Publications by authors named "Toshiyuki Miura"

87 Publications

Safety analysis of Lexiva tablets 700 (fosamprenavir calcium hydrate) in post-marketing surveillance in Japan.

Curr Med Res Opin 2020 03 17;36(3):455-464. Epub 2019 Dec 17.

ViiV Healthcare K.K, Tokyo, Japan.

Fosamprenavir, a protease inhibitor (PI) to treat human immunodeficiency virus (HIV)-infected patients, has been approved in more than 40 countries and mainly used with nucleoside reverse transcriptase inhibitors. In Japan, Lexiva tablet (fosamprenavir calcium hydrate) has been marketed since January 2005 and used in clinical practice. The safety and effectiveness of fosamprenavir in HIV-infected Japanese patients were evaluated in an observational surveillance study (OTH112334). A post-marketing surveillance study (PMS) of fosamprenavir usage in HIV-infected Japanese subjects evaluating drug safety was conducted under Good Post-marketing Study Practice from January 2005 to December 2014. Of 364 patients receiving fosamprenavir, 51% received emtricitabine/tenofovir disoproxil fumarate. Adverse events whose causal relationship could not be completely ruled out (adverse drug reactions; ADRs) were reported in 43.7%; the most common were diarrhoea (10.4%), hyperlipidaemia (8.5%) and hypertriglyceridaemia (6.9%). Serious ADRs were reported in 26 patients (32 events), including 1 death attributed to hepatic failure. Most ADRs occurred within 180 days after fosamprenavir was started. ADRs were more frequent in patients with the Centers for Disease Control and Prevention category B (AIDS or lipid disorders) or in those taking fosamprenavir combined with abacavir and lamivudine. Although spontaneous bleeding has been reported in hemophiliac patients taking other PIs, in this survey, only one muscle haemorrhage case was reported in 24 hemophiliac patients. The results of this PMS analysis in Japan support its known safety profile and identified no new safety risks for people living with HIV/AIDS in Japan currently on, or beginning treatment with, fosamprenavir.
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http://dx.doi.org/10.1080/03007995.2019.1700495DOI Listing
March 2020

The angiotensin II type 1 receptor blocker azilsartan can overwhelm the sympathetic nerve activation stimulated by coadministration of calcium channel blockers.

J Renin Angiotensin Aldosterone Syst 2019 Jan-Mar;20(1):1470320319839525

1 Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Japan.

Objective:: In our recent study, non-Gaussianity of heart rate variability (λ), an indicator of sympathetic nerve activity, did not change during two-day treatment with the angiotensin II type 1 receptor blocker (ARB) azilsartan. Coadministration of calcium channel blockers (CCBs) might affect the study results.

Methods:: In this subanalysis, 20 patients with chronic kidney disease (14 men; age 61±15 years) were divided into three groups: patients with coadministration of L-type CCB, patients without coadministration of CCB, and patients with coadministration of sympathoinhibitory (L/T- or L/T/N-type) CCB. λ was calculated separately in daytime and nighttime.

Results:: Daytime λ at baseline was higher in patients with L-type CCB coadministration (0.62±0.18, n = 5) compared with those without CCB (0.49±0.13, n = 11) and those with sympathoinhibitory CCB (0.46±0.06, n = 4). The relationship between the changes in daytime λ and systolic blood pressure was positive in patients with L-type CCB coadministration, whereas the relationship was inverse in the other two groups. A larger decrease in daytime λ was shown in patients with L-type CCB coadministration compared with those in the other two groups.

Conclusions:: CCBs, as well as diuretics, are recommended as second-line antihypertensive agents. Our results suggested that ARBs can overwhelm the activation of sympathetic nerve activity stimulated by coadministration of L-type CCBs.
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http://dx.doi.org/10.1177/1470320319839525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6437324PMC
July 2019

Exit Site Infection due to Mycobacterium chelonae in an Elderly Patient on Peritoneal Dialysis.

Case Rep Nephrol Dial 2018 Jan-Apr;8(1):1-9. Epub 2018 Jan 19.

aDivision of Nephrology and Rheumatology, Department of Internal Medicine, Kariya Toyota General Hospital, Kariya, Japan.

Nontuberculous mycobacteria (NTM) are rarely isolated from peritoneal dialysis (PD)-associated catheter infections. However, NTM infection is usually difficult to treat and leads to catheter loss. Prompt diagnosis is essential for appropriate treatment. A 70-year-old Japanese man who had been on PD for 2 years and with a medical history of 2 episodes of exit site infections (ESIs) due to methicillin-resistant was admitted to the hospital due to suspected ESI recurrence. However, Gram staining of the pus revealed no gram-positive cocci. Instead, weakly stained gram-positive rods were observed after 7 days of incubation, which were also positive for acid-fast staining. Rapidly growing NTM was isolated on day 14. Despite administering a combination antibiotic therapy, ESI could not be controlled, and catheter removal surgery was performed on day 21. Although PD was discontinued temporarily, the patient did not require hemodialysis, without any uremic symptoms. The catheter was reinserted on day 48, and PD was reinitiated on day 61. The patient was discharged on day 65. Antibiotic therapy was continued for 3 months after discharge, with no indications of recurrent infections observed. It is important to consider the risk of NTM infections in patients on PD. Acid-fast staining could be a key test for prompt diagnosis and provision of an appropriate treatment.
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http://dx.doi.org/10.1159/000486159DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5836155PMC
January 2018

Impact of HLA Allele-KIR Pairs on Disease Outcome in HIV-Infected Thai Population.

J Acquir Immune Defic Syndr 2018 07;78(3):356-361

National Institute of Health, Ministry of Public Health, Nonthaburi, Thailand.

Background: Class I human leukocyte antigen (HLA) molecules contribute to HIV control through antigen presentation to both cytotoxic T lymphocytes and natural killer cells. Contribution of cytotoxic T lymphocytes to HIV clinical outcome by HLA alleles has been well studied. However, reports about the role of natural killer cells in HIV clinical outcome, particularly, about the effect of HLA-killer immunoglobulin-like receptor (KIR) pairs, remain incomplete.

Methods: The effects of HLA allele-KIR pairs on HIV clinical outcome were statistically analyzed in a Thai cohort of treatment-naive chronically infected population (n = 209).

