Efficacy and safety of grazoprevir + ribavirin for 12 or 24 weeks in treatment-naïve patients with hepatitis C virus genotype 1 infection.

Grazoprevir (GZR) is a second-generation hepatitis C virus NS3/4A protease inhibitor. The aim of this study was to evaluate GZR plus ribavirin (RBV) in patients with HCV GT1 infection. Noncirrhotic, IL28B CC patients with HCV genotype 1 infection were randomized to GZR 100 mg once daily and RBV for 12 or 24 weeks. Patients in the 12-week arm with detectable HCV RNA at treatment week 4 (TW4) had treatment extended to 24 weeks (response-guided therapy, RGT). The primary endpoint was sustained virologic response (SVR12) at follow-up week 12 (HCV RNA <25 IU/mL) in the per-protocol (PP) population (excluding patients with important protocol deviations). Twenty-six patients were randomized and 22 were included in the PP population. SVR12 was 58.3% (7 of 12) and 90% (9 of 10) in the RGT and 24-week arms, respectively. Seven PP patients had virologic failure, including one patient in the 24-week arm who relapsed after follow-up week 12. All three breakthrough patients had wild-type (WT) virus at baseline and developed breakthrough at TW6 or TW12 with Y56H, A156T and D168A/N mutations. Of the five relapse patients, four had WT at baseline (at relapse three had WT and one had V55A and D168A), and one had S122A/T at baseline and S122T at relapse. There were no serious adverse events (AEs), discontinuations due to AEs or grade 3/4 elevations in total and/or direct bilirubin. Grazoprevir plus RBV was associated with a rapid and sustained suppression of HCV RNA. These results support further evaluation of grazoprevir-based regimens (NCT01716156; protocol P039).

Chronic hepatitis C infection and sex hormone levels: effect of disease severity and recombinant interferon-alpha therapy.

BACKGROUND: We aimed to investigate the associations between androgen status and markers of liver disease severity and to determine the effect of interferon-alpha (IFN-alpha) treatment on sex hormone levels in the context of hepatitis C infection. METHODS: We audited liver biopsy and sex hormone data from 35 men with chronic hepatitis C and a separate group of 11 men with hepatitis C who received IFN-alpha treatment at Fremantle Hospital. RESULTS: We found that men with low fibrosis scores (0-2) on the modified Knodell histological activity index were more likely to have lower sex hormone-binding globulin (SHBG) levels (38.2 +/- 13.2 vs 66.6 +/- 43.3 nmol/L, P < 0.001) and higher free testosterone levels (380.4 +/- 102.0 vs 255.9 +/-83.0 pmol/L, P = 0.01) than those with higher fibrosis scores (3-6). SHBG directly correlated with fibrosis scores (r = 0.37, P = 0.032). Free testosterone levels inversely correlated with liver fibrosis scores (r = -0.43, P = 0.011). A transient reduction in total testosterone of 5.7 +/- 4.2 nmol/L (P = 0.014) occurred within the first 6 months of IFN-alpha therapy although free testosterone was unaffected. CONCLUSION: More severe liver disease was associated with lower free testosterone and higher SHBG. IFN-alpha therapy reduced total testosterone but not to hypogonadal levels, with no decline in free testosterone. These data suggest that liver disease in hepatitis C infection modulates androgen status indirectly via increased SHBG. Screening for androgen deficiency in the context of hepatitis C infection should selectively target men with more severe liver disease or documented higher grade fibrosis.

Induction interferon and ribavirin for re-treatment of chronic hepatitis C patients unresponsive to interferon alone.

BACKGROUND: The optimal treatment for hepatitis C patients unresponsive to interferon is unclear. High-dose induction interferon may enhance early viral clearance, whilst ribavirin reduces relapse; in combination, they may improve sustained virological response rates. AIM: To compare the efficacy and safety of re-treatment with interferon induction, with or without ribavirin, in interferon non-responders. METHODS: We randomized 218 biochemical interferon non-responders to 10 MU interferon alpha 2b daily for 4 weeks, followed by 5 MU thrice weekly for 48 weeks plus ribavirin (II + R), or to the same interferon regimen plus placebo (II + P). All patients were viraemic at entry. RESULTS: The sustained virological response in the II + R group was 39%[95% confidence interval (CI), 30-48%], compared with 16% (95% CI, 9-23%) in the II + P group (P < 0.002). The study drug was discontinued for intolerable symptoms during induction in 9% of the II + R group and in 5% of the II + P group. By logistic regression, a sustained virological response was more likely following II + R treatment (odds ratio, 4.4; 95% CI, 2.1-9.7) and less likely in patients with genotype 1 or 4 (odds ratio, 0.16; 95% CI, 0.07-0.36). CONCLUSION: High-dose induction interferon plus ribavirin is well tolerated and effective for patients unresponsive to interferon alone.

