HCV Therapy of Genotype 3: Is It Still a Challenge?

Hepatitis C genotype 3 accounts for 30 percent of all infections secondary to hepatitis C and is the second most common genotype worldwide, behind genotype 1. Estimates report that in the U.S., it accounts for 8 to 13 percent of infections. Historically, genotype 3 has been uniquely challenging to manage in large part due to lower response to therapy combined with high rates of steatosis, fibrosis progression and a disproportionately high rate of hepatocellular carcinoma. With the launch of the first wave of interferon-free treatment, many of the direct-acting antivirals (DAA) had higher overall sustained virologic response (SVR) to genotype 3 but did not compare to the SVR rate for treatments approved for genotype 1. Thus, recent drug development has focused on pan-genotypic agents to equalize efficacy across all genotypes.

For decades, genotype 3 had been associated with longer treatment and poorer results. Previously, genotype 2 and 3 had been grouped together in management as both responded to interferon-based therapy with higher SVR rates compared to genotype 1. However, several experts suggested separating the genotypes in light of different SVR rates as pegylated interferon (PEG-IFN) plus ribavirin was achieving SVR rates as high as 93 percent for genotype 2 compared to 65 to 80 percent for genotype 3. With the approval of the first DAAs — telaprevir and boceprevir — treatment efficacy significantly improved in HCV genotype 1 patients but had no impact on genotype 3.

Since then, several all-oral regimens have been approved for the treatment of HCV, many of which have efficacy against genotype 3 infection, including sofosbuvir (a nonstructural protein 5B inhibitor) plus ribavirin for 24 weeks as demonstrated in the FISSION, FUSION, POSITRON and VALENCE trials and more recently daclatasvir (nonstructural protein 5A inhibitor) plus sofosbuvir. Tolerability and efficacy improved dramatically, but SVR rates still failed to achieve rates similar to those with other genotypes, especially in challenging populations such as those with cirrhosis. Strategies to improve viral eradication included the addition of PEG-IFN, extension of therapy to 24 weeks and the addition of ribavirin, yet real-world data showed that SVR rates often fell below 90 percent and below 80 percent in those with more advanced disease. The recent push to develop pan-genotypic regimens with simple algorithms is erasing this gap.

On June 28, 2016, FDA approved the pan-genotypic, fixed-dose combination of sofosbuvir/velpatasvir for the treatment of HCV. Given once daily for 12 weeks despite genotype, this is again a major advance for individuals with hepatitis C, especially those with genotype 3.

The ELECTRON-2 trial investigated the use of the NS5A inhibitor velpatasvir, with sofosbuvir and demonstrated a 96 to 100 percent SVR12 rate in genotype 3 treatment-naïve patients without cirrhosis. This success was further supported in the Phase 3 ASTRAL-3 trial, which revealed a 95 percent SVR 12 using the combination of sofosbuvir and velpatasvir for 12 weeks in 277 treatment-naïve and experienced genotype 3 patients, including 30 percent with cirrhosis.

This regimen was superior to sofosbuvir and ribavirin for 24 weeks, which achieved SVR in only 80 percent of 275 subjects. Other promising pan-genotypic combinations include the nonstructural protein 5A inhibitor ABT-530 and the NS3/4A ABT 530, which recently demonstrated 100 percent SVR12 rates with eight weeks of therapy in treatment-naïve genotype 3 without cirrhosis and with 12 weeks of therapy for treatment-naïve patients with cirrhosis.

The transition of therapy from an interferon-and-ribavirin-based regimen to DAA treatments has resulted in a marked improvement in eradicating genotype 1 infection. As a result, genotype 3 has emerged not only as the most virulent but also as the most difficult genotype to treat. The success of sofosbuvir in combination with agents such as daclatasvir has provided more avenues for treatment in patients with genotype 3 infections.

Though barriers in treatment still exist, including the high cost of therapy, the success of more recent trials holds promise that equal success to treating genotype 1 may be seen in the near future for genotype 3. In particular, the combination of pan-genotypic agents has a goal to shorten treatment courses while eliminating the need for ribavirin and providing high rates of SVR. Thus, while there is a pressing need to improve treatment options for genotype 3, new opportunities are on the horizon.

Dr. Behara has no conflicts to disclose.

Dr. Reau has advised for Abbvie, Gilead, BMS, Merck and Intercept, and has received research support from Abbvie and Gilead. She serves on the AGA Education and Training Committee.

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