Investigating the Moderating Effect of HIV Status Disclosure on the Link Between Discrimination Experience and Psychological Distress Among People Living with HIV in Japan Infected Through Sexual Contact.

BACKGROUND: There is a scarcity of research on the potential impact of disclosing HIV status to friends and family in moderating the adverse effects of discrimination on the mental health of people living with HIV (PLWH). This study assessed the experiences of discrimination and HIV status disclosure among PLWH in Japan, and evaluated their potential associations with psychological distress. METHOD: Data were derived from a nationwide cross-sectional survey of PLWH conducted in Japan between 2019 and 2020. The interaction effects of HIV-related discrimination and HIV status disclosure on the psychological distress were examined using logistic and linear regression analyses. RESULTS: The median age of the 804 respondents was 46 years old. Most respondents were male and 85.4% (687/804) identified as homosexuals or bisexuals. A total of 12.7% (102/804) of the respondents reported that they had recently experienced discrimination because of their HIV status. Experience of HIV-related discrimination was independently associated with high psychological distress (adjusted OR 2.02; 95% CI, 1.15-3.57), and HIV status disclosure to friends partially weakened the association between discrimination and the level of psychological distress (regression coefficient -3.115; p = 0.004). CONCLUSION: While measures that aim to end discrimination remain vital, increasing the opportunities of PLWH to communicate with friends they feel comfortable disclosing their HIV status may also be helpful in protecting their mental health.

Pathogenesis, clinical course, and recent issues in HIV-1-infected Japanese hemophiliacs: a three-decade follow-up.

Nearly 30% of Japanese hemophiliacs were infected with HIV-1 in the early 1980s. They have unique characteristics compared to HIV-1-infected individuals through other routes, including date of infection of 1986 or earlier, mean age of nearly 50 years, and common co-infection with hepatitis C, but rarely with other sexually transmitted diseases. Antiretroviral therapy (ART) was introduced in Japan in 1997. The clinical courses before and after 1997 were quite different. Careful analysis of the pre-1997 clinical data allowed expansion of our knowledge about the natural course and pathogenesis of the disease. Switching to the second receptor agents proved critical in subsequent disease progression. HIV-1 continued to escape immune pressure, pushing disease progression faster. In contrast, ART was effective enough to overcome the natural course. Prognosis improved dramatically and cause of death changed from AIDS-related opportunistic infections and malignancies before 1997, to hepatitis C virus-related cirrhosis and hepatocellular carcinoma (HCC) around 2010, and again to non-AIDS defining malignancies recently. In most cases, hepatitis C was cured with direct acting antiviral therapy. However, HCV progressed to cirrhosis in some cases and risk of HCC is still high among these patients. Together with improvement in anticoagulants and aging of the patients, risk of myocardial infarction has increased recently. In addition, the numbers of patients with life-style related co-morbidities, such as diabetes mellitus, hypertension, and chronic kidney disease have been also increasing. Finally, stigma is still an important barrier to a better life in HIV-1-positive individuals.

What Triggers a Diagnosis of HIV Infection in the Tokyo Metropolitan Area? Implications for Preventing the Spread of HIV Infection in Japan.

BACKGROUND: Japan has not succeeded in reducing the annual number of new HIV-infected patients, although the prevalence of HIV infection is low (0.02%). METHODS: A single-center observational study was conducted at the largest HIV clinic in Tokyo, which treats 15% of the total patients in Japan, to determine the reasons for having diagnostic tests in newly infected individuals. HIV-infected patients who visited our clinic for the first time between 2011 and 2014 were analyzed. RESULTS: The 598 study patients comprised one-third of the total reported number of new patients in Tokyo during the study period. 76% were Japanese MSM. The reasons for being tested which led to the diagnosis was voluntary testing in 32%, existing diseases in 53% (AIDS-defining diseases in 22%, sexually transmitted infections (STI) in 8%, diseases other than AIDS or STIs in 23%) and routine pre-surgery or on admission screening in 15%. 52% and 74% of the study patients and patients presented with AIDS, respectively, had never been tested. The median CD4 count in patients with history of previous testing (315/µL) was significantly higher than that of patients who had never been tested (203/µL, p<0.001). CONCLUSIONS: Only 32% of the newly HIV diagnosed patients were diagnosed because of voluntary testing, and 53% were diagnosed due to presence of other diseases. These results remain unchanged from our previous report 10 years earlier (2000-2004) on newly diagnosed patients at the same clinic. HIV testing has not been widely used by newly diagnosed patients in the Tokyo metropolitan area.

