Kathleen Viveiros

Hepatitis B Virus Reactivation and Prophylaxis During Solid Tumor Chemotherapy: A Systematic Review and Meta-analysis

More than 350 million persons worldwide have hepatitis B virus (HBV) infection (1, 2) and are at risk for virus reactivation when given immunosuppressive therapy for various diseases (3, 4). In oncology, reported reactivation rates range from 30% to 80% depending on the chemotherapy regimen and HBV serologic status (3). Although reactivation can be asymptomatic, it can also delay chemotherapy and lead to severe hepatitis, liver failure, or death (5). Multiple studies (510) have shown that antiviral prophylaxis before initiation of immunosuppressive treatment can markedly decrease the risk for HBV reactivation. With increasing recognition of reactivation risk and the availability of effective prophylactic treatment, interest in appropriate HBV screening before chemotherapy initiation has grown (3, 11). Current national guidelines, however, disagree on which populations to screen and which tests to use (1214). Hepatitis B virus screening is recommended in patients receiving rituximab chemotherapy and hematopoietic stem cell transplantation (14, 15). However, despite the risk for reactivation (3, 16), oncologic guidelines do not recommend universal screening for patients receiving chemotherapy for solid tumors because of insufficient evidence (14). Recent meta-analyses (17, 18) have reported the risk for HBV reactivation with rituximab therapy for hematologic tumors, but none have examined HBV reactivation with chemotherapy for solid tumors. Therefore, the purpose of this study was to determine the absolute risk for HBV reactivation with and without antiviral prophylaxis and the effectiveness of prophylaxis in reducing the risk for reactivation in patients with chronic or resolved HBV infection across solid tumors. Methods All steps of the systematic review and meta-analysis were conducted using standard methods in accordance with the MOOSE (Meta-analysis of Observational Studies in Epidemiology) guidelines (19). We developed and followed an unregistered protocol. Data Sources and Searches We searched MEDLINE through 1 July 2015 and Web of Science, Cochrane Central Register of Controlled Trials, TOXNET, and Scopus through 31 March 2015. Three index search terms for hepatitis B virus, virus reactivation, and cancer chemotherapy were combined (Appendix Table 1). The search was limited to English-language articles, and conference abstracts were excluded. References from relevant review articles were examined to identify other potential studies. Two investigators (S.P. and A.S.) independently reviewed all articles for study inclusion. Discrepancies were resolved by consensus or by a third investigator (J.B.W.). Appendix Table 1. MEDLINE Search Strategy Study Selection We included published studies of patients with HBV receiving chemotherapy for any solid tumor. Hepatitis B virus was defined serologically (before chemotherapy initiation) as either chronic HBV infection (positive surface antigen [HBsAg], positive core antibody [HBcAb], and negative surface antibody [HBsAb] with various HBV DNA levels) or resolved infection (negative HBsAg, positive HBcAb, variable HBsAb, and negative HBV DNA). Please see the Glossary for more details. We included randomized, controlled trials (RCTs) and observational studies and required at least 5 patients per group with a minimum 1-month follow-up after chemotherapy initiation. Case series; review articles; and studies involving pediatric populations (aged <18 years), autoimmune conditions, HIV, hepatitis C, or hepatocellular carcinoma were excluded. We included studies that used chemotherapy for solid tumors with or without concomitant HBV prophylactic therapy. Antiviral therapy included lamivudine, telbivudine, adefovir, tenofovir, or entecavir. Patients could receive long-term antiviral treatment or prophylaxis before chemotherapy initiation. The comparator of interest, although not required, was chemotherapy without antiviral prophylaxis. Our primary outcome was HBV reactivation as defined by a greater than 10-fold increase in HBV DNA levels from baseline or an absolute increase greater than 105 copies/mL (in chronic HBV infection) or the reemergence of HBsAg when previously negative (in resolved HBV infection). Secondary outcomes included HBV-related hepatitis, interrupted or delayed chemotherapy, acute liver failure (with coagulopathy and hepatic encephalopathy), and death. Although each study defined the degree of alanine aminotransferase (ALT) elevation needed for HBV-related hepatitis, virologic breakthrough was required. Withdrawal hepatitis, which refers to increased ALT or HBV DNA levels after antiviral cessation, was not included. Data Extraction and Quality Assessment All data were extracted by 1 researcher (S.P.) and verified by another independent researcher (A.S.) and included study author, publication date, country, patient age and sex, baseline HBV serology, baseline laboratory ALT and total