Association of demographics, HCV co-infection, HIV-1 subtypes and genetic clustering with late HIV diagnosis: a retrospective analysis from the Japanese Drug Resistance HIV-1 Surveillance Network.

INTRODUCTION: Late diagnosis of the human immunodeficiency virus (HIV) is a major concern epidemiologically, socially and for national healthcare systems. Although the association of certain demographics with late HIV diagnosis has been reported in several studies, the association of other factors, including clinical and phylogenetic factors, remains unclear. In the present study, we conducted a nationwide analysis to explore the association of demographics, clinical factors, HIV-1 subtypes/circulating recombinant form (CRFs) and genetic clustering with late HIV diagnosis in Japan, where new infections mainly occur among young men who have sex with men (MSM) in urban areas. METHODS: Anonymized data on demographics, clinical factors and HIV genetic sequences from 39.8% of people newly diagnosed with HIV in Japan were collected by the Japanese Drug Resistance HIV-1 Surveillance Network from 2003 to 2019. Factors associated with late HIV diagnosis (defined as HIV diagnosis with a CD4 count <350 cells/µl) were identified using logistic regression. Clusters were identified by HIV-TRACE with a genetic distance threshold of 1.5%. RESULTS: Of the 9422 people newly diagnosed with HIV enrolled in the surveillance network between 2003 and 2019, 7752 individuals with available CD4 count at diagnosis were included. Late HIV diagnosis was observed in 5522 (71.2%) participants. The overall median CD4 count at diagnosis was 221 (IQR: 62-373) cells/µl. Variables independently associated with late HIV diagnosis included age (adjusted odds ratio [aOR] 2.21, 95% CI 1.88-2.59, ≥45 vs. ≤29 years), heterosexual transmission (aOR 1.34, 95% CI 1.11-1.62, vs. MSM), living outside of Tokyo (aOR 1.18, 95% CI 1.05-1.32), hepatitis C virus (HCV) co-infection (aOR 1.42, 95% CI 1.01-1.98) and not belonging to a cluster (aOR 1.30, 95% CI 1.12-1.51). CRF07_BC (aOR 0.34, 95% CI 0.18-0.65, vs. subtype B) was negatively associated with late HIV diagnosis. CONCLUSIONS: In addition to demographic factors, HCV co-infection, HIV-1 subtypes/CRFs and not belonging to a cluster were independently associated with late HIV diagnosis in Japan. These results imply the need for public health programmes aimed at the general population, including but not limited to key populations, to encourage HIV testing.

The Iowa Gambling Task on HIV-infected subjects.

HIV-associated neurocognitive disorders (HAND) are characterized by cognitive, behavioral, and motor dysfunctions, which impact daily functioning and are predictive of poor survival among patients. The diagnosis of HAND is marked by clinically significant declines in multiple domains of neurocognitive functioning. Some patients diagnosed with HAND have social problem; however, higher brain dysfunction is not detected in general neuropsychological assessments and the intelligence quotient may remain unchanged. Impaired decision-making may reduce social and occupational qualities of life. The Iowa Gambling Task (IGT) has been developed as a task to evaluate risk predictions at the time of decision-making. In the present study, 38 HIV-infected patients enrolled in our hospital performed IGT and we investigated whether the results obtained are associated with HAND. The median net IGT score of all HIV-infected subjects was significantly lower than that of healthy controls. Patients diagnosed with HAND accounted for 43.8% of the negative net score group. We elucidated the relationship between the net IGT score and HAND for the first time. We think that IGT is a good tool to detect decision-making impairment for ANI and MND. Careful follow-ups of the progression of HAND and increased awareness among HIV-infected patients and medical care workers of the risk of social behavioral disorders, which negatively impact daily life before they are detected, are needed in order to prevent deteriorations in the quality of life of these patients.

Large abscess formed in the abdominal wall by Mycobacterium avium complex: A case of unmasking immune reconstitution inflammatory syndrome.

Immune reconstitution inflammatory syndrome (IRIS) is a clinical entity with a broad presentation that is complicated in patients with acquired immunodeficiency syndrome after initiating antiretroviral therapy. A 51-year-old Japanese man was diagnosed with disseminated Mycobacterium avium complex (MAC) infection presenting as unmasking IRIS, which formed a large abscess in the patient's abdominal wall. MAC-IRIS commonly involves the lymph nodes, bone marrow, and gastrointestinal tract. To our knowledge, this is the first case report of an abdominal wall abscess caused by MAC-IRIS.

An attempt to support by the Japanese society of travel and health for increasing travel clinics.

