Haruhito Honda

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.

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.

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.

Pharmacogenetic information derived from analysis of HLA alleles

A large amount of pharmacogenetic information has, in particular, accumulated on the association between human leukocyte antigen (HLA) alleles and hypersensitivity to certain drugs. Prospective HLA typing has dramatically reduced the risk of abacavir hypersensitivity because of its strong association with HLA-B*5701. Significant predisposition to nevirapine hypersensitivity has been reported in Caucasian Australians harboring HLA-DRB1*0101 with high CD4+ T-cell counts, and Sardinians and Japanese harboring HLA-Cw8. A strong association between carbamazepine hypersensitivity and HLA-B*1502 has been reported in Han Chinese. Most Han Chinese individuals with allopurinol-induced severe cutaneous adverse reactions are positive for HLA-B*5801. HLA typing can stratify risk of hypersensitivity to certain drugs and allow personalized treatment, although the patients should be monitored closely even if they are negative for HLA alleles associated with hypersensitivity.

Whole-body 18F-fluorodeoxyglucose positron emission tomography/computed tomography images before and after chemotherapy for Kaposi sarcoma and highly active antiretrovirus therapy

Kaposi sarcoma is an acquired immunodeficiency syndrome-related disease that mainly involves the skin, gastrointestinal gut, and lungs. Whole-body 18F-fluorodeoxyglucose-positron emission tomography and computed tomography (FDG-PET/CT) scanning is useful for simultaneous detection of multiple lesions of Kaposi sarcoma. We present a 67-year-old man with a history of infection with human immunodeficiency virus who presented with numerous cutaneous lesions. FDG-PET/CT images showed lesions in the skin, lung, and lymph nodes. The gastrointestinal lesions were detected using gastric fiberscopy (GF) and colon fiberscopy (CF). After Kaposi sarcoma therapy, the uptake in the lesions of the skin, lung, and lymph nodes decreased, but new lesions were detected in the pancreas and lumbar spine. He had pancreatitis and Candida spondilitis. Whole-body FDG-PET/CT is useful for detecting lesions and determining the extension to which the disease has spread, adding the gastrointestinal lesions by GF and CF. After therapy, FDG-PET/CT can be used to demonstrate which lesions remain active and to determine the overall response to treatment. In this case, we show how useful FDG-PET/CT is and how difficult it is to treat Kaposi sarcoma.

Case of relapsed AIDS-related plasmablastic lymphoma treated with autologous stem cell transplantation and highly active antiretroviral therapy

Plasmablastic lymphoma is a rare and aggressive malignancy strongly associated with HIV infection. The refractory/relapsed disease rate is high, and the survival rate is characteristically poor. There are no satisfactory salvage regimens for relapsed cases. We successfully performed autologous stem cell transplantation using a regimen consisting of MCNU (ranimustine), etoposide, cytarabine, and melphalan in a Japanese patient with relapsed AIDS-related plasmablastic lymphoma of the oral cavity. Highly active antiretroviral therapy continued during the therapy. Therapy-related toxicity was tolerable, and a total of 40 Gy of irradiation was administered after autologous stem cell transplantation. The patient has remained in complete remission for 16 months since transplantation.

Pharmacokinetics of Rifabutin in Japanese HIV-Infected Patients with or without Antiretroviral Therapy

Objective Based on drug-drug interaction, dose reduction of rifabutin is recommended when co-administered with HIV protease inhibitors for human immunodeficiency virus (HIV)-associated mycobacterial infection. The aim of this study was to compare the pharmacokinetics of rifabutin administered at 300 mg/day alone to that at 150 mg every other day combined with lopinavir-ritonavir in Japanese patients with HIV/mycobacterium co-infection. Methods Plasma concentrations of rifabutin and its biologically active metabolite, 25-O-desacetyl rifabutin were measured in 16 cases with HIV-mycobacterial coinfection. Nine were treated with 300 mg/day rifabutin and 7 with 150 mg rifabutin every other day combined with lopinavir-ritonavir antiretroviral therapy (ART). Samples were collected at a median of 15 days (range, 5–63) of rifabutin use. Results The mean Cmax and AUC0–24 of rifabutin in patients on rifabutin 150 mg every other day were 36% and 26% lower than on 300 mg/day rifabutin, while the mean Cmax and AUC0–24 of 25–O-desacetyl rifabutin were 186% and 152% higher, respectively. The plasma concentrations of rifabutin plus its metabolite were similar between the groups within the first 24 hours, but it remained low during subsequent 24 to 48 hours under rifabutin 150 mg alternate day dosing. Conclusion Rifabutin dose of 150 mg every other day combined with lopinavir-ritonavir seems to be associated with lower exposure to rifabutin and its metabolite compared with rifabutin 300 mg/day alone in Japanese patients. Further studies are needed to establish the optimal rifabutin dose during ART. The results highlight the importance of monitoring rifabutin plasma concentration during ART. Trial registration UMIN-CTR (https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr.cgi?function=search&action=input&language=E) UMIN000001102

Endoscopic appearance of AIDS-related gastrointestinal lymphoma with c-MYC rearrangements: Case report and literature review

Acquired immune deficiency syndrome (AIDS)-related lymphoma (ARL) remains the main cause of AIDS-related deaths in the highly active anti-retroviral therapy (HAART) era. Recently, rearrangement of MYC is associated with poor prognosis in patients with diffuse large B-cell lymphoma. Here, we report a rare case of gastrointestinal (GI)-ARL with MYC rearrangements and coinfected with Epstein-Barr virus (EBV) infection presenting with various endoscopic findings. A 38-year-old homosexual man who presented with anemia and was diagnosed with an human immunodeficiency virus infection for the first time. GI endoscopy revealed multiple dish-like lesions, ulcerations, bloody spots, nodular masses with active bleeding in the stomach, erythematous flat lesions in the duodenum, and multiple nodular masses in the colon and rectum. Magnified endoscopy with narrow band imaging showed a honeycomb-like pattern without irregular microvessels in the dish-like lesions of the stomach. Biopsy specimens from the stomach, duodenum, colon, and rectum revealed diffuse large B-cell lymphoma concomitant with EBV infection that was detected by high tissue EBV-polymerase chain reaction levels and Epstein-Barr virus small RNAs in situ hybridization. Fluorescence in situ hybridization analysis revealed a fusion between the immunoglobulin heavy chain (IgH) and c-MYC genes, but not between the IgH and BCL2 loci. After 1-mo of treatment with HAART and R-CHOP, endoscopic appearance improved remarkably, and the histological features of the biopsy specimens revealed no evidence of lymphoma. However, he died from multiple organ failure on the 139(th) day after diagnosis. The cause of his poor outcome may be related to MYC rearrangement. The GI tract involvement in ARL is rarely reported, and its endoscopic findings are various and may be different from those in non-AIDS GI lymphoma; thus, we also conducted a literature review of GI-ARL cases.