bilirubin levels, type of tumor, chemotherapy, HBV prophylaxis given, presence of lamivudine resistance, study follow-up period, and the risk for each study outcome. If a study involved both solid and hematologic tumors, only the solid tumor data were extracted. Discrepancies were resolved through discussion or by a third investigator (J.B.W.). Attempts were made to contact authors of included studies to clarify or collect additional data. Glossary Two independent investigators (S.P. and A.S.) assessed study quality using the NewcastleOttawa Scale (NOS) for observational studies (20). For RCTs, we applied the Cochrane Collaborations tool for assessing risk of bias (21) in sequence generation, allocation concealment, blinding, outcome data, and selective outcome reporting. Data Synthesis and Analysis All meta-analyses were performed using random-effects models, and results were pooled using the maximum likelihood estimation. The arcsine transformation was used to estimate the absolute risk for HBV reactivation and 95% CI with and without antiviral prophylaxis for each study. Because of the small number of events, the arcsine transformation was applied to the risk estimates to stabilize the variance (22). We also estimated the pooled odds ratio (OR) with 95% CI of HBV reactivation with versus without prophylaxis. Because of sparse event data and imbalanced study groups, the treatment group continuity correction (the reciprocal of the opposite treatment group size) was added when no events were observed in 1 group of a study (23). Study heterogeneity was assessed using the Cochrane I 2 statistic (24). Data were not pooled if the I 2 statistic was greater than 40%. Sensitivity analyses explored the effect of low-quality data, various outcome definitions, and lamivudine resistance. A statistical sensitivity analysis was performed by using a MantelHaenszel analysis without a continuity correction factor. When heterogeneity was low and the number of studies was greater than 10, the relation between study precision and treatment effect was assessed with funnel plots and the Rcker test (25). The Rcker test was used because it avoids false-positive results in the presence of substantial between-study heterogeneity or a substantial intervention effect (26). Statistical analyses were performed with OpenMetaAnalyst (27) and the meta and metafor packages in R, version 3.2.1 (R Foundation for Statistical Computing) (28). Role of the Funding Source This project was supported by the National Center for Advancing Translational Sciences and National Institutes of Health. Dr. Paul received grant support through the 2013 to 2014 Bristol-Myers Squibb Virology Research Training Program. The funding sources had no role in data abstraction, analysis, or interpretation; synthesizing of conclusions; or manuscript preparation. Results We identified 2192 citations though database searches, and 26 original reports met eligibility criteria (Appendix Figure 1): 23 involved chronic infection (2951), and 3 involved resolved infection (5254). Nine studies were not funded, 8 had government or hospital funding, 3 were supported by industry, and 6 mentioned no funding sources (Appendix Table 2). Appendix Figure 1. Summary of evidence search and selection. HBV = hepatitis B virus. Appendix Table 2. Characteristics of Studies Involving Solid Tumors and Chronic or Resolved HBV Infection Study and Patient Characteristics Appendix Table 2 summarizes baseline study characteristics for patients with chronic and resolved HBV infection. We noted 13 double-group comparative studies, 9 single-group studies, 1 RCT of patients with chronic HBV, and 3 single-group studies of patients with resolved HBV. The 26 studies included 22 from Asia and 4 from Europe and involved cancer of the gastrointestinal tract, breast, lung, head and neck, and other sites. Chemotherapy regimens and corticosteroid use varied across studies. There were 1751 patients (range, 6 to 258) with chronic HBV infection, and 328 (range, 14 to 291) with resolved HBV. When reported, the median patient age across studies was 47 years (range, 20 to 80 years), with 357 men (24%) and 937 women. Further, 774 patients with chronic HBV received HBV prophylaxis (mostly lamivudine). None of the patients with resolved HBV infection received HBV prophylaxis. Baseline serum HBV DNA levels were inconsistently reported. The HBsAb status was reported in only 1 study (53) of resolved infection in which all 24 patients had positive HBsAb. Study quality is reported in Appendix Table 3. All observational studies scored well on patient selection, with variable quality with respect to cohort comparability and outcome. In the 1 RCT, complete outcome data were reported but there was no allocation concealment or selective outcome reporting. None of the studies had blind assessment of outcomes. Appendix Table 3. Quality Assessment for Cohort Studies Using the NewcastleOttawa Scale Absolute Risk for HBV Reactivation in Patients With Chronic HBV Across All Solid Tumors The risk for HBV re

