Clinical and therapeutic implications of hepatitis C virus compartmentalization.
OBJECTIVE
Blood mononuclear cells (BMCs) frequently are infected by hepatitis C virus (HCV) variants that are not found in plasma. The influence of this compartmentalization on the natural and therapeutic outcome of hepatitis C is unknown.


METHODS
We studied 119 patients with previously untreated chronic HCV infection. Sixty-five of these patients started first-line treatment with pegylated interferon-alfa and ribavirin after enrollment in the study. The internal ribosomal entry site (IRES) of HCV RNA was amplified and compared between plasma and BMCs by means of single-strand conformational polymorphism (SSCP) analysis, line-probe assay, and cloning sequencing.


RESULTS
The IRES SSCP patterns differed between plasma and BMCs in 54 (48%) of 113 assessable patients. Twenty-seven (24%) of these patients were co-infected by 2 HCV types or subtypes, only 1 of which was detectable in BMCs (n = 25) or in plasma (n = 2). SSCP-defined compartmentalization was more frequent in former drug users than in others (35/56 [60%] vs 19/56 [34%]; P < .01), and less frequent in patients with genotype 1 HCV in plasma (26/73 [24%] vs 28/40 [65%]; P < .01). The only variables that were independently predictive of a sustained virologic response were SSCP-defined compartmentalization (25/31 vs 10/32; P = .0001) and genotype 2 or 3 infection of BMCs (22/31 vs 8/34; P = .002).


CONCLUSIONS
A significant proportion of patients with hepatitis C are co-infected by 2 or more HCV variants with distinct IRES sequences and distinct cellular tropism. This compartmentalization is a strong independent predictor of treatment efficacy.
Di Liberto
Gaëtana
G
Institut National de la Santé et de la Recherche Médicale, INSERM, Centre de Recherche Biomedicale Beaujon-Bichat, Faculté de Médecine Xavier Bichat, Paris, France.
Roque-Afonso
Anne-Marie
AM
Kara
Rachid
R
Ducoulombier
Delphine
D
Fallot
Guillaume
G
Samuel
Didier
D
Feray
Cyrille
C
D000328:Adult; D000998:Antiviral Agents / Q000627:therapeutic use; D002451:Cell Compartmentation; D005260:Female; D005838:Genotype; D016174:Hepacivirus / Q000235:genetics*; D019698:Hepatitis C, Chronic / Q000188:drug therapy / Q000473:pathology* / Q000821:virology; D006801:Humans; D016898:Interferon-alpha / Q000627:therapeutic use; D007963:Leukocytes, Mononuclear / Q000473:pathology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D018807:Polymorphism, Single-Stranded Conformational; D012367:RNA, Viral / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012254:Ribavirin / Q000627:therapeutic use; D019562:Viral Load
D000998:Antiviral Agents; D016898:Interferon-alpha; D012367:RNA, Viral; D012254:Ribavirin