Ochsner Medical Center

This AASLD 2018 Hepatitis B Guidance is intended to complement the AASLD 2016 Practice Guidelines for Treatment of Chronic Hepatitis B The 2018 updated guidance on chronic hepatitis B (CHB) includes (1) updates on treatment since the 2016 HBV guidelines (notably the use of tenofovir alafenamide) and guidance on (2) screening, counseling, and prevention; (3) specialized virological and serological tests; (4) monitoring of untreated patients; and (5) treatment of hepatitis B in special populations, including persons with viral coinfections, acute hepatitis B, recipients of immunosuppressive therapy, and transplant recipients.

Potential conflict of interest: Dr. Jonas consults and received grants from Gilead. She received grants from Bristol‐Myers Squibb and Roche. Dr. Chang advises Genentech, Alnylam, and Arbutus. Dr. Terrault consults for Bristol‐Myers Squibb and received grants from Gilead. Dr. Bzowej received grants from Gilead, Synageva, and Ocera. The funding for the development of this Practice Guideline was provided by the American Association for the Study of Liver Diseases. This Practice Guideline was approved by the AASLD on August 1, 2015. This Practice Guideline published with accompanying Reviews by Lok et al., Jonas et al., and Brown et al. See Editorial on Page 31 Objectives and Guiding Principles Guiding Principles This document presents official recommendations of the American Association for the Study of Liver Diseases (AASLD) on the treatment of chronic hepatitis B (CHB) virus (HBV) infection in adults and children. Unlike previous AASLD practice guidelines, this guideline was developed in compliance with the Institute of Medicine standards for trustworthy practice guidelines and uses the Grading of Recommendation Assessment, Development and Evaluation (GRADE) approach.1 Multiple systematic reviews of the literature were conducted to support the recommendations in this practice guideline. An enhanced understanding of this guideline will be obtained by reading the applicable portions of the systematic reviews. This guideline focuses on using antiviral therapy in chronic HBV infection and does not address other related and important issues, such as screening, prevention, and surveillance. For broader issues related to diagnosis, surveillance, and prevention as well as treatment in special populations (e.g., liver transplant recipients) that are not addressed by this guideline, the previous AASLD guideline2 and recent World Health Organization (WHO) guideline3 are excellent additional resources. Objectives Guideline developers from the AASLD formulated a list of discrete questions that physicians are faced with in daily practice. These questions were: Should adults with immune active CHB be treated with antiviral therapy to decrease liver‐related complications? Should adults with immune‐tolerant infection be treated with antiviral therapy to decrease liver‐related complications? Should antiviral therapy be discontinued in hepatitis B e antigen (HBeAg)‐positive persons who have developed HBeAg seroconversion on therapy? Should antiviral therapy be discontinued in persons with HBeAg‐negative infection with sustained HBV DNA suppression on therapy? In HBV‐monoinfected persons, does entecavir therapy, when compared to tenofovir therapy, have a different impact on renal and bone health? Is there a benefit to adding a second antiviral agent in persons with persistent low levels of viremia while being treated with either tenofovir or entecavir? Should persons with compensated cirrhosis and low levels of viremia be treated with antiviral agents? Should pregnant women who are hepatitis B surface antigen (HBsAg) positive with high viral load receive antiviral treatment in the third trimester to prevent perinatal transmission of HBV? Should children with HBeAg‐positive CHB be treated with antiviral therapy to decrease liver‐related complications? Target Audience This guideline is intended primarily for health care professionals caring for patients with CHB. Additionally, this guideline may assist policy makers in optimizing the care of individuals living with CHB. Background Burden of Disease Globally, an estimated 240 million persons have CHB with a varying prevalence geographically, highest in Africa and Asia.4 In the United States, the National Health and Nutrition Examination Survey (1999 to 2008) identified approximately 704,000 adults with CHB,5 but with adjustments for hepatitis B infection among foreign‐born persons, the upper estimate of CHB in the United States may be as high as 2.2 million.6 Globally, deaths from cirrhosis and hepatocellular carcinoma (HCC) were estimated at 310,000 and 340,000 per year, respectively.7 To reduce the morbidity and mortality of CHB in the United States and worldwide, there is a need for continued efforts to identify infected individuals through targeted screening, prevent new infections through vaccination, and monitor and treat those at risk for complications of their CHB, including surveillance for HCC.8 Natural History in Adults and Children CHB has been traditionally characterized into four phases (Table 1), reflecting the dynamic relationship between viral replication and evolution and the host immune response. These phases are of variable duration and not every person infected with CHB will evolve through all phases. Given the dynamic nature of CHB infection, serial monitoring of HBV DNA and alanine aminotransferase (ALT) levels is important to characterize the phase of infection. A single ALT and HBV DNA level are insufficient to assign phase of infection and/or need for treatment. Of note, some persons will be in the “gray zones,” meaning that their HBV DNA and ALT levels do not fall into the same phase. Longitudinal follow‐up of ALT and HBV DNA levels and/or assessment of liver histology can serve to clarify the phase of infection. Immune‐tolerant phase: In this highly replicative/low inflammatory phase, HBV DNA levels are elevated, ALT levels are normal (<19 U/L for females and <30 U/L for males), and biopsies are without signs of significant inflammation or fibrosis. The duration of this phase is highly variable, but longest in those who are infected perinatally. With increasing age, there is an increased likelihood of transitioning from immune‐tolerant to the HBeAg‐positive immune‐active phase. HBeAg‐positive immune‐active phase: Elevated ALT and HBV DNA levels in conjunction with liver injury characterize this phase. Median age of onset is 30 years among those infected at a young age. The hallmark of transition from the HBeAg‐positive immune‐active to ‐inactive phases is HBeAg seroconversion. The rate of spontaneous seroconversion from HBeAg to antibody to HBeAg (anti‐HBe) is less than 2% per year in children younger than 3 years of age and increases during puberty and among adults to 8% and 12% per year, respectively. Inactive CHB phase: In this phase, HBV DNA levels are low or undetectable, ALT levels are normal, and anti‐HBe is present. Liver histology shows minimal necroinflammation, but variable fibrosis reflecting previous liver injury during the HBeAg‐positive immune‐active phase. Among persons who undergo spontaneous HBeAg seroconversion, 67%‐80% will continue to remain in the inactive CHB phase. Approximately 4%‐20% of inactive carriers have one or more reversions back to HBeAg positive. HBeAg‐negative immune reactivation phase: Among those who seroconvert from HBeAg to anti‐HBe positive, 10%‐30% continue to have elevated ALT and high HBV DNA levels, and roughly 10%‐20% of inactive carriers may have reactivation of HBV replication and exacerbations of hepatitis after years of quiescence. Most of these persons harbor HBV variants in the precore or core promoter region, and liver histology shows necroinflammation and fibrosis. Persons with HBeAg‐negative CHB tend to have lower serum HBV DNA levels than those with HBeAg‐positive CHB and are more likely to experience a fluctuating course. Table 1 - Phases of CHB Infection ALT HBV DNA HBeAg Liver Histology Immune‐tolerant phase Normal Elevated, typically >1 million IU/mL Positive Minimal inflammation and fibrosis HBeAg‐positive immune‐active phase Elevated Elevated ≥20,000 IU/mL Positive Moderate‐to‐severe inflammation or fibrosis Inactive CHB phase Normal Low or undetectable <2,000 IU/mL Negative Minimal necroinflammation but variable