[Viva] Fwd: CATIE News - Sofosbuvir + velpatasvir - Very high rates of cure against major strains of hepatitis C
Tami Starlight
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Wed Nov 25 15:29:53 PST 2015
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*Tami M. Starlight*
Unceded & occupied Coast Salish Territory
Vancouver, Canada
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CATIE News - Bite-sized HIV and hepatitis C news bulletins
CATIE News - Sofosbuvir + velpatasvir - Very high rates of cure against
major strains of hepatitis C
There are six major strains, or genotypes, of hepatitis C virus (HCV): 1,
2, 3, 4, 5 and 6. These can be further divided into sub-types, such as 1a,
1b and so on.
The potent all-oral regimens—Harvoni
<http://www.catie.ca/en/fact-sheets/hepatitis/harvoni-ledipasvir-sofosbuvir>
and Holkira Pak
<http://www.catie.ca/en/fact-sheets/hepatitis/holkira-pak>—available
in many high-income countries today were designed primarily to be effective
against genotype 1. This genotype is relatively common in Canada and other
similar countries. However, due to travel and immigration, other genotypes
can be found in people with HCV living in high-income countries.
Although Harvoni and Holkira Pak are being tested against some other
strains of HCV, they are not effective against every genotype. Therefore,
pharmaceutical companies are developing combinations of drugs that can be
used to treat *every* genotype. Researchers call such drugs “pan-genotypic.”
The company Gilead Sciences has developed a fixed-dose formulation of the
following two drugs:
- sofosbuvir (sold as Sovaldi
<http://www.catie.ca/en/fact-sheets/hepatitis/sofosbuvir-sovaldi> and
found in Harvoni)
- velpatasvir (formerly called GS-5816)
Sofosbuvir works by interfering with the activity of an enzyme (NS5B) used
by HCV-infected cells. Velpatasvir works by interfering with another HCV
enzyme called NS5A.
The fixed-dose formulation of both drugs contains 400 mg of sofosbuvir and
100 mg of velpatasvir. In phase II clinical trials
<http://www.catie.ca/en/catienews/2015-11-23/debut-velpatasvir-hepatitis-c>,
the addition of the broad-spectrum antiviral drug ribavirin did not
significantly increase the effectiveness of sofosbuvir and velpatasvir.
In this *CATIE News* bulletin we review the first of several phase III
clinical trials of sofosbuvir + velpatasvir against multiple genotypes of
HCV. Leading researchers in Canada, including hepatitis experts Jordan
Feld, MD, and Stephen Shafran, MD, as well as others in Western Europe,
Hong Kong and the U.S. collaborated in a large randomized
placebo-controlled study called Astral-1. They enrolled participants with
HCV genotypes 1, 2, 4, 5 and 6. The researchers found that the combination
of sofosbuvir + velpatasvir taken once daily for 12 consecutive weeks was
extraordinarily potent—cure rates of around 99% were seen across *all*
genotypes.
A pill containing sofosbuvir + velpatasvir is the first of several
pan-genotypic anti-HCV regimens to complete phase III. We expect it to be
licensed in Canada, the European Union and the U.S. sometime in 2016.
In upcoming *CATIE News* bulletins we will present data from other phase
III trials of sofosbuvir + velpatasvir in participants with the following
genotypes and/or issues:
- HCV genotypes 2 and 3 (genotype 3 is relatively difficult to treat)
- HCV genotypes 1, 2, 3, 4 and 6 who had symptoms associated with severe
scarring of the liver (cirrhosis)
Study details
Researchers at 81 clinics in Canada and elsewhere recruited participants
with genotypes 1, 2, 4, 5 and 6 for this study and randomized them in a 5:1
ratio to receive one of the following interventions for 12 consecutive
weeks:
- sofosbuvir + velpatasvir
- placebo (fake sofosbuvir + velpatasvir)
The average profile of participants at the start of the study was as
follows:
- age – 54 years
- 60% men, 40% women
- major ethno-racial groups: white – 79%; Asian 10%; black 8%
- geographic distribution: Western Europe – 51%; North America – 46%;
Hong Kong – 3%
Additional information related to HCV and its treatment was as follows:
- HCV viral load in the blood – 6.3 log
- 19% of participants had cirrhosis (severe scarring of the liver)
- 32% of participants had previously been treated for HCV
- 69% of participants had genes that have been associated with a poor
response to interferon therapy
None of the participants had co-infections such as hepatitis B virus or HIV.
Since participants were randomized in a 5:1 ratio favouring sofosbuvir +
velpatasvir, we will focus on the genotypes of participants who took those
drugs:
- genotype 1a – 34%
- genotype 1b – 19%
- genotype 2 – 17%
- genotype 4 – 19%
- genotype 5 – 6%
- genotype 6 – 7%
Results
Overall, 99% of participants who took sofosbuvir + velpatasvir were cured
of hepatitis C 12 weeks after the cessation of therapy. Such high cure
rates occurred regardless of the genotype or subtype of HCV. This cure,
referred to as a sustained virological response, is written as SVR12. None
of the participants who received placebo were cured.
Results with specific genotypes
Here are the cure rates that occurred with each genotype and subtype:
- genotype 1a – 98% were cured
- genotype 1b – 99% were cured
- genotype 2 – 100% were cured
- genotype 4 – 100% were cured
- genotype 5 – 100% were cured
- genotype 6 – 100% were cured
The impact of cirrhosis on cure rates
A total of 121 participants had cirrhosis when they entered the study.
