Sofosbuvir/velpatasvir is safe and effective for the
treatment of hepatitis C genotype 4 variants that have naturally occurring
resistance to some direct-acting antivirals in the NS5A inhibitor class, a
study in Rwanda has shown.
Numerous subtypes of genotype 4 have been identified in
sub-Saharan Africa. Some of these subtypes contain naturally occurring
mutations in the NS5A region that confer resistance to the NS5A inhibitors ledipasvir
and daclatasvir. Several studies have shown high rates of treatment failure
when sofosbuvir/ledipasvir (Harvoni) or sofosbuvir/daclatasvir were used
to treat people with genotype 4r, one of the genotype 4 variants. A
study in Rwanda found a markedly lower response to sofosbuvir/ledipasvir in
people with the 4r subtype compared to other subtypes of genotype 4.
Sofosbuvir/velpatasvir (Epclusa) is active against
genotypes 1-6 but it has been unclear if the activity of the NS5A inhibitor
velpatasvir is compromised in non-a, non-d genotype 4 subtypes, as
clinical trials included few African participants with non-a, non-d genotype 4
- decompensated cirrhosis
The later stage of
cirrhosis, during which the liver cannot perform some vital functions and
complications occur. See also ‘cirrhosis’ and ‘compensated cirrhosis’.
EASL guidelines recommend treatment with sofosbuvir/velpatasvir/voxilaprevir
(Vosevi) in settings where genotype 4 variants show resistance to NS5A
inhibitors. However, this information may not be readily available and Vosevi
is potentially costly owing to low demand for a generic version, emphasising
the importance of testing whether the pangenotypic regimen of sofosbuvir/velpatasvir
is effective in all settings.
The SHARED-3 study investigated whether sofosbuvir/velpatasvir
is an effective regimen in people with hepatitis C genotype 4 in Rwanda.
The Simplifying Hepatitis C Antiviral Therapy in Rwanda for
Elsewhere in the Developing World (SHARED) research programme was sponsored by
Partners in Health, a Boston-based organisation that has worked extensively to
develop models of care suitable for management of conditions including cancer,
tuberculosis and HIV in resource-limited settings such as Malawi and Rwanda.
SHARED-3 was a single-arm study that recruited previously
untreated people without decompensated cirrhosis. The study recruited 61 people
all with non-a/d genotype 4 infections. Genotyping showed that 48 participants
had subtype 4k, 11 had 4r, 8 had 4v, 5 had 4q and 4 had a variety of non-a,
non-d subtypes. Subtype could not be sequenced in three participants. Genotyping
of the NS5A gene was possible in 55 of 61 participants; all had at least two
mutations associated with resistance to NS5A inhibitors. Sequencing of the NS5B
gene was possible for 27 participants and showed that 15 had mutations
associated with resistance to NS5B inhibitors (including sofosbuvir).
Participants received a 12-week course of treatment with
sofosbuvir/velpatasvir. Twelve weeks after the completion of treatment, 59 of
61 participants had a sustained virological response.
One participant with subtype 4r and one with subtype 4k
failed to have a sustained virological response. One participant with two
resistance mutations and one with three resistance mutations failed to achieve a
sustained virological response. No new resistance mutations emerged during
treatment in either of the participants who did not have a sustained virological
response. Both had greater than 95% adherence by pill count at weeks 4, 8 and 12.
Serious adverse events were uncommon, experienced by 7% of
participants, and none were related to the study drugs.
The study investigators say that their findings indicate
that sofosbuvir/velpatasvir is a safe and effective treatment regimen for use
in regions where non-a or non-d genotype 4 subtypes are common and support the
use of sofosbuvir/velptasvir as a pangenotypic first-line regimen for use in
lower- and middle-income countries.
The investigators note that in many settings where genotype
4 is prevalent, treatment with sofosbuvir/daclatasvir predominates due to cost
and availability. A course of treatment with sofosbuvir/daclatasvir cost an
average of $86 in 2019 compared to $225 for sofosbuvir/ledipasvir. But the
effectiveness of sofosbuvir/daclatasvir against non-a or non-d is uncertain and
national programmes in settings where genotype 4 is prevalent will need to
weigh the extra cost of sofosbuvir/velpatasvir against the potentially higher
risk of treatment failure and its associated costs, the investigators note.
More research is needed to develop robust investment cases for use of specific
regions based on local epidemiology and prevalence of resistance, in order to ensure
that countries with a higher prevalence of harder-to-treat HCV subtypes do not
fall behind in their HCV elimination efforts.
A further study in the SHARED-3 research programme looked at
the effectiveness of sofosbuvir/velpatasvir/voxilaprevir in 40 people who had experienced
the failure of sofosbuvir/ledipasvir or another regimen as first-line treatment
in Rwanda. All but two had non-a subtypes of genotype 4, 25 had at least three
NS5A mutations and 33 had at least two mutations. All but one participant had a
sustained virological response. The participant who did not have a sutianed
virologic response had experienced failure of two previous courses of treatment
with sofosbuvir/ledipasvir and sofosbuvir/daclatasvir and had resistance-associated
mutations in the NS5A and NS5B genes. This participant also developed
resistance mutations in the NS3 region during treatment.
The study investigators say that as hepatitis C treatment is
scaled up in sub-Saharan Africa, the need for second-line treatment will
increase. Affordable generic versions of sofosbuvir/velpatasvir/voxilaprevir
are needed, especially where first-line treatment consists of sofosbuvir/ledipasvir