Unexpected cause of urticaria

A 30-year-old man presented with acute generalised urticaria (Figure, A) 6 hours after ingestion of raw fish. While most adult food allergies occur within 1–2 hours of ingestion, allergy to the live fish parasite Anisakis simplex which has penetrated the gastrointestinal mucosa manifests 1 hour to a few days after ingestion.1 Emergency upper endoscopy detected the live larva in the stomach (Figure, B) and disinfestation resolved his symptoms. Allergy to A. simplex can be confirmed by testing for allergen-specific IgE or skin prick testing with Anisakis extract. Gastrointestinal anisakidosis can be an unexpected cause of urticaria owing to delay between the ingestion of fish and the appearance of symptoms. While most cases of anisakidosis currently occur in Japan, this may become an increasing problem in Australia due to increasing consumption of sushi and sashimi.2

Figure

First reported outbreak of locally acquired hepatitis E virus infection in Australia

Hepatitis E virus (HEV) outbreaks have not previously been reported in Australia. HEV infection mostly occurs in developing countries where transmission occurs via the faecal–oral route and contaminated water, causing large outbreaks.1 HEV genotypes 1 and 2 predominate in these settings.2 Like other forms of acute viral hepatitis, symptoms of HEV include jaundice, malaise, anorexia, fever and abdominal pain.1 The incubation period is 15–64 days.3

Recently, HEV transmission has been reported in developed countries, where infection has occurred via HEV-contaminated food. Consumption of pork products, deer meat, wild boar and shellfish has been implicated, with HEV genotypes 3 and 4 being detected in infected persons.2,4–8

Pigs, in particular, may play a role in human HEV transmission.9 An increased risk of HEV infection associated with the consumption of processed pork products was found by a recent case–control study in the United Kingdom.10 Human and swine HEV strains exhibit a high degree of sequence homology.5,11,12 Occupational exposure may be important, as seroprevalence rates have been found to be higher in pig veterinarians, pig farmers and abattoir workers than in healthy controls.13–15

In Australia, HEV infection is notifiable to state and territory public health authorities. Common laboratory practice has been to test for HEV infection only in those with a history of overseas travel. Each year, 30 to 40 infections in returned travellers from HEV-endemic regions are reported, including 10 to 20 in New South Wales.16

In October and November 2013, NSW Health was notified of two apparently unrelated cases of HEV infection within 2 weeks. Each person had been tested because of preceding overseas travel, albeit outside the incubation period for HEV infection. The HEV RNA isolated from these two people was genetically identical. A family member of one of the patients presented with symptoms of HEV infection 4 weeks later.

In May 2014, we received a further HEV notification, an infection in a man who reported that a work colleague from another state was also infected with HEV. Neither had travelled overseas during their incubation periods. The only common exposure was a meal shared with seven other colleagues at restaurant X, and the index patient reported that three of the seven were symptomatic. All co-diners were interviewed and tested, and HEV RNA was detected in the three symptomatic co-diners. HEV RNA from the five infected persons was genotypically identical, and also with that from two of the three 2013 cases. During routine interview of the three HEV-infected people in 2013, one had reported eating at restaurant X during their incubation period, while another had not. During a follow-up interview in 2014, the third person was specifically asked about this exposure, and reported eating at restaurant X during their incubation period.

In this article we report our epidemiological investigation of the source and extent of the apparent outbreak.

Methods

Epidemiological investigation

Case definition

We defined a case of HEV infection as a person who resided in NSW with laboratory-confirmed HEV, verified by IgG seroconversion or detection of HEV-specific IgM or HEV RNA, with an onset date (or specimen collection date, if onset date was unknown) between 1 January 2013 and 31 December 2014.

Case finding and data collected

We identified cases in three ways:

Routine notification: As part of routine surveillance, pathology laboratories are required by the NSW Public Health Act 2010 to notify public health units of HEV infections. Surveillance specialists interview infected persons, using a standardised questionnaire. The information collected includes symptoms of illness, occupation, travel history, and water and food sources (including restaurants) during the incubation period. When an infected person had eaten at restaurant X, the interviewer asked about details of the food consumed there.
Testing of co-diners from restaurant X: Co-diners of infected persons from restaurant X were interviewed and tested for HEV.
Retrospective serological surveys: We tested all sera stored at a large public laboratory, with specimen dates between 1 September 2013 and 31 May 2014, for which HEV testing had been requested but not conducted because laboratory protocols excluded testing in the absence of a relevant travel history (survey 1). We also tested sera stored at a major NSW private pathology laboratory, with specimen dates between 1 January and 31 May 2014, where the alanine transaminase (ALT) level was > 200 IU/L and hepatitis A, hepatitis B, hepatitis C, Epstein–Barr virus and cytomegalovirus infections had been excluded, but HEV testing was not performed (survey 2).

Laboratory investigation

Serology

Anti-HEV IgM and IgG were detected using HEV IgM ELISA 3.0 and HEV ELISA kits respectively (MP Diagnostics) according to the manufacturer’s instructions. Reactive sera were re-tested and reported as positive if again reactive.

Viral detection and sequencing

Serum samples from confirmed cases were analysed at the Victorian Infectious Diseases Reference Laboratory. HEV RNA was extracted from serum using the QIAamp Viral RNA Mini kit (QIAGEN) and initially tested using a commercial HEV RNA polymerase chain reaction (PCR) assay (RealStar HEV RT-PCR). Samples containing HEV RNA were re-assayed by an in-house PCR assay using primers designed to amplify a portion of open reading frame (ORF) 2. The resulting PCR product was directly sequenced with internal primers. Sequences were aligned and compared with sequences in GenBank.

Environmental investigation

Investigation and food testing linked to restaurant X

Food handling and safety procedures at restaurant X were reviewed on 15 May 2014. Preparation of pork liver pâté was observed in detail. The internal temperature of sliced pork livers was measured by inserting a thermometer into the thickest part after 3 and 4 minutes’ cooking.

Three lots of chorizo sausage, three batches of cooked pork liver pâté, one sample of raw pork shoulder and raw pork jowl, one batch of cooked pork liver and eight raw pork liver samples from restaurant X were collected on 15 and 22 May 2014.

After extraction and purification using the MagMax Total RNA Isolation Kit (Life Technologies), samples were tested for HEV by Advanced Analytical Australia with real-time PCR, using Hepatitis E@ceeram Tools (Ceeram).

Pork products were traced back to their source by identifying the supplier from restaurant records; through the supplier we identified the farms from which the products originated.

Testing of pork liver sausages linked with an HEV case not linked to restaurant X

One of the infected persons without a link to restaurant X reported eating pork liver sausages during their incubation period, and had stored frozen uncooked sausages in a domestic freezer. Multiple samples were collected from several sausages and analysed for HEV at the Virology Laboratory of the Elizabeth Macarthur Agriculture Institute. Nucleic acid was purified and tested by real-time quantitative reverse transcription PCR (qRT-PCR)17 using previously published primers and probe sequences.18

Data analysis

Responses to questionnaires administered to interviewees were transferred to a Microsoft Excel spreadsheet for analysis. Responses about food histories were analysed, and relative risks and confidence intervals calculated using Epi Info 7 (Centers for Disease Control). The Fisher exact test (two-tailed) was used to test for differences between groups; P < 0.05 was defined as statistically significant.

Ethics approval

These studies were conducted as part of a public health investigation under the NSW Public Health Act 2010 and review by a human research ethics committee was not required.

Results

Epidemiological investigation

Notified HEV cases

Between January 2013 and December 2014, 55 cases of HEV infection were notified (Box 1). The median age of the patients was 45 years (range, 4–77 years), 36 (65%) were male, and all but one (98%) lived in metropolitan Sydney. Twenty-four (44%) required hospitalisation, with a reported median length of stay (where known) of 7 days (range, 1–67 days). Three people (identified as co-diners of notified patients) were asymptomatic, and details about symptoms were unknown in one case. ALT levels were elevated in 33 of the 37 patients for whom they were recorded, with a median value of 1058 IU/L (range, 26–4868 IU/L; reference interval, 10–40 IU/L). None were pregnant.

Of the 55 patients, 30 (55%) reported a history of overseas travel during their incubation periods: to South Asia (17), East Asia (six), South-East Asia (two), Africa (two), Europe (two), or the Middle East (one). One patient could not be contacted; the remaining 24 (44%) did not report overseas travel.

Restaurant X outbreak

Restaurant X mainly served dishes suitable for sharing by a group. The menu included more than 28 meat, seafood and vegetarian options. Seventeen cases of HEV infection in nine separate groups who dined between October 2013 and May 2014 were linked to restaurant X. Of these 17, seven were identified by routine surveillance, eight by testing co-diners, and two by the retrospective serosurveys. Two people refused further interview; food histories were collected from the remaining 15 infected persons and from seven dining companions who tested HEV-negative by serology.

The demographic data for the diners is summarised in Box 2; the food items most commonly consumed are listed in Box 3. The highest attack rates were in those who consumed pork liver pâté, pork chorizo or roast pork. All 15 patients who provided a food history reported consuming pork liver pâté, compared with four of the seven uninfected co-diners (P < 0.05).

Locally acquired cases not linked to restaurant X

During interviews, the seven infected persons not linked to restaurant X reported eating a number of pork products during their incubation periods, including supermarket ham, prosciutto, pork liver, homemade pork liver sausage, pork chops and pork belly.

Retrospective serological surveys

Of 136 serosurvey samples (31 in survey 1, 105 in survey 2), nine (6.6%) were IgG-positive, four (2.9%) were IgM-positive, and four (2.9%) were both IgM- and IgG-positive for HEV. Of the eight people who were IgM-positive, HEV RNA was detected in four; sequencing confirmed infection with genotype 3. Two of these four people reported eating at restaurant X but not overseas travel, one reported travel to an HEV-endemic country, and one could not be contacted.

Laboratory investigation

HEV RNA was detected in samples from ten of the 17 restaurant X cases; of the others, five with mild or no symptoms were PCR-negative, one was PCR-negative but showed seroconversion, and a sample was unavailable in one case. Sequencing of the ORF2 region was successful for all ten samples, and the HEV isolate was classified as genotype 3. There was at least 99% between-sample sequence homology in the targeted portion of ORF2 among restaurant X isolates.

HEV RNA was also detected in six of the seven locally acquired infections not linked to restaurant X (the specimen supplied by one person was insufficient for testing): five were genotype 3, and one sample was insufficient for genotyping. The viral sequence of these samples was about 90% homologous with samples from the restaurant-linked cases.

Environmental investigation

Investigation of restaurant X

Restaurant X was found to be well managed; no breaches in food safety or handling were identified. Staff were trained in handwashing and general food safety, including understanding cross-contamination and temperature control. During the observed cooking process, the internal temperature of the pork livers reached 51°C at 3 minutes, and between 82°C and 97°C at 4 minutes.

The livers used for pâté preparation were traced to a single farm. The pork shoulder, jowl and chorizo products were all sourced from different suppliers to the pork livers. HEV was not detected in any of the food samples obtained from the restaurant.

