Use Of Entecavir Research Articles

Entecavir for treatment of chronic hepatitis B: A clinical update for the treatment of patients with decompensated cirrhosis

The introduction of nucleos(t)ide analogues for the treatment of chronic hepatitis B virus (HBV) infection was transformative in reducing morbidity and mortality. Entecavir, a potent selective nucleoside analogue first approved in 2005 for treatment of chronic HBV, is associated with significant antiviral, biochemical, serologic, and histologic responses. Rapid reductions in HBV DNA levels, low risk of resistance development, and a favorable adverse event profile have contributed to its clinical usefulness. Re-cent developments in the use of entecavir have increased its utility in the management of difficult-to-treat patients with chronic HBV, including those patients with decompensated liver disease. Recent studies in this population have demonstrated that entecavir 1.0 mg/d given for up to 48 weeks had superior antiviral activity when compared with adefovir and was generally safe and well tolerated. Long-term outcomes of entecavir in difficult-to-treat populations are eagerly anticipated.

Emergence of entecavir-resistant mutations in nucleos(t)ide-naive Japanese patients infected with hepatitis B virus: Virological breakthrough is also dependent on adherence to medication

Objective. Currently, five nucleos(t)ide analogues (NUCs) are available for the treatment of chronic hepatitis B in the world. We examined the prevalence of hepatitis B virus (HBV) DNA and alanine aminotransferase normalization in patients receiving entecavir (ETV) and the frequency of ETV-resistant mutations during an approximately 27-month use of ETV in chronic hepatitis B patients in an urban hospital in Japan. Materials and methods. A retrospective analysis of 81 NUC-naive chronic hepatitis B patients who received 0.5 mg of ETV daily was performed. HBV DNA was measured and sequence analysis of HBV DNA was performed in virological breakthrough patients. Results. Hepatitis B e antigen (HBeAg)-positive patients with HBV DNA 5.0–7.0 log IU/mL group and all HBeAg-negative patients achieved serum HBV DNA negativity by 12 months. Four patients experienced virological breakthrough during ETV therapy. Two patients had no genotypic mutations, and medical interviews revealed that they had poor adherence to ETV. Conclusions. We found that some of the HBV virological breakthroughs during ETV treatment were related to poor adherence to medication, highlighting that clinicians should pay attention to the emergence of resistant mutants as well as adherence to ETV.

Eficácia do adefovir dipivoxil, entecavir e telbivudina para o tratamento da hepatite crônica B: revisão sistemática

Chronic hepatitis B is one of the most frequent infectious disease in the world and represents a serious problem of public health A systematic review of randomized clinical trials was conducted to evaluate the efficacy of the nucleoside/nucleotide analogues (adefovir, entecavir and telbivudine) used for the treatment of chronic hepatitis B. The databases PubMed and LILACS were consulted, among others Twenty nine articles published between January/1970 to December/2009 were selected All nucleoside/nucleotide analogues demonstrate upper or similar efficacy to lamivudine. The entecavir can be appropriate for patients with chronic hepatitis B, HBeAg positive and negative treatment-naive as alternative to lamivudine, considering its low potential of viral resistance. The addition of adefovir to lamivudine presented good results in lamivudine resistant patients. The use of entecavir and telbivudine in those patients presents risk of crossed resistance. TBV is one of the most recent antivirals available, but antiviral resistance already documented represents limitation to its use as therapeutic option to LAM. Adverse events of nucleoside/nucleotide analogues were similar in characteristics, gravity and incidence when compared to the lamivudina and placebo.

Reactivation of hepatitis B virus after rituximab‐containing treatment in patients with CD20‐positive B‐cell lymphoma