fibrosis HBeAg‐negative immune reactivation phase Elevated Elevated ≥2,000 IU/mL Negative Moderate‐to‐severe inflammation or fibrosis Resolved CHB infection is defined by clearance of HBsAg with acquisition of antibody to HBsAg. Approximately 0.5% of persons with inactive CHB will clear HBsAg yearly; most will develop antibody to HBsAg (anti‐HBs). Low levels of HBV DNA are transiently detected in the serum in the minority of persons achieving seroclearance.10 Clearance of HBsAg, whether spontaneous or after antiviral therapy, reduces risk of hepatic decompensation and improves survival. Risk of liver‐related complications is variable. Among untreated adults with CHB, cumulative 5‐year incidence of cirrhosis is 8%‐20%, and among those with cirrhosis, 5‐year cumulative risk of hepatic decompensation is 20%, and risk of HCC is 2%‐5%.12 Viral, host, and environmental factors influence risks of cirrhosis and HCC13 (Table 2). HBV DNA levels, ALT levels, and HBeAg status are among the most important determinants of risk of progression to cirrhosis,15 whereas HBV DNA levels (>2,000 IU/mL), HBeAg status, and cirrhosis are key predictors of HCC risk.15 A biological gradient of risk has been shown in adults with HBV DNA levels above 2,000 IU/mL; a higher HBV DNA level is associated with progressively higher rates of cirrhosis and HCC.15 Table 2 - Host, Viral/Disease, and Environmental Factors Associated With Cirrhosis and HCC Cirrhosis HCC Host >40 years of age Male sex Immune compromised >40 years of age Male sex Immune compromised Positive family history Born in Sub‐Saharan Africa Viral/disease High serum HBV DNA (>2,000 IU/mL) Elevated ALT levels Prolonged time to HBeAg seroconversion Development of HBeAg‐negative CHB Genotype C Presence of cirrhosis High serum HBV DNA (>2,000 IU/mL) Elevated ALT Prolonged time to HBeAg seroconversion Development of HBeAg‐negative CHB Genotype C Environmental Concurrent viral infections (HCV, HIV, and HDV) Heavy alcohol use Metabolic syndrome (obesity, diabetes) Concurrent viral infections (HCV, HIV, and HDV) Heavy alcohol use Metabolic syndrome (obesity, diabetes) Aflatoxin Smoking Diagnosis, Staging and Monitoring of Persons With CHB The initial evaluation of persons with CHB should include a thorough history and physical examination, with special emphasis on risk factors for coinfection, alcohol use, and family history of HBV infection and liver cancer. Laboratory tests should include assessment of liver disease activity and function, markers of HBV replication, and tests for coinfection with hepatitis C virus (HCV), hepatitis delta virus (HDV), or human immunodeficiency virus (HIV) in those at risk (Table 3). Owing to the fluctuating nature of CHB, the accuracy of one high HBV DNA level at a single time point in predicting prognosis is poor and regular monitoring of disease status is imperative to determine need for antiviral therapy. The upper limits of normal (ULNs) for ALT values based on healthy subjects are lower than laboratory values derived from all populations, including those with subclinical liver disease.19 Table 3 - Initial Evaluation of HBsAg‐Positive Patient History/Physical Examination Routine Laboratory Tests Serology/Virology Imaging/Staging Studies All patients Symptoms/signs of cirrhosis Alcohol and metabolic risk factors Family history of HCC Vaccination status CBC including platelet count, AST, ALT, total bilirubin, alkaline phosphatase, albumin, INR HBeAg/anti‐HBe HBV DNA quantitation Anti‐HAV to determine need for vaccination Abdominal ultrasound Vibration‐controlled transient elastography or serum fibrosis panel (APRI, FIB‐4, or FIbroTest) Select patients Tests to rule out other causes of chronic liver diseases if elevated liver test(s) AFP, GGT HBV genotype Anti‐HDV Anti‐HCV Anti‐HIV in those who have not undergone one‐time screening (ages 13‐64) Liver biopsy Abbreviation:s INR, international normalized ratio; GGT, gamma‐glutamyl transpeptidase. Determination of the stage of liver disease is important in guiding antiviral therapy decisions and need for surveillance. Liver biopsy provides an assessment of the severity of necroinflammation and fibrosis, rules out other causes of liver disease, and may be especially useful for persons who lack clear‐cut indications for treatment. Whereas liver biopsy is regarded as the best method to assess the severity of inflammatory activity and fibrosis, noninvasive methods to assess fibrosis severity are also useful. Acute‐on‐chronic exacerbations of hepatitis B may lead to overestimation of fibrosis stage by noninvasive tests, and different cutoffs for significant and advanced fibrosis depending on ALT levels have been proposed.20 Serum markers of fibrosis, such as aspartate aminotransferase (AST)‐to‐platelet ratio index (APRI), FIB‐4, FibroTest, and vibration‐controlled transient elastography, have only moderate accuracy in identifying persons with significant fibrosis (fibrosis stage 2 or greater on the Metavir scale), but good diagnostic accuracy in excluding advanced fibrosis21 and may be useful aids in decision making. Antiviral Therapy The goals of antiviral treatment are to decrease the morbidity and mortality related to CHB. The achievement of a sustained suppression of HBV replication has been associated with normalization of serum ALT, loss of HBeAg with or without detection of (anti‐HBe), and improvement in liver histology. Historically, the term “cure” was avoided in treatment of CHB, given that persistence of covalently closed circular DNA (cccDNA), the transcriptional template of HBV,23 in the nucleus of hepatocytes, even in persons with serological markers of resolved infection, poses a lifelong risk for reactivation of infection. However, an immunological cure may be defined by HBsAg loss and sustained HBV DNA suppression and a virological cure defined by eradication of virus, including the cccDNA form. The latter is not currently an attainable goal. There are six therapeutic agents approved for the treatment of adults with CHB in the United States and five therapeutic agents approved for the treatment of children with CHB (Table 4). Side effects are more frequent with interferon (IFN) therapy than with nucleos(t)ide analogs (NAs) therapy. Overall, all NAs have an excellent safety profile across a wide spectrum of persons with CHB, including those with decompensated cirrhosis and transplant recipients.25 The side effects listed in Table 4 for NAs are infrequent. For persons with HDV coinfection, the only effective treatment is pegylated interferon (Peg‐IFN). For persons with HIV coinfection, treatment of HBV needs to be coordinated with HIV therapy given that several HBV drugs have anti‐HIV activity (tenofovir, entecavir, lamivudine, and telbivudine).26 Table 4 - Approved Antiviral Therapies in Adults and Children Drug Dose in Adultsa Use in Childrena Pregnancy Category Potential Side Effectsb Monitoring on Treatmentb Peg‐IFN‐2a(adult) IFN‐α‐2b (children) 180 μg weekly ≥1 year Dose: 6 million IU/m2 TIWc C Flu‐like symptoms, fatigue, mood disturbances, cytopenias, autoimmune disorders in adults Anorexia and weight loss in children CBC (monthly to every 3 months) TSH (every 3 months) Clinical monitoring for autoimmune, ischemic, neuropsychiatric, and infectious complications Lamivudine 100 mg daily ≥2 years Dose: 3 mg/kg daily to max 100 mg C Pancreatitis Lactic acidosis Amylase if symptoms Lactic acid levels if clinical concern Telbivudine 600 mg daily — B Creatine kinase elevations and myopathy Peripheral neuropathy Lactic acidosis Creatine kinase if symptoms Cinical evaluation if symptoms Lactic acid levels if clinical concern Entecavir 0.5 or 1.0 mg dailyd ≥2 years Dose: weight‐based to 10‐30 kg; above 30 kg 0.5 mg daily[Link] C Lactic acidosis Lactic acid levels if clinical concern Adefovir 10 mg daily ≥12 years 10 mg daily C Acute renal failure Fanconi syndrome Nephrogenic diabetes insipidus Lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and protein at least annually Consider bone density study at baseline and during treatment in persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern Tenofovir 300 mg daily ≥12 years 300 mg daily B Nephropathy, Fanconi syndrome Osteomalacia Lactic acidosis Creatinine clearance at baseline If at risk for renal impairment, creatinine clearance, serum phosphate, urine glucose, and protein at least annually Consider