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AASLD 2015: HCV Triple Regimen Cures Rapid Responders in 3 Weeks

Response-guided therapy using an all-oral regimen of 3 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 AASLD Liver Meeting last week in San Francisco. Further research will be needed to see if these promising results hold for 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 Viekira Pak, is typically indicated for 12 weeks, although sofosbuvir/ledipasvirfor 8 weeks works well for previously untreated genotype 1 patients without cirrhosis.

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 National Institutes of Health SYNERGY study, sofosbuvir/ledipasvir plus 1 or 2 other Gilead DAAs had a cure rate of just 20%-40% with 4 weeks of therapy.

George Lau from Humanity and Heath Medical Centre in Hong Kong and an international team of colleagues evaluated a 3-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 (Incivek). But so far it has not been widely used for interferon-free DAA treatment.

The open-label SODAPI study (NCT02470858) 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 approximately 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 favorable 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 3-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).

Results

• Overall, 18 participants (67%) -- 6 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.
• The median time to achieve undetectable HCV RNA was significantly shorter in Group 1 compared to Group 3, with Group 2 falling in between.
• People who achieved RVR had lower baseline viral load on average than those without RVR (about 6 vs 7 logIU/mL), and were less likely to have high baseline viral load >800,000 IU/mL (55% vs 100%, respectively) -- 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 $37,454 and $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 from 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."

11/24/15

Reference

GK Lau, Y Benhamou, C Chen, RF Schinazi, et al. Complete cure after three weeks of all-oral triple-direct acting antiviral (DAA) regimens in non-cirrhotic chronic hepatitis C genotype 1b Chinese subjects (SODAPI STUDY). AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract LB-32.

Other Source

J Cohen. Study suggests unprecedented 3-week hepatitis C cure. Science Magazine. October 30, 2015.