Reactivation of hepatitis B virus (HBV) after rituximab-containing chemotherapy in patients with B-cell lymphoma has been recognized as a potentially serious complication in HBV immune patients. To determine the HBV reactivation in patients treated with rituximab, a retrospective study of HBV-related markers was performed before and after rituximab-containing treatment in 261 consecutive patients with CD20-positive B-cell lymphoma. Of the 261 patients, 230 patients were tested for both hepatitis B surface antigen (HBsAg) and antibody to hepatitis B core antigen (anti-HBc) before treatment. Fifty-six (24.3%) of 230 patients were anti-HBc positive, and the remaining 174 (75.6%) patients were anti-HBc negative. Among the 56 anti-HBc-positive patients, 5 (8.9%) became HBsAg positive (HBV reactivation), whereas none of the 174 anti-HBc-negative patients became HBsAg positive with a median follow-up of 24 months (P = .001). Among the 5 patients with HBV reactivation, 4 were negative for antibody to HBsAg (anti-HBs), and 1 patient was positive for anti-HBs. All 5 of these patients were treated successfully with entecavir on detection of HBsAg, although 4 of the 5 patients exhibited mild to moderate elevation of alanine aminotransferase. Among 56 anti-HBc-positive patients, those negative for anti-HBs had a higher probability of developing HBV reactivation compared with those positive for anti-HBs (4 of 19; 21.1% vs 1 of 37; 2.7%, P = .014). Patients with isolated anti-HBc are at high risk of HBV reactivation and should be monitored closely for HBsAg, anti-HBs, HBV-DNA, and transaminase levels during and after rituximab-containing treatment. Although preemptive use of entecavir enabled successful management of HBV reactivation, mild to moderate hepatic flare was still observed. These approaches should be further evaluated in a prospective study with regard to clinical usefulness, safety, and cost-effectiveness.

Treatment Options in Chronic Hepatitis B: Focus on Entecavir

Chronic hepatitis B virus (HBV) infection is a major cause of liver-related morbidity and mortality worldwide and is endemic in many areas of Asia and Africa. Adequate treatment of hepatitis B with effective antiviral agents can improve disease burden. Entecavir is a potent, selective nucleoside analogue with activity against HBV. In recent years, studies have been done on the safety, efficacy, resistance profile and therapeutic use of entecavir. This review will discuss pharmacological and clinical aspects of oral entecavir for use in adults with chronic hepatitis B virus infection.

Long-term use of entecavir in nucleoside-naïve Japanese patients with chronic hepatitis B infection

To evaluate the long-term efficacy of entecavir in nucleoside-naïve chronic hepatitis B patients. One hundred and sixty-seven patients treated with entecavir 0.01mg, 0.1mg or 0.5mg for 24-52weeks in Phase II studies entered rollover study ETV-060 and received entecavir 0.5mg daily. Responses were evaluated among patients with available samples. After 96weeks in ETV-060 (120-148weeks total entecavir treatment time), 88% (127/144) of patients had HBV-DNA <400 copies/ml; 90.1% (128/142) had alanine aminotransferase (ALT) 1x the upper limit of normal (ULN) among those with abnormal baseline ALT; and 26% (32/121) achieved HBe seroconversion among those HBeAg(+) at baseline. A subset of 66 patients received entecavir 0.5mg (approved dose) from Phase II baseline: at week 96 in ETV-060, 83% (48/58) had HBV-DNA <400 copies/ml, 88% (52/59) had ALT 1x ULN, and 20% (10/49) achieved HBe seroconversion. Twenty-one out of 66 patients had paired baseline and on-treatment biopsies: 100% (21/21) and 57% (12/21) demonstrated histologic improvement, and improvement in fibrosis, respectively, over 3years. The 3-year cumulative probability of resistance was 3.3% for all patients and 1.7% for the 0.5mg subset. Long-term entecavir for nucleoside-naïve patients resulted in high rates of virological, biochemical, and histological response, with minimal resistance.

High Risk of Hepatitis B Virus Reactivation in Isolated Anti-Hbc Positive Patients with B-Cell Lymphoma Receiving Rituximab Containing Chemotherapy.