Investigation of pork products of locally acquired cases not linked to restaurant X

Pork products eaten by the seven infected persons not linked to restaurant X were bought from four different butchers and three different supermarkets. Pork livers from two of these butcheries could be traced back to two abattoirs supplied by several farms; further tracing was not undertaken. Pork liver sausages still held by one patient were found to contain very low levels of HEV RNA; the levels were too low for sequencing.

Public health interventions

NSW Health convened an expert panel involving public health, clinical, laboratory, agricultural and industry experts to assess the risks and to guide the investigation. On 15 May 2014, restaurant X was informed about its possible link with a number of cases of HEV infection. The importance of thorough cooking of pork products, including of pork liver pâté, was stressed, and the restaurant voluntarily removed this item from its menu. No further cases of HEV infection were linked to restaurant X.

As part of case finding, NSW Health issued an alert to gastroenterologists and public and private pathology laboratories in May 2014. The information garnered was then used to inform general practitioners in an alert, issued in September 2014, which requested that they consider HEV infection in people with a compatible illness, regardless of overseas travel. A joint media release with the New South Wales Food Authority, also issued in September 2014, urged the public to cook pork products thoroughly and, in particular, to cook pork livers to 75°C at the thickest part for 2 minutes.19

Discussion

This is the first reported Australian outbreak of locally acquired HEV infection and one of the largest linked with a restaurant reported anywhere. Seventeen cases were linked to consuming pork liver pâté at restaurant X during a 9-month period, and seven cases were linked to eating pork products bought from four butchers and three supermarkets with at least two different suppliers.

Retrospective serological testing identified a further eight previously undiagnosed cases of HEV infection (anti-HEV IgM). In two of these cases, HEV RNA was detected in people who reported no overseas travel but who had dined at restaurant X during their incubation periods. A further six cases were notified after the restaurant outbreak, probably as a result of increased vigilance and testing by clinicians. Data from a large public health laboratory confirmed this, with more than triple the number of HEV tests requested and carried out from July to December 2014 (after the laboratory began testing for HEV in people without a travel history) than during the same period in 2013 (unpublished data).

Active case finding among co-diners of restaurant cases detected locally acquired HEV infections that were either asymptomatic or mildly symptomatic, suggesting under-recognition and under-diagnosis of infection. A recent HEV serosurvey of blood donors by the Australian Blood Service identified past HEV infection in 14 of 194 blood donors without a history of overseas travel (7%).20 A case report in the Northern Territory21 and a study in Victoria22 each described single cases of HEV infection in which overseas travel was not implicated and no other risk factors were identified.

Common source outbreaks of HEV infection in high-income countries are rare. However, our investigation concurs with previous French,5 English10 and Japanese11 studies that have linked HEV infection with consumption of undercooked pork products. In these countries, locally acquired HEV infections predominate, and in 2013 accounted for 99% of all cases in France23 and almost 70% of cases in the UK.24

HEV is inactivated by heating to 71°C.19 Review of pork liver pâté preparation at restaurant X found that it was adequately cooked at the time of inspection, and testing available pork samples did not detect HEV RNA. It is nevertheless possible that, at the time of the restaurant infections (some weeks earlier), pork livers contaminated with HEV could have been undercooked at the thickest part before blending into pâté. This may explain the relatively low proportion of patrons infected with HEV at this popular restaurant. While we did not have access to leftover pâté samples from meals served to people infected at restaurant X that could be tested for HEV RNA, it was detected in pork liver sausages retained by one of the non-restaurant X patients.

Most fresh pork products in Australia are locally produced. The presence of HEV in Australian pigs was first noted in 1999 by a study that reported seropositivity rates of 17% in wild-caught pigs and more than 90% in commercial pigs by 16 weeks of age.25 To our knowledge, no further studies investigating the epidemiology of HEV in Australian pigs have been conducted. Despite the link between HEV outbreaks and pork products overseas, this discovery of HEV in Australian pigs did not translate into clinical practice, perhaps because HEV was not widely recognised as being endemic to Australian pigs, and because of a lack of awareness among Australian clinicians of the veterinary literature.

A limitation to this investigation was the time lag between some infected persons and co-diners being exposed, interviewed and tested for HEV, particularly co-diners of symptomatic persons from restaurant X. A lag in interviewing some infected persons and co-diners, coupled with the long incubation period of HEV (15–64 days), may have led to a recall bias in responses to the questionnaires and providing food histories. The limited sample size made it difficult to achieve statistically significant results. However, our findings are biologically plausible, and important associations could be deduced.

This study adds to our current understanding of the potential for HEV to be a food-borne illness in developed countries. Clinicians should request HEV testing in patients with acute hepatitis, irrespective of travel history, particularly where no aetiology has been determined. Laboratories should test for HEV where indicated to prevent under-recognition of infection. Health departments must be aware of the possibility of underestimating the prevalence of hepatitis E when using surveillance data. Pork products, particularly pork livers, should be cooked until they reach 75°C at the thickest part for 2 minutes.

Increased awareness, ongoing research and collaboration between primary industries, animal and human health authorities should help detect and prevent this and other emerging infectious diseases in Australia.

Box 1 –
Notifications of hepatitis E virus infections in New South Wales with onset dates between January 2013 and December 2014, by likely source of acquisition*

* Excludes three asymptomatic cases and one case with unknown symptom history. † May 2014: restaurant X was inspected, and pork pâté identified as the possible source of infection; restaurant voluntarily removed pork pâté from their menu. An alert was issued to gastroenterologists and pathology laboratories. ‡ September 2014: alert issued to general practitioners and the general public. § July–December 2014: increased HEV testing reported by the main public pathology laboratory.

Box 2 –
Characteristics of infected diners and healthy co-diners at restaurant X, October 2013 – May 2014

	Infected persons (cases)	Healthy co-diners

Number	17	7
Median age (range), years	48 (29–75)	45 (29–47)
≤ 39 years	5 (29%)	1 (14%)
40–59 years	6 (35%)	5 (71%)
≥ 60 years	6 (35%)	0
Unknown	0	1 (14%)
Sex: men	12 (71%)	4 (57%)

Box 3 –
Commonly reported food items consumed by infected diners and healthy co-diners at restaurant X between October 2013 and May 2014*

	Number of people who ate the item			Number of people who did not eat the item			Risk ratio (95% CI)	P
	Infected persons (cases)	Healthy co-diners	Attack rate (%)	Infected persons (cases)	Healthy co-diners	Attack rate (%)	Risk ratio (95% CI)	P

Brussel sprouts	5	3	63%	8	4	67%	1 (0.5–1.8)	1.00
Calamari	3	2	60%	10	5	67%	1 (0.5–2.0)	1.00
Eggplant	7	5	58%	6	2	75%	0.8 (0.5–1.5)	0.66
Pork chorizo	7	2	78%	6	5	55%	1.5 (0.8–2.7)	0.36
Pork pâté	15	4	79%	0	3	0	Undefined	0.02
Roast pork	9	4	69%	4	3	57%	1.2 (0.6–2.6)	0.64

* Food histories were available for 15 of the 17 infected persons (13 were complete and two were incomplete) and for all seven well co-diners.

New recommendations for Hepatitis C treatment

New recommendations have been released for the management of hepatitis C virus (HCV) infection in a consensus statement.

The statement was drawn up by Gastroenterological Society of Australia, the Australasian Society of Infectious Diseases, the Australasian Hepatology Association, the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine, Hepatitis Australia and the Royal Australian College of General Practitioners.

A summary, published in the Medical Journal of Australia, says that the recommendations for Hepatitis C treatment were drawn up in the wake of the new direct-acting antiviral therapies that were added to the Pharmaceutical Benefits Scheme earlier this month.

“The introduction of DAA therapies for HCV that are highly effective and well tolerated is a major medical advance,” said Professor Alexander Thompson, director of gastroenterology at St Vincent’s Hospital in Melbourne.

“All Australians living with HCV should now be considered for antiviral therapy.”

Recommendations in the consensus statement include:

All individuals with a risk factor for HCV infection should be tested.
Annual HCV serological testing is recommended for seronegative individuals with risk factors for HCV transmission.
People with confirmed HCV infection should be tested for HCV genotype (Gt).
All concomitant medications should be reviewed before starting treatment, using the University of Liverpool’s Hepatitis Drug Interactions website.
The use of any DAA regimen during pregnancy is not recommended.
People who are not cured by a first-line interferon-free treatment regimen should be referred to a specialist centre.
All people with decompensated liver disease, extra-hepatic manifestations of HCV, HCV–HIV or HCV–HBV co-infection, renal impairment or acute HCV infection, as well as people who have had a liver transplant should be referred for management by a specialist who is experienced in the relevant areas.
All people living with HCV infection should have a liver fibrosis assessment before treatment to evaluate for the presence of cirrhosis.
People with no cirrhosis can be treated by general practitioners working in consultation with specialists.

Read the full recommendations on the Gastroenterological Society of Australia’s website.

Latest news:

Australian recommendations for the management of hepatitis C virus infection: a consensus statement

Chronic hepatitis C virus (HCV) infection is a major public health challenge for Australia, affecting about 230 000 people who are consequently at risk of progressive liver fibrosis leading to cirrhosis, liver failure and hepatocellular carcinoma (HCC). HCV infection is the most common cause of liver disease requiring liver transplantation in Australia. The burden of liver disease due to HCV is projected to triple by 2030. However, HCV infection is curable, and viral eradication is associated with multiple clinical benefits, including improvement in quality of life, loss of infectivity, regression of cirrhosis, lower risk of liver failure and HCC, and reduction in mortality. Until recently, the treatment of HCV involved interferon therapy, which had limited efficacy and was poorly tolerated. The introduction of direct-acting antiviral (DAA) therapies for HCV that are highly effective and well tolerated is a major medical advance. All Australians living with HCV should now be considered for antiviral therapy. Several of these new HCV medicines were listed on the Pharmaceutical Benefits Scheme (PBS) on 1 March 2016. DAAs may be prescribed by specialists experienced in treating HCV or by general practitioners in consultation with one of these specialists, meaning that treatment can occur in the community.

Here, we present a summary of the Australian recommendations for the management of hepatitis C virus infection: a consensus statement 2016. The consensus statement was prepared by an expert panel representing the Gastroenterological Society of Australia (Australian Liver Association), the Australasian Society for Infectious Diseases, the Australasian Society for HIV, Viral Hepatitis and Sexual Health Medicine, the Australasian Hepatology Association, Hepatitis Australia and the Royal Australian College of General Practitioners. The consensus statement is a living document that will be updated as new data emerge and is available at http://www.gesa.org.au.

Models of care for HCV

Despite one of the highest HCV diagnosis rates in the world, treatment uptake in Australia has been low (2000–4000 people/year). Upscaling treatment rates to the desired level to reduce population burdens of HCV and secondary liver disease (> 10 000 people/year)1 will require the development of new models of care for HCV treatment. These should include traditional tertiary centre-led models of care, particularly for people with cirrhosis or special populations (eg, those with decompensated liver disease or renal impairment; see below), as well as community-based models of care involving GPs, specialist nurses and nurse practitioners. Specific models of care are needed for people who inject drugs, opioid substitution treatment centres, the prison system, rural and regional settings, Aboriginal and Torres Strait Islander people and migrants from high-prevalence regions (see full consensus statement).

