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Hepatitis D virus (HDV) infection represents the most serious form of chronic hepatitis. Turkey is among the countries with high HDV and intermediate hepatitis B virus prevalence. In Turkey, hepatitis B virus (HBV) vaccine series was included in the routine vaccination program in 1998. There have been regional differences in prevalence of HBV and HDV. Although a decline in HDV prevalence is estimated, there are uncertainties about the epidemic patterns of it. HDV prevalence was studied in varying groups and geographic regions. In this study, we aimed to analyse hepatitis D epidemiology in all groups and geographic regions in recent 35 years. During the study period of 35 years, 111 publications were noted. The analysis was done on the basis of three periods: 1999 and before (Period 1), 2000–2009 (Period 2), and 2010 and after (Period 3). The groups studied included inactive carrier state, chronic hepatitis B, all HBsAg‐positive individuals and special groups. Among inactive HBV carriers, HDV prevalence did not change significantly over three decades. Among patients with chronic hepatitis, studies reported decreasing (from Period 1 to Period 2) and then increasing (from Period 2 to period 3) HDV prevalence. The studies including all HBsAg‐positive patients reported decreasing (from Period 1 to Period 2) and then increasing (from Period 2 to period 3) HDV prevalence. Cumulative data of these 3 groups were taken to reveal HDV prevalence in HBV‐infected patients, and it showed decreasing (from Period 1 to Period 2) and then increasing (from Period 2 to period 3) HDV prevalence. Cumulative data of these 3 groups analysed according to the geographic regions of the country showed that Eastern and Southeastern Anatolia regions still have a high burden of HDV. The study showed that although HDV prevalence decreased from 8.3% in Period 1 to 4.8% in Period 2, it tended to increase 5.5% in Period 3. HDV infection is still a healthcare problem in Turkey. [ABSTRACT FROM AUTHOR]

Hepatitis delta virus (HDV) infection causes the most severe form of viral hepatitis. PEG‐interferon alpha‐2a (PEG‐IFNα‐2a) is the only effective treatment but its long‐term clinical impact is unclear. The aim of this study was to investigate the long‐term outcome after 48 weeks of pegylated interferon alpha‐2a therapy. We performed a retrospective follow‐up study of the Hep‐Net‐International‐Delta‐Hepatitis‐Intervention‐Study 1 (HIDIT‐I trial). Patients had received 48 weeks of treatment with either PEG‐IFNα‐2a plus adefovir dipivoxil (ADV) (Group I), PEG‐IFNα‐2a alone (Group II) or adefovir dipivoxil alone (Group III). Liver‐related complications were defined as liver‐related death, liver transplantation, liver cancer and hepatic decompensation defined as development of Child‐Pugh scores B or C or an increase in Model for End‐stage Liver Disease (MELD) scores of five or more points in relation to baseline values. Patients were considered for further analysis when they were retreated with PEG‐IFNα‐2a. Follow‐up data (at least 1 visit beyond post‐treatment week 24) were available for 60 patients [Group I, (n = 19), Group II (n = 20), Group III (n = 21)]. Mean time of follow‐up was 8.9 (1.6 ‐ 13.4) years. 19 patients were retreated with IFN‐based therapy: 42% (n = 8) in PEG‐IFNα‐2a arms and 58% (n = 11) in the adefovir only arm. Clinical complications on long‐term follow‐up occurred in 17 patients and were associated with nonresponse to therapy and baseline cirrhosis. The annual event‐free survival rate in patients with cirrhosis vs noncirrhotic patients at year 5 and 10 was 70% vs 91% and 35% vs 76%. Long‐term follow‐up of a large randomized clinical trial suggests that off‐treatment HDV RNA response to PEG‐IFNα‐2a treatment leads to improved clinical long‐term outcome. [ABSTRACT FROM AUTHOR]

