Bernhard Schlevogt

Origin, prevalence and response to therapy of hepatitis C virus genotype 2k/1b chimeras

BACKGROUND & AIMS Little is known about the epidemiology and frequency of recombinant HCV genotype 2/1 strains, which may represent a challenge for direct antiviral therapy (DAA). This study aims to identify the epidemiology and phylogeny of HCV genotype 2/1 strains and encourages genotype screening, to select the DAA-regimen that achieves the optimal sustained virologic response. METHODS Consecutive samples from HCV genotype 2 infected patients, according to commercial genotyping, from Germany, Italy and Israel were re-genotyped by Sanger-based sequencing. Virologic, epidemiological, and phylogenetic analyses including other published chimeras were performed. RESULTS Sequence analysis of 442 supposed HCV genotype 2 isolates revealed 61 (genotype 2k/1b (n=59), 2a/1b (n=1) or 2b/1a (n=1)) chimeras. No chimeras were observed in Italy, but the frequency was 14% and 25% in Germany and Israel. Treatment of viral chimera with sofosbuvir/ribavirin led to virologic relapse in 25/27 patients (93%). Nearly all patients treated with genotype 1-based DAA-regimens initially (n=8/9), or after relapse (n=13/13), achieved a sustained virologic response. Most patients with 2k/1b chimeras (88%) were originally from eight different areas of the former Soviet Union. All known 2k/1b chimeras harbour the same recombination breakpoint and build one phylogenetic cluster, while all other chimeras have different phylogenies. CONCLUSIONS The HCV genotype 2k/1b variant derives from one single recombination event most likely in the former Soviet Union, while other chimeras are unique and develop independently. A relatively high frequency has been observed along the migration flows, in Germany and Israel. In countries with little migration from the former Soviet Union the prevalence of 2k/1b chimeras is expected to be low. Treatment with sofosbuvir plus ribavirin is insufficient, but genotype 1-based regimens seem to be effective. Lay summary: The frequency of recombinant HCV is higher than expected. A novel recombinant variant (HCV genotype 2a/1b) was identified. Screening for recombinant viruses would contribute to increased response rates to direct antiviral therapy.

Letter: can persisting liver stiffness indicate increased risk of hepatocellular cell carcinoma after successful anti-HCV therapy? – authors’ reply

SIRS, We read with interest the letter by the group of Dr Wiegand describing their experience on the potential value of liver stiffness measurement in patients receiving interferon (IFN)-free therapies of hepatitis C. Indeed, the findings are interesting and the important question to what extent liver function and liver stiffness are improving after cure of hepatitis C virus (HCV) infection should be determined in larger studies. In our study involving 80 patients with advanced liver cirrhosis, we described an overall improvement of parameters associated with liver synthesis in the far majority of patients already during therapy while platelet counts showed different (delayed) kinetics of improvement. Together with the preliminary findings by Karlas et al., and the Austrian experience recently present in this journal, we would propose that future studies need to address the following issues:(i) what is relative contribution of inflammation vs. fibrotic scarving to portal hypertension?(ii) what will be the longterm kinetics of liver function parameters and liver stiffness values after HCV clearance?(iii) which parameters are useful to identify patients at risk to develop hepatocellular carcinoma (HCC) even after HCV clearance? Our previous findings, as well as the paper by Mandorfer et al., suggest that rapid reduction of liver inflammation by blocking HCV replication has already a major influence on liver function and portal hypertension. Thus, the risk for variceal bleeding should be reduced already early during therapy which would be an argument to treat all patients with decompensated liver cirrhosis. In hepatitis B, successful antiviral therapy leads to regression of liver fibrosis 4 – which should translate also in improvements of liver stiffness values. We here describe our preliminary experience of patients followed with fibroscan for 24 weeks after the end of therapy. Indeed and in line with the data by the Wiegand group, a significant and in some patients marked decline of fibroscan values was evident in 26 of the 30 patients (Fig. 1). Overall, we suggest a two-phasic decline of portal hypertension in the context of IFN-free HCV therapies: a rapid first phase which occurs already during treatment (associated with improvement of liver inflammation) followed by a slower second phase becoming relevant only after 6–12 months of stopping HCV replication (correlate of fibrosis regression). The last question whether fibroscan values indicate a higher risk for HCC after HCV clearance remains to be answered in future studies as the case series by Karlas and colleagues included only patients who had HCC already before therapy.

Real-world effect of ribavirin on quality of life in HCV-infected patients receiving interferon-free treatment

Ribavirin (RBV) is commonly used for the treatment of hepatitis C virus (HCV) infection. However, RBV is associated with a reduced quality of life (QOL). We aim to assess the impact of RBV on QOL in a real‐world setting.

HCC Immune Surveillance and Antiviral Therapy of Hepatitis C Virus Infection

Objective: HCV clearance by current antiviral therapies improves clinical outcomes but falls short in eliminating the risk for hepatocellular carcinoma (HCC) emergence. As the HCC immune surveillance establishment is vital for the control of neoplastic development and growth, we investigated its correlation with on-/post-treatment HCC emergence, and further analyzed the influence of viral eradication on this setup in patients with HCV-related liver cirrhosis. Design: PBMC isolated at baseline and longitudinally during therapy were analyzed for tumor-associated antigen (TAA)-specific CD8+ T cell responses against glypican-3 overlapping peptides in vitro using high-definition flow cytometry. Multianalyte profiling of fifty soluble inflammatory mediators (SIM) in the plasma was also performed using Luminex-based multiplex technology. Results: Cirrhosis patients were characterized by an altered profile of distinct SIMs at baseline. At this time point, immune-surveilling T cells targeting specific HCC-associated antigens were readily detectable in HCV-free cirrhosis patients whilst being rather weak in such patients who further developed HCC upon virus eradication. Therapy-induced cure of HCV infection analogously reduced the strength of the prevailing HCC immune surveillance machinery, particularly by CD8+ T cells in cirrhosis patients. These results were further validated by T cell reactivities to six immuno-dominant HCC-associated HLA-A2-restricted epitopes. Further, we demonstrated that this phenomenon was likely orchestrated by alterations in SIMs – with evidence of IL-12 being a major culprit. Conclusion: Given the relationship between the baseline HCC-specific immune surveilling T cell responses and therapy-associated HCC emergence, and the impact of HCV clearance on its strength and magnitude, we recommend a continued HCC screening in cirrhotic HCV patients despite HCV resolution.

Successful retreatment of a patient with chronic hepatitis C genotype 2k/1b virus with ombitasvir/paritaprevir/ritonavir plus dasabuvir

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