Immune Reconstitution Inflammatory Syndrome-like Condition Associated with Pneumocystis jirovecii Pneumonia During Folinic Acid Treatment in a Rheumatoid Arthritis Patient.

A 94-year-old woman with rheumatoid arthritis who had been treated with low-dose methotrexate was referred to our hospital because of a 3-day history of a fever and pancytopenia. With a diagnosis of febrile neutropenia of unknown origin, empirical antibiotic treatment and folinic acid therapy were initiated. Despite a recovery from pancytopenia, the high fever remained, and dyspnea developed. She was clinically diagnosed with Pneumocystis jirovecii pneumonia (PCP) and successfully treated with trimethoprim/sulfamethoxazole and adjunctive corticosteroid therapy. Folinic acid treatment effectively brought about rapid immune recovery but might have led to a clinical manifestation of PCP resembling immune reconstruction inflammatory syndrome.

Features of resistance-associated substitutions after failure of multiple direct-acting antiviral regimens for hepatitis C.

BACKGROUND & AIMS: We aimed to clarify the features of resistance-associated substitutions (RASs) after failure of multiple interferon (IFN)-free regimens in HCV genotype 1b infections. METHODS: A total of 1,193 patients with HCV for whom direct-acting antiviral (DAA) treatment had failed were enrolled from 67 institutions in Japan. The RASs in non-structural protein (NS)3, NS5A, and NS5B were determined by population sequencing. RESULTS: Failure of 1, 2, and 3 regimens was observed in 1,101; 80; and 12 patients, respectively. Among patients with failure of 1 regimen, Y56H and D168V in NS3 were more frequently detected after failure of paritaprevir, whereas D168E was more frequently detected after failure of regimens including asunaprevir. R30H and L31-RAS in NS5A were frequently detected after failure of regimens including daclatasvir. The prevalence of Y93-RAS was high irrespective of the regimen. S282T RAS in NS5B was detected in 3.9% of ledipasvir/sofosbuvir failures. The prevalence of D168-RAS increased significantly according to the number of failed regimens (p <0.01), which was similar to that seen with L31-RAS and Y93-RAS. The prevalence of patients with RASs in either NS3 or NS5A, or in both, increased significantly with increasing numbers of failed regimens. The P32del, which is unique to patients for whom DAA had failed, was linked to the absence of Y93H, the presence of L31F, and previous exposure to IFN plus protease inhibitor regimens. CONCLUSIONS: Failure of multiple DAA regimens can lead to the generation of multiple RASs in the NS3 and NS5A regions of the HCV 1b genome. These mutations contribute to viral resistance to multiple treatment regimens and, therefore, should be considered during decision making for treatment of chronic HCV. LAY SUMMARY: Resistance-associated substitutions (RAS) in the genome of the hepatitis C virus are 1 of the major causes for failed treatment. We investigated RASs after failure of various treatments for chronic hepatitis C, and found that more complicated RASs accumulated in the viral genome with successive failed treatments. The highly resistant P32del RAS at NS5A region was uniquely found in patients for whom DAA treatments had failed, and was linked to the presence and absence of specific RASs.

Multicenter prospective study to optimize the efficacy of triple therapy with telaprevir in patients with genotype 1b hepatitis C virus infection according to an algorithm based on the drug Adherence, IL-28B Gene Allele and Viral Response Trial (AG & RGT).

AIM: To optimize the therapeutic efficacy of NS3/4A protease inhibitors, a multicenter prospective study was performed according to an algorithm based on the Adherence, IL-28B Gene Allele and Viral Response Trial (AG & RGT). METHODS: A total of 340 patients with genotype 1b hepatitis C virus (HCV) showing serum RNA levels of >5 log were enrolled. The duration of ribavirin/pegylated interferon (PEG IFN)-α-2b therapy was prolonged to 48 weeks in patients with unfavorable IL28B alleles showing adherence rates of less than 80% for either drug during the first 12 weeks even if RVR had been achieved, and in those in whom cEVR, but not RVR, was achieved; furthermore, to 72 weeks in those showing partial early viral response. RESULTS: The therapeutic outcomes were assessed in 282 patients, and the therapy was set to complete at 24 weeks in 181 patients (64%) and to prolong to 48 weeks or 72 weeks in 71 patients (25%). The former group showed a SVR rate of 84%, while the latter group showed an SVR rate of 69% with a relapse rate of 7%. The SVR rate was 33% in the 30 patients (11%) in whom the therapy had to be discontinued in less than 12 weeks. Thus, the results of intention-to-treat analysis revealed an overall SVR rate of 75%. Multivariate analysis identified prolongation of the duration of therapy as a significant factor associated with SVR. CONCLUSION: Triple therapy yielded a high SVR rate in the AG & RGT trial via attenuation of viral relapse by prolonged ribavirin/PEG IFN-α-2b administration. © 2015 The Japan Society of Hepatology.