Clues to diagnosis for unusual mucosal pemphigus demonstrating undetectable anti-desmoglein 3 serum antibodies by routine tests.

Pemphigus is an autoimmune blistering disease caused by immunoglobulin (Ig)G autoantibodies against desmogleins (Dsg). In mucosal-dominant pemphigus vulgaris (PV), anti-Dsg3 antibodies play a critical role in acantholysis. We followed two mucosal-dominant PV cases who suffered from refractory oral mucosal erosions. In these cases, anti-Dsg3 serum antibodies were not detected by indirect immunofluorescence and enzyme-linked immunosorbent assay (ELISA). However, direct immunofluorescence showed the intercellular IgG deposition in the epidermis and histopathological findings revealed suprabasal acantholysis. In order to analyze the pathomechanisms in these cases, we first examined the Dsg3 expression patterns in lesional sites and compared them with those of typical mucosal-dominant PV cases. In typical PV cases, the alteration of Dsg3 distribution was observed in lesional sites by immunostaining. The aggregation of Dsg3, which is the characteristic change in PV mucosal lesions, was observed as the initial change prior to acantholysis. In our cases, a clustering of Dsg3 was observed at mucosal lesions, and the expression levels of Dsg3 in acantholytic lesions were decreased, as observed in typical mucosal-dominant PV cases. Although anti-Dsg3 serum antibodies could not be detected by routine tests, anti-Dsg3 serum antibodies were detected by Dsg3 ELISA using 10-times more concentrated sera (highly sensitive ELISA). Moreover, purified and concentrated PV IgG showed high pathogenicity when examined by dissociation assay. In conclusion, the detection of morphological changes in Dsg3 distribution and highly sensitive ELISA method could be useful for the early diagnosis of PV recurrence.

[Reliability and validity of the Japanese version of the DAST-20].

OBJECTIVE: Assessing the degree of problems related to drug abuse is important in each treatment setting. The Drug Abuse Screening Test-20 (DAST-20) is a brief, simple 20-item instrument to measure the degree of problems related to drug use. The objective of the present study is to examine the reliability and validity of the Japanese version of the DAST-20. METHODS: We translated the DAST-20 into Japanese using back translation. The anonymous self-administered questionnaire was completed by 310 drug users at the Drug Addiction Rehabilitation Centers (DARC group, n = 113) and at HIV/AIDS regional hospitals (HIV group, n = 197) in Japan. RESULTS: The average DAST-20 score was 7.6 (DARC group = 14.7, HIV group = 2.8). Each item score was highly correlated with the total score (r = 0.45-0.88). A high internal consistency (Cronbach's α = 0.95) was observed (men = 0.95, women = 0.84). Overall test-retest reliability was 0.86 (men = 0.85, women = 0.90). The total DAST-20 score was strongly positively correlated with the Severity of Dependence Scale-J score (r = 0.85), but moderately positively correlated with the Alcohol Use Disorders Identification Test score (r = 0.41). In addition, confirmatory factor analysis indicated an acceptable fit to the data (goodness-of-fit index [GFI] = 0.893, adjusted goodness-of-fit index [AGFI] = 0.854, comparative fit index [CFI] = 0.948, root mean square residual [RMR] = 0.008, root mean square error of approximation [RMSEA] = 0.073). CONCLUSION: Our results clearly suggest that the Japanese version of the DAST-20 has sufficient internal consistency and acceptable levels of concurrent validity and construct validity.

Immune escape phenomenon in molluscum contagiosum and the induction of apoptosis.

