Nucleoside Analogues Lamivudine Research Articles

Lamivudine and Entecavir for Acute Hepatitis B: A Systematic Review and Meta-Analysis.

Acute hepatitis B infection is associated with severe liver disease and chronic sequelae in some cases. The purpose of this review was to determine the efficacy of nucleoside analogues (NA) (lamivudine versus entecavir) compared to placebo or no intervention for treating acute primary HBV infection. A meta-analysis for drug intervention was performed, following a fixed-effect model. Randomized controlled trials (RCTs) and quasi-randomized studies that evaluated the outcomes of NA in acute hepatitis B infection were included. The following outcomes were considered: virological cure (PCR negative), elimination of acute infection (seroconversion of HBsAg), mortality, and serious adverse events. Five trials with 627 adult participants with severe acute hepatitis B defined by biochemical and serologic parameters were included. Virological cure did not favor any intervention: OR 0.96, 95% CI 0.54 to 1.7 (p = 0.90), I2 = 58%. Seroconversion of HBsAg to negative favored placebo/standard-of-care compared to lamivudine: OR 0.54, 95% CI 0.33 to 0.9 (p = 0.02), I2 = 31%. The only trial that compared entecavir and lamivudine favored entecavir over lamivudine (OR: 3.64, 95% CI 1.31-10.13; 90 participants). Adverse events were mild. There is insufficient evidence that NA obtain superior efficacy compared with placebo/standard-of-care in patients with acute viral hepatitis, based on low quality evidence.

Successful treatment of infantile hepatitis B with lamivudine: A case report

BACKGROUNDHow to treat infantile hepatitis B virus (HBV) infection remains a controversial issue. The nucleoside analogue lamivudine (LAM) has been approved to treat children (2 to 17 years old) with chronic hepatitis B. Here, we aimed to investigate the benefit of LAM treatment in infantile hepatitis B.CASE SUMMARYA 4-mo-old infant born to a hepatitis B surface antigen (HBsAg)-positive woman was found to be infected by HBV during a health checkup. Liver chemistry and HBV seromarker tests showed alanine aminotransferase of 106 U/L, HBsAg of 685.2 cut-off index, hepatitis B “e” antigen of 1454.0 cut-off index, and HBV DNA of > 1.0 × 109 IU/mL. LAM treatment (20 mg/d) was initiated, and after 19 mo, serum HBsAg was entirely cleared and hepatitis B surface antibody was present. The patient received LAM treatment for 2 years in total and has been followed for 3 years. During this period, serum hepatitis B surface antibody has been persistently positive, and serum HBV DNA was undetectable.CONCLUSIONEarly treatment of infantile hepatitis B with LAM could be safe and effective.

Structural features in common of HBV and HIV-1 resistance against chirally-distinct nucleoside analogues entecavir and lamivudine

Chronic hepatitis B virus (HBV) infection is a major public health problem that affects millions of people worldwide. Nucleoside analogue reverse transcriptase (RT) inhibitors, such as entecavir (ETV) and lamivudine (3TC), serve as crucial anti-HBV drugs. However, structural studies of HBV RT have been hampered due to its unexpectedly poor solubility. Here, we show that human immunodeficiency virus type-1 (HIV-1) with HBV-associated amino acid substitutions Y115F/F116Y/Q151M in its RT (HIVY115F/F116Y/Q151M) is highly susceptible to ETV and 3TC. Additionally, we experimentally simulated previously reported ETV/3TC resistance for HBV using HIVY115F/F116Y/Q151M with F160M/M184V (L180M/M204V in HBV RT) substituted. We determined crystal structures for HIV-1 RTY115F/F116Y/Q151M:DNA complexed with 3TC-triphosphate (3TC-TP)/ETV-triphosphate (ETV-TP)/dCTP/dGTP. These structures revealed an atypically tight binding conformation of 3TC-TP, where the Met184 side-chain is pushed away by the oxathiolane of 3TC-TP and exocyclic methylene of ETV-TP. Structural analysis of RTY115F/F116Y/Q151M/F160M/M184V:DNA:3TC-TP also demonstrated that the loosely bound 3TC-TP is misaligned at the active site to prevent a steric clash with the side chain γ-methyl of Val184. These findings shed light on the common structural mechanism of HBV and HIV-1 resistance to 3TC and ETV and should aid in the design of new agents to overcome drug resistance to 3TC and ETV.

