Search

Background The incidence and risk factors for adefovir-resistant HBV have not been clearly defined. Aims To characterize the virologic response to adefovir, to determine the rate of adefovir resistance and to explore factors associated with initial virologic response (IVR) and adefovir resistance. Methods All hepatitis B patients who received adefovir for ≥6 months at our center were prospectively monitored for virologic response and adefovir resistance. Results Forty three patients were included; mean treatment duration was 18 months (range 6–45). Thirty four (79%) patients had prior lamivudine. IVR was observed in 44% patients and associated with higher pretreatment ALT ( P =0.05) and the absence of HBeAg ( P =0.02). Six (14%) patients were found to have adefovir-resistant mutations. The cumulative probability of genotypic resistance to adefovir at month 24 was 22%. Patients with adefovir resistance were more likely to have been switched from lamivudine to adefovir monotherapy ( P =0.01), to be older ( P =0.04), and to be infected with HBV genotype D ( P =0.02). Conclusions Roughly 50% of patients failed to achieve IVR on adefovir. The cumulative probability of adefovir resistance at 2 years was 22%. Our data suggest that combination of lamivudine and adefovir may prevent emergence of adefovir resistance in patients with lamivudine-resistant HBV.

Purpose of review This article highlights recent advances in viral hepatitis published from December 2003 to November 2004. Studies reporting novel and clinically relevant findings were selected after a PubMed search. The aim is to provide an up-to-date summary of important developments in viral hepatitis. Recent findings Lamivudine was shown to reduce the rate of long-term complications of hepatitis B virus-induced cirrhosis. Adefovir was effective in suppressing lamivudine-resistant hepatitis B virus. Pegylated interferon alone was as effective as pegylated interferon plus lamivudine in the management of HBeAg-negative chronic hepatitis B. A 24-week course of pegylated interferon plus low-dose ribavirin was optimal in patients with hepatitis C virus infected with genotype 2 or 3, but a 48-week course and standard dose of ribavirin were needed in patients with genotype 1. Pegylated interferon plus ribavirin was fairly well tolerated in HIV-hepatitis C virus coinfected patients with stable HIV infection and resulted in response rates that were only slightly lower than that in patients with hepatitis C virus infection only. A dramatic reduction in hepatitis C virus RNA level was observed after 2 days of treatment with an hepatitis C virus protease inhibitor. Summary The optimal management of chronic viral hepatitis is evolving rapidly. Newer treatment options for hepatitis B, including pegylated interferon, tenofovir, and combination regimens were shown to be effective in treatment-naive and treatment-experienced patients. In addition, impressive gains were made in the treatment of hepatitis C virus infection in difficult-to-treat patients, including African Americans and those with HIV-hepatitis C virus coinfection.

Approximately 350 million people worldwide are chronically infected with hepatitis B virus (HBV). If left untreated, approximately 20% will develop cirrhosis and complications of end-stage liver disease [1,2]. Antiviral therapy may decrease the progression to cirrhosis, hepatic decompensation and hepatocellular carcinoma (HCC). Until recently, the only treatment for chronic hepatitis B was standard interferon (IFN). Interferon has limited efficacy, and may be associated with severe sepsis and worsening of hepatic failure in patients with decompensated cirrhosis [3,4]. The availability of oral antiviral agents with a better safety profile has significantly changed the management of end-stage liver disease caused by HBV. Lamivudine has been shown to suppress HBV replication, and to improve or stabilize liver function in patients with compensated as well as in those with decompensated cirrhosis [5,6]. Adefovir dipivoxil has also demonstrated efficacy in patients with decompensated cirrhosis and lamivudine-resistant HBV [7]. Oral nucleos(t)ide agents have delayed or obviated the need for liver transplantation in some patients, but transplantation is still required for those who present with advanced liver failure [8,9]. This article will focus on the use of antiviral agents for the treatment of HBV-cirrhosis.

In the past decade, substantial advances have been made in the treatment of chronic hepatitis B. Approved treatments include interferon-alpha, the nucleoside analog inhibitor lamivudine, and the nucleotide analog inhibitor adefovir dipivoxil. This review provides insights into the benefits and limitations of lamivudine and adefovir dipivoxil for the treatment of chronic hepatitis B. Lamivudine and adefovir dipivoxil have similar antiviral efficacies. Lamivudine has negligible side effects but a high rate of drug resistance, whereas adefovir dipivoxil has a low rate of drug resistance but long-term use is associated with a small risk of nephrotoxicity. Several other nucleoside and nucleotide analogs are being evaluated in phase II/III clinical trials for hepatitis B.

