Viral Load Measurements in Individuals with Hepatitis C Virus Infection: on the European Association for the Study of the Liver Recommendations on Treatment of Hepatitis C 2018

LETTER

The European Association for the Study of the Liver (EASL) Recommendations on Treatment of Hepatitis C 2018, published in the Journal of Hepatology, specify that the recommendations are “primarily based on evidence from existing publications and presentations at international meetings” (1). We believe that this approach is appropriate since it prioritizes published data from randomized clinical trials over personal experiences or preclinical information. Regard screening for hepatitis C virus (HCV) infection, the recommendations are as follows: screening of populations at risk of infection, birth cohort testing, and general population testing in areas of intermediate to high seroprevalence (≥2%). It is important to highlight that EASL guidelines recommend that screening for HCV infection should be based on the detection of anti-HCV antibodies in serum or plasma by means of enzyme immunoassay. If anti-HCV antibodies are detected, HCV RNA should be determined by a sensitive molecular method with a lower limit of detection ≤15 IU/ml. In high-income countries, this diagnostic algorithm is sometimes difficult to apply among those who face hurdles accessing health care services, as would be the case for people who inject drugs or immigrants populations. Nonetheless, one of the guideline recommendations is that qualitative HCV RNA assays with a lower limit of detection ≤1,000 IU/ml (3.0 log₁₀ IU/ml) can be used to provide broad affordable access to HCV diagnosis and care in low- and middle-income countries and in specific settings in high-income countries (which we understand to refer to groups of people who face hurdles accessing health care services). This grade B2 recommendation is based on the findings of two observational studies involving participants in clinical trials (2, 3) and patients treated in private practice (2). In addition, the study that analyzed clinical trial patients only found no evidence of other chronic liver disease or infection with HIV-1, hepatitis A virus, or hepatitis B virus (3). We therefore believe that the results of these two studies cannot be extrapolated to people who inject drugs.

The clinical laboratories at University Hospital Vall d’Hebron in Barcelona, Spain, serve a population of 1.2 million citizens, in addition to 12 drug abuse and rehabilitation centers and a women’s prison. In April 2018, the hospital implemented a one-step screening and diagnosis strategy for viremic HCV infection (reflex testing). In other words, screening is based on the detection of anti-HCV antibodies; if antibodies are positive, a sensitive HCV RNA assay is performed on the same specimen. However, antibodies may be negative in early acute hepatitis C, but this can be suspected if the clinical signs and symptoms are compatible with acute hepatitis (an alanine aminotransferase level >10 times the upper limit of normal and/or jaundice). In these cases, HCV RNA assay also is performed as part of the initial evaluation. We retrospectively analyzed test results from the period April 2018 to May 2019 and found that 1.1% (7/619, 95% confidence interval [CI] = 0.5 to 2.3) of hepatitis C viremic patients, 3.7% (11/295, 95% CI = 1.9 to 6.6) of infected drug users, and 25.0% (5/20, 95% CI = 8.7 to 49.1%) of infected prison inmates had an HCV RNA level of <1,000 IU/ml. We therefore consider that HCV RNA assays with a lower limit of detection of ≤1,000 IU/ml (3.0 log₁₀ IU/ml) are inappropriate for diagnosing HCV infection in current or former injection drug users and probably also inappropriate for prison inmates (small size sample) due to the high risk of false-negative results.

Injection drug users constitute the core of the hepatitis C epidemic and effective diagnostic and treatment strategies are essential for curtailing the epidemic (4). Caring for drug users is particularly challenging for health care teams and requires patience, experience, and tolerance (4). Hepatitis C elimination among injection drug users requires close collaboration between hepatitis experts (including clinicians) and experts in caring for substance users, in addition to reliable, high-quality diagnostic tests (4) and health care planning strategies to identify and treat all infected people. Although HCV elimination has a cost, and a few patients will necessarily be missed to allow the others to be found and treated, this fact should be minimized by the use of the most sensitive as possible HCV viral load testing, like that used in central laboratories (e.g., Cobas 6800 system [Roche]). However, if this is not possible, highly sensitive point-of-care testing systems are available (e.g., GenXpert [Cepheid]).