Paul Smith

IN an age where the instinctive medical reaction to talk of wonder drugs is hardened scepticism, the reaction to the direct-acting antivirals( DAAs) for hepatitis C may seem like an exception.

A year ago, then federal Minister for Health Sussan Ley announced a billiondollar investment in the therapies, declaring they could“ eradicate the virus within a generation”.

Given the lives of some 230,000 patients in Australia are blighted by chronic infection with the virus, her dramatic announcement could have been seen as the health policy high-point not only of her career but of the entire Federal Government.

But then last month, a Cochrane review applied its evidence-based blast.

The headlines went round the world: The therapies were not proven to save lives or prevent harm. The trials were generally weak, and the risk of bias very high.

The implication was obvious: the vast sums invested— around $ 80,000 a patient— were being squandered on a baseless hope.

Professor Greg Dore, head of the viral hepatitis clinical research program at the Kirby Institute for Infection and Immunity in Society,

echoed the alarmed sentiments of clinicians, describing the review’ s conclusions as“ bizarre”.

The clinical consensus, he said, was that cure rates were above 90 %.

Look at the trials, do the systematic review, he said, but be aware that they were never designed to look at morbidity or mortality at population levels.

The Cochrane controversy seemed a classic example of mismatched realities— the realities experienced by n = 1 clinicians and the epidemiological realities of those distant individuals engaged in number-crunching of metaanalyses.

So Australian Doctor spoke with Dr Janus Jakobsen, the chief physician at the Copenhagen Trial Unit at Copenhagen University Hospital and the lead author of the Cochrane review.

He admitted being shocked at the reaction— but not in the way you would expect.

“ We were expecting a stronger reaction,” he said.“ The reaction was quite modest. We thought we would be criticised more intensively.”

He added:“ You have to understand these therapies have been described as a cure and as a revolution. If you look at the drug company

posters on the conference circuit, you see a very aggressive marketing of a cure and a wonder drug.

“ So when we saw the results of our review, we were aware they were going to get a reaction from the clinicians, the authorities recommending drugs.”

The heart of the dispute about the review and its validity seemed to lie with one specific issue.

Professor Dore took particular exception to the Cochrane declaration that although the trials focused and assessed the effects of DAAs on sustained virological response, it was“ questionable if sustained virological response has any clinical relevance to the person with chronic hepatitis C”.

This made the therapies sound like junk that dealt only with surrogate outcomes. Professor Dore was bewildered because he had assumed the academic debate about the absence of the hepatitis

C RNA in the blood equating to elimination of the virus in the body had been settled some years ago.

Dr Jakobsen dismissed this:“ This evidence [ of a valid surrogate marker for a cure ] is non-existing for these drugs. If they have the evidence, then please show me. They have not offered this evidence because it doesn’ t exist.”

The way he used the word‘ evidence’ might be the nub of the problem. For Dr Jakobsen, valid evidence was the evidence you only get from randomised controlled trials, the only evidence a Cochrane review used.

“ If you read medical journals and follow the evidence, you can see every month some medical intervention we thought worked based on clinical experience or on nonrandomised studies.

“ But when we examine them in a robust way, we find they are not effective, or maybe even that they are harmful.

A difference of opinion about the word‘ evidence’ might be to blame.

“ History is full of those examples. When we need to validate intervention effects with certainty we can’ t trust the non-validated surrogate outcomes, we cannot trust our clinical experience or our observational studies.”

Professor Dore said he was worried about the impact of the review.

Cochrane reviews were meant to carry weight and he feared that some patients might be put off treatments or that doctors could think twice before prescribing DAAs.

He agreed research had to continue into DAAs to quantify their populationlevel efficacy and safety. But, he said:“[ The Cochrane reviewers ] come from a perspective that is pure as the driven snow.

“ And that is all very well, but if it’ s not underpinned by a full understanding of the context of the clinical trials, the context of outcomes being evaluated, you risk becoming snowblind.”

Doctor loses manslaughter appeal

A DOCTOR who killed her abusive husband with a heavy metal mallet as he slept in their WA home has lost an appeal against her conviction and sentence. Dr Chamari Liyanage was sentenced to four years in prison after being convicted of the manslaughter of Dr Dinendra Athukorala in Geraldton in June 2014. Dr Liyanage, who has now been released on parole, claimed the sentence was excessive and that the original judge had made errors in their directions to the jury. But the WA Court of Appeal ruled unanimously that none of the alleged errors had been established and the appeal should be dismissed.

Booklet helps beat CFS A SELF-help approach to a graded exercise program can help people with chronic fatigue syndrome, a UK study shows. In a 12-week trial involving 211 patients, those given self-help booklets showing how to gradually and safely increase physical activity levels had lower fatigue levels than those in a control group. Such a program might help patients who were unable to access a physiotherapist, said an accompanying commentary in the Lancet. Lancet 2017; online.

Only 1-2 % were aware of implants, IUDs or diaphragms.

MICHAEL WOODHEAD MEN want to share in decisionmaking about contraception, but know little beyond condoms and vasectomy, an Australian study shows.

When surveyed about their favoured contraceptive methods. But men had positive attitudes and high levels of knowledge for male-controlled methods.

However, many were vague or had misperceptions about female-controlled methods, such as implants and vaginal rings.

And worryingly, the responses from more than

2400 men to an online survey conducted by Family Planning NSW indicated that one in three believed emergency contraception was harmful to the health of the user.

In the survey, men most commonly reported they were currently using condoms( 35 %) or vasectomy( 22 %) for contraception, while only 1-2 % were aware that their partner was using methods such as contraceptive implants, IUDs or diaphragms.

Men had most knowledge about the least reliable methods of contraception, including condoms, and

non-reversible methods, such as vasectomy, said the researchers from Family Planning NSW.

“ Notably, the methods that men reported being most unsure about with regard to effect on the health of the user and effect on sexual interest or pleasure include the most effective, reversible, femalecontrolled methods,” they said.

“ Almost half of [ men ] were unsure whether each of the long-acting reversible contraceptive( LARC) methods( intrauterine contraception, the implant and the injection) was harmful to health,” they added.

Given that 90 % of men said they believed contraception decision-making should be shared between partners, the researchers said it was a particular concern that many men believed methods such as emergency contraception and oral contraceptives were harmful to health.

“ Increasing men’ s knowledge and attitude towards contraception, particularly the LARC methods, is an important strategy to increase uptake of these highly effective methods,” they suggested. Sexual Health 2017; online.