New HCV NS5A inhibitor EDP-239 looks good in early studies, more evidence supports early hepatitis C treatment

A new hepatitis C virus (HCV) NS5A inhibitor being developed by Enanta – EDP-239 – was well-tolerated and demonstrated promising antiviral activity against genotype 1 HCV in a single-dose monotherapy study presented at the 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC) last week in San Diego, USA. Other researchers reported that HCV co-infection and progressive liver disease contribute to mortality among people with HIV, offering further evidence in support of prompt hepatitis C treatment.

ICAAC was once one of the major annual venues for the presentation of HIV and AIDS treatment research, and in some years it has also included substantial viral hepatitis content, but this year there were few reports on new hepatitis C treatments. This year's conference, jointly organised by the American Society for Microbiology and the International Society of Chemotherapy, was the last under the ICAAC name; next year it will be incorporated into the new ASM Microbe 2016 meeting.

Susanna Naggie of Duke University presented an update on therapies for hepatitis C (during the HIV antiretroviral therapy session) and overviews of treatment of hepatitis C in people with HIV and HCV co-infection.

Glossary

fibrosis

Thickening and scarring of connective tissue. Often refers to fibrosis of the liver. See also ‘cirrhosis’, which is more severe scarring.

antiviral

A drug that acts against a virus or viruses.

placebo

A pill or liquid which looks and tastes exactly like a real drug, but contains no active substance.

enzyme

A protein which speeds up a chemical reaction.

chemotherapy

The use of drugs to treat an illness, especially cancer.

Historically, people with HIV and HCV co-infection did not respond as well to interferon-based therapy and were considered 'difficult to treat' for hepatitis C. But this is no longer the case with new direct-acting HCV antiviral agents that can be used in interferon-free regimens. Current guidelines recommend that people with both viruses should take the same hepatitis C treatment regimens and for the same duration as HIV-negative people with hepatitis C, except for taking into account potential drug-drug interactions with antiretrovirals.

Highly effective and well-tolerated interferon-free therapies are now available, including Gilead Sciences' sofosbuvir (Sovaldi) and sofosbuvir/ledipasvir (Harvoni), AbbVie's paritaprevir/ritonavir/ombitasvir and dasabuvir (Viekirax and Exviera), and Bristol-Myers Squibb's daclatasvir (Daklinza). But there is still room for improvement – especially for HCV genotypes other than 1 and 2 – and more competition could lower the high cost of treatment.

EDP-239

K Tack from Enanta presented results from a randomised, double-blind, placebo-controlled clinical trial to evaluate the safety and efficacy of EDP-239. This investigational HCV NS5A inhibitor is being developed solely by Enanta after Novartis withdrew from a collaboration. (Enanta was also a partner in the development of paritaprevir.)

The study included 28 people with previously untreated chronic hepatitis C, without liver cirrhosis, with equal numbers of people having genotype 1a and 1b. Participants were allocated to receive EDP-239 at single oral doses of 10, 30, 100, or 200mg, or else placebo.

EDP-239 led to a rapid decline in HCV RNA levels starting about two hours after administration, with the maximum effect seen at day 2 to 4 post-dosing. Maximum viral load reductions in the EDP-239 arms of the study ranged from approximately -2 to more than -4 log. The mean terminal half-life of EDP-239 in the body was approximately 24 hours.

The 100mg dose of EDP-239 produced the most potent antiviral activity, followed by the 200mg dose. The drug was more active against HCV genotype 1b than harder-to-treat 1a.

EDP-239 was generally safe and well-tolerated. Five people taking EDP-239 (21%) and one person taking placebo (25%) reported self-limited adverse events, but there were no serious adverse events.

Two related posters reported promising data on the pharmacokinetics, safety and tolerability of EDP-239 in both HCV-negative volunteers and people with hepatitis C, finding that therapeutic drug levels could be reached with achievable doses and no safety or tolerability issues were identified.

Based on these results, the researchers concluded that EDP-239 is a potent NS5A inhibitor for treating HCV infection and the findings support the development of EDP-239 as part of combination regimens to treat HCV infection.