Results: Five HLA allele-KIR pairs scored significantly in viral load (VL) differences. Among them, opposing effects on VL were identified among subjects expressing KIR2DL2 ligands within the HLA-C1 group: higher VL in individuals expressing HLA-B*46:01+KIR2DL2+ compared with individuals without KIR (HLA-B*46:01+KIR2DL2-) (5.0 vs 4.6 log10 copies/mL, P = 0.02), in HLA-C*01:02+KIR2DL2+ (5.0 vs 4.6 log10 copies/mL; P = 0.02), and lower VL in HLA-C*12:03+KIR2DL2+ (4.3 vs 5.6 log10 copies/mL; P = 0.01). In the longitudinal analysis of a ten-year follow-up, HLA-B*46:01+KIR2DL2+ve subjects also had a higher mortality rate compared with the subjects without that pair, independent of variables including antiretroviral treatment, as well as CD4 T-cell count, sex, and age (adjusted hazard ratio 5.9, P = 0.02).

Conclusion: We identified several HLA allele-KIR pairs associated with clinical outcome differences including opposing effects on VL within 1 HLA group with the same KIR. Among them, HLA-B*46:01 emerged in Southeast Asia about 50,000 years ago and is now the most prevalent HLA-B allele in that area. These findings highlight that each endemic area has unique features of anti-HIV innate immunity that impact clinical outcome.
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http://dx.doi.org/10.1097/QAI.0000000000001676DOI Listing
July 2018

Successful Recovery from Spontaneous Spinal Epidural Hematoma in a Patient Undergoing Hemodialysis.

Am J Case Rep 2017 Dec 20;18:1357-1364. Epub 2017 Dec 20.

Division of Nephrology and Rheumatology, Department of Internal Medicine, Kariya Toyota General Hospital, Kariya, Aichi, Japan.

BACKGROUND Spontaneous spinal epidural hematoma (SSEH) occurs in the spinal epidural space in the absence of traumatic or iatrogenic causes, and is considered to be a neurological emergency, as spinal cord compression may lead to neurological deficit. Prompt diagnosis of SSEH can be difficult due to the variety of presenting symptoms, which may resemble those of stroke. Patients who undergo hemodialysis (HD) are at risk of bleeding due to anticoagulation during dialysis and uremia. However, SSEH in HD patients undergoing HD has rarely been reported. CASE REPORT A 70-year-old Japanese man, who has been undergoing maintenance HD for the previous three years, was admitted to Kariya Toyota General Hospital, Aichi, Japan, with acute chest and abdominal pain, and with complete paraplegia. The patient denied any recent trauma or medical procedures. Magnetic resonance imaging showed an extensive hematoma in the thoracic and lumbar epidural space, extending from T8 to L5. The patient's symptoms improved within three hours following hospital admission, and after three days without HD treatment, the SSEH decreased in size, and the patient successfully recovered without residual neurological deficits and without requiring surgery. CONCLUSIONS The management of SSEH in patients undergoing HD can be difficult, due to anticoagulation during dialysis and uremia. Prompt diagnosis and close neurological monitoring are important for appropriate management. In patients whose symptoms improve within a short period, conservative management may be considered.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5745891PMC
http://dx.doi.org/10.12659/ajcr.905953DOI Listing
December 2017

Acute kidney injury caused by decompression illness successfully treated with hyperbaric oxygen therapy and temporary dialysis.

CEN Case Rep 2017 Nov 12;6(2):200-205. Epub 2017 Sep 12.

Division of Nephrology and Rheumatology, Department of Internal Medicine, Kariya Toyota General Hospital, 5-15, Sumiyoshi-cho, Kariya, Aichi, 448-8505, Japan.

A 52-year-old Japanese male professional diver was referred to our hospital for decompression illness (DCI). After 1 h of diving operation at 20 m below sea level, he complained of dyspnea, chest pain, and abdominal pain. He dove again, intending to ease the symptoms, but the symptoms were never relieved. He dove for a total of 4 h. No neurological abnormalities were observed. Computed tomography images revealed portal venous gas and mesenteric venous gas, in addition to bubbles in the femoral veins, pelvis, lumbar canal, intracranial sinuses, and joints. Hyperbaric oxygen therapy (HBOT) was immediately administered. His symptoms improved after the first course of HBOT, however, the patient had anuria for almost 36 h after admission and exhibited acute kidney injury (AKI). Serum creatinine and creatine kinase (CK) levels were increased to maximal values of 6.16 mg/dL and 18,963 U/L, respectively. Blood flow signals were not detected on kidney Doppler ultrasound. We considered that AKI was caused by blood flow impairment and capillary leak syndrome due to DCI in addition to rhabdomyolysis secondary to arterial gas embolism in the skeletal muscles. Temporary dialysis was required to correct the acidemia and electrolyte disturbance. Diuretic phase was initiated, and the patient was put off dialysis on day 3. Serum creatinine and CK levels returned to normal on day 11. He was successfully treated without any complications. Although AKI is a rare manifestation, we should consider AKI risk in patients with severe DCI.
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http://dx.doi.org/10.1007/s13730-017-0275-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694412PMC
November 2017

Peritoneal dialysis-associated catheter infection caused by Mycobacterium abscessus in an elderly patient who was successfully treated with catheter removal.

CEN Case Rep 2017 Nov 9;6(2):175-179. Epub 2017 Aug 9.

Division of Nephrology and Rheumatology, Department of Internal Medicine, Kariya Toyota General Hospital, 5-15, Sumiyoshi-cho, Kariya, Aichi, 448-8505, Japan.

An 89-year-old Japanese man on peritoneal dialysis (PD) was suspected of having a PD-associated catheter infection. He visited the hospital because of the discharge of pus from the exit site of his catheter. Gram staining of the pus showed Gram-positive bacilli, but these were acid-fast bacilli. The rapidly growing nontuberculous mycobacteria, Mycobacterium abscessus, was isolated. PD catheter removal and debridement were immediately performed. The patient received combination antibiotic therapy. His clinical course was good, but he required hemodialysis due to the discontinuation of PD. However, the patient and his family chose not to continue hemodialysis even when the symptoms of uremia appeared. Best supportive care was arranged by his primary care physician. M. abscessus is a rare causative organism for PD-associated catheter infections and is difficult to treat. In our case, a rapid and precise diagnosis was made using acid-fast staining and Mycobacterium culture. The risk of nontuberculous mycobacterial infections should be considered in patients on PD.
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http://dx.doi.org/10.1007/s13730-017-0270-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5694407PMC
November 2017

Sodium balance, circadian BP rhythm, heart rate variability, and intrarenal renin-angiotensin-aldosterone and dopaminergic systems in acute phase of ARB therapy.