Immunomodulatory Mechanism of Acyclic Nucleoside Phosphates in Treatment of Hepatitis B Virus Infection

Current treatment with nucleos(t)ide analogs (NUCs) safely controls the replication of hepatitis B virus (HBV) and improves prognosis in patients with HBV. However, the inability to completely clear HBV is problematic, and novel therapies are desired. It has been believed that all NUCs have similar functions to inhibit HBV reverse transcriptase. However, our recent findings that only acyclic nucleoside phosphonates (ANPs; adefovir dipivoxil and tenofovir disoproxil fumarate) had an additional effect of inducing interferon (IFN)-λ3 in the gastrointestinal tract suggests that ANPs are not only distinct from nucleoside analogs (lamivudine and entecavir) in their structures but also in their functions. Because enteric lipopolysaccharide (LPS) can cross the intestine and affect peripheral blood mononuclear cells (PBMCs), we hypothesized that orally administered ANPs could have further additional effects to modulate LPS-mediated cytokine profile in PBMCs. This study showed that pretreatment of PBMCs, from either healthy volunteers or patients with HBV, with ANPs inhibited LPS-mediated interleukin (IL)-10 production, which reciprocally induced IL-12p70 and tumor necrosis factor-α production in a dose-dependent manner. Furthermore, the combination of IFN-α and ANPs synergistically enhanced LPS-mediated IL-12p70 production in PBMCs. Mechanistic analyses revealed that cellular metabolites of ANPs directly bound the Akt protein, inhibiting its translocation to the plasma membrane, thereby impairing Akt phosphorylation. Therefore, pretreatment of PBMCs with ANPs impairs LPS-mediated IL-10 production. Among NUCs, only ANPs have an additional pharmacological effect modulating LPS-mediated cytokine production, which is expected to produce favorable immune responses toward HBV elimination. This additional immunomodulation by ANPs in PBMCs, as well as IFN-λ3 induction in the gastrointestinal tract, provides insights into HBV treatment.

Establishment of stable cell lines in which the HBV genome replicates episomally for evaluation of antivirals.

IntroductionDue to the increasing resistance to nucleot(s)ide analogs in patients with chronic hepatitis B, development of new antiviral drugs to eradicate hepatitis B virus is still urgently needed.Material and methodsTo date, most studies on evaluating anti-HBV drugs have been performed using cell lines where the HBV genomic DNA is chromosomally integrated, e.g. Hep2.2.15 in HBV-infected livers of the viral episomal genome replicates in the nucleus and covalently closed circular DNA (cccDNA) serves as a transcriptional template. Another option involves the use of HBV-infected cells of HepaRG or NTCP-overexpressing cells. However, the development of the infection system is expensive and laborious, and its HBV expression level remained low.ResultsCompared to HuH7 cells, the established stable cell lines based on episomal-type pEB-Multi vectors can been expressed HBV wild-type by qRT-PCR and immunoblotting (p < 0.05). These two vectors are also sensitive to Entecavir and against nucleoside analog Lamivudine in mutants cellines.ConclusionsIt is worth demonstrating how useful the established cell system is for evaluating antiviral agents and their mechanisms of action.

Distinct notch signaling expression patterns between nucleoside and nucleotide analogues treatment for hepatitis B virus infection

Nucleos(t)ide analogues therapies are currently approved for the treatment of chronic hepatitis B virus (HBV) infection, which effectively suppress HBV replication and correlate with the anti-HBV-specific immune response. Notch signaling serves pleiotropic roles in the immune system that also contribute to virus-specific immunity. In this study, we assessed Notch signal-related gene expression after administrating nucleoside or nucleotide analogues to HBV-replicating cells and clinical liver tissues. We found distinct Notch signaling expression patterns under nucleos(t)ide analogues therapies, with high expression for nucleotide analogues (adefovir pivoxil or tenofovir disoproxil fumarate) and low expression for nucleoside analogues (lamivudine or entecavir) in the presence of HBV infection. Furthermore, activation of mammalian target of rapamycin (mTOR)-Akt (Ser473) phosphorylation was also observed after nucleotide analogue treatment. In conclusion, nucleoside and nucleotide analogues displayed different patterns of Notch signaling activity under HBV infection, and the induction of mTORC2-Akt (Ser473) phosphorylation may contribute to nucleotide analogues-mediated Notch signaling activation.