Serum Hepatitis B core‐related antigen (HBcrAg) level moderately correlates with cccDNA. We examined whether HBcrAg can add value in monitoring the effect of peginterferon (PEG‐IFN) therapy for HBeAg‐negative chronic hepatitis B (CHB) infection. Thus, serum HBcrAg level was measured in 133 HBeAg‐negative, mainly Caucasian CHB patients, treated with 48 weeks of PEG‐IFN alfa‐2a. We assessed its association with response (ALT normalization & HBV DNA < 2000 IU/mL) at week 72. HBcrAg level strongly correlated with HBV DNA level (r = 0.8, P < 0.001) and weakly with qHBsAg and ALT (both r = 0.2, P = 0.01). At week 48, mean HBcrAg decline was −3.3 log U/mL. Baseline levels were comparable for patients with and without response at week 72 (5.0 vs 4.9 log U/mL, P = 0.59). HBcrAg decline at week 72 differed between patients with and without response (−2.4 vs −1.0 log U/mL, P = 0.001), but no cut‐off could be determined. The pattern of decline in responders resembled that of HBV DNA, but HBcrAg decline was weaker (HBcrAg −2.5 log U/mL; HBV DNA: −4.0 log IU/mL, P < 0.001). For early identification of nonresponse, diagnostic accuracy of HBV DNA and qHBsAg decline at week 12 (AUC 0.742, CI‐95% [0.0.629‐0.855], P < 0.001) did not improve by adding HBcrAg decline (AUC 0.747, CI‐95% [0.629‐0.855] P < 0.001), nor by replacing HBV DNA decline by HBcrAg decline (AUC 0.754, CI‐95% [0.641‐0.867], P < 0.001). In conclusion, in Caucasian patients with HBeAg‐negative CHB, decline of HBcrAg during PEG‐IFN treatment was stronger in patients with treatment response. However, HBcrAg was not superior to HBV DNA and qHBsAg in predicting response during PEG‐IFN treatment. [ABSTRACT FROM AUTHOR]

Summary: Background: Various treatment combinations of peginterferon (PEG‐IFN) and nucleos(t)ide analogues have been evaluated for chronic hepatitis B (CHB), but the optimal regimen remains unclear. Aims: To study whether PEG‐IFN add‐on increases response compared to entecavir (ETV) monotherapy, and whether the duration of ETV pretreatment influences response. Methods: Response was evaluated in HBeAg positive patients previously treated in two randomized controlled trials. Patients received ETV pretreatment for at least 24 weeks and were then allocated to 24‐48 weeks of ETV+PEG‐IFN add‐on, or continued ETV monotherapy. Response was defined as HBeAg loss combined with HBV DNA <200 IU/mL 48 weeks after discontinuing PEG‐IFN. Results: Of 234 patients, 118 were assigned PEG‐IFN add‐on and 116 continued ETV monotherapy. Response was observed in 38/118 (33%) patients treated with add‐on therapy and in 23/116 (20%) with monotherapy (P = 0.03). The highest response to add‐on therapy compared to monotherapy was observed in PEG‐IFN naive patients with HBsAg levels below 4000 IU/mL and HBV DNA levels below 50 IU/mL at randomization (70% vs 34%; P = 0.01). Above the cut‐off levels, response was low and not significantly different between treatment groups. Duration of ETV pretreatment was associated with HBsAg and HBV DNA levels (both P < 0.005), but not with response (P = 0.82). Conclusions: PEG‐IFN add‐on to ETV therapy was associated with higher response compared to ETV monotherapy in patients with HBeAg positive CHB. Response doubled in PEG‐IFN naive patients with HBsAg below 4000 IU/mL and HBV DNA below 50 IU/mL, and therefore identifies them as the best candidates for PEG‐IFN add‐on (Identifiers: NCT00877760, NCT01532843). [ABSTRACT FROM AUTHOR]