Molluscum contagiosum (MC) may persist for many weeks, evading host immunity. We studied the mechanism of immune escape phenomenon in MC, and the possible inducer of apoptosis. Using tissue samples of MC, we examined the numbers of epidermal Langerhans cells (LC), the expression levels of macrophage inflammatory protein-3α (MIP-3α) and thymic stromal lymphopoietin (TSLP), and the apoptotic signals. After molluscum contagiosum virus (MCV) genotyping, we studied the expression of MCV-encoded MC148 mRNA and MC159 mRNA which correspond to viral antagonist for CCR8 and viral Fas-linked interleukin (IL)-1ß converting enzyme (FLICE)-like inhibitor protein (vFLIP), respectively. The nutlin-3-induced apoptosis in MC was observed ex vivo. The numbers of CD1a(+) or Langerin(+) epidermal LC and the expression levels of MIP-3α were markedly decreased in MC. The expression of TSLP was enhanced in the lesional epidermis of atopic dermatitis and human papillomavirus-induced warts, whereas the expression was observed locally in MC. All 14 MC samples examined harbored MCV type 1. The MC148 mRNA was detected in all 14 samples and the MC159 mRNA was detected in 13 samples. Apoptotic cells were absent or at a background level in the living layers of MC, but their numbers were increased in the molluscum bodies by overnight incubation with 5 µmol/L nutlin-3 in culture medium. In conclusion, molluscum bodies are protected from host immune responses and apoptotic signals by being surrounded by LC-depleted epidermal walls and viral immunosuppressive molecules, but could be eradicated by reagents inducing p53-dependent apoptosis.

Mental health of patients with human immunodeficiency virus in Japan: a comparative analysis of employed and unemployed patients.

In developed countries, human immunodeficiency virus (HIV) has become a chronic disease. The aims of this study were to clarify the physical, social, and psychological factors affecting Japanese HIV patients in a stable condition and to identify factors related to mental health of employed and unemployed HIV patients. The target subjects were people with HIV infection who were treated as outpatients at core hospitals for acquired immune deficiency syndrome (AIDS) treatment in Japan. A questionnaire including items from the Hospital Anxiety and Depression Scale (HADS) was sent to each medical facility with a request for participation from the HIV-infected outpatients. Responses from 1199 patients were analyzed. Mental health was reportedly better in the employed patients than in the unemployed patients. The unemployed patients were more likely to have resigned from their jobs because of poor health, to have resigned voluntarily, or to have been unfairly dismissed. Once the patients stopped working because of HIV, returning to work became difficult. In the employed patients, a good workplace environment was strongly related to lower scores on HADS. Higher HADS scores were recorded for employed patients infected with HIV for six years or more. For the unemployed patients, a relationship was observed between strong feelings of stigmatization and HADS scores. Quitting a job because of an experience related to HIV status may be related to feelings of stigmatization.

Increase of DC-LAMP+ mature dendritic cell subsets in dermatopathic lymphadenitis of mycosis fungoides.

BACKGROUND: Little is known about the immunological milieu of the skin-draining lymph nodes (LNs) in mycosis fungoides (MF). OBJECTIVES: We studied dendritic cell (DC) subsets in the dermatopathic lymphadenitis of MF patients. METHODS: We immunohistochemically examined DC subsets and their distribution in 16 LN samples from 14 patients with MF (N1 LN, eight patients; N2, four; and N3, four), and we compared them with non-metastatic sentinel LNs from eight patients with melanoma. RESULTS: The number of S-100 protein+ DCs was markedly increased in the LNs from the MF patients and the major component was DC-LAMP+ mature DCs in the outer and paracortex areas, where DC-SIGN+ immature DCs were relatively decreased in proportion. In contrast, DC-SIGN+ cells were relatively increased in proportion compared to DC-LAMP+ cells in the medulla. Although no significant difference was observed in the proportions of CD1a+ or Langerin+ DCs among the N1, N2, and N3 nodes, CD163+ M2-type macrophages were increased in number in the N2 and N3 nodes. CONCLUSIONS: Our observations indicate that mature DCs accumulate in the outer and paracortex areas in dermatopathic lymphadenitis and M2-type macrophages might increase in number during disease progression.

High prevalence of illicit drug use in men who have sex with men with HIV-1 infection in Japan.

