Duration of HCV Therapy: How Short Can Therapy Be and Who Would Qualify?

Combination direct-acting antiviral (DAA) therapy of eight to 24 weeks for the treatment of chronic hepatitis C is highly effective. Current guidelines do not encourage treatment for less than 12 weeks. However, mounting evidence indicates that many patients can achieve sustained virologic response (SVR) with only eight weeks of treatment. Thus, treatment for shorter durations may be feasible for select groups of patients in the U.S. and globally.

Recently, we reviewed the rationale and the clinical evidence for using shorter duration therapy for hepatitis C.1 The rationale for shorter duration therapy includes reducing treatment cost and increasing adherence.1 In the U.S., the wholesale acquisition cost of ledipasvir/sofosbuvir is reduced from $94,500 to $63,000 when treatment is reduced from 12 to eight weeks. Shorter duration therapies may also improve treatment adherence, given that some have argued adherence decreases as dosing frequency and duration increase.2 However, there are still issues that need to be addressed with shorter duration therapy including optimal retreatment strategies and the emergence of resistance-associated variants (RAVs).

Currently, therapy for eight weeks duration is only approved with ledipasvir/sofosbuvir for genotype 1, treatment-naive non-cirrhotic patients with hepatitis C virus (HCV) RNA cohorts [98 percent]), but because of concerns about SVR rates in African-Americans and those with compromised immune system, the AASLD guidelines only recommend this in patients who are non-black and HIV-uninfected. However, recently real-life cohorts enriched for black patients have also demonstrated high SVR with the use of ledipasvir/sofosbuvir. The fixed dose combination of glecaprevir/pibrentasvir was also recently approved for a treatment duration of eight weeks (based on the ENDURANCE-1 trial) for treatment-naive non-cirrhotic patients. While many regimens have explored shorter duration therapy, no other regimen is approved for shorter than 12 weeks of therapy.

Several attempts have been made to reduce treatment duration below eight weeks in clinical trials.1 While SVR after four or six weeks of therapy have not been comparable to those observed in large clinical trials of patients treated with eight or 12 weeks, these clinical trials have identified potential predictors of SVR with shorter duration treatment such as lower baseline hepatitis C virus (HCV) viral load, younger age, HCV genotype 1b and absence of RAVs that confer greater than 20-fold resistance in vitro.1 So having a predictive algorithm that provides an individualized estimate of SVR with a given DAA regimen and duration based on baseline viral and host characteristics could streamline clinical decision-making in light of ultra-short DAA duration.1

Recently, a response-guided therapy clinical trial performed in China demonstrated HCV genotype 1b patients without cirrhosis who exhibit an ultra-rapid viral response by the second day of therapy, may be effectively treated for just three weeks with a combination of three DAAs.3 Baseline HCV viral load was a predictor of ultra-rapid viral response leading to SVR, which emphasizes that baseline HCV viral load needs to be part of the clinical algorithm, to predict which patients may respond favorably to short duration therapy. Further validation of this concept in larger clinical trials of HCV genotype 1b could be important in wider use of short duration studies for countries where HCV genotype 1b predominates (China, Japan, Mongolia and South Korea).

Just as the current treatment guidelines consider patient characteristics in recommendations regarding durations of 12 to 24 weeks, effective use of shorter DAA treatment durations will likely require identifying the appropriate patient population. A simple, cost-effective clinical algorithm to predict which individuals are likely to respond favorably to shorter duration therapy could provide a simpler management strategy to all type of providers and enhance a broad U.S. uptake of DAA therapy.1 This algorithm could be based on clinical characteristics such as age, sex, baseline HCV viral load levels, fibrosis stage, IFNL4 genotype, absence of RAVs, and in patients without HIV or HBV coinfection. Such a strategy is preferable over a response-guided therapy from an implementation stand point.

Shortening HCV therapy in targeted populations seems possible and should be further explored. Factors that may predict SVR with ultra-short duration combination DAA therapy (younger age, lower HCV viral load, genotype 1b, no RAVs, no cirrhosis, no decompensation, no HIV or HBV coinfection, and maybe females and IL28B CC genotype) need to be validated further in large clinical trials. This will allow for the creation of a clinical algorithm to predict which individuals are likely to respond favorably to shorter duration therapy and improve the HCV care continuum and reduce public health burden of the disease.

Mr. Emmanuel has no conflicts to disclose.
Dr. Wilson has received research support from Gilead Sciences.
Dr. Kottilil has received research support from Gilead Sciences

References
1. Emmanuel, B., Wilson, E.M., O’Brien, T.R. et al, Shorter Duration Therapy for Hepatitis C. Lancet Gastroenterol Hepatol. 2017. In Press.
2. Petersen, T., Townsend, K., Gordon, L.A. et al, High adherence to all-oral directly acting antiviral HCV therapy among an inner-city patient population in a phase 2a study. Hepatol Int. 2015;10(2):310-319.
3. Lau, G., Benhamou, Y., Chen, G. et al, Efficacy and safety of 3-week response-guided triple direct-acting antiviral therapy for chronic hepatitis C infection: a phase 2, open-label, proof-of-concept study. Lancet Gastroenterol Hepatol. 2016;1(2):97-104.

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