Persistence of hepatitis C virus in patients successfully treated for chronic hepatitis C

Abstract

It is unclear whether the current antiviral treatment for chronic hepatitis C virus (HCV) infection results in complete elimination of the virus, or whether small quantities of virus persist. Our study group comprised 17 patients with chronic HCV who had sustained virological response (SVR) after interferon/ribavirin treatment. Serum and peripheral blood mononuclear cells were collected 2 to 3 times at 3-to 6-month intervals starting 40 to 109 months (mean, 64.2 ؎ 18.5 months) after the end of therapy. In addition, lymphocyte and macrophage cultures were established at each point. In 11 patients, frozen liver tissue samples were available from follow-up biopsies performed 41 to 98 months (mean, 63.6 ؎ 16.7 months) after therapy. Presence of HCV RNA was determined by sensitive reversetranscriptase polymerase chain reaction, and concentration of positive and negative strands was determined by a novel quantitative real-time reverse transcriptase polymerase chain reaction. Only 2 of 17 patients remained consistently HCV RNA negative in all analyzed compartments. HCV RNA was detected in macrophages from 11 patients (65%) and in lymphocytes from 7 patients (41%). Viral sequences were also detected in 3 of 11 livers and in sera from 4 patients. Viral replicative forms were found in lymphocytes from 2 and in macrophages from 4 patients. In conclusion, our results suggest that in patients with SVR after therapy, small quantities of HCV RNA may persist in liver or macrophages and lymphocytes for up to 9 years. This continuous viral presence could result in persistence of humoral and cellular immunity for many years after therapy and could present a potential risk for infection reactivation. (HEPATOLOGY 2005;41:106 -114.)

Clearance of hepatitis C virus RNA from the peripheral blood mononuclear cells of blood donors who spontaneously or therapeutically control their plasma viremia

“…These results contrast with those from studies that reported the detection of HCV RNA in the PBMC of spontaneously resolved and treatment-induced aviremic subjects. [20][21][22] These authors speculated that persistent HCV RNA in PBMC may reflect the presence of a long-lived HCV reservoir [20][21][22] (reviewed by Feld and Liang 19 ). The difference with our results may be due to the more stringent definition of plasma aviremia used here.…”

“…20,21,36 The PBMC tested here were purified directly from blood without external stimulation. It therefore remains formally possible that nonspecific PBMC stimulation could have increased residual PBMCassociated HCV RNA to detectable levels.…”

“…[15][16][17][18] The continued presence of viral RNA in the PBMC of subjects who had either spontaneously cleared their plasma viremia or cleared viremia following antiviral therapy has recently been reported, raising concerns that PBMC may serve as a long-lived HCV reservoir capable of rekindling systemic infection. [19][20][21][22] In this study, plasma and corresponding PBMC were prepared from recalled confirmed HCV-seropositive blood donors who had tested either HCV RNA-positive or HCV RNA-negative in their original index donation. The presence of plasma viremia was tested for using a highly sensitive transcription-mediated amplification (TMA) assay.…”

HCV persistence: Cure is still a four letter word

“…In this issue of HEPATOLOGY, Radkowski et al 7 confirm and expand upon the important finding of HCV persistence. Using similar methods to those employed by Pham's group, they looked for the presence of HCV RNA in serum and PBMCs from patients who were persistently HCV RNA negative by conventional assays after spontaneous or treatment-induced recovery.…”

“…Of those, only 2 (1.2% of all sustained responders) had a serological relapse up to 3.5 years later. 19 It is likely that using the sensitive techniques of Radkowski et al, 7 HCV RNA would have been detected in a significant proportion of these cohorts; the implication being that despite low-level viral persistence, clinical improvement is still the most common outcome. Whether the presence, quantity, and location of replicating virus has any impact on clinical outcome remains to be seen.…”