Intrahepatic Viral Kinetics During Direct-Acting Antivirals for Hepatitis C in Human Immunodeficiency Virus Coinfection: The AIDS Clinical Trials Group A5335S Substudy.
2-Naphthylamine
Acquired Immunodeficiency Syndrome
/ complications
Adult
Anilides
Antiviral Agents
/ pharmacokinetics
Carbamates
Coinfection
/ drug therapy
Cyclopropanes
Female
Hepatitis C, Chronic
/ complications
Humans
Kinetics
Lactams, Macrocyclic
Male
Middle Aged
Proline
/ analogs & derivatives
Ribavirin
Ritonavir
/ therapeutic use
Sulfonamides
Treatment Outcome
United States
Uracil
/ analogs & derivatives
Valine
Viral Load
DAA therapy
HIV/HCV coinfection
intrahepatic viral kinetics
single-cell laser capture microdissection
Journal
The Journal of infectious diseases
ISSN: 1537-6613
Titre abrégé: J Infect Dis
Pays: United States
ID NLM: 0413675
Informations de publication
Date de publication:
23 07 2020
23 07 2020
Historique:
received:
06
12
2019
accepted:
20
03
2020
pubmed:
24
3
2020
medline:
17
2
2021
entrez:
24
3
2020
Statut:
ppublish
Résumé
Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection. We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S. Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4. We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.
Sections du résumé
BACKGROUND
Direct-acting antivirals (DAAs) targeting hepatitis C virus (HCV) have revolutionized outcomes in human immunodeficiency virus (HIV) coinfection.
METHODS
We examined early events in liver and plasma through A5335S, a substudy of trial A5329 (paritaprevir/ritonavir, ombitasvir, dasabuvir, with ribavirin) that enrolled chronic genotype 1a HCV-infected persons coinfected with suppressed HIV: 5 of 6 treatment-naive enrollees completed A5335S.
RESULTS
Mean baseline plasma HCV ribonucleic acid (RNA) = 6.7 log10 IU/mL and changed by -4.1 log10 IU/mL by Day 7. In liver, laser capture microdissection was used to quantify HCV. At liver biopsy 1, mean %HCV-infected cells = 25.2% (95% confidence interval [CI], 7.4%-42.9%), correlating with plasma HCV RNA (Spearman rank correlation r = 0.9); at biopsy 2 (Day 7 in 4 of 5 participants), mean %HCV-infected cells = 1.0% (95% CI, 0.2%-1.7%) (P < .05 for change), and DAAs were detectable in liver. Plasma C-X-C motif chemokine 10 (CXCL10) concentrations changed by mean = -160 pg/mL per day at 24 hours, but no further after Day 4.
CONCLUSIONS
We conclude that HCV infection is rapidly cleared from liver with DAA leaving <2% HCV-infected hepatocytes at Day 7. We extrapolate that HCV eradication could occur in these participants by 63 days, although immune activation might persist. Single-cell longitudinal estimates of HCV clearance from liver have never been reported previously and could be applied to estimating the minimum treatment duration required for HCV infection.
Identifiants
pubmed: 32201883
pii: 5810960
doi: 10.1093/infdis/jiaa126
pmc: PMC7377286
doi:
Substances chimiques
Anilides
0
Antiviral Agents
0
Carbamates
0
Cyclopropanes
0
Lactams, Macrocyclic
0
Sulfonamides
0
ombitasvir
2302768XJ8
Ribavirin
49717AWG6K
Uracil
56HH86ZVCT
Proline
9DLQ4CIU6V
2-Naphthylamine
CKR7XL41N4
dasabuvir
DE54EQW8T1
Valine
HG18B9YRS7
Ritonavir
O3J8G9O825
paritaprevir
OU2YM37K86
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
601-610Subventions
Organisme : NIAID NIH HHS
ID : P30 AI094189
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI069415
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068634
Pays : United States
Organisme : CSRD VA
ID : I01 CX001104
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI069465
Pays : United States
Organisme : NIAID NIH HHS
ID : K23 AI108355
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI068636
Pays : United States
Organisme : BLRD VA
ID : I01 BX001894
Pays : United States
Organisme : NIDA NIH HHS
ID : K24 DA034621
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI106701
Pays : United States
Organisme : NIAID NIH HHS
ID : R01 AI116868
Pays : United States
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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