A single nucleotide polymorphism in IL28B affects viral evolution of hepatitis C quasispecies after pegylated interferon and ribavirin therapy.

Interleukin-28B (IL28B) polymorphisms are associated with viral response to peginterferon and ribavirin (RBV) in chronic hepatitis C (HCV). Their recognition represents a breakthrough in the understanding of the role of the host in viral eradication. How these polymorphisms determine viral eradication is unknown. The IL-28B variants are hypothesized to have a differential impact on HCV quasispecies evolution during treatment with pegylated interferon (PEG-IFN) and RBV. In this study, HCV RNA levels were measured at early time points in 33 naïve genotype 1 hepatitis C patients and clonal analysis of the entire NS5A region was performed on sera from baseline and Day 7. Site rs12979860 polymorphisms were determined by direct sequencing of PCR products and classified into CC, CT, and TT and were identified in 13, 11, and 9 patients, respectively. The CC polymorphism more commonly was seen in Whites versus Blacks [12/21 (57%) vs. 1/12 (8%), P = 0.009] and HIV-infected versus mono-infected [13/25 (52%) vs. 0/8 (0%), P = 0.009]. Patients with CC and non-CC had similar baseline viral loads. More patients with the CC polymorphism had amino acid substitutions in NS5A compared to non-CC patients. Despite similar baseline viral diversity, by Day 7, significantly more patients with CC had higher non-synonymous substitution values compared to non-CC (P = 0.02). Chronic hepatitis C patients with the CC IL28B polymorphism have a higher number of amino acid substitutions in the NS5A region and early viral evolution due to greater interferon induced selective pressure during this critical period of treatment.

Update of chronic hepatitis B.

PURPOSE OF REVIEW: We review here new developments in chronic hepatitis B (CHB) treatment, based on review of published articles between December 2009 and November 2010. RECENT FINDINGS: It is estimated that two-thirds of US CHB patients have not been identified, evaluated and appropriately treated, largely due to lack of knowledge and awareness of CHB among medical professionals and at-risk populations. Seven medications have been approved to treat CHB in adults, but only four medications have been approved to treat CHB in children.Hepatitis B e antigen (HBeAg) seroconversion is still an important treatment endpoint in HBeAg-positive patients. Durability of nucleoside analogue treatment-related HBeAg seroconversion is still questionable. Hepatitis B surface antigen (HBsAg) seroclearance has been achieved in some patients with antiviral therapy. HBsAg quantitation and kinetics is now being studied to determine its role in the natural history of CHB and whether these measures may predict future response to current antiviral therapy. SUMMARY: Great advances have been made in understanding the HBeAg seroconversion durability. The clinical significance of serum HBsAg kinetics has been recognized in naive CHB patients and patients with antiviral therapy. More education programs are needed to improve the public awareness of the importance of CHB to the health of whole population.

Nonresponse to treatment for hepatitis C: current management strategies.

Chronic hepatitis C affects >170 million people worldwide, causing cirrhosis and liver cancer in a sizeable proportion of patients. Substantial progress has been made in the treatment of chronic hepatitis C. More than 50% of patients can achieve sustained virological response after 24-48 weeks of interferon and ribavirin combination therapy, making chronic hepatitis C a potentially curable disease. However, a large proportion of patients with chronic hepatitis C do not clear the virus after current standard therapy. Hepatitis C virus develops two pathways to counteract the antiviral effect of interferon. Some chronic hepatitis C patients may have a virus that is more resistant to interferon therapy, while other patients appear to have defective immune responses or poor tolerance or compliance to interferon-based antiviral therapy. The possible strategies to improve antiviral efficiency in these nonresponders are to increase the dosage, prolong the duration of treatment and improve the compliance of patients. A total of 6-15% of prior nonresponders to standard interferon plus ribavirin therapy will respond to re-treatment with peginterferon plus ribavirin, while 32-50% of patients who have relapsed will respond to re-treatment. New small molecules are under development to treat chronic hepatitis C and may be important particularly in the treatment of prior nonresponders to current standard therapy.

Pegylated interferon and ribavirin promote early evolution of nonstructural 5A protein in individuals with hepatitis C who demonstrate a response to treatment.

BACKGROUND: Hepatitis C virus (HCV) quasispecies diversity is more likely to affect early viral decline during treatment of hepatitis C than is having human immunodeficiency virus (HIV) infection. We evaluated the influence of HCV therapy on changes in the nonstructural 5A (NS5A) protein. METHODS: Fifteen patients with HCV genotype 1 infection with or without HIV infection were recruited for the present study, and the decrease in the HCV RNA level was measured at early time points. The evolution of HCV NS5A quasispecies within the first week was analyzed by comparing the clones observed at later times in the study with the baseline consensus sequence of individual patients. The response to therapy was defined as an early response (ER; ie, an HCV RNA level <615 IU/mL at week 4) or a slow response (SR; ie, a detectable HCV RNA level at week 4). RESULTS: HIV infection did not affect early viral kinetics. At baseline, lower diversity was seen in NS5A and in the amino and carboxyl termini of patients with an ER, compared with those with an SR. Rapid evolution of the NS5A genetic region occurred in patients with an ER (P = .01) but not in those with an SR (P = .73). The evolution was the result of an increase in the number of amino acid substitutions in the carboxyl region (P = .02) in patients with an ER. CONCLUSIONS: Selective pressure appears to result in more-marked changes in individuals with an ER than in those with an SR. The carboxyl terminus was subject to the most change and may be an important determinant of phenotypic resistance to interferon-based therapy.