Physiol Rep 2017 Jun;5(11)

Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

We have revealed that even in humans, activated intrarenal renin-angiotensin-aldosterone system (RAAS) enhances tubular sodium reabsorption to facilitate salt sensitivity and nondipper rhythm of blood pressure (BP), and that angiotensin receptor blocker (ARB) could increase daytime urinary sodium excretion rate (UV) to produce lower sodium balance and restore nondipper rhythm. However, the sympathetic nervous system and intrarenal dopaminergic system can also contribute to renal sodium handling. A total of 20 patients with chronic kidney disease (61 ± 15 years) underwent 24-h ambulatory BP monitoring before and during two-day treatment with ARB, azilsartan. Urinary angiotensinogen excretion rate (UV, g/gCre) was measured as intrarenal RAAS; urinary dopamine excretion rate (UV, pg/gCre) as intrarenal dopaminergic system; heart rate variabilities (HRV, calculated from 24-h Holter-ECG) of non-Gaussianity index as sympathetic nerve activity; and power of high-frequency (HF) component or deceleration capacity (DC) as parasympathetic nerve activity. At baseline, glomerular filtration rate correlated inversely with UV ( = -0.47,  = 0.04) and positively with UV ( = 0.58,  = 0.009). HF was a determinant of night/day BP ratio (= -0.50,  = 5.8), rather than DC or During the acute phase of ARB treatment, a lower steady sodium balance was not achieved. Increase in daytime UV preceded restoration of BP rhythm, accompanied by decreased UV ( = -0.88,  = 0.05) and increased UV ( = 0.87,  = 0.05), but with no changes in HRVs. Diminished sodium excretion can cause nondipper BP rhythm. This was attributable to intrarenal RAAS and dopaminergic system and impaired parasympathetic nerve activity. During the acute phase of ARB treatment, cooperative effects of ARB and intrarenal dopaminergic system exert natriuresis to restore circadian BP rhythm.
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http://dx.doi.org/10.14814/phy2.13309DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5471446PMC
June 2017

Association of cytologic grade of anal "Pap" smears with viral loads of human papillomavirus types 16, 18, and 52 detected in the same specimens from men who have sex with men.

J Clin Virol 2016 12 6;85:48-55. Epub 2016 Nov 6.

Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.

Background: Human papilloma virus (HPV) load has been linked to cellular abnormalities of the uterine cervix, and proposed as predictors of HPV persistence and progression of dysplasia to cervical cancer. However, the association of HPV viral load and anal dysplasia and cancer has not been as thoroughly investigated.

Objectives: To examine the association of the viral loads of high-risk HPV types 16, 18, and 52, with the cytologic severity grading in anal-swab specimens of MSM with and without HIV-1 co-infection.

Study Design: A cross-sectional study recruited 200 MSM in northern Thailand from July 2012 to January 2013. Real-time qPCR amplified portion of the HPV E6E7 gene, as well as the human β-globin gene to validate adequacy of the anal specimens and to normalize interpatient viral-load comparisons. Genotyping by linear-array assay identified and distinguished types 16, 18, and 52.

Results: HPV-16, and -18 viral loads increased with respect to the abnormality of the cytologic diagnoses (p<0.05 for HPV-16, p<0.01 for HPV-18). HIV-1 positivity was associated with higher HPV-18 viral load (p=0.006). HPV-16 viral loads ≥10 copies per 5000 anal cells, and HPV-18 loads ≥10, were independently associated with abnormal cytology on logistic regression (p=0.022, p=0.041, respectively). Positive predictive values were 85.2% (23/27) and 80.0% (44/55) for the high viral load of a particular HPV-16 and the combined HPV-16, -18 and -52 types, respectively.

Conclusions: High viral loads of HPV types 16 and 18 appear to be associated with anal cytologic abnormalities. The clinical utility of HPV viral loads to predict risk for anal cancer remains to be determined by a larger prospective cohort with sufficient frequency of high-grade dysplasia.
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http://dx.doi.org/10.1016/j.jcv.2016.11.001DOI Listing
December 2016

Need for public awareness regarding low birth weight and bottle feeding.

Hypertens Res 2016 11 23;39(11):825-826. Epub 2016 Jun 23.

Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

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http://dx.doi.org/10.1038/hr.2016.77DOI Listing
November 2016

Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease.

J Renin Angiotensin Aldosterone Syst 2016 Apr-Jun;17(2):1470320316652032. Epub 2016 Jun 9.

Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Japan.

Objective: Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR).

Methods: The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease.

Results: Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (t(Na)), although 24-hour urinary Na excretion (U(Na)V) remained constant. Daily urinary angiotensinogen excretion (U(AGT)V, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r(2)=0.26) and t(Na) (r(2)=0.25) correlated with baseline 24-hour U(AGT)V. Changes in filtered Na load correlated with changes in nighttime systolic BP (r(2)=0.17), but not with changes in daytime systolic BP. The change in the t(Na) to filtered Na load ratio was influenced by the change in daytime U(Na)V (β=-0.67, F=16.8), rather than the change in nighttime U(Na)V.

Conclusions: Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of U(AGT)V by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events.
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http://dx.doi.org/10.1177/1470320316652032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940185PMC
January 2017

Addition of hydrochlorothiazide to angiotensin receptor blocker therapy can achieve a lower sodium balance with no acceleration of intrarenal renin angiotensin system in patients with chronic kidney disease.

J Renin Angiotensin Aldosterone Syst 2016 Apr-Jun;17(2):1470320316652032. Epub 2016 Jun 9.

Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Japan.

Objective: Angiotensin receptor blockers (ARBs) produce a lower sodium (Na) balance, and the natriuretic effect is enhanced under Na deprivation, despite falls in blood pressure (BP) and glomerular filtration rate (GFR).

Methods: The effect of additional hydrochlorothiazide (HCTZ; 12.5 mg/day) to ARB treatment (valsartan; 80 mg/day) on glomerulotubular Na balance was evaluated in 23 patients with chronic kidney disease.

Results: Add-on HCTZ decreased GFR, tubular Na load, and tubular Na reabsorption (t(Na)), although 24-hour urinary Na excretion (U(Na)V) remained constant. Daily urinary angiotensinogen excretion (U(AGT)V, 152±10→82±17 μg/g Cre) reduced (p=0.02). Changes in tubular Na load (r(2)=0.26) and t(Na) (r(2)=0.25) correlated with baseline 24-hour U(AGT)V. Changes in filtered Na load correlated with changes in nighttime systolic BP (r(2)=0.17), but not with changes in daytime systolic BP. The change in the t(Na) to filtered Na load ratio was influenced by the change in daytime U(Na)V (β=-0.67, F=16.8), rather than the change in nighttime U(Na)V.