Nucleoside‐Based Self‐Assembling Drugs for Localized Drug Delivery

We have synthesized a range of gelators based on the nucleoside analogues gemcitabine and lamivudine, characterizing representative gels from the series using rheology and transmission electron microscopy. Growth inhibition studies of gemcitabine derivatives confirmed the feasibility of these compounds as novel treatments, indicating the potential of nucleoside-based gelators for localized drug delivery.

Synergistic Interactions between Hepatitis B Virus RNase H Antagonists and Other Inhibitors.

Combination therapies are standard for management of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) infections; however, no such therapies are established for human hepatitis B virus (HBV). Recently, we identified several promising inhibitors of HBV RNase H (here simply RNase H) activity that have significant activity against viral replication in vitro Here, we investigated the in vitro antiviral efficacy of combinations of two RNase H inhibitors with the current anti-HBV drug nucleoside analog lamivudine, with HAP12, an experimental core protein allosteric modulator, and with each other. Anti-HBV activities of the compounds were tested in a HepG2-derived cell line by monitoring intracellular core particle DNA levels, and cytotoxicity was assessed by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium (MTS) assay. The antiviral efficiencies of the drug combinations were evaluated using the median-effect equation derived from the mass-action law principle and combination index theorem of Chou and Talalay. We found that combinations of two RNase H inhibitors from different chemical classes were synergistic with lamivudine against HBV DNA synthesis. Significant synergism was also observed for the combination of the two RNase H inhibitors. Combinations of RNase H inhibitors with HAP12 had additive antiviral effects. Enhanced cytotoxicity was not observed in the combination experiments. Because of these synergistic and additive effects, the antiviral activity of combinations of RNase H inhibitors with drugs that act by two different mechanisms and with each other can be achieved by administering the compounds in combination at doses below the respective single drug doses.

Induction of IFN-λ3 as an additional effect of nucleotide, not nucleoside, analogues: a new potential target for HBV infection

ObjectiveThe clinical significance of polymorphisms in the interleukin-28B gene encoding interferon (IFN)-λ3, which has antiviral effects, is known in chronic HCV but not in HBV infection. Thus, we measured IFN-λ3...

Chronic Liver Diseases

The term chronic hepatitis encompasses many distinct clinical and pathologic diseases affecting the liver, the most important of which are autoimmune hepatitis (AIH), chronic hepatitis B with or without hepatitis D, and chronic hepatitis C caused by hepatitis C virus (HCV). The standard treatment of AIH is immunosuppressive therapy either with prednisolone alone or in combination with azathioprine. Although mycophenolate mofetil or cyclosporine can be used for retherapy in the case of treatment failure, controlled clinical trials are missing for these immunosuppressive drugs; thus, they are not part of the American Association for the Study of Liver Diseases (AASLD) practice guidelines for AIH. Chronic hepatitis B is a major global health care problem as 5% of the world’s population, or approximately 350 million persons, is chronically infected. Anti–hepatitis B virus (HBV) drugs can be divided into three classes: alfa interferons, nucleoside analogue (lamivudine, entecavir, telbivudine), and nucleotide analogue (adefovir dipivoxil, tenofovir dipivoxil). Interferon alfa has a number of potential side effects, and careful consideration must be given to its use. Tenofovir, which falls under the nucleotide analogue class, was approved by the Food and Drug Administration in 2008 and has been shown in clinical trials to have more potent activity in serum-suppressing HBV DNA levels than the comparable adefovir. More prevalent than chronic hepatitis B is chronic hepatitis C due to the high chronicity rate of HCV infection (approximately 160 million people are chronically infected with HCV worldwide). Until 2011, the only treatment for chronic HCV was a combination therapy of pegylated interferon alfa and ribavirin (RBV); however, new treatments for chronic hepatitis C include the directly acting antivirals (DAAs) sofosbuvir and simeprevir, although host-targeting agents are also being developed. The side effects of pegylated interferon/RBV therapy and DAAs should be considered, of which only sofosbuvir has shown no specific side effects so far in clinical studies. This module contains 5 highly rendered figures, 6 tables, 61 references, and 5 MCQs.

