Hep C drug mystery

The Federal Government has not disclosed how much it intends to spend on its goal of virtually eradicating hepatitis C from the country within a generation.

In one of the Government’s most ambitious public health measures, all adults with chronic hepatitis C have been provided subsidised access to hugely expensive frontline drugs that have a high rate of success in eliminating the disease within months.

More than 230,000 are estimated to be currently living with hepatitis C, which kills around 700 a year, but for most the drugs that could cure their ailment – Sofosbuvir, Daclatasvir and Ribavirin – were prohibitively expensive, costing as much as up to $100,000 for a course of treatment.

But hepatitis C have, since 1 March, had subsidised access to the drugs through the Pharmaceutical Benefits Scheme – an arrangement confirmed in the Budget.

Announcing the measure at the time, Health Minister Sussan Ley said it provided “great hope we can not only halt the spread of this deadly infectious virus, but eliminate it altogether in time”.

The Minister has explicitly linked the decision with the highly controversial move to axe bulk billing incentives for pathology services and cut them for diagnostic imaging – a measure expected to save $650 million over four years.

But in the Budget the Health Department said the cost of the measure was “not for publication”.

By contrast, it has announced that $57.6 million has been set aside to fund new and amended listings of drugs on the PBS and the Life Saving Drugs Program.

The Department said the PBS would cost $10.1 billion overall in 2016-17.

In addition, the Government has revealed it will spend $20.4 million to improve speed and efficiency of the system to regulate therapeutic goods, with the aim of bringing new drugs to market more quickly – in some cases up to two years sooner.

Under the plan, the number of committees advising the TGA will be cut from 11 to seven, costs and administrative burden for industry will be reduced, and the time taken to assess products will be reduced by up to three months by drawing on the work of comparable regulators overseas, such as the US Food and Drug Administration.

In addition, commercial organisations approved by the TGA will be allowed to undertake assessments of medical devices, and there will be new approval pathways for sponsors to add medicines and devices.

Adrian Rollins

[Comment] Vilanterol fluticasone and mortality in comorbid COPD GOLD B

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Due to common risk factors such as smoking and ageing, COPD often coexists with cardiovascular diseases, which have a major effect on prognosis. Cardiovascular death is the most important cause of death in patients with symptomatic moderate COPD (ie, COPD GOLD B).1,2 However, as highlighted by the GOLD guidelines, none of the current treatments of COPD, except smoking cessation, has been shown to significantly decrease all-cause mortality.

[Correspondence] Objection to chronic disease based restrictions during the Hajj

The call by Saber Yezli and colleagues (Feb 27, p 845)1 to restrict the Hajj pilgrimage based on non-communicable diseases (NCDs) is extremely disturbing to many Muslims. The Hajj is a deep, spiritual journey mandatory to financially and physically able Muslims once in their life-time. Two-thirds of the Hajj pilgrims originate from developing countries who make life-long savings to achieve their spiritual objectives. Thus, for most pilgrims, the Hajj is feasible only in older age; 43% of pilgrims are 56 years of age or older.

Flu vaccine more effective in the morning: study

Research has shown administering the flu vaccine in the morning could be more effective for immunity than in the afternoon.

The research, published in Vaccine, was conducted on 24 general practices in the UK, and involved 276 adults over the age of 65.

The adults were vaccinated for three strains of influenza in two time slots, either 9-11am or 3-5pm.

For two of the strains, there was a significantly larger increase in antibody concentration detected a month later for the group who were vaccinated in the morning compared to those who were vaccinated in the afternoon. There was no difference in antibodies for the third strain.

According to Principal Investigator of the study from the University of Birmingham, Dr Anna Phillips, “We know that there are fluctuations in immune responses throughout the day and wanted to examine whether this would extend to the antibody response to vaccination. Being able to see that morning vaccinations yield a more efficient response will not only help in strategies for flu vaccination, but might provide clues to improve vaccination strategies more generally.”

Co-investigator Professor Janet Lordsaid, “Our results suggest that by shifting the time of those vaccinations to the morning we can improve their efficiency with no extra cost to the health service.”

A larger scale study will investigate whether vaccinating in the morning would benefit people with impaired immunity, such as those with diabetes, liver and kidney disease.