In recent years, both the number of Japanese travelers to foreign countries and foreign travelers who visit Japan have increased remarkably, and the risk of travelers suffering various infectious diseases is also increasing. In many western countries travel clinics commonly perform medical consultations, vaccinations, and issue prescriptions. However, travel clinics are not yet popular in Japan. In 2011, Japanese society of travel and health (JSTH) began a support project for travel clinic with a goal of increasing their number throughout the country. The project included the release of a manual for education, training, equipment, details of medical treatment, sources of information for travel clinic opening on the JSTH website (http://jstah.umin.jp/20TravelClinicSupport/manual_20120726.pdf), and mediation of short-term visitation to experienced travel clinics registered in the JSTH to facilitate learning above information and aftercare services. JSTH accepted requests for visitation to travel clinics from 39 medical institutions between 2011 and 2018. By 2018, 26 (66.7%) of the 39 medical institutions had opened travel clinics within two years and the 25 travel clinics had registered in the JSTH and one was a campus-limited clinic, while most of the remaining institutions are still in preparation stages. The number of travel clinics registered in the JSTH has increased from 45 in 2011 to 108 in 2018. Twenty-five travel clinics registered in the JSTH between 2011 and 2018 were eventually receiving support from JSTH. Our data indicates travel clinics in Japan have gradually increased and establishment areas are expanding after the beginning of support project for travel clinics by JSTH.

Association of age and time of disease with HIV-associated neurocognitive disorders: a Japanese nationwide multicenter study.

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

An HBV-HIV co-infected patient treated with tenofovir-based therapy who achieved HBs antigen/antibody seroconversion.

The present report describes a case of a patient with hepatitis B virus (HBV)-human immunodeficiency virus (HIV) co-infection who was treated with tenofovir disoproxil (TDF)-based highly active antiretroviral therapy (HAART) and who achieved HBs antigen (Ag)/antibody (Ab) seroconversion. An 18-year-old Japanese man with HIV and HBV co-infection presented to our hospital. His CD4 count was decreased, and TDF-based HARRT was started. At 30 months after initiation of therapy, HBsAg was not detected. At 36 months after initiation of therapy, HBsAb was detected. We conclude that TDF-based therapy is useful for the management of patients with HBV and HIV co-infection.

Switching tenofovir/emtricitabine plus lopinavir/r to raltegravir plus Darunavir/r in patients with suppressed viral load did not result in improvement of renal function but could sustain viral suppression: a randomized multicenter trial.

BACKGROUND: Whether tenofovir nephrotoxicity is reversible after its withdrawal is unknown. Furthermore, there are no data on the viral efficacy of raltegravir (RAL) plus ritonavir-boosted Darunavir (DRV/r) in patients with suppressed viral load. METHODS: This multicenter, randomized trial compared renal function and viral efficacy in patients with suppressed viral load treated with RAL+DRV/r and ritonavir-boosted lopinavir (LPV/r) plus tenofovir/emtricitabine (TVD), who had been previously on LPV/r+TVD. The primary endpoint was the proportion of patients with >10% improvement in estimated glomerular filtration rate (eGFR) at 48 weeks calculated with Cockcroft-Gault equation. RESULTS: 58 randomized and treatment-exposed patients were analyzed (28 on RAL+DRV/r and 30 on LPV/r+TVD). Greater than 10% improvement in eGFR was noted in 6 (25%) out of 24 with RAL+DRV/r and 3 (11%) of 28 with LPV/r+TVD, and the difference was not statistically significant (p=0.272, 95% CI -0.067 to 0.354). Sensitivity analyses using three other equations for eGFR showed the same results. Urinary ß2 microglobulin, a sensitive marker of tenofovir tubulopathy, significantly improved with RAL+DRV/r than with LPV/r+TVD (-271 versus -64 µg/gCr, p=0.026). Per protocol analysis showed that the HIV-RNA was <50 copies/mL at week 48 in all patients of both arms (24 in RAL+DRV and 29 in LPV/r+TVD). CONCLUSIONS: Switching LPV/r+TVD to RAL+DRV/r did not significantly increase the proportion of patients who showed >10% improvement in renal function among those with relatively preserved eGFR. However, the switch improved urinary ß2 microglobulin, suggesting that discontinuation of TDF might be beneficial in the long-term. RAL+DRV/r showed favorable viral efficacy in patients with suppressed viral load. TRIAL REGISTRATION: ClinicalTrials.gov NCT01294761 http://clinicaltrials.gov/ct2/show/NCT01294761?term=SPARE&rank=2, Umin Clinical Trials Registry UMIN000005116 http://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=brows&action=brows&type=summary&recptno=R000006083&language=J).