Chronic Liver Diseases

The term chronic hepatitis encompasses many distinct clinical and pathologic diseases affecting the liver, the most important of which are autoimmune hepatitis (AIH), chronic hepatitis B with or without hepatitis D, and chronic hepatitis C caused by hepatitis C virus (HCV). The standard treatment of AIH is immunosuppressive therapy either with prednisolone alone or in combination with azathioprine. Although mycophenolate mofetil or cyclosporine can be used for retherapy in the case of treatment failure, controlled clinical trials are missing for these immunosuppressive drugs; thus, they are not part of the American Association for the Study of Liver Diseases (AASLD) practice guidelines for AIH. Chronic hepatitis B is a major global health care problem as 5% of the world’s population, or approximately 350 million persons, is chronically infected. Anti–hepatitis B virus (HBV) drugs can be divided into three classes: alfa interferons, nucleoside analogue (lamivudine, entecavir, telbivudine), and nucleotide analogue (adefovir dipivoxil, tenofovir dipivoxil). Interferon alfa has a number of potential side effects, and careful consideration must be given to its use. Tenofovir, which falls under the nucleotide analogue class, was approved by the Food and Drug Administration in 2008 and has been shown in clinical trials to have more potent activity in serum-suppressing HBV DNA levels than the comparable adefovir. More prevalent than chronic hepatitis B is chronic hepatitis C due to the high chronicity rate of HCV infection (approximately 160 million people are chronically infected with HCV worldwide). Until 2011, the only treatment for chronic HCV was a combination therapy of pegylated interferon alfa and ribavirin (RBV); however, new treatments for chronic hepatitis C include the directly acting antivirals (DAAs) sofosbuvir and simeprevir, although host-targeting agents are also being developed. The side effects of pegylated interferon/RBV therapy and DAAs should be considered, of which only sofosbuvir has shown no specific side effects so far in clinical studies. This module contains 5 highly rendered figures, 6 tables, 61 references, and 5 MCQs.

Transporter-mediated uptake of UDP-glucuronic acid by human liver microsomes: assay conditions, kinetics, and inhibition.

This study characterized the kinetics, variability, and factors that affect UDP-glucuronic acid (UDP-GlcUA) uptake by human liver microsomes (HLM). Biphasic kinetics were observed for UDP-GlcUA uptake by HLM. Uptake affinities (assessed as Kd) of the high- and low-affinity components differed by more than an order of magnitude (13 ± 6 vs. 374 ± 175 µM), but were comparable in terms of the maximal rate of uptake, with mean Vmax values differing less than 2.3-fold (56 ± 26 vs. 131 ± 35 pmol/min per mg). Variability in total intrinsic transporter activity (Uint) for microsomal UDP-GlcUA uptake across 12 livers was less than 4-fold. Experiments performed to optimize the conditions for microsomal UDP-GlcUA uptake demonstrated that both components were trans-stimulated by preloading (luminal addition) with an alternate UDP-sugar, and essentially abolished by the thiol-alkylating agent N-ethylmaleimide. Furthermore, interaction studies undertaken with a panel of drugs, alternate UDP-sugars, and glucuronide conjugates, at low (2.5 μM) and high (1000 μM) UDP-GlcUA concentrations, demonstrated that both components were inhibited to varying extents. Notably, the nucleoside analogs zidovudine, stavudine, lamivudine, and acyclovir inhibited both the high- and low- affinity components of microsomal UDP-GlcUA uptake by >45% at an inhibitor concentration of 100 μM. Taken together, these data demonstrate that human liver microsomal UDP-GlcUA uptake involves multiple protein-mediated components, and raises the possibility of impaired in vivo glucuronidation activity resulting from inhibition of UDP-GlcUA uptake into the endoplasmic reticulum membrane by drugs and other compounds.

