Yasuyuki Yamamoto

Beta interferon therapy for chronic hepatitis C in patients with haemophilia and other haemorrhagic disorders.

Summary. Beta interferon therapy was given to seven chronic hepatitis C patients with haemophilia or other haemorrhagic disorders who had received clotting factor replacement therapy. Serum alanine aminotransferase (ALT) levels ranged from 82 to 275 UL‐1 and hepatitis C virus (HCV)‐RNA ranged from 106 to 109 copies mL‐1. HCV‐genotypes were I+II in one patient, II in one, II+III in four and IV in one. Patients received 6 mega units (MU) daily of natural type beta interferon by intravenous infusion for 6 weeks. In three of seven patients, the protocol was modified to intermittent administration because neutrocytopenia (under 500 × 106 L‐1) developed in two patients and thrombocytopenia (under 50 × 109 L‐1) was observed in one during treatment. No modification was necessary with regard to daily and total dose. All patients received administration without any haemorrhagic complications. Six of seven patients showed improvement in serum ALT levels, and one of the patients showed normalization of ALT levels for 6 months after treatment. HCV‐RNA disappeared in four patients by the end of treatment, although no one remained negative 6 months after treatment. The results of our study were similar to those reported in previous papers which described the use of alpha interferon in haemophiliacs. The reason none of the patients showed sustained loss of HCV‐RNA after therapy might be associated with high HCV‐RNA levels, characteristics of the HCV‐genotype and prolonged duration of the disease.

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.

Mutations to the probe of Cobas TaqMan HIV-1 ver. 1.0 assay causing undetectable viral load in a patient with acute HIV-1 infection

We encountered a human immunodeficiency virus (HIV)-1 in which the viral load was undetectable with the Cobas TaqMan HIV-1 ver. 1.0 (CTM v.1.0) in a patient with acute HIV-1 infection. The CTM v.1.0 assay showed more than 1,000-fold underestimation compared with the subsequent Cobas Amplicor Monitor v.1.5 assay. Because five mismatches to the CTM v.1.0 assay probe in the HIV-1 virus in the patient were disclosed by the manufacturer, partial gag regions of the HIV genome were directly sequenced from the patient’s plasma viral RNA. The detected single nucleotide point mutations were located near the 5′-end of the Cobas Amplicor Monitor probe. Clinicians should be very careful in making interpretations when indeterminate Western blot analysis results and a low or even undetectable HIV-1 viral load are encountered with the CTM HIV-1 ver. 1.0 assay in patients with suspected acute HIV infection. Repeating Western blot analysis is essential before considering a low HIV-1 viral load to be a false-positive result.

Serological and virological markers of human parvovirus B19 infection in patients with haemophilia

Clotting factor concentrates prepared from human plasma are a potential route of parvovirus B19 (B19) infection in patients with coagulation disorders. However, it is not clear whether B19 transmits and persistently infects patients with haemophilia, especially those with HIV infection. We examined serological and virological markers of B19 in samples from 40 patients with haemophilia who had been receiving several brands of clotting factor concentrates. All of them were anti‐B19 IgG seropositive and anti‐B19 IgM seronegative. The levels of anti‐B19 IgG were significantly higher in haemophiliacs than in healthy donors, whereas there was no difference between the level of anti‐B19 IgG in haemophiliacs with HIV infection and those without HIV infection. Moreover, there was no difference between the level of anti‐B19 IgG in haemophiliacs receiving recombinant factor VIII and that in those receiving plasma‐derived clotting factors. Although by using polymerase chain reaction (PCR) B19 DNA was detected at very low levels (< 40 DNA copies mL−1, in 3 out of 40 haemophiliacs, persistent B19 infection was negligible.

Factor VIII haplotypes of Japanese population show similarity to those of Caucasian populations