bone density study at baseline and during treatment in persons with history of fracture or risks for osteopenia Lactic acid levels if clinical concern aDoses need to be adjusted in persons with renal dysfunction.bPer package insert.cPeg‐IFN‐α‐2a is not approved for children with CHB, but is approved for treatment of chronic hepatitis C. Providers may consider using this drug for children with chronic HBV. The duration of treatment indicated in adults is 48 weeks.dEntecavir dose in adults is 1 mg daily if lamivudine or telbivudine experienced or decompensated cirrhosis.Entecavir doses in treatment‐naïve children older than 2 and at least 10 kg are: 0.15 mg (10‐11 kg), 0.2 mg (>11‐14 kg), 0.25 mg (>14‐17 kg), 0.3 mg (>17‐20 kg), 0.35 mg (>20‐23 kg), 0.4 mg (>23‐26 kg), 0.45 mg (>26‐30 kg), and 0.5 mg (>30 kg). For treatment‐experienced children older than 2 and at least 10 kg, the entecavir doses are: 0.30 mg (10‐11 kg), 0.4 mg (>11‐14 kg), 0.5 mg (>14‐17 kg), 0.6 mg (>17‐20 kg), 0.7 mg (>20‐23 kg), 0.8 mg (>23‐26 kg), 0.9 mg (>26‐30 kg), and 1.0 mg (>30 kg).Abbreviations: CBC, complete blood counts; TSH, thyroid‐stimulating hormone. Biochemical, serological, virological, and histological endpoints are used to assess the success of therapy (Table 5). Assessments are performed on continuous therapy (NAs)27 and after therapy discontinuation (Peg‐IFN).2 The best predictor of sustained remission off‐treatment is HBsAg loss, but this is infrequently achieved with current therapies. Table 5 - Efficacy of Approved Preferred Antiviral Therapies in Adults With Treatment‐Naïve CHB and Immune Active Disease (Not Head‐to‐Head Comparisons) Peg‐IFNa (%) Entecavirb (%) Tenofovirb (%) HBeAg‐Positive HBV DNA suppressionc 30‐42 (<2,000‐40,000 IU/mL) 8‐14 (<80 IU/mL) 61 (<50‐60 IU/mL) 76 (<60 IU/mL) HBeAg loss 32‐36 22‐25 — HBeAg seroconversion 29‐36 21‐22 21 Normalization ALT[Link] 34‐52 68‐81 68 HBsAg loss 2‐7 (6 mos post‐treatment) 11 (at 3 yrs post‐treatment) 2‐3 (1 yr) 4‐5 (2 yrs) 3 (1 yr) 8 (3 yrs) (References) 31 36 30 HBeAg‐Negative HBV DNA suppressiond 43 (<4,000 IU/mL) 19 (<80 IU/mL) 90‐91 93 Normalization ALT[Link] 59 78‐88 76 HBsAg loss (%) 4 (6 mos post‐treatment) 6 (at 3 yrs post‐treatment) 0‐1 (1 yr) 0 (1 yr) (References) 40 42 39 aAssessed 6 months after completion of 12 months of therapy.bAssessed after 2‐3 years of continuous therapy.cHBV DNA <2,000‐40,000 IU/mL for Peg‐IFN; <60 IU/mL for entecavir and tenofovir.dHBV DNA <20,000 IU/mL for Peg‐IFN; <60 IU/mL for entecavir and tenofovir.ALT normalization defined by laboratory normal. Methods of Guideline Development The specific questions specified a priori for evaluation by the guidelines committee are shown in Table 6. Table 6 - Clinical Questions Evaluated Question Population Intervention Comparison Outcome(s) 1 Immune‐active CHB Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, loss of HBsAg 2 Immune‐tolerant CHB, adults Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, loss of HBsAg 3 HBeAg‐positive immune‐active chronic hepatitis, with HBeAg seroconversion on therapy Continued antiviral therapy Stopping antiviral therapy Cirrhosis, HCC, reactivation, seroreversion, decompensation, loss of HBsAg 4 HBeAg‐negative immune‐active chronic hepatitis, with viral suppression on antiviral therapy Continued antiviral therapy Stopping antiviral therapy Reactivation, decompensation, loss of HBsAg 5 CHB on treatment with oral therapy Tenofovir Entecavir Renal function, hypophosphatemia, bone health 6 CHB on treatment with oral therapy with persistent viremia Continue therapy Change or switch therapy HBV resistance, clinical flare, decompensation, loss of HBeAg 7 CHB with cirrhosis, with HBV DNA <2,000 IU/mL Antiviral therapy No treatment Decompensation, HCC, death 8 Pregnant women with CHB Antiviral therapy in third trimester No treatment CHB in the infant, safety HBeAg‐positive CHB, Antiviral therapy No treatment Cirrhosis, decompensation, HCC, death, HBeAg seroconversion, loss of HBsAg A and the of A of AASLD with an with in systematic reviews to the these key and the systematic the (Table In this the of in is as or low based on the of and risk of and The based recommendations on the of of and values and and clinical are as to most patients with minimal or to the of patients values and are with the of are to recommendations to to five of the key questions are as an to this For the questions with and are after Table 7 - The the of Study Initial of of when Risk of when High (e.g., (e.g., Dose gradient Low All the low of the of a Recommendation of of and Patient values and and of the of Recommendation Most in this the of and only a Health care Most should receive the of The can be as a policy in most The of in this the of but Health care to patients a decision that is with their values using decision aids and decision making. There is a need for and of of Persons With CHB The AASLD antiviral therapy for adults with immune‐active CHB or HBeAg to decrease the risk of liver‐related of of The AASLD entecavir, or tenofovir as initial therapy for adults with immune‐active CHB. of Low of Immune‐active CHB is defined by an of ALT or of significant histological disease elevated HBV DNA above 2,000 IU/mL or above IU/mL The for ALT in healthy adults is 30 U/L for and 19 U/L for There is insufficient for or use of ALT other than ALT ≥2 The decision to treat persons with ALT above the but of severity of liver disease by biopsy or noninvasive Therapy is for persons with immune‐active CHB and cirrhosis if HBV DNA of ALT factors in the decision to treat persons with immune‐active CHB but ALT and HBV DNA are: age is associated with higher likelihood of significant histological Family history of HCC treatment of and HBsAg may months to years after treatment discontinuation is a risk for drug Presence of for treatment of liver disease severity of HBV DNA should be with immune‐active disease and the cutoffs should be as a but not for treatment. of antiviral to of one therapy in achieving risk in liver‐related However, in and entecavir as the most important was the lack of with factors that need to be in between entecavir, and tenofovir for therapy of treatment side effects (Table 4). is in persons with autoimmune disease, disease, cytopenias, disease, and decompensated history of lamivudine is not in this Family A therapy with or use of oral antiviral that is in is best (Table 4). HBV A and B are more likely to HBeAg and HBsAg loss with than is for For persons treated with 48 duration is used in most and is This treatment duration HBeAg seroconversion rates of and sustained off‐treatment HBV DNA suppression <2,000 IU/mL in of persons who HBeAg to anti‐HBe The of and NAs has not higher rates of off‐treatment serological or virological and is not of therapy for therapy is variable and by HBeAg status, duration of HBV DNA and of All NAs dose in persons with creatinine clearance Evaluation for stage of disease using noninvasive methods or liver biopsy is useful in guiding treatment decisions including duration of therapy. with does not the risk of HCC, and surveillance for HCC should continue in persons who are at Background CHB is a dynamic disease characterized by variable of immune activity that in the development of cirrhosis, liver and liver‐related death in a of Elevated serum ALT and HBV DNA levels are of risk of liver factors include older age, a family history of HCC, alcohol use, HIV infection, HBV genotype and HBV precore and core promoter The of HBV therapy is to prevent liver‐related morbidity and Persons in the immune‐active phases of infection positive and elevated ALT, histological of liver injury inflammation and/or and elevated HBV DNA levels with a greater risk of liver disease and associated and The profile is in Table A total of 42 were to treatment and of cirrhosis, HCC, decompensation, or were and were a total of provided in persons with cirrhosis, and provided in persons with decompensated specific antiviral compared to treatment and compared therapy to treatment. A to antiviral was not to the of per The of was higher for low to low to of per was lower than per For specific the of was and highly variable. The of the treatment in liver‐related cirrhosis, decompensation, HCC, and and of risk across and among to of the lower of the Antiviral therapy to was associated with significant risk in cirrhosis in risk and a risk in HCC and