Mycoplasma hominis pneumonia in aboriginal adults.

Mycoplasma hominis (M. hominis) is a well recognized extragenital pathogen. Its role as a pathogen of the respiratory tract, however, remains difficult to determine. Four cases of pneumonia are presented in which M. hominis was isolated from blood, tracheal aspirates or post-mortem lung tissue. All 4 of these isolates were in young Aboriginal adult males. M. hominis is the least fastidious of the human mycoplasmas and grows well on most blood-containing bacteriological media. The recognition and identification of M. hominis is important as it is commonly resistant to erythromycin which would be the drug of choice in most atypical pneumonias. Early recognition and treatment with tetracycline instead may influence outcome.

Diphtheria: another risk of travel.

A 19-year-old woman presented with cellulitis of her foot 10 days after returning from Bali. Swabs of a central necrotic area grew toxigenic Corynebacterium diphtheriae biotype gravis. The patient was treated with parenteral penicillin and made a complete recovery. Diphtheria immunisation should be regularly updated for travellers to the tropics. Clinical and laboratory recognition of this infection is essential for appropriate public health measures to be undertaken.

Cerebral infarction following thoracic herpes zoster.

OBJECTIVE: To present a case of cerebral infarction following thoracic herpes zoster presenting as Gerstmann's syndrome. CLINICAL FEATURES: A 61 year old male developed herpes zoster of T 1-2 dermatomes. Four months later he developed a confusional state together with expressive aphasia, dyscalculia, dysgraphia and finger agnosia with no long tract signs. CT scan of head showed recent infarction of this left parietal lobe. He received a five day course of acyclovir 800 mg four times daily and showed slow but steady improvement. CONCLUSION: Herpes zoster is uncommonly followed by cerebral infarction. Acyclovir may have a role in therapy of this complication.

Invasive pneumococcal disease in central Australia.

Invasive pneumococcal disease remains a major problem in certain groups of people. We undertook a hospital-based review of all cases of invasive pneumococcal disease in central Australia over a 2-year period. We observed 79 cases of invasive disease in 78 patients. The incidence of invasive pneumococcal disease was highest in Aborigines under 5 years of age (1,025 cases per 100,000 population per year). The relative risk for Aborigines compared with non-Aborigines was 31.6 (95% CI, 12.8-78.1). Pneumonia was the commonest disease observed (82% of patients). Eight patients died (10.1%), and all of these patients had identifiable risk factors for pneumococcal disease. Serotyping showed that all except two isolates were covered by the existing 23-valent pneumococcal vaccine. These data reveal that Aborigines in central Australia have the highest reported rate of invasive pneumococcal disease in the world. A vaccination program in central Australia should decrease admissions and deaths due to pneumococcal disease.

Group C streptococcal meningitis.

Group C streptococci have been infrequently described as human pathogens. A case of meningitis caused by Streptococcus dysgalactiae, in a 73-year-old man with alcoholic liver disease, was treated successfully with penicillin and chloramphenicol.

Red-back spider envenomation in the red centre of Australia.

OBJECTIVE: To examine the incidence, symptoms and treatment of red-back spider envenomation at a rural hospital. METHODS: A retrospective review of all patients admitted to the intensive care unit of Alice Springs Hospital with red-back spider envenomation from 1 January 1991 until 31 December 1992. RESULTS: Thirty-two patients were identified, of whom 12 were Australian Aboriginals (35%). Mean time from bite to presentation was 21 hours. Twenty-six patients required antivenom. All patients responded well to therapy and adverse reactions to the antivenom were observed. Two antivenom recipients had had previous bites requiring treatment. Aboriginals received antivenom later than non-Aboriginals (27.0 h v. 16.5 h) and this delay was associated with more sweating and fever in Aboriginals. CONCLUSION: Red-back spider envenomation is common in Central Australia. Aboriginals and non-Aboriginals are equally at risk but later presentation is more common in Aboriginals who thereby suffer greater systemic symptoms. Antivenom use is safe and effective.

Hypothyroidism due to destruction of the thyroid by Kaposi's sarcoma.

A case of hypothyroidism that manifested as depression and deteriorating functional status and that ultimately resulted in the death of a 41-year-old patient with AIDS is described. Postmortem examination revealed destruction of the thyroid gland by Kaposi's sarcoma. Analysis of stored serum samples revealed that the patient had become profoundly hypothyroid during his terminal illness. Practitioners are reminded of the need to exclude metabolic causes when treating encephalopathy in patients infected with human immunodeficiency virus.

Prostaglandin E1 for the treatment of primary non-function of the donor organ in liver transplantation.