Conclusions: Lower Na balance was produced by add-on HCTZ to ARB treatment without an increase of intra-renal renin-angiotensin system activity, leading to restoration of nocturnal hypertension. A further study is needed to demonstrate that the reduction of U(AGT)V by additional diuretics to ARBs prevents the progression of nephropathy or cardiovascular events.
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http://dx.doi.org/10.1177/1470320316652032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4940185PMC
January 2017

L/T-type calcium channel blocker reduces non-Gaussianity of heart rate variability in chronic kidney disease patients under preceding treatment with ARB.

J Renin Angiotensin Aldosterone Syst 2016 Apr-Jun;17(2):1470320316643905. Epub 2016 Apr 18.

Department of Cardio-Renal Medicine and Hypertension, Nagoya, Japan.

Introduction: Increased sympathetic nerve activity has been suggested in patients with chronic kidney disease (CKD). Pathologic sympathetic activity can alter heart rate variability (HRV), and the altered HRV has prognostic importance, so that reducing sympathetic activity may be an important strategy. Novel nonlinear HRVs, including deceleration capacity (DC), have greater predictive power for mortality. We have recently proposed an increase in a non-Gaussianity index of HRV, λ(25s), which indicates the probability of volcanic heart rate deviations of departure from each standard deviation level, as a marker of sympathetic cardiac overdrive. L/T-type calcium channel blocker (L/T-CCB), azelnidipine, decreases sympathetic nerve activity in experimental and clinical studies.

Methods: In 43 hypertensive patients with CKD under treatment with an angiotensin receptor blocker (ARB), we investigated whether 8-week add-on L/T-CCB treatment could restore HRV.

Results: Means of all normal-to-normal intervals over 24 h (p<0.0001) and DC (p=0.002) increased, and λ(25s) (p=0.001) decreased regardless of gender, age, renal function or blood pressure, while no significant changes were observed in the other HRVs.

Conclusions: Reduction of λ(25s) is useful to assess the effect of sympathoinhibitory treatment. Further studies are needed to investigate if the restoration of HRV is directly associated with the improvement of prognosis in patients with CKD.
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http://dx.doi.org/10.1177/1470320316643905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5843923PMC
January 2017

The effect of KIR2D-HLA-C receptor-ligand interactions on clinical outcome in a HIV-1 CRF01_AE-infected Thai population.

AIDS 2015 Aug;29(13):1607-15

aDepartment of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan bDepartment of Paediatrics, University of Oxford, Oxford, UK cThai National Institute of Health, Department of Medical Sciences, Ministry of Public Health, Nonthaburi dDay Care Centre, Lampang Hospital, Lampang, Thailand eNagasaki University Global COE Program, Institute of Tropical Medicine, Nagasaki University, Nagasaki, Japan.

Objective: Class I human leukocyte antigen (HLA) alleles interact with both cytotoxic T lymphocytes through their T-cell receptors, and natural killer cells through their killer immunoglobulin-like receptors (KIRs). Compared with the reported protective effect of KIR3DL1/S1-HLA-Bw4 interactions in HIV-infected patients, the effect of KIR2D-HLA-C combinations on HIV control remains unclear. Here, we investigate the effect of KIR2D-HLA-C combinations on HIV disease progression.

Design: We performed a cross-sectional and longitudinal analysis of a Thai HIV cohort.

Methods: Two hundred and nine HIV-1 CRF01_AE-infected, treatment-naive Thai patients (CD4 T-cell counts of >200/μl) and 104 exposed seronegatives were studied. The effect of KIR-HLA receptor-ligand combinations on viral transmission and survival rate was statistically analyzed.

Results: We found the following results: higher frequency of patients expressing both KIR2DL3 and HLA-C1 among infected patients compared with exposed seronegative (odds ratio 4.8, P = 0.004), higher viral load in patients expressing HLA-C1 with KIR2DL3 compared with those without this receptor-ligand combination (median 4.8 vs. 4.2 log copies/ml, P = 0.033), higher numbers of KIR2DL3-HLA-C1 interactions was associated with a higher viral load (β = 0.13, P = 0.039 by linear regression model), and higher mortality rate in carriers of the KIR2DL3-HLA-C1 combination (adjusted hazard ratio 1.9, P = 0.012 by Cox hazard model).

Conclusion: We have identified a deleterious effect of the KIR2DL3-HLA-C1 receptor-ligand combination on HIV clinical outcomes in a Thai cohort. Further investigation into mechanisms underlying this susceptibility may aid the understanding of the role of natural killer cells in HIV disease control and pathogenesis.
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http://dx.doi.org/10.1097/QAD.0000000000000747DOI Listing
August 2015

Differential Ability of Primary HIV-1 Nef Isolates To Downregulate HIV-1 Entry Receptors.

J Virol 2015 Sep 15;89(18):9639-52. Epub 2015 Jul 15.

Center for AIDS Research, Kumamoto University, Kumamoto, Japan International Research Center for Medical Sciences, Kumamoto University, Kumamoto, Japan

Unlabelled: HIV-1 Nef downregulates the viral entry receptor CD4 as well as the coreceptors CCR5 and CXCR4 from the surface of HIV-infected cells, and this leads to promotion of viral replication through superinfection resistance and other mechanisms. Nef sequence motifs that modulate these functions have been identified via in vitro mutagenesis with laboratory HIV-1 strains. However, it remains unclear whether the same motifs contribute to Nef activity in patient-derived sequences and whether these motifs may differ in Nef sequences isolated at different infection stages and/or from patients with different disease phenotypes. Here, nef clones from 45 elite controllers (EC), 46 chronic progressors (CP), and 43 acute progressors (AP) were examined for their CD4, CCR5, and CXCR4 downregulation functions. Nef clones from EC exhibited statistically significantly impaired CD4 and CCR5 downregulation ability and modestly impaired CXCR4 downregulation activity compared to those from CP and AP. Nef's ability to downregulate CD4 and CCR5 correlated positively in all cohorts, suggesting that they are functionally linked in vivo. Moreover, impairments in Nef's receptor downregulation functions increased the susceptibility of Nef-expressing cells to HIV-1 infection. Mutagenesis studies on three functionally impaired EC Nef clones revealed that multiple residues, including those at novel sites, were involved in the alteration of Nef functions and steady-state protein levels. Specifically, polymorphisms at highly conserved tryptophan residues (e.g., Trp-57 and Trp-183) and immune escape-associated sites were responsible for reduced Nef functions in these clones. Our results suggest that the functional modulation of primary Nef sequences is mediated by complex polymorphism networks.