Haemophilia A is the most common inherited bleeding disorder which is X-linked recessive. This disease is caused by a quantitative or qualitative abnormality of plasma factor VIII (FVIII), which is affected by a genetic mutation located in the coagulation FVIII gene. Diagnosis and replacement therapy strategies in haemophilia A patients are well established; however, some issues remain to be addressed. The most important issue concerning replacement therapy in haemophilia A patients is the development of inhibitors (alloantibody) against FVIII. This development leads to marked attenuation in the effectiveness of replacement therapy, leading to a substantial deterioration in the quality of life of patients. In general, the incidence of inhibitor development in treatment-naive patients with haemophilia A is estimated to be 20–30% [1]. However, it has been shown that its incidence in the Black population is markedly higher, about twice as high as in other racial groups [2]. The question of why this inhibitor develops with such high incidence in the Black population remains undetermined. Recently, Viel et al. reported that six wild-type FVIII proteins, the H1–H6 haplotypes, had different prevalence rates among racial groups [3]. They speculated that a mismatch of the FVIII haplotype between the FVIII concentrate and its recipients, particularly in immunodominant epitopes, caused an increase in the frequency of inhibitor development. In particular, they focused on four different amino acid polymorphisms (R484H, R776G, D1241E and M2238V), based on a non-synonymous single nucleotide polymorphism. By using a combination of those amino acids, they classified the FVIII protein into six haplotypes, namely, H1: RRDM, H2: RREM, H3: RREV, H4: HREM, H5: RRDV and H6: RGEM. It is presumed that amino acid positions 484 and 2238, located in the A2 and C2 domains, respectively, are components of the immunodominant epitope of FVIII. In Caucasian participants, positions 484 and 2238 have been observed as R and M , respectively, and have only shown the haplotypes of H1 and H2. However, Viel et al. confirmed the presence of H in place of R at position 484, or V in place of M at position 2238, in approximately 25% of Black participants. Thus, the haplotype frequencies in Black participants (H1: 0.354; H2: 0.374; H3: 0.222; H4: 0.040 and H5: 0.010) are different from those in Caucasian participants. Furthermore, they also analysed haplotypes in ethnic Chinese participants, and observed the H6 haplotype, but not the H3, H4 or H5 haplotype. We set out to analyse the haplotypes of FVIII proteins among 106 unrelated Japanese subjects at our institution (63 with haemophilia A and 43 with haemophilia B as a control group), as shown in Table 1. The study was approved by the Ethics Committee of Tokyo Medical University and written informed consent was obtained from each patient. The studies were carried out in accordance with the principles of the Declaration of Helsinki. Among the Japanese participants, only the H1 and H2 haplotypes (H1: 0.896 and H2: 0.104) were found at frequencies not significantly different from the Caucasian frequencies (H1: 0.926 and H2: 0.074). Despite the Chinese being geographical neighbours of the Japanese, the H6 haplotype which was observed in approximately 8% of Chinese was not detected in any Japanese. Currently in Japan, approximately 80% of haemophilia A patients receive replacement therapy using the recombinant FVIII concentrates Kogenate (Bayer) or Advate (Baxter). Data regarding the incidence of inhibitor development in Japanese patients with severe haemophilia A were previously presented as poster presentations on post-authorisation safety studies for Kogenate or Advate at the 22nd Congress of the International Society on Thrombosis and Hemostasis (ISTH) (2009) and the Hemophilia World Congress (World Federation of Hemophilia) (2010) by Fukutake et al., who reported that the incidence was similar to that in Caucasians. Although the role of the haplotypes of FVIII proteins as a risk factor for inhibitor development is not yet determined, the similarities of haplotype incidence may partially explain the similarities in inhibitor incidence between Japanese patients and Caucasian patients. Further studies are needed to clarify the role and characteristics of FVIII haplotypes in Japanese population.

The Prevalence of High Antiretroviral Coverage and Viral Suppression in Japan: an Excellent Profile for a Downstream Human Immunodeficiency Virus Care Spectrum

We investigated the effectiveness of the Japanese health care system for human immunodeficiency virus/acquired immunodeficiency virus (HIV/AIDS), in terms of prevention, diagnosis, access to antiretroviral treatment, and treatment outcomes. Clinical information on HIV/AIDS cases was collected via questionnaires sent to 377 registered HIV/AIDS clinics in Japan. Data on 9,040 and 14,569 cases were collected in 2009 and 2014, respectively. The percentages of cases undergoing treatment were 69.6% and 87.8% in 2009 and 2014, respectively, demonstrating an improvement in treatment coverage over the 5 years between the 2 surveys. The proportion of cases with undetectable HIV RNA in the 2014 survey was 87.7%. Thus, our survey revealed that the 2 of the United Nations AIDS Fast-Track targets, 90% treated and 90% virally suppressed, are close to being achieved. However, Japan appears to have fallen short of the upstream target of 90% diagnosed. Japan needs to radically reform its strategies for encouraging people to undergo HIV testing and to develop a system for estimating the number of people living with HIV.

Acute alveolar haemorrhage in a patient with haemophilia B

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1604Chronic Kidney Disease Is Associated with Bone Mineral Density Loss among Elderly HIV-infected Individuals in Japan

Loss among Elderly HIV-infected Individuals in Japan Takashi Muramatsu, MD; Yasuyuki Yamamoto, MD, PhD; Naoki Yanagisawa, MD; Ikuo Seita, MD, PhD; Mihoko Yotsumoto, MD, PhD; Manabu Otaki, MD, PhD; Takeshi Hagiwara, MD, PhD; Takashi Suzuki, MD, PhD; Kagehiro Amano, MD, PhD; Katsuyuki Fukutake, MD, PhD; Department of Laboratory Medicine, Tokyo Medical University Hospital, Tokyo, Japan; Department of Infectious Diseases, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan