Naveen Gara

Bio: Naveen Gara is an academic researcher from National Institutes of Health. The author has contributed to research in topics: Hepatitis C & Cirrhosis. The author has an hindex of 11, co-authored 21 publications receiving 465 citations. Previous affiliations of Naveen Gara include Mayo Clinic & MedStar Washington Hospital Center.

Renal tubular dysfunction during long-term adefovir or tenofovir therapy in chronic hepatitis B.

Abstract: Summary Background Adefovir and tenofovir are nucleotide analogues used as long-term therapy of chronic hepatitis B. Side effects are few, but prolonged and high-dose therapy has been associated with proximal renal tubular dysfunction (RTD). Aim To assess the incidence of RTD during long-term nucleotide therapy of chronic hepatitis B. Methods A total of 51 patients being treated at the Clinical Center, National Institutes of Health were studied. Diagnosis of RTD required de novo appearance of at least three of five features: hypophosphataemia, hypouricaemia, serum creatinine elevation, proteinuria or glucosuria. Results Among 51 patients treated for 1–10 (mean 7.4) years with adefovir (n = 42), tenofovir (n = 4) or adefovir followed by tenofovir (n = 5), 7 (14%) developed RTD. Time to onset ranged from 22 to 94 (mean 49) months with an estimated 10-year cumulative rate of 15%. All seven had low urinary percent maximal tubular reabsorption of phosphate (<82%). Patients with RTD were older (58 vs. 44 years; P = 0.01) and had lower baseline glomerular filtration rates (82 vs. 97 cc/min; P = 0.08) compared to those without; but did not differ in other features. Six patients with RTD were switched to entecavir, all subsequently had improvements in serum phosphate (2.0–3.0 mg/dL), creatinine (1.6–1.1 mg/dL), uric acid (2.7–3.8 mg/dL) and proteinuria. Conclusions Renal tubular dysfunction develops in 15% of patients treated with adefovir or tenofovir for 2–9 years and is partially reversible with change to other antivirals. Monitoring for serum phosphate, creatinine and urinalysis is prudent during long-term adefovir and tenofovir therapy.

Serum bile acid patterns are associated with the presence of NAFLD in twins, and dose-dependent changes with increase in fibrosis stage in patients with biopsy-proven NAFLD.

Abstract: BACKGROUND: The fasting-state serum bile acid profile in nonalcoholic fatty liver disease (NAFLD) has been reported to differ when nonalcoholic steatohepatitis is compared to nonalcoholic fatty liver. However, there are few data comparing changes in NAFLD vs non-NAFLD, or whether the bile acid profile differs according to the degree of fibrosis. AIM: To examine the serum bile acid profile across the entire spectrum of NAFLD. METHODS: We performed a cross-sectional analysis of two complementary cohorts: a Twin and Family cohort of 156 participants, and a biopsy-proven-NAFLD cohort of 156 participants with fasting bile acid profiling using liquid chromatography/mass spectrometry. RESULTS: In the Twin and Family cohort (mean age 46.3 years and body mass index (BMI) 26.6 kg/m(2) ), 36 (23%) participants had NAFLD (magnetic resonance imaging proton density fat fraction \textgreater/= 5%). Higher chenodeoxycholyl conjugates (9.0% vs 6.5%, P = 0.019) and lower glycohyocholate (1.2% vs 3.6%, P \textless 0.001) were observed in NAFLD compared to non-NAFLD-controls. In the biopsy-proven-NAFLD cohort (mean age 49.8 years, BMI 32.0 kg/m(2) ), no differences in total bile acid were seen between nonalcoholic fatty liver vs nonalcoholic steatohepatitis. The total unconjugated bile acid significantly decreased across nonalcoholic steatohepatitis categories (P = 0.044). The distribution of stage of fibrosis was F0: 42.3%, F1: 32.7%, F2: 10.3%, F3: 8.3% and F4: 6.4%. The total serum bile acid increased with increase in fibrosis stage (P \textless 0.001). The primary conjugated bile acid proportion increased (P \textless 0.001) whereas unconjugated bile acid (P = 0.006), unconjugated cholyl (P \textless 0.001) and chenodeoxycholyl conjugates (P \textless 0.002) significantly decreased with increase in liver fibrosis stage. CONCLUSIONS: Fasting-state serum bile acid profile alterations are seen across the entire spectrum of NAFLD. The total serum bile acids did not differ significantly between NAFLD vs non-NAFLD and nonalcoholic fatty liver vs nonalcoholic steatohepatitis, but were significantly perturbed progressively as liver fibrosis increases.