OBJECTIVE: To examine the prevalence of illicit drug use among men who have sex with men (MSM) with HIV-1 infection in Japan, where the life-time prevalence of illicit drug use in the general population is only 2.9%. DESIGN: A single-center cross-sectional study at a large HIV clinic in Tokyo, which treats approximately 15% of HIV-1 infected patients in Japan. METHODS: The prevalence of illicit drug use and the association of characteristics and social demographics of the patients with illicit drug use were examined. Patients who visited the clinic for the first time from 2005 to 2010 were enrolled. Relevant variables were collected using a structured interview and from the medical records. Multivariate logistic regression analyses were applied to estimate the odds of association of MSM over non-MSM HIV-infected patients with illicit drug use. RESULTS: 1,196 patients were enrolled. They were mostly Japanese men of relatively young age. Illicit drug use (including injection drugs) was reported by 35% of the patients (by 40% of MSM), and 4% were IDU while 5% were on methamphetamine. 2% of the population was arrested due to illicit drugs. MSM was significantly associated with illicit drug use (adjusted OR = 4.60; 95% CI, 2.88-7.36; p<0.01). Subgroup analysis of the patients stratified by three age groups (≤ 30, 31 to 40, and >40) showed that the odds of association of MSM with illicit drug use was the strongest in the youngest age group (≤ 30 years: adjusted OR = 7.56; 95% CI, 2.86-20.0; p<0.01), followed by the oldest (>40 years: adjusted OR = 6.15; 95% CI, 2.40-15.8; p<0.01), and the weakest in the group aged 31 to 40 (adjusted OR = 3.39; 95% CI, 1.73-6.63; p<0.01). CONCLUSIONS: The prevalence of illicit drug use is high among MSM patients with HIV-1 infection in Japan. Effective intervention for illicit drug use in this population is warranted.

Illicit drug use is a significant risk factor for loss to follow up in patients with HIV-1 infection at a large urban HIV clinic in Tokyo.

BACKGROUND: Loss to follow up (LTFU) is an important prognostic factor in patients with HIV-1 infection. The impact of illicit drug use on LTFU of patients with HIV-1 infection is unknown in Japan. METHODS: A single center observational study was conducted to elucidate the impact of illicit drug use on LTFU at a large HIV clinic in Tokyo. LTFU was defined as those who discontinued their visits to the clinic for at least 12 months and were not known to be under the care of other facilities or have died within 12 months of their last visit. Patients who first visited the clinic between January 2005 and August 2010 were enrolled. Information on illicit drug use was collected in a structured interview and medical charts. Comparison of the effects of illicit drug use and no use on LTFU was conducted by uni- and multi-variate Cox hazards models as the primary exposure. RESULTS: The study subjects were 1,208 patients, mostly Japanese men, of relatively young age, and infected through homosexual contact. A total of 111 patients (9.2%) were LTFU (incidence: 24.9 per 1,000 person-years). Among illicit drug users and non users, 55 (13.3%) and 56 (7.1%) patients, respectively, were LTFU, with incidence of 35.7 and 19.2 per 1,000 person-years, respectively. Uni- and multi-variate analyses showed that illicit drug use was a significant risk for LTFU (HR=1.860; 95% CI, 1.282-2.699; p=0.001) (adjusted HR=1.544; 95% CI, 1.028-2.318; p=0.036). Multivariate analysis also identified young age, high CD4 count, no antiretroviral therapy, and no health insurance as risk factors for LTFU. CONCLUSIONS: The incidence of LTFU among illicit drug users was almost twice higher than that among non users. Effective intervention for illicit drug use in this population is warranted to ensure proper treatment and prevent the spread of HIV.

Using whole-exome sequencing to identify inherited causes of autism.

Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.

Proteomic study identified HSP 70 kDa protein 1A as a possible therapeutic target, in combination with histone deacetylase inhibitors, for lymphoid neoplasms.

Histone deacetylase inhibitors (HDACi) demonstrate possible anticancer activities in various malignancies including lymphoid neoplasms. However, the anticancer effects of HDACi are often limited, and combination therapy with other drugs has been undertaken to improve the outcome of patients. Here we conducted proteomic investigation of 33 lymphoid cell lines to identify novel therapeutic targets for enhancing the effects of HDACi. Using the proteomic data in our published 2D-DIGE database, we examined the proteins associated with resistance to valproic acid (VPA). The lymphoid neoplasm cell lines in the database were grouped according to their sensitivity to VPA treatment. A comparative proteomic study of the cell line groups resulted in the identification of 10 protein spots, whose intensity was associated with chemosensitivity. Among the identified proteins, HSPA1A showed higher expression in cell lines with resistance to VPA, and the results were validated by Western blotting. In vitro experiments demonstrated that treatment with KNK-437, an inhibitor of HSPA1A, enhanced the cytotoxic effects of VPA, as well as vorinostat, in the lymphoid neoplasm cell line. Treatment with KNK-437 facilitated the apoptotic effects of VPA. In conclusion, we identified HSPA1A as a possible therapeutic target, in combination with HDACi, for lymphoid neoplasms.