OBJECTIVE: To present a case in which acute failure of a liver graft was treated with an infusion of prostaglandin E1 (PGE1). CLINICAL FEATURES: A nine-year-old girl underwent liver transplantation for Wilson's disease. Her course was complicated by primary non-function of the graft as evidenced by poor bile production, rising bilirubin and liver enzyme levels and a severe coagulopathy. INTERVENTION AND OUTCOME: PGE1 was infused and there was recovery of graft function. The need for urgent re-transplantation was avoided. CONCLUSIONS: PGE1 may have an important role in liver transplantation considering the logistic difficulties of obtaining donor livers for urgent transplantation in Australia.

Bullous pemphigoid in an Aborigine.

OBJECTIVE: To present the first case of bullous pemphigoid in an Australian Aborigine. CLINICAL FEATURES: A 47 year old female aborigine presented with a three week history of a generalised skin eruption consistent with bullous pemphigoid. Immunohistological examination confirmed the diagnosis. Therapy required high dose oral steroids, azathioprine and erythromycin as well as topical agents. Treatment was complicated by isolation and poor compliance but was ultimately successful in inducing and retaining remission. CONCLUSION: This is the first description of bullous pemphigoid in an Australian Aborigine. We recommend early biopsy to confirm diagnosis and plan therapy, and careful attention to patient education to encourage compliance.

Australian doctors' beliefs and practice regarding Helicobacter pylori.

OBJECTIVE: To determine beliefs and behaviours of Australian doctors regarding Helicobacter pylori. DESIGN: Anonymous reply-paid postal survey mailed in December 1995 and again in March 1996. SUBJECTS: All members on the mailing lists of the Gastroenterological Society of Australia Endoscopy Section (n = 397) and the Australian Society of Infectious Diseases (n = 264; those without medical qualifications were asked not to reply), and 400 general practitioners (GPs) randomly selected from the Royal Australian College of General Practitioners. MAIN OUTCOME MEASURES: Differences between specialist groups in belief in a causative association between H. pylori and peptic disease and in use of eradication therapy and pre- and post-treatment testing for H. pylori. RESULTS: 92.6% of doctors believed H. pylori causes duodenal ulcer, with GPs significantly less likely to believe than gastroenterologists (odds ratio [OR], 0.22; 95% confidence interval [CI], 0.00-0.81). In duodenal ulcer, 93.4% of doctors believed H. pylori eradication therapy should be given, but fewer (83.4%) claimed to give it "always or mostly", with GPs less likely to report giving it than gastroenterologists (OR, 0.06; 95% CI, 0.02-0.19). For non-ulcer dyspepsia, gastrointestinal surgeons were more likely than gastroenterologists to believe in a causative link with H. pylori (OR, 5.6; 95% CI, 3.0-10.7) and in a need for eradication therapy (OR, 3.6; 95% CI, 1.7-7.7). Most doctors (79.3%) believed in confirming the presence of H. pylori before eradication therapy in duodenal ulcer. Only 51.6% believed post-eradication testing necessary (45.5%), yet 79.1% reported performing it. CONCLUSIONS: Significant differences exist between specialist groups in beliefs and self-reported behaviours regarding H. pylori.

Antibiotic resistance in Helicobacter pylori.

OBJECTIVE: To describe antibiotic resistance patterns in Helicobacter pylori. DESIGN: Culture and antibiotic sensitivity testing of antral and gastric body biopsy samples from patients having gastroscopy. PARTICIPANTS: Consecutive consenting patients aged 18 years or more presenting for gastroscopy from 1 July 1998 to 30 June 1999. SETTING: An open-access gastroscopy service at an urban university tertiary hospital. MAIN OUTCOME MEASURES: Number of H. pylori isolates showing resistance to antibiotics; correlates of such resistance with demographic and clinical information. RESULTS: Of 1580 patients undergoing endoscopy, 434 agreed to participate in the study. 108 (24.9%) had positive cultures for H. pylori, and 88 of these isolates (81%) were available for further testing. Resistance to metronidazole and clarithromycin was detected in 36% and 11%, respectively. No resistance was found to tetracycline or amoxycillin. Metronidazole resistance was commoner in younger patients (P = 0.0004) and macrolide resistance was commoner in those born outside Australia or New Zealand (P = 0.03). CONCLUSIONS: We found substantial resistance to metronidazole, and emerging clarithromycin resistance, but complete susceptibility to amoxycillin, tetracycline, gentamicin and cefaclor. These factors may influence the effectiveness of presently recommended eradication regimens.

Tropical spastic paraparesis in an aborigine.

