Hard News by Russell Brown

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More on the repurposed hepatitis C drugs and their potential as a Covid-19 treatment

Back in April, I wrote about trials in Iran of a fixed-dose combination of two existing anti-viral drugs used to treat hepatitis C – sofosbuvir and daclatasvir –  that could point to an effective treatment for Covid-19 symptoms.

At the time, data from those trials was not available outside the hospitals that conducted them and their identification was a matter of some detective work at a distance by the Australian doctor James Freeman.

Overnight, per the press release below in the names of doctors in Iran, Brazil and the UK, those results were formally presented to the International Covid-19 Conference.  It's important to note that the three trials were small – totalling only 176 patients – and open-label. They do not confirm that   "sof-dac" is an effective treatment. But, in the words of the doctors, patients given the combination showed "significantly faster rates of clinical recovery and improved survival for patients hospitalised with COVID-19 infection."

In particular, as a Financial Times story this morning notes, the death rate for patients given the drug combination was 5% versus 20% for those who were not. The FT also quotes Dr Anthony Fauci:

Anthony Fauci, the head of the US National Institute of Allergy and Infectious Diseases and a member of the coronavirus task force, told reporters the results were “really quite interesting and provocative and encouraging”.

“We desperately need antivirals that can be given early on in the course [of the disease] to prevent individuals from requiring hospitalisation,” he said. “I’d encourage that we do further studies to nail this down.”

That's happening. There are now five randomised trials involving 2000 patients in Iran, Brazil, Egypt and South Africa, which should by October give a better idea of the viability of the treatment. If the results are positive, it would be good news for the world. The two drugs are generically manufactured as Hep C treatments in several countries and, if shown to be effective, would represent a Covid treatment that could be provided cheaply ( $US7 per 14-day treatment) and at scale.

That remains to be seen. But how we got to this point is interesting. There is no pharmaceutical company money behind the new trials and the key one in Brazil, representing half the total patients, only got off the ground because Dr Freeman personally provided some funding. A further $500,000 from the NGO Unitaid let it go ahead.

By contrast, huge resources have gone into the global Solidarity clinical trial project overseen by the WHO, which last week announced that its trials of hydroxychloroquine and an HIV antiviral combination have been discontinued. Only Gilead's remdesivir antiviral remains in active trials under Solidarity.

That doesn't mean there are no other treamtent trials in progress – to take the most notable example, dexamethasone has emerged as an effective treatment in trials in the UK. But it does raise real questions about the allocation of the really major resources.

New Zealand Hep C activist Hazel Heal, a longtime collaborator with Dr Freeman, also brought in donations from her colleagues in the Edmund Hillary fellowship. She's strongly of the view that the international research effort into Covid treatments is broken – and focused too much on vaccine development and too little on treatment options.

"Treatments have been starved of research dollars and patients to try them on because all the eggs are in the vaccine basket, which is a long way off giving us a solution. There are 150 funded vaccine trials around the world at the moment – and for treatment, just Solidarity, which was for three drugs and is now only for one.

"Even if remdesivir is shown to be effective at ICU, the US has bought up all the global production for the next several months. So the world has given up its ICUs and its research dollars to research one drug that's not very good which will only be available to Americans."

Even after Brazilian researchers conducted in vitro research that showed that daclatasvir was active against the SARS-CoV-2 virus and published the results as a pre-print three weeks ago, efforts to have their work replicated in the US were stymied because all necessary resources were committed to vaccine development.

She says in the longer term, the sof-dac combination is probably "an answer, rather than the answer," comparing it to AZT in the early days of HIV treatments, but adds:

"Repurposing small-molecule drugs that come in tablets is the important work that shoud have been done methodically around the world– and it just hasn't been. It's a failure at the international organisational level."

––––

Hepatitis C Treatment shows promising efficacy against COVID-19 in first studies.

Definitive results expected in October

Results presented today at the International COVID-19 conference show significantly faster rates of clinical recovery and improved survival for patients hospitalised with COVID-19 infection given two Hepatitis C drugs - sofosbuvir plus daclatasvir.  These results are from three relatively small, open-label clinical trials in a total of 176 patients.  These trials were conducted in three cities in Iran (Abadan, Tehran and Sari), during their first wave of the COVID-19 epidemic.

After 14 days of treatment, 94% of patients taking sofosbuvir/daclatasvir showed clinical recovery versus 70% on control treatment.  The death rate for people taking sofosbuvir plus daclatasvir was 5%, versus 20% for people taking control treatment.  One of these trials was not properly randomised, but clinical recovery rates were still significantly higher for sofosbuvir/daclatasvir in the two randomised trials (96% versus 80%).  Small, open-label trials could be prone to biases, so these results need to be seen as preliminary, unless confirmed with larger double-blinded placebo controlled trials.  

“Laboratory studies have shown that daclatasvir has antiviral activity against SARS-CoV-2.  Daclatasvir also penetrates well into the lungs, where COVID-19 infection can be concentrated.  In laboratory studies, sofosbuvir has only marginal antiviral activity against SARS-CoV-2.  Sofosbuvir plus daclatasvir already has a well-established safety profile in the treatment of Hepatitis C.  Worldwide, millions of people have been cured of Hepatitis C using this treatment.”  Dr Thiago Souza, Laboratório de Imunofarmacologia, Rio de Janeiro, Brazil.

“This treatment is being developed with no support from the large pharmaceutical companies.  All our funding is from governments, Universities, or donor agencies such as Unitaid. If this treatment proves to be effective, it could be made available worldwide as a cheap generic treatment costing approximately $7 per 14-day treatment course.  Sofosbuvir plus daclatasvir is already available at these prices in India, Pakistan, Iran and Egypt.  There is already enough generic sofosbuvir and daclatasvir mass produced to treat millions of people if this drug proves effectiveness in large trials.  We want this treatment to be affordable for anyone with COVID-19 infection, in any country.”  Dr Andrew Hill, Liverpool University, UK. 

“In spite of the encouraging initial results, we believe it is too early to reach a verdict.  Larger, well-designed studies are required to confirm our results.  A network of 5 randomised clinical trials has been set up, to test sofosbuvir plus daclatasvir in over 2000 patients with COVID-19, in Iran, Brazil, Egypt and South Africa.  The largest of these trials is double-blinded and placebo controlled.  By October, we should know from the trial results if this treatment could be approved for worldwide use.  Conducting research amidst a pandemic with overwhelmed hospitals is a challenge and we cannot be sure of success.  Sometimes treatments look promising in early trials but then fail later on.  

In the future, we will also be evaluating daclatasvir at higher doses and as part of dual or triple combination treatments.”  Professor Shahin Merat, Tehran University of Medical Sciences, Iran. 

Dr Andrew Hill, Senior Visiting Research Fellow, Liverpool University

Dr Thiago Souza: Laboratório de Imunofarmacologia, Instituto Oswaldo Cruz (IOC), Fundação Oswaldo 10 Cruz (Fiocruz), Rio de Janeiro

Professor Shahin Merat: Digestive Disease Research Institute, Tehran University of medical sciences

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