Immunological Correlates of Prevention of the Onset of Seasonal H3N2 Influenza.

On influenza virus infection or vaccination, immune responses occur, including the production of antibodies with various functions that contribute to protection from seasonal influenza virus infection. In the current study, we attempted to identify the antibody functions that play a central role in preventing the onset of seasonal influenza by comparing the levels of several antibody titers for different antibody functions between 5 subclinically infected individuals and 16 patients infected with seasonal H3N2 virus. For antibody titers before influenza virus exposure, we found that the nAb titers and enzyme-linked immunosorbent assay titers against hemagglutinin and neuraminidase (NA) proteins in the subclinically infected individuals were significantly higher than those in the patients, whereas the NA inhibition titers and antibody-dependent cellular cytotoxicity activities did not significantly differ between subclinically infected individuals and infected patients. These results suggest that nAb and enzyme-linked immunosorbent assay titers against hemagglutinin and NA serve as correlates of symptomatic influenza infection.

Predictors associated with a better response to the Japanese aluminum-free hepatitis A vaccine, Aimmugen® , for people living with HIV.

AIM: After the hepatitis A virus (HAV) outbreak among men who have sex with men (MSM) around 2018, the importance of HAV vaccination was emphasized, especially for MSM-living with human immunodeficiency virus (MSM-LWHIV). Aimmugen® is licensed and distributed exclusively in Japan. While administration of three doses is recommended, 85% of recipients in the general population were reported to acquire seroprotection after the second dose. In this study, we evaluated the efficacy of two or three vaccine doses along with predictors associated with the response to Aimmugen® in MSM-LWHIV. METHODS: We retrospectively examined anti-HA-IgG titers of MSM-LWHIV vaccinated with Aimmugen® in our hospital. Patients' data were collected from medical records. RESULTS: Between January 2018 and October 2019, 141 subjects whose median age was 46 years old, were examined. All the subjects were on antiretroviral therapy (ART) and the median CD4 count was 615/µL. The acquisition rate of protectable anti-HA-IgG titers after the second and third dose was 71.1% and 98.6%, respectively. In 114 subjects whose anti-HA-IgG titers were tested after the second-dose, factors significantly associated with better response were prolonged ART duration and higher CD4 count. The titers of anti-HA-IgG after the third dose were higher in those who became seropositive after the second-dose than those who did not. CONCLUSIONS: Three-dose of Aimmugen® for MSM-LWHIV was effective while two-dose was less effective compared to non-HIV-infected people. People-LWHIV with shorter duration of ART and lesser CD4 cell count achieved lower titers of anti-HA-IgG and might require an additional vaccination.

Changes in survival and causes of death among people living with HIV: Three decades of surveys from Tokyo, one of the Asian metropolitan cities.

INTRODUCTION: Survival among people living with HIV (PLWH) has dramatically improved in the antiretroviral therapy (ART) era. This is the first study in Asia to describe three decades of surveys on survival and causes of death among PLWH. METHODS: We included 1121 HIV-infected patients, categorized into three period groups according to date of first visit: 1986-1996 (Pre-ART); 1997-2007 (Early-ART); and 2008-2018 (Late-ART). RESULTS: Ten-year all-cause mortality has reduced from Pre-ART (49.6/1000 person-years) to Late-ART (6.3/1000 person-years). Mortality for AIDS-defining illnesses (ADIs) has also reduced from Pre-ART (34.4/1000 person-years) to Late-ART (2.9/1000 person-years), and mortality for non-ADIs has reduced from Pre-ART (11.7/1000 person-years) to Late-ART (2.9/1000 person-years). In the ART-era, deaths from non-AIDS-defining malignancies and unnatural events including suicide represented the majority of non-ADI-related deaths and mortality rates of non-AIDS defining malignancies and unnatural cause event were not different between each group (3.4, 1.9 and 2.5/1000 person-years). Crude cumulative survival improved over the study period, and 10-year survival ratios of HIV-infected patients to the general Japanese population approached 1.00, from Pre-ART (0.66) to Late-ART (0.99). Even in the Late-ART period, survival remained lower in patients with a history of ADIs than in those without, but the difference in 5-year mortality between these groups has shrunk in the Late-ART compared to the Pre-ART. CONCLUSIONS: Mortality for ADIs and non-ADIs in PLWH has reduced in the Early-ART and Late-ART. To improve survival for PLWH further, early HIV detection and treatment and good management of non-AIDS-defining malignancies and mental disorders are needed. (248/250).

