Kunihisa Tsukada

Serum (1→3) β-d-Glucan as a Noninvasive Adjunct Marker for the Diagnosis of Pneumocystis Pneumonia in Patients with AIDS

High serum (1-->3) beta-D-glucan levels are described in patients with Pneumocystis pneumonia (PCP). We evaluated the diagnostic value of beta-D-glucan in 111 patients with AIDS who had PCP and confirmed its usefulness. However, it does not correlate with disease severity and is not suitable for monitoring response to treatment.

Impact of small body weight on tenofovir-associated renal dysfunction in HIV-infected patients: a retrospective cohort study of Japanese patients.

Background Treatment with tenofovir is sometimes associated with renal dysfunction. Limited information is available on this side effect in patients with small body weight, although the use of tenofovir will spread rapidly in Asia and Africa, where patients are likely to be of smaller body weight. Methods In a single-center cohort, Japanese patients with HIV infection who started tenofovir-containing antiretroviral therapy were retrospectively analyzed. The incidence of tenofovir-associated renal dysfunction, defined as more than 25% decrement of estimated glomerular filtration rate (eGFR) from the baseline, was determined. The effects of small body weight and body mass index (BMI) on tenofovir-associated renal dysfunction, respectively, were estimated in univariate and multivariate Cox hazards models as the primary exposure. Other possible risk factors were evaluated by univariate analysis and those found significant were entered into the multivariate analysis. Results The median weight of 495 patients was 63 kg. Tenofovir-related renal dysfunction occurred in 97 (19.6%) patients (incidence: 10.5 per 100 person-years). Univariate analysis showed that the incidence of tenofovir-related renal dysfunction was significantly associated with smaller body weight and BMI, respectively (per 5 kg decrement, HR = 1.23; 95% CI, 1.10–1.37; p<0.001)(per 1 kg/m2 decrement, HR = 1.14; 95% CI, 1.05–1.23; p = 0.001). Old age, high baseline eGFR, low serum creatinine, low CD4 count, high HIV viral load, concurrent nephrotoxic drugs, hepatitis C infection, and current smoking were also associated with tenofovir-related renal dysfunction. Multivariate analysis identified small body weight as a significant risk (adjusted HR = 1.13; 95% CI, 1.01–1.27; p = 0.039), while small BMI had marginal significance (adjusted HR = 1.07; 95% CI 1.00–1.16; p = 0.058). Conclusion The incidence of tenofovir-associated renal dysfunction in Japanese patients was high. Small body weight was identified as an independent risk factor for tenofovir-associated renal dysfunction. Close monitoring of renal function is advocated for patients with small body weight treated with tenofovir.

High Incidence of Renal Stones Among HIV-Infected Patients on Ritonavir-Boosted Atazanavir Than in Those Receiving Other Protease Inhibitor–Containing Antiretroviral Therapy

BACKGROUND Little information is available on the incidence of renal stones with ritonavir-boosted atazanavir (ATV/r) use. METHODS In a single-center study, the incidence of renal stones was compared between human immunodeficiency virus (HIV)-infected patients who commenced ritonavir-boosted atazanavir (ATV/r)-containing antiretroviral (ARV) therapy (the ATV/r group) and those who were receiving other protease inhibitors (the other PIs group). The effects of ATV/r were estimated by univariate and multivariate Cox proportional hazards regression models. Other possible risk factors were evaluated by univariate analysis, and those found to be significant were entered into multivariate analysis. RESULTS Renal stones were diagnosed in 31 patients (23.7 cases per 1000 person-years) in the ATV/r group (n = 465) and 4 in patients (2.2 cases per 1000 person-years) in the other PIs group (n = 775). ATV/r use was significantly associated with renal stones, by univariate and multivariate analyses (adjusted hazard ratio, 10.44; 95% confidence interval [CI], 3.685-29.59; P < .001). ATV/r remained a significant risk factor for renal stones in all subgroups stratified by the median values of baseline variables. In the 31 patients receiving ATV/r who developed renal stones, the median time from commencement of ATV/r to diagnosis was 24.5 months (interquartile range, 14.7-34.6 months). Of the 18 patients who continued ATV/r despite the diagnosis of renal stones, 6 (33.3%) experienced recurrence. No patient who discontinued ATV/r experienced recurrence during the observation period (250.6 person-months). CONCLUSIONS The incidence of renal stones was substantially higher among patients in the ATV/r group, compared with patients in the other PIs group. Continuation of ATV/r after diagnosis of renal stones was associated with a high rate of recurrence. Switching ATV/r to other ARVs is warranted in patients who develop renal stones.

