In Hepatitis C, Could Shorter Treatment Regimens Become the New Norm?

Shorter duration could reduce the economic impact on health care spending and make treatment more convenient.

In a phase 2a study, investigators Anita Kohli, MD, and colleagues associated with the National Institutes of Health (NIH) investigated a short-course 6-week regimen of sofosbuvir/ledipasvir (Harvoni) with placebo, or an experimental third agent.

Although existing direct-acting antivirals such as those in Harvoni target specific sites on the hepatitis C virus that hijack the virus's ability to persist in the body, NIH researchers posit that adding another targeted inhibitor might further shorten the virus's persistence. The experimental 3-drug regimens in the NIH trial incorporated either GS-9669 (Figure 1), which inhibits the NS5B “thumb” site; or GS-9451 (Figure 2), which inhibits the activity of HCV NS3/4A protease.

Current approved regimens with Harvoni range in length from 8 to 24 weeks, with the shortest 8-week course being recommended only for a certain small segment of patients—individuals with chronic hepatitis C virus infection (HCVI) with genotype 1 disease who have never received anti-HCV treatment before, do not have cirrhosis, and have HCV RNA serum levels lower than 6 million IU/mL before receipt of therapy.

Current therapies offer HCV cures within 8 to 12 weeks in the majority of cases, and 24 weeks of therapy in hard-to-treat cases. By contrast, before direct-acting agents were available (that is, prior to 2013), standard treatment for HCV infection consisted of weekly interferon injections in combination with oral ribavirin for at least 6 months and up to 1 year of therapy.

By adding a third drug to this treatment course, NIH investigators believe it may be possible to expand the group of patients eligible for short-course treatment while simultaneously decreasing the minimum length of therapy from 8 weeks to 6. Success with such a strategy would reduce the economic impact of anti-HCV treatment on the US government's health care spending, while simultaneously making treatment more convenient.

The clinical trial, registered under the ClinicalTrials.gov designator NCT01805882, was imitated in January of 2013, and continued through December of the same year. A total of 60 patients were assigned equally to receive treatment with 1) sofosbuvir and ledipasvir for 12 weeks; 2) sofosbuvir, ledipasvir, and GS-9669 for 6 weeks; or 3) sofosbuvir, ledipasvir, and GS-9451 for 6 weeks.

Patients in each 20-patient group were all adults over the age of 18, and had chronic genotype 1 HCV infection with serum RNA concentrations exceeding 2000 IU/mL. Liver biopsy and ultrasonic liver elasticity scans as well as serum liver enzyme tests ensured that all patients in the trial were free of cirrhosis.

Patients in active treatment arms received the components of Harvoni (90 mg of ledipasvir and 400 mg of sofosbuvir daily) with either GS-9669 (as 2 tablets of 250 mg each, once daily), or GS-9451 (a single 80-mg tablet daily).

Patients were assessed for treatment response through HCV RNA level reductions in the 4 weeks after completing therapy. A 100-fold reduction in HCV RNA levels signified a response, and undetectable HCV RNA levels 12 weeks after completion of treatment (SVR12) indicated sustained viral response—a functional cure.

Four weeks after completion of therapy, all 20 of the 20 evaluable patients in the placebo group, 18 of the 19 evaluable patients in the GS-9669 group, and 20 of 20 evaluable patients in the GS-9451 group experienced sustained viral response. These responses remained durable at week 12 in all patients receiving placebo with Harvoni for 12 weeks, in 18 of 19 evaluable patients in the GS-9669 group, and in 18 of 19 evaluable patients in the GS-9451 group.

The most common side effects were diarrhea, headache, and fatigue. Although most adverse events in the clinical trial were of mild severity, grade 3 adverse events included 1 case of liver biopsy—related pain, and 1 case of vertigo resulting in a hospital admission (in a patient with a history of vertigo).

Regarding these favorable results, researchers concluded, “We can now speculate that a 6 week course of three direct-acting antiviral drugs can result in SVR12 in at least 75%, and perhaps nearly 100%, of people infected with HCV.” Noting the benefits of this strategy, the team wrote, “This quick and simple treatment for HCV might prove relevant for the global elimination of hepatitis C, in which simple and well tolerated therapy of short duration is needed to ensure adherence.”

References

• AASLD/IDSA HCV Guidelines. www.hcvguidelines.org/fullreport. Accessed June 2015.
• Kohli A, Osinusi A, Sims Z, et al. Virological response after 6 week triple-drug regimens for hepatitis C: a proof-of-concept phase 2A cohort study. Lancet. 2015;385(9973):1107-1113.
• HARVONI (ledipasvir and sofosbuvir) tablets [package insert]. Foster City, CA: Gilead Sciences, Inc; 2015.
• PubChem Open Chemistry Database. Compound Summary for CID 53259022. https://pubchem.ncbi.nlm.nih.gov/compound/53259022#section=3D-Conformer. Accessed June 2015.
• PubChem Open Chemistry Database. Compound Summary for CID 25167947. https://pubchem.ncbi.nlm.nih.gov/compound/25167947#section=Top. Accessed June 2015.