Black hepatitis C patients do well on sofosbuvir oral regimens

Interferon-free treatment using a single once-daily combination pill containing sofosbuvir plus ledipasvir demonstrated potent activity against hepatitis C virus (HCV)  and was generally well tolerated in a primarily African-American inner city population with HCV genotype 1a, researchers reported at The Liver Meeting 2013, the 64th annual meeting of the American Association for the Study of Liver Diseases (AASLD) held this month in Washington, DC. Adding a third drug resulted in high early post-treatment sustained response rates with shorter treatment.

Combining direct-acting antiviral agents (DAAs) that target different steps of the hepatitis C virus lifecycle allows for effective treatment without the prolonged duration and side-effects associated with the former standard of care, pegylated interferon plus ribavirin.

Most clinical trials of next-generation hepatitis C drugs have been sponsored by pharmaceutical companies. In parallel, the US National Institute of Allergy and Infectious Diseases (NIAID) has conducted studies in underserved populations with the aim of finding simple, brief and well tolerated treatment for people prone to difficulties with poor adherence and side-effects.

In the previous SPARE study, Anu Osinusi and colleagues tested a simple two-drug regimen consisting of Gilead Science's nucleotide HCV polymerase inhibitor sofosbuvir (formerly GS-7977) plus either standard weight-based or low-dose ribavirin in primarily African-American, treatment-naive, genotype 1 hepatitis C patients in inner-city neighbourhoods of Washington, DC. Because ribavirin can cause anaemia, especially in black patients, they assessed whether starting with a lower dose could reduce side-effects without compromising effectiveness.

As previously reported, treatment was generally safe and well-tolerated, with 24-week post-treatment sustained virological response (SVR24) rates of 68% for the weight-based ribavirin arm, falling to 48% for the low-dose arm. These rates compare favourably to pegylated interferon/ribavirin for difficult-to-treat patients. However, numerous studies have since shown that even better response rates are possible with DAA combination regimens.

In the NIAID SYNERGY study, described in a poster at the Liver Meeting, Osinusi, Anita Kohli and colleagues evaluated ribavirin-free oral DAA regimens using a fixed-dose co-formulation containing sofosbuvir and the NS5A inhibitor ledipasvir (GS-5885).

This phase 2 study included 60 people with previously untreated genotype 1 chronic hepatitis C. Most (88%) were African-American, 72% were men, 70% had harder-to-treat HCV subtype 1a, 80% had unfavourable non-CC IL28B gene patterns, 23% had advanced liver fibrosis (stage F3) and three people had cirrhosis (stage F4); people with hepatitis B or HIV co-infection were excluded.

People of African descent were traditionally regarded as poor responders to interferon-based therapy, but it is now known that this is largely attributable to a low frequency of the favourable IL28B CC variant associated with good interferon responsiveness.

Participants were consecutively enrolled into three arms. People in arm A received the once-daily sofosbuvir/ledipasvir coformulation (400/90mg) alone for 12 weeks; people in arm B received sofosbuvir/ledipasvir plus the non-nucleoside polymerase inhibitor GS-9669 (500mg/day) for six weeks; and people in arm C received sofosbuvir/ledipasvir plus the HCV protease inhibitor GS-9451 (80mg/day) for six weeks.

HCV viral load declined rapidly in all three arms soon after starting treatment. People in arm C, who used drugs that interfered with three distinct targets of HCV replication, saw the greatest decline in viral load by day seven of treatment. One hundred per cent of participants in all arms achieved viral suppression by the end of treatment.

In arm A, 100% of patients who received sofosbuvir/ledipasvir alone achieved 12-week post-treatment sustained virological response (SVR12). In arm B – using two types of HCV polymerase inhibitor – 90% maintained viral suppression through 4 weeks post-treatment (SVR4). In arm C, 100% achieved SVR4.

One person in arm B relapsed two weeks after stopping therapy, and one who achieved SVR at two weeks post-treatment missed the next visit to determine SVR4.

All three sofosbuvir/ledipasvir regimens were generally well-tolerated, with no serious adverse events related to study drugs or discontinuations due to adverse events. The most common side-effect was diarrhoea, reported by 8 people. Alanine aminotransferase normalisation occurred within a median of seven days in all arms.

"Subjects with poor prognostic factors for traditional interferon-based therapy can be effectively treated with interferon- and ribavirin-free DAA-only regimens," the researchers concluded.

"The single combination pill of [sofosbuvir/ledipasvir fixed-dose combination] for 12 weeks is an effective regimen to treat HCV in this population," they continued. This study provided "proof of concept that multiple DAAs targeting various stages of the HCV lifecycle in combination can effectively reduce HCV treatment durations," though these findings will need to be confirmed with longer follow-up (SVR12) and in larger clinical trials.