium and Mycobacterium chelonae were identified in 48 (55.8%), 36 (41.9%) and 2 (2.3%) isolates, respectively. The obtained RFLP patterns of M. tuberculosis isolates from both the HIV-seropositive and -seronegative groups were variable, suggesting no obvious clustering among the isolates. Similar results were obtained in isolates of M. avium . Conclusions This is the first report on the molecular epidemiology of Mycobacterium spp. isolated from HIV-seropositive patients in Japan. The results indicate that no particular clones of M. tuberculosis or M. avium prevail in HIV-seropositive patients in Japan. Further monitoring of mycobacterial infection associated with HIV infection in Japan should be continued.