Chronic hepatitis B infection continues to be a major public health concern worldwide. The natural history of the disease can be divided into 4 different phases: immune tolerance, immune clearance, inactive carrier, and reactivation. The goals of treatment are sustained viral suppression, normalization of ALT, and improvement in liver histology. Antiviral agents in current use include standard interferon-alpha, lamivudine, and adefovir. With an improved understanding of the natural history of the disease and a growing repertoire of antiviral drugs, the important questions are: who should receive treatment, what is the best agent to use, and what is the optimal duration of therapy? Treatment is indicated for patients in the immune clearance and reactivation phases. Patients with high pretreatment ALT level, detectable HBV DNA in the serum, and active inflammation on liver biopsy are predicted to have the highest chance of response to treatment. The choice of a particular agent must balance long-term benefits such as the likelihood of a sustained response against long-term risks such as drug resistance. Interferon treatment leads to a more durable response but is associated with unpleasant side effects. Lamivudine is effective and well tolerated but requires long-term therapy and is associated with drug resistance. Adefovir has proven efficacy and a very low rate of drug resistance but is associated with a small risk of reversible nephrotoxicity. For HBeAG-positive chronic hepatitis B and HBeAG-negative chronic hepatitis B, the duration of interferon therapy is 4-6 months and 12 months, respectively. Duration of treatment is at least 1 year with lamivudine and adefovir; longer duration of treatment is needed in most patients, but the optimal duration of treatment and the criteria for stopping treatment have not been established.

Drug resistance is an expected consequence of antiviral therapy for chronic hepatitis B because of the high rate of hepatitis B virus (HBV) replication, the lack of proofreading during reverse transcription of the pregenomic RNA and the low efficacy of available therapies in eliminating covalently closed circular HBV DNA. Mutations involving the YMDD motif of the catalytic domain of HBV reverse transcriptase have been reported in patients who have received lamivudine, emtricitabine and telbivudine. Drug-resistant mutations affecting other regions of HBV polymerase have also been reported, but at much lower rates in patients who have received adefovir dipivoxil or entecavir. Antiviral resistance is initially manifested as virological breakthrough infection. In most patients, this is followed by biochemical breakthrough and, in some patients, hepatitis flares and hepatic decompensation. Monitoring drug resistance may improve the management of patients with antiviral-resistant HBV and can guide the selection of salvage therapy. The optimal management of patients with antiviral-resistant HBV continues to evolve. The ideal approach is to prevent antiviral resistance through judicious use of antiviral therapy and the use of more potent antiviral agents, possibly in combination.

Purpose of review This article discusses over 40 studies in the field of viral hepatitis that were published in 2003. Studies that reported novel findings of clinical relevance were selected after a MEDLINE search. This article focuses on hepatitis B and hepatitis C. Recent findings In the United States, all genotypes of hepatitis B virus were reported, and precore and core promoter mutations were found in approximately a third of patients. The response to lamivudine was less durable than that induced by interferon. Adefovir dipivoxil was safe and effective for treatment-naive patients as well as for lamivudine-resistant patients. In acute hepatitis C infection, close monitoring of hepatitis C virus RNA and treatment of patients with persistent viremia is a reasonable alternative to immediate treatment of all patients. Noninvasive indices to predict liver fibrosis are currently being tested. Failure to achieve an early virologic response to pegylated interferon plus ribavirin can identify more than 95% patients who will not have a sustained response. Summary The clinical significance of hepatitis B virus genotypes and viral variants continues to be elucidated worldwide. Long-term lamivudine treatment is safe, despite a rising rate of resistance. Adefovir appears to be safe and effective as initial therapy for chronic hepatitis B virus infection or for the management of lamivudine-resistant hepatitis B infection. Noninvasive indices for liver fibrosis require validation but may reduce the need for liver biopsy in the future. Newer agents for the treatment of hepatitis C virus infection show promise.

Lamivudine, adefovir, and entecavir are safe and effective orally administered inhibitors of hepatitis B virus (HBV) replication, but drug-resistant strains of HBV with point mutations in the HBV polymerase gene are being reported with prolonged treatment that can lead to viral rebound and serum alanine aminotransferase flares. Salvage treatment with antiviral agents including investigational nucleoside/nucleotide analogues is available but highlights the limitations and hazards of sequential antiviral monotherapy for chronic HBV. Studies of pegylated interferon combined with an antiviral agent or dual nucleoside/nucleotide combination therapy are awaited to minimize the incidence of drug-resistant HBV and improve long-term outcomes.