The PBS listing allows the new HCV medicines to be prescribed by gastroenterologists, hepatologists or infectious diseases physicians who are experienced in treating chronic HCV infection, as well as by GPs in consultation with one of these specialists. The new HCV medicines will be available through the PBS General Schedule (Section 85), meaning approved pharmacists in the community can dispense the new HCV medications, as well as through the Section 100 Highly Specialised Drugs Program, which makes provision for treatment of prisoners.

Screening and diagnosis

Transmission of HCV infection is associated with identifiable risk factors (Box 1), and most diagnoses result from screening of at-risk populations. All individuals with a risk factor for HCV infection should be tested. The appropriate screening test for HCV is serology (HCV antibodies), which indicates exposure to HCV, either current or past infection. Current HCV infection should be confirmed by a polymerase chain reaction (PCR) assay for HCV RNA. Annual HCV serological testing is recommended for seronegative individuals with ongoing risk factors for HCV transmission. For individuals who are seropositive but have undetectable HCV RNA (indicating past infection), annual HCV RNA testing is recommended only in the setting of ongoing risk factors for HCV transmission. Harm reduction strategies (eg, needle and syringe programs, opioid substitution treatment) are important.

People with confirmed HCV infection should be tested for HCV genotype (Gt). The most common HCV genotypes in Australia are Gt 1 (50–55% of cases; Gt 1a : 1b = 2 : 1) and Gt 3 (35–40%).2 HCV Gt 4–6 occur but are less common. As approved HCV treatment regimens are genotype-specific, HCV genotyping is necessary before treatment initiation.

Pre-treatment assessment

All people living with chronic HCV infection should be considered for antiviral treatment. Active psychosocial and substance use problems, including high-risk alcohol consumption, should be managed before starting therapy. People with stable psychiatric disease or stable injecting drug use are candidates for DAA treatment. People with no cirrhosis may continue to drink alcohol at low-risk levels during treatment (no more than two standard drinks on any day3). Complete abstinence from alcohol is recommended for people with cirrhosis or alcohol dependence.

It is important that all individuals undergo a comprehensive pre-treatment assessment (Box 2). Key elements include confirming the HCV diagnosis and genotype; documenting HCV treatment history; identifying comorbid liver disease or other bloodborne viral infections (hepatitis B virus [HBV], human immunodeficiency virus [HIV]); evaluating for the presence of cirrhosis; and considering concomitant medications, including over-the-counter and illicit drugs, for risk of drug–drug interactions.

All Australians with chronic HCV infection are eligible for DAA therapy, regardless of liver fibrosis stage. However, the presence of cirrhosis influences HCV treatment duration and regimen (see below) and requires long-term management. Documentation of the presence or absence of cirrhosis is required for PBS eligibility for DAA therapy. Formal evaluation for cirrhosis with a non-invasive test, such as elastography (eg, FibroScan [EchoSens], acoustic radiation force impulse technology, shear wave elastography) or a serum biomarker (eg, APRI [aspartate aminotransferase to platelet ratio index], Hepascore, Enhanced Liver Fibrosis [ELF] test, FibroGENE), is recommended for all individuals. FibroScan is available in most metropolitan centres. A liver stiffness of > 12.5 kPA measured using FibroScan can be used to define cirrhosis.4–6 More details regarding non-invasive tests for liver fibrosis assessment are provided in the full consensus statement, including alternatives to FibroScan in regions where this is not accessible. Liver biopsy may still be required in a small proportion of patients. People with cirrhosis should be further evaluated for HCC and portal hypertension (Box 2); bone densitometry is recommended to screen for osteoporosis.

People with cirrhosis should be referred for specialist assessment due to the complexity of management. All individuals with decompensated liver disease should be considered for liver transplant assessment. Indications for assessment by a liver transplant centre include a Child–Pugh score ≥ B7, Model for End-Stage Liver Disease (MELD) score ≥ 13 or one of the following clinical events: refractory ascites, spontaneous bacterial peritonitis, hepatorenal syndrome, recurrent or chronic hepatic encephalopathy, small HCC or severe malnutrition (see full consensus statement).7

Treatment for chronic HCV infection

The goal of treatment is cure, defined as undetectable plasma HCV RNA at least 12 weeks after treatment has ceased (sustained virological response [SVR]). Several genotype-specific interferon-free DAA treatment regimens have been PBS-listed for treating people with HCV Gt 1–3. Peginterferon-alfa (pegIFN) + ribavirin remains the backbone of PBS-listed treatments for HCV Gt 4–6. Treatment regimens described here are based on the most up-to-date international data, consistent with the wording of the PBS listing.

Genotype 1 HCV

The two interferon-free DAA regimens that are available for PBS prescription for treating Gt 1 HCV are the combinations of sofosbuvir + ledipasvir and sofosbuvir + daclatasvir ± ribavirin. The interferon-free DAA regimen of paritaprevir–ritonavir + ombitasvir + dasabuvir ± ribavirin has also been Therapeutic Goods Administration-approved and is expected to be PBS-listed in the near future, so has been included in the consensus statement. These regimens are all effective and can be considered first-line. In addition to the treatment considerations outlined below, the decision of which regimen to use will generally be based on the number of pills and avoiding ribavirin where possible. Treatment of Gt 1 HCV with pegIFN-containing regimens is now actively discouraged.

Sofosbuvir + ledipasvir for genotype 1 HCV

Sofosbuvir + ledipasvir is a coformulated, once-daily, single-pill regimen. The recommended treatment duration is 12 weeks, except for people with cirrhosis who have not responded to pegIFN-based therapy, who should receive treatment for 24 weeks (Appendix 1).4,5 Rates of SVR ≥ 95% are achieved in all patient groups.4,5 A shortened 8-week treatment duration may be considered in treatment-naive people with no cirrhosis who have baseline HCV RNA levels < 6 × 10⁶ IU/mL (see full consensus statement).8 Adverse effects of fatigue, headache and nausea occur but are uncommon and typically mild.4,5,8 Sofosbuvir is renally excreted. As safety data are lacking in people with an estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73m², this regimen is not recommended in this setting.

Sofosbuvir + daclatasvir ± ribavirin for genotype 1 HCV

Sofosbuvir + daclatasvir ± ribavirin therapy is also approved as first-line treatment for Gt 1 HCV.9,10 SVR rates are ≥ 95%. Sofosbuvir + daclatasvir (no ribavirin) for 12 weeks’ duration is recommended for people with no cirrhosis who are treatment-naive or in whom treatment with pegIFN and ribavirin has previously failed (Appendix 1). People with cirrhosis are harder to cure and should be treated with either sofosbuvir + daclatasvir + ribavirin for 12 weeks or sofosbuvir + daclatasvir (no ribavirin) for 24 weeks. Sofosbuvir + daclatasvir (no ribavirin) for 24 weeks is recommended for people with or without cirrhosis who have not responded to prior treatment with a protease inhibitor + pegIFN + ribavirin (Appendix 1). Sofosbuvir + daclatasvir is well tolerated, with low (≤ 1%) discontinuation rates due to adverse events. The most common treatment-related adverse effects are fatigue, headache and nausea; again, these are typically infrequent and mild.

Paritaprevir–ritonavir, ombitasvir + dasabuvir ± ribavirin for genotype 1 HCV

The combination of paritaprevir (ritonavir-boosted), ombitasvir and dasabuvir (PrOD) is used with ribavirin for HCV Gt 1a, or without ribavirin for Gt 1b (Appendix 1).11–15 Treatment is for 12 weeks, except for Gt 1a patients with cirrhosis and prior null response to pegIFN + ribavirin, who should receive treatment for 24 weeks. SVR rates ≥ 95% are observed in all groups. PrOD therapy is not recommended for prior non-responders to protease inhibitor therapy. The regimen should be used with caution in people with compensated cirrhosis and is contraindicated in patients with decompensated cirrhosis or history of liver decompensation. In people with renal impairment, dose adjustment is not required for PrOD but is required for ribavirin.

PrOD is well tolerated, with low (≤ 1%) discontinuation rates.11 The most commonly reported adverse effects are nausea, pruritus and insomnia; these are uncommon and mild in most people. Rises in serum alanine aminotransferase (ALT) levels have been rarely observed, particularly among women taking ethinyl estradiol-containing contraceptives, which should be stopped before treatment. Alternative contraceptive agents (eg, progestin-only contraception) or methods are recommended. Transient isolated hyperbilirubinaemia may be seen early (Weeks 1–2) but typically resolves with ongoing therapy. Elevation of ALT level above baseline or elevation of the bilirubin level to greater than twice the upper limit of normal during treatment should prompt close monitoring of liver function test results, and specialist opinion (see full consensus statement).

Ribavirin-related adverse events

Adverse events associated with ribavirin therapy include anaemia, rash, cough, dyspnoea, insomnia and anxiety. The mean reduction in haemoglobin level associated with PrOD + ribavirin is 24 g/L. Ribavirin is teratogenic, and both women and men should be counselled that two forms of contraception (but not ethinyl estradiol preparations in combination with PrOD) are required while taking ribavirin and for 6 months after treatment. Ribavirin is renally excreted and dose adjustment is required according to eGFR or if anaemia develops during treatment (see full consensus statement).

Genotype 2 HCV

The approved interferon-free treatment regimen for HCV Gt 2 is sofosbuvir + ribavirin for 12 weeks (Appendix 2). This regimen is highly effective in people with no cirrhosis, with cure rates of 90–95%.16–19 Extending treatment duration to 24 weeks in people with cirrhosis may increase SVR rates but is not currently listed under the PBS.16 Treatment is well tolerated, with the adverse event profile typical for ribavirin.

Genotype 3 HCV

The approved treatment regimens available under the PBS for Gt 3 HCV are sofosbuvir + daclatasvir for 12 or 24 weeks, sofosbuvir + ribavirin for 24 weeks, and the combination of sofosbuvir + pegIFN + ribavirin for 12 weeks (Appendix 2).18,20,21

Sofosbuvir + daclatasvir for genotype 3 HCV

Sofosbuvir + daclatasvir for 12 weeks is very effective for treating Gt 3 HCV in people with no cirrhosis, with SVR rates of 94–97%.21 In people with cirrhosis, treatment should be extended to 24 weeks, which increases SVR rates from 58–69% to 85–90% (Appendix 2).22,23

Sofosbuvir + ribavirin for genotype 3 HCV

Treatment with sofosbuvir + ribavirin for 24 weeks is associated with SVR rates of 90–95% in treatment-naive people with no cirrhosis, and 58–76% in treatment-experienced people with cirrhosis.16,18,19 Thus, this is an effective regimen for treatment-naive people with no cirrhosis but is not the preferred regimen for people with cirrhosis, particularly those who are treatment-experienced (Appendix 2).

Sofosbuvir + peginterferon-alfa + ribavirin for genotype 3 HCV

Triple therapy with sofosbuvir + pegIFN + ribavirin for 12 weeks is very effective for the treatment of Gt 3 HCV. This regimen is more effective than 16 or 24 weeks of sofosbuvir + ribavirin, including among treatment-experienced people with cirrhosis,19 but is associated with pegIFN-related toxicity. This regimen may be useful as salvage therapy for people in whom first-line DAAs fail (Appendix 2).