Summary: Addition of peginterferon alpha (PEG‐IFN add‐on) to entecavir (ETV) treatment after a short lead‐in phase results in more response than ETV monotherapy in HBeAg‐positive chronic hepatitis B infection (CHB). This study is the first to assess long‐term efficacy of this treatment strategy. Patients who received ETV ± 24 weeks of PEG‐IFN add‐on in a global trial (ARES study) and completed follow‐up were eligible to participate in this observational LTFU study if they had at least one combined HBeAg and HBV DNA measurement beyond week 96 of the ARES study. The primary endpoint was combined response (HBeAg loss and HBV DNA <200 IU/mL) at LTFU. In total, 48 patients treated with PEG‐IFN add‐on and 48 patients treated with ETV monotherapy were included. The median follow‐up duration was 226 (IQR 51) weeks, and 86/96 (90%) patients were initial non‐responders. At LTFU, combined response was present in 13 (27%) vs 11 (23%) patients (P = 0.81), and 1 log10 HBsAg decline in 59% vs 28% (P = 0.02) for PEG‐IFN add‐on and ETV monotherapy, respectively. In 41 initial non‐responders who continued ETV therapy, combined response at LTFU was present in 9 patients (PEG‐IFN add‐on: 5/22 [23%]; ETV monotherapy: 4/19 [21%]). Beyond week 96 of follow‐up, rates of serological response became comparable between PEG‐IFN add‐on and ETV monotherapy. Although in this LTFU study initial non‐responders were overrepresented in the add‐on arm, PEG‐IFN add‐on possibly leads rather to accelerated HBeAg loss than to increased long‐term HBeAg loss rates. [ABSTRACT FROM AUTHOR]

Background & Aims Immunohistochemical assessment of liver tissue in chronic delta hepatitis ( CDH) is underinvestigated. Aim of the study was (i) to assess variables associated with hepatitis D antigen ( HDAg), hepatitis B surface antigen ( HBsAg) and hepatitis B core antigen ( HBcAg) staining in the liver. Methods Demographic, biochemical and virologic data collected from the HIDIT 1 study were used. HBsAg, HBcAg and HDAg immunohistochemical ( IHC) staining was semiquantitatively assessed. Results Hepatitis D antigen immunohistochemical staining displayed positive correlations with age and alanine aminotransferase ( ALT) and negative correlations with serum HBsAg ( P = 0.01 for all). HBsAg IHC displayed a negative correlation with gamma glutamyl transferase and positive correlations with serum HBV DNA, serum HBsAg levels and HBeAg serology ( P < 0.001, P = 0.02 and P = 0.007 respectively). HBcAg staining was mainly nuclear and displayed negative correlations with serum HBsAg and histologic activity ( P = 0.002 and P = 0.02 respectively). Pegylated IFN based treatment led to a decline of all IHC markers, however, these markers had no impact on treatment outcome. Conclusions These data suggest an association of liver injury with HDAg expression in CDH whereas the negative correlation between HBcAg expression and liver injury and the overall nuclear localization of HBcAg suggest that HBcAg does not contribute to liver injury in CDH. HDV cases with high level of HBV replication, high serum HBsAg levels, HBeAg positivity, that are probably in the earlier stages of disease (low gamma-glutamyl transferase), had a more intense HBsAg staining profile. Overall, the data enforce the importance of HDAg and HBsAg in different phases of CDH infection. [ABSTRACT FROM AUTHOR]

Background and Aim: Delta hepatitis is characterized by rapidly progressive liver disease with adverse prognosis in most patients. Patients benefit from high doses and prolonged courses of interferon (IFN) therapy; however, lamivudine as a single agent has been disappointing. Data relating to the efficacy of IFN and lamivudine in combination is limited. The aim of this study was to test the efficacy of IFN-α 2b and lamivudine combination treatment in comparison to IFN-α 2b alone in patients with chronic delta hepatitis. Methods: Twenty-six patients with chronic delta hepatitis were randomized into two groups. Twelve patients received IFN-α 2b alone (eight men, four women; mean ± SD age: 43.83 ± 8.57 years), and 14 patients received IFN-α 2b plus lamivudine combination (seven men, seven women; mean ± SD age: 42.5 ± 11.02 years). The dose of IFN-α 2b was 10 MU t.i.w. and of lamivudine was 100 mg/day. The groups were comparable in reference to serum alanine aminotransferase (ALT), aspartate aminotransferase, bilirubin, albumin levels, histological activity and stage. Four patients (33.3%) in the IFN group and two (14.3%) in the combination group had cirrhosis ( P = 0.2). The duration of treatment was 48 weeks with an untreated follow-up period of at least 96 weeks (mean ± SD, 3.1 ± 1.9 years). A liver biopsy was performed at the end of treatment. Results: Eight patients from the IFN group and 11 from the combination group completed treatment. Serum ALT values became normal in 8/14 patients (57.1%) treated with IFN plus lamivudine and in 5/12 patients (41.7%) treated with IFN alone ( P = 0.43). Serum hepatitis delta virus RNA was no longer detectable in nine of 14 (64.3%) patients treated with IFN plus lamivudine as compared to five of 12 (41.6%) patients treated with IFN alone ( P = 0.024). In both groups female patients had significantly better virological response rate ( P = 0.007). There was a significant improvement in histological activity in the combination group (mean decrease 5.27 ± 1.08 score, P = 0.001), but not in the IFN group (mean decrease 1.44 ± 1.59 score, P = 0.39). No significant improvement was observed in regards to fibrosis. Four of the 14 patients (28.6%) treated with combination therapy as compared to two of 12 patients treated with IFN (16.7%) were sustained virological responders ( P = 0.47). The 5-year survival rate was 65% in the IFN group and 85% in the combination group ( P > 0.05). Conclusion: Interferon and lamivudine in combination is an encouraging treatment method and may be superior to IFN alone in chronic delta hepatitis. [ABSTRACT FROM AUTHOR]

