In this issue:
HEPATITIS C VIRUS
- Grazoprevir + elbasvir and other emerging drugs
- Enter ledipasvir
- Sirius—ledipasvir + sofosbuvir in cases of severe liver injury
- Using ledipasvir + sofosbuvir when prior treatment with sofosbuvir failed
- Grading severe liver disease and predicting survival
- Ledipasvir + sofosbuvir with or without ribavirin in people with liver transplants
- Solar-1—ledipasvir + sofosbuvir in people with symptoms of severe liver injury
- Ledipasvir + sofosbuvir with or without ribavirin in compensated cirrhosis
- Ledipasvir + sofosbuvir in HCV genotype 6—a pilot study
- Ledipasvir + sofosbuvir in HIV co-infection
Merck has been developing several drugs to treat hepatitis C virus (HCV). In this report we mainly discuss the two drugs that are in late-stage clinical trials: grazoprevir and elbasvir.
Formerly called GS-5885, ledipasvir has been partnered with a slightly older drug, sofosbuvir (Sovaldi), and both drugs are sold as a fixed-dose combination called Harvoni. In laboratory studies with cells and HCV, ledipasvir is extremely potent against the following sub-types or strains of HCV: 1a, 1b, 4a and 6a. Lab experiments also suggest that ledipasvir is less effective against genotypes 2 and 3. In studies with people, the drug has powerful anti-HCV activity, reducing the amount of HCV in the blood one-thousand-fold.
A fixed-dose combination of ledipasvir + sofosbuvir (sold as Harvoni) has been licensed in Canada, the European Union and the U.S. for the treatment of HCV genotype 1. In a trial called Sirius, researchers enrolled participants with the following clinical features: HCV genotype 1 infection; severe liver injury (cirrhosis); and previously unsuccessful treatment with interferon and ribavirin with or without the first generation of direct-acting antivirals boceprevir or telaprevir.
In the time before ledipasvir was available, clinical trials with sofosbuvir-based regimens (such as sofosbuvir + ribavirin or, sofosbuvir + interferon + ribavirin) resulted in generally high rates of sustained virological response. However, there have been cases where HCV was not cured in people who used those sofosbuvir-containing regimens. Researchers enrolled 51 people who were not cured with sofosbuvir-based regimens and retreated them with the potent combination of ledipasvir + sofosbuvir for 12 weeks.
Researchers have developed a scoring system to predict the likelihood of people with severe liver injury surviving. This system is called the Child-Turcotte-Pugh (or Child-Pugh) score, simplified as CTP. This scoring system takes into account a number of lab test results and severity of symptoms. CTP can be divided into three grades—A, B and C. In general, the greater the CTP score, the lower the chances of survival.
Researchers recruited 233 participants, all of whom had HCV genotype 1 or 4 and who had received a liver transplant. Overall, in people who had HCV infection after a liver transplant, 12 or 24 weeks of a regimen based on ledipasvir + sofosbuvir resulted in relatively high rates of cure.
Most studies of emerging and new oral therapies for HCV have enrolled participants with generally mild-to-moderate liver injury. However, corporations are increasingly testing these new therapies in HCV-infected people with severe liver injury. In a clinical trial called Solar-1, researchers enrolled 108 participants with severe liver injury who had symptoms of cirrhosis. Researchers noted that dramatic improvements in liver health and overall health occurred in many participants within the first four weeks of receiving study medications.
Some people with severe liver injury (cirrhosis) caused by hepatitis C virus (HCV) have no symptoms, at least initially. Doctors describe this symptom-free stage of severe liver injury as “compensated cirrhosis.” Researchers collected data from several studies where ledipasvir + sofosbuvir were used, with or without ribavirin, and analysed the results.
The combination of ledipasvir + sofosbuvir was highly effective in a small study of people with HCV genotype 6. After 12 weeks of ledipasvir + sofosbuvir, 96% (24 of 25 participants) achieved a sustained virological response. However, note that the study was small and the results, although very promising, require confirmation in a larger clinical trial.
Co-infection with HIV and hepatitis C virus (HCV) is relatively common because of shared routes of transmission. Researchers enrolled 50 co-infected people with severe liver injury (cirrhosis) and assigned them to receive 12 weeks of ledipasvir + sofosbuvir.