daclatasvir, two antiviral drugs used to
treat hepatitis C, were associated with faster recovery, shorter
hospitalisation and improve survival among people with moderate or severe
COVID-19, researchers reported this month at the COVID-19 Conference that concluded the 23rd International AIDS
Conference (AIDS 2020: Virtual).
Speaking at a conference press briefing, Dr Andrew Hill of Liverpool
University, a well-known expert on drug pricing, said
that if larger studies confirm these findings, generic versions of sofosbuvir and daclatasvir could potentially be an affordable and widely
accessible treatment for the new coronavirus.
Researchers are attempting
to repurpose a wide variety of existing medications for COVID-19, including HIV
and influenza drugs. To date, there is only weak evidence
that antiretrovirals, including lopinavir/ritonavir
(Kaletra or Aluvia), can prevent or treat the new coronavirus.
Although not closely related, hepatitis C virus (HCV) and
the new coronavirus – officially named SARS-CoV-2 – are both single-stranded
RNA viruses. This has led some scientists to suggest that the same antiviral
drugs might work against both.
Dr Anahita Sadeghi of Tehran University of Medical Sciences presented findings from a
randomised trial evaluating sofosbuvir plus daclatasvir for adults with
moderate or severe COVID-19 at four university
hospitals in Iran.
Sofosbuvir, marketed as Sovaldi and a component of the Harvoni,
Epclusa and Vosevi co-formulations, inhibits HCV's NS5B enzyme, the
RNA-dependent RNA polymerase the virus uses to copy its genetic material.
Daclatasvir, marketed as Daklinza, is
an HCV NS5A inhibitor.
Prior laboratory studies showed that sofosbuvir
and daclatasvir are active against SARS-CoV-2 in vitro, and daclatasvir appears to penetrate well into the lungs.
Both drugs have been shown to be safe and well tolerated for hepatitis C
The trial enrolled 66 patients
with fever and low oxygen levels who tested PCR positive for SARS-CoV-2 and had
diagnostic chest CT scans indicating COVID-19. Just over half were men and the
median age was approximately 60 years. Co-morbidities were common, including
diabetes, hypertension, chronic pulmonary disease and obesity. Those with poor
kidney function or multi-organ failure were excluded.
The participants were randomised
1:1 to receive sofosbuvir
plus daclatasvir with lopinavir/ritonavir for 14 days or standard-of-care treatment consisting of lopinavir/ritonavir with or without hydroxychloroquine, according to Sadeghi. Studies of these drugs for COVID-19
have produced mixed but largely negative results.
Sadeghi reported that 88% of people taking sofosbuvir plus daclatasvir
experienced clinical recovery – defined
as normalisation of fever, respiratory rate and oxygen saturation – compared with 67% of those on
standard therapy. This difference fell short of statistical significance, but
the time to recovery was significantly shorter in the sofosbuvir plus
daclatasvir arm (six versus 11 days, respectively).
The study also showed that three people
taking sofosbuvir plus daclatasvir (9%) required mechanical ventilation
compared with seven standard-care recipients (21%); three (9%) versus five (15%)
patients in the respective groups died. These differences also were not
statistically significant, but the numbers were small, making it is difficult
to draw definitive conclusions.
Hill and Sadeghi also described findings from a
meta-analysis of three clinical trials (including this one) conducted in Tehran
and two other Iranian cities. In Abadan, participants were randomised to
receive sofosbuvir plus daclatasvir plus hydroxychloroquine
or else lopinavir/ritonavir plus hydroxychloroquine plus ribavirin (an older
drug used to treat hepatitis C in combination with interferon). In Sari, they
were randomised to receive either sofosbuvir plus daclatasvir plus
ribavirin or else lopinavir/ritonavir plus
hydroxychloroquine. (One study was not properly randomised due to changes
in the standard-of-care arm.)
The pooled analysis included 176 participants. Again,
about half were men, the median age was approximately 60 years and co-existing
conditions were common.
The recovery rate was 94% for those taking sofosbuvir plus daclatasvir compared with 70% for those taking standard-of-care regimens, and the time to recovery
was significantly shorter in the sofosbuvir plus daclatasvir group.
Five (5%) and 17 (20%) patients died in the respective groups, also a significant
Sadeghi noted that because PCR testing was limited in
Iran at the time, the studies lack viral load data, which could show if the
drugs actually had an effect on SARS-CoV-2 replication.
A larger randomised, placebo-controlled trial called
DISCOVER will compare sofosbuvir plus daclatasvir with lopinavir/ritonavir
versus lopinavir/ritonavir alone in 600 people with moderate to severe COVID-19
who have had symptoms for seven days or less.
In addition, a network of five clinical trials has been established
to test sofosbuvir plus daclatasvir in over 2000 patients with COVID-19 in
Iran, Brazil, Egypt and South Africa, according to a press statement.
"By October, we should know from the trial results if this
treatment could be approved for worldwide use," said Prof Shahin Merat of
Tehran University of Medical Sciences. "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
If the larger trials do pan out, this would be good
news, as the drugs are readily available. Although sofosbuvir plus daclatasvir
has a list price of about $18,600 in the US and about £6000 in the UK for a
14-day course, cheap generic versions are available for about $7 or £5 in
India. Around 2.5 million courses could be formulated with the current supply.
“This treatment is being developed with no support from the large
pharmaceutical companies," Hill said. "All our funding is from
governments, universities or donor agencies such as Unitaid. 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