We aimed to determine the following things: the frequency of patients with Mediterranean spotted fever (MSF) during the last 10 years among those patients admitted with fever and rash, their clinical features, and the factors predicting the diagnosis of MSF among patients admitted with fever and rash. Between 1993–2002, the files of all patients admitted to our hospital with fever and rash were collected. The clinical features and serologic results of the patients diagnosed with MSF were further investigated. The diagnosis of MSF was established by epidemiological and clinical features and also by the clinical response within 2 days after doxycycline treatment. During the previous 10 years, 140 patients were admitted with fever and rash, and 15 (10%; four females, 11 males; mean age: 41 years; range: 17–70) of them were diagnosed with MSF. Clinical features were as follows: fever (100%), rash (100%), myalgia and/or arthralgia (93%), headache (87%), petechiae (27%), tache noire (13%), leucocytosis (74%), thrombocytopenia (33%), and accelerated erythrocyte sedimentation rate (100%). In nine of these patients, the diagnosis of MSF was established by epidemiological and clinical features and was confirmed by serologic studies. As a complication, one patient developed facial paralysis. Six (40%) were given several antibiotics. In conclusion, MSF should be considered in the differential diagnosis when a patient is admitted with fever, maculopapular rash, headache, myalgia and/or arthralgia, especially in spring, summer, or autumn. [ABSTRACT FROM AUTHOR]

Abstract: Metronidazole and ornidazole, synthetic nitroimidazole derivatives, are used in the treatment of infections caused by anaerobic bacteria and protozoa. The drugs are well tolerated and serious side effects are very rarely encountered. Hepatotoxicity is a rare side effect and hitherto only six cases have been reported. We describe three patients who developed hepatitis after ornidazole use and review the previously reported cases. All three cases used ornidazole in conventional doses and developed hepatitis and associated cholestasis. They improved 1–2 months after discontinuation. We concluded that nitroimidazole derivatives may cause hepatotoxic damage resembling acute cholestatic hepatitis. Early recognition and withdrawal of the drug may prevent further damage. [ABSTRACT FROM AUTHOR]

Abstract Aims: The aim was to test the efficacy of a pre-S2-containing vaccine (Genhevac-B) in chronic hepatitis B (CHB). Twenty-five naive patients (22 male, three female; median age 35; range: 6–69 years) with CHB were recruited. The inclusion criteria were: hepatitis B e antigen (HBeAg) positive or HBV-DNA detectable with liquid hybridization; alanine aminotransferase (ALT) is at least 1.5-fold the upper normal limit and histological evidence of chronic hepatitis. Methods: In the first period, all patients received monthly injections of 20, 40 and 60 μg of the vaccine. One month after the last injection, patients who still had HBV-DNA were divided into two randomly assigned groups. While the patients in the first group and the patients who lost HBV-DNA in the first period continued to receive monthly injections of 20 μg vaccine for a further 6 months, the patients in the second group received 9 MU interferon α-2b (Roferon-A), three times per week using the same method as for the first group. Patients were followed up after 12 months without treatment. Response was defined as the loss of HBV-DNA and normalization of ALT. Results: Six of the 25 patients lost HBV-DNA after 3 months. Nine of the remainder were randomly placed in the first group (vaccine-only) and 10 were placed in the second group (vaccine + interferon). End-of-treatment response was achieved, overall, 8/15 from the vaccine group and 6/10 from the combination. One patient from each group relapsed during the follow up. Overall, the sustained response (SR) rate was 46% (7/15) in the vaccine group, and 50% (5/10) in the combination group. Histological improvement was achieved in 6/7 SR with vaccine-only and all five with combination treatment, while 1/8 of failures of vaccine and 2/5 of failures of combination improved. Conclusions: It was concluded that Genhevac-B decreases serum HBV-DNA levels in the majority of patients with CHB and sustained clearance was achieved in some... [ABSTRACT FROM AUTHOR]