Renal function declines more in tenofovir- than abacavir-based antiretroviral therapy in low-body weight treatment-naïve patients with HIV infection.

Objective To compare the rate of decline of renal function in tenofovir- and abacavir-based antiretroviral therapy (ART) in low-body weight treatment-naïve patients with HIV infection. Design We conducted a single-center retrospective cohort study of 503 Japanese patients who commenced on either tenofovir- or abacavir-based initial ART. Methods The incidence of renal dysfunction, defined as more than 25% fall in estimated glomerular filtration rate (eGFR) from the baseline, was determined in each group. The effect of tenofovir on renal dysfunction was estimated by univariate and multivariate Cox hazards models as the primary exposure. Changes in eGFR until 96 weeks were estimated in both groups with a repeated measures mixed model. Results The median body weight of the cohort was 64 kg. The estimated incidence of renal dysfunction in the tenofovir and the abacavir arm was 9.84 per 100 and 4.55 per 100 person-years, respectively. Tenofovir was significantly associated with renal dysfunction by univariate and multivariate analysis (HR = 1.747; 95% CI, 1.152–2.648; p = 0.009) (adjusted HR = 2.080; 95% CI, 1.339–3.232; p<0.001). In subgroup analysis of the patients stratified by intertertile baseline body weight, the effect of tenofovir on renal dysfunction was more evident in patients with lower baseline body weight by multivariate analysis (≤60 kg: adjusted HR = 2.771; 95%CI, 1.494–5.139; p = 0.001) (61–68 kg: adjusted HR = 1.908; 95%CI, 0.764–4.768; p = 0.167) (>68 kg: adjusted HR = 0.997; 95%CI, 0.318–3.121; p = 0.995). The fall in eGFR was significantly greater in the tenofovir arm than the abacavir arm after starting ART (p = 0.003). Conclusion The incidence of renal dysfunction in low body weight patients treated with tenofovir was twice as high as those treated with abacavir. Close monitoring of renal function is recommended for patients with small body weight especially those with baseline body weight <60 kg treated with tenofovir.

Detection of HIV Type 1 Load by the Roche Cobas TaqMan Assay in Patients with Viral Loads Previously Undetectable by the Roche Cobas Amplicor Monitor

OR, 6.2; 95% CI, 2.5–15.4). There was no increase in the risk of T. vaginalis infection among women who were infected with T. vaginalis during the immediately preceding interval (4.4%), compared with women who were not (3.9%). However, 13 (62%) of 21 new infections occurred in women who had been previously infected with T. vaginalis, and 11 (85%) of 13 had negative test results during the immediately preceding interval (figure 1). Some of the women might have acquired infections during sexual contact that they did not report, and some might have had infections that were not detected at the baseline visit. However, many women were treated for infection, had negative test results, and then had positive test results again, which suggests that T. vaginalis was undetected by testing but still present for months after treatment. The possibility of long-term asymptomatic carriage is consistent with the age distribution of infected women; T. vaginalis is found more often in older women [8, 9]. This pattern is different from the pattern for bacterial sexually transmitted diseases but similar to that for incurable viral infections, such as herpes simplex virus type 2 [10]. Trials have suggested cure rates of 190%, but most have tested women once within a few weeks after treatment [11]. When women were tested again a few months after treatment, some of the previously cured women had infection detected again [11], and none of the studies continued testing women beyond a few months. Cultures might not detect infections if the concentration of T. vaginalis is low, which would be expected in asymptomatic infections [6, 12, 13]. Nucleic acid amplification tests may be better, but reports are inconsistent and the tests are not commercially available in the United States [14]. Similarly, self-obtained vaginal swab specimens occasionally miss infections, but the sensitivity of tests performed with self-obtained specimens has compared favorably with that of tests performed with clinician-obtained specimens [15]. Treatment failure could explain many of our findings, because 13 women had a documented preceding infection. However, our results were not simply attributable to treatment failure. Most of the women ( ) had an intervening negn p 11 ative test result before having a positive result during an interval when they reported not having sex. This suggests that, after treatment, T. vaginalis infection can become nondetectable for months and then reappear. Because these findings were unexpected and obtained with a small number of participants, additional studies are needed to confirm or refute these observations.