IMPORTANCE: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden. OBJECTIVE: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019. EVIDENCE REVIEW: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs). FINDINGS: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles. CONCLUSIONS AND RELEVANCE: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Chronic hepatitis C (non-A, non-B hepatitis) is a common and often progressive viral liver disease. To assess the efficacy of therapy with the antiviral agent interferon alfa, we randomly assigned 166 patients with chronic hepatitis C to treatment with either 3 million or 1 million units of recombinant interferon alfa three times weekly for 24 weeks, or to no treatment. The probability of normalization or near normalization of the serum alanine aminotransferase levels after six months of interferon therapy was 46 percent in patients treated with 3 million units of interferon (P less than 0.001) and 28 percent in those treated with 1 million units (P less than 0.02), but only 8 percent in untreated patients. The serum alanine aminotransferase level became completely normal in 22 of the 26 patients (85 percent) who responded to treatment with 3 million units of interferon and 9 of the 16 patients (56 percent) who responded to treatment with 1 million units. The patients who received 3 million units of interferon had histologic improvement because of the regression of lobular and periportal inflammation. Relapse within six months after the completion of treatment occurred in 51 percent of the patients treated with 3 million units of interferon and 44 percent of those treated with 1 million units. We conclude that a 24-week course of interferon therapy is effective in controlling disease activity in many patients with hepatitis C, although relapse after the cessation of treatment is common.