Objective: The aim of the study was to determine the clinical, radiographic and laboratory characteristics, diagnostic methods, and prognostic variables in patients with miliary tuberculosis (TB). Methodology: The records of 38 patients (15 male, 23 female; mean age 41 years, range 16–76 years) with miliary TB from 1978 to 1998 were analyzed. Patients were evaluated also as to whether they presented with a fever of unknown origin (FUO). Criteria for the diagnosis of miliary TB were (i) miliary pattern on chest X-ray or (ii) biopsy or autopsy evidence of miliary organ involvement. Paraffin-embedded tissues with granulomata (n = 15) were re-evaluated for the presence of Mycobacterium tuberculosis DNA by polymerase chain reaction (PCR). Results: Predisposing conditions were present in 24% of the patients. The findings were fever, weakness, night sweats, anorexia/weight loss (100% for each), hepatomegaly (37%), splenomegaly (32%), choroidal tubercles (13%), neck stiffness (11%), altered mental status (8%), anaemia (76%), leukopenia (26%), thrombocytopenia (16%), lymphopenia (76%), pancytopenia (8%) and hypertransaminasemia (55%). Eighteen patients (47%) met the criteria for a FUO. Miliary infiltrates were found on chest X-rays of 32 of 38 cases (84%). In six cases without miliary infiltrates, the diagnosis was made by laparotomy in four cases, and autopsy in two cases. Tuberculin skin test was positive in 32% of cases. Acid-fast bacilli were demonstrated in 37% (16/43), and cultures for M. tuberculosis were positive in 90% (9/10) of tested specimens (predominantly sputum and bronchial lavage). Granulomas were found in 85% (11/13) of lung, 100% (15/15) of liver, and 56% (9/16) of bone marrow tissue specimens. Acid-fast bacilli staining was negative in all (0/21), while PCR was positive in 47% (7/15) of specimens with granulomata. Mortality was 18%. Stepwise logistic regression identified male sex (P = 0.005), non-typical miliary pattern (P = 0.015), altered mental status (P = 0.002) and failure to treat for TB (P = 0.00001) as independent predictors of mortality. Conclusions: Miliary infiltrates on chest X-ray or FUO should raise the possibility of miliary TB. Therapy should be administered urgently to prevent an otherwise fatal outcome. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the development of acrocyanosis with amphotericin B deoxycholate and not amphotericin B lipid complex.

Studies the diagnosis of tuberculosis. Evaluation of biopsy tissue for acid-fast bacilli; Polymerase chain reaction assay to detect Mycobacterium tuberculosis.

Erythema nodosum (EN) is seen only in the primary tuberculosis (TB) form of tuberculous diseases. Among the etiologies of EN, TB is the most frequent disorder in developing countries. We aimed to assess our patients with EN in reference to primary TB. We evaluated 335 patients with the diagnosis of TB during last 20 years; retrospectively 61 (18%) of these cases had pulmonary and 274 (82%) had extrapulmonary TB. Ten (16%) of the pulmonary TB cases were primary. All 10 patients with primary TB presented with EN. Among 50 patients with EN diagnosed and followed during the last 10 years, the etiology was determined in 56%, and primary TB was the most frequent: 20%.

Pyrimethamine is used for the treatment of toxoplasmosis and the prophylaxis of malaria. Among the well-documented side effects are megaloblastic anemia, leukopenia, thrombopenia, rash, vomiting, and diarrhea. Hyperpigmentation is a very rare side effect. In some patients, associated HIV infection makes it difficult to distinguish the reasons for the etiology. We herein describe an HIV-negative patient who developed hyperpigmentation after pyrimethamine use.