Abstract 1944Poster Board I-967Reactivation of hepatitis B virus (HBV) infection in patients receiving chemotherapy, immunosuppressive therapy, and organ transplantation is well-recognized complication in patients with HBsAg positive patients. Although, prophylaxis with anti-viral drug is proposed for HBV surface antigen (HBsAg) positive patients and is considered as a standard managements, the risk of developing HBV reactivation and optimal therapy in HBsAg negative but anti-HBV core antigen (anti-HBc) positive patients remained to be elucidated. In addition the use of rituximab has been reported to cause even fatal HBV related hepatic failure in these patients. We retrospectively investigated the occurrence of HBV reactivation after rituximab containing chemotherapy in HBsAg negative 261 consecutive patients with CD20 positive B-cell lymphoma who admitted Kameda General Hospital over past 5 years. Prior to September 2006, anti-HBc and antibody to HBsAg (anti-HBs) were performed at the discretion of the treating physician. After October 2006, anti-HBc and anti-HBs tests were performed for all patients. HBV reactivation was defined by the seroconversion from HBsAg negative to positive with or without an increase of HBV-DNA from base line levels (>2.6 log copies/ml). Hepatitis attributable to reactivation was defined as a serum alanine aminotransferase (ALT) level greater than 3 folds above the normal upper limit of 2 consecutive determinations more than 5 days apart without feature of hepatitis A, hepatitis C or other causes. Lymphoma subtypes were diffuse large B cell lymphoma (DLBCL; 162 cases, 61%), follicular lymphoma (FL; 58 cases, 22%), mantle cell lymphoma (MCL; 11 cases, 4%), Burkitt lymphoma (BL; 6 cases, 2%), chronic lymphocytic leukemia (CLL; 6 cases, 2%), and other B cell lymphomas (18 cases, 7%) and various courses and treatments containing rituximab were performed such as CHOP, ESHAP, hyper-CVAD etc. Among the 261 patients, the prevalence of HBsAg positive is 9 (3.4%) and all of them were successfully treated by rituximab containing regimens and concurrent use of antiviral agents without development of severe hepatitis. Twenty-two patients were not tested both anti-HBc and anti-HBs before rituximab administration. Therefore, 230 patients were tested both HBsAg and anti-HBc before treatment. Fifty-six of 230 patients (24.3%) were isolated anti-HBc positive and the rest of 174 patients were anti-HBc negative. Anti-HBc IgM was tested in 29 of 56 anti-HBc positive patients and all of the 29 patients were negative for anti-HBc IgM. Anti-HBs was positive in 5/174 patients (2.8%) and 36/56 patients (65.4%) in anti-HBc negative patients and positive patients, respectively. Among 56 patients with positive anti-HBc, 5 patients (13.9%) became HBsAg positive after rituximab containing therapy, while none of 174 patients with negative anti-HBc became positive for HBsAg with median follow up of 24 months. Among 5 patients with HBV reactivation, 4 patients were isolated anti-HBc and one patient who received allogeneic stem cell transplantation was both anti-HBs and anti-HBc positive before the start of rituximab, although his anti-HBs decline and disappeared after transplantation with the use of prednisone for chronic GVHD. All of the 5 patients received entecavir on detection of HBsAg and showed prompt decrease of HBV-DNA, however, 4 of 5 patients exhibited mild to moderate elevation of ALT. None of them developed fulminant hepatic failure. We conclude that patients with isolated anti-HBc are at high risk for HBV reactivation (p=0.011, by Fisher's exact test) and should be monitored closely for HBsAg, anti-HBs, HBV-DNA, transaminase levels during and after rituximab containing treatment. Although preemptive use of entecavir from detection of HBsAg or HBV-DNA enabled us to manage hepatitis B virus reactivation and liver injury successfully, mild to moderate hepatic flare could not prevented in our patients. Therefore, these approaches should be further evaluated in the context of clinical usefulness, safety, cost-effectiveness. Disclosures:No relevant conflicts of interest to declare.

Successful use of entecavir for a severe case of reactivation of hepatitis B virus following polychemotherapy containing rituximab

Hepatitis B virus (HBV) reactivation following treatment with rituximab has been reported in patients with either HBsAg-positive, or HBsAg-negative and anti-HBc positive infection. Patients with severe reactivation often have a fatal outcome despite treatment with lamivudine. The use of entecavir has not been reported in patients with severe HBV reactivation. We present a case of a HBsAg-negative patient diagnosed with chronic lymphocytic leukemia who received a chemotherapeutic regimen that included rituximab, who subsequently presented with severe HBV reactivation with ascites, jaundice and coagulopathy and was treated with entecavir. A review of the literature and underlying HBV associated mutations are discussed. Entecavir produced a rapid and sustained suppression of HBV that was associated with rapid clinical improvement without any side effects. Entecavir is an efficacious and safe treatment for severe HBV reactivation.

