Special Article

A French consensus conference on hepatitis C: screening and treatment

Background/Aims: Fatigue and other extra hepatic manifestations of hepatitis C have never been studied prospectively in a large cohort. The aim was to assess the prevalence of these symptoms prior to any treatment, and on prolonged follow-up in treated and untreated patients.

Methods: A single-center cohort of consecutive patients with chronic hepatitis C was investigated prior to any treatment. A questionnaire was completed every 6 months for 18 months of follow-up.

Results: Of 1614 patients, 431 met the inclusion criteria (56% male; age 49 years; 60% with significant fibrosis or cirrhosis; 46% with cryoglobulinemia). Seventy-six were untreated; of the treated patients, 83 were sustained responders, 47 relapsers and 225 non-responders. At baseline, fatigue and other extrahepatic manifestations were present in 254 (59%) and 225 (52%) patients. Fatigue was improved in 29 of 83 (35%) responders versus 75 of 348 (22%) patients with detectable hepatitis C virus (HCV)-RNA (P=0.01). The impact of virologic response on fatigue persisted after adjusting for age, gender, fibrosis stage, and depression (odds ratio: 0.34, P<0.001). A cryoglobulin was detectable in two of 34 (6%) responders versus 38 of 115 (33%) patients with detectable HCV-RNA (P<0.001).

Conclusions: In hepatitis C, a sustained virologic response is associated with a reduction in fatigue and cryoglobulin, but fatigue frequently persists despite a virologic response.

Insofar as chronic hepatitis C virus (HCV) infection in many individuals is asymptomatic, and as the prevalence of antibodies to hepatitis C virus (anti-HCV) among blood donors in Lebanon is scarce, this study addressed the prevalence of anti-HCV in 5115 blood donors. Data obtained were compared to other world regions. Of the blood donors screened, 57 were initially tested positive or doubtful for anti-HCV Ab. Subsequent testing by two-third generation enzyme immunoassays confirmed that, of the 57 initially tested positive/doubtful, only 18 were positive for anti-HCV giving a prevalence rate of 0.4%. While there was no difference in HCV prevalence with respect to age or gender, a higher rate was seen in non-Lebanese compared to Lebanese subjects (3.4% vs 0.3%, P<0.001). These results demonstrate a low prevalence of HCV infection among Lebanese blood donors, which was comparable to those established for western countries.

We developed a homogeneous format reverse transcription-polymerase chain reaction assay for quantitating hepatitis C virus (HCV) RNA based on the TaqMan principle, in which signal is generated by cleaving a target-specific probe during amplification. The test uses two probes, one specific for HCV and one specific for an internal control, containing fluorophores with different emission spectra. Titers are calculated in international units (IU)/ml by comparing the HCV signal generated by test samples to that generated by a set of external standards. Endpoint titration experiments demonstrated that samples containing 28 IU/ml give positive results 95% of the time. Based on these data, the limit of detection was set conservatively at 40 IU/ml. All HCV genotypes were amplified with equal efficiency and accurately quantitated: when equal quantities of RNA were tested, each genotype produced virtually identical fluorescent signals. The test exhibited a linear range extending from 64 to 4,180,000 IU/ml and excellent reproducibility, with coefficients of variation ranging from 21.6 to 30.4%, which implies that titers that differ by a factor of twofold (0.3 log₁₀) are statistically significant (P = 0.005). The test did not react with other organisms likely to co-infect patients with hepatitis C and exhibited a specificity of 99% when evaluated on a set of samples from HCV seronegative blood donors. In interferon-treated patients, the patterns of viral load changes revealed by the TaqMan HCV quantitative test distinguished responders from nonresponders and responder-relapsers. These data indicate that the TaqMan quantitative HCV test provides an attractive alternative for measuring HCV viral load and should prove useful for prognosis and for monitoring the efficacy of antiviral treatments.