Role of Surface Antibody in Hepatitis B Reactivation in Patients with Resolved Infection and Hematologic Malignancy: A Meta‐Analysis

Patients with resolved hepatitis B virus (HBV) infection who are treated for hematological malignancies remain at risk for HBV reactivation. Because of conflicting studies about whether the antibody to hepatitis B surface antigen (anti‐HBs) protects against reactivation in patients with resolved infection (hepatitis B surface antigen negative) receiving chemotherapy for hematological malignancies, we conducted a meta‐analysis to determine if anti‐HBs reduces HBV reactivation risk. We sought English‐language studies through March 1, 2016, in Medline and other sources that examined reactivation in patients with resolved HBV infection receiving chemotherapy for hematologic malignancies. The absolute risks and odds ratio (OR) of reactivation with versus without anti‐HBs were estimated in random‐effects model meta‐analyses. In 20 studies involving 1,672 patients not receiving antiviral prophylaxis, the reactivation risk was 14% (95% confidence interval [CI] 9.4%‐19%) in 388 patients who had antibodies to hepatitis B core antigen only versus 5.0% (95% CI 3.0%‐7.0%) in 1,284 patients who also had anti‐HBs. Anti‐HBs reduced reactivation risk with a pooled OR of 0.21 (95% CI 0.14‐0.32) versus patients with antibody to hepatitis B core antigen only. Similar results were found when limiting the analysis to rituximab chemotherapy (OR = 0.19, 95% CI 0.11‐0.32) and lymphoma (OR = 0.18, 95% CI 0.11‐0.28). Conclusion: In patients with resolved HBV receiving chemotherapy for hematological malignancies without antiviral prophylaxis, anti‐HBs positivity is associated with a decreased risk of reactivation; HBV screening in this patient population should include the routine use of anti‐HBs, and those who are anti‐HBs‐negative should receive antiviral prophylaxis. Future studies should examine the effect of anti‐HBs serum titers, the potential role for booster vaccinations, and antiviral prophylaxis prior to chemotherapy in this patient population. (Hepatology 2017;66:379–388).

Neopterin as a Marker of Response to Antiviral Therapy in Hepatitis C Virus Patients

Predicting the efficacy of antiviral treatment of hepatitis C virus (HCV) is of importance for both patient well-being and health care expense. The expression of interferon-stimulated genes (IFN-SGs) in the liver was suggested as a marker of response to anti-viral therapy. IFN-SGs encode the guanosine triphosphate cyclohydrolase 1 (GTPCH), a rate-limiting enzyme of pteridines biosynthesis. Neopterin, a stable byproduct of GTPCH-catalyzed reaction, is used as a marker of interferon-induced GTPCH activation. We hypothesized that assessment of neopterin concentrations might predict the response to antiviral therapy. Neopterin concentrations were evaluated in 260 HCV patients treated by pegylated interferon combined with ribavirin. Mean and median pretreatment neopterin concentrations were lower in patients with sustained virological response than in nonresponders. The rate of response was twofold higher among patients with pretreatment neopterin levels <16 nmol/L than in patients with neopterin levels ≥16 nmol/L, even after controlling for HCV genotype status. Our study suggests that the pretreatment level of neopterin might be used in routine clinical practice as rapid and cost-effective marker to predict the response to antiviral therapy in HCV patients.

Clostrium cadaveris intra-peritoneal abscess.