Use of entecavir to prevent hepatitis B virus reactivation during cytotoxic chemotherapy for solid malignancy.

Reactivation of hepatitis B virus (HBV) infection is a frequent complication of cytotoxic chemotherapy that includes steroids. International studies have shown that lamivudine reduces the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy to treat malignancies. However, prolonged lamivudine therapy is associated with an increased risk of drug-resistant tyrosine-methionine-aspartate-aspartate (YMDD) mutations. Here, we studied the role of entecavir in preventing morbidity and mortality associated with HBV reactivation. Three patients with both solid malignancies and hepatitis B surface antigen-positive hepatitis B underwent cytotoxic chemotherapy with steroids. They were followed up for at least 6months after the completion of chemotherapy. The chemotherapeutic regimens comprised carboplatin and paclitaxel for non-small-cell lung cancer, and docetaxel monotherapy or cyclophosphamide plus epirubicin for breast cancer, respectively. All patients completed chemotherapy with steroids without developing severe hepatitis that could be attributable to HBV reactivation. Entecavir prevented the incidence and severity of hepatitis in HBV carriers undergoing chemotherapy for malignancies. Although further studies are required to evaluate whether entecavir can prevent the increased risk of YMDD mutation and decrease the rates of disrupted chemotherapy due to severe hepatitis more effectively than lamivudine, entecavir should be considered before lamivudine for such patients.

Entecavir: a potent antiviral with minimal long-term resistance in nucleoside-naive chronic hepatitis B patients

Entecavir has demonstrated safety and efficacy in the treatment of chronic hepatitis B infection. It is the prototype for the cyclopentane class of nucleoside/nucleotide chronic hepatitis B antiviral agents. It has a high potency and, due to its structural formula and mechanism of action, entecavir is associated with emergence of minimal resistance in the long-term treatment of nucleoside-naive patients. Research suggests that long-term treatment may be required for chronic hepatitis B patients, especially those who acquire HBV early in life, to achieve maximum viral suppression and improve outcomes. Several recent studies have evaluated the long-term safety, efficacy and development of resistance in nucleoside-naive patients treated with entecavir. Results indicate that the long-term use of entecavir is well tolerated and associated with continuous clinical improvement – with an increasing number of patients achieving undetectable levels of HBV DNA, HBeAg seroconversion and minimal resistance. These data underscore the position of entecavir for first-line therapy and highlight its role in the long-term treatment of chronic hepatits B.

The Use of Entecavir Following Liver Transplantation

Purpose: We performed a retrospective review to assess the safety and tolerability of Entecavir (ETV) following liver transplantation. ETV was safe and tolerable over a median follow-up period of 10 months. Methods: Our institution performed 492 adult liver transplants between February 1995 and July 2006. 68 (14%) out of 492 patients were transplanted for hepatitis B virus (HBV) related hepatic decompensation. Excluded from our analysis were 6 patients who died prior to discharge. Post-transplant management data were available for 60 (97%) of the remaining patients. Standard post-transplant immunosuppression was instituted, and all patients received hepatitis B immune globulin (HBIG). A total of 9 patients, consisting of 7 men and 2 women (ages ranging between 39 and 72, median 61 years), received ETV and were monitored closely for development of recurrent HBV allograft infection, allograft rejection, and medication side-effects over median post-transplant duration of 10 months (range 4 to 18 months). Results:Table 1 summarizes post-transplant antiviral treatment regimens, both immediately post-transplant and at the end of follow-up period. Four (4) patients were started on ETV 0.5–1.0 mg daily, and an additional 5 patients were switched to ETV due to suspicion of adefovir (ADV)-induced renal insufficiency. In the ETV group (N = 9), 1 patient developed an episode of acute cellular rejection (ACR), and 1 patient developed recurrent hepatocellular carcinoma (HCC), but all 9 remained alive and negative for HBV surface antigen at the end of follow-up. ACR (N = 1, noncompliance) and recurrent HCC (N = 1, explant pathology showed vascular invasion) were not related to ETV use. Compared with other treatment regimens, ETV demonstrated a lower rate of clinical resistance than lamivudine (LAM) (0% vs. 12.9%, P= 0.26) and a favorable side effect profile than ADV (0% vs. 55.6%, P= 0.047).Table 1: Post-Transplant HBV TreatmentConclusion: Based on our limited experience, ETV is safe and well-tolerated in post-transplant patients. Primary prophylaxis with ETV (plus HBIG) is effective in preventing recurrent HBV allograft infection up to a median treatment follow-up of 10 months. We recommend a larger clinical trial to confirm the safety, tolerability and efficacy of ETV in post-transplant population.