Importance: HIV-1 Nef, a key factor for viral pathogenesis, downregulates functionally important molecules from the surface of infected cells, including the viral entry receptor CD4 and coreceptors CCR5 and CXCR4. This activity enhances viral replication by protecting infected cells from cytotoxicity associated with superinfection and may also serve as an immune evasion strategy. However, how these activities are maintained under selective pressure in vivo remains elusive. We addressed this question by analyzing functions of primary Nef clones isolated from patients at various infection stages and with different disease phenotypes, including elite controllers, who spontaneously control HIV-1 viremia to undetectable levels. The results indicated that downregulation of HIV-1 entry receptors, particularly CCR5, is impaired in Nef clones from elite controllers. These functional impairments were driven by rare Nef polymorphisms and adaptations associated with cellular immune responses, underscoring the complex molecular pathways responsible for maintaining and attenuating viral protein function in vivo.
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http://dx.doi.org/10.1128/JVI.01548-15DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4542390PMC
September 2015

Association between a naturally arising polymorphism within a functional region of HIV-1 Nef and disease progression in chronic HIV-1 infection.

Arch Virol 2015 Aug 10;160(8):2033-41. Epub 2015 Jun 10.

Center for AIDS Research, Kumamoto University, 2-2-1 Chuo-ku, Honjo, Kumamoto, 860-0811, Japan.

HIV-1 Nef mediates downregulation of HLA class I (HLA-I) through a number of highly conserved sequence motifs. We investigated the in vivo implication(s) of naturally arising polymorphisms in functional motifs in HIV-1 Nef that are associated with HLA-I downregulation, including the acidic cluster, polyproline, di-arginine and Met-20 regions. Plasma samples from treatment-naive, chronically HIV-1 infected subjects were collected after obtaining informed consent, and viral RNA was extracted and amplified by nested RT-PCR. The resultant nef amplicons were sequenced directly, and subtype-B sequences with an intact open reading frame (n = 406) were included in our analyses. There was over-representation of isoleucine at position 20 (Ile-20) in our dataset when compared to sequences in the Los Alamos sequence database (17.7 vs. 6.9 %, p = 0.0309). The presence of having Ile-20 in Nef was found to be associated with higher median plasma viral load (p = 0.013), independent of associated codons or viral lineage effects, whereas no clinical association was found with polymorphisms in the other functional motifs. Moreover, introduction of a Met-20-to-Ile mutation in a laboratory strain SF2 Nef resulted in a modest, albeit not statistically significant, increase in HLA class I downregulation activity (p = 0.06). Taken together, we have identified a naturally arising polymorphism, Ile-20, within HIV-1 subtype B Nef that is associated with poorer disease outcome.
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http://dx.doi.org/10.1007/s00705-015-2480-5DOI Listing
August 2015

High Prevalence and Genotype Diversity of Anal HPV Infection among MSM in Northern Thailand.

PLoS One 2015 1;10(5):e0124499. Epub 2015 May 1.

Research Institute for Health Sciences, Chiang Mai University, Chiang Mai, Thailand.

Background: HPV infection is common and may cause cancer among men who have sex with men (MSM). Anal HPV infection (HPV+) was found in 85% of HIV-positive (HIV+) and 59% of HIV-negative (HIV-) MSM in Bangkok, central Thailand. As little is known about HPV in this group in northern Thailand, we studied MSM subgroups comprised of gay men (GM), bisexual men (BM), and transgender women (TGW).

Methods: From July 2012 through January 2013, 85 (42.5% of 200) GM, 30 (15%) BM, and 85 (42.5%) TGW who practiced receptive anal intercourse were recruited after informed consent, followed by self-assisted computer interview, HIV testing, and anal swabs for HPV genotyping.

Results: Of 197 adequate specimens, the overall prevalence of any HPV was 157 (80%). Prevalence was 89% (76/85) in GM, 48% (14/29) in BM, and 81% (67/83) in TGW. The most common high-risk types were HPV16 (27% of 197), HPV58 (23%), and HPV51 (18%). Prevalence of high-risk types was 74% in 85 GM, 35% in 29 BM, and 71% in 83 TGW. Prevalence of any HPV type, or high-risk type, was 100% and 94%, respectively, among 48 HIV+ MSM, 70% and 54% among 120 HIV- MSM. Of the 197 specimens, 36% (70) had HPV types 16 and/or 18 in the bivalent vaccine, compared to 48% (95) with ≥1 of types 16/18/06/11 in the quadrivalent, 56% (111) for 16/18/31/33/45/52/58 in the 7-valent, and 64% (126) for 16/18/31/33/45/52/58/06/11 in the 9-valent. HIV+, GM, and TGW were independently associated with HPV infection.

Conclusions: We found higher rates of both any HPV and high-risk types than previous studies. Among the heretofore unstudied TGW, their equivalent HPV rates were comparable to GM. Current and investigational HPV vaccines could substantially protect GM, BM, and TGW from the serious consequences of HPV infection especially among HIV + MSM.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0124499PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4416722PMC
January 2016

Modest attenuation of HIV-1 Vpu alleles derived from elite controller plasma.

PLoS One 2015 20;10(3):e0120434. Epub 2015 Mar 20.

Department of Infectious Diseases, Integrative Virology, University Hospital Heidelberg, INF 324, Heidelberg, Germany; German Center for Infection Research, Heidelberg University, Heidelberg. Germany.

In the absence of antiretroviral therapy, infection with human immunodeficiency virus type 1 (HIV-1) can typically not be controlled by the infected host and results in the development of acquired immunodeficiency. In rare cases, however, patients spontaneously control HIV-1 replication. Mechanisms by which such elite controllers (ECs) achieve control of HIV-1 replication include particularly efficient immune responses as well as reduced fitness of the specific virus strains. To address whether polymorphisms in the accessory HIV-1 protein Vpu are associated with EC status we functionally analyzed a panel of plasma-derived vpu alleles from 15 EC and 16 chronic progressor (CP) patients. Antagonism of the HIV particle release restriction by the intrinsic immunity factor CD317/tetherin was well conserved among EC and CP Vpu alleles, underscoring the selective advantage of this Vpu function in HIV-1 infected individuals. In contrast, interference with CD317/tetherin induced NF-κB activation was little conserved in both groups. EC Vpus more frequently displayed reduced ability to downregulate cell surface levels of CD4 and MHC class I (MHC-I) molecules as well as of the NK cell ligand NTB-A. Polymorphisms potentially associated with high affinity interactions of the inhibitory killer immunoglobulin-like receptor (KIR) KIR2DL2 were significantly enriched among EC Vpus but did not account for these functional differences. Together these results suggest that in a subgroup of EC patients, some Vpu functions are modestly reduced, possibly as a result of host selection.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0120434PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4368696PMC
February 2016

Anti-APOBEC3G activity of HIV-1 Vif protein is attenuated in elite controllers.

