Successful dual antiviral therapy with remdesivir and ensitrelvir in a case of prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma.

Prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma is characterized by repeated cycles of remission followed by symptom recurrence, persistent detection of SARS-CoV-2, and profound humoral immunodeficiency. To the best of our knowledge, the present report is the first to describe dual antiviral therapy with remdesivir and ensitrelvir for prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma. A 59-year-old, female patient with a history of follicular lymphoma treated with obinutuzumab and bendamustine contracted COVID-19 despite receiving a single course of standard remdesivir therapy. She received dual antiviral therapy with remdesivir following a five-day course of oral ensitrelvir, which improved her clinical symptoms and chest radiology findings and cleared SARS-CoV-2 from respiratory samples. Dual antiviral therapy with remdesivir and ensitrelvir may be sufficient to stop viral replication and promote clinical resolution in prolonged COVID-19 following B-cell depleting immunotherapy for malignant lymphoma.

[Current Topics of Cancer and HIV].

Antiretroviral therapy(ART)has been associated with reduced AIDS- and non-AIDS-related morbidity and mortality in people living with HIV/AIDS(PLWH). Nevertheless, the incidence of many comorbid conditions remains higher in PLWH than in the general population, including AIDS-defining malignancies(ADM)as well as several non-AIDS-defining malignancies (NADM). It's important to prevent ADM/NADM, like periodic health checkup for early diagnosis, to quit smoking, and cooperation with cancer and HIV specialists.

Prevalence of Chronic Kidney Disease and Poor Diagnostic Accuracy of Dipstick Proteinuria in Human Immunodeficiency Virus-Infected Individuals: A Multicenter Study in Japan.

BACKGROUND: Chronic kidney disease (CKD) has become one of the common comorbid conditions affecting the human immunodeficiency virus (HIV) population. Human immunodeficiency virus-infected individuals are at increased risk of developing CKD, and they are likely to experience faster progression of renal dysfunction compared with HIV-uninfected individuals. Albuminuria represents not only kidney damage but also manifests metabolic syndrome and vascular dysfunction. METHODS: We conducted a multicenter, cross-sectional study involving 2135 HIV-infected individuals in Japan to test the prevalence of CKD and proteinuria/albuminuria. Urine sample was analyzed by both dipstick test and albumin-to-creatinine ratio (ACR) assay. Chronic kidney disease was classified according to the Kidney Disease Outcomes Quality Initiative (K/DOQI) and Kidney Disease: Improving Global Outcomes (KDIGO) guidelines. The diagnostic performance of dipstick test to detect albuminuria (ACR ≥30 mg/g) was evaluated. RESULTS: The prevalence of CKD, evaluated by K/DOQI and KDIGO guidelines, was 15.8% and 20.4%, respectively. Age, total cholesterol level, prevalence of hypertension, diabetes mellitus, and hepatitis C infection tended to increase, whereas levels of hemoglobin, serum albumin, and CD4 cell count tended to decrease as CKD risk grades progressed. Proteinuria and albuminuria were present in 8.9% and 14.5% of individuals, respectively. Dipstick test ≥1+ to detect albuminuria had an overall sensitivity of 44.9% and specificity of 97.2%. CONCLUSIONS: The KDIGO guideline may enable physicians to capture HIV-infected patients at increased risk more effectively. The sensitivity of dipstick proteinuria to detect albuminuria is so poor that it may not serve as an alternative in HIV-infected individuals.

HIV positivity may not have a negative impact on survival in Epstein-Barr virus-positive Hodgkin lymphoma: A Japanese nationwide retrospective survey.