A case of invasive central nervous system aspergillosis treated with micafungin with monitoring of micafungin concentrations in the cerebrospinal fluid

Invasive aspergillosis has an extremely high mortality rate. In Japan, micafungin, an echinocandin drug that has a new mechanism of action as an antifungal agent and has a clinical effect against Aspergillus species, became available in 2002. However, little is known about its penetration into the central nervous system (CNS), or its efficacy for the treatment of invasive CNS aspergillosis. We report a 65-y-old female with diabetes mellitus and CNS aspergillosis who was treated with micafungin. During treatment, micafungin concentrations were measured in the cerebrospinal fluid and plasma. On a dose of 300 mg/d, the ratio of the micafungin concentration in the cerebrospinal fluid to that in plasma was extremely low (0.2%–0.05%); nevertheless, the patient did not have a relapse of invasive CNS aspergillosis after micafungin treatment.

Long-term exposure to tenofovir continuously decrease renal function in HIV-1-infected patients with low body weight: results from 10 years of follow-up.

Objectives:To investigate the effect of long-term tenofovir disoproxil fumarate (TDF) use on renal function, especially in patients with low body weight who are vulnerable to TDF nephrotoxicity. Design:A single-center, observational study in Tokyo, Japan. Methods:We performed a 10 years cohort study of 792 HIV-1-infected patients. The effect of long-term TDF use on estimated glomerular filtration rate (eGFR) was investigated on treatment-naive patients who started TDF-containing antiretroviral therapy (n = 422) and those who started abacavir-containing antiretroviral therapy as control (n = 370). Three renal endpoints were examined by the logistic regression model: decrement in eGFR of higher than 10 ml/min per 1.73 m2 relative to the baseline, more than 25% decrement in eGFR, and eGFR lower than 60 ml/min per 1.73 m2 at least 3 months apart. The loss in eGFR was estimated using linear mixed models for repeated measures. Results:The median weight at baseline was 63 kg. TDF use increased the risk of all three renal outcomes compared with the control group: higher than 10 ml/min per 1.73 m2 decrement in eGFR [adjusted odds ratio (OR) = 2.1, 95% confidence interval (CI) 1.45–3.14, P < 0.001], more than 25% decrement (adjusted OR = 2.1, 95% CI 1.50–2.90, P < 0.001), and eGFR lower than 60 ml/min per 1.73 m2 at least 3 months apart (adjusted OR = 3.9, 95% CI 1.62–9.36, P = 0.002). The cumulative mean loss relative to the control after 1, 2, 3, 4, and 5 years of TDF exposure was −3.8, −3.6, −5.5, −6.6, and −10.3 ml/min per 1.73 m2, respectively, indicating that the loss in eGFR increased over time (P < 0.001). Conclusion:In this cohort of patients with low body weight, TDF exposure increased the risk of renal dysfunction. Furthermore, the loss in eGFR relative to the control increased continuously up to 5 years.