Sedentary behavior and physical inactivity are among the leading modifiable risk factors worldwide for cardiovascular disease and all-cause mortality. The promotion of physical activity and exercise training (ET) leading to improved levels of cardiorespiratory fitness is needed in all age groups, race, and ethnicities and both sexes to prevent many chronic diseases, especially cardiovascular disease. In this state-of-the-art review, we discuss the negative impact of sedentary behavior and physical inactivity, as well as the beneficial effects of physical activity /ET and cardiorespiratory fitness for the prevention of chronic noncommunicable diseases, including cardiovascular disease. We review the prognostic utility of cardiorespiratory fitness compared with obesity and the metabolic syndrome, as well as the increase of physical activity /ET for patients with heart failure as a therapeutic strategy, and ET dosing. Greater efforts at preventing sedentary behavior and physical inactivity while promoting physical activity, ET, and cardiorespiratory fitness are needed throughout the healthcare system worldwide and particularly in the United States in which the burden of cardiometabolic diseases remains extremely high.

Cardiovascular diseases (CVDs) are the major causes of mortality in persons with diabetes, and many factors, including hypertension, contribute to this high prevalence of CVD. Hypertension is approximately twice as frequent in patients with diabetes compared with patients without the disease. Conversely, recent data suggest that hypertensive persons are more predisposed to the development of diabetes than are normotensive persons. Furthermore, up to 75% of CVD in diabetes may be attributable to hypertension, leading to recommendations for more aggressive treatment (ie, reducing blood pressure to <130/85 mm Hg) in persons with coexistent diabetes and hypertension. Other important risk factors for CVD in these patients include the following: obesity, atherosclerosis, dyslipidemia, microalbuminuria, endothelial dysfunction, platelet hyperaggregability, coagulation abnormalities, and "diabetic cardiomyopathy." The cardiomyopathy associated with diabetes is a unique myopathic state that appears to be independent of macrovascular/microvascular disease and contributes significantly to CVD morbidity and mortality in diabetic patients, especially those with coexistent hypertension. This update reviews the current knowledge regarding these risk factors and their treatment, with special emphasis on the cardiometabolic syndrome, hypertension, microalbuminuria, and diabetic cardiomyopathy. This update also examines the role of the renin-angiotensin system in the increased risk for CVD in diabetic patients and the impact of interrupting this system on the development of clinical diabetes as well as CVD.

CONTEXT: Despite evidence of efficacy of antihypertensive agents in treating hypertensive patients, safety and efficacy of antihypertensive agents for coronary artery disease (CAD) have been discerned only from subgroup analyses in large trials. OBJECTIVE: To compare mortality and morbidity outcomes in patients with hypertension and CAD treated with a calcium antagonist strategy (CAS) or a non-calcium antagonist strategy (NCAS). DESIGN, SETTING, AND PARTICIPANTS: Randomized, open label, blinded end point study of 22 576 hypertensive CAD patients aged 50 years or older, which was conducted September 1997 to February 2003 at 862 sites in 14 countries. INTERVENTIONS: Patients were randomly assigned to either CAS (verapamil sustained release) or NCAS (atenolol). Strategies specified dose and additional drug regimens. Trandolapril and/or hydrochlorothiazide was administered to achieve blood pressure goals according to guidelines from the sixth report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC VI) of less than 140 mm Hg (systolic) and less than 90 mm Hg (diastolic); and less than 130 mm Hg (systolic) and less than 85 mm Hg (diastolic) if diabetes or renal impairment was present. Trandolapril was also recommended for patients with heart failure, diabetes, or renal impairment. MAIN OUTCOME MEASURES: Primary: first occurrence of death (all cause), nonfatal myocardial infarction, or nonfatal stroke; other: cardiovascular death, angina, adverse experiences, hospitalizations, and blood pressure control at 24 months. RESULTS: At 24 months, in the CAS group, 6391 patients (81.5%) were taking verapamil sustained release; 4934 (62.9%) were taking trandolapril; and 3430 (43.7%) were taking hydrochlorothiazide. In the NCAS group, 6083 patients (77.5%) were taking atenolol; 4733 (60.3%) were taking hydrochlorothiazide; and 4113 (52.4%) were taking trandolapril. After a follow-up of 61 835 patient-years (mean, 2.7 years per patient), 2269 patients had a primary outcome event with no statistically significant difference between treatment strategies (9.93% in CAS and 10.17% in NCAS; relative risk [RR], 0.98; 95% confidence interval [CI], 0.90-1.06). Two-year blood pressure control was similar between groups. The JNC VI blood pressure goals were achieved by 65.0% (systolic) and 88.5% (diastolic) of CAS and 64.0% (systolic) and 88.1% (diastolic) of NCAS patients. A total of 71.7% of CAS and 70.7% of NCAS patients achieved a systolic blood pressure of less than 140 mm Hg and diastolic blood pressure of less than 90 mm Hg. CONCLUSION: The verapamil-trandolapril-based strategy was as clinically effective as the atenolol-hydrochlorothiazide-based strategy in hypertensive CAD patients.

Stress response elements, which mediate induction of the mouse heme oxygenase-1 (HO-1) gene by several agents, resemble the binding site for the activator protein-1 (Jun/Fos), Maf, and Cap'n'Collar/basic leucine zipper (CNC-bZIP) families of proteins. In L929 fibroblasts, significant activation of an HO-1 enhancer-reporter fusion gene was observed only with the CNC-bZIP class of proteins with Nrf2 exhibiting the highest level of trans-activation, between 25- and 30-fold. To further examine the role of this factor in HO-1 gene regulation, a dominant-negative mutant, Nrf2M, was generated and conditionally expressed in L929 cells. The mutant protein was detected in cytoplasmic and nuclear fractions but did not affect cell growth. Under conditions of Nrf2M overexpression, HO-1 mRNA accumulation in response to heme, cadmium, zinc, arsenite, and tert-butylhydroquinone was inhibited by 85-95%. In contrast, overexpression of a dominant-negative mutant of c-Jun decreased L929 cell growth but did not inhibit HO-1 gene activation. Nrf2 does not homodimerize, but CNC-bZIP.small Maf protein heterodimers and Nrf2. Jun protein complexes are proposed to function as trans-activators. Co-expression of Jun proteins or p18, however, had no significant affect or inhibited Nrf2-mediated trans-activation. Taken together, these results implicate Nrf2 in the induction of the HO-1 gene but suggest that the Nrf2 partner in this function is a factor other than p18 or Jun proteins.