Future research will also look at whether the time of day may vary for different vaccines, as they stimulate diverse immune responses for protection.

Latest news:

[Comment] No more excuses: viral hepatitis can be eliminated

The 2030 Agenda for Sustainable Development has recognised an infectious disease that the Millennium Development Goals omitted. UN Member States have now made a commitment to combat hepatitis under Goal 3.3 of the Sustainable Development Goals (SDGs),1 as a threat comparable to the “big three” communicable diseases—HIV/AIDS, tuberculosis, and malaria. Viral hepatitis is not an emerging infectious disease, but the cause of a silent epidemic of serious and often fatal liver disease, including liver cancer; the causative agents (hepatitis A, B, C, D, and E viruses) have been circulating in the human population for millennia.

Diabetes affects almost one in 10

Diabetes is rapidly emerging as one of the world’s most serious public health problems, affecting almost 500 million adults and contributing to the deaths of close to four million people a year.

An alarming report from the World Health Organization has found that incidence of diabetes, once mainly confined to high income countries, is rapidly spreading, and by 2014 422 million adults were living with the disease – almost one in every 10 adults worldwide. In 1980, its prevalence among adults was less than 5 per cent.

WHO Director-General Dr Margaret Chan said the disease’s emergence in low- and middle-income countries was particularly problematic because they often lacked the resources to adequately diagnose and manage the disease, resulting in needless complications and premature deaths.

According to the WHO’s Global Report on Diabetes, the condition was directly responsible for 1.5 million deaths in 2012 and contributed to a further 2.2 million fatalities by increasing the risk of cardiovascular and other diseases.

Diabetes takes a relatively heavy toll of younger people, particularly in less wealthy countries. Of the 3.7 million deaths linked to diabetes in 2012, 43 per cent occurred in people younger than 70 years of age, and the proportion was even higher in low- and middle-income countries.

The rise in diabetes has coincided with an increase in associated risk factors, most particularly a jump in global rates of overweight and obesity. Currently, 10.8 per cent of men and 14.9 per cent of women worldwide are considered to be obese, and on current trends that will increase to 18 per cent of men and 21 per cent of women by 2025.

While rates of obesity and diabetes are continuing to climb in rich countries, the WHO said this is being outstripped in other parts of the world, particularly middle-income nations.

The relative lack of resources to prevent, diagnose and manage diabetes in less wealthy countries is exacerbating its spread and impact.

Programs and policies to encourage physical activity, promote health diets, avoid smoking and controlling blood pressure and lipids are generally better funded in rich countries, where GPs and other frontline health services are better equipped to detect diabetes early and patients generally have good access to insulin and other treatments.

The WHO said that even though most countries have national diabetes policies in place, often they lack for funding and implementation.

“In general, primary health care practitioners in low-income countries do not have access to the basic technologies needed to help people with diabetes properly manage their disease,” the agency said. “Only one in three low- and middle-income countries report that the most basic technologies for diabetes diagnosis and management are generally available in primary health care facilities.”

In particular, it highlighted serious problems with access to treatments.

“The lack of access to affordable insulin remains a key impediment to successful treatment and results in needless complications and premature deaths,” the WHO report said. “Insulin and oral hypoglycaemic agents are reported as generally available in only a minority of low-income countries. Moreover, essential medicines critical to gaining control of diabetes, such as agents to lower blood pressure and lipid levels, are frequently unavailable in low- and middle-income countries.”

Diabetes has been identified as one of four priority non communicable diseases targeted under the 2030 Agenda for Sustainable Development, but Dr Chan said the WHO report showed there was “an enormous task at hand”.

“From the analysis it is clear we need stronger responses not only from different sectors of government, but also from civil society and people with diabetes themselves, and also producers of food and manufacturers of medicines and medical technologies,” the WHO leader said.

Adrian Rollins

A case of subacute sclerosing panencephalitis in a 23-year-old recent immigrant to Australia

A 23-year-old woman presented with a generalised tonic–clonic seizure on a background of 9 months of progressive neurological decline (characterised by involuntary jerks, monocular visual disturbance and reduced speech) resulting in falls, impaired ability to perform activities of daily living and urinary incontinence. Examination showed right-sided myoclonus, bilateral parkinsonism, primitive reflexes present, akinetic mutism and retinal scarring apparent on fundoscopy.