Prevalence of Hepatitis A Immunity and Decision-tree Analysis Among Men Who Have Sex With Men and Are Living With Human Immunodeficiency Virus in Tokyo.

BACKGROUND: Hepatitis A virus (HAV) can be sexually transmitted. However, the level of HAV immunity among patients living with human immunodeficiency virus (HIV) in Japan is unknown. Determining the epidemiology of HAV infections among men who have sex with men (MSM) and who are living with HIV is essential for an HAV vaccination program. This study examined HAV immunity in patients living with HIV and applied the decision-tree analysis to explore the factors of immunoglobulin G (IgG)-hepatitis A (HA) antibodies in MSM living with HIV. METHODS: We examined the presence of IgG-HA antibodies among patients living with HIV from January to December 2017 in The Hospital of The Institute of Medical Science, The University of Tokyo. We recorded each patient's age, sex, mode of HIV transmission, year of HIV diagnosis, HAV vaccine status, history of HAV infection, and history of other infectious diseases. A decision-tree algorithm was used to reveal the factors and profiles most relevant to the anti-HAV prevalence. RESULTS: Overall, 378 MSM patients living with HIV were examined for IgG-HA antibodies. After excluding 24 patients who had received a HAV vaccine, the data of 354 MSM were analyzed (median age 45 years, interquartile range 39-51 years). Of the 354 patients, 60 (16.9%) were positive for IgG-HA antibodies. The HA positivity rate increased with patients' age, and age (> 63.5 years) was extracted as the most important variable by classification of the decision-tree algorithm. CONCLUSIONS: Our study, conducted just before the HAV outbreak among MSM in Tokyo, showed that age was the most relevant factor in anti-HAV prevalences. An extensive HAV vaccination program for MSM patients living with HIV is urgently needed, particularly for younger people.

Utility of the Rapid Antigen Detection Test E. histolytica Quik Chek for the Diagnosis of Entamoeba histolytica Infection in Nonendemic Situations.

Entamoeba histolytica infection is an increasingly common sexually transmitted infection in Japan. Currently, stool ova and parasite examination (O&P) is the only approved diagnostic method. Here, we assessed the utility of the commercially available rapid antigen detection test (Quik Chek) for E. histolytica A multicenter cross-sectional study was conducted. Stool samples that had been submitted for O&P were included. The samples were subjected to both Quik Chek and PCR, and the Quik Chek results were assessed in comparison with PCR as the reference standard. E. histolytica infection was confirmed in 5.8% (38/657) of the samples and comprised 20 diarrheal and 18 nondiarrheal cases. The overall sensitivity and specificity of Quik Chek were 44.7% (95% confidence interval, 30.1 to 60.3) and 99.8% (99.1 to 100), respectively. The sensitivity of Quik Chek was higher for diarrheal cases (60.0%) than for nondiarrheal cases (27.8%). Furthermore, the combined use of Quik Chek with O&P increased the sensitivity (78.9%), especially for diarrheal cases (up to 90%). The E. histolytica burden assessed by quantitative PCR was similar between Quik Chek-positive and -negative samples. The Quik Chek assay sensitivity was lower for cyst-containing stools than for trophozoite-containing stools, although it was shown that cultured E. histolytica clinical strains from Quik Chek-negative cyst-containing stools exhibited antigenicity in vitro The present study confirmed the high specificity of Quik Chek for E. histolytica infection. Combined use with O&P increased the sensitivity of detection, facilitating the use of Quik Chek in point-of-care settings in nonendemic situations.

CD4/CD8 ratio predicts the cellular immune response to acute hepatitis C in HIV-coinfected adults.