Abacavir/lamivudine versus tenofovir/emtricitabine with atazanavir/ritonavir for treatment-naive Japanese patients with HIV-1 infection: a randomized multicenter trial.

OBJECTIVE: To compare the efficacy and safety of fixed-dose abacavir/lamivudine (ABC/3TC) and tenofovir/emtricitabine (TDF/FTC) with ritonavir-boosted atazanavir (ATV/r) in treatment-naïve Japanese patients with HIV-1 infection. METHODS: A 96-week multicenter, randomized, open-label, parallel group pilot study was conducted. The endpoints were times to virologic failure, safety event and regimen modification. RESULTS: 109 patients were enrolled and randomly allocated (54 patients received ABC/3TC and 55 patients received TDF/FTC). All randomized subjects were analyzed. The time to virologic failure was not significantly different between the two arms by 96 weeks (HR, 2.09; 95% CI, 0.72-6.13; p=0.178). Both regimens showed favorable viral efficacy, as in the intention-to-treat population, 72.2% (ABC/3TC) and 78.2% (TDF/FTC) of the patients had an HIV-1 viral load <50 copies/mL at 96 weeks. The time to the first grade 3 or 4 adverse event and the time to the first regimen modification were not significantly different between the two arms (adverse event: HR 0.66; 95% CI, 0.25-1.75, p=0.407) (regimen modification: HR 1.03; 95% CI, 0.33-3.19, p=0.964). Both regimens were also well-tolerated, as only 11.1% (ABC/3TC) and 10.9% (TDF/FTC) of the patients discontinued the allocated regimen by 96 weeks. Clinically suspected abacavir-associated hypersensitivity reactions occurred in only one (1.9%) patient in the ABC/3TC arm. CONCLUSION: Although insufficiently powered to show non-inferiority of viral efficacy of ABC/3TC relative to TDF/FTC, this pilot trial suggested that ABC/3TC with ATV/r is a safe and efficacious initial regimen for HLA-B*5701-negative patients, such as the Japanese population.

Germ cell tumor concomitant with acquired immune deficiency syndrome.

Patients with acquired immune deficiency syndrome (AIDS) are susceptible to secondary malignant tumors. Among those malignancies, the increased incidence of germ cell tumor (GCT) in patients with AIDS has recently been documented in Western countries, while that is still rare in Japan. Here, we report a man patient with advanced GCT (seminoma) complicated with AIDS who was continuously treated with highly active antiretroviral therapy (HAART). A partial response was obtained after resection of the primary left testis and three courses of chemotherapy. During the clinical course, he contracted unexpected gastric bleeding that made it impossible to take HAART agents and prophylactic agents for opportunistic infection. Thereafter, he suffered from a severe pulmonary infection and consequently died of severe respiratory failure. The lymphopenia related to both chemotherapy and AIDS synergistically rendered this patient immunoincompetent and thus he suffered from this fatal pulmonary infection. The recent progress in AIDS treatment has been reported to prolong the survival of tumor-bearing AIDS patients, especially GCT-bearing AIDS patients. Because of the current increase in the number of AIDS patients in Japan, it is important to report the present case which indicated that careful chemotherapy against GCT with strict management of the immunoincompetence can provide a good prognosis for GCT-bearing AIDS patients.

Problems in three Japanese drug users with Human Immunodeficiency Virus infection.

Numbers of individuals infected with Human Immunodeficiency Virus (HIV) are increasing in Japan. The majority of them are Men who have sex with men and a part of them take drugs as 'Sex drug' at their sexual intercourse. Especially, Amyl nitrite, Methamphetamine, 5-methoxy-N, N-diisopropyltryptamine (5-MeO-DIPT; Foxy), and 3, 4-methylenedioxy- methamphetamine (MDMA; Ecstasy) are used, and they sometimes cause the physical and mental disorders. However, the actual drug inducing troubles among Japanese HIV-infected drug users had not yet been discussed enough. In this report, we describe three cases with HIV infection; a case developed severe neuroleptic malignant syndrome (NMS) after taking 5-MeO-DIPT, a case with persistent convulsion due to multiple drug intake and a case with rhabdomyolysis due to the non-subjective methamphetamine intake. Through these cases, we raise and discuss several underlying problems associated with drug use among HIV-infected individuals.

[Case of relapsing polychondritis followed by cognitive impairment].