Genotypes 4, 5 and 6 HCV

The first-line treatment regimen for Gt 4, 5 and 6 HCV that is currently listed on the PBS is the combination of sofosbuvir + pegIFN + ribavirin for 12 weeks (Appendix 3). In a Phase III study involving a small number of treatment-naive individuals with Gt 4–6 HCV, this regimen was associated with SVR rates of 96–100%.17 There are no interferon-free treatment regimens for Gt 4–6 HCV currently available on the PBS. The combination of sofosbuvir + ledipasvir is effective for Gt 4 and 6 HCV.24–27 Paritaprevir–ritonavir + ombitasvir + ribavirin is also effective for Gt 4 HCV.28 It is likely that these regimens will be approved in Australia in the future.

Interferon-based therapy is associated with considerable morbidity, and intensive on-treatment monitoring is required (see full consensus statement). The most common adverse effects of pegIFN include influenza-like symptoms, fatigue, bone marrow suppression, mood disturbance and alopecia. PegIFN is contraindicated in people with untreated major depression or psychosis, immune-mediated disease (eg, inflammatory arthritis, lupus, ulcerative colitis) or decompensated liver disease. PegIFN-based treatment may precipitate hepatic decompensation in people with advanced liver disease; a platelet count < 100 × 10⁹/L and albumin level < 35 g/dL identify those at highest risk.29 Despite the significant adverse event profile, the discontinuation rate among patients treated with 12 weeks of sofosbuvir + pegIFN + ribavirin was only 2% in clinical trials,17 similar to that reported for interferon-free regimens.

Drug–drug interactions

Drug–drug interactions are a potential problem for all interferon-free treatment regimens. Important drugs to consider for potential interactions with DAAs include proton pump inhibitors, statins, St John’s wort, antimicrobials, anti-epileptic agents, amiodarone, immunosuppressive agents and antiretroviral agents. All concomitant medications should be reviewed before starting treatment, using the University of Liverpool’s Hepatitis Drug Interactions website (http://www.hep-druginteractions.org). We recommend working with an experienced pharmacist to confirm the safety of concomitant medications before starting DAA regimens. Patients should be advised to seek advice before starting any new medication during DAA therapy.

Pregnancy, breastfeeding and children

As there are no safety data for the use of any DAA regimen during pregnancy, treatment of pregnant women is not recommended. Ribavirin (classed as Category X) and pegIFN are contraindicated during pregnancy. Both women and men should be counselled about the risk of teratogenicity and the importance of avoiding pregnancy during and for 6 months after ribavirin treatment. As noted above, women treated with PrOD should avoid ethinyl estradiol-containing contraceptives. The safety of the listed DAA regimens during lactation has not yet been established, so treatment of women who are breastfeeding is not recommended. Children under the age of 18 years are not currently eligible for treatment with the new PBS-listed HCV medicines. Studies in paediatric populations are ongoing. People under the age of 18 years should be referred to a paediatric gastroenterologist who is experienced in treating HCV for discussion about therapy.

Direct-acting antivirals and drug resistance

Resistance-associated variants (RAVs) have been identified for all of the approved DAAs. However, given the high SVR rates observed with combination therapy, there is currently no role for baseline HCV resistance testing in treatment-naive people or prior non-responders to pegIFN-based therapy. Resistance testing for NS3, NS5B and NS5A RAVs should be considered following DAA treatment failure, to guide salvage therapy. Resistance testing involves direct sequencing of the HCV genome and is available through specialised laboratories. HCV sequencing may also identify cases of reinfection.

Salvage therapy

For people with Gt 1 HCV who did not respond to treatment with a protease inhibitor + pegIFN + ribavirin, the preferred regimen is the combination of sofosbuvir + ledipasvir or sofosbuvir + daclatasvir (Appendix 1). Response rates are similar to those observed in treatment-naive individuals.

People who are not cured by a first-line interferon-free treatment regimen should be referred to a specialist centre where there is greater access to evolving salvage treatment strategies and HCV resistance testing to help guide management.

On-treatment monitoring

In contrast to interferon-based treatment regimens, intense monitoring of most people undergoing DAA therapy is not necessary. For most people, one assessment at Week 4 of treatment will be sufficient during an 8-week or 12-week course (Appendix 4). More intensive monitoring is warranted for people in whom adherence is a concern, those with risk factors for ribavirin intolerance (eg, cardiac disease) or who develop ribavirin-induced anaemia, or people with advanced liver disease (portal hypertension or hepatic decompensation). Routine on-treatment assessment of HCV RNA levels is not required but may be considered if there are concerns regarding adherence to therapy.

Post-treatment follow-up

Confirm SVR

SVR is defined as undetectable plasma HCV RNA using a highly sensitive PCR assay 12 weeks after completion of DAA therapy (Appendix 4). Those who are not cured should be assessed for explanations for treatment failure, especially lack of adherence or reinfection. Referral to a specialist treatment centre is advisable for non-responders.

Long-term management of liver disease

People who do not have cirrhosis and who have normal liver function test results (males, ALT < 30 U/L; females, ALT < 19 U/L) after SVR do not need follow-up (Appendix 4). There is no reason to repeat anti-HCV serological tests. People who are cured should be told that persistence of anti-HCV antibodies is expected and does not represent active infection, nor does it confer immunity to reinfection. Individuals whose liver function test results remain abnormal after SVR should be assessed by a specialist for alternative causes of liver disease (Appendix 4). All individuals with cirrhosis need surveillance for HCC and oesophageal varices. Complications of chronic liver disease, including malnutrition and osteoporosis, should also be addressed.

Special populations

There are several patient groups in whom the treatment of HCV infection is complex. These special populations include people with decompensated liver disease, extrahepatic manifestations of HCV, HCV–HIV or HCV–HBV coinfection, renal impairment or acute HCV infection, as well as people who have had a liver transplant. All these people should be referred for management by a specialist who is experienced in the relevant areas (see full consensus statement). The optimal treatment regimen for patients with decompensated liver disease secondary to HCV, as well as whether face-to-face assessment by a transplant centre is warranted, should be discussed with a liver transplant physician before commencing antiviral therapy. Recommended treatment regimens for people with decompensated liver disease differ from those for people with compensated liver disease (see full consensus statement).

Box 1 –
High-risk populations for hepatitis C virus (HCV) infection

People who inject drugs or who have ever injected drugs
Sex workers
People in custodial settings
People with tattoos or body piercing
People who received a blood transfusion or organ transplant before 1990
Children born to HCV-infected mothers
Sexual partners of an HCV-infected person
People infected with human immunodeficiency virus or hepatitis B virus
People with evidence of liver disease (persistently elevated alanine aminotransferase level)
People who have had a needlestick injury
Migrants from high-prevalence regions (Egypt, Pakistan, Mediterranean and Eastern Europe, Africa and Asia)

Box 2 –
Pre-treatment assessment of people with chronic hepatitis C virus (HCV) infection

History

Estimated duration of HCV infection
Previous HCV treatment experience — date, regimen and response
Cofactors for liver disease progression: alcohol intake, marijuana use, virological cofactors (HIV, HBV), diabetes, obesity
For those planned to receive ribavirin, note history of ischaemic heart disease or cardiovascular risk factors
Vaccinations against HBV and HAV
Physical and psychiatric comorbidities
Ongoing risk factors for viral transmission and reinfection
Social issues — potential barriers to medication adherence

Medication

Concomitant medications (prescription, over-the-counter, illicit)

Physical examination

Features of cirrhosis: hard liver edge, spider naevi, leukonychia
Features of decompensation or portal hypertension: jaundice, ascites, oedema, bruising, muscle wasting, encephalopathy
Body weight and body mass index

Virology

HCV genotype and subtype
HCV RNA level (quantitative)
HBV (HBsAg, anti-HBc, anti-HBs), HIV, HAV serology

Investigations

Full blood examination, liver function tests, urea and electrolytes, eGFR, INR
Pregnancy test for women of childbearing potential
Liver fibrosis assessment, eg:
- Elastography (FibroScan, ARFI, SWE)
- Serum biomarker (APRI, Hepascore, ELF test, FibroGENE*)
Liver ultrasound should be performed in people with cirrhosis to exclude hepatocellular carcinoma
Electrocardiogram should be performed if ribavirin therapy is planned and patient is > 50 years of age or has cardiac risk factors

anti-HBc = hepatitis B core antibody. anti-HBs = hepatitis B surface antibody. APRI = aspartate aminotransferase to platelet ratio index. ARFI = acoustic radiation force impulse. eGFR = estimated glomerular filtration rate. ELF = enhanced liver fibrosis. HAV = hepatitis A virus. HBsAg = hepatitis B surface antigen. HBV = hepatitis B virus. HIV = human immunodeficiency virus. INR = international normalised ratio. SWE = shear wave elastography. * Online calculator available at: http://www.fibrogene.com/viral_hepatitis.html.

Barriers to reforming low-value care

In their article in the MJA discussing low-value care, Scott and Duckett noted that “some physicians are establishing programs in their areas of practice that identify and remove low-value care”.1

However, a major barrier to reforming low-value care is that we have a rigid and only slowly moving mechanism for funding new initiatives, which prevents us from implementing new evidence-based care pathways.

An example with which I am well acquainted is low-value colonoscopy, performed in people who are extremely unlikely to have relevant colonic pathology, because patients, general practitioners and specialists fear missed pathology. We know that most young people with gastrointestinal symptoms without alarm features will have a normal colonoscopy2 and do not need this costly and invasive test to diagnose irritable bowel syndrome. We also know from data now widely published and endorsed by the National Institute for Health and Care Excellence in the United Kingdom (https://www.nice.org.uk/guidance/dg11) that using faecal calprotectin to screen this group would better target colonoscopy resources, as it has a high negative predictive value for organic disease and thus provides great reassurance to patients and doctors that colonoscopy is not required.

Yet, despite this and the huge number of colonoscopies performed annually, we do not yet have access to faecal calprotectin testing on the Medicare Benefits Schedule, with the submission on this matter having now been under consideration for over four years (the initial Medical Services Advisory Committee discussion occurred in August 2011). If physicians are being entreated to fix the system, we need our regulatory agencies to partner us in this by being sufficiently nimble to assess the tools we need to drive these changes proactively and promptly.

A case of acute phosphate nephropathy

A 74-year-old woman presented with a 2-day history of abdominal pain and nausea, 1 week after undergoing upper and lower endoscopies. Her comorbidities included hypertension, dyslipidaemia, sigmoid diverticulosis, transient ischaemic attack, peripheral vascular disease and mild valvular heart disease.

Medications taken before admission included telmisartan–hydrochlorothiazide, sustained-release verapamil, prazosin, rosuvastatin and aspirin.