Bioequivalence of a Dolutegravir, Abacavir, and Lamivudine Fixed-Dose Combination Tablet and the Effect of Food

The integrase inhibitor dolutegravir and nucleoside analogues abacavir and lamivudine are once-daily treatment options for HIV. This study (NCT01622790) evaluated, first, the bioequivalence (BE) of a fixed-dose combination (FDC) tablet containing dolutegravir 50 mg, abacavir 600 mg, and lamivudine 300 mg (dolutegravir/abacavir/lamivudine FDC) vs coadministered dolutegravir 50 mg and abacavir/lamivudine combination tablets (Epzicom) and, second, the effect of food on the dolutegravir/abacavir/lamivudine FDC tablet. Study part A (66 healthy subjects) was a single-dose, open-label, randomized, 2-period crossover study to evaluate the BE of the dolutegravir/abacavir/lamivudine FDC tablet and dolutegravir + abacavir/lamivudine tablets in the fasted state. In study part B, 12 subjects from part A received the dolutegravir/abacavir/lamivudine FDC tablet with a high-fat meal. BE and food effect were assessed by analysis of variance to determine the ratio of geometric least squares means and associated 90% confidence intervals for key pharmacokinetic parameters for each of dolutegravir, abacavir, and lamivudine. Sixty-two subjects completed part A. The dolutegravir/abacavir/lamivudine tablet was bioequivalent to the dolutegravir + abacavir/lamivudine tablets; 90% confidence intervals for the geometric least squares mean ratios fell within the 0.8-1.25 BE criteria. The effect of food on the dolutegravir/abacavir/lamivudine FDC tablet was similar to previous food effects observed with the separate formulations. The safety profile was comparable between treatments, with no observed serious or grade 3/4 adverse events. The BE of the dolutegravir/abacavir/lamivudine FDC tablet was demonstrated; it may be administered without regard to meals.

Seroconversion of Hepatitis B Envelope Antigen by Entecavir in a Child with Hepatitis B Virus-related Membranous Nephropathy

Membranous nephropathy (MN) is caused by subepithelial deposition of immune complexes in the glomerular basement membrane, with secondary MN arising in association with infection. In secondary MN caused by hepatitis B virus (HBV), seroconversion has been known to occur after the onset of MN, particularly in children. In patients with high serum concentrations of HBV DNA, treatment with interferon-α2b or a nucleoside analog has been reported to induce seroconversion and suppress HBV-DNA levels. We treated a 7-year-old boy who presented with proteinuria and liver dysfunction. He had a history of HBV infection since shortly after birth, as his mother was HBV-positive, and he was neither vaccinated nor treated with immunoglobulin at birth. Chronic hepatitis related to HBV was diagnosed following percutaneous needle biopsy of the liver. Percutaneous renal biopsy revealed HBV-related glomerulonephritis with diffuse global subepithelial and focal segmental mesangial and subendothelial deposits. Therefore, HBV-associated MN was diagnosed. Treatment with the nucleoside analog lamivudine was started to reduce serum HBV-DNA levels, but lamivudine was discontinued and treatment with entecavir was started at a dosage of 0.5 mg/day after 6 weeks because of possible adverse effects. Tests for HB envelope antibody were positive in week 16 of treatment, and proteinuria had resolved by week 22. Elevated levels of aspartate aminotransferase and alanine aminotransferase were seen with both treatments but were probably attributable to the developing immune response to HBV. In the present case, HBV levels needed to be reduced to: 1) lower elevated serum HBV-DNA titers, which put the patient at high risk of hepatocellular carcinoma; and 2) remove the immune complexes causing MN. Use of nucleoside analogs to suppress the HBV load may facilitate early remission of MN, and entecavir therapy did not cause any serious adverse reactions in this case. Given the advent of lamivudine-resistant HBV, entecavir appears promising for patients with elevated serum levels of HBV DNA.