J Virol 2015 May 25;89(9):4992-5001. Epub 2015 Feb 25.

The Institute of Medical Science, the University of Tokyo, Tokyo, Japan

Unlabelled: HIV-1-infected individuals who control viremia to below the limit of detection without antiviral therapy have been termed elite controllers (EC). Functional attenuation of some HIV-1 proteins has been reported in EC. The HIV-1 accessory protein Vif (virion infectivity factor) enhances viral infectivity through anti-retroviral factor apolipoprotein B mRNA editing enzyme catalytic polypeptide-like 3G (APOBEC3G) degradation; however, little is known regarding Vif function in EC. Here, the anti-APOBEC3G activities of clonal, plasma HIV RNA-derived Vif sequences from 46 EC, 46 noncontrollers (NC), and 44 individuals with acute infection (AI) were compared. Vesicular stomatitis virus glycoprotein (VSV-G)-pseudotyped viruses were generated by cotransfecting 293T cells with expression plasmids encoding patient-derived Vif, human APOBEC3G, VSV-G, and a vif/env-deficient luciferase-reporter HIV-1 proviral DNA clone. Viral stocks were used to infect 293T cells, and Vif anti-APOBEC3G activity was quantified in terms of luciferase signal. On average, the anti-APOBEC3G activities of EC-derived Vif sequences (median log10 relative light units [RLU], 4.54 [interquartile range {IQR}, 4.30 to 4.66]) were significantly lower than those of sequences derived from NC (4.75 [4.60 to 4.92], P < 0.0001) and AI (4.74 [4.62 to 4.94], P < 0.0001). Reduced Vif activities were not associated with particular HLA class I alleles expressed by the host. Vif functional motifs were highly conserved in all patient groups. No single viral polymorphism could explain the reduced anti-APOBEC3G activity of EC-derived Vif, suggesting that various combinations of minor polymorphisms may underlie these effects. These results further support the idea of relative attenuation of viral protein function in EC-derived HIV sequences.

Importance: HIV-1 elite controllers (EC) are rare individuals who are able to control plasma viremia to undetectable levels without antiretroviral therapy. Understanding the pathogenesis and mechanisms underpinning this rare phenotype may provide important insights for HIV vaccine design. The EC phenotype is associated with beneficial host immunogenetic factors (such as HLA-B*57) as well as with functions of attenuated viral proteins (e.g., Gag, Pol, and Nef). In this study, we demonstrated that HIV-1 Vif sequences isolated from EC display relative impairments in their ability to counteract the APOBEC3G host restriction factor compared to Vif sequences from normal progressors and acutely infected individuals. This result extends the growing body of evidence demonstrating attenuated HIV-1 protein function in EC and, in particular, supports the idea of the relevance of viral factors in contributing to this rare HIV-1 phenotype.
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http://dx.doi.org/10.1128/JVI.03464-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4403497PMC
May 2015

Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence.

Proc Natl Acad Sci U S A 2014 Dec 1;111(50):E5393-400. Epub 2014 Dec 1.

Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa;

It is widely believed that epidemics in new hosts diminish in virulence over time, with natural selection favoring pathogens that cause minimal disease. However, a tradeoff frequently exists between high virulence shortening host survival on the one hand but allowing faster transmission on the other. This is the case in HIV infection, where high viral loads increase transmission risk per coital act but reduce host longevity. We here investigate the impact on HIV virulence of HIV adaptation to HLA molecules that protect against disease progression, such as HLA-B*57 and HLA-B*58:01. We analyzed cohorts in Botswana and South Africa, two countries severely affected by the HIV epidemic. In Botswana, where the epidemic started earlier and adult seroprevalence has been higher, HIV adaptation to HLA including HLA-B*57/58:01 is greater compared with South Africa (P = 7 × 10(-82)), the protective effect of HLA-B*57/58:01 is absent (P = 0.0002), and population viral replicative capacity is lower (P = 0.03). These data suggest that viral evolution is occurring relatively rapidly, and that adaptation of HIV to the most protective HLA alleles may contribute to a lowering of viral replication capacity at the population level, and a consequent reduction in HIV virulence over time. The potential role in this process played by increasing antiretroviral therapy (ART) access is also explored. Models developed here suggest distinct benefits of ART, in addition to reducing HIV disease and transmission, in driving declines in HIV virulence over the course of the epidemic, thereby accelerating the effects of HLA-mediated viral adaptation.
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http://dx.doi.org/10.1073/pnas.1413339111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4273423PMC
December 2014

Improved efficiency of definitive endoderm induction from human induced pluripotent stem cells in feeder and serum-free culture system.

In Vitro Cell Dev Biol Anim 2015 Jan 15;51(1):1-8. Epub 2014 Aug 15.

Department of Life Sciences, Graduate School of Arts and Sciences, University of Tokyo, 3-8-1, Komaba, Meguro-ku, Tokyo, 153-8902, Japan.

Improvement of methods to produce endoderm-derived cells from pluripotent stem cells is important to realize high-efficient induction of endodermal tissues such as pancreas and hepatocyte. Difficulties hampering such efforts include the low efficiency of definitive endoderm cell induction and establishing appropriate defined culture conditions to ensure a safe cell source for human transplantation. Based on previous studies, we revised the experimental condition of definitive endoderm induction in feeder- and serum-free culture. Our results suggested that CHIR99021 is more effective than Wnt3A ligand in feeder- and serum-free conditions. In addition, keeping cell density low during endoderm induction is important for the efficiency. On the other hand, we showed that overtreatment with CHIR99021 converted the cells into BRACHYURY-expressing posterior mesoderm cells rather than endoderm, indicating strict CHIR99021 treatment requirements for endoderm differentiation. Nevertheless, these results should enable better control in the production of definitive endoderm-derived cells.
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http://dx.doi.org/10.1007/s11626-014-9801-yDOI Listing
January 2015

Impaired Nef function is associated with early control of HIV-1 viremia.