Admission blood tests indicated acute kidney injury, with a serum creatinine concentration of 218 μmol/L (reference interval [RI], 46–99 μmol/L) and an estimated glomerular filtration rate of 19 mL/min/1.73 m² (RI, > 60 mL/min/1.73 m²); her creatinine level 7 months earlier was 69 μmol/L. She was also hypokalaemic (potassium level, 2.9 mmol/L [RI, 3.5–5.1 mmol/L]), hypocalcaemic (corrected calcium concentration, 1.97 mmol/L [RI, 2.15–2.6 mmol/L]) and uraemic (urea concentration, 14.4 mmol/L [RI, 2.9–8.2 mmol/L]). However, she was normophosphataemic (phosphate level, 1.14 mmol/L [RI, 0.81–1.45 mmol/L]). Her urinary sediment was relatively benign, with a protein-to-creatinine ratio of 17 g/mol (RI, < 15 g/mol), an albumin-to-creatinine ratio of 3.4 g/mol (RI, < 1 g/mol) and no red cells present. Renal ultrasound showed normal sized kidneys with no evidence of obstruction.

A medication review revealed she had taken 48 g of oral sodium phosphate before undergoing colonoscopy. Given the lack of improvement in renal function following intravenous hydration and withholding telmisartan–hydrochlorothiazide, a renal biopsy was performed. Light microscopy demonstrated non-polarising calcifications within the tubular cells and interstitium consistent with acute phosphate nephropathy (APN). A von Kossa stain confirmed calcium phosphate crystals (Box).

Our patient’s serum creatinine level stabilised at 130–140 μmol/L before discharge. A review in the outpatient’s clinic 1 month after discharge showed no further improvement in serum creatinine levels (131 μmol/L).

The incidence of APN is underestimated because many cases are clinically silent and can occur without evidence of hyperphosphataemia.1,2 APN occurs due to a combination of hypovolaemia and a sudden increase in serum phosphate concentration. Hypovolaemia induces proximal tubule salt and water reabsorption, resulting in a large phosphate load to the distal nephron and subsequent precipitation of calcium phosphate in the distal tubule and collecting duct.3

Associated risk factors for developing APN include increasing age, female sex, hypertension, diabetes, degree of hyperphosphatemia, pre-existing chronic kidney disease, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers, diuretics, lithium and non-steroidal anti-inflammatory drugs.1,2

Patients who develop APN have a high probability of progressing to chronic kidney disease.1 Markowitz and colleagues studied a cohort of 21 patients with biopsy-proven APN. The mean serum creatinine level 17 months after oral sodium phosphate ingestion was 240 μmol/L. Four patients progressed to end-stage renal failure, requiring dialysis at the mean follow-up of 16.7 months.1 In an Icelandic study, the baseline serum creatinine level was 82 μmol/L in 15 patients before their diagnosis of APN. The mean serum creatinine level at 4-month follow-up was 180 μmol/L, with one patient becoming dialysis dependent.4

APN is an important adverse event to consider when using oral sodium phosphate for bowel preparation in at-risk populations. The consequences of APN may be significant and long term, as there is increased risk of progression to chronic kidney disease and end-stage renal failure. Thus, the clinician needs to demonstrate heightened pharmacovigilance when prescribing such agents and an increased clinical suspicion in diagnosing this condition.

Box –
Positive von Kossa stain (× 200 magnification) displaying black staining, indicating calcium phosphate crystals

[Correspondence] Hepatology training in the UK

As an elected trainees section representing more than 800 UK gastroenterology registrars, we read with interest the Lancet publications,1,2 which highlight the increasing burden of chronic liver disease in the UK generally, and the specific issues surrounding hepatology training in the UK.

Comparing colorectal cancer treatment and survival for Aboriginal and non-Aboriginal people in New South Wales

Previous studies of colorectal cancer survival in New South Wales,1 South Australia,2 Queensland3 and the Northern Territory4 have found that survival tended to be poorer for Aboriginal than for non-Aboriginal people. These studies identified disease factors and less access to primary and follow-up treatments as possible reasons for the survival disparities.

The recommended treatment for colorectal cancer is generally surgery combined with adjuvant chemotherapy or radiotherapy, depending on the cancer type and extent of disease.5,6 Treatment guidelines also highlight the importance of post-surgical follow-up care, as one in three people will die from disease recurrence after initial treatment.3 However, the Australian guidelines available during the study period for this article did not describe a specific protocol for follow-up care.5,6

Our main aim was to compare the treatment and survival rates for Aboriginal and non-Aboriginal people diagnosed with colorectal cancer in NSW using routinely collected, population-based linked data. We also estimated the proportions of a sample of NSW Aboriginal people with colorectal cancer who received chemotherapy or radiotherapy.

We respectfully use the descriptor “Aboriginal people” throughout this report to refer to the original people of Australia and their descendants.

Methods

We analysed two different linked datasets, both of which have been described previously:7,8 data from the NSW Population-wide Study (2001–2007) and data from the Patterns of Care study (2001–2011). The NSW Population-wide Study data comprised incident cancer cases linked with hospital separations data and death records; the Patterns of Care study data comprised information collected in an audit of medical records of Aboriginal people with colorectal cancer (diagnosed during the period 2000–2011) linked to incident cancer cases, hospital separations data and death records. People were eligible for inclusion in the study if they were NSW residents diagnosed with primary colorectal cancer (International Classification of Diseases, revision 10, topography codes C18–C20, and International Classification of Diseases for Oncology morphology codes ending /3) and 18 years or older.

NSW Population-wide Study

Data sources

Demographic and disease information for all eligible people diagnosed with colorectal cancer during the period 2001–2007 was obtained from the NSW Central Cancer Registry. Cases were matched by the Centre for Health Record Linkage (CHeReL) with inpatient records from the NSW Admitted Patient Data Collection (APDC), death records from the NSW Registry of Births, Deaths and Marriages, and coded causes of death in Australian Bureau of Statistics (ABS) data. A person was determined to be Aboriginal if they were identified as Aboriginal in any of their linked records.

Variables for analysis

Information from the Clinical Cancer Registry included month and year of diagnosis, age at diagnosis, and spread of disease at diagnosis (reported as localised, regional, distant, or unknown). Cancers were also categorised by site (colon, rectum, or rectosigmoid junction).

Using the Accessibility and Remoteness Index for Australia (ARIA+),9 the Local Government Area (LGA) of residence of participants at diagnosis was categorised as major city, inner regional or rural (“rural” comprising outer regional, remote, and very remote). The LGA of residence at diagnosis was also assigned to a quintile of socio-economic disadvantage according to the Index of Relative Socio-economic Advantage and Disadvantage.10

We restricted our analysis to surgical treatment, both planned and emergency, as other studies have shown a high concordance between surgery recorded in the APDC and clinical audits of medical records.11

Comorbidities were any non-cancer conditions described in the Charlson Comorbidity Index12 that were recorded for any hospital admission in the 12 months before and the 6 months after diagnosis with colorectal cancer. People not admitted to hospital during this period were recorded as having “no comorbidity information available”.

Statistical methods

Analyses were performed with SAS 9.2 (SAS Institute) and R 3.0.0 (R Foundation for Statistical Computing). We used Pearson χ² tests to compare demographic data for Aboriginal and non-Aboriginal people. Logistic regression was initially used to compare the unadjusted odds of Aboriginal and non-Aboriginal people having surgery within 12 months of diagnosis. We then fitted a multivariable model by adding the variables sex, age at diagnosis, year of diagnosis, site of cancer, spread of disease, comorbidities, socio-economic disadvantage, and place of residence.

Colorectal cancer-specific survival was analysed with cumulative incidence curves and Cox regression models. Follow-up was censored at 31 December 2008 for all people whose deaths were not recorded. People who died from other causes were censored at the date of death. Variables were entered into the model described above, with the addition of surgical treatment as a variable. We included the statistically significant interaction between surgery and Aboriginal status in the final model. The proportional hazards assumption for Aboriginal status was satisfied in the final model.13

The probabilities of having a colonoscopy between 3 months and 3 years post-surgery were estimated for Aboriginal and non-Aboriginal people with localised or regional spread at diagnosis using cumulative incidence curves, with the competing risk of death without a colonoscopy included in the analysis.14

Patterns of Care (POC) study

Variables for analysis

The information collected from 23 public hospitals and three clinical cancer registries included age, sex, year of diagnosis, spread of disease, postcode of residence, and comorbidities. Postcode of residence was used to assign quintiles of socio-economic disadvantage10,15 and ARIA+ category.9 Treatment information (surgery, chemotherapy and radiotherapy) included start and end dates, and reasons for incomplete or no treatment. We merged data for people who attended several hospitals, and data were checked for appropriate ranges of responses and any anomalies.

Ethics approval

The collection of the POC data was approved by the Royal Prince Alfred Hospital Human Research Ethics Committee (reference, 08/RPAH/374) and the Aboriginal Health and Medical Research Council (AH&MRC; reference, 636/08). Local Regional Governance Offices granted site-specific approval for data collection in participating hospitals and clinical cancer registries. Linkage of the POC data to the population datasets was approved by the NSW Population and Health Services Research Ethics Committee (reference, 2011/04/319) and the AH&MRC Ethics Committee (reference, 791/11). Analysis of the NSW population data was approved by the NSW Population and Health Services Research Ethics Committee (reference, 2006/04/004) and the AH&MRC committee (reference, 550/06).

Results

NSW Population-wide Study

Characteristics

During 2001–2007, 30 448 people were diagnosed with primary colorectal cancer in NSW. We excluded 281 people notified to the Clinical Cancer Registry by death certificate only (0.9% of all cases) and 390 people (1.3%) with no matching hospital inpatient record (Box 1). This resulted in a final sample of 29 777 people, of whom 278 (0.9%) were identified as Aboriginal.

Compared with non-Aboriginal people (median age, 71 years), the Aboriginal people in our study were younger (median age, 64 years), more likely to live outside major cities and in socio-economically disadvantaged areas, and to have diabetes and chronic pulmonary disease at the time of their cancer diagnosis. Cancer site, disease spread at diagnosis, and the proportions of men and women were similar for Aboriginal and non-Aboriginal people (Box 2).

Surgical treatment

Aboriginal and non-Aboriginal people had the same median time to surgical treatment (13 days; interquartile range [IQR] for non-Aboriginal people, 1–33 days; IQR for Aboriginal people, 2–28 days), and the proportions who had received surgical treatment within 12 months of diagnosis were also similar (76% and 79% respectively) (Box 2). After accounting for differences in sex, age at diagnosis, year of diagnosis, spread of disease at diagnosis, cancer site, place of residence at diagnosis, comorbidities, and socio-economic disadvantage, there was no significant difference in the likelihood of Aboriginal and non-Aboriginal people receiving surgical treatment (odds ratio for Aboriginal people receiving surgical treatment, 0.93; 95% confidence interval [CI], 0.68–1.27).

Survival

For the first 18 months after diagnosis, mortality among people with colorectal cancer was similar for Aboriginal and non-Aboriginal people (Box 3). However, from 18 months a difference between the two groups was apparent, and by 5 years after diagnosis the cumulative mortality from colorectal cancer was 43% for Aboriginal people, compared with 33% for non-Aboriginal people (Box 4).