Hepatitis C virus (HCV) coinfection is a strong risk factor for death of HIV-infected patients. Immune dysfunction affects the clinical course of acute hepatitis C (AHC). CD4/CD8 ratio is a biomarker of both persistent inflammation and immunosenescence in HIV-infected adults on effective antiretroviral therapy. A low CD4/CD8 ratio predicts immunosenescence and is associated with increased morbidity and mortality in both HIV-infected adults and elderly HIV-uninfected adults. Additionally, immunosenescence is associated with unresponsiveness to vaccine and could affect the immune reaction to pathogens during their primary infection. We retrospectively evaluated 12 AHC patients to assess the association between CD4/CD8 ratio and liver damage in AHC. We used the Spearman rank correlation test to assess the correlation. We found that CD4/CD8 ratio and peak alanine aminotransferase level (peak ALT) were positively correlated (r = 0.8322, p = 0.0013). The CD4 counts did not correlate with peak ALT (r = 0.5245, p = 0.0839). CD8+ T cells expansion for AHC did not affect these results, because the CD4/CD8 ratio before the onset of AHC and peak ALT positively correlate (n = 11; r = 0.7909, p = 0.0055) and there was no significant difference between CD4/CD8 ratios before and after the onset of AHC (n = 11; p = 0.9766). Immunosenescence may be negatively associated with the cellular immune response to acute HCV infection. We suggest that clinicians consider using CD4/CD8 ratio as a marker of immunosenescence in their management of patients with HIV infection and other complications.

Short Intracellular HIV-1 Transcripts as Biomarkers of Residual Immune Activation in Patients on Antiretroviral Therapy.

UNLABELLED: HIV-1 patients continue to remain at an abnormal immune status despite prolonged combination antiretroviral therapy (cART), which results in an increased risk of non-AIDS-related diseases. Given the growing recognition of the importance of understanding and controlling the residual virus in patients, additional virological markers to monitor infected cells are required. However, viral replication in circulating cells is much poorer than that in lymph nodes, which results in the absence of markers to distinguish these cells from uninfected cells in the blood. In this study, we identified prematurely terminated short HIV-1 transcripts (STs) in peripheral blood mononuclear cells (PBMCs) as an efficient intracellular biomarker to monitor viral activation and immune status in patients with cART-mediated full viral suppression in plasma. STs were detected in PBMCs obtained from both treated and untreated patients. ST levels in untreated patients generally increased with disease progression and decreased after treatment initiation. However, some patients exhibited sustained high levels of ST and low CD4(+) cell counts despite full viral suppression by treatment. The levels of STs strongly reflected chronic immune activation defined by coexpression of HLA-DR and CD38 on CD8(+) T cells, rather than circulating proviral load. These observations represent evidence for a relationship between viral persistence and host immune activation, which in turn results in the suboptimal increase in CD4(+) cells despite suppressive antiretroviral therapy. This cell-based measurement of viral persistence contributes to an improved understanding of the dynamics of viral persistence in cART patients and will guide therapeutic approaches targeting viral reservoirs. IMPORTANCE: Combination antiretroviral therapy (cART) suppresses HIV-1 load to below the detectable limit in plasma. However, the virus persists, and patients remain at an abnormal immune status, which results in an increased risk of non-AIDS-related complications. To achieve a functional cure for HIV-1 infection, activities of viral reservoirs must be quantified and monitored. However, latently infected cells are difficult to be monitored. Here, we identified prematurely terminated short HIV-1 transcripts (STs) as an efficient biomarker for monitoring viral activation and immune status in patients with cART-mediated full viral suppression in plasma. This cell-based measurement of viral persistence will contribute to our understanding of the impact of residual virus on chronic immune activation in HIV-1 patients during cART.

[Investigation of the Pathophysiology and Diagnostic Methods Through a Case of Acute HIV Infection in which the Western Blot Method Remained Negative Over the Long Term and the 4th Generation Screening Assay Became Negative for a Certain Period of Time after Initiating Antiretroviral Therapy].