BACKGROUND AND METHODS: Although the nucleoside analogue lamivudine has shown promise in patients with chronic hepatitis B, long-term data on patients from the United States are lacking. We randomly assigned previously untreated patients with chronic hepatitis B to receive either 100 mg of oral lamivudine or placebo daily for 52 weeks. We then followed them for an additional 16 weeks to evaluate post-treatment safety and the durability of responses. The primary end point with respect to efficacy was a reduction of at least 2 points in the score on the Histologic Activity Index. On this scale, scores can range from 0 (normal) to 22 (most severe abnormalities). RESULTS: Of the 143 randomized patients, 137 were included in the efficacy analysis: 66 in the lamivudine group and 71 in the placebo group. The other six patients were excluded at the base-line visit because of the absence of a documented history of hepatitis B surface antigen for at least six months. After 52 weeks of treatment, lamivudine recipients were more likely than placebo recipients to have a histologic response (52 percent vs. 23 percent, P<0.001), loss of hepatitis B e antigen (HBeAg) in serum (32 percent vs. 11 percent, P=0.003), sustained suppression of serum hepatitis B virus (HBV) DNA to undetectable levels (44 percent vs. 16 percent, P<0.001), and sustained normalization of serum alanine aminotransferase levels (41 percent vs. 7 percent, P<0.001), and they were less likely to have increased hepatic fibrosis (5 percent vs. 20 percent, P=0.01). Lamivudine recipients were also more likely to undergo HBeAg seroconversion, defined as the loss of HBeAg, undetectable levels of serum HBV DNA, and the appearance of antibodies against HBeAg (17 percent vs. 6 percent, P=0.04). HBeAg responses persisted in most patients for 16 weeks after the discontinuation of treatment. Lamivudine was well tolerated. Self-limited post-treatment elevations in serum alanine aminotransferase were more common in lamivudine recipients: 25 percent had serum alanine aminotransferase levels that were at least three times base-line levels, as compared with 8 percent of placebo recipients (P=0.01). The clinical condition of all patients remained stable during the study. CONCLUSIONS: In U.S. patients with previously untreated chronic hepatitis B, one year of lamivudine therapy had favorable effects on histologic, virologic, and biochemical features of the disease and was well tolerated. HBeAg responses were generally sustained after treatment.

The distinction between bactericidal and bacteriostatic agents appears to be clear according to the in vitro definition, but this only applies under strict laboratory conditions and is inconsistent for a particular agent against all bacteria. The distinction is more arbitrary when agents are categorized in clinical situations. The supposed superiority of bactericidal agents over bacteriostatic agents is of little relevance when treating the vast majority of infections with gram-positive bacteria, particularly in patients with uncomplicated infections and noncompromised immune systems. Bacteriostatic agents (e.g., chloramphenicol, clindamycin, and linezolid) have been effectively used for treatment of endocarditis, meningitis, and osteomyelitis--indications that are often considered to require bactericidal activity. Although bacteriostatic/bactericidal data may provide valuable information on the potential action of antibacterial agents in vitro, it is necessary to combine this information with pharmacokinetic and pharmacodynamic data to provide more meaningful prediction of efficacy in vivo. The ultimate guide to treatment of any infection must be clinical outcome.

IMPORTANCE: Evidence about the efficacy of laparoscopic resection of rectal cancer is incomplete, particularly for patients with more advanced-stage disease. OBJECTIVE: To determine whether laparoscopic resection is noninferior to open resection, as determined by gross pathologic and histologic evaluation of the resected proctectomy specimen. DESIGN, SETTING, AND PARTICIPANTS: A multicenter, balanced, noninferiority, randomized trial enrolled patients between October 2008 and September 2013. The trial was conducted by credentialed surgeons from 35 institutions in the United States and Canada. A total of 486 patients with clinical stage II or III rectal cancer within 12 cm of the anal verge were randomized after completion of neoadjuvant therapy to laparoscopic or open resection. INTERVENTIONS: Standard laparoscopic and open approaches were performed by the credentialed surgeons. MAIN OUTCOMES AND MEASURES: The primary outcome assessing efficacy was a composite of circumferential radial margin greater than 1 mm, distal margin without tumor, and completeness of total mesorectal excision. A 6% noninferiority margin was chosen according to clinical relevance estimation. RESULTS: Two hundred forty patients with laparoscopic resection and 222 with open resection were evaluable for analysis of the 486 enrolled. Successful resection occurred in 81.7% of laparoscopic resection cases (95% CI, 76.8%-86.6%) and 86.9% of open resection cases (95% CI, 82.5%-91.4%) and did not support noninferiority (difference, -5.3%; 1-sided 95% CI, -10.8% to ∞; P for noninferiority = .41). Patients underwent low anterior resection (76.7%) or abdominoperineal resection (23.3%). Conversion to open resection occurred in 11.3% of patients. Operative time was significantly longer for laparoscopic resection (mean, 266.2 vs 220.6 minutes; mean difference, 45.5 minutes; 95% CI, 27.7-63.4; P < .001). Length of stay (7.3 vs 7.0 days; mean difference, 0.3 days; 95% CI, -0.6 to 1.1), readmission within 30 days (3.3% vs 4.1%; difference, -0.7%; 95% CI, -4.2% to 2.7%), and severe complications (22.5% vs 22.1%; difference, 0.4%; 95% CI, -4.2% to 2.7%) did not differ significantly. Quality of the total mesorectal excision specimen in 462 operated and analyzed surgeries was complete (77%) and nearly complete (16.5%) in 93.5% of the cases. Negative circumferential radial margin was observed in 90% of the overall group (87.9% laparoscopic resection and 92.3% open resection; P = .11). Distal margin result was negative in more than 98% of patients irrespective of type of surgery (P = .91). CONCLUSIONS AND RELEVANCE: Among patients with stage II or III rectal cancer, the use of laparoscopic resection compared with open resection failed to meet the criterion for noninferiority for pathologic outcomes. Pending clinical oncologic outcomes, the findings do not support the use of laparoscopic resection in these patients. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00726622.

The transcription factor Nrf2, which normally exists in an inactive state as a consequence of binding to a cytoskeleton-associated protein Keap1, can be activated by redox-dependent stimuli. Alteration of the Nrf2-Keap1 interaction enables Nrf2 to translocate to the nucleus, bind to the antioxidant-responsive element (ARE) and initiate the transcription of genes coding for detoxifying enzymes and cytoprotective proteins. This response is also triggered by a class of electrophilic compounds including polyphenols and plant-derived constituents. Recently, the natural antioxidants curcumin and caffeic acid phenethyl ester (CAPE) have been identified as potent inducers of haem oxygenase-1 (HO-1), a redox-sensitive inducible protein that provides protection against various forms of stress. Here, we show that in renal epithelial cells both curcumin and CAPE stimulate the expression of Nrf2 in a concentration- and time-dependent manner. This effect was associated with a significant increase in HO-1 protein expression and haem oxygenase activity. From several lines of investigation we also report that curcumin (and, by inference, CAPE) stimulates ho-1 gene activity by promoting inactivation of the Nrf2-Keap1 complex, leading to increased Nrf2 binding to the resident ho-1 AREs. Moreover, using antibodies and specific inhibitors of the mitogen-activated protein kinase (MAPK) pathways, we provide data implicating p38 MAPK in curcumin-mediated ho-1 induction. Taken together, these results demonstrate that induction of HO-1 by curcumin and CAPE requires the activation of the Nrf2/ARE pathway.