The unadjusted risk of death from colorectal cancer for Aboriginal people was 33% greater than for non-Aboriginal people (hazard ratio [HR], 1.33; 95% CI, 1.09–1.61; P = 0.006). For those who did not have surgical treatment, the risk of death after adjusting for sex, age at diagnosis, year of diagnosis, spread of disease, site of cancer, comorbidities, socio-economic disadvantage, and place of residence, was similar for Aboriginal and non-Aboriginal people (HR, 1.05; 95% CI, 0.70–1.50). However, the adjusted risk of death among those who had received surgical treatment was 68% greater for Aboriginal than for non-Aboriginal people (HR, 1.68; 95% CI, 1.32–2.09) (Box 4). The risk of death for those who had had surgical treatment was similar for Aboriginal and non-Aboriginal people during the first 18 months after diagnosis (Box 5).

Aboriginal and non-Aboriginal people who had received surgical treatment had similar rates of emergency surgery (Box 2) and median lengths of stay in hospital (10 days). During the admission for surgical treatment, 15% of Aboriginal and 13% of non-Aboriginal people had post-surgical complications (difference, 2%; 95% CI, −2.7% to 6.9%); 2% of Aboriginal people and 3% of non-Aboriginal people died within 30 days of surgery (difference, −1%; 95% CI, –2.9% to 1.2%).

By 18 months after surgery, 45% of Aboriginal people had had a colonoscopy, compared with 55% of non-Aboriginal people (Box 6). However, the proportions after 3 years were 59% for Aboriginal people and 65% for non-Aboriginal people.

Patterns of Care study

Characteristics

Compared with the Aboriginal people recorded in the NSW Population-wide Study data, the 145 Aboriginal people with colorectal cancer whose medical records we reviewed were, on average, younger at diagnosis (median age, 61 years), more likely to live outside major cities, and less likely to have been diagnosed with rectal cancer (Box 2, Box 7). As the two samples overlapped, formal statistical comparisons could not be made.

Surgical treatment

Overall, 117 people (81%) had received surgical treatment within 12 months of diagnosis. The proportions of people receiving surgical treatment were 82% for people with colon cancer, 77% for people with rectal cancer, and 82% for people with cancer in the rectosigmoid junction.

Adjuvant chemotherapy and radiotherapy

Of those who received surgical treatment, 48% also received adjuvant chemotherapy and/or radiotherapy. Of the 56 people with regional spread of disease, ten (18%) did not receive adjuvant treatment. Reasons for not receiving adjuvant treatment included the choice of the patient, and advice from their doctor that the associated harms would probably outweigh the benefits. Of the 42 people with localised disease who had surgery, three (7%) also received adjuvant treatment.

Discussion

We found that the 5-year survival rate was lower for Aboriginal people in NSW with colorectal cancer than for non-Aboriginal people, despite their being, on average, younger at diagnosis and having a similar spread of disease, similar surgical treatment rates, and similar times to surgery. This disparity in survival was evident from 18 months after diagnosis, and was largely confined to those who had received surgical treatment, although we found no differences in post-surgical complications or in the 3-year rates of follow-up colonoscopy. We also found that the Aboriginal people in our POC data received adjuvant chemotherapy and radiotherapy at levels similar to those reported in a previous population-based survey of colorectal cancer care in NSW16,17 and in a more recent analysis of node-positive cases.18

The survival disparity was only observable from 18 months post-surgery, suggesting that Aboriginal people may have had higher rates of disease recurrence, recurrence that was not identified because of poorer follow-up, lower rates of follow-up colonoscopies to detect new tumours, or lower rates of adjuvant therapies. However, we observed no significant differences (when compared with non-Aboriginal people) in planned or emergency post-surgical admissions, or in the receipt of adjuvant therapies, and no differences in the rates of colonoscopy up to 3 years after surgery. Alternatively, the observed difference in mortality between Aboriginal and non-Aboriginal people may be due to differences in the proportions of people with microsatellite unstable tumours or to other tumour characteristics; information in this regard, however, was not available for this study.

As we found that Aboriginal people with colorectal cancer had poorer survival outcomes than non-Aboriginal people, but no obvious differences in the treatment or follow-up they received, it is plausible that small differences and delays along the treatment pathway, perhaps caused by cultural barriers, contribute to lower survival. This has been found for M&amacr;ori people accessing chemotherapy for stage III colon cancer in New Zealand.19

That Aboriginal people with cancer generally have poorer survival outcomes than non-Aboriginal people with cancer has been reported by other Australian studies, with health care access and cultural differences generally being identified as factors underlying this disparity.1–3,7 The Cancer Institute NSW recently reported that Aboriginal people had a 63% increased risk of death from bowel cancer after adjusting for age and year of diagnosis and for spread of disease;1 this report did not, however, adjust for comorbidities, surgical treatment, sex, place of residence, socio-economic disadvantage, or cancer site. Similarly, a South Australian study reported that Aboriginal people with bowel cancer had a 5-year survival rate of 34.1%, compared with 56.1% for non-Aboriginal people.2 An older study of cancer survival in the Northern Territory4 attributed the higher risk of death for Aboriginal people to their having poorer access to quality health services, perhaps because of a lack of “social proximity” to these services.

Qualitative research on the health care received by Aboriginal people with cancer20 has identified several cultural barriers that may contribute to delays in their accessing mainstream health services (such as follow-up colonoscopies), including feelings of fatalism, shame, and embarrassment about colorectal cancer. More recent studies have identified lower health literacy,21 feelings of social exclusion when in hospital,22 and health services not fully responding to cultural differences as potential barriers to optimal care for Aboriginal people.23

Our analysis of the NSW Population-wide Study data is the first to include detailed information about the influence of comorbidities on surgical treatment and survival for Aboriginal people with colorectal cancer. However, it does have some limitations. First, the identification of Aboriginal people is dependent on correct recording of their status in the source datasets. As 98% of the Australian population is non-Aboriginal, the chance of positive misclassification is low, and we attempted to minimise under-identification of Aboriginal people by accepting any record of Aboriginal status in any linked record, including admissions not related to cancer. Second, using ABS information on deaths to identify Aboriginal people may have biased our survival results. In a sensitivity analysis we found, however, that using the APDC alone to determine Aboriginal status reduced the proportion of Aboriginal people who died from colorectal cancer within 5 years of diagnosis from 43% to 37%, and the overall survival patterns were similar to those reported here. Other potential sources of error include the possibility that we did not fully account for potential confounding factors that might contribute to the observed differences in survival, and measurement errors in the recording of covariates, such as comorbidities and spread of disease at the time of diagnosis. In addition, socio-economic disadvantage and place of residence were determined at the LGA level, and may thus be a source of measurement error. Further, although the POC data included more detailed information on the medical treatment of Aboriginal people with colorectal cancer than any other published study, the representativeness of the results may be limited, as we included only people from 23 hospitals and three clinical cancer registries.

Conclusion

Aboriginal people with colorectal cancer who had received surgery had lower survival rates than non-Aboriginal people, even though we found no overall differences in time to surgery, surgical rates, post-surgical complications, or receipt of adjuvant therapies or follow-up colonoscopies. However, small differences and delays along the cancer treatment pathway, possibly caused by cultural barriers to health care, may have resulted in lower survival for Aboriginal people with colorectal cancer. To ensure that survival rates improve, further work is needed to understand and reduce potential barriers to Aboriginal people with colorectal cancer receiving the best care.

Box 1 –
Inclusion and exclusion criteria for the NSW Population-wide Study of colorectal cancer diagnosed during 2001–2007 in New South Wales

Box 2 –
Comparison of socio-demographic and clinical data for 29 777 Aboriginal and non-Aboriginal people diagnosed with colorectal cancer during 2001–2007 in New South Wales

	Aboriginal		Non-Aboriginal		P
	Number	%	Number	%	P

Total number	278		29 499
Sex					0.864
Men	150	54%	16 068	54%
Women	128	46%	13 431	46%
Age at diagnosis, years					< 0.001
18–49	47	17%	1901	6%
50–59	49	18%	4256	14%
60–69	81	29%	7678	26%
70–79	77	28%	9216	31%
≥ 80	24	9%	6448	22%
Place of residence at diagnosis*					< 0.001
Major cities	114	41%	20 184	68%
Inner regional	103	37%	7177	24%
Rural^†	61	22%	2138	7%
Site of cancer					0.555
Colon	174	63%	19 342	66%
Rectum	81	29%	7785	26%
Rectosigmoid	23	8%	2372	8%
Spread of disease at diagnosis					0.551
Localised	98	35%	9985	34%
Regional	102	37%	11 801	40%
Distant	54	19%	4977	17%
Unknown	24	9%	2736	9%
Socio-economic disadvantage*					< 0.001
Least disadvantaged	15	5%	5296	18%
Second least disadvantaged	34	12%	6324	21%
Third least disadvantaged	43	15%	4762	16%
Second most disadvantaged	67	24%	6218	21%
Most disadvantaged	119	43%	6899	23%
Comorbid conditions^‡
Diabetes	56	21%	4321	15%	0.009
Cardiovascular disease^§	52	19%	4405	15%	0.071
Chronic pulmonary disease	33	12%	2360	8%	0.016
Renal disease	14	5%	1262	4%	0.518
Liver disease	8	3%	810	3%	0.879
Other comorbid conditions	17	6%	2511	9%	0.162
Surgical treatment by 12 months post-diagnosis					0.480
Emergency presentation	36	13%	3651	12%
Planned surgical treatment	176	63%	19 641	67%
No surgical treatment	66	24%	6207	21%

* Based on Local Government Area of residence at time of diagnosis. † “Rural” includes outer regional, remote and very remote. ‡ Comorbidities were not available for 453 people, of whom six were Aboriginal and 447 were non-Aboriginal. § Myocardial infarction, congestive heart failure, peripheral vascular disease, or cerebrovascular disease.

Box 3 –
Cumulative mortality from colorectal cancer for 278 Aboriginal and 29 499 non-Aboriginal people diagnosed in New South Wales during 2001–2007

Box 4 –
Mortality and hazard ratios for death from colorectal cancer for 278 Aboriginal people, compared with those for 29 499 non-Aboriginal people in New South Wales during 2001–2007

Hazard ratios for death from colorectal cancer (v non-Aboriginal people)

Aboriginal (unadjusted)

1.33 (95% CI, 1.09–1.61)

Aboriginal (adjusted)*

Surgical treatment

1.68 (95% CI, 1.32–2.09)

No surgical treatment

1.05 (95% CI, 0.70–1.50)

Unadjusted mortality 5 years after diagnosis

Aboriginal

43%

Non-Aboriginal

33%

* Adjusted for sex, age at diagnosis, year of diagnosis, place or residence, site of cancer, spread of disease at diagnosis, socio-economic disadvantage, and comorbid conditions.

Box 5 –
Cumulative mortality from colorectal cancer for 278 Aboriginal and 29 499 non-Aboriginal people diagnosed in New South Wales during 2001–2007, by surgical treatment received

Box 6 –
Cumulative incidence of colonoscopy after surgery for colorectal cancer for 212 Aboriginal and 23 292 non-Aboriginal people diagnosed in New South Wales during 2001–2007*

* Shaded areas represent the 95% confidence intervals.