Effect of ribavirin on viral kinetics and liver gene expression in chronic hepatitis C

Abstract: Objective Ribavirin improves treatment response to pegylated-interferon (PEG-IFN) in chronic hepatitis C but the mechanism remains controversial. We studied correlates of response and mechanism of action of ribavirin in treatment of hepatitis C. Design 70 treatment-naive patients were randomised to 4 weeks of ribavirin (1000–1200 mg/d) or none, followed by PEG-IFNα-2a and ribavirin at standard doses and durations. Patients were also randomised to a liver biopsy 24 h before or 6 h after starting PEG-IFN. Hepatic gene expression was assessed by microarray and interferon-stimulated gene (ISG) expression quantified by nCounter platform. Temporal changes in ISG expression were assessed by qPCR in peripheral-blood mononuclear cells (PBMC) and by serum levels of IP-10. Results After 4 weeks of ribavirin monotherapy, hepatitis C virus (HCV) levels decreased by 0.5±0.5 log 10 (p=0.009 vs controls) and ALT by 33% (p Conclusions Ribavirin is a weak antiviral but its clinical effect seems to be mediated by a separate, indirect mechanism, which may act to reset IFN-responsiveness in HCV-infected liver.

Durability of Antibody Response Against Hepatitis B Virus in Healthcare Workers Vaccinated as Adults

Abstract: The implementation of vaccination programs worldwide against hepatitis B virus (HBV) has reduced the morbidity and mortality of acute and chronic HBV infection and the incidence of hepatocellular carcinoma, particularly in endemic regions [1–3]. Vaccination against HBV consists of 3 or 4 intramuscular injections of recombinant hepatitis B surface antigen (HBsAg) at varying schedules [4]. Response rates to primary vaccination are high, with 85%–100% of vaccinees developing antibody to HBsAg (anti-HBs) ≥10 mIU/mL [5], a level that is considered protective [5–9]. Factors found to be associated with nonresponse include male sex, increasing age at vaccination (>40 years old), obesity, alcoholism, smoking, and genetic factors [10–12]. Asymptomatic breakthrough infections (detected by the presence of antibody to hepatitis B core antigen [anti-HBc] or HBV DNA in serum) have been reported in vaccinated persons with a documented initial antibody response [13, 14]. Long-term follow-up studies of persons who were vaccinated as infants have reported absence of anti-HBs in 50%–70% of persons 15–30 years later [13, 15–18]. In contrast, data on the longevity of immunity afforded by hepatitis B vaccine in a healthy adult population are scarce. The few available studies in young adults who initially responded to a past primary vaccine series with antibody concentrations of ≥10 mIU/mL reported that 17%–50% have low or undetectable anti-HBs (reflecting anti-HBs loss) 10–15 years after vaccination [14, 19]. Whether low or undetectable levels of anti-HBs predispose to subsequent infection is unknown. Moreover, whether individuals may respond to a hepatitis B vaccine booster to maintain long-term protection is unknown. Current guidelines do not recommend booster doses, but the duration of long-term protection is unknown [4, 20]. Healthcare workers (HCWs) in the United States are mandated to receive hepatitis B vaccine and are at risk for hepatitis B through occupational exposure. Therefore, they would be an ideal population to assess durability of antibody response and long-term (≥10 years) vaccine protection and to determine response to a booster dose in those who did not maintain the immune response to primary vaccination as adults.

SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls.