Two years previously, she had migrated to Australia from the Philippines; her family reported that her neurodevelopment was normal and that she had received routine childhood vaccinations.

The results of computed tomography and angiography of the brain were normal. Magnetic resonance imaging of the brain showed cerebral volume loss and extensive white matter changes with ill-defined subcortical T2 hyperintensities. An electroencephalogram showed non-specific focal epilepsy disorder involving frontal regions. Results of extensive investigations for autoimmune, hereditary and infective causes were unremarkable with the exception of cerebrospinal fluid (CSF) analysis, which revealed unmatched oligoclonal IgG. Enzyme immunoassay of CSF and serum (with corrected optical density values of 2.24 and 4.21, respectively) gave a strongly positive result for measles IgG. Intrathecal measles antibody production was confirmed by the concurrent absence of varicella-zoster virus IgG in the CSF, despite it being detected in the serum.

A raised CSF:serum ratio of measles antibodies, oligoclonal IgG in CSF and clinical features of progressive mental deterioration with myoclonus fulfilled Dyken’s diagnostic criteria of probable subacute sclerosing panencephalitis (SSPE), outlined in the Box. Supportive measures were undertaken and isoprinosine treatment for SSPE was initiated. The patient’s neurological condition stabilised but there was no improvement in her condition.

SSPE is a fatal, progressive neurodegenerative disease caused by persistent infection with an altered measles virus. Although rare, SSPE should be considered in the differential diagnosis of subacute neurological deterioration and myoclonus, especially in incompletely vaccinated patients. SSPE is rare following measles infection, with an incidence of 4–22 cases per million measles cases.1 SSPE is rarer in adults, who account for 1–12.7% of cases.2 There is no association with the attenuated measles vaccine and SSPE; no vaccine strains have ever been isolated from tissue specimens of patients with SSPE.3 Vaccination unfortunately does not confer 100% protection against measles infection (and hence against developing SSPE, which may occur after subclinical measles infection). A single dose of MMR vaccine is 95% effective, and two doses are 99% effective for measles protection.

This case is important as it highlights a terrible consequence of a vaccine-preventable disease. Achieving whole-population vaccination is instrumental in preventing measles infections through the development of herd immunity. However, 96–99% of a population are required to be vaccinated to prevent sustained measles transmission. In Australia in 2012, only 91.9% of children aged 5 years had received two doses of measles vaccine.4 Lower immunisation rates have been observed in certain areas, such as parts of the New South Wales north coast. In Australia, there were 154 confirmed measles cases reported in 2013 and 335 cases in 2014.5 Our case highlights one of the possible consequences if measles vaccination rates are not improved.

Box –
Dyken’s criteria for diagnosis of subacute sclerosing panencephalitis1

Criterion

Description

1. Characteristic clinical features

Progressive, subacute mental deterioration with typical signs like myoclonus

2. Electroencephalogram

Periodic, stereotyped high-voltage discharges

3. Cerebrospinal fluid (CSF)

Raised γ-globulin level or oligoclonal pattern

4. Measles antibodies

Raised titre in serum (≥ 1 : 256) and/or CSF (≥ 1 : 4) with a CSF : serum ratio < 1 : 200

5. Brain biopsy or autopsy

Showing typical histopathology and/or culturing altered measles virus and/or detection of measles RNA by polymerase chain reaction

Definitive diagnosis: criterion number 5, plus 3 other criteria. Probable diagnosis: 3 or more of the 5 criteria.

Immunisation for medical researchers: an ethical and practical imperative

Participants in medical research are the most valuable resource within health research, and their wellbeing must be regarded as paramount. Australia’s national statement on ethical conduct in human research1 establishes that the burden is on researchers to safeguard the health, wellbeing and autonomy of their research participants. We argue that additional guidance is required in an area that has not been widely considered in the ethical research literature and policy: immunisation coverage of the research team.

It is acknowledged that health care workers with immunisation-preventable diseases infect their patients.2,3 There is no reason to believe that researchers are exempt from transmitting these diseases to their participants. There are national guidelines4 that provide evidence-based recommendations on immunisation for people at occupational risk, but this guidance does not specifically refer to researchers.