The anti-HIV antiviral activity of entecavir: The loss of a trusted friend?

The HBV drug entecavir - effects on HIV-1 replication and resistance. McMahon MA, Jilek BL, Brennan TP, Shen L, Zhou Y, Wind-Rotolo M, Xing S, Bhat S, Hale B, Hegarty R, Chong CR, Liu JO, Siliciano RF, Thio CL. Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens. [Abstract reproduced by permission of N Engl J Med 2007;356:2614-2621].

The HBV Drug Entecavir — Effects on HIV-1 Replication and Resistance

Entecavir, a drug approved by the Food and Drug Administration for the treatment of chronic hepatitis B virus (HBV) infection, is not believed to inhibit replication of human immunodeficiency virus type 1 (HIV-1) at clinically relevant doses. We observed that entecavir led to a consistent 1-log(10) decrease in HIV-1 RNA in three persons with HIV-1 and HBV coinfection, and we obtained supportive in vitro evidence that entecavir is a potent partial inhibitor of HIV-1 replication. Detailed analysis showed that in one of these patients, entecavir monotherapy led to an accumulation of HIV-1 variants with the lamivudine-resistant mutation, M184V. In vitro experiments showed that M184V confers resistance to entecavir. Until more is known about HIV-1-resistance patterns and their selection by entecavir, caution is needed with the use of entecavir in persons with HIV-1 and HBV coinfection who are not receiving fully suppressive antiretroviral regimens.

Caution Regarding Use of Entecavir in HIV/HBV Coinfected Patients

The guanosine analogue entecavir effectively inhibits hepatitis B virus (HBV) replication. In a previous study, entecavir did not appear to inhibit HIV replication at concentrations achieved in vivo, and several treatment guidelines have recommended using the drug in coinfected patients who need HBV therapy but do not yet require treatment for HIV …

Hepatitis B Virus DNA Suppression with Entecavir Therapy in a HBeAg-Negative Decompensated Chronic HBV

Entecavir has not been approved for the treatment of chronic hepatitis B (HBV)-related decompensated cirrhosis. Therefore, we report the first case of successful outcome of decompensated chronic HBV-related cirrhosis with entecavir therapy. Case: A 58 year old Arab-American male with HBeAg-negative chronic HBV-related cirrhosis presented with ascites, variceal bleeding, hepatic encephalopathy, elevated transaminases and high HBV DNA level (Table). He was treated with entecavir 0.5 mg daily and had a significant reduction in HBV DNA, but maintained high bilirubin and INR with ascites. Since his clinical status did not improve (MELD Score 40) despite having significant reduction in HBV DNA with entecavir therapy, he underwent cadaveric liver transplantation. He has complicated postoperative course including intra-abdominal bleeding and a repair of anastomotic bile duct. However, with the continued use of entecavir and hepatitis B immunoglobin including other immunosuppresive agents after transplantation he maintained non-detectable HBV DNA with normalization of transaminases after 12 weeks post-transplantation.TableDiscussion: There is no data in literature on entecavir for the treatment of chronic HBV-related decompensated cirrhosis. However, entecavir is much more effective compared to lamivudine for the treatment of chronic HBV with well compensated liver disease and has no drug-related resistance after 1 year of therapy among naive patients. To the best of our knowledge, this is the first report to show the effectiveness of entecavir in suppressing HBV DNA in a chronic HBV-related decompensated cirrhotic patient with successful post-transplant outcome without having any drug-related complication. It appears that entecavir is safe to use among patients with decompensated HBV-related cirrhosis. Hence, we recommend a large randomized clinical trial of entecavir among chronic HBV patients with decompensated cirrhosis.