There has been no comparative clinical study focused on differences in the clinical features of Epstein-Barr virus (EBV)+ Hodgkin lymphoma (HL) between HIV-positive and -negative cases. In a nationwide survey from 511 institutions in Japan, the present study investigated 16 EBV+ HIVpositive HL patients. To further clarify their characteristics in comparison with EBV+ HIVnegative HL (n=34) in the combination antiretroviral therapy era in Japan, the present study was performed. Results indicated that EBV+ HIVpositive HL frequently occurred in a younger population compared with EBV+ HIVnegative HL (P=0.0295), and that the EBV+ HIVpositive HL group was not associated with the nodular sclerosis subtype in the population who were below the age of 40. Notably, the EBV+ HIVpositive HL group had a significantly higher frequency of extra-nodal involvement (P=0.0214), including marrow invasion. In the advanced stage, 80% of those with EBV+ HIVpositive HL did not require dose-reduction and in the majority of cases, chemotherapy was completed. There were no significant differences in the complete remission rate (P=0.1961), overall survival (P=0.200) and progression-free survival (P=0.245) between EBV+ HIVpositive HL (median observational period, 23.5 months) and EBV+ HIVnegative HL (median observational period, 64.5 months), suggesting that HIV positivity may not have a negative impact on the clinical outcome of EBV+ HL. Notably, standard chemotherapy is effective and tolerable for EBV+ HL, regardless of HIV infection.

Severe Thrombocytopenia and Acute Cytomegalovirus Colitis during Primary Human Immunodeficiency Virus Infection.

We herein report the case of a 25-year-old man who was referred to our hospital due to acute cytomegalovirus (CMV) colitis. The initial blood tests showed that the patient had concurrent primary human immunodeficiency virus (HIV) infection and severe thrombocytopenia. Raltegravir-based antiretroviral therapy (ART) was initiated without the use of ganciclovir or corticosteroids and resulted in a rapid clinical improvement. Platelet transfusions were only necessary for a short period, and subsequent colonoscopy revealed a completely healed ulcer. This case implies that ART alone could be effective for treating severe thrombocytopenia during primary HIV and CMV coinfection.

Clinical and pathological aspects of human immunodeficiency virus-associated plasmablastic lymphoma: analysis of 24 cases.

Plasmablastic lymphoma (PBL) is a rare AIDS-related malignancy with a poor prognosis. Little is known about this entity, and no standard treatment regimen has been defined. To establish an adequate treatment strategy, we investigated 24 cases of PBL arising in human immunodeficiency virus-positive individuals. Most of the patients were in the AIDS stage, with a median CD4 count of 67.5/µL. Lymph nodes (58 %), gastrointestinal tract (42 %), bone marrow (39 %), oral cavity (38 %), and CNS (18 %) were the most commonly involved sites. Histology findings for the following were positive at varying rates, as follows: CD10 (56 %); CD30 (39 %); CD38 (87 %); MUM-1 (91 %); CD138 (79 %); EBER (91 %); and LMP-1 (18 %). There was a marked increase in patients in 2011-12, and the cases found in that period appeared to be more aggressive, showing a higher rate of advanced-stage PBL. Fourteen cases were treated with CHOP, while the others were treated with more intensive regimens, including bortezomib and hematopoietic stem cell transplantation. The overall median survival time was 15 months. A CD4 count of >100/µL at diagnosis and attaining complete remission in the first-line chemotherapy were associated with better outcomes (P = 0.027 and 0.0016, respectively). Host immune status and chemosensitivity are associated with improved prognosis in PBL.

[Ocular Syphilis Complicated with HIV Infection: A Report of 3 Cases].

We present 3 cases of ocular syphilis in patients who had been newly diagnosed as having HIV. All the patients had only complained of ophthalmologic symptoms at the time of their initial visit. Treatment with penicillin was successful, resulting in no significant sequelae. Ocular syphilis may lead to reduced visual acuity or even blindness if left untreated. However, the diagnosis may be challenging, since patients may lack symptoms that are commonly observed in cases with primary and secondary syphilis. Considering the recent increase in the number of syphilis patients, clinicians should be aware of ocular syphilis and should have a high index of suspicion for syphilis in any patient at risk so as to ensure a prompt diagnosis.

CD8 Encephalitis Caused by Persistently Detectable Drug-resistant HIV.