OBJECTIVE: To present the first documented case of human T-lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis in the Australian population. CLINICAL FEATURES: A 31-year-old Aboriginal man with an 18-month history of progressive weakness of the legs was found to have an upper motor neurone weakness of all limbs associated with sphincteric disturbance and impotence. HTLV-I antibodies were detected in his serum and no other cause for the patient's myelopathy could be found. INTERVENTION AND OUTCOME: He was counselled regarding HTLV-I associated myelopathy/tropical spastic paraparesis. CONCLUSION: This is the first description of HTLV-I associated myelopathy/tropical spastic paraparesis in an Australian. In cases of spinal cord disorder without evidence of compression we recommend serological testing for HTLV-I, especially in Aboriginal patients. Additionally, testing of blood donors for this retrovirus needs consideration.

Hepatitis due to nitrofurantoin.

OBJECTIVE: To report three cases of hepatitis related to the use of nitrofurantoin. CLINICAL FEATURES: Two patients who had been taking nitrofurantoin for several years, presented with severe liver failure. In both, the drug had been continued despite evidence of liver injury. A third patient presented with acute hepatitis after six weeks of nitrofurantoin therapy. INTERVENTION AND OUTCOME: One of the patients with liver failure died and the other underwent a successful liver transplantation. The third patient recovered after withdrawal of the drug. CONCLUSION: These cases emphasise the potential for serious hepatic reactions with nitrofurantoin, the danger of continuing the drug once liver damage has occurred and the need for careful monitoring of liver function during long-term therapy.

Upper gastrointestinal endoscopy in central Australian aborigines.

OBJECTIVES: To examine the upper gastrointestinal endoscopic findings in Australian Aborigines in central Australia; to determine if peptic ulceration occurs in this group; and to discover whether this population shares Helicobacter pylori as a risk factor for peptic ulceration. METHODS: A retrospective analysis of the records of all Aboriginal patients undergoing endoscopy at a general hospital over a two-year period. RESULTS: Eighty-five endoscopies were performed in 64 patients. Haematemesis and melaena was the indication for 24 patients (more commonly in men) and a cause was identified in 83% of these patients; varices were the cause in 17%. Pain was an indication for 25 patients (more commonly in females) and abnormalities were detected in 64%. Peptic ulceration was found in nine patients and a further 23 had gastritis or duodenitis. Cases of oesophageal, gastric and duodenal malignancy were seen, as well as late complications of simple diseases, including gastric outlet obstruction, oesophageal stricture and cholecystoduodenal fistula formation. Of 17 gastric biopsies with evidence of inflammation, H. pylori was found in 15 (88%). CONCLUSION: This, the first study of upper gastrointestinal endoscopy in Aborigines, shows its usefulness in the investigation of their gastrointestinal complaints. Oesophageal varices were found to be an important cause of bleeding. Peptic ulceration associated with H. pylori was found to be common.

A prospective study of septic complications of endoscopic retrograde cholangiopancreatography.

Prophylactic antibiotics are used in an attempt to avoid the septic complications of endoscopic retrograde cholangiopancreatography (ERCP). We prospectively performed blood cultures and surveyed patients for complications. The aims were first, to determine the incidence of bacteraemia associated with ERCP, second, to assess the incidence of clinical sepsis following the procedure and third, to evaluate the effectiveness of our antibiotic prophylaxis. One hundred and fifty successive patients underwent 179 ERCP. Bacteraemia related to the procedure or the underlying pathology was found in nine procedures (5.2%). Bacteraemias were more likely to complicate therapeutic procedures (P = 0.015), biliary obstruction (P = 0.045) or underlying pathology (P = 0.022). Although 61% of ERCP received antibiotics, 22 septic events occurred. Five bacteraemic patients were septic despite antibiotics. Septic complications were associated with the same factors as bacteraemia. It was concluded that patients with biliary obstruction and undergoing therapeutic endoscopic procedures are at greatest risk of bacteraemia. Single dose prophylactic antibiotics may not prevent sepsis in these patients and longer-acting drugs or repeated dosing may be necessary.

High-dose oral acyclovir reduces the incidence of cytomegalovirus infection in liver transplant recipients.

To determine the impact of high-dose oral acyclovir on cytomegalovirus (CMV) infection or disease after liver transplantation, CMV cultures were prospectively collected for 6 months after transplantation. The incidence and timing of infection and disease in patients receiving high-dose oral acyclovir (3200 mg/day) from day 7 until 3 months after transplantation were compared with an historical control group who received no acyclovir. All patients who did not receive acyclovir (group 1, n = 12) but only 57% of those who did (group 2, n = 22) had CMV infection (P = .008). Nine (75%) group 1 but only 3 (14%) group 2 patients had positive leucocyte cultures (P = .0007). Three group 1 patients developed CMV disease; 1 group 2 patient developed CMV hepatitis. Each of these 4 patients had CMV viremia (P = .01). The frequency of CMV infection after liver transplantation appears to be reduced by high-dose oral acyclovir.