EntecavirINTRODUCTION

Approximately two billion people have serologic evidence of hepatitis B virus (HBV) infection, and almost 350 million individuals worldwide are chronic carriers of the virus. In the U.S. alone, approximately 1 million individuals have chronic HBV infection.

HBV infection remains endemic in many areas throughout the world, including Africa, Eastern Europe, Central Asia, China, Southeast Asia, the Pacific Islands, the Middle East, and the Amazon basin of South America. Yet certain developing countries continue to have only limited resources and lack appropriate treatment regimens against this infection. Consequently, health care costs continue to escalate with diminishing quality of life in patients afflicted with this chronic, debilitating disease. buy levitra uk

HBV belongs to the family of hepad-naviruses and is considered a small, enveloped, partially double-stranded DNA virus. Following viral exposure, the HBV incubation period may vary anywhere from six weeks to six months.

HBV can be acquired in several ways (e.g., sexual contact, instruments, percutaneous or mucosal exposure to blood or body fluids of an infected person not immune to HBV). Table 1 lists the various modes of transmission, Higher concentrations of HBV have been found in the blood, in comparison with lower concentrations identified in other body fluids (e.g., vaginal secretions, semen, sweat, and tears). Adults 18 to 39 years of age tend be at high risk for the development of HBV infection because of specific behavioral practices.

Table 1   Modes of Hepatitis B Virus (HBV) Transmission

Perinatal transmission High infection rate among infants born to
HBeAg-positive mothers; can be acquired in utero,
during birth, or after birth.
Horizontal transmission Children may acquire HBV infection via minor cuts on
the skin or the mucous membranes of other infected
children.
Sexual transmission A major mode of transmission, especially with
homosexual activity.
Percutaneous inoculation Examples include intravenous drug users sharing
needles or syringes with infected persons and
household contacts sharing toothbrushes and razors.
Tattooing, body piercing, and acupuncture have also
been associated with HBV transmission.
Nosocomial infection HBV is the most common blood-borne virus in the
health care setting; it can be spread from patient to
patient or through contaminated instruments and
needlestick accidents.
Organ transplantation HBV infection has been reported after extrahepatic
transplantation.

The diagnosis of HBV infection is made on the basis of clinical evidence and serologic testing. Serologic markers can indicate when the infection is acute or chronic, whether the person has been immunized, or whether the infection has been resolved. Table 2 lists serologic markers for HBV infection. buy antibiotics canada

Acute cases reveal immunoglobulin M (IgM) antibody-positive against hepatitis B core antigen (IgM anti-HBc). Hepatitis B surface antigen (HBsAg) may be present in either acute or chronic cases of infection. Antibodies to HBsAg (anti-HBsAg) are produced upon resolution of infection or following immunization.

Table 2 Serologic Markers for Hepatitis B Virus (HBV) Infection

HBsAg    Anti-HBs    IgM Anti-HBc

IgG Anti-HBc

HBeAg     Anti-HBe

HBV-DNA
Acute +              –                  + +-

+

Chronic
HBeAg+ +              –                  –

+

+-

+

HBeAg- +-                   –

+

-+

+

Immunized -+                   –

Resolved infection -+                   –

+

-+

anti-HBe = hepatitis B envelope antibody; anti-HBs = hepatitis B surface antibody; HBeAg = hepatitis B envelope antigen; HBsAg = hepatitis B surface antigen; Ig = immunoglobulin; IgM anti-HBc = hepatitis B core antibody IgM; IgG anti-HBc = hepatitis B core antibody IgG.Modified from Centers for Disease Control and Prevention. Sexually Transmitted Diseases Treatment Guidelines, 2002: Recommendations and Reports. MMWR Morb MortalWkly Rep 2002;I0;5l(RR-6):62.

Primary HBV infections can be self-limiting, and they usually resolve. However, HBV can develop into a persistent form, progressing to a chronic state, which can lead to serious sequelae, including chronic liver disease, hepatic decompensation, cirrhosis, hepatocellu-lar carcinoma, extrahepatic manifestations, and death. Table 3 lists the clinical manifestations of HBV infection (see page 315).

Three regimens have been approved by the Food and Drug Administration (FDA) for the treatment of chronic HBV infection: interferon alfa-2b (Intron A, Schering), lamivudine (3TC, GlaxoSmithKline), and adefovir dipivoxil (Hepsera, Gilead). Table 4 compares the current regimens (see page 316).

Table 3 Clinical Manifestations of Hepatitis B Virus (HBV) Infection

Acute Infection

Chronic Infection

• Fatigue • HBsAg-positive for more than six months
• Anorexia • Arthralgia
• Nausea and vomiting • Rash
• Myalgia • Elevated ALT/AST
•     Low-grade fever•     Right upper-quadrant pain

•     Elevated ALT/AST, PT

•     Jaundice

• Scleral icterus

•   PT, albumin, and bilirubin typically within normal ranges;however, with progression to cirrhosis, values change significantly•   Persistent mild hepatomegaly and splenomegaly may be observed
• Dark urine
• Light-colored stools
• Pruritus
• “Serum sickness-like syndrome” (fever, rash, arthritis)
Acute phase: Manifestations range from subclinical or anicteric to icteric hepatitis and, in some cases, to fulminate hepatitis.Chronic phase: Manifestations range from an asymptomatic carrier state to chronic hepatitis to development of cirrhosis and hepatocellular carcinoma.