A 64-year-old man developed cognitive impairment. A neurological examination showed hypereactive tendon reflex. A cerebrospinal fluid (CSF) examination showed a mild increase in both the number of mononuclear cells (14 cells/mm3) and the protein level (45 mg/dl). An electroencephalogram showed diffuse slow wave activity. Brain MR images revealed multifocal lesions in the limbic area and white matter regions. He was suspected to have autoimmune encephalitis and his symptoms improved after treated with methylprednisolone (1 g/day for 3 days). Despite this treatment, his mental disorders later relapsed. His condition improved after undergoing repeated treatment. Thereafter, he developed bacterial meningoencephalitis which had been caused by Listeria monocytogenes during the period of the internal administration of steroids. Antibiotics successfully cured his Listeria meningoencephalitis. He thereafter developed conjunctivitis, polyarthritis, hearing difficulties, dizziness and auricular chondritis. Based on these findings, we diagnosed the patient to have relapsing polychondritis (RP). It was thus conceivable that his cognitive impairment has been caused by CNS vasculitis associated with RP. RP therefore should be carefully taken into consideration and be included in the differential diagnosis as a possible cause for CNS vasculitis.

[Multiple metastases from renal carcinoma 15 years after nephrectomy].

A 72-year-old man was admitted to our hospital complaining of an axillary mass. He underwent left total nephrectomy for renal cell carcinoma (RCC) 15 years previously (in 1990). Since further evaluation yielded no evidence of extra renal metastases, he was followed up in the outpatient clinic. On admission, there was a hard tumor in the right axilla. Ultrasonography demonstrated a vascular tumor with a smooth surface, 26 by 24mm. Laboratory findings were generally close to normal, including tumor markers. Chest contrast-enhanced dynamic CT showed that the tumor was enhanced. Furthermore, abdominal contrast-enhanced dynamic CT revealed some enhancing lesions within the right side of the rectus muscle of abdomen and pancreas head as well. Open simple axillary mass biopsy was performed on August 2 and the tumor was histologically confirmed as a metastasis of the RCC to the axillary. His overall status was normal, and he underwent an operation for the pancreas tumor and the tumor in the rectus muscle of the abdomen. On histological examination, both excised specimens were found to be metastases of RCC. During 2 years follow-up period in the outpatient clinic, additional metastasis has not been observed in any organ. Since this case confirms the potential of RCC for late and multiple distant metastases, careful long-term follow-up after radical nephrectomy is needed.

[Esophageal stricture following complete remission after chemotherapy for malignant lymphoma in an elderly patient].

A 75-year-old woman was given a diagnosis of malignant lymphoma (non-Hodgkin, diffuse large B cell type, stage IIA) at our hospital on August 2003. She received six courses of rituximab-based chemotherapy (R-CHOP regimen) and then she achieved complete remission. On August 16, 2004, she was readmitted in our hospital for difficulty in swallowing. Upper gastrointestinal endoscopy reveled esophageal stricture and an ulcerative lesion on the esophageal mucosa. The X-ray examination of the upper gastrointestinal tract reveled a severe esophageal stricture with niches and hiatus hernia. No malignancy was seen on CT scanning, gallium radioisotope scanning and histological examination of biopsy specimens with the upper gastrointestinal endoscopy. The physical examination showed gibbosity, and MR imaging showed multiple compression spined fractures. Finally, we diagnosed benign esophageal stricture with reflux esophagitis. She underwent laparoscopic partial esophagectomy in September 21, 2004, and the postoperative course was satisfactory. The pathological findings showed benign esophageal stricture caused by esophagitis. We report here a case of esophageal stricture following complete remission after chemotherapy for malignant lymphoma in an elderly patient.

Existence of leukemic clones resistant to both imatinib mesylate and rituximab before drug therapies in a patient with Philadelphia chromosome-positive acute lymphocytic leukemia.

Imatinib mesylate and rituximab are molecularly targeted drugs against the BCR-ABL fusion protein and the CD20 antigen, respectively. Although these drugs have excellent anticancer effects, a major concern is drug resistance. We have investigated the case of a patient with Philadelphia chromosome-positive and CD20+ acute lymphocytic leukemia who acquired resistance to imatinib and rituximab. Imatinib therapy resulted in prompt cytogenetic remission, but resistance developed shortly thereafter. Sequencing of the kinase domain of the ABL gene and allele-specific polymerase chain reaction analysis revealed a point mutation resulting in an E255V substitution that was present before the therapy. After the patient received mild chemotherapy followed by rituximab administration, hematologic and cytogenetic remission was sustained for 5.5 months. The recurrent leukemic cells after the rituximab therapy showed not only the E255V mutation in the ABL gene but also loss of the CD20 antigen due to impaired transcription of the CD20 gene. The results of 2-color flow cytometry analysis showed that a small population of CD20(-) leukemic cells existed before the imatinib therapy. These results suggest that leukemic subclones carrying a genetic perturbation of the targeted molecules for both imatinib and rituximab were present before the therapies. The preexistence of primary resistant clones suggests the inability of combination therapy with 2 molecularly targeted drugs to overcome drug resistance in leukemia.