Box 7 –
Characteristics of 145 Aboriginal people in the Patterns of Care Study data diagnosed with colorectal cancer in New South Wales during 2001–2010

	Number	%

Sex
Men	83	57%
Women	62	43%
Age at diagnosis, years
18–49	38	26%
50–59	27	19%
60–69	50	34%
70–79	25	17%
≥ 80	5	3%
Place of residence at diagnosis*
Major cities	44	30%
Inner regional	42	29%
Rural^†	59	41%
Site of cancer
Colon	88	61%
Rectum	35	24%
Rectosigmoid	22	15%
Spread of disease at diagnosis
Localised	51	35%
Regional	57	39%
Distant	34	23%
Unknown	3	2%
Socio-economic disadvantage*
Least disadvantaged	3	2%
Second least disadvantaged	14	10%
Third least disadvantaged	30	21%
Second most disadvantaged	42	29%
Most disadvantaged	56	39%
Comorbidities^‡
Diabetes	26	18%
Cardiovascular disease	25	17%
Chronic pulmonary disease	28	19%
Liver disease	6	4%
Other comorbid conditions	7	5%
Tumour size at diagnosis, mm
0–29	24	17%
30–44	28	19%
45–59	30	21%
≥ 60	29	20%
Not available	34	23%

* Based on postcode of residence at time of diagnosis. † “Rural” includes outer regional, remote and very remote. ‡ Comorbidities not available for five people.

A survey of Sydney general practitioners’ management of patients with chronic hepatitis B

In Australia, the prevalence of chronic hepatitis B (CHB) infection has increased over the past decade, with an estimated 218 000 Australians living with the disease.1 The annual number of deaths attributable to CHB is also expected to rise from 450 in 2008 to 1550 in 2017.2 Cost-effective treatments to reduce morbidity and mortality are available;2–4 however, up to 44% of infected Australians remain undiagnosed1,5 and only 2%–13% of those infected are receiving adequate treatment.2,6

The highest prevalence of CHB in New South Wales is in the Sydney and South Western Sydney Local Health Districts (LHDs), with respective estimated prevalence rates of 1.67% and 1.61% (the NSW average is 1.11%).7 In these LHDs, a large proportion of the population was born in countries with an intermediate or high prevalence of CHB.8,9 To relieve the pressure on specialist liver services, the National Hepatitis B Strategy 2014–20175 recommends an increased role for general practitioners in the management of CHB. We therefore examined the CHB assessment and management practices of GPs in the two LHDs, and the confidence that these GPs have in different models of care.

Methods

We used a descriptive cross-sectional study design to survey GPs about case management. A questionnaire (Appendix) was developed by a steering group that included hepatologists, nurses, public health physicians, an infectious diseases physician and a GP. The survey also included a separate section on contact management; this is not discussed in this article.

Eligible GPs were those practising in Sydney LHD (SLHD) or South Western Sydney LHD (SWSLHD) who had had at least one patient aged 18 years or over who had been notified as having CHB to the Public Health Unit under the NSW Public Health Act 2010 between 1 June 2012 and 31 May 2013. A survey was posted to each GP, and those who had not returned it within 4 weeks received a telephone call and another copy of the survey. GPs were excluded if they no longer practised at the same location.

Returned surveys were coded and the data entered into Excel 2010 (Microsoft) and analysed with Excel 2010 (Microsoft), SAS Enterprise Guide 6.1 (SAS Institute) and Stata 10.0 (StataCorp). Blank responses were coded as “unknown”. Demographic information for all GPs in SLHD and SWSLHD was obtained from the Inner West Sydney and South Western Sydney Medicare Locals.

Human research ethics approval was granted by the SLHD Ethics Review Committee (RPAH Zone), protocol number X13-0035.

Results

Completed questionnaires were returned by 123 of 213 eligible GPs (57.7% response rate), with no statistically significant difference in response rate between SLHD and SWSLHD GPs (P = 0.41).

There were significant differences in sex, age distribution, and type of practice between the study participants and those of all GPs in SLHD and SWSLHD (Box 1). The average number of patients with CHB notified by responding GPs during the study period was 1.88, compared with 1.96 for non-responders (P = 0.73). Most GPs (97 of 123, 78.9%) estimated that they cared for 50 or fewer patients with CHB. GPs from SWSLHD were more likely than SLHD GPs to have cared for more than 50 patients with CHB (odds ratio [OR], 3.24; 95% CI, 1.08–9.68).

GPs were asked how confident they were about different aspects of CHB assessment and management (Box 2). GPs who reported that they were “not very” or “not at all” confident were more likely than GPs who were “very” or “reasonably confident” to have cared for 50 or fewer patients (OR, 1.26; 95% CI, 1.14–1.40).

Box 3 summarises responses by GPs who were asked how comfortable they would be managing a patient with CHB in a number of different scenarios. GPs who were at least reasonably confident without specialist or hepatitis nurse input were more likely than those who were not to have cared for more than 50 patients with CHB (OR, 4.68; 95% CI, 1.28–17.16).

Discussion

This is the largest survey of Australian GPs to have examined their CHB assessment and management practices, and their views about specific models of care. Our results have important implications for service development. We found that GPs were generally confident about diagnosing and managing CHB, and were most comfortable with a model of care that included an initial specialist review. However, a significant number of GPs were not confident about managing CHB, particularly without the support of a specialist. If there is to be a successful shift toward a CHB model of care in which primary health care plays an increased role,5 this problem will need to be addressed by policy makers and medical educators. A framework that provides GPs with the support and resources necessary for appropriate CHB management is needed.

Most GPs felt confident about CHB management, but it is notable that almost one-fifth were “not very” or “not at all” confident. These GPs were more likely to have had a lower CHB patient load, and may thus have had less experience in this area. Previous surveys of Australian GPs have identified knowledge gaps about different aspects of CHB management.8,10,11 Our findings are consistent with these reports, but also indicate that a supportive CHB model that enables GPs to easily access appropriate resources and specialised advice is required.

The current Australian CHB model of care is focused on specialist hepatological care; however, these services are facing huge demands, and it has been suggested that increased involvement of GPs is needed to deal with the growing burden of CHB,2,5,12 as well as integrated nursing models and an exploration of the role of nurse practitioners.5 The majority of surveyed GPs were most comfortable with a care model that included initial review by a specialist and continuing GP management, with less support for a model in which there was no specialist input, and a reluctance to accept review by a hepatitis clinical nurse consultant alone. The stated preference of GPs in our study for specialist input in CHB management has implications for future health service planning. If nursing support for GPs is to be successful in an alternative CHB model of care, background specialist support needs to be clearly promoted to gain the confidence of GPs and to optimise the management of CHB.

Our study has limitations. While the response rate compares favourably with other recent written GP surveys about CHB,11,13 the possibility of response bias cannot be excluded. The significant difference in sex, age distribution, and type of practice between study participants and all GPs in the surveyed LHDs affects the external validity of our findings. While the steering group provided GP input into questionnaire development to improve its face validity for GPs, we did not test the questionnaire on another group of GPs; the applicability of the instrument to other settings is therefore unclear. Closed-ended and multiple-choice questions were used to facilitate the comparability of responses; however, their use may have prevented GPs from expressing other views.

This study identified that some GPs working in areas where the prevalence of CHB is high lack confidence about managing CHB. GPs in areas where CHB is less prevalent may encounter these problems to a greater extent, but further research is necessary to confirm this assumption and to thereby inform educational programs and service planning. As the CHB burden in Australia rises and the capacity of specialist liver services is tested, a new model of care focusing on primary health care needs to be developed, but must be considered carefully, noting the clear preference of GPs for specialist support. Our results suggest that well designed and targeted support programs that include specialist support are needed as part of a model of care which ensures that GPs feel confident about managing CHB.

Box 1 –
Demographic characteristics of the study participants (n = 123) and of all general practitioners in the Sydney and South Western Sydney Local Health Districts (n = 1135)

	Study participants	All GPs	P (χ² test)

Sex			< 0.001
Female	31.7%	40.3%
Male	67.5%	59.7%
Not recorded	0.8%	0
Age group			< 0.001
< 30 years	0	0
30–39 years	10.6%	6.2%
40–49 years	26.0%	16.6%
50–59 years	32.5%	18.2%
≥ 60 years	30.1%	22.2%
Not recorded	0.8%	36.7%
Local Health District			NA
Sydney	48.0%
South Western Sydney	52.0%
Type of practice			< 0.001
Solo	35.8%	19.0%
Group	63.4%	80.8%
Not recorded	0.8%	0.3%

NA = not applicable.

Box 2 –
Confidence of general practitioners (n = 123) about different aspects of the assessment and management of patients with chronic hepatitis B (CHB)

	Very confident	Reasonably confident	Not very confident	Not at all confident	Unknown

Identifying patients at risk of CHB	49.6%	48.8%	1.6%	0	0
Screening patients at risk of CHB	52.0%	45.5%	1.6%	0	0.8%
Ordering appropriate tests for diagnosing CHB	57.7%	39.0%	2.4%	0	0.8%
Interpreting hepatitis B serology and DNA results	43.1%	47.2%	7.3%	1.6%	0.8%
Managing patients with CHB	22.8%	56.1%	17.9%	1.6%	1.6%
Undertaking surveillance of liver cancer	30.9%	57.7%	8.9%	1.6%	0.8%
Referring for fibroscan	12.2%	35.8%	35.0%	16.3%	0.8%

Box 3 –
Confidence of general practitioners (n = 123) about managing patients with chronic hepatitis B in various models of care

	Very	Reasonably	Not very	Not at all	Unknown

With no specialist input	8.9%	48.0%	29.3%	12.2%	1.6%
Initial referral to a specialist for assessment, then managed by GP	43.1%	45.5%	8.9%	0.8%	1.6%
Initial referral to a specialist for assessment, then managed by GP with support from a hepatitis clinical nurse consultant	37.4%	45.5%	9.8%	5.7%	1.6%
Initial review by a hepatitis clinical nurse consultant, then managed by GP	18.7%	40.7%	22.8%	16.3%	1.6%

Fulminant liver failure and transplantation after use of dietary supplements

Clinical record

A 26-year-old Indigenous man presented with icteric sclera and skin on a background of 6 weeks of fatigue. He worked as a dockyard labourer, had no previous medical history, was not taking any medications regularly, did not smoke cigarettes or use any illicit substances, and did not drink alcohol to excess. Results of a physical examination were otherwise unremarkable — he had no features to suggest chronic liver impairment.

Blood tests conducted on admission showed a hepatocellular pattern of liver injury with mild derangement in synthetic function. Results of all other investigations were unremarkable (Box 1). Although not disclosed initially by the patient, repeat questioning revealed that, 10 weeks before presentation, he had used two dietary supplements for a 1-week period. These were a whey protein powder and a weight loss supplement containing 70% Garcinia cambogia. He had discontinued use of both products after consistently developing rigors shortly after ingesting them.