Entecavir: A New Treatment for Chronic Hepatitis B Infection

Hepatitis B virus can cause both acute and chronic liver disease in humans. Entecavir, a new, potent, orally administered guanosine analog for the treatment of chronic hepatitis B, has recently approved in the USA and Europe. Monotherapy with entecavir in nucleoside-naive patients has been associated with statistically superior histological improvement, greater reduction in hepatitis B virus-DNA levels, and improved normalization of alanine aminotransferase levels when compared with lamivudine. After 2 years of treatment, viral resistance to entecavir has not developed in the antiviral-naive patient population. Similar findings in terms of efficacy have also been observed in patients with lamivudine-resistant hepatitis B virus. The use of entecavir in the lamivudine-resistant patient population could lead to the development of entecavir-resistant mutants at the rate of 9% by 2 years. Entecavir is well tolerated with a good safety profile and should be considered as primary therapy for chronic hepatitis B. Entecavir may also be considered for use in the lamivudine-resistant patient at twice the dose recommended for nucleoside-naive patients, with the recognition that virologic breakthrough could develop.

Entecavir for the treatment of chronic hepatitis B virus infection

Objective: This article reviews the pharmacology/pharmacokinetics and therapeutic efficacy of entecavir, which was approved on March 29, 2005, for the management of adult patients with chronic hepatitis B virus (HBV) infection who have active viral replication and/or elevations in liver transaminases or signs of active liver disease on histologic examination. Potential drug interactions and adverse events associated with the use of entecavir are also reviewed. Methods: Relevant literature was identified through searches of MEDLINE (1996–July 2005) and BIOSIS (1993–July 2005). Search terms included, but were not limited to, entecavir, BMS-200475, hepatitis B, pharmacology, pharmacokinetics, adverse events, and therapeutic use. Further publications were identified from the reference lists of the identified articles and through correspondence with the manufacturer of entecavir. Results: Entecavir is highly selective for the HBV and inhibits all 3 steps of viral replication. Results of early studies indicated a 6% resistance potential after 48 weeks of therapy, although the potential may be higher in patients who harbor lamivudine-resistant mutants. The approved dosage in treatment-naive patients is 0.5 mg/dPO, administered on an empty stomach; in patients who have failed lamivudine therapy or are known to harbor lamivudine-resistant mutants, the approved dosage is 1.0 mg/d PO. The oral tablet and solution can be used interchangeably. Entecavir is well absorbed orally, achieving a dose-related C max between 0.6 and 1.5 hours after administration. It is metabolized to a small extent and is not a substrate for the cytochrome P450 enzyme system. The mean elimination t 1/2 ranges from 77 to 149 hours in patients with normal kidney function. Entecavir is eliminated primarily in the urine via glomerular filtration and tubular secretion (62%–73%). No dose adjustment apears to be necessary in patients with moderate to severe liver disease alone. The potential for drug interactions with entecavir appears to be minimal, although medications that inhibit tubular secretion of drugs (eg, probenecid) may be expected to prolong serum concentrations of entecavir. One of the Phase III studies of entecavir found statistically significant benefits compared with lamivudine in terms of improvements in liver histology after 48 weeks of therapy (72% vs 62%, respectively; P<0.009), the proportions of patients with undetectable HBV DNA titers on branched DNA signal amplification assay after 48 weeks of therapy (91% vs 65%; P<0.001), and the proportion with undetectable HBV DNA on polymerase chain reaction (PCR) assay after 48 weeks of therapy (69% vs 38%; P<0.001). In another Phase III study, patients who had failed to respond to lamivudine therapy responded to entecavir: after 48 weeks of therapy, significant differences between entecavir and lamivudine were seen in histologic improvement (55% vs 28%; P<0.001) and the proportion of patients with undetectable HBV DNA on PCR assay (21% vs 1%; P<0.001). Adverse events associated with entecavir therapy were similar in character, severity, and incidence to those associated with placebo or lamivudine therapy. The most common adverse events in clinical trials of entecavir were headache (17%–23% of patients), upper respiratory tract infection (18%–20%), cough (12%–15%), nasopharyngitis (9%–14%), fatigue (10%–13%), dizziness (9%), upper abdominal pain (9%–10%), and nausea (6%–8%). Conclusions: Entecavir is a new antiviral agent for the management of chronic HBV infection. Questions concerning the ideal length of therapy, long-term efficacy, and resistance rates over time await the results of ongoing clinical trials.