Bacterial flagellin inhibits T cell receptor‐mediated activation of T cells by inducing suppressor of cytokine signalling‐1 (SOCS‐1)

Flagellin, the structural component of bacterial flagella, is secreted by pathogenic and commensal bacteria, and is recognized by Toll‐like receptor (TLR) 5. Flagellin is a common bacterial antigen present on most motile bacteria and is speculated to contribute to the activation of CD4+ T cells in the intestine. However, molecular mechanisms by which flagellin regulate T cell activation remains to be determined. Using Jurkat T cells or human primary T cell, we showed that flagellin stimulation induced tyrosine phosphorylation of TLR5 and activation of both mitogen‐activated protein kinases and nuclear factor κB. In addition, stimulation by flagellin did not induce nuclear factor of activated T cells (NFAT) activation, while stimulation via the T cell receptor (TCR) leads to activation of NFAT. However, TCR‐mediated NFAT activation and tyrosine phosphorylation of zeta‐associated protein 70 (Zap‐70) were inhibited in cells pre‐stimulated by flagellin. Furthermore, flagellin stimulation induced suppressor of cytokine signalling‐1 (SOCS‐1), which formed a complex with Zap‐70 after stimulation via TCR, and inhibition of SOCS‐1 expression by SOCS‐1‐specific small interfering RNA reinstated TCR‐mediated activation of NFAT in cells pre‐stimulated with flagellin. These results collectively indicate that bacterial flagellin inhibits TCR‐mediated activation of T cells by inducing SOCS‐1.

Living Donor Liver Transplantations in Hiv- and Hepatitis C Virus-coinfected Hemophiliacs: Experience in a Single Center

Background. Although almost all human immunodeficiency virus (HIV)-infected Japanese hemophiliacs are coinfected with hepatitis C virus (HCV), the outcome of living donor liver transplantation (LDLT) in such patients in terms of survival rate, perioperative complications, and recovery of coagulation activity is poorly understood. Patients and Methods. Six HIV-positive hemophiliacs underwent LDLT for HCV-associated advanced cirrhosis. The mean CD4 T-cell count at transplantation was 376±227/&mgr;L. Results. The 1-, 3-, and 5-year survival rates were 66%, 66%, and 50%, respectively. Fatal perioperative bleeding related to hemophilia was not observed. Two patients died within 6 months after transplantation due to graft failure. HIV infection was well controlled in all patients who survived longer than 6 months. Two patients (genotype 2a and 2+3a) achieved a sustained viral response and both of them were alive at the end of follow-up period, whereas one patient (genotype 1a+1b) died of decompensated cirrhosis 4 years after transplantation due to recurrent HCV infection. Conclusions. HIV/HCV-coinfected hemophiliacs can safely undergo LDLT. Hemophilia was clinically cured after successful transplantation. A good outcome can be expected as long as postoperative hepatitis C is controlled with interferon/ribavirin combination therapy.

Raf1 plays a pivotal role in lipopolysaccharide-induced activation of dendritic cells.

Activation of extracellular-regulated kinases 1/2 (ERK) is involved in lipopolysaccharide (LPS)-induced cellular responses such as the increased production of proinflammatory cytokines. However, mitogen-activated protein kinases (MAPKs) such as p38 are also activated by LPS and have been postulated to be important in the control of these end points. Therefore, establishing the relative contribution of MAPKs in each cell type is important, as is elucidating the molecular mechanisms by which these MAPKs are activated in LPS-induced signaling cascades. We demonstrated in DC2.4 dendritic cells that ERK regulates tyrosine phosphorylation of phosphatidyl-inositol-3-kinase (PI3-K) and the production of TNF-alpha. We also demonstrated that Raf1 is phosphorylated and involved in the production of TNF-alpha and tyrosine phosphorylation of PI3-K via ERK. Raf1 also regulates the activation of NF-kappaB. We propose that Raf1 plays a pivotal role in LPS-induced activation of the dendritic cells.