Confirmatory tests using Western blot (WB) and HIV-1 nucleic acid testing (HIV-1 RNA) following a positive screening test are required for the diagnosis of HIV-1 infection according to the current Japanese guidelines for HIV-1/2 diagnosis. We report herein on a rare case in a patient who remained negative for WB over 10 months in spite of being positive by fourth-generation immunoassays (4thGIA) and who subsequently seroreverted by 4thGIA for three months after initiating antiretroviral therapy. Case: A man in his early twenties previously visited a hospital because of fever in October 2012. Laboratory data revealed leukocytopenia, thrombocytopenia and increased serum ferritin, suggesting hemophagocytic syndrome (HPS). During that visit, he tested positive for a 4thGIA, but negative for HIV-1 WB and his result of HIV-1 RNA result was detected invalid because of the presence of some inhibitory material in his RNA preparation. Thereafter, he was diagnosed as having cytomegalovirus-associated HPS treatment was for which initiated. In January 2013, he developed Pneumocystis jirovecii pneumonia, and his HIV-1 RNA viral load was 7.7 × 105 copies/mL in February 2013. Acute HIV infection was suspected, because the HIV-1 WB remained negative. He was started on antiretroviral therapy in April 2013. His 4thGIA was converted to negative in May 2013 and was reconverted to positive in August 2013. HIV-1 WB, however, continued to be indeterminant until February 2014, in which it turned positive for the first time according to the CDC criteria. Methods and Results: The genetic analyses of HIV-1 were done on the gag, env, nef and pol region of the HIV-1 gene from the patient. There was no clear element to delay antibody production on the virus side. Preserved specimens of the patient were measured with eight kinds of HIV screening assay. It was thought that the fourth generation assay was positive only by the presence of the antigen until March 2013 because the antibody had not been detected. Discussion: We encountered a case of acute HIV infection in which the WB result was negative for 10 months after the first positive response of the 4thGIA. The 4thGIA is essential for the early diagnosis and early treatment of HIV infection; therefore, the 4thGIA should be strictly recommended to avoid the use of older generations of immunoassay in the diagnostic guidelines. The role of the WB test should be examined closely from various aspects for use as a confirmatory test under recent laboratory situations in which highly sensitive and specific methods, e.g. the 4th GIA, have become available. In addition, unnecessary confusion due to the diversities of antibody formation should be avoided. The antibody detection tests for HIV are still necessary and indispensable for the confirmation of the disease or the diagnosis of the acute infection stage. Therefore development of a newer antibody measuring method which could achieve an easier operation and should have a higher sensitivity and specificity for HIV confirmation is strongly expected.

Epigenetic repression of interleukin 2 expression in senescent CD4+ T cells during chronic HIV type 1 infection.

The molecular mechanisms for IL2 gene-specific dysregulation during chronic human immunodeficiency virus type 1 (HIV-1) infection are unknown. Here, we investigated the role of DNA methylation in suppressing interleukin 2 (IL-2) expression in memory CD4(+) T cells during chronic HIV-1 infection. We observed that CpG sites in the IL2 promoter of CD4(+) T cells were fully methylated in naive CD4(+) T cells and significantly demethylated in the memory populations. Interestingly, we found that the memory cells that had a terminally differentiated phenotype and expressed CD57 had increased IL2 promoter methylation relative to less differentiated memory cells in healthy individuals. Importantly, early effector memory subsets from HIV-1-infected subjects expressed high levels of CD57 and were highly methylated at the IL2 locus. Furthermore, the increased CD57 expression on memory CD4(+) T cells was inversely correlated with IL-2 production. These data suggest that DNA methylation at the IL2 locus in CD4(+) T cells is coupled to immunosenescence and plays a critical role in the broad dysfunction that occurs in polyclonal T cells during HIV-1 infection.

Switching and emergence of CTL epitopes in HIV-1 infection.

BACKGROUND: Human Leukocyte Antigen (HLA) class I restricted Cytotoxic T Lymphocytes (CTLs) exert substantial evolutionary pressure on HIV-1, as evidenced by the reproducible selection of HLA-restricted immune escape mutations in the viral genome. An escape mutation from tyrosine to phenylalanine at the 135th amino acid (Y135F) of the HIV-1 nef gene is frequently observed in patients with HLA-A*24:02, an HLA Class I allele expressed in ~70% of Japanese persons. The selection of CTL escape mutations could theoretically result in the de novo creation of novel epitopes, however, the extent to which such dynamic "CTL epitope switching" occurs in HIV-1 remains incompletely known. RESULTS: Two overlapping epitopes in HIV-1 nef, Nef126-10 and Nef134-10, elicit the most frequent CTL responses restricted by HLA-A*24:02. Thirty-five of 46 (76%) HLA-A*24:02-positive patients harbored the Y135F mutation in their plasma HIV-1 RNA. Nef codon 135 plays a crucial role in both epitopes, as it represents the C-terminal anchor for Nef126-10 and the N-terminal anchor for Nef134-10. While the majority of patients with 135F exhibited CTL responses to Nef126-10, none harboring the "wild-type" (global HIV-1 subtype B consensus) Y135 did so, suggesting that Nef126-10 is not efficiently presented in persons harboring Y135. Consistent with this, peptide binding and limiting dilution experiments confirmed F, but not Y, as a suitable C-terminal anchor for HLA-A*24:02. Moreover, experiments utilizing antigen specific CTL clones to recognize endogenously-expressed peptides with or without Y135F indicated that this mutation disrupted the antigen expression of Nef134-10. Critically, the selection of Y135F also launched the expression of Nef126-10, indicating that the latter epitope is created as a result of escape within the former. CONCLUSIONS: Our data represent the first example of the de novo creation of a novel overlapping CTL epitope as a direct result of HLA-driven immune escape in a neighboring epitope. The robust targeting of Nef126-10 following transmission (or in vivo selection) of HIV-1 containing Y135F may explain in part the previously reported stable plasma viral loads over time in the Japanese population, despite the high prevalence of both HLA-A*24:02 and Nef-Y135F in circulating HIV-1 sequences.