New Drugs: Entecavir, Ibandronate Sodium, and Pegaptanib Sodium

Agent for Hepatitis B Virus Infection Approximately 1.25 million Americans have chronic hepatitis B virus (HBV) infection. Spread via infected blood or body fluids, sexual contact, drug abuse by injection, or perinatally from mother to child, it is characterized by early symptoms such as loss of appetite, fever, aches and pains, and itching. Later symptoms include nausea, vomiting, jaundice, dark brown urine, and right-sided abdominal pain. Many patients experience a worsening of the infection, resulting in cirrhosis of the liver, liver cancer, and death. Although vaccines have been developed to provide immunization against HBV, there has been only partial success in the treatment of chronic HBV infection. The infection cannot be cured and only a limited number of treatment options are available. Interferon alfa-2b (Intron A) was the first drug to be approved for the treatment of chronic HBV infection, but its effectiveness is limited, it must be administered parenterally, and most patients experience adverse events. Lamivudine (Epivir HBV) was initially approved for the treatment of human immunodeficiency virus (HIV) infection/acquired immunodeficiency syndrome (AIDS) and, subsequently, for chronic HBV infection. It is administered orally and is better tolerated than interferon alfa-2b; however, many patients have developed resistance to its use. In 2002, adefovir dipivoxil (Hepsera) was marketed and its anti-HBV activity includes some isolates that are resistant to lamivudine. Entecavir (Baraclude— Bristol-Myers Squibb) has been recently approved for the treatment of chronic HBV infection and represents an important addition to the small group of agents that may be considered for the treatment of this infection. It is a guanosine nucleoside analogue, phosphorylated to its triphosphate form, that has activity against HBV polymerase (reverse transcriptase). Entecavir is specifically indicated for the treatment of chronic HBV infection in adults with evidence of active viral replication and either evidence of persistent elevations in serum aminotransferases (ALT or AST) or histologically active disease. In two of the clinical trials, entecavir or lamivudine was used in nucleoside-treatment-naive patients. Entecavir was determined to be superior to lamivudine on the primary efficacy endpoint of histologic improvement and on the secondary efficacy measures of reduction of viral load and ALT normalization. In a third study, entecavir was evaluated in lamivudine-refractory patients, and many patients experienced improvement with the use of the new agent. Entecavir has also been studied in patients co-infected with HBV and HIV who experienced recurrence of HBV viremia while being treated with a lamivudine-containing highly active antiretroviral treatment (HAART) regimen. Either entecavir or placebo was added to the regimen, and approximately one third of the patients receiving the new drug experienced ALT normalization compared with 8% of those receiving placebo. Unlike lamivudine and adefovir, entecavir does not appear to exhibit activity against HIV. The concurrent use of entecavir with HIV nucleoside reverse transcriptase inhibitors is not likely to reduce the efficacy of any of the antiviral agents. Entecavir was well tolerated by almost all patients in the clinical studies with only headache (4%) and fatigue (3%) being reported by more than 1% of the patients. Approximately 12% of patients experienced elevations in ALT to greater than 5 times the upper limit of normal, although the incidence of this response was lower than in the patients treated with lamivudine and the elevations generally resolved with continued treatment. Lactic acidosis and severe hepatomegaly with steatosis have been infrequently associated with the use of nucleoside analogues (e.g., reverse transcriptase inhibitors indicated for the treatment of HIV infection) and this possibility is the subject of a “black box” warning in the labeling for entecavir. Entecavir is classified in pregnancy category C and should only be used in a pregnant woman if the anticipated benefit outweighs the risk. In these situations health care providers are encouraged to register patients in a pregnancy registry by calling 800-2584263. It is not known whether entecavir is excreted in human milk, and mothers treated with the drug should be instructed not to breast-feed. The effectiveness and safety of entecavir in patients below the age of 16 years have not been established. Following oral administration, peak plasma concentrations of entecavir are attained in approximately 1 hour. Administration of the drug with a high-fat meal may delay absorption and decrease its peak concentration and bioavailability. Accordingly, it is recommended that entecavir be administered on an empty stomach at least 2 hours before or after a meal. Entecavir is metabolized to N E W D R U G S