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AASLD 2015: Intensification with Sofosbuvir Permits Cure after Previous HCV Treatment Failure

Re-treating with an interferon-free regimen that previously failed to cure hepatitis C can result in success if treatment is intensified with the addition of sofosbuvir (Sovaldi), a pair of studies presented at the AASLD Liver Meeting this week in San Francisco have shown.

[Produced in collaboration with Aidsmap.com]

Although direct-acting antiviral treatment results in cure rates above 90% in most groups of patients with hepatitis C genotypes 1 and 2, including people with cirrhosis, a small proportion of patients experience viral relapse. For those with advanced liver disease it may not be possible to wait until new drugs become available, and other options are needed.

One concern is that failure of a regimen that contains an NS5A inhibitor (ledipasvir in Harvoni, ombitasvir in Viekira Pak or Technivie) may result in the emergence of NS5A-resistant virus that can take up to 96 weeks to disappear. NS5A inhibitors may have some activity against these variants, but further treatment with an NS5A inhibitor could result in higher-level resistance if HCV is not rapidly suppressed. Adding an agent from a different class could increase antiviral activity.

Two companies presented data at the Liver Meeting showing successful re-treatment when sofosbuvir was added to the regimen used previously, or people when were re-treated with a new regimen to which they might have some resistance. Merck reported findings from a study of treatment intensification in people who failed a short course of treatment lasting less than 8 weeks with its investigational protease inhibitor/NS5A inhibitor combination, while AbbVie reported findings from a study of treatment intensification for people who failed treatment with paritaprevir/ritonavir, ombitasvir, and dasabuvir.

Merck: C-SWIFT Retreatment Study

Merck’s C-SWIFT retreatment study looked at the effect of adding sofosbuvir and ribavirin to elbasvir (NS5A inhibitor) and grazoprevir (protease inhibitor) in people with genotype 1 HCV who had experienced viral relapse after treatment with elbasvir and grazoprevir given for 4, 6, or 8 weeks. The study enrolled 25 people who had experienced relapse in the cirrhotic and non-cirrhotic arms of the C-SWIFT study, a median of 214 days after virological failure in C-SWIFT.

Participants were predominantly male (88%) with a mean age of 54 years. 88% had harder-to-treat genotype 1a infection and 20% had liver cirrhosis. 80% had baseline NS5A resistance mutations, 52% had baseline NS3 protease mutations, and 44% had some resistance to both drug classes. None had resistance mutations in the NS5B polymerase region targeted by sofosbuvir.

Treatment was given for 12 weeks, and 12 weeks after the completion of treatment all participants had a sustained virological response at 12 weeks post-treatment (SVR12). There were 2 participants lost to follow-up, at day 3 and week 4.

Overall, treatment was well-tolerated with only 1 serious adverse event. In addition, 2 people discontinued ribavirin, due to pruritus and anemia, but they went on to achieve SVR12.

AbbVie: QUARTZ-1 Study

AbbVie’s QUARTZ-1 study examined the impact of adding sofosbuvir and ribavirin, or sofosbuvir alone, to its Viekira Pak. This open-label study recruited 22 participants who had experienced virological failure or relapse after first-line treatment with a variety of regimens, not restricted to AbbVie’s own combination.

Participants were assigned as follows:

• Genotype 1a, no cirrhosis (n=14): 12 weeks of treatment with paritaprevir/ritonavir, ombitasvir, and dasabuvir, plus sofosbuvir and ribavirin;
• Genotype 1a, with cirrhosis (n=6): 24 weeks of treatment with paritaprevir/ritonavir, ombitasvir, and dasabuvir, plus sofosbuvir and ribavirin;
• Genotype 1b, with or without cirrhosis (n=2): 12 weeks of treatment with paritaprevir/ritonavir, ombitasvir, and dasabuvir, plus sofosbuvir.

All participants with genotype 1a and cirrhosis had been treated previously with paritaprevir/ritonavir, ombitasvir, and dasabuvir. 10 out of 14 genotype 1a participants without cirrhosis had received paritaprevir/ritonavir, ombitasvir, and dasabuvir (n=8) or paritaprevir/ritonavir and ombitasvir alone (n=2). Of the remaining 6 patients, 4 had received an HCV protease inhibitor in combination with either sofosbuvir or an experimental agent.

Participants receiving treatment for 12 weeks had the option of continuing treatment for a further 12 weeks if HCV was still detectable at week 12; 1 participant with genotype 1a infection received extended treatment.

At 12 weeks after the completion of treatment, 14 of 15 participants who had received 12 weeks of treatment had SVR12. A single participant experienced virological relapse; this patient had no evidence of baseline resistance.

Among those who received 24 weeks of treatment, post-treatment virological data to week 4 (SVR4) show no cases of viral relapse.

Over half of participants had at least 1 mutation associated with resistance to NS3 protease inhibitors, and over half had at least 1 mutation associated with resistance to NS5A inhibitors.

The single virological failure occurred in a participant previously treated with telaprevir (Incivek or Incivo, a first-generation HCV protease inhibitor), pegylated interferon, and ribavirin.

11/20/15

References

E Lawitz, F Poordad, JA Gutierrez, et al. C-SWIFT Retreatment (Part B): 12 weeks of Elbasvir/ Grazoprevir with Sofosbuvir and Ribavirin Successfully Treated GT1-infected Subjects who Failed Short-Duration All-Oral Therapy. AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract LB-12.

F Poordad, M Bennett, TE Sepe, et al. Retreatment of HCV Genotype 1 DAA-failures with Ombitasvir/Paritaprevir/r, Dasabuvir, and Sofosbuvir. AASLD Liver Meeting 2015. San Francisco, November 13-17, 2015. Abstract LB-20.