Abstract: Memory T cells induced by previous pathogens can shape susceptibility to, and the clinical severity of, subsequent infections1. Little is known about the presence in humans of pre-existing memory T cells that have the potential to recognize severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we studied T cell responses against the structural (nucleocapsid (N) protein) and non-structural (NSP7 and NSP13 of ORF1) regions of SARS-CoV-2 in individuals convalescing from coronavirus disease 2019 (COVID-19) (n = 36). In all of these individuals, we found CD4 and CD8 T cells that recognized multiple regions of the N protein. Next, we showed that patients (n = 23) who recovered from SARS (the disease associated with SARS-CoV infection) possess long-lasting memory T cells that are reactive to the N protein of SARS-CoV 17 years after the outbreak of SARS in 2003; these T cells displayed robust cross-reactivity to the N protein of SARS-CoV-2. We also detected SARS-CoV-2-specific T cells in individuals with no history of SARS, COVID-19 or contact with individuals who had SARS and/or COVID-19 (n = 37). SARS-CoV-2-specific T cells in uninfected donors exhibited a different pattern of immunodominance, and frequently targeted NSP7 and NSP13 as well as the N protein. Epitope characterization of NSP7-specific T cells showed the recognition of protein fragments that are conserved among animal betacoronaviruses but have low homology to 'common cold' human-associated coronaviruses. Thus, infection with betacoronaviruses induces multi-specific and long-lasting T cell immunity against the structural N protein. Understanding how pre-existing N- and ORF1-specific T cells that are present in the general population affect the susceptibility to and pathogenesis of SARS-CoV-2 infection is important for the management of the current COVID-19 pandemic.

Blood Tests to Diagnose Fibrosis or Cirrhosis in Patients With Chronic Hepatitis C Virus Infection: A Systematic Review

Abstract: Background Many blood tests have been proposed as alternatives to liver biopsy for identifying fibrosis or cirrhosis. Purpose To evaluate the diagnostic accuracy of blood tests to identify fibrosis or cirrhosis in patients with hepatitis C virus (HCV) infection. Data sources MEDLINE (1947 to January 2013), the Cochrane Library, and reference lists. Study selection Studies that compared the diagnostic accuracy of blood tests with that of liver biopsy. Data extraction Investigators abstracted and checked study details and quality by using predefined criteria. Data synthesis 172 studies evaluated diagnostic accuracy. For identifying clinically significant fibrosis, the platelet count, age-platelet index, aspartate aminotransferase-platelet ratio index (APRI), FibroIndex, FibroTest, and Forns index had median positive likelihood ratios of 5 to 10 at commonly used cutoffs and areas under the receiver-operating characteristic curve (AUROCs) of 0.70 or greater (range, 0.71 to 0.86). For identifying cirrhosis, the platelet count, age-platelet index, APRI, and Hepascore had median positive likelihood ratios of 5 to 10 and AUROCs of 0.80 or greater (range, 0.80 to 0.91). The Goteborg University Cirrhosis Index and the Lok index had slightly lower positive likelihood ratios (4.8 and 4.4, respectively). In direct comparisons, the APRI was associated with a slightly lower AUROC than the FibroTest for identifying fibrosis and a substantially higher AUROC than the aspartate aminotransferase-alanine aminotransferase ratio for identifying fibrosis or cirrhosis. Limitation Only English-language articles were included, and most studies had methodological limitations, including failure to describe blinded interpretation of liver biopsy specimens and inadequate description of enrollment methods. Conclusion Many blood tests are moderately useful for identifying clinically significant fibrosis or cirrhosis in HCV-infected patients. Primary funding source Agency for Healthcare Research and Quality.

The Liver as an Endocrine Organ-Linking NAFLD and Insulin Resistance.

Abstract: The liver is a dynamic organ that plays critical roles in many physiological processes, including the regulation of systemic glucose and lipid metabolism. Dysfunctional hepatic lipid metabolism is a cause of nonalcoholic fatty liver disease (NAFLD), the most common chronic liver disorder worldwide, and is closely associated with insulin resistance and type 2 diabetes. Through the use of advanced mass spectrometry "omics" approaches and detailed experimentation in cells, mice, and humans, we now understand that the liver secretes a wide array of proteins, metabolites, and noncoding RNAs (miRNAs) and that many of these secreted factors exert powerful effects on metabolic processes both in the liver and in peripheral tissues. In this review, we summarize the rapidly evolving field of "hepatokine" biology with a particular focus on delineating previously unappreciated communication between the liver and other tissues in the body. We describe the NAFLD-induced changes in secretion of liver proteins, lipids, other metabolites, and miRNAs, and how these molecules alter metabolism in liver, muscle, adipose tissue, and pancreas to induce insulin resistance. We also synthesize the limited information that indicates that extracellular vesicles, and in particular exosomes, may be an important mechanism for intertissue communication in normal physiology and in promoting metabolic dysregulation in NAFLD.