After admission, the patient’s liver synthetic function deteriorated (international normalised ratio rose to 2.5 and serum albumin level fell to 23 g/L). He also developed asterixis, without cognitive features of encephalopathy. Consequently, a liver biopsy was performed, with results of histopathology tests revealing submassive hepatic necrosis but no disease-specific features (Box 1). Liver transplantation was performed 2 months after presentation (results of histopathology tests are shown in Box 1). The patient’s transplanted liver appears to be functioning well and the patient is making a slow recovery.

In the absence of any alternative cause of hepatotoxicity, an adverse event notification was made to the Therapeutic Goods Administration, detailing the use of the two dietary supplements. The public health division of the relevant state health department was also informed, and the two supplements were tested for heavy metals (arsenic, cadmium, chromium, copper, mercury, nickel, lead and zinc) and pharmaceuticals; however, no unexpectedly high levels of these substances were detected.

Over 900 drugs and herbs have been reported to cause hepatotoxicity.1 In the United States, the use of herbal and dietary supplements is the second most common cause of idiosyncratic drug-induced liver injury (DILI), after antimicrobial therapy.1 Of the herbal and dietary supplements, weight loss and body building supplements are most commonly implicated.2 In addition, contamination and adulteration of herbal supplements is common,3 with reported contaminants including undeclared antimicrobials, pharmaceuticals and heavy metals.2 Diagnosis of DILI is complicated by the tendency for herbal supplements to contain multiple ingredients,2 many of which are poorly characterised and could act synergistically. The protein supplement ingested by the patient in this case contained many ingredients, including green tea (Camellia sinensis) extract, green coffee extract, African mango extract, guarana, whey protein, and various vitamins and minerals. This, combined with his ingestion of a second supplement containing G. cambogia (active ingredient hydroxycitric acid), prohibits definitive identification of the causative agent or agents.

Historically, DILI has been overdiagnosed, with up to 48.5% of suspected cases of herb-induced hepatotoxicity being eventually attributed to other causes.4 To reduce the risk of misdiagnosis, causality assessments are routinely used. Many tools are available, but the Council for International Organizations of Medical Sciences (CIOMS) scale is most commonly used.4 This scale is liver specific and attributes a score based on seven items (Box 2), translating to causality grades of excluded, unlikely, possible, probable and highly probable for DILI. Using this scale, DILI secondary to the protein supplement in combination with the G. cambogia supplement is probable for the patient in this case (total score, 6).

Of the supplements ingested by the patient in this case, the main ingredients previously associated with hepatotoxicity are green tea extract and G. cambogia. Green tea and green tea extract have been demonstrated to have beneficial effects on total cholesterol levels, low density lipoprotein cholesterol levels, blood pressure,5 and fasting blood glucose levels.6 However, over 60 case reports linking green tea extract with hepatotoxicity have been published.3 In many of these cases, the ascertainment of causality was complicated by the ingestion of more than one potential hepatotoxin.3 Green tea differs from black tea in that it is unfermented, preserving the catechins that are the probable toxic agent. Green tea is present in many dietary supplements and protein powders available in supermarkets, health food shops and pharmacies. The usual clinical picture is a hepatocellular pattern of liver injury occurring within 3 months of ingestion (range, 10 days to 7 months).7 Although most patients recover rapidly on cessation, fatal instances of acute liver failure have been described. Results of liver histopathology tests typically resemble acute hepatitis, with necrosis, inflammation and eosinophils present. Autoimmune features are usually absent.7 This patient’s clinical picture, biochemistry results and histopathology results are consistent with a green tea extract-induced liver injury.

Products containing G. cambogia are widely available and advertised as weight loss supplements, although the evidence supporting this effect is conflicting. In comparison with green tea extract, the evidence for G. cambogia as a hepatotoxin is less robust and the safety profile of G. cambogia has not been extensively studied. The substance has been associated with hepatocellular pattern DILI in several case reports,8,9 but other potentially hepatotoxic pharmaceuticals or herbal supplements had also been ingested in these cases.

In 2009, the US Food and Drug Administration (FDA) recalled several Hydroxycut slimming supplements (Iovate Health Sciences International) following 23 case reports associating liver injury with ingestion of these products, including several cases in which the patient required liver transplantation or died.10 The implicated products varied in formulation, with some containing G. cambogia and all containing green tea extract. Following an investigation by the FDA Health Hazard Evaluation Board, it was concluded that Hydroxycut could cause idiosyncratic hepatotoxicity, although the exact causative agent was not identified. A subsequent case series examined the product constituents and concluded that green tea extract was the most likely causative agent, although this could not be definitively proven.10 There are similarities between the Hydroxycut scenario and the case described here, but, to our knowledge, no other cases of hepatotoxicity associated with whey protein powder and a weight loss supplement containing G. cambogia have been reported.

Lessons from practice

Health professionals should specifically question patients on their use of dietary supplements. Patients often do not mention use of such products owing to perceptions of product safety.
Ascertaining causality is challenging. Scoring systems are available to help diagnose drug-induced liver injury and systematically exclude alternative causes.
Increased regulation of herbal and dietary supplements, including better surveillance of adverse events associated with these products, could improve knowledge of their safety profiles.

Box 1 –
Results of tests conducted on admission and histopathology tests of liver biopsy specimen and explanted liver for a patient who developed fulminant liver failure after using dietary supplements

Test

Result (reference interval)

Serum alanine aminotransferase

1520 U/L (< 40 U/L)

Serum aspartate transaminase

1430 U/L (< 45 U/L)

Serum alkaline phosphatase

156 U/L (35–135 U/L)

Serum gamma-glutamyl transferase

260 U/L (< 60 U/L)

Serum bilirubin

174 μmol/L (< 20 μmol/L)

Serum albumin

36 g/L (35–50 g/L)

International normalised ratio

1.3 (0.9–1.3)

Anti-HAV IgM

Not detected

HBs antigen, anti-HBc IgM, HBV-DNA

Not detected

Anti-HCV antibody, HCV-RNA

Not detected

Imaging (dual-phase computed tomography)

No portal vein thrombosis

Anti-EBV IgM, anti-EBV IgG

IgM negative, IgG positive

Anti-HEV IgM, anti-HEV IgG

Not tested

Anti-HSV IgM, anti-HSV IgG

IgM negative, type 1 IgG positive, type 2 IgG negative

Anti-VZV IgM, anti-VZV IgG

IgM negative, IgG positive

Anti-CMV IgM, anti-CMV IgG

IgM negative, IgG positive

Anti-nuclear antibody

4 IU/mL (< 7 IU/mL)

Anti-smooth muscle antibody

0 IU/mL (0 IU/mL)

Serum caeruloplasmin

0.23 g/L (0.17–0.45 g/L)

Serum copper

12 μmol/L (11–23 μmol/L)

Histopathology tests — liver biopsy specimen

Multiple fragmented cores of hepatic parenchyma with panlobular and multilobular necrosis, consistent with submassive hepatic necrosis; no evidence of autoimmune hepatitis or significant copper or iron deposition

Histopathology tests — explanted liver

Loss of viable hepatocytes, collapse of liver parenchyma, reactive biliary hyperplasia, no cirrhosis or steatosis; between the necrotic areas were islands of regenerative nodules containing viable hepatocytes with disorganised architecture and without well formed portal tracts

HAV = hepatitis A virus. HBs = hepatitis B surface antigen. HBc = hepatitis B virus core antibody. HBV = hepatitis B virus. HCV = hepatitis C virus. EBV = Epstein–Barr virus. HEV = hepatitis E virus. HSV = herpes simplex virus. VZV = varicella-zoster virus. CMV = cytomegalovirus.

Box 2 –
Summary of the Council for International Organizations of Medical Sciences scale4 for the hepatocellular pattern of liver injury in cases of suspected drug- and herb-induced liver injury, and scores for a patient who developed fulminant liver failure after using dietary supplements

Items scored for hepatocellular injury

Potential score

Patient’s score

1. Time to onset from beginning/cessation of drug/herb ingestion

1 to 2

2. Course of serum alanine aminotransferase levels after cessation of drug/herb ingestion

−2 to 3

3. Risk factors (age and alcohol use)

0 to 2

4. Concomitant ingestion of drug(s) or herbs(s)

−3 to 0

5. Search for non-drug/herb causes^∗

−3 to 2

6. Previous information on hepatotoxicity of the drug/herb

0 to 2

7. Response to unintentional re-administration

−2 to 3

Total score^†

* Item 5 is scored according to the exclusion of 12 non-drug/herb causes of hepatotoxicity, of which 11 were excluded for the patient described in this article because serological exclusion of hepatitis E virus was not performed (it was clinically unlikely and is not seen locally in the absence of travel to an endemic area); as such, the patient scored 1 for this item. † Causality grades for total scores: ≤ 0, excluded; 1–2, unlikely; 3–5, possible; 6–8, probable; ≥ 9, highly probable.

Methods

Epidemiological investigation

Case definition

Case finding and data collected

Laboratory investigation

Serology

Viral detection and sequencing

Environmental investigation

Investigation and food testing linked to restaurant X

Testing of pork liver sausages linked with an HEV case not linked to restaurant X

Data analysis

Ethics approval

Results

Epidemiological investigation

Notified HEV cases

Restaurant X outbreak

Locally acquired cases not linked to restaurant X

Retrospective serological surveys

Laboratory investigation

Environmental investigation

Investigation of restaurant X

Investigation of pork products of locally acquired cases not linked to restaurant X

Public health interventions

Discussion

Models of care for HCV

Screening and diagnosis

Pre-treatment assessment

Treatment for chronic HCV infection

Genotype 1 HCV

Sofosbuvir &plus; ledipasvir for genotype 1 HCV

Sofosbuvir &plus; daclatasvir ± ribavirin for genotype 1 HCV

Paritaprevir–ritonavir, ombitasvir &plus; dasabuvir ± ribavirin for genotype 1 HCV

Ribavirin-related adverse events

Genotype 2 HCV

Genotype 3 HCV

Sofosbuvir &plus; daclatasvir for genotype 3 HCV

Sofosbuvir &plus; ribavirin for genotype 3 HCV

Sofosbuvir &plus; peginterferon-alfa &plus; ribavirin for genotype 3 HCV

Genotypes 4, 5 and 6 HCV

Drug–drug interactions

Pregnancy, breastfeeding and children

Direct-acting antivirals and drug resistance

Salvage therapy

On-treatment monitoring

Post-treatment follow-up

Confirm SVR

Long-term management of liver disease

Special populations

Methods

NSW Population-wide Study

Data sources

Variables for analysis

Statistical methods

Patterns of Care (POC) study

Variables for analysis

Ethics approval

Results

NSW Population-wide Study

Characteristics

Surgical treatment

Survival

Patterns of Care study

Characteristics

Surgical treatment

Adjuvant chemotherapy and radiotherapy

Discussion

Conclusion

Methods

Results

Discussion

Sofosbuvir + ledipasvir for genotype 1 HCV

Sofosbuvir + daclatasvir ± ribavirin for genotype 1 HCV

Paritaprevir–ritonavir, ombitasvir + dasabuvir ± ribavirin for genotype 1 HCV

Sofosbuvir + daclatasvir for genotype 3 HCV

Sofosbuvir + ribavirin for genotype 3 HCV

Sofosbuvir + peginterferon-alfa + ribavirin for genotype 3 HCV