We present a case study to illustrate the issue. We undertook a cross-generational longitudinal study examining environmental, lifestyle and genetic factors influencing health and wellbeing across the lifespan. The study, based at a medical research institute, involved recruiting pregnant women in collaboration with the local health district. University researchers sought honorary appointments for recruitment and data collection in the hospital setting, with the expectation that we would be required to prove immunisation currency, according to relevant state health policy.5 When the resultant honorary researcher appointment applications were approved, we were not required to show any immunisation status. There may be several reasons for this: first that individuals classifying risk may interpret the rules differently; and second, employment status in clinical research studies with multiple researchers from different organisations is complex.

The study researchers reviewed the university immunisation guidelines and found that those on clinical placements in state health facilities required immunisation coverage, but for all others, including researchers, immunisation was voluntary. After careful consideration, we decided that ensuring the research team was fully immunised was the most ethical way to approach our research. In consultation with an infection control specialist at the local health district, we agreed on several immunisations or evidence of serological immunity.

To fulfil our responsibilities as ethical researchers, we believe it is essential that all researchers who have direct contact with participants are fully immunised, using national guidelines, against relevant diseases. The prevention of avoidable harm appears to be an ethical imperative, but we can find no consistent guidance in this area for researchers at a national or international level. We suggest that it is appropriate for the National Health and Medical Research Council to consider guidance on immunisation coverage of researchers who have direct contact with participants, rather than leaving it to individual research ethics committees.

Polymerase chain reaction testing for faecal parasites: risks and alternatives

In this short report, written on behalf of the Australian Society of Infectious Diseases (ASID) and endorsed by its council, we highlight recent changes to stool pathogen testing (particularly for parasites) within Australasian laboratories and alert clinicians to our concerns regarding result interpretation.

Since 2013, many laboratories in Australasia have changed the technique used for stool parasite detection from subjective, time-consuming microscopy to multiplex polymerase chain reaction (PCR), which can detect multiple enteric bacterial and parasitic pathogens. A turnaround time of under 3 hours increases efficiency and reduces costs.1 Five protozoa are generally included in multiplex PCR assay: Giardia lamblia, Cryptosporidium spp., Entamoeba histolytica, Dientamoeba fragilis and Blastocystis spp.1

ASID and the Royal College of Pathologists of Australasia (RCPA) have significant concerns regarding two parasites included in multiplex PCR assay — D. fragilis and Blastocystis spp. — as their role as putative gastrointestinal pathogens is controversial and unproven. Both D. fragilis and Blastocystis spp., which are of uncertain clinical significance and may be colonising flora, have been detected at much higher rates by PCR than by routine microscopy, with prevalence rates of 17% for D. fragilis and Blastocystis.2 Similar rates have been found in Australian laboratories.3 Children aged under 10 years are the main population affected by the significant increase in detection.2,3 To date the best evidence in children, a double-blind randomised controlled trial, showed no difference between treatment and placebo for dientamoebiasis.4 A second peak occurs at 30–40 years of age, presumably among parents of children who test positive for D. fragilis.2 This has resulted in increased consultations to medical practitioners, unnecessary use of antimicrobials, and anxiety and uncertainty for families. Symptoms are often falsely attributed to these organisms, leading to overtreatment.

The results of these tests as part of the multiplex have resulted in confusion for clinicians. To optimise the use of faecal multiplex PCR in clinical practice and to minimise unwarranted treatment and anxiety, we recommend that practitioners:

do not request stool pathogen assessment (including multiplex faecal PCR) on formed stool samples;
do not request specific testing for D. fragilis or Blastocystis spp.;
should reflect the markedly increased sensitivity with unclear significance in their clinical interpretation of pathology laboratory reports of detection of these parasites;
adhere to comments appended to the laboratory report regarding the significance of D. fragilis and Blastocystis spp. and avoid specific treatment and further testing; and
discuss with a paediatric or adult infectious diseases specialist or medical microbiologist, if clarification is required.

To eliminate uncertainties, the RCPA has released guidelines (http://www.rcpa.edu.au/Library/College-Policies/Guidelines/Faecal-pathogen-testing-by-PCR.aspx) recommending that laboratories do not include D. fragilis or Blastocystis spp. within enteric multiplex PCR testing. Where laboratories continue to test and report such results, ASID and the RCPA recommend that laboratories add a comment regarding the uncertainty of the significance of these organisms.

