Response-guided therapy using an all-oral regimen of three direct-acting antivirals cured a majority of easier-to-treat genotype 1b hepatitis C patients in just 3 weeks, according to results from the small SODAPI pilot study, presented in a late-breaking poster at the 2015 AASLD Liver Meeting last week in San Francisco. Further research will be needed to see if these promising results are borne out in larger patient populations.

Direct-acting antiviral agents (DAAs) used in interferon-free regimens have already brought about a revolution in treatment for chronic hepatitis C, but researchers continue to search for therapies that are more effective, easier to use and less expensive. Targeting multiple steps of the hepatitis C virus (HCV) lifecycle could potentially shorten therapy and reduce the risk of viral rebound and drug resistance.

Treatment using currently approved hepatitis C regimens, including Gilead Science's sofosbuvir/ledipasvir (Harvoni) and AbbVie's paritaprevir-based Viekirax/Exviera, is typically indicated for 12 weeks, although sofosbuvir/ledipasvir for 8 weeks works well for previously untreated genotype 1 patients without cirrhosis.

Glossary cirrhosis Severe fibrosis, or scarring of organs. The structure of the organs is altered, and their function diminished. The term cirrhosis is often used in relation to the liver. sustained virological response (SVR) The continued, long-term suppression of a virus as a result of treatment. In hepatitis C, refers to undetectable hepatitis C RNA after treatment has come to an end. Usually SVR refers to RNA remaining undetectable for 12 or 24 weeks after ending treatment and is considered to be a cure (SVR12 or SVR24). subtype In HIV, different strains which can be grouped according to their genes. HIV-1 is classified into three ‘groups,’ M, N, and O. Most HIV-1 is in group M which is further divided into subtypes, A, B, C and D etc. Subtype B is most common in Europe and North America, whilst A, C and D are most important worldwide. log Short for logarithm, a scale of measurement often used when describing viral load. A one log change is a ten-fold change, such as from 100 to 10. A two-log change is a one hundred-fold change, such as from 1,000 to 10. antiviral A drug that acts against a virus or viruses.

A few studies have looked at multidrug regimens taken for 6 weeks or less. The C-SWIFT study, which tested sofosbuvir plus Merck's grazoprevir and elbasvir, found that nearly 90% of treatment-naive people without cirrhosis could be cured in 6 weeks, but only about a third of those treated for 4 weeks achieved sustained response. Likewise in the US National Institutes of Health SYNERGY study, sofosbuvir/ledipasvir plus one or two other Gilead DAAs had a cure rate of just 20 to 40% with 4 weeks of therapy.

George Lau of Humanity and Heath Medical Centre in Hong Kong and an international team of colleagues evaluated a three-drug DAA regimen using response-guided therapy to see if patients who responded rapidly at the outset of treatment could be cured in just 3 weeks.

Rapid virological response (previously usually defined as response at treatment week 4) was used in the interferon era to predict which patients were unlikely to be cured and therefore could be taken off the poorly tolerated therapy, or to guide treatment duration using interferon/ribavirin plus the first-generation HCV protease inhibitors boceprevir (Victrelis) or telaprevir (Incivo). But so far it has not been widely used for interferon-free DAA treatment.

The open-label SODAPI study included 26 Chinese patients with HCV subtype 1b, which is easier to treat than subtype 1a. A majority were women and the median age was about 37 years. Just over half had been previously treated for hepatitis C. Most had absent or mild liver fibrosis (stage F0-F1) and none had cirrhosis. About two-thirds had the favourable IL28B 'CC' gene pattern associated with good interferon response. At baseline the mean HCV viral load was approximately 6.5 log IU/ml.

Participants were randomly assigned to receive three-drug regimens consisting of the NS5B nucleotide polymerase inhibitor sofosbuvir (sold separately as Sovaldi), one of the NS5A replication complex inhibitors ledipasvir or daclatasvir (Daklinza), and one of the HCV NS3/4A protease inhibitors asunaprevir (Sunvepra) or simeprevir (Olysio).

Group 1: sofosbuvir/ledipasvir and asunaprevir (n = 12)

Group 2: sofosbuvir, daclatasvir and simeprevir (n = 6)

Group 3: sofosbuvir, daclatasvir and asunaprevir (n = 8)

Participants with rapid virological response (RVR), defined as HCV RNA < 500 IU/ml by day 2, stopped treatment after 3 weeks, while the remainder continued for 8 to 12 weeks. The primary endpoint was sustained virological response, or continued undetectable HCV viral load (< 25 IU/ml) at 12 weeks post-treatment (SVR12).

Overall, 18 participants (67%) – six in each treatment arm – experienced RVR at day 2 of therapy. By week 3 all participants in all treatment arms had HCV RNA below the limit of quantification. All 18 people who had RVR at day 2 and completed treatment at 3 weeks achieved SVR12.

People who achieved RVR had lower baseline viral load on average than those without RVR (about 6 vs 7 log IU/m), and were less likely to have high baseline viral load (55% vs 100%, respectively) – these were the only significant predictors. People with prior treatment experience and those with more fibrosis appeared somewhat less likely to achieve RVR, but the subgroup numbers were small and differences did not reach statistical significance.

Treatment was generally well-tolerated with no serious adverse events or treatment discontinuations.

Compared to standard treatment using sofosbuvir/ledipasvir for 8 weeks or sofosbuvir plus daclatasvir for 12 weeks, the researchers calculated that the 3-week regimen could save between US$37,454 and US$107,045 per patient.

"In this proof-of-concept study, all (100%) non-cirrhotic chronic hepatitis C genotype 1b Chinese treated with triple DAAs [who had] RVR by day 2 achieve SVR12," the researchers concluded. These results, they added, warrant further study of "DAAs with high potency and non-overlapping resistance profiles tailored to specific characteristics of the subjects and viruses."

These results suggest that while 4 weeks of treatment does not work well in general, shortening therapy even down to 3 weeks may be adequate for some easy-to-treat patients, and that early response can help determine who should continue therapy for the usual 8- or 12-week course. The findings also indicate that people with HCV subtype 1b – most people in C-SWIFT and SYNERGY had 1a – may be the best candidates for abbreviated therapy.

Senior investigator Raymond Schinazi of Emory University – one of the co-discoverers of sofosbuvir – suggested that the fact that the drugs used in SODAPI are produced by different companies has hampered research looking at cross-company combinations. "I want to show these companies that they should have done this study a long time ago themselves," Schinazi told Jon Cohen of Science Magazine. "When you put the best drugs together, you get fabulous results."