Acute or chronic HBV infection: Extrahepatic manifestations may arise during either phase.

ALT = alanine transaminase; AST = aspartamine transaminase; HBsAg = hepatitis B surface antigen; PT = prothrombin time.

Adverse drug events (ADEs) and viral resistance are vital components when one is differentiating between the various regimens. Additional considerations include an evaluation and screening of possible co-infection with human immunodeficiency virus (HIV), hepatitis C virus (HCV) or hepatitis D virus (HDV), illnesses that are increasing drastically, thus warranting alternative treatment approaches.

In March 2005, the FDA approved entecavir (Baraclude, Bristol-Myers Squibb), a nucleoside analogue that demonstrates selective activity against HBV. As with any treatment against chronic HBV, the goals of therapy include decreasing active liver inflammation by correcting serologic parameters and liver enzymes in hepatitis, stopping the progression of hepatitis to cirrhosis, preventing hepatocellular carcinoma, and improving the patient’s quality of life by prolonging survival.

INDICATION AND USAGE

Entecavir is indicated for adults with chronic HBV who have evidence of viral replication and persistent elevations in serum aminotransferases (ALT, AST) or active disease based on histologic findings. Entecavir is approved for patients with HBeAg-positive, HBeAg-negative, and lamivudine-resistant infection.

Table 4 Comparison of Therapies for Patients with Chronititis B Virus (HBV) Infection

Interferon alfa-2b (Intron-A,Schering) Lamivudine (GlaxoSmithKline) Adefovir Dipivoxil (Hepsera, Gilead)
Effect and mechanism of action Effects on HBV infection only:•    Immunomodulatory effects

•    Direct antiviral effects

•      Inhibition of viral RNA

• Pre-genomic packing in core

•      Particles and enhancement

• Expression of HBsAg on hepatocytes

• Analogue of nucleoside cytosine• Intracellular conversion to 3TC-TP (the active form)

• Incorporation into DNA during replication causes disruption

in chain

•   Nucleotide analogue of adenosine monophosphate•   Phosphorylated to adefovir diphosphate (the active form)

•   Inhibits viral DNA

Adult dose 5 MU q.d.or 10 MU t.i.w.SQolder than i year of age 100 mg PO q.d. i0 mg PO q.d.
Pediatric dose 6 MU/m2 t.i.w. (maximum, 10 MU) 3 mg/kg per day (maximum,i00 mg/day) Not established
Dosage adjustments None, but use caution in severe renal impairment Renal Renal
Route SQ injection Oral Oral
Adverse events Multiple effects*• Flu-like syndrome;fever chills, headache, and myalgias (especially when beginning treatment;early onset)

• Granulocytopenia, thrombocytopenia, anemia

•     Depression, psychosis

•     Anorexia, alopecia

•     Hyperglycemia

•     Hyperlipidemia (TG)

•     SIADH

•     Thyroid dysfunction

Well tolerated•      Headache

•      Fatigue

•      Nausea

•      Abdominal discomfort

Well tolerated•      Nephrotoxicity

•      Hypophosphatemia

Resistance None Increasing Less incidence;increasing
Monitoring •   Liver enzymes• HBsAg and HBeAg at end of therapy;three and six months after treatment

•   HBV-DNA in selected patients

•   Liver biopsy when applicable

•   CBC and platelets

•   Quality-of-life assessment

•   Liver enzymes• HBV-DNA regularly during therapy and several months after therapy ends

• Check hepatitis antigen and antibody periodically

• Body weight, vital signs, chest x-ray, appetite

•   Quality-of-life assessment

•   Liver enzymes•   Hepatitis B antibody and antigen

•   Quality-of-life assessment

Cost $$$ $ $$$
* Many precautions for use.CBC = complete blood count; HBeAg = hepatitis B envelope antigen; HBsAg = hepatitis B surface antigen; MU = million units; q.d. = once daily; SIADH = syndrome of inappropriate antidiuretic hormone (secretion); SQ = subcutaneous;TG = triglycerides; t.i.w. = three times per week; 3TC-TP = lamivudine triphosphate.

Data from Lok ASF, McMahon BJ. Hepatology 2001(34):1224-1241; 2004(39):i-S;2-3 and Micromedex Healthcare Series. Drugdex Evaluations. Thomson Micromedex 1974-2005.

CLINICAL PHARMACOLOGY

Entecavir is an oral analogue of 2′-de-oxyguanosine. Following phosphory-lation to its active triphosphate form via enzymatic pathways, entecavir is a potent inhibitor of HBV replication. Inhibition of HBV viral production occurs through three mechanisms:

  • priming of HBV-DNA polymerase
  • reverse transcription of the negative strand from the pre-genomic RNA
  • synthesis of the positive DNA strand
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Entecavir also has a weak inhibitory action against DNA polymerases alpha, beta, and delta and mitochondrial DNA polymerase gamma. The net effect of entecavir is thus a reduction in the viral load and prevention of disease progression in infected patients.