[Double B-cell malignancies with simultaneous onset].

We encountered a case of a 59-year-old female who simultaneously contracted a non-Hodgkin lymphoma (NHL) and a plasma cell neoplasm. The patient consulted her physician about her abdominal tumor and anemia in March 1999. She was diagnosed as having NHL (follicular center lymphoma, grade I, stage IIA) after an open tumor biopsy, and treated by cycles of CHOP chemotherapy which resulted in complete remission. However, the patient's abdominal tumor appeared again in March 2000 and she was hospitalized at the Ehime University Hospital. A tumor biopsy was performed laparoscopically at that time. Follicular lymphoma (with positive LCA, L-26, and bcl-2 immuno-staining) with the development of retroperitoneal fibrosis was diagnosed again. When a bone marrow puncture was performed because of a condition of monoclonal gammopathy which had continued for two years, a smoldering myeloma was additionally diagnosed. This diagnosis was made after the presence of IgG-lambda M protein when the marrow showed an increase in the number of plasma cells. In a Southern blot analysis which studied the abdominal tumor and the bone marrow cells, each B-cell tumor had a different IgH gene rearrangement pattern. Therefore, this case was diagnosed as an example of the simultaneous existence of two different B-cell tumors. Double cancers in hematological malignancies are very rare and this was thought to be an interesting case.

[A case of pyomyositis following influenza virus infection].

A 45-year-old man visited the first hospital complained of high fever on January 2003. He was diagnosed as having Influenza virus type A infection and prescribed of Oseltamivir. He was afebrile next day, but severe myalgia of neck, shoulder, lumbar region and right femoral region was appeared. His illness was considered as polymyalgia rheumatica and started of oral steroid therapy. His symptom was deteriorated and transferred to our hospital. Echography, Ga scintigraphy, computed tomography and magnetic resonance imaging revealed the multiple abscesses and the diagnosis of pyomyositis was made. Pyomyositis following Influenza virus infection must be considered as a differential diagnosis of myalgia after Influenza virus infection.

Non-Hodgkin's lymphoma developing in a pacemaker pocket.

A 29-year-old man developed diffuse large B-cell lymphoma in a subpectoral pacemaker pocket that 6 years previously had been created in the chest for a titanium-covered pulse generator. The patient had an 8-cm-diameter dark red tumor with necrotic tissue on a keloidal surgical scar in the left side of the chest. Left axillary lymphadenopathy also was present. Laboratory studies showed an increased level of soluble interleukin 2 receptor and a normal level of lactose dehydrogenase. A biopsy specimen showed a diffuse large B-cell phenotype and monoclonal immunoglobulin H gene rearrangement. A gallium scintigraphy study showed abnormal accumulation in the left chest and left axilla. On the basis of these findings, we diagnosed diffuse large B-cell lymphoma, stage II. The patient received THP-COP chemotherapy (pirarubicin, cyclophosphamide, vincristine, and prednisolone) and radiotherapy, achieved complete remission, and was free of disease for 16 months after treatment. This case suggests that there was a relationship between the development of non-Hodgkin's lymphoma and the presence of chronic inflammation in the pulse generator pocket.

Dramatic efficacy of fludarabine in the treatment of an aggressive case of splenic lymphoma with villous lymphocytes.

Splenic lymphoma with villous lymphocytes (SLVL) is an indolent lymphoproliferative disorder of mature B lymphocytes. Splenectomy is primarily recommended for treating this disease, and splenic irradiation or alkylating agents may be effective; however, frequent recurrence is observed after these therapies. We report here an unusual case of SLVL in which the degree of splenomegaly and the serum IgM level increased rapidly. Although the effects of splenic irradiation and combination chemotherapy were both unsatisfactory and transient, complete remission lasting for more than 15 months was achieved after two courses of treatment with low-dose fludarabine (15 mg m(-2) daily for 3 d). The present case indicates that treatment with fludarabine is effective for SLVL and recommended as the first-line therapy for elderly patients and those with an aggressive form of the disease.