Cochrane review of hepatitis C treatment strongly criticised

A systematic review of hepatitis C direct-acting antiviral (DAA) studies published by the Cochrane Collaboration has been strongly criticised by doctors and advocates for its conclusion that there is no evidence that the expensive drugs prolong life or reduce liver-related disease in people who achieve a sustained virologic response to treatment – a cure, in current understanding.

Systematic reviews have become highly influential in health policy-making and the development of clinical guidelines. The reviewers carry out a systematic search for all published and unpublished scientific studies relevant to a scientific question, rate the quality of those studies and calculate the overall effect of an intervention or treatment. In particular, systematic reviews seek to minimise bias caused by poor study design, inadequate follow-up or incomplete publication of results. The Cochrane Collaboration has published numerous systematic reviews in all areas of medicine and its reviews are highly regarded.

The Cochrane Collaboration’s review of the impact of DAAs on mortality, morbidity and serious adverse events, published this month, identified 138 randomised trials. Only eleven studies with follow-up on 2996 people reported on mortality and morbidity; meta-analysis of these studies found no significant difference in outcomes in people who received DAAs or placebo. A grand total of 16 deaths were reported in these studies.

The Cochrane reviewers acknowledge a major limitation of their review: most trials had short follow-up periods, so “our results can neither confirm nor reject that DAAs have clinical long-term effects”. In fact, the average follow-up period was just 34 weeks, far too short to detect any effect on mortality except in people with decompensated cirrhosis and end-stage liver disease.

In a letter to The Guardian, Professor Graham Foster of Queen Mary University of London and senior colleagues from the United Kingdom said: “The trials were neither designed, nor powered, to assess mortality, so it is not at all surprising that the Cochrane review was unable to identify any impact on mortality.“

In contrast, a systematic review of 31 studies of the effect of pegylated interferon and ribavirin on the survival of people after being cured of hepatitis C was able to draw on studies that followed people for a median of 5.4 years, allowing researchers from Imperial College, London, to conclude that a sustained virological response to treatment reduced the risk of death by 50-80% over five years.

The authors of the review also described the well-accepted relationship between sustained virologic response and long-term outcomes of liver disease as a “non-validated surrogate outcome”.

“I'm not sure how the Cochrane Collaboration could claim that curing Hepatitis C with new direct-acting antiviral drugs does not improve survival,” commented Dr Andrew Hill, one of the authors of the Imperial College review.

“They could claim that being cured of hepatitis C from the new drugs is somehow different in terms of survival, compared to being cured on the old interferon-based treatments. But this would be hard to understand – for most experts, curing Hepatitis C should have the same clinical consequences, no matter what treatment is used to achieve this.”

The Australian professional groups of liver experts have issued a statement noting that “Clearing the hepatitis C virus has been shown in natural history and prior treatment studies to substantially reduce the risk of liver cancer and liver failure, reducing mortality from cirrhosis and liver cancer.”

In the United States, the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) reiterated evidence from 14 studies supporting the link between hepatitis C cure and subsequent reductions in illness and death, and urged the Cochrane review authors “to retract or to revise their conclusions.”

“As a patient-led and patient-driven organisation, we have seen, heard and experienced the real evidence of being treated with DAAs. The true story is one of remarkable, if surprising, success over just a decade, transforming an unpleasant and sometimes fatal disease into one that is readily cured,” said Charles Gore, President of the World Hepatitis Alliance (WHA). “What is absolutely imperative is that this Review should not be used as another excuse not to treat when currently only 1.5% of people living with hepatitis C are accessing treatment worldwide.”

New pangenotypic drug combinations

Two new pangenotypic direct-acting antiviral combinations have received positive opinions from the scientific committee of the European Medicines Agency and should receive European Union marketing approval in the next few months, manufacturers announced last week.

Pangenotypic treatments are suitable for all genotypes of hepatitis C.

Maviret, a combination of the NS3/NS4 protease inhibitor glecaprevir and the NS5A inhibitor pibrentasvir, is recommended for approval as a treatment for hepatitis C genotypes 1-6. Maviret is manufactured by AbbVie.

Clinical trials of glecaprevir/pibrentasvir showed very high rates of sustained virologic response (97.5% across genotypes 1-6) and in harder-to-treat groups of people such as those with genotype 3, severe kidney disease or compensated cirrhosis.

The second product, Vosevi, is a combination of the NS5B polymerase inhibitor sofosbuvir, the NS5A inhibitor velpatasvir and the NS3/NS4 protease inhibitor voxilaprevir. Like Maviret, Vosevi is dosed once daily.

Vosevi is also recommended for approval as a treatment for hepatitis C genotypes 1-6. Clinical trials to support the approval of Vosevi showed that the combination cured 95% of people with and without cirrhosis, and 96% of people with genotype 3 infection and cirrhosis, one of the hardest patient groups to cure.

Sofosbuvir and velpatasvir are already approved as a combination product, Epclusa, for the treatment of genotypes 1-6.

Final details of the duration of treatment with each product will be available when full marketing approval is granted by the European Commission later this year. Vosevi is expected to receive US marketing approval by August 2017 and Maviret is also undergoing US review.

