Chronic liver disease is frequently observed in HIV-infected patients and is multifactorial. Attenuation of fibrotic progression may improve liver-related morbidity and mortality. Cenicriviroc (CVC) is an oral, dual antagonist of CCR2/CCR5, which are involved in key pro-inflammatory and fibrogenic pathways. We evaluated effects of 2 doses of CVC on serum hepatic fibrosis biomarkers in HIV+ subjects treated in a Phase 2b study (NCT01338883).
Patients with CCR5-tropic HIV-1 were randomized to receive CVC 100 mg (n=59), CVC 200 mg (n=56) or Efavirenz (EFV) (n=28), each combined with emtricitabine/tenofovir for 48 weeks. The Enhanced Liver Fibrosis (ELF) biomarker index was evaluated in a subset of patients who completed 48 weeks of treatment and had paired baseline and 48-week samples. The ELF index has been validated previously in patients with NASH, HCV and HBV infection, and by our lab in HIV patients with liver disease. The ELF index was calculated from the results of 3 serum biomarkers of collagen and extracellular matrix deposition: hyaluronic acid, propeptide of type III procollagen, and tissue inhibitor of metalloproteinase-1.
Paired baseline and 48-week samples were randomly selected for 72/100 subjects completing the study: CVC 100 mg arm (n= 20/42), CVC 200 mg arm (n= 36/41) and EFV controls (n= 16/17). No subjects were coinfected with HCV or HBV. Among subjects receiving CVC 100 mg and 200 mg, the ELF scores at baseline were 9.80 ± 0.96 and 10.53 ± 2.12 and after 48 weeks were 9.93 ± 1.00 and 8.28±0.09, respectively. Subjects who received EFV had a mean ELF score of 9.13±0.98 at baseline and 9.28 ± 1.06 after 48 weeks. ELF scores decreased significantly in patients who received CVC 200 mg after 48 weeks of treatment (p<0.0001) but remained unchanged in patients who received EFV or CVC 100 mg. HIV suppression was similar in all groups.
Daily administration of CVC 200 mg for 48 weeks was associated with a significant decrease in specific biomarkers of hepatic fibrosis encompassed by the ELF index. This was not observed in control subjects treated with EFV nor with the lower dose of CVC (100 mg) (with caveat that < 50% of paired samples tested to date). Clinical trials of CVC are underway in adults with NASH and liver fibrosis, using a new single tablet formulation of CVC 150 mg providing drug levels comparable to CVC 200 mg in the HIV Phase 2 trial. Evaluation of CVC in HIV patients who are at risk of liver fibrosis progression is warranted.