We herein report a 52-year-old man infected with human immunodeficiency virus (HIV) who was referred to our hospital due to the development of severe neurocognitive disorders and bilateral leukoencephalopathy. He has been treated with antiretroviral agents for 17 years, but low-level viremia has been detected consistently prior to admission. Drug resistant testing of the serum and the cerebrospinal fluid (CSF) both demonstrated a M184V mutation. A brain biopsy revealed perivascular CD8(+) T-lymphocyte infiltration, leading to the diagnosis of CD8 encephalitis. The clinical symptoms improved drastically after changing to a nucleoside reverse transcriptase inhibitor sparing regimen, which subsequently decreased the HIV viral load to an undetectable level in both the serum and CSF.

Laryngeal Kaposi's Sarcoma Complicated by the Immune Reconstitution Inflammatory Syndrome in an HIV-infected Patient.

We herein report a case of laryngeal Kaposi's sarcoma (KS) complicated by immune reconstitution inflammatory syndrome in a human immunodeficiency virus (HIV)-infected patient. The patient initially presented with KS involving the larynx, which was successfully treated with pegylated liposomal doxorubicin (PLD) and antiretroviral therapy (ART). PLD was discontinued after 2 courses because of a marked clinical improvement; however, the patient experienced progressive odynophagia and dyspnea 2 months after the initiation of ART. Laryngoscopy revealed a severely swollen, inflamed epiglottis. The readministration of PLD was successful, and the patient was thereafter discharged without any subsequent complications.

End-of-life care for HIV-infected patients with malignancies: A questionnaire-based survey.

BACKGROUND: The number of HIV-infected patients who require palliative or end-of-life care is increasing, and the status of end-of-life care for HIV patients with malignancies is unclear. AIM: This study aimed to evaluate the end-of-life care provided to HIV patients with malignancies in Japan. DESIGN: National cross-sectional questionnaire-based survey. SETTING/PARTICIPANTS: Questionnaires were delivered to the medical staff of 378 regional core hospitals/core hospitals for AIDS and 285 palliative care units in Japan. Data were collected between August and October 2013. RESULTS: Overall, 226 regional core hospitals/core hospitals for AIDS (59.8%) responded. A total of 55 institutions (24.3%) provided end-of-life care to HIV patients with malignancies. Regarding the place of death of the patients, 69.1% died at the institution whereas 18.2% were transferred to palliative care units. The requests of 16 (29.1%) institutions to transfer patients to palliative care units were rejected. Of the 378 palliative care units, 179 (62.8%) responded. While 13 palliative care units (4.6%) provided care to hospitalized HIV patients with malignancies, 20 (11.2%) refused to accept these patients for treatment because of a lack of experience in treating these patients and a lack of knowledge regarding HIV infection. CONCLUSION: Our findings suggest that in Japan, HIV patients with malignancies have difficulties obtaining hospitalization at a palliative care unit, which is likely due to a lack of experience among the professionals in treating such patients as well as a lack of knowledge about HIV.

[Kaposi's Sarcoma Herpesvirus-associated Inflammatory Cytokine Syndrome (KICS) Improved by Antiretroviral Therapy in an HIV-infected Patient].

We report a case of a 63-year-old HIV-positive Japanese male with a CD4 cell count of 127/µL who was admitted to our hospital because of suspected malignant lymphoma. Initial blood tests revealed anemia, thrombocytopenia, hypoalbuminemia, and hypergammaglobulinemia. Imaging tests revealed a lung nodule, bilateral pleural effusion, hepatosplenomegaly and generalized lymphadenopathy. No evidence of malignant lymphoma or multicentric Castleman's disease was noted on biopsy specimens; however, Kaposi sarcoma-associated herpesvirus (KSHV)-encoded latency-associated nuclear antigen-1-positive cells were observed as well as an elevated interleukin (IL)-6, IL-10 and KSHV viral load. He fulfilled the novel diagnostic criteria for KSHV-associated inflammatory cytokine syndrome (KICS). After initiating antiretroviral therapy, his symptoms and radiological abnormalities drastically improved. After 1-year follow-up, his HIV was well controlled without any relapsing symptoms.