Dynamics of hepatitis B virus quasispecies heterogeneity and virologic response in patients receiving low‐to‐moderate genetic barrier nucleoside analogs

We characterized the early dynamics of hepatitis B virus (HBV) quasispecies evolution during the first weeks of antiviral therapy with low-to-moderate genetic barrier antiviral drugs and associated these data with antiviral response patterns. Fifteen chronic hepatitis B patients (men, 10; mean age, 34; HBeAg positive, 6) who received lamivudine or telbivudine for at least 52 weeks were included. HBV DNA was extracted from serum, and a 910-bp fragment covering domains A-F of the reverse transcriptase region was amplified, cloned and sequenced. Parameters of quasispecies heterogeneity, genetic diversity and complexity were calculated and were correlated with complete virologic response, defined as undetectable HBV DNA at week 52. Nine patients achieved complete virologic response during the observational period. While baseline HBV DNA levels and HBeAg status were associated with virologic response, baseline quasispecies complexity and diversity of responders showed no significant difference to those of nonresponders (P > 0.05). However, at week 4, quasispecies complexity of nonresponders was significantly higher compared with that of responders on the nucleotide level (P = 0.01) and the aa level (P = 0.04). The number of synonymous substitutions per synonymous site dropped significantly in responders at week 4 (P = 0.04), while there was no difference in nonresponders. The HBV quasispecies complexity at the early stage of antiviral therapy (week 4) with the low-to-moderate genetic barrier nucleoside analogs lamivudine or telbivudine was associated with subsequent virologic response. Further studies are needed to confirm HBV quasispecies evolution as additional predictive marker for beneficial treatment outcome.

Transarterial Chemoembolization for Hepatitis B Virus–associated Hepatocellular Carcinoma: Improved Survival after Concomitant Treatment with Nucleoside Analogues

PurposeTo determine whether nucleoside analogue therapy is associated with improved survival in patients with hepatitis B virus (HBV)–associated hepatocellular carcinoma (HCC) who are treated solely with transarterial chemoembolization. Materials and MethodsA retrospective chart review of patients diagnosed with HBV-associated HCC was performed to identify patients treated solely with chemoembolization. Relevant demographic and clinical data were extracted and recorded. The influence of therapy with nucleoside analogues (lamivudine, adefovir dipivoxil, or entecavir) was determined by estimating the survival function using the Kaplan-Meier product-limit method. ResultsThe inclusion criteria for chemoembolization were met by 81 patients (67 men and 14 women, mean age 60.6 years ± 9.2); 21 (25.9%) of these patients had been treated with nucleoside analogues. The number of chemoembolization treatments was significantly greater in the patients who were treated with nucleoside analogues (3.43 ± 2.32) than in the patients who did not receive nucleoside analogues (1.82 ± 0.95; P = .0022). The 1-year, 3-year, and 5-year survival rates were 89.5%, 66.8%, and 40.5% in the patients treated with nucleoside analogues and 72.6%, 27.5%, and 14.3% in the patients not treated with nucleoside analogues. The survival rate was significantly higher in the patients who received nucleoside analogues (P = .0051). Nucleoside analogue intake was an independent factor that was associated with increased survival (P = .0063). ConclusionsAdministration of nucleoside analogues was associated with longer survival in patients with HBV-associated HCC who were treated with transarterial chemoembolization.

Intensification of a failing regimen with zidovudine may cause sustained virologic suppression in the presence of resensitising mutations including K65R

The reverse transcriptase (RT)-mutation K65R limits further therapeutic options and has been selected by unfavorable RT-combinations, e.g. tenofovir in combination with abacavir and/or didanosine. We identified HIV-1 infected patients from a large treatment cohort who experienced virological failure (HIV-1 RNA >1000 copies/mL) with evidence of resistance mutations including the K65R, but without thymidine analogue mutations (TAMs) in genotypic resistance assay. Phenotype was performed from previously collected frozen plasma. The patients were followed for clinical and resistance outcome after treatment intensification with only zidovudine. Five patients had experienced antiretroviral treatment failure on various nucleoside analogue combinations, containing abacavir, didanosine, lamivudine, nevirapine, reverset and/or tenofovir. RT-sequence revealed mutations at position K65R in combination with other non-TAMs. The patients' median viral load prior to zidovudine intensification was 3.551 Log10 (range 3.053-4.681) and despite evidence for resistance to the failing drug regimen, all responded within 4 weeks to undetectable levels (<1.699 Log10 or <50 copies/mL) and remained virologically suppressed during follow-up (20 months through 6.5 years). In virologically failing patients due to K65R- and other non-thymidine-mutations, simple regimen intensification with zidovudine resulted in sustained HIV-1 suppression. The finding of re-sensitized HIV-1 in patients may be clinically relevant.