OBJECTIVE: To determine the efficacy and safety of liraglutide (a glucagon-like peptide-1 receptor agonist) when added to metformin and rosiglitazone in type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week, double-blind, placebo-controlled, parallel-group trial randomized 533 subjects (1:1:1) to once-daily liraglutide (1.2 or 1.8 mg) or liraglutide placebo in combination with metformin (1 g twice daily) and rosiglitazone (4 mg twice daily). Subjects had type 2 diabetes, A1C 7-11% (previous oral antidiabetes drug [OAD] monotherapy >or=3 months) or 7-10% (previous OAD combination therapy >or=3 months), and BMI <or=45 kg/m(2). RESULTS: Mean A1C values decreased significantly more in the liraglutide groups versus placebo (mean +/- SE -1.5 +/- 0.1% for both 1.2 and 1.8 mg liraglutide and -0.5 +/- 0.1% for placebo). Fasting plasma glucose decreased by 40, 44, and 8 mg/dl for 1.2 and 1.8 mg and placebo, respectively, and 90-min postprandial glucose decreased by 47, 49, and 14 mg/dl, respectively (P < 0.001 for all liraglutide groups vs. placebo). Dose-dependent weight loss occurred with 1.2 and 1.8 mg liraglutide (1.0 +/- 0.3 and 2.0 +/- 0.3 kg, respectively) (P < 0.0001) compared with weight gain with placebo (0.6 +/- 0.3 kg). Systolic blood pressure decreased by 6.7, 5.6, and 1.1 mmHg with 1.2 and 1.8 mg liraglutide and placebo, respectively. Significant increases in C-peptide and homeostasis model assessment of beta-cell function and significant decreases in the proinsulin-to-insulin ratio occurred with liraglutide versus placebo. Minor hypoglycemia occurred more frequently with liraglutide, but there was no major hypoglycemia. Gastrointestinal adverse events were more common with liraglutide, but most occurred early and were transient. CONCLUSIONS: Liraglutide combined with metformin and a thiazolidinedione is a well-tolerated combination therapy for type 2 diabetes, providing significant improvements in glycemic control.

BACKGROUND: Better treatments for chronic hepatitis B are needed. Lamivudine, the (-)enantiomer of 3'-thiacytidine, is a potent inhibitor of hepatitis B virus (HBV). METHODS: In a double-blind trial, we randomly assigned 32 patients with chronic hepatitis B (including 17 who had no response to earlier treatment with interferon) to receive 25, 100, or 300 mg of oral lamivudine daily for 12 weeks. The patients were then followed for 24 additional weeks. All the patients had hepatitis B antigen in serum. RESULTS: Levels of HBV DNA became undetectable (< or = 1.5 pg per milliliter) in 70 percent of the patients who received the 25-mg dose of lamivudine and 100 percent of those treated with the 100-mg or 300-mg dose. In most patients, HBV DNA reappeared after therapy was completed; however, six patients (19 percent), including five who had not responded to interferon, had sustained suppression of HBV DNA accompanied by normalization of alanine aminotransferase levels. Hepatitis B e antigen disappeared in four of these six patients (12 percent), three of whom had had no response to interferon. Levels of HBV DNA fell in all patients, including those who had had high levels at base line or normal alanine aminotransferase levels at base line, but sustained responses were more likely in patients with initially low HBV DNA levels and high alanine aminotransferase levels. During and after therapy, alanine aminotransferase levels at least doubled in five patients (50 percent) given the 25-mg dose and eight patients (36 percent) given the 100-mg or 300-mg dose. Minor adverse events occurred that were not related to the dose, as did transient, asymptomatic elevations of amylase, lipase, and creatine kinase levels. CONCLUSIONS: In a preliminary trial, 12 weeks of lamivudine therapy was well tolerated, and daily doses of 100 mg and 300 mg reduced HBV DNA to undetectable levels.

BACKGROUND: As the population that is infected with the hepatitis C virus (HCV) ages, the number of patients with decompensated cirrhosis is expected to increase. METHODS: We conducted a phase 3, open-label study involving both previously treated and previously untreated patients infected with HCV genotypes 1 through 6 who had decompensated cirrhosis (classified as Child-Pugh-Turcotte class B). Patients were randomly assigned in a 1:1:1 ratio to receive the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir once daily for 12 weeks, sofosbuvir-velpatasvir plus ribavirin for 12 weeks, or sofosbuvir-velpatasvir for 24 weeks. The primary end point was a sustained virologic response at 12 weeks after the end of therapy. RESULTS: Of the 267 patients who received treatment, 78% had HCV genotype 1, 4% genotype 2, 15% genotype 3, 3% genotype 4, and less than 1% genotype 6; no patients had genotype 5. Overall rates of sustained virologic response were 83% (95% confidence interval [CI], 74 to 90) among patients who received 12 weeks of sofosbuvir-velpatasvir, 94% (95% CI, 87 to 98) among those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 86% (95% CI, 77 to 92) among those who received 24 weeks of sofosbuvir-velpatasvir. Post hoc analysis did not detect any significant differences in rates of sustained virologic response among the three study groups. Serious adverse events occurred in 19% of patients who received 12 weeks of sofosbuvir-velpatasvir, 16% of those who received 12 weeks of sofosbuvir-velpatasvir plus ribavirin, and 18% of those who received 24 weeks of sofosbuvir-velpatasvir. The most common adverse events were fatigue (29%), nausea (23%), and headache (22%) in all patients and anemia (31%) in the patients receiving ribavirin. CONCLUSIONS: Treatment with sofosbuvir-velpatasvir with or without ribavirin for 12 weeks and with sofosbuvir-velpatasvir for 24 weeks resulted in high rates of sustained virologic response in patients with HCV infection and decompensated cirrhosis. (Funded by Gilead Sciences; ASTRAL-4 ClinicalTrials.gov number, NCT02201901.).