Shigellosis: high rates of antibiotic resistance necessitate new treatment recommendations

Shigella species cause a potentially severe diarrhoeal illness that is frequently travel-associated and is both foodborne and sexually acquired. There is evidence of increasing antibiotic resistance in Shigella isolates from international studies.1,2 However, there is limited published research on this issue in an Australian context. The current Australian Therapeutic Guidelines recommend either co-trimoxazole or quinolone therapy for suspected or proven shigellosis, but do comment that quinolone resistance is increasing in developing countries and recommend azithromycin as an alternative option, if required.3 Successful treatment of shigellosis reduces the duration of illness and infectivity.

We conducted a study to describe antimicrobial resistance patterns among Shigella isolates in New South Wales during 2013 and 2014, and to identify predictors of resistance using laboratory and epidemiological data from the NSW Notifiable Conditions Information Management System (NCIMS).

A cross-sectional analysis was conducted using cases of shigellosis notified to public health authorities in NSW through NCIMS, with specimens received by the enteric pathogen reference laboratory for NSW — the Institute for Clinical Pathology and Medical Research (ICPMR) at Westmead Hospital — collected from 1 May 2013 to 30 April 2014. During the study period, a notified case was classified as confirmed if there was laboratory definitive evidence (isolation or detection of Shigella species). The study used routinely collected surveillance data from NCIMS collected by NSW Health for the purposes of analysis and reporting, for which ethics committee approval was not required. Susceptibility to azithromycin was measured via Etest (Biomérieux) using a breakpoint of ≤ 16 μg/mL, in line with the method of previous investigators.4 Susceptibility of isolates to all other drugs was tested using the BD Phoenix (BD Diagnostics) automated broth microdilution instrument and interpreted using Clinical and Laboratory Standards Institute criteria.5

Among the 160 Shigella isolates tested, 98% were susceptible to ceftriaxone, 87% to azithromycin, 73% to ampicillin, 65% to ciprofloxacin, and only 24% to co-trimoxazole (Box). Rates of resistance varied with both place of acquisition (overseas or Australia) and method of acquisition (sexual or other). Of note, ciprofloxacin resistance was more common in locally acquired than in overseas acquired infection.

We recommend the use of azithromycin, rather than ciprofloxacin or co-trimoxazole, as the first-line agent in suspected or proven shigellosis, regardless of place or method of acquisition. Our findings indicate that it is time for Therapeutic Guidelines to review its guidelines for the treatment of shigellosis in light of changing resistance patterns. Ceftriaxone remains a suitable option for seriously unwell or hospitalised patients before the availability of susceptibility testing. We strongly recommend culture and susceptibility testing for suspected and proven shigellosis, particularly among men who have sex with men, who have a higher risk of both being infected with a resistant strain and transmitting infection.

Box –
Antimicrobial resistance of Shigella isolates, by antibiotic and place and method of acquisition, 1 May 2013 to 30 April 2014*

	No.	Resistance
	No.	Azithromycin	Ciprofloxacin	Co-trimoxazole	Ampicillin

Total isolates	160	21 (13.1%)	56 (35.0%)	122 (76.3%)	59 (36.9%)
Overseas acquired^†
Yes	55	2 (3.6%)	13 (23.6%)	39 (70.9%)	19 (34.5%)
No	91	13 (14.3%)	37 (40.7%)	72 (79.1%)	32 (35.2%)
Reported sex with faecal exposure
Yes	58^‡	11 (19.0%)	27 (46.6%)	45 (77.6%)	21 (36.2%)
No	102	10 (9.8%)	29 (28.4%)	77 (75.5%)	38 (37.3%)

* Shigella isolates obtained from the New South Wales reference laboratory (Institute for Clinical Pathology and Medical Research, Westmead Hospital). The first isolate for each illness event was used; subsequent isolates were excluded where patients had multiple specimens collected for one illness event. 98% of isolates were susceptible to ceftriaxone. † 14 unknown. ‡ All men, 57 of whom also reported that they were men who have sex with men.