To the Editor: Clostridium cadaveris is commonly known for being one of the most prominent bacteria found in decaying human corpses, but it is an extremely rare pathogen in living humans (1,2) . We report a case of an intra-peritoneal abscess caused by C. cadaveris . A 79year-old woman with a remote history of total abdominal hysterectomy with bilateral salpingo-oophorectomy (TAHBSO) underwent an abdominal surgery for incarcerated left inguinal hernia on 31 December 2008. She underwent a second surgery on post-op day 3 for small-bowel obstruction secondary to adhesions. An enterotomy was found and repaired with a GIA-stapler (United States Surgical Corporation, MI). She was discharged to rehabilitation on 8 January 2009. Aft er discharge, she experienced intermittent vague abdominal pain and watery diarrhea. A workup at the local facility, including stool Clostridium diffi cile toxin and abdominal X-ray, was negative. She was discharged home on 1 February 2009. She was referred to us on 11 February 2009 for evaluation of persistent diarrhea, abdominal pain and a weight loss of 10 lb. On presentation, she was afebrile and physical examination was only remarkable for a palpable mass in the left lower quadrant with localized tenderness. Laboratory studies were signifi cant for a leukocyte count of 11.8 k / μ l with 90 % neutrophils. A computed tomography (CT) scan of the abdomen and pelvis showed a 17 × 19 × 9 cm intra-peritoneal abscess in the left lower quadrant ( Figure 1 ). Small-bowel follow-through did not show any extravasations of contrast material. A 12-French pigtail catheter was placed percutaneously under CT guidance for abscess drainage. Th e Gram stain of the aspirant showed 4 + poly and 3 + beaded Gram-positive rods ( Figure 2 ). She was empirically treated with piperacillin / tazobactam for intraperitoneal abscess. Th ree sets of anaerobic culture grew C. cadaveris aft er 48 h. Th e Remel RapID ANA II System (Remel, Lenexa, Kansas), which identifi es anaerobes on the basis of their unique combination of enzymes, was used to identify the bacteria. Piperacillin / tazobactam was then switched to metronidazole. Serial blood culture remained negative. Her abdominal pain and diarrhea resolved promptly with abscess drainage and antibiotic therapy. On 20 February 2009, she was discharged to a rehabilitation facility with oral metronidazole and the pigtail catheter. A repeat CT the following week showed a resolution of the abscess and therefore the pigtail catheter was removed. Metronidazole was discontinued a week aft er. She recovered uneventfully and was discharged home on 28 February 2009. Diseases causing intra-peritoneal abscesses include appendicitis, diverticulitis, biliary tract lesions, pancreatitis, perforated peptic ulcers, infl ammatory bowel disease, trauma, and abdominal surgery, such as in our case (3) . Anaerobes are isolated from intra-peritoneal abscesses in 60 – 70 % of the cases, with Bacteroides fragilis as the most common isolate. Other common anaerobes Figure 1 . Computer tomography scan showing a large left intra-abdominal abscess.

S1265 Risk of Non-Melanoma Skin Cancer in Autoimmune Hepatitis

Background Most patients with autoimmune hepatitis (AIH) require long-term immunosuppressive therapy (IS). While it is well established that solid organ transplant recipients have a high risk of developing non-melanoma skin cancer (NMSC) as a result of immunosuppression, little is known about the risk of NMSC associated with IS in patients with AIH.

730 Hepatitis B Virus Reactivation During Chemotherapy for Solid Malignancies: A Systematic Review and Meta-Analysis

likely to have poor adherence or no screening. On multivariate regression also inclusive of age, sex, family history of CHB and HCC, and cirrhosis diagnosis, independent predictors for optimal or sub-optimal adherence were history of antiviral therapy for CHB (OR=1.8, p<0.001), more frequent clinical visits per year (OR=2.5, p<0.001) and university-based care (OR=5.0, p<0.001). Overall, adherence persistency rates dropped to 83% at 2 years and 70% at 5 years and were similar between community and university patients, but there was a trend for higher persistency in patients with cirrhosis compared to those without cirrhosis with 5-year persistency rates of 83% vs. 68%, respectively (Fig. 1 and 2). Conclusion: Adherence to HCC surveillance in CHB patients is poor with only one-fifth of patients without cirrhosis and one-third of those with cirrhosis having optimal adherence initially; and of those who initially had at least 1 imaging test per year, only 80% continued to have HCC surveillance persistency after 2 years and 70% at 5 years. History of antiviral therapy, more frequent clinic visits and university-based care were significant and strong predictors for optimal HCC surveillance adherence.