Human leukocyte antigen genotypes and antibody profiles associated with familial pemphigus in Japanese.

Previous population-based, genetic studies have shown that human leukocyte antigen (HLA) class II loci such as HLA-DR4 (DRB1*04) and HLA-DR14 (DRB1*14) alleles are consistently associated with the occurrence of pemphigus vulgaris (PV) in Japanese as well as other ethnic populations. Among PV-related HLA-DRB1 alleles (*0406, *1401, *1405, *1406) in Japan, HLA DRB1*1405 and DRB1*0406 were found to be associated with both PV and pemphigus foliaceus (PF) phenotypes. We report four familial cases of pemphigus in two unrelated families, together with analysis of their HLA-DR and -DQ alleles, and their antibody profiles. One family comprised a woman with PF and her mother with PV: both patients shared a HLA haplotype of A31(19), B54(22), CW1 and DRB1*1405. Another family included two sisters with PF and PV, respectively: both of these patients shared a DRB1*1405-DQA1*0104-DQB1*0503 haplotype. Clinicopathological and serological monitoring revealed that the elder sister with PF presented with a PV phenotype later, and gained anti-desmoglein (Dsg)3 antibodies in addition to having a low titer of anti-Dsg1 antibodies. Conversely, the younger sister with PV developed PF with only anti-Dsg1 antibody detected. These results indicate that an HLA-DRB1*1405 (DQB1*0503) haplotype may confer susceptibility to both PV and PF, and that genetic susceptibility alone is not always responsible for the clinical phenotype and autoantibody profile.

Paediatric HIV and elimination of mother-to-child transmission of HIV in the ASEAN region: a call to action.

Recent achievements in scaling up paediatric antiretroviral therapy (ART) have changed the life of children living with HIV, who now stay healthy and live longer lives. However, as it becomes more of a chronic infection, a range of new problems have begun to arise. These include the disclosure of HIV serostatus to children, adherence to ART, long-term toxicities of antiretroviral drugs and their sexual and reproductive health, which are posing significant challenges to the existing health systems caring for children with HIV with limited resources, experiences and capacities. While intensified efforts and actions to improve care and treatment for these children are needed, it is crucial to accelerate the prevention of mother-to-child transmission (PMTCT) of HIV, which is the main cause of paediatric HIV in the ASEAN region so as to eliminate the fundamental cause of the problem. This report argues that given over 70% of women have access to at least one antenatal care visit in the region and acceptance of HIV testing after receiving counselling on PMTCT could be as high as 90%, there is an opportunity to strengthen PMTCT services and eventually eliminate new paediatric HIV infections in the ASEAN countries.

Influences of Allocating HIV/AIDS Specialized Nurses on Clinical Outcomes in Japan.

PURPOSE: This retrospective cohort study was conducted to demonstrate how allocation of nurses specialized in HIV care influences clinical outcomes of antiretroviral therapy (ART) for people living with HIV (PLWH). METHODS: The medical records of 116 PLWH who started ART between January 2002 and December 2004 were analyzed. Occurrence of viral suppression and viral relapse after suppression achievement and their time from baseline were observed as clinical outcomes related to ART. Clinical outcomes were obtained from medical records between January 2002 and December 2006. PLWH were classified into two groups according to allocation (n = 95, nurse allocated group) or nonallocation (n =21, nurse nonallocated group) of nurses specialized in HIV. RESULTS: Survival analysis showed that HIV viral load was suppressed more rapidly and continuously in nurse allocated group than nonallocated group (p < .0001). Viral relapse after suppression achievement occurred easily in nurse nonallocated group than allocated group (p = .003). CONCLUSIONS: The present findings demonstrated that the role of specialized nurses is critically important from the viewpoint of clinical outcome.