J Virol 2014 Sep 25;88(17):10200-13. Epub 2014 Jun 25.

Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, Canada Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada

Unlabelled: Host and viral factors influence the HIV-1 infection course. Reduced Nef function has been observed in HIV-1 controllers during the chronic phase, but the kinetics and mechanisms of Nef attenuation in such individuals remain unclear. We examined plasma RNA-derived Nef clones from 10 recently infected individuals who subsequently suppressed viremia to less than 2,000 RNA copies/ml within 1 year postinfection (acute controllers) and 50 recently infected individuals who did not control viremia (acute progressors). Nef clones from acute controllers displayed a lesser ability to downregulate CD4 and HLA class I from the cell surface and a reduced ability to enhance virion infectivity compared to those from acute progressors (all P<0.01). HLA class I downregulation activity correlated inversely with days postinfection (Spearman's R=-0.85, P=0.004) and positively with baseline plasma viral load (Spearman's R=0.81, P=0.007) in acute controllers but not in acute progressors. Nef polymorphisms associated with functional changes over time were identified in follow-up samples from six controllers. For one such individual, mutational analyses indicated that four polymorphisms selected by HLA-A*31 and B*37 acted in combination to reduce Nef steady-state protein levels and HLA class I downregulation activity. Our results demonstrate that relative control of initial HIV-1 viremia is associated with Nef clones that display reduced function, which in turn may influence the course of HIV-1 infection. Transmission of impaired Nef sequences likely contributed in part to this observation; however, accumulation of HLA-associated polymorphisms in Nef that impair function also suggests that CD8+ T-cell pressures play a role in this phenomenon.

Importance: Rare individuals can spontaneously control HIV-1 viremia in the absence of antiretroviral treatment. Understanding the host and viral factors that contribute to the controller phenotype may identify new strategies to design effective vaccines or therapeutics. The HIV-1 Nef protein enhances viral pathogenesis through multiple mechanisms. We examined the function of plasma HIV-1 RNA-derived Nef clones isolated from 10 recently infected individuals who subsequently controlled HIV viremia compared to the function of those from 50 individuals who failed to control viremia. Our results demonstrate that early Nef clones from HIV controllers displayed lower HLA class I and CD4 downregulation activity, as well as a reduced ability to enhance virion infectivity. The accumulation of HLA-associated polymorphisms in Nef during the first year postinfection was associated with impaired protein function in some controllers. This report highlights the potential for host immune responses to modulate HIV pathogenicity and disease outcome by targeting cytotoxic T lymphocyte (CTL) epitopes in Nef.
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http://dx.doi.org/10.1128/JVI.01334-14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4136354PMC
September 2014

Safety analysis of Epzicom® (lamivudine/abacavir sulfate) in post-marketing surveillance in Japan.

Pharmacoepidemiol Drug Saf 2014 Apr 3;23(4):372-81. Epub 2014 Mar 3.

ViiV Healthcare K.K., Tokyo, 151-8566, Japan.

Purpose: To obtain safety and effectiveness data on a combined anti-HIV drug, Epzicom (abacavir 600 mg/lamivudine 300 mg), a post-marketing surveillance on Epzicom that was required by the Japanese regulatory authority was conducted between January 2005 and December 2010.

Methods: A joint survey (HIV-related drug [HRD] survey) has been conducted involving manufacturers of drugs for treatment of HIV infection in Japan. Safety and effectiveness data from total 624 cases (1107.3 person-years) registered to the HRD surveys and received Epzicom were obtained. Adverse drug reactions (ADRs) were defined as adverse events (AE) of which association with Epzicom could not be 'ruled out'.

Results: It was found that the incidence of ADR was 32.4% (202/624 cases) on the case basis. In addition, the frequently reported ADR included hyperlipidaemia (59 cases), hypertriglyceridaemia (21 cases), blood bilirubin increased (19 cases), gamma-glutamyltransferase increase (14 cases), blood triglyceride increase (14 cases) and rash (14 cases). Serious AEs were seen in 19 patients (30 events), including one death (no evident association with Epzicom). There were four cases (0.6%) of survey-defined 'hypersensitivity', and the incidence was 0.9% (4/445) among abacavir naïve patients; none of which was reported as serious. No case of myocardial infarction was reported. One pregnant case who delivered a normal baby by caesarean section was reported to have experienced aggravation of anaemia and nausea.

Conclusions: The post-marketing surveillance indicated that the incidence of both ischaemic heart disease and hypersensitivity associated with Epzicom was considerably low, suggesting that this drug can be safely used in the Japanese population.
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http://dx.doi.org/10.1002/pds.3588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230469PMC
April 2014

Safety analysis of Ziagen® (abacavir sulfate) in postmarketing surveillance in Japan.

Pharmacoepidemiol Drug Saf 2014 Apr 3;23(4):361-71. Epub 2014 Mar 3.

ViiV Healthcare K. K., Tokyo, 151-8566, Japan.

Purpose: Abacavir is a nucleoside reverse transcriptase inhibitor indicated for human immunodeficiency virus (HIV) infection. In Japan, Ziagen® (300-mg abacavir sulfate) has been marketed since 1999. To obtain safety data on Ziagen, a mandatory postmarketing surveillance was conducted between September 1999 and September 2009.

Methods: A joint survey [HIV-related Drug Surveys (HRD)] has been conducted involving manufacturers of drugs for HIV treatment in Japan. Safety data from total 643 cases (1345.7 person-years) registered to the HRD surveys and received Ziagen were obtained. Adverse drug reaction (ADR) was defined as adverse event of which association with abacavir could not be "ruled out."

Results: It was found that the overall frequency of ADR was 47.6% (306/643); the common ADRs were "hyperlipidemia," "nausea," "increased γ-glutamyltransferase level," "increased blood triglycerides," "abnormal hepatic function," and so on. Serious adverse events were reported in 65 subjects; however, none of the three fatal cases were clearly associated with Ziagen use. The survey-defined hypersensitivity has been infrequently reported in 15 subjects (2.3%). Although some studies had indicated of the association between abacavir and myocardial infarction, no ischemic heart diseases were reported in the present survey. Two of the three pregnant cases delivered normal neonates (one induced abortion).

Conclusions: During the mandatory postmarketing survey of Ziagen, there were no cases of ischemic heart diseases, and the incidence of hypersensitivity was considerably low. These indicated that abacavir can be safely used in Japanese HIV+ population. However, the safety profile of Ziagen should be continued to be monitored through pharmacovigilance.
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http://dx.doi.org/10.1002/pds.3589DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4230480PMC
April 2014

Development of irreversible inactivators of spermine oxidase and N1-acetylpolyamine oxidase.

