Potential effect of lamivudine‐induced S gene mutations on liver‐related pathogenesis in hepatitis D virus infection
Authors: Anders Boyd, Patrick Miailhes, Karine Lacombe, Fabien Zoulim
Journal: Hepatology (2017)

Potential conflict of interest: Karine Lacombe advises, is on the speakers' bureau, and has received grants from Gilead. She also advises and has received grants from MSD and AbbVie. This study was funded in part by the Agence Nationale de Recherche sur le Sida et les Hépatites (ANRS). Gilead Sciences, Inc. provided unrestricted grants for the French HIV‐HBV Cohort Study. Gilead Sciences, Inc. was not involved in any part of the data collection, analysis, or manuscript writing. Anders Boyd was awarded postdoctoral fellowships from the ANRS and Sidaction. TO THE EDITOR: We read with interest the article published by Wranke et al.1 in which liver‐related complications were assessed among mostly treated hepatitis D virus (HDV)‐infected patients. One noteworthy feature of this cohort was the data on hepatitis B virus (HBV) genetic variability, which has been problematic to assess in past studies given that HBV replication is often suppressed during HDV infection and makes the detection of mutant variants difficult. Interestingly, many of the patients in the Wranke et al. study were undergoing lamivudine (LAM) therapy, the use of which during HDV infection has raised concerns. Prolonged exposure to LAM confers mutations on the pol gene, resulting in changes to the overlapping S gene. Some of these mutations, such as sW196L/S, can inhibit HDV secretion in vitro, suggesting a potential mechanism for increased liver cell cytopathology through accumulation of HBV/HDV proteins.2 Unfortunately, the clinical implications of these HBV mutants were not addressed by Wranke et al. in their article. Using data from a cohort of 169 patients coinfected with HBV and human immunodeficiency virus (HIV) with comprehensive information on LAM‐induced S gene mutations (Affymetrix DNA‐chip array; bioMérieux, Marcy‐l'Etoile, France3), we sought to determine whether harboring these mutations while infected with HDV had any effect on HDV replication or liver‐related morbidity. We analyzed eight of these patients with HDV‐positive serology and available HDV RNA levels during follow‐up (through real‐time quantitative polymerase chain reaction assay). All patients provided written informed consent, and the protocol was approved by the appropriate ethics committee. At inclusion, the median HDV RNA level was 5.05 log10 copies/mL (interquartile range, 3.76‐7.24 log10 copies/mL) and genotypes 1 (n = 4) and 5 (n = 1) were identified. Baseline LAM use was observed in seven of eight patients. During a median 66 months (range, 36‐101 months), six of eight patients switched to more potent anti‐HBV agents (adefovir, n = 1; tenofovir, n = 1; tenofovir + LAM/emtricitabine, n = 4) and one initiated tenofovir + LAM. Two patients harbored the rtM204V/sI195M LAM‐resistant mutation, and one patient harbored the rtM204I/sW196L mutation. No differences were observed overall in HBV DNA (Fig. 1A; P = 0.5), HDV RNA (Fig. 1B; P = 0.2), or platelets (Fig. 1C; P = 0.2), yet albumin was significantly higher in patients with S gene mutations (Fig. 1D; P = 0.03). The median liver fibrosis levels at inclusion were no different between patients with S gene mutations (F3; range, F3‐F3) compared with patients without S gene mutations (F3; range, F1‐F4), nor was change in fibrosis over time (Fig. 1E). No liver‐related complications occurred, possibly owing to the high proportion with past or current exposure to interferon (six of eight patients), hepatitis B e antigen–negative serology (five of eight patients), and absence of cirrhosis (five of eight patients).1 Nevertheless, one patient died of cardiac arrest and another died of hemorrhagic stroke.Figure 1: Description of viral replication, biochemical parameters, and liver fibrosis during follow‐up. (A‐D) Levels of HBV DNA (A), HDV RNA (B), platelet counts (C), and albumin (D) are given for individual patients during follow‐up; black lines summarize the linear fit of levels among patients with or without lamivudine‐induced S gene mutations (sI195M and/or sW196L/S). (E) Changes in METAVIR fibrosis score (using either liver biopsies or FibroTest) from inclusion to last follow‐up visit are provided for each patient, noting that the three patients with no changes did not harbor any sI195M or sW196L/S mutations.Inasmuch as we could establish from this cohort of tri‐infected patients, we were unable to find decreases in serum HDV RNA or increased risk of liver‐related pathology when sI195M/sW196L mutations were present. These findings suggest that other factors are probably more critical to patient prognosis; nevertheless, validation from larger HBV‐monoinfected cohorts would be helpful.