Almost all patients with hepatitis C virus (HCV) alone or HIV and HCV co-infection who achieved sustained virological response (SVR) to treatment with sofosbuvir (Sovaldi) plus ribavirin or sofosbuvir/ledipasvir (Harvoni) still had undetectable HCV RNA up to two years later, confirming that SVR represents a cure, according to a poster presented at the recent Conference on Retroviruses and Opportunistic Infections (CROI 2015) in Seattle, USA.
The advent of interferon-free therapy using combinations of direct-acting antiviral drugs has brought about a revolution in hepatitis C treatment. Sustained virological response, or continued undetectable HCV RNA at 12 or 24 weeks post-treatment, is considered a cure, but rare cases of apparent late relapse have been observed after this point. (More often, HCV recurrence is due to reinfection.)
While some studies have detected residual bits of HCV in the blood or the liver after successful treatment, this does not appear to indicate ongoing active disease. Interferon-based therapy has been shown to have a late relapse rate below 5% – usually occurring within two years after treatment – but this is not yet well defined for interferon-free therapy because it is so new.
Aurielle Thomas from the US National Institutes of Health (NIH) and colleagues analysed data from three studies of sofosbuvir-based therapy, looking at the durability of SVR and associated changes in liver function biomarkers.
They included 159 participants who achieved SVR in the following phase 2 clinical trials, the results of which have been previously reported:
- SPARE: 38 genotype 1 HCV monoinfected patients treated with sofosbuvir plus ribavirin for 24 weeks (68% SVR12 with standard-dose and 48% with low-dose ribavirin).
- SYNERGY: 20 genotype 1 HCV monoinfected patients treated with sofosbuvir/ledipasvir for 12 weeks (100% SVR12), and 38 patients treated with sofosbuvir/ledipasvir plus an experimental third drug, either GS-9669 or GS-9451, for 6 weeks (95% SVR12).
- ERADICATE: 49 genotype 1 HIV and HCV co-infected patients treated with sofosbuvir/ledipasvir for 12 weeks (98% SVR12).
- SYNERGY-D: 14 non-responders from SPARE re-treated with sofosbuvir/ledipasvir.
All three studies, conducted by the NIH, 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 cirrhosis (Metavir stage F3-F4).
For the current analysis, participants were followed with ongoing measurement of HCV viral load and serum biomarker levels. Follow-up time ranged from 1 to 125 weeks (2.4 years) after SVR12, for a maximum of SVR137. However, only participants in the SPARE study – which started first – had reached SVR73 or later, and only 15 people had data for SVR116 or later.
The researchers used a viral load test that is able to measure HCV RNA down to a limit of quantification of <12 IU/ml. (Although there is no standard conversion, for most tests 1 IU/ml is between 1 and 5 copies/ml.)
Of the 159 patients, all but one maintained undetectable HCV viral load throughout follow-up. There was no evidence of late HCV relapse. However, one HIV-positive ERADICATE participant experienced HCV recurrence that was determined by genetic analysis to be due to reinfection, likely attributable to sexual transmission.
At the time of SVR12, 92% of patients had ALT (alanine aminotransferase) liver enzyme levels within the normal range. This rose to 93% for those followed through SVR47-SVR51, and reached and remained at 100% for those followed through SVR55 or longer.
"This study shows the long-term durability of SVR associated with [direct-acting antiviral]-based therapy in patients with HCV monoinfection and HIV/HCV coinfection during an on-going assessment of up to 125.2 weeks," the investigators concluded.
Only a small proportion of patients had persistently elevated ALT despite undetectable HCV viral load, leading the researchers to suggest, "It is plausible that this reflects the long-term histologic regression of necroinflammation and fibrosis described in patients who achieve SVR."
They added that monitoring and data collection, including liver biopsies, is ongoing.
Thomas AM et al. SVR durability: HCV patients treated with IFN-free DAA regimens . 2015 Conference on Retroviruses and Opportunistic Infections (CROI), Seattle, abstract 653, 2015.