Review article: Hepatitis B and dialysis

The incidence of hepatitis B virus (HBV) infection in dialysis populations has declined over recent decades, largely because of improvements in infection control and widespread implementation of HBV vaccination. Regardless, outbreaks of infection continue to occur in dialysis units, and prevalence rates remain unacceptably high. For a variety of reasons, dialysis patients are at increased risk of acquiring HBV. They also demonstrate different disease manifestations compared with healthy individuals and are more likely to progress to chronic carriage. This paper will review the epidemiology, modes of transmission and diagnosis of HBV in this population. Prevention and treatment will be discussed, with a specific focus on strategies to improve vaccination response, new therapeutic options and selection of patients for therapy.

Antiviral Therapy of Chronic Hepatitis B with Nucleotide Analogs

In recent years, significant progress has been made in the treatment of chronic hepatitis B. Currently four nucleoside analogues (lamivudine, adefovir, entecavir, and telbivudine) are available for the treatment of chronic hepatitis B virus (HBV) infection. The oral nucleos(t)ide analogues are generally better tolerated than interferon, but when administered for lengthy periods, a major concern is the antiviral-resistant mutation of HBV. Lamivudine, the first approved nucleoside analogue for the treatment of HBV infection, has been shown to be effective in suppressing HBV replication, so to ameliorate liver disease and prolong treatment with lamivudine has been shown to reverse fibrosis and cirrhosis. Among the approved nucleos(t)ide analogues (NAs) for hepatitis B, lamivudine has the highest and entacevir the lowest resistant rate for HBV. Adefovir is effective in suppressing wild type as well as lamivudine-resistance mutants. Telbivudine is more potent than lamivudine in suppressing HBV replication. On the other hand, telbivudine is associated with high rate of resistance. Combination therapy has been recently developed in order to increase efficacy and to decrease the occurrence of viral resistance. However, so far few combinations have been evaluated. No combination therapy demonstrated greater benefit as compared with monotherapy in inducing a higher rate of sustained response. However, in lamivudine-resistant HBV-infected individuals combination therapy of lamivudine and adefovir is more effective than adefovir monotherapy. More potent drugs and new combinations together with the understanding of the mechanisms of resistance to therapy are important challenges to improve the efficacy of treatment and to reduce the global disease burden related to chronic hepatitis B. Keywords: Antiviral Therapy, Nucleotide Analogs, lamivudine, adefovir, chronic hepatitis B

The Human Immunodeficiency Virus Type 1 Nonnucleoside Reverse Transcriptase Inhibitor Resistance Mutation I132M Confers Hypersensitivity to Nucleoside Analogs

We previously identified a rare mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT), I132M, which confers high-level resistance to the nonnucleoside RT inhibitors (NNRTIs) nevirapine and delavirdine. In this study, we have further characterized the role of this mutation in viral replication capacity and in resistance to other RT inhibitors. Surprisingly, our data show that I132M confers marked hypersusceptibility to the nucleoside analogs lamivudine (3TC) and tenofovir at both the virus and enzyme levels. Subunit-selective mutagenesis studies revealed that the mutation in the p51 subunit of RT was responsible for the increased sensitivity to the drugs, and transient kinetic analyses showed that this hypersusceptibility was due to I132M decreasing the enzyme's affinity for the natural dCTP substrate but increasing its affinity for 3TC-triphosphate. Furthermore, the replication capacity of HIV-1 containing I132M is severely impaired. This decrease in viral replication capacity could be partially or completely compensated for by the A62V or L214I mutation, respectively. Taken together, these results help to explain the infrequent selection of I132M in patients for whom NNRTI regimens are failing and furthermore demonstrate that a single mutation outside of the polymerase active site and inside of the p51 subunit of RT can significantly influence nucleotide selectivity.