Significant reductions in Gag-protease-mediated HIV-1 replication capacity during the course of the epidemic in Japan.

Human immunodeficiency virus type 1 (HIV-1) evolves rapidly in response to host immune selection pressures. As a result, the functional properties of HIV-1 isolates from earlier in the epidemic may differ from those of isolates from later stages. However, few studies have investigated alterations in viral replication capacity (RC) over the epidemic. In the present study, we compare Gag-Protease-associated RC between early and late isolates in Japan (1994 to 2009). HIV-1 subtype B sequences from 156 antiretroviral-naïve Japanese with chronic asymptomatic infection were used to construct a chimeric NL4-3 strain encoding plasma-derived gag-protease. Viral replication capacity was examined by infecting a long terminal repeat-driven green fluorescent protein-reporter T cell line. We observed a reduction in the RC of chimeric NL4-3 over the epidemic, which remained significant after adjusting for the CD4(+) T cell count and plasma virus load. The same outcome was seen when limiting the analysis to a single large cluster of related sequences, indicating that our results are not due to shifts in the molecular epidemiology of the epidemic in Japan. Moreover, the change in RC was independent of genetic distance between patient-derived sequences and wild-type NL4-3, thus ruling out potential temporal bias due to genetic similarity between patient and historic viral backbone sequences. Collectively, these data indicate that Gag-Protease-associated HIV-1 replication capacity has decreased over the epidemic in Japan. Larger studies from multiple geographical regions will be required to confirm this phenomenon.

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.

Liver dysfunction in patients with early syphilis: a retrospective study.

Syphilis is one of the unrecognized etiologies of liver dysfunction. The incidence of syphilitic hepatitis is currently unknown. We conducted a retrospective study of causative agents of liver dysfunction at the time of diagnosis of early syphilis. Our study shows that 39 % (44/112) of early syphilis patients have liver enzyme abnormalities at the time of diagnosis and that 2.7 % (3/112) of patients are diagnosed with syphilitic hepatitis. Clinicians should include syphilitic hepatitis in the differential diagnosis for those patients with sexually transmitted diseases presenting with liver enzyme abnormalities.

[Anti-HIV drugs].

Anti-HIV drugs are fall into the following 5 categories: nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), protease inhibitors (PIs), integrase strand transfer inhibitors (INSTIs), and C-C chemokine receptor type 5 (CCR5) inhibitors. An appropriate combination of anti-HIV drugs, which is called ART (anti-retroviral therapy), can suppress HIV replication for prolonged periods. Since many anti-HIV drugs with relatively few side effects as well as high-potency have been developed recently, early initiation of ART is recommended regardless of the patients' CD4+ T-cell counts. However, ART does not lead to eradication or cure of HIV because of latent infection. Interruption of ART leads to a rapid rebound of viremia, necessitating life-long treatment. Thus, strategies to eradicate HIV from latently infected cells are urgently needed.

Outbreak of infections by hepatitis B virus genotype A and transmission of genetic drug resistance in patients coinfected with HIV-1 in Japan.