This chapter explores the viral markers and quasi-species during hepatitis C infection for therapeutic functions. Infection of a human host by hepatitis C virus (HCV) leads to active viral replication, mainly in the liver. Nonspecific antiviral defenses are triggered in the very early stages of infection, and various cytokines appear to play an important role. Later, specific humoral and cellular responses participate in the control of viral replication. When the infection becomes chronic, an unstable equilibrium is reached between HCV replication and host defenses. The state of this cold war can be assessed at any time of the infection by measuring several virological parameters. Clinical laboratories routinely diagnosing HCV infection need (i) ultrasensitive HCV RNA quantitation assays with a large dynamic range, high precision, and no risk of carryover or cross-contamination. Real-time amplification techniques could meet these needs in the near future. (ii) Also needed are biologic, serological, or molecular markers for permanent HCV clearance. Recovery is currently assessed on the basis of repeatedly negative HCV RNA detection in serial samples because “seroreversion” is rare and occurs very late. (iii) Reliable in situ hybridization and in situ PCR assays and (iv) Qualitative and quantitative HCV resistance assays round out the list.

This review discusses the benefits and drawbacks of public health screening for hepatitis C, its cost effectiveness, and the various strategies to identify individuals infected with the hepatitis C virus (HCV). Of the estimated 4 million people infected with hepatitis C in the United States, approximately 50% are unaware of their infection. Both the high incidence and recent improvements in the treatment of hepatitis C make it likely that a screening program for this disease would be beneficial to patients, their families, and to the public. Testing for anti-HCV antibody is now widely available, automated, sensitive (>95%), and relatively inexpensive (approximately $80 per test). Interferons and the introduction of ribavirin into the treatment armamentarium have improved the effectiveness of therapy. Lifestyle modifications can be made to decrease the risk of transmission, and patients can be counseled to avoid alcohol consumption and receive hepatitis A and hepatitis B vaccinations, if appropriate. An additional benefit of early detection is that family members can be alerted to the risk factors for hepatitis C. Such education increases overall public awareness of the disease and may improve prevention efforts. Several national agencies within the United States and in Europe have issued guidelines for hepatitis C screening. Each of these calls for screening of high-risk populations, which include individuals who have received blood products and intravenous drug users. Targeted screening and improved treatment outcomes will likely show identification of those with hepatitis C to be cost effective in the future.

Background/Aims: There is consensus that interferon for hepatitis C should be stopped if alanine aminotransferase (ALT) remains elevated after 12 weeks; however, this may lead to unjust treatment withdrawal in around 20% of potential sustained responders. No consensus exists for interferon-ribavirin combination therapy. The aim of this study was to assess the predictive value of an HCV RNA test at 4 weeks in comparison with ALT, both in interferon monotherapy and in interferon-ribavirin combination therapy.

Methods: Plasma HCV RNA was tested at 4 weeks in 149 naive patients undergoing 6 months and 187 undergoing up to 12 months of interferon monotherapy, and in 40 non-responders treated for 6 months with interferon-ribavirin combination therapy.

Results: For 6 and up to 12 months of interferon monotherapy, the predictive value for non-response was 99% resp. 97% for a positive HCV RNA at week 4, versus 97% resp. 91% for an elevated ALT at week 12. Using a positive HCV RNA at week 4 as a stopping rule would lead to missing 5% resp. 12% of potential sustained responders, versus 10% resp. 28% for an elevated ALT at week 12. In interferon-ribavirin combination therapy, the predictive value for non-response was 100% for week 4 HCV RNA versus 95% for week 12 ALT, and 0% potential sustained responders were missed by a test for week 4 HCV RNA versus 20% for week 12 ALT. The overall sensitivity and specificity of a week 4 HCV RNA test was significantly better (area under ROC 0.85) as compared to testing ALT at week 4 (0.78, p<0.001), week 8 (0.76, p<0.001) or week 12 (0.78, p<0.001).

Conclusion: A positive HCV RNA test (≥10³ copies/ml) at 4 weeks is highly predictive for non-response and leads to significantly less misidentification of potential sustained responders than ALT at week 4, 8 or 12, both in 6 or up to 12 months interferon monotherapy and in 6 months interferon-ribavirin combination therapy of chronic hepatitis C.