Jérémie Guedj of INSERM in Paris and colleagues performed a related analysis
looking at HCV viral kinetics among people treated with sofosbuvir-containing
interferon-free regimens in the SPARE and SYNERGY trials, while Sreetha
Sidharthan of Leidos Biomedical Research and colleagues
looked at the utility of HCV viral load monitoring in the SYNERGY and ERADICATE
All three trials,
conducted by the US National Institutes of Health, enrolled primarily
low-income people in the Washington, DC, area. A majority were men, 85% were
African-American and the median age was around 55 years. Most (72%) had
harder-to-treat HCV subtype 1a and one-quarter had advanced fibrosis or
- SPARE: People with genotype
1 HCV mono-infection treated with sofosbuvir plus ribavirin for 24 weeks (68%
SVR12 with standard-dose and 48% with low-dose ribavirin).
- SYNERGY: People with genotype
1 HCV mono-infection treated with sofosbuvir/ledipasvir (Harvoni) for 12 weeks (100% SVR12) or with sofosbuvir/ledipasvir
plus an experimental third drug – either GS-9669 or GS-9451 – for 6 weeks (95% SVR12).
- ERADICATE: People with genotype
1 HCV and HIV co-infection treated with sofosbuvir/ledipasvir for 12 weeks (98%
The researchers used
a mathematical model to predict HCV viral load decline over time based on which
steps of the viral lifecycle the different direct-acting antivirals (DAAs) target.
They predicted that during the first phase of decline HCV RNA would decrease
more rapidly and steeply when using sofosbuvir with other DAAs versus only with
ribavirin. They further predicted that combining DAAs that act at different
steps would speed up the second phase of viral decline, allowing for shorter
They found that
viral load decline was initially more rapid and steeper among SYNERGY
participants treated with sofosbuvir/ledipasvir compared to SPARE participants
who received sofosbuvir with ribavirin alone. The researchers concluded that
this was due to ledipasvir – an NS5A replication complex inhibitor – blocking
viral assembly and release, while the delayed response in SPARE suggests that
sofosbuvir itself has only a minimal effect at this stage of viral replication.
However, by day 3 of
treatment, people treated with sofosbuvir and ribavirin reached low viral load
levels similar to those seen in SYNERGY, indicating that sofosbuvir – a
nucleotide analogue HCV polymerase inhibitor – is highly effective at blocking
production of HCV RNA (viral genetic material). Surprisingly, the triple DAA
combinations appeared to block viral RNA production to a lesser extent than
sofosbuvir/ledipasvir alone. But people who received GS-9451 – an HCV protease inhibitor
– showed a larger final phase viral decline.
Overall, the model dramatically underestimated cure rates for
sofosbuvir-containing regimens, predicting SVR12 rates of 34% for
sofosbuvir/ledipasvir for 12 weeks, 6% for sofosbuvir/ledipasvir plus GS-9669
for 6 weeks, and 16% for sofosbuvir/ledipasvir plus GS-9451 for 6 weeks. In
fact, 65%, 40% and 50% of study participants, respectively, had undetectable
HCV RNA at the end of treatment, and 93%, 95% and 95% went on to achieve SVR12.
The model predicted that people with any detectable virus at the end of
6 weeks of treatment should experience viral rebound, since at that point there
would still be a million new viral particles being produced every day. But this
usually did not happen. (This study used a more sensitive assay with an LLOQ of
12 IU/ml and an LLOD of 3 IU/ml.)
"There must be other reasons to explain
the high SVR," Guedj said. "We think most of the [newly produced]
virus may be uninfectious...treatment may have the effect of replacing a
working replication complex with a defective replication complex, which
explains how most patients could clear the virus in 6 weeks."
Using the estimated decay rate of functional replication complexes, the
researchers predicted that the SVR12 rate would fall to just 42% for
sofosbuvir/ledipasvir plus GS-9451 taken for only 4 weeks, and even lower for
the other regimens. This is, in fact, quite close to the observed 39% SVR4/8
rate seen in the C-SWIFT
study of a triple regimen containing sofosbuvir plus Merck's experimental
NS5A inhibitor elbasvir and HCV protease inhibitor grazoprevir.
Based on these findings, the researcher concluded that direct-acting
antivirals may have a "hidden effect [of treatment] not reflected in
measured HCV RNA," and that "viral load kinetics, in particular at
[end of treatment], may not be a reliable marker of SVR."