The major routes of hepatitis B virus (HBV) infection in Japan has been mother-to-child transmission (MTCT) and blood transfusion. However, HBV cases transmitted through sexual contact are increasing, especially among HIV-1-seropositive patients. To understand the molecular epidemiology of HBV in HBV/HIV-1 coinfection, we analyzed HBV genotypes and HIV-1 subtypes in HBV/HIV-1-coinfected patients at Nagoya Medical Center from 2003 to 2007. Among 394 HIV-1-infected Japanese men having sex with men (MSM) who were newly diagnosed during the study period, 31 (7.9%) tested positive for the hepatitis B virus surface antigen. HBV sequence analyses were successful in 26 cases, with 21 (80.7%) and 5 (19.3%) cases determined as genotypes A and C, respectively. Our finding that HBV genotype A was dominant in HIV-1-seropositive patients alerts clinicians to an alternative outbreak of HBV genotype A in the HIV-1-infected MSM population and a shift in HBV genotype from C to A in Japan. The narrow genetic diversity in genotype A cases suggests that genotype A has been recently introduced into the MSM population and that sexual contacts among MSM were more active than speculated from HIV-1 tree analyses. In addition, we found a lamivudine resistance mutation in one naïve case, suggesting a risk of drug-resistant HBV transmission. As genotype A infection has a higher risk than infection with other genotypes for individuals to become HBV carriers, prevention programs are urgently needed for the target population.

Cerebral schistosomiasis due to Schistosoma haematobium confirmed by PCR analysis of brain specimen.

The case of a 25-year-old Japanese male who had cerebral schistosomiasis caused by Schistosoma haematobium is reported here. Although serum antibody tests showed a cross-reaction with other helminths and no ova were excreted in urine or feces, the existence of Schistosoma haematobium in the brain was confirmed by PCR analysis.

Case of secondary syphilis presenting with unusual complications: syphilitic proctitis, gastritis, and hepatitis.

We report the first known case of syphilis with simultaneous manifestations of proctitis, gastritis, and hepatitis. The diagnosis of syphilitic proctitis and gastritis was established by the demonstration of spirochetes with anti-Treponema pallidum antibody staining in biopsy specimens. Unusual manifestations of secondary syphilis completely resolved after 4 weeks of antibiotic therapy.

Pulmonary nocardiosis caused by Nocardia exalbida complicating Pneumocystis pneumonia in an HIV-infected patient.

A 47-year-old man with optimally controlled type-2 diabetes mellitus and chronic hepatitis B was admitted to a local hospital because of a 1-week history of cough and high-grade fever. He was diagnosed with Pneumocystis pneumonia (PCP) and Klebsiella pneumonia from a chest radiograph and sputum. Simultaneously, he was found to have HIV infection with a CD4 count of 76/µl. Despite alteration of treatment secondary to the development of allergic reaction to trimethoprim-sulfamethoxazole (TMP-SMX), the patient was able to complete a 3-week therapy for PCP after being switched to pentamidine isetionate. After the treatment of PCP, he was referred to our hospital for the initiation of anti-HIV therapy. He presented with recurrent high-grade fever of a few days' duration prior to his initial visit, which subsequently led to his admission. Chest computed tomography (CT) showed the enlargement of a previously identified infiltrate in the left upper lung field, and the sputum culture upon admission was positive for Gram-positive branching rods; the organism was later identified as Nocardia exalbida. Due to his allergy to sulfonamide, the patient was treated with imipenem (IMP) and amikacin (AMK) given intravenously for 17 days, followed by garenoxacin (GRNX) taken orally for 6 months, without any adverse effects. The chest infiltrate resolved completely, and he remains stable without relapse 8 months after the completion of the therapy. Pulmonary nocardiosis should be considered as a differential diagnosis of recurring pneumonia in immunocompromised patients, especially in HIV-infected individuals. Oral administration of GRNX following IMP and AMK can be used as an alternative to TMP-SMX therapy in cases of pulmonary nocardiosis caused by N. exalbida.

Long-term successful control of super-multidrug-resistant human immunodeficiency virus type 1 infection by a novel combination therapy of raltegravir, etravirine, and boosted-darunavir.

Drug-resistant virus infection has been a major hurdle in the management of human immunodeficiency virus type 1 (HIV-1) infection. Recently, three novel antiretrovirals [raltegravir (RAL), etravirine (ETR), and darunavir (DRV)] were introduced into the market almost simultaneously, and salvage regimens containing these three antiretrovirals have been reported to exhibit strong potency against drug-resistant HIV-1 infection. However, the sustainability of such regimens remains unclear, particularly for patients infected with multidrug-resistant viruses. Here we report a case of super-multidrug-resistant HIV-1 infection which has been successfully controlled by novel combination therapy including RAL, ETR, and DRV for over 2 years, indicating that the novel combination could become an ultimate weapon against drug-resistant HIV infection and could alter the landscape of HIV salvage therapy.