A multi-institutional study of clinicopathological features and molecular epidemiology of epidermal growth factor receptor mutations in lung cancer patients living with human immunodeficiency virus infection.

PURPOSE: Lung cancer has become a crucial problem among individuals living with the human immunodeficiency virus (HIV) and causes high mortality in Western countries. Japan has an increasing number of newly infected HIV patients, and lung cancer is becoming a theme in this population. However, clinical factors of this particular population in East Asian are unclear given the identification of ethnic differences in lung cancer in the general population. METHODS: From 1986 to 2013, a retrospective nationwide study involving Japanese patients living with HIV and diagnosed with lung cancer was undertaken. RESULTS: Forty-three lung cancer patients with HIV were identified (median age, 60.0 years; males, 97.7%; early-stage cancer, 37.2%; metastatic cancer, 34.9%), 41 (95.3%) of whom developed lung cancer in the antiretroviral era. The median CD4-positive T-cell count was 326 cells/µL. Adenocarcinoma was the most frequent histology (55.8%), followed by squamous cell carcinoma (27.9%). Epidermal growth factor receptor (EGFR) status was examined in 14 patients; five (35.7%) had EGFR mutations. The median overall survival time was 25.1 months for all stages and 7.9 months for advanced-stage cancer. Using univariate analysis, the only favorable prognostic factor for overall survival was cancer stage (p = 0.02). CONCLUSIONS: The incidence of lung cancer among HIV patients in Japan has been increasing in the past decade. The present Japanese cohort showed similar EGFR mutation status similar to that of general population. The ethnic differences known in the general population were seen even in the population living with HIV, implying distinct clinical characteristics and outcomes from those reported in Western countries.

Comparison of cystatin C and creatinine to determine the incidence of composite adverse outcomes in HIV-infected individuals.

BACKGROUND: Cystatin C is an overall biomarker of pathophysiologic abnormalities that accompany chronic kidney disease (CKD). The utility of cystatin C is not fully understood in an HIV-infected population. METHODS: This prospective study investigated 661 HIV-infected individuals for 4 years to determine the incidence of adverse outcomes, including all-cause mortality, cardiovascular disease, and renal dysfunction. The risk of developing the outcomes was discriminated with a 4 color-coded classification in a 3 × 6 contingency table, that combined 3 grades of dipstick proteinuria with 6 grades of estimated glomerular filtration rate (eGFR) calculated using either serum creatinine (eGFRcr) or cystatin C (eGFRcy): green, low risk; yellow, moderately increased risk; orange, high risk; and red, very high risk. The cumulative incidence of the outcomes was assessed by the Kaplan-Meier method, and the association between color-coded risk and the time to outcome was evaluated using multivariate proportional hazards analysis. RESULTS: Compared with eGFRcr, the use of eGFRcy reduced the prevalence of risk ≥ orange by 0.8%. The adverse outcomes were significantly more likely to occur to the patients with baseline risk category ≥orange than those with ≤ yellow, independent of risk categories based on eGFRcr or eGFRcy. However, in multivariate analysis, risk category ≥orange with eGFRcy-based classification was significantly associated with adverse outcomes, but not the one with eGFRcr. CONCLUSIONS: Replacing creatinine by cystatin C in the CKD color-coded risk classification may be appropriate to discriminate HIV-infected patients at increased risk of a poor prognosis.

Clinical presentation and diagnosis of toxoplasmic encephalitis in Japan.