Safety and tolerance of sorafenib in Japanese patients with advanced hepatocellular carcinoma.

PURPOSE: Sorafenib provides a survival benefit for patients with advanced hepatocellular carcinoma (HCC). However, there has been little experience with it in Japan. This study evaluated the safety and tolerance of sorafenib in Japanese patients with HCC. METHODS: Clinical data for patients given sorafenib for advanced HCC were captured from eight institutions. All patients were classified as Child-Pugh A and the treatment was started at 400 mg twice daily. We recorded adverse events, treatment duration, and survival retrospectively. Adverse events were graded using Common Terminology Criteria, version 3.0; tumor response was assessed according to Response Evaluation Criteria in Solid Tumor, version 1.1. RESULTS: Of the 54 patients treated, their median age was 69 years (range 48-82), 91% were males, 52% had HCV infection, and 22% had HBV infection. The most common drug-related adverse events were hand-foot skin reactions (HFSR) (72%), aspartate transaminase elevation (55%), alanine aminotransferase elevation (52%), rash (50%), fatigue (41%), and diarrhea (32%). Liver failure occurred in 19%. The median time to treatment failure was 2 months. Dose reduction was required in 83% of the patients, and this occurred within 2 weeks in 44%. The median overall survival was 6.9 months. CONCLUSIONS: These data suggest that sorafenib is generally tolerated in Japanese patients with HCC. Nevertheless, the majority needed a dose reduction. Adverse events including HFSR, rash, and liver failure occurred more frequently in our patients than those reported elsewhere. Careful attention must be paid to these adverse events during sorafenib administration.

Small hepatocellular carcinoma: assessment with T1-weighted spin-echo magnetic resonance imaging with and without fat suppression.

OBJECTIVE: We examined the detectability of small hepatocellular carcinomas (HCCs) and the factors that affect hyperintensity of small HCC on T1-weighted images (T1W) by using T1-weighted fat-suppressed images (T1FS). METHODS: Thirty-nine HCCs (29 patients) measuring 30 mm or less were enrolled. The mean size of HCCs was 21.0+/-4.9 mm. Spin-echo T1W, T2-weighted images (T2W), and T1FS were obtained using a 1.5 T system. We evaluated the detectability in each sequence by receiver-operating-characteristic (ROC) analysis and the tumor-to-hepatic parenchyma contrast-to-noise ratio (CNR), the variance in the detectability among all interpreters with each sequence, and the presence or absence of improvement in the detectability by interpreting T1FS in addition to conventional T1W plus T2W. The contents of fat, copper, and iron in histologically diagnosed HCCs showing hyperintensity on both T1W and T1FS were measured. For determination of heavy metals, we used a particle induced X-ray emission analytical instrument. RESULTS: ROC analyses revealed that T1FS were superior to T1W and T2W in detecting small HCCs (0.900+/-0.017 for T1FS, 0.859+/-0.019 for T1W, and 0.745+/-0.030 for T2W). The detectability by interpreting T1FS in addition to conventional T1W plus T2W was improved (0.931+/-0.013 for the conventional images and 0.973+/-0.008 for the conventional images plus T1FS, P<0.001). The detected lesions on T1FS demonstrated favorable CNR values. The copper content in the cancer and the ratio of the copper content in the cancer to that in the non-cancerous tissue were 275.4+/-219.0 microg/g dry weight, 6.9+/-5.5 in HCCs showing hyperintensity on both T1W and T1FS. Both were significantly higher (P<0.05). CONCLUSION: T1FS showed excellent sensitivity and specificity in detecting small HCCS irrespective of the experience of interpreters. The use of T1FS suggested the involvement of copper might be one of the factors in hyperintensity of HCCs on T1W.