Historically, cure rates in people with cirrhosis are lower than in people
without cirrhosis. However, in the present study 120 participants (99%)
were cured.
Virological failure
In two participants, treatment was initially able to suppress levels of
HCV; however, after treatment cessation virus levels rose. The reason(s)
for their relapse is not clear.
General side effects
Below are some side effects that were relatively common in the present
study. Note that there were no statistically significant differences in the
distribution of these side effects between people who received study drugs
or placebo:
Headache:
- study drugs – 28%
- placebo – 29%
Fatigue:
- study drugs – 20%
- placebo – 20%
Nausea:
- study drugs – 11%
- placebo – 12%
Diarrhea:
- study drugs – 7%
- placebo – 8%
Weakness:
- study drugs – 8%
- placebo – 7%
Sleeping problems:
- study drugs – 9%
- placebo – 8%
Bone and/or joint pain:
- study drugs – 8%
- placebo – 6%
Premature departures
Of the 624 participants who received sofosbuvir + velpatasvir, only one
stopped taking treatment prematurely because of an adverse event. On the 13
th day of therapy, researchers reported that she developed an “anxiety
attack” and quit the study. The cause of this disturbance is not known.
Among the 116 participants who received placebo, two left the study
prematurely because the levels of liver enzymes in their blood rose,
suggestive of liver inflammation and/or injury. Note that 77% of
participants who received placebo reported at least one adverse effect, as
did 78% of participants who received sofosbuvir + velpatasvir.
Serious adverse events
Overall, 2% of (or 15) participants taking sofosbuvir + velpatasvir
developed serious adverse events. The figure among placebo users was zero.
The serious adverse events were diverse in nature. Below are some examples
of serious adverse events that occurred in the study. Note that it is not
clear what role, if any, the study therapy played in these events, as many
participants had pre-existing medical conditions related to these serious
adverse events:
- A 55-year-old man who did not have cirrhosis and who had a history of
abnormal cholesterol levels died in his sleep eight days after he completed
his course of therapy. He was also taking medicines to treat his
cholesterol (ezetimibe and simvastatin). His was the only death in the
study.
- One patient developed bacterial infections in his foot four days after
the end of therapy. He had a history of type 2 diabetes, foot pain and
nerve injury in the affected foot.
- One patient developed bronchitis 26 days after the end of his course
of therapy. Researchers described him as a “long-term smoker with likely an
underlying chronic obstructive pulmonary disease.”
- A patient developed lung cancer during the 7th week of therapy.
Researchers stated that he was “a long-term smoker.”
- A 66-year-old woman with a history of cardiovascular disease completed
her course of therapy. Ten days later she developed a heart attack.
Researchers noted that she had serious pre-existing cardiovascular disease.
- A 45-year-old woman developed an episode of mania 10 days after the
cessation of therapy. She had a history of anxiety and sleeping problems.
Bone marrow
Less than 1% of participants who took sofosbuvir + velpatasvir developed
signals of injury to the bone marrow. In other words, significant
reductions in the level of lymphocytes, hemoglobin, neutrophils or
platelets were rare.
Key points
A fixed-dose combination of sofosbuvir + velpatasvir taken once daily for
12 consecutive weeks resulted in a tremendous cure rate—99%—in participants
with HCV genotypes 1, 2, 4, 5 or 6. Participants with cirrhosis (but who
had no symptoms of cirrhosis) and those who had previously attempted
treatment with other drugs were successfully cured. Common general side
effects included headache, fatigue and nausea.
Eradicating HCV at the population level
That a pill taken once daily can cure, with a high degree of safety, such a
high proportion of participants with a broad range of HCV genotypes
suggests the possibility of mass treatment campaigns. However, this
exciting possibility will remain merely a dream unless at least the
following events occur:
- treatment is priced at a level that is affordable for health systems
- widespread and barrier-free HCV testing is available, advertised and
encouraged
- positive test results are followed by swift linkage to care
In addition, psychosocial support and treatment of addiction disorders need
to become more accessible so that the drivers of HCV infection in
high-income countries today can be addressed. If all of these steps can be
put in place and their availability sustained, then it is possible to start
discussing and planning for the eradication of HCV from an entire city or
region.
Smallpox was the first virus to be eradicated from the globe. Now perhaps
we can start to think about doing the same for HCV.
Upcoming *CATIE News* bulletins will explore results from additional phase
III trials of sofosbuvir + velpatasvir.
*Resources*
The debut of velpatasvir
<http://www.catie.ca/en/catienews/2015-11-23/debut-velpatasvir-hepatitis-c>
– *CATIE News*
CATIE’s hepatitis C information <http://www.catie.ca/en/hepatitis-c>
*—Sean R. Hosein*
REFERENCES:
1. Feld JJ, Jacobson IM, Hézode C, et al. Sofosbuvir and Velpatasvir for
HCV Genotype 1, 2, 4, 5, and 6 Infection. *New England Journal of
Medicine*. 2015; *in press*.
2. Ward JW, Mermin JH. Simple, effective, but out of reach? Public
health implications of HCV drugs. *New England Journal of Medicine*.
2015; *in press*.
3. Bach PB. New math on drug cost-effectiveness. *New England Journal of
Medicine*. 2015 Nov 5;373(19):1797-9.
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