Multi-drug resistant hepatitis B virus (HBV) has been reported in hepatitis B patients who received sequential antiviral therapy. In vitro studies showed that HBV constructs with mutations resistant to lamivudine and adefovir have marked reduction in sensitivity to combination of lamivudine and adefovir, whereas constructs with mutations resistant to either drug remain sensitive to the other drug. We conducted this study to determine whether mutations conferring resistance to multiple antiviral agents co-locate on the same HBV genome in vivo and to describe the evolution of these mutations. Sera from six patients who had been found to have multi-drug resistant HBV mutations to lamivudine + adefovir, lamivudine + hepatitis B immunoglobulin (HBIG), or lamivudine + entecavir on direct sequencing were cloned after nested polymerase chain reaction (PCR). Analysis of 215 clones from 11 samples with multi-drug resistant mutations on direct sequencing showed that 183 (85%) clones had mutations to both therapies on the same genome; 31 clones had lamivudine-resistant mutants only. Clonal analysis of serial samples from three patients showed progressive evolution from all clones with lamivudine-resistant HBV mutations only to mixtures of clones that have multi-drug resistant mutations and clones that have lamivudine-resistant HBV mutations only, and ultimately all clones having multi-drug resistant HBV mutations. In conclusion, mutations conferring resistance to multiple antiviral agents co-locate on the same viral genome, suggesting that combination therapy directed against mutants resistant to each treatment may not be adequate in suppressing multi-drug resistant HBV. De novo combination therapy may prevent the emergence of multi-drug resistant mutants. (HEPATOLOGY 2006;44:703–712.)

The INNO-LiPA HBV DR v2 assay is designed to detect hepatitis B virus mutations conveying resistance to lamivudine and adefovir. Our study confirms that this assay can simultaneously detect the presence of lamivudine and adefovir resistance mutations in clinical samples, has a high degree of concordance with sequencing, and can detect mutants earlier.

Background/Aims The susceptibility of adefovir-resistant hepatitis B virus (HBV) mutants is only reduced by 3–10-fold in in vitro studies, suggesting that virologic breakthrough and clinical deterioration are unlikely. The aim of this study was to describe the clinical course of patients with adefovir-resistant HBV infection. Methods Testing for adefovir-resistant mutations was performed on patients who had a suboptimal response or virologic breakthrough on adefovir. Adefovir-resistant mutations were detected using a line probe assay and direct sequencing of the HBV P-gene. Results Eight male patients with pre-existing lamivudine resistance or breakthrough (mean age 47±13 years) were found to have adefovir-resistant mutations rtA181V/T or rtN236T. Baseline median ALT was 66 IU/L (range, 27–1161) and median HBV DNA 7.9 log 10 copies/ml (range, 6–8.3). At the time of adefovir resistance (mean of 20±9 months), HBV DNA increased to ≥5 log 10 copies/ml in 7 patients. After detection of adefovir resistance, hepatic decompensation occurred in 2 patients, 1 of whom died. Salvage therapy with lamivudine, entecavir or tenofovir was given to 7 patients and a reduction in HBV DNA by ≥3 log 10 was seen in 3 patients. Conclusions In conclusion, adefovir resistance can be associated with significant viral rebound and hepatic decompensation which may be fatal.

SUMMARY. Lamivudine has demonstrated efficacy for the treatment of hepatitis B e antigen-negative chronic hepatitis B (e-CHB). However, treatment withdrawal after 1 year has been associated with a high rate of relapse while long-term treatment is associated with increasing risks of drug resistance. We report our treatment experience of 50 ChineseCanadian patients with e-CHB. All patients received lamivudine for 2 years. Treatment was withdrawn at month 24 in patients who had undetectable hepatitis B virus (HBV) DNA by PCR and normal aminotransferases during the second year of therapy. All patients had HBV genotype B or C. Biochemical response at months 6, 12 and 24 was 74%, 71% and 66%, respectively. HBV DNA was undetectable at months 6, 12 and 24 by hybrid capture and PCR assays in 100%, 92% and 86%; and 94%, 88% and 74% patients, respectively. The cumulative rates of genotypic resistance (GR) after 1 and 2 years were 15% and 25%, respectively. Four (44%) patients with GR experienced a hepatitis flare. The probability of clinical and virological relapse 6, 12, and 18 months after treatment withdrawal were 12% and 30%, 18% and 50%, and 30% and 50%, respectively. Reinstitution of lamivudine resulted in prompt virological and biochemical responses. Our study demonstrates that a sustained response can be achieved after a 2-year course of lamivudine in a subset of patients with e-CHB.