The Journal of Infectious Diseases, March 2020
Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in HIV coinfection. A5335S examined early events in liver and plasma with detailed characterization as a substudy of trial A5329. A5329 provided DAAs (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) to participants with chronic HCV (genotype 1a) who were coinfected with HIV but virologically suppressed. A5356 evaluated five out of six treatment-naive enrollees in A5329. The mean baseline plasma HCV ribonucleic acid (RNA) level was 6.7 log10 IU/mL before treatment and decreased massively by Day 7. In the liver, single-cell laser capture microdissection (scLCM) was used to quantify the persistence of hepatitis C virions. At liver biopsy 1, the mean %HCV-infected cells in the liver was 25.2% (95% confidence interval [CI], 7.4%-42.9%) and correlated strongly with plasma HCV RNA levels (Spearman rank correlation r = 0.9). At biopsy 2 (Day 7 in four of five participants), the mean %HCV-infected cells decreased to only 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and concentrations of the DAA medications were detectable in the liver.
This is the first study to look at the clearance of HCV virions from the liver with administration of DAAs. The study concludes HCV infection is rapidly cleared from the liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. Researchers extrapolate HCV eradication could occur in these participants by 63 days, although immune activation might still persist. This is the first time single-cell longitudinal estimates of HCV clearance from liver have ever been reported, and these findings could be applied to estimating the minimum treatment duration required for HCV infection and in other types of viral hepatitis.
Balagopal, A., Smeaton, L. M., Quinn, J., Venuto, C. S., Morse, G. D., Vu, V., Alston-Smith, B., Cohen, D. E., Santana-Bagur, J. L., Anthony, D. D., Sulkowski, M. S., Wyles, D. L., & Talal, A. H. (2020). Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy. The Journal of Infectious Diseases, 222(4), 601–610. doi.org/10.1093/infdis/jiaa126