Aspergillosis comprises a variety of manifestations of infection. These guidelines are directed to 3 principal entities: invasive aspergillosis, involving several organ systems (particularly pulmonary disease); pulmonary aspergilloma; and allergic bronchopulmonary aspergillosis. The recommendations are distilled in this summary, but the reader is encouraged to review the more extensive discussions in subsequent sections, which show the strength of the recommendations and the quality of the evidence, and the original publications cited in detail. Invasive aspergillosis. Because it is highly lethal in the immunocompromised host, even in the face of therapy, work-up must be prompt and aggressive, and therapy may need to be initiated upon suspicion of the diagnosis, without definitive proof (BIII). Intravenous therapy should be used initially in rapidly progressing disease (BIII). The largest therapeutic experience is with amphotericin B deoxycholate, which should be given at maximum tolerated doses (e.g., 1-1.5 mg/kg/d) and should be continued, despite modest increases in serum creatinine levels (BIII). Lipid formulations of amphotericin are indicated for the patient who has impaired renal function or who develops nephrotoxicity while receiving deoxycholate amphotericin (AII). Oral itraconazole is an alternative for patients who can take oral medication, are likely to be adherent, can be demonstrated (by serum level monitoring) to absorb the drug, and lack the potential for interaction with other drugs (BII). Oral itraconazole is attractive for continuing therapy in the patient who responds to initial iv therapy (CIII). Therapy should be prolonged beyond resolution of disease and reversible underlying predispositions (BIII). Adjunctive therapy (particularly surgery and combination chemotherapy, also immunotherapy), may be useful in certain situations (CIII). Aspergilloma. The optimal treatment strategy for aspergilloma is unknown. Therapy is predominantly directed at preventing life-threatening hemoptysis. Surgical removal of aspergilloma is definitive treatment, but because of significant morbidity and mortality it should be reserved for high-risk patients such as those with episodes of life-threatening hemoptysis, and considered for patients with underlying sarcoidosis, immunocompromised patients, and those with increasing Aspergillus-specific IgG titers (CIII). Surgical candidates would need to have adequate pulmonary function to undergo the operation. Bronchial artery embolization rarely produces a permanent success, but may be useful as a temporizing procedure in patients with life-threatening hemoptysis. Endobronchial and intracavitary instillation of antifungals or oral itraconazole may be useful for this condition. Since the majority of aspergillomas do not cause life-threatening hemoptysis, the morbidity and cost of treatment must be weighed against the clinical benefit. Allergic bronchopulmonary aspergillosis (APBA). Although no well-designed studies have been carried out, the available data support the use of corticosteroids for acute exacerbations of ABPA (AII). Neither the optimal corticosteroid dose nor the duration of therapy has been standardized, but limited data suggest the starting dose should be approximately 0.5 mg/kg/d of prednisone. The decision to taper corticosteroids should be made on an individual basis, depending on the clinical course (BIII). The available data suggest that clinical symptoms alone are inadequate to make such decisions, since significant lung damage may occur in asymptomatic patients. Increasing serum IgE levels, new or worsening infiltrate on chest radiograph, and worsening spirometry suggest that corticosteroids should be used (BII). Multiple asthmatic exacerbations in a patient with ABPA suggest that chronic corticosteroid therapy should be used (BIII). Itraconazole appears useful as a corticosteroid sparing agent (BII). (ABSTRACT TRUNCATED)

Exposure of rats to hypoxia (7% O2) markedly increased the level of heme oxygenase-1 (HO-1) mRNA in several tissues. Accumulation of HO-1 transcripts was also observed after exposure of rat aortic vascular smooth muscle (VSM) cells to 1% O2, and this induction was dependent on gene transcription. Activation of the mouse HO-1 gene by all agents thus far tested is mediated by two 5'-enhancer sequences, SX2 and AB1, but neither fragment was responsive to hypoxia in VSM cells. Hypoxia-dependent induction of the chloramphenicol acetyltransferase (CAT) reporter gene was mediated by a 163-bp fragment located approximately 9.5 kilobases upstream of the transcription start site. This fragment contains two potential binding sites for hypoxia-inducible factor 1 (HIF-1). A role for HIF-1 in HO-1 gene regulation was established by the following observations: 1) HIF-1 specifically bound to an oligonucleotide spanning these sequences, 2) mutation of these sequences abolished HIF-1 binding and hypoxia-dependent gene activation in VSM cells, 3) hypoxia increased HIF-1alpha and HIF-1beta protein levels in VSM cells, and 4) hypoxia-dependent HO-1 mRNA accumulation was not observed in mutant hepatoma cells lacking HIF-1 DNA-binding activity. Taken together, these data demonstrate that hypoxia induces HO-1 expression in animal tissues and cell cultures and implicate HIF-1 in this response.

HYPERTENSIVE heart disease can be defined as the response of the heart to the afterload imposed on the left ventricle by the progressively increasing arterial pressure and total peripheral resistance produced by hypertensive vascular disease. Although the response sometimes appears to be out of proportion to the level of the arterial pressure, it is primarily the result of the hemodynamic overload. Hypertension can cause or is related to various cardiac manifestations, among them left ventricular hypertrophy, congestive heart failure, cardiac dysrhythmias, and ischemic heart disease. Although the risk of atherosclerotic coronary heart disease is related to the systolic and diastolic . . .

Real-world studies have become increasingly important in providing evidence of treatment effectiveness in clinical practice. While randomized clinical trials (RCTs) are the "gold standard" for evaluating the safety and efficacy of new therapeutic agents, necessarily strict inclusion and exclusion criteria mean that trial populations are often not representative of the patient populations encountered in clinical practice. Real-world studies may use information from electronic health and claims databases, which provide large datasets from diverse patient populations, and/or may be observational, collecting prospective or retrospective data over a long period of time. They can therefore provide information on the long-term safety, particularly pertaining to rare events, and effectiveness of drugs in large heterogeneous populations, as well as information on utilization patterns and health and economic outcomes. This review focuses on how evidence from real-world studies can be utilized to complement data from RCTs to gain a more complete picture of the advantages and disadvantages of medications as they are used in practice.Funding: Sanofi US, Inc.

For commissioning a linear accelerator for clinical use, medical physicists are faced with many challenges including the need for precision, a variety of testing methods, data validation, the lack of standards, and time constraints. Since commissioning beam data are treated as a reference and ultimately used by treatment planning systems, it is vitally important that the collected data are of the highest quality to avoid dosimetric and patient treatment errors that may subsequently lead to a poor radiation outcome. Beam data commissioning should be performed with appropriate knowledge and proper tools and should be independent of the person collecting the data. To achieve this goal, Task Group 106 (TG-106) of the Therapy Physics Committee of the American Association of Physicists in Medicine was formed to review the practical aspects as well as the physics of linear accelerator commissioning. The report provides guidelines and recommendations on the proper selection of phantoms and detectors, setting up of a phantom for data acquisition (both scanning and no-scanning data), procedures for acquiring specific photon and electron beam parameters and methods to reduce measurement errors (<1%), beam data processing and detector size convolution for accurate profiles. The TG-106 also provides a brief.discussion on the emerging trend in Monte Carlo simulation techniques in photon and electron beam commissioning. The procedures described in this report should assist a qualified medical physicist in either measuring a complete set of beam data, or in verifying a subset of data before initial use or for periodic quality assurance measurements. By combining practical experience with theoretical discussion, this document sets a new standard for beam data commissioning.