Low viral load in hepatitis C treatment: Is a third drug necessary?

When resources for hepatitis C treatment with new directly acting antivirals are limited, findings from the United States suggest that previously untreated people with low viral loads may stand a good chance of achieving a sustained virologic response without adding telaprevir or boceprevir to pegylated interferon and ribavirin, researchers from Atlanta reported at the 63rd annual meeting of the American Association for the Study of Liver Diseases in Boston this month.

Presenter Brian Pearlman told the conference that people with hepatitic C genotype 1 with low viral loads, represent about 20% of all genotype 1 infections and that an abbreviated 24-week course of pegylated interferon plus ribavirin is recommended for those who achieve an RVR (rapid virologic response, at 4 weeks), which is observed in up to half of patients with low viral load.

While the current standard-of-care for people with genotype 1 is pegylated interferon plus ribavirin plus an oral protease inhibitor, no prospective trial has yet evaluated whether the use of a protease inhibitor results in superior virological outcomes in people with low viral loads. An abbreviated treatment course that does not include a directly acting antiviral may prove to be better tolerated, but may be less effective in achieving sustained virologic response. It is also unclear if African American patients can benefit from this same treatment abbreviation strategy, mainly due to the lower frequency among African-Americans of the IL-28B 'CC' host genotype that predicts interferon response.

The study recruited treatment-naive people with viral loads of less than 600,000 IU/ml at two Atlanta clinics. Participants received four weeks of pegylated interferon alfa-2b (1.5 mcg/kg/wk) plus weight-based ribavirin (1-1.2 gm/day). If they achieved a rapid virological response at week 4, they were  randomised 1:1 to receive either 24 weeks of additional pegylated interferon plus ribavirin plus boceprevir (800mg three times a day) (28 weeks total therapy) or a further 20 weeks of pegylated interferon plus ribavirin (24 weeks total therapy). Patients were stratified by IL-28B host genotype. The primary endpoint was a sustained virologic response (undetectable HCV RNA at 12 weeks post-therapy) (SVR₁₂).

Of the 198 patients reported who started treatment, 49% (n = 101) achieved undetectability at 4 weeks (RVR) and were randomised to add boceprevir (n = 49) or not (n = 52).

There were no significant differences in baseline characteristics between the groups. Participants were in their mid-50s and, had a high BMI (28 vs 29). Almost two-thirds were male, one-third had HCV genotype 1a and two-thirds had the IL-28B 'CC' host genotype. Approximately 20% had advanced liver disease (F3/F4 fibrosis) and one third were African-American.

Overall, SVR₁₂ rates did not differ significantly between the two arms (90% vs 89%), and nor did relapse rates (4% triple therapy vs 6% pegylated interferon / ribavirin). When stratified by IL-28B host genotype SVR₁₂ rates were similar by treatment allocation (96% in both CC groups; 77% in both non-CC groups). There was no significant difference in treatment outcomes among the African-American sub-set of the trial population (82% vs 84%).

People with hepatitis C genotype 1b achieved higher SVR rates both arms (triple therapy genotype 1b 93%, 1a 84%; double therapy genotype 1b 93%, 1a 85%). Dose reductions (33% in both arms) and discontinuations were similar between arms.

This prospective, randomised trial shows that for genotype 1 patients with low viral load (below 600,000 copies) who achieve a rapid response with pegylated interferon plus ribavirin, the addition of boceprevir does not result in a higher success rate, irrespective of IL-28B genotype, viral subtype or African-American ethnicity.

Since people with low viral load who achieve RVR success at four weeks comprise approximately 10% of all genotype 1 infections, this treatment strategy of not using a protease inhibitor could mean substantial cost savings. Dr Pearlman said that the Atlanta group planned to evaluate the impact of raising the “low viral load” threshold to 800,000 copies to see if they can repeat these results in more people.

The present study is ongoing, and results will need to be duplicated in larger, multicentre trials before this strategy can be considered for wider adoption.