Biol Pharm Bull 2014 ;37(3):475-80

Translational Medical Research Center, Tokyo Metropolitan Institute of Medical Science.

Three functional groups (2-propenyl, 2-propynyl, and 2,3-butadienyl) were introduced onto one of the terminal amino groups of spermidine. Of the six compounds synthesized, N-(3-aminopropyl)-N'-2,3-butadienyl-1,4-butanediamine (N(8)-butadienyl Spd) and N-[3-(2,3-butadienylamino)propyl]-1,4-butanediamine (N(1)-butadienyl Spd) irreversibly inactivated human spermine oxidase (SMO) and N(1)-acetylpolyamine oxidase (APAO). Interestingly, N(8)-butadienyl Spd inactivated SMO far more potently than N,N'-di-2,3-butadienyl-1,4-butanediamine (MDL 72527).
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http://dx.doi.org/10.1248/bpb.b13-00913DOI Listing
October 2014

HLA-B*35: 05 is a protective allele with a unique structure among HIV-1 CRF01_AE-infected Thais, in whom the B*57 frequency is low.

AIDS 2014 Apr;28(7):959-67

Department of Clinical Medicine, Institute of Tropical Medicine, Nagasaki University, Sakamoto, Nagasaki City, Nagasaki, Japan.

Objective: To identify protective human leukocyte antigen (HLA) alleles in an HIV-infected south-east Asian population, in whom HLA-B*57 prevalence is lower than other ethnic groups, and HIV-1 CRF01_AE is the dominant circulating subtype.

Design: Cross-sectional study of Thai patients with chronic HIV infection.

Methods: Five hundred and fifty-seven HIV-1 CRF01_AE-infected Thais were recruited. Their HLA type and viral load were determined to statistically analyze the association of each allele in viral control. In-silico molecular dynamics was also used to evaluate the effect of HLA structure variants on epitope binding.

Results: HLA-B*35:05 was identified as the most protective allele (P=0.003, q=0.17), along with HLA-B*57:01 (P=0.044, q=0.31). Structurally, HLA-B*35:05 belonged to the HLA-B*35-PY group of HLA-B*35 alleles; however, unlike the other HLA-B*35 alleles that carry Arg (R) at residue 97, it has unique sequences at T94, L95, and S97, located within the peptide-binding groove. Analysis of the three-dimensional HLA structure and molecular dynamics indicates that S97 in HLA-B*35:05 leads to less flexibility in the groove, and shorter distances between the α-helixes compared with the disease-susceptible HLA-B*35-PY allele, HLA-B*35:01.

Conclusion: These data indicate the existence of a protective effect of HLA-B*57 across ethnic groups and highlight HLA-B*35:05 as an allele uniquely protective in subtype CRF01_AE-infected Thais. The divergence of HLA-B*35:05 from conventional HLA-B*35-PY structural sequences at the peptide-binding groove is consistent with previous studies that have identified HLA residue 97 as strongly influential in shaping HLA impact on immune control of HIV, and that a more restricted peptide-binding motif may be associated with improved control.
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http://dx.doi.org/10.1097/QAD.0000000000000206DOI Listing
April 2014

Awaiting the OSCAR subanalysis of subjects according to the presence of proteinuria.

Kidney Int 2013 Nov;84(5):1047

Department of Cardio-Renal Medicine and Hypertension, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.

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http://dx.doi.org/10.1038/ki.2013.310DOI Listing
November 2013

Efficacy and safety of paromomycin for treating amebiasis in Japan.

Parasitol Int 2013 Dec 12;62(6):497-501. Epub 2013 Jul 12.

Division of Infectious Diseases, Advanced Clinical Research Center, Institute of Medical Science, University of Tokyo, Tokyo, Japan.

The clinical management of amebiasis is a growing concern, particularly among human immunodeficiency virus (HIV)-infected individuals who are predisposed to severe illness. Treatment with a luminal amebicide is strongly recommended following acute-stage treatment with a nitroimidazole. In 2004, the Japanese Research Group on Chemotherapy of Tropical Diseases introduced paromomycin, which was not nationally licensed, and offered it to a number of patients. From 2004 to 2011, 143 case records of amebiasis (123 with amebic colitis, 16 with amebic liver abscess, and 4 with both) in which patients were treated with paromomycin, mainly 1,500 mg/day for 9 or 10 days following metronidazole treatment, were submitted. Among 123 evaluable cases, 23 (18.7%) experienced possible adverse effects, the most common being diarrhea (17/123, 13.8%) and other gastrointestinal problems that were resolved after the completion or discontinuation of treatment. In addition, single cases of bloody stools associated with Clostridium difficile colitis, skin rash, and the elevation of liver enzymes were also reported, although the causal relationship was not clear. HIV infection did not appear to increase the incidence of adverse drug effects. Each of the 11 asymptomatic or mildly symptomatic amebic colitis cases became negative for stool cysts after paromomycin treatment. Paromomycin was shown to be safe and well tolerated, as well as effective in a special subset of amebic colitis cases.
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http://dx.doi.org/10.1016/j.parint.2013.07.004DOI Listing
December 2013

Cutting edge: Prolonged exposure to HIV reinforces a poised epigenetic program for PD-1 expression in virus-specific CD8 T cells.

J Immunol 2013 Jul 14;191(2):540-4. Epub 2013 Jun 14.

Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322, USA.

Ag-specific CD8 T cells play a critical role in controlling HIV infection but eventually lose antiviral functions in part because of expression and signaling through the inhibitory programmed death-1 (PD-1) receptor. To better understand the impact of prolonged TCR ligation on regulation of PD-1 expression in HIV-specific CD8 T cells, we investigated the capacity of virus-specific CD8 T cells to modify the PD-1 epigenetic program after reduction in viral load. We observed that the transcriptional regulatory region was unmethylated in the PD-1(hi) HIV-specific CD8 T cells, whereas it remained methylated in donor-matched naive cells at acute and chronic stages of infection. Surprisingly, the PD-1 promoter remained unmethylated in HIV-specific CD8 T cells from subjects with a viral load controlled by antiviral therapy for >2 y or from elite controllers. Together, these data demonstrate that the epigenetic program at the PD-1 locus becomes fixed after prolonged exposure to HIV virus.
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http://dx.doi.org/10.4049/jimmunol.1203161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3702641PMC
July 2013