Preliminary study on the efficacy of sequential therapy with nucleotide analogues followed by interferon alpha in chronic hepatitis B patients with low HBsAg level / 中国感染与化疗杂志

Objective To investigate the efifcacy of interferon alpha (IFNα) followed by nucleotide analogues (NAs) treatment in patients with negative hepatitis B e antigen (HBeAg), undetectable serum HBV-DNA and low hepatitis B surface antigen (HBsAg) levels.Methods The enrolled HBeAg-negative chronic hepatitis B patients had undetectable HBV-DNA level (HBV-DNA<1000 copies/mL for at least 12 months) and low HBsAg level (HBsAg≤2000 U/mL) with long-term NAs treatment. These patients switched their therapy sequentially from NAs regimens to IFNα for 48 weeks. The treatment response was evaluated in terms of serum HBV DNA load, serological HBV markers, liver function tests and routine blood test before treatment and 12, 24 and 48 weeks of treatment. The patients were followed up for 24 weeks after treatment. The primary endpoint was HBsAg loss or seroconversion and HBsAg<10 U/mL. Logistic regression analysis was conducted to examine relevant predictive factors. Receiver operating characteristic curve was used to evaluate the value of prior HBeAg seroconversion and on-treatment HBsAg dynamics in predicting HBeAg seroconversion than in HBsAg persistence group (χ2=9.527,P=0.002). HBsAg loss was more likely in the patients who had HBsAg decline at least 0.5 log U/mL from baseline at week 12 of treatment (χ2=16.576,P<0.001). The area under the ROC curve for prediction of HBsAg loss was 0.810 (95 %CI, 0.686 to 0.935,P<0.001).Conclusions The HBeAg-negative chronic hepatitis B patients with positive virological response and low HBsAg level after NAs treatment are more likely to achieve HBsAg clearance when switched to IFNα treatment. Prior HBeAg seroconversion and on-treatment HBsAg dynamics are useful in predicting and guiding IFNα sequential therapy.

Options for the management of antiviral resistance during hepatitis B therapy: reflections on battles over a decade

Although much advancement has been achieved in the treatment of chronic hepatitis B, antiviral resistance is still a challenging issue. Previous generation antiviral agents have already developed resistance in a number of patients, and it is still being used especially in resource limited countries. Once antiviral resistance occurs, it predisposes to subsequent resistance, resulting in multidrug resistance. Therefore, prevention of initial antiviral resistance is the most important strategy, and appropriate choice and modification of therapy would be the cornerstone in avoiding treatment failures. Until now, management of antiviral resistance has been evolving from sequential therapy to combination therapy. In the era of tenofovir, the paradigm shifts again, and we have to decide when to switch and when to combine on the basis of newly emerging clinical data. We expect future eradication of chronic hepatitis B virus infection by proper prevention and optimal management of antiviral resistance.

Effect of LNA- and OMeN-modified oligonucleotide probes on the stability and discrimination of mismatched base pairs of duplexes.

Locked nucleic acid (LNA) and 2′-O-methyl nucleotide (OMeN) are the most extensively studied nucleotide analogues. Although both LNA and OMeN are characterized by the C3′-endo sugar pucker conformation, which is dominant in A-form DNA and RNA nucleotides, they demonstrate different binding behaviours. Previous studies have focused attention on their properties of duplex stabilities, hybridization kinetics and resistance against nuclease digestion; however, their ability to discriminate mismatched hybridizations has been explored much less. In this study, LNA- and OMeN-modified oligonucleotide probes have been prepared and their effects on the DNA duplex stability have been examined: LNA modifications can enhance the duplex stability, whereas OMeN modifications reduce the duplex stability. Next, we studied how the LNA:DNA and OMeN:DNA mismatches reduced the duplex stability. Melting temperature measurement showed that different LNA:DNA or OMeN:DNA mismatches indeed influence the duplex stability differently. LNA purines can discriminate LNA:DNA mismatches more effectively than LNA pyrimidines as well as DNA nucleotides. Furthermore, we designed five LNA- and five OMeN-modified oligonucleotide probes to simulate realistic situations where target–probe duplexes contain a complementary LNA:DNA or OMeN:DNA base pairs and a DNA:DNA mismatch simultaneously. The measured collective effect showed that the duplex stability was enhanced by the complementary LNA:DNA base pair but decreased by the DNA:DNA mismatch in a position-dependent manner regardless of the chemical identity and position of the complementary LNA:DNA base pair. On the other hand, the OMeN-modified probes also showed that the duplex stability was reduced by both the OMeN modification and the OMeN:DNA mismatch in a position-dependent manner.