Distinguishing life-threatening toxoplasmic encephalitis (TE) from brain lymphoma in patients with acquired immunodeficiency syndrome (AIDS) may be difficult. Empiric anti-toxoplasmosis treatment is often initiated because of the reluctance in performing brain biopsies, which may delay the diagnosis and treatment of brain lymphoma in Japan. In this study, we retrospectively examined the clinical characteristics of 13 AIDS patients with TE in Japan, including magnetic resonance imaging and thallium 201 (201TI) single photon emission computed tomography (SPECT) findings, cerebral spinal fluid analysis, serology, and polymerase chain reaction (PCR) results. All patients improved on anti-toxoplasmosis treatment. Of the 11 patients who underwent serological testing, 6 (55%) had a positive serological result. Of the 7 patients who underwent PCR testing, 3 (42.9%) had a positive PCR result. Nine of 11 patients with TE (81.8%) had multiple lesions. Analysis of the sites of TE lesions did not reveal a difference in site predilection between TE and brain lymphoma. Uptake was negative in all 9 patients who underwent 201Tl SPECT. The study findings suggest that toxoplasma serostatus and PCR may be used to discriminate TE from brain lymphoma. No focal accumulation of 201TI is strongly suggestive of TE in patients with AIDS in Japan.

Subjective adverse reactions to metronidazole in patients with amebiasis.

Subjective adverse reactions to metronidazole were analyzed in 111 patients with amebiasis. Metronidazole was administered to 36 patients at a daily dose of 2250 mg and 75 patients at daily doses lower than 2250 mg. The reactions reported included nausea without vomiting in 11 (9.9%) patients, nausea with vomiting in 2 (1.8%), dysgeusia in 2 (1.8%), diarrhea in 1 (0.9%), headache in 1 (0.9%), numbness in 1 (0.9%), dizziness in 1 (0.9%), urticaria in 1 (0.9%), exanthema in 1 (0.9%), and discomfort in 1 (0.9%). Nausea was reported by 28% (10/36) of the patients receiving metronidazole at a daily dose of 2250 mg and 4% (3/75) of the patients receiving lower daily doses. The duration of the metronidazole administration in days was not associated with the appearance of nausea. No life-threatening adverse reactions were identified, and good clinical therapeutic effects were observed in 96% (107/111) of the patients. While metronidazole appears to be a safe anti-protozoal agent for patients with amebiasis, our results indicate that a daily metronidazole dose of 2250 mg is excessive for amebiasis, as it often induces nausea.

[Evaluation of HIV-infected patients suspected as having HIV-associated neurocognitive disorders].

BACKGROUND: HIV-associated neurocognitive disorders (HAND) have emerged as a problem among HIV-infected individuals in the era of antiretroviral therapy. However, there are insufficient data on HAND regarding its prevalence and clinical features in Japan. METHODS: A test battery composed of eight neuropsycological tests proposed by the Ministry of Health, Labour and Welfare (MHLW test battery) was applied to assess 30 subjects at Tokyo Metropolitan Komagome Hospital. Among them, 5 subjects were excluded due to central nervous system complications. The background of each patient along with the results of head magnetic resonance imaging (MRI), cerebrospinal fluid (CSF) analysis and neuropsychological tests were compared to each HAND category. In addition, the clinical utility of a combination of neuropsychological tests as an abbreviated test battery of HAND was evaluated. RESULTS: A total of 19 (76%) subjects were diagnosed as having a HAND. Among them, HIV-associated dementia, mild neurocognitive disorders and asymptomatic neurocognitive disorders were diagnosed in 7, 8, and 4 subjects, respectively. Neither the patient's background nor the results of the head MRI and CSF analysis showed relevance to disease severity. The conventional International HIV Dementia Scale with the Digit Symbol Substitute Test was capable of detecting 94.7% cases of HAND. CONCLUSIONS: Most HIV-infected subjects clinically suspected as having neurocognitive disorders were diagnosed as having a HAND. Neuropsychological tests of the MHLW test battery were in some part useful to diagnose HAND. However, more precise neuropsychological tests are warranted to screen and diagnose HAND, based on the current criteria.

[Murine typhus in a Japanese traveler returning from Indonesia: a case report].

We report herein on a 20-year-old Japanese man who was referred to our hospital for fever and diarrhea after returning from Indonesia. On admission, his blood test was essentially normal, besides a slight elevation in inflammatory markers. After excluding malaria and dengue fever, empiric use of ceftriaxone was initiated for suspected enteric fever, which was unsuccessful. However, drastic clinical improvement was observed after initiation of minocycline. The polymerase chain reaction test for Rickettsia typhi was positive from serum samples on admission, confirming the diagnosis of murine typhus. Although rarely seen in Japan, clinicians should be aware of this disease when examining patients with fever coming back from murine typhus endemic areas.

[Immunodeficiency related malignant lymphoma: diagnosis and therapy of AIDS-related lymphoma].

AIDS-related lymphoma (ARL) remains a significant burden for specialists in HIV/AIDS medicine. Pathological findings of ARL are often non-typical in various histological types. Diagnosis of correct histological type of ARL by the skilled pathologist is essential. Therapy of patients with ARL is the challenge of integrating treatment appropriate for the stage and histological subset of non-Hodgkin lymphoma. In addition to chemotherapy, essential components of an optimal ARL treatment strategy include antiretroviral therapy and prophylaxis for opportunistic infections.

Pyoderma gangrenosum successfully treated with antiretroviral therapy alone in a human immunodeficiency virus-infected individual.

We report a case of a 60-year-old man infected with human immunodeficiency virus (HIV) who was transferred to our hospital for management of multiple non-healing, painful ulcers on the lower extremities. The histological findings of the biopsy specimen were compatible with the diagnosis of pyoderma gangrenosum (PG). An association between HIV infection and the development of PG was considered after a thorough investigation. Antiretroviral therapy without the use of adjunctive immunosuppressive agents resulted in clinical improvement. Our case implies that antiretroviral therapy alone could heal PG in untreated HIV-infected patients.

The prevalence of opportunistic infections and malignancies in autopsied patients with human immunodeficiency virus infection in Japan.

BACKGROUND: Opportunistic infections and malignancies such as malignant lymphoma and Kaposi sarcoma are significant complications of human immunodeficiency virus (HIV) infection. However, following the introduction of antiretroviral therapy in Japan in 1997, the incidence of clinical complications has decreased. In the present study, autopsy cases of HIV infection in Japan were retrospectively investigated to reveal the prevalence of opportunistic infections and malignancies. METHODS: A total of 225 autopsy cases of HIV infection identified at 4 Japanese hospitals from 1985-2012 were retrospectively reviewed. Clinical data were collected from patient medical records. RESULTS: Mean CD4 counts of patients were 77.0 cells/µL in patients who received any antiretroviral therapy during their lives (ART (+) patients) and 39.6 cells/µL in naïve patients (ART (-) patients). Cytomegalovirus infection (142 cases, 63.1%) and pneumocystis pneumonia (66 cases, 29.3%) were the most frequent opportunistic infections, and their prevalence was significantly lower in ART (+) patients than ART (-) patients. Non-Hodgkin lymphoma and Kaposi sarcoma were observed in 30.1% and 16.2% of ART (-) patients, and 37.9% and 15.2% of ART (+) patients, respectively. Malignant lymphoma was the most frequent cause of death, followed by cytomegalovirus infection regardless of ART. Non-acquired immunodeficiency syndrome (AIDS)-defining cancers such as liver and lung cancer caused death more frequently in ART (+) patients (9.1%) than in ART (-) patients (1.5%; P = 0.026). CONCLUSIONS: The prevalence of infectious diseases and malignancies were revealed in autopsy cases of HIV infection in Japan. The prevalence of cytomegalovirus infection and pneumocystis pneumonia at autopsy were lower in ART (+) patients than ART (-) patients. Higher prevalence of non-AIDS defining malignancies among ART (+) patients than ART (-) patients suggests that onsets of various opportunistic infections and malignancies should be carefully monitored regardless of whether the patient is receiving ART.