Co-infection and mortality

People with HIV and HCV co-infection experience more rapid liver disease progression, on average, than HIV-negative people with hepatitis C, though the reasons for this are not fully understood. As effective antiretroviral therapy (ART) has dramatically reduced the risk of AIDS-related conditions, liver disease has become a leading cause of illness and death for people with HIV.

P Nasta of Spedali Civili in Brescia, Italy, and colleagues looked at the association between liver fibrosis and mortality among people with HIV and HCV co-infection on ART.

This analysis included 3338 participants with co-infection in the Italian MASTER cohort. Liver fibrosis was estimated using the FIB-4 score, a biomarker index based on age, platelet count, and ALT and AST liver enzyme levels. People with hepatitis B triple infection or severe liver enzyme abnormalities at baseline were excluded.

A total of 291 participants (8.7%) died during the course of more than 45,000 patients-years of follow-up. Death rates rose with increasing fibrosis severity. About 40% of people who died had FIB-4 scores suggesting advanced fibrosis, compared with 16% of those who survived. People with high FIB-4 score were not only more likely to die from liver-related causes, as expected, but they were also more likely to die due to any cause.

People with a FIB-4 score above 3.25 (indicating advanced fibrosis) had a twofold higher risk of all-cause death, while those with scores below 1.44 (indicating absent or mild fibrosis) reduced their risk of death by about half. Having clinical AIDS at baseline was also an independent risk factor for all-cause death, while HCV clearance was associated with reduced mortality.

Based on these findings, the researchers concluded that advanced fibrosis is independently associated with all-cause and liver-related mortality in people with HIV and HCV co-infection and that FIB-4 can be used to determine if liver disease is progressing and when hepatitis C treatment is needed.

In a related study, V Berthaud of Meharry Medical College in Nashville and colleagues looked at factors predicting survival among people with HIV at a clinic in Tennessee, in the US 'deep south'.

The researchers analysed medical records of 745 people living with HIV seen at the clinic from 2004 through 2014. Most (80%) were African American, 35% were women, 16% had a history of injecting drugs and 14% were homeless. Overall 24% had HCV co-infection, but the rate rose to 54% among patients who died, according to the study abstract.

Just over three-quarters of participants were retained in care, 76% were prescribed antiretroviral therapy and 64% achieved undetectable HIV viral load. Hepatitis C treatment was less common: about a quarter of people with co-infection received interferon-based therapy, with a cure rate of 68%.

Shorter survival was associated with HIV and HCV co-infection, fewer clinic visits, last viral load measurement >75 copies/ml, CD4 count <200 cells/mm3 and older age. The researchers concluded that HCV co-infection plays a major role in survival of people with HIV – perhaps even more so than detectable HIV viral load.

"In the context of HIV plasma viral load suppression, scale-up of hepatitis C treatment will further reduce mortality among medically underserved minority communities disproportionately impacted by HIV/HCV co-infection in the Deep South," they concluded.

References

Lawitz E et al. (Tack K presenting) EDP-239, a novel HCV NS5A inhibitor, demonstrates potent antiviral activity after a single dose treatment of genotype 1 HCV patients. 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, 2015.

Jiang L et al. Pharmacokinetics, safety, and tolerability of EDP239, a novel hepatitis C NS5A inhibitor, in healthy volunteers. 55th Interscience Conference on Antimicrobial Agents and Chemmotherapy (ICAAC). San Diego, abstract V-446, 2015.

Jiang J et al. Pharmacokinetics, safety and tolerability of EDP-239, a novel hepatitis C (HCV) NS5A inhibitor, in patients with HCV infection. 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, abstract V-448, 2015.

Nasta P et al. Assessing mortality in patients with hepatitis C virus and HIV, using indirect markers of fibrosis (MASTER cohort). 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, abstract H-1217, 2015.

Berthaud V Survival analysis of patients co-infected with HIV and hepatitis C in a medically underserved minority community of the deep south: a retrospective 10-year cross-sectional study. 55th Interscience Conference on Antimicrobial Agents and Chemotherapy (ICAAC). San Diego, abstract H-1216, 2015.