Recent infection with hepatitis C and testing for hepatitis C

Infection with hepatitis C is becoming more common among gay and bisexual men who are living with HIV, especially in larger cities in the United Kingdom and Europe. Almost one in ten were co-infected in 2011 in the United Kingdom and the prevalence is even higher in some other European countries. The number of new infections remains high.

The hepatitis C virus (HCV) is detectable in blood, semen and rectal fluid. Recent hepatitis C infection (acute infection) may be cleared spontaneously, or can be cleared with a short course of treatment in most cases – if it is diagnosed within six months of infection. Early diagnosis and cure also prevent hepatitis C being passed on to others.

Current recommendations encourage antibody testing for HCV for gay and bisexual men every six months in Europe for men at high risk. An unexplained increase in liver enzymes should also trigger an HCV test, but not everyone recently infected with hepatitis C has an increase in liver enzymes.

Not all health care providers follow the guidelines for testing, and some people may benefit from more frequent testing. The British HIV Association recommends that HCV testing should take place whenever high-risk practices are reported, but both doctors and people living with HIV may be unaware of which sexual and drug-using practices place people at higher risk of catching hepatitis C.

Recent research in the Netherlands shows that six questions can identify HIV-positive gay men who are at higher risk of having acute (recent) hepatitis C infection and who would benefit from further testing.

The six questions in the risk score concern self-reported behaviours:

  • Condomless receptive anal intercourse in the past six months (score 1.1)
  • Sharing of sex toys in the past six months (score 1.2)
  • Fisting without gloves in the past six months (score 0.9)
  • Injecting drug use in the past 12 months (score 1.4)
  • Sharing of straws to snort drugs in the past 12 months (score 1.0)
  • An ulcerative sexually transmitted infection in the past 12 months (e.g. syphilis) (score 1.4)

All of these practices have been linked to hepatitis C infection in gay and bisexual men in recent studies.

A man scoring a total of 2.0 or more would be recommended to be tested for acute hepatitis C. The researchers found that at least 73% of men with a risk score of 2 or above turned out to have a recent hepatitis C infection when they tested the scoring system using data from the Netherlands, Belgium and England on hepatitis C infections in gay and bisexual men living with HIV.

The researchers say that the risk scoring system should not be used as the only way of identifying men who need a hepatitis C test, but the scoring system could prove useful outside clinic systems as a way of encouraging men to seek hepatitis C testing and look at behaviours that might put them at risk of acquiring hepatitis C.

For more information on hepatitis C transmission read NAM's leaflet 'How hepatitis C is passed on'.

Sofosbuvir treatment for adolescents and children

Experts estimate that up to 0.4% of children in the US and Europe, and up to 6% in resource-limited countries such as Egypt, are living with hepatitis C, mostly attributable to mother-to-child transmission.

The advent of direct-acting antivirals used in interferon-free regimens has transformed treatment of chronic hepatitis C, but the new drugs have not been extensively tested in adolescents or children, and until recently interferon-based therapy remained the standard of care for paediatric patients.

Results of a small study of a two-drug regimen of sofosbuvir (Sovaldi) and ribavirin were presented at the 2017 Pediatric Academic Societies Meeting last month in San Francisco. Sofosbuvir and ribavirin taken for 12 weeks led to sustained virological response in all 13 treated adolescents with hepatitis C virus genotype 2, while a 24-week course cured all but one teen (36 out of 37) with harder-to-treat genotype 3.

US monitoring and surveillance recommendations

The Hepatitis C Policy Project at the O’Neill Institute for National and Global Health Law, Georgetown University, has released results of an expert consultation on how surveillance and monitoring can be improved to support the elimination of hepatitis C in the United States.

The findings are likely to be applicable to many other countries with underdeveloped or fragmented disease surveillance systems.

They recommend:

  • All states and territories should be scaling up surveillance of chronic hepatitis C virus (HCV) infections and recent infections, in order to identify new 'hot spots' of transmission.
  • The US Centers for Disease Control and Prevention's Division of Viral Hepatitis should work to raise awareness among lawmakers of the need for surveillance, the benefits of better surveillance and a timeline for funding improved surveillance.
  • States should be funded to establish an electronic medical record system that will allow monitoring of the cascade of care.
  • HCV monitoring should be linked to monitoring of the opioid use epidemic to ensure that responses to the two epidemics are integrated.
  • Public agencies and states should be encouraged to develop their own hepatitis C elimination plans and monitor progress towards elimination.

Coming soon: IAS 2017

The 9th IAS Conference on HIV Science (IAS 2017), organised by the International AIDS Society, is taking place in Paris, France, from 23-26 July 2017.

We'll be bringing you news from the conference. The programme is available on the official conference website.

The 4th International HIV/Viral Hepatitis Co-Infection Meeting, organised by the International AIDS Society, will take place prior to IAS 2017 from 22-23 July.

The meeting will focus on addressing the challenges of achieving elimination of hepatitis B and C in people living with HIV around the world. Registration is open online and closes on 3 July.

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