RECENT ADVANCE IN MANAGEMENT OF CHRONIC HEPATITIS B INFECTION

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ABSTRACT

Viral Hepatitis (HBV) is one of the commonest viral infection of liver having a worldwide incidence of significance. Commonly transmitted by parental routes. The viral infection not only effects the liver it involves other organs giving rise to varied clinical presentation. The incidence of carrier state and chronic infection is high. Though many antiviral drugs have been tried safer only three drugs. Interferon - a, Lamivudine and Adefovir  are effective. The newer drug trials and other modalities of treatment are yet to be established.

INTRODUCTION 

Though the existence of a potentially transmitted form of hepatitis was documented by Lurman in 1885 the term hepatitis A & hepatitis B were introduced by Mac calluman in 1947 to categorize infectious & serum hepatitis. By 1968 other investigators notably  Pince, Okochi & Murakami had established  that Australia Antigen (Hbs Ag)  was found specifically in serum of hepatitis B patients. In 1970 Dane et al, detected the complete hepatitis B Virion, a 42 nm double shelled particle (Dane particle). After that various researchers and epidemiological study undergone for this particle till date & it was found that an estimated 350 million people world wide and around 43 million in India carry this pathogen that can lead to cirrhosis and hepatocellular carcinoma. Management of hepatitis B and its complication requires significant knowledge of pharmacotherapeutic option which are evolving rapidly . To date 3 drugs have been approved for treatment of chronic hepatitis B that are Injectable  interferon a and oral agents like lamivudine and adefovir dipivoxil. Various new drugs and immunologic modulators hold promise for treatment of chronic HBV infection and are various stages of development.

MODE OF TRANSMISSION

            Transmission of HBV can occur percutaneously, sexually, perinatally, by blood transfusion , organ transplantation and may be transmitted between high risk individuals like  health care workers, IV drug abusers, homosexuals and promiscuous heterosexuals.

GLOBAL SCENARIO

The prevalence of hepatitis B varies throughout the world. The infection is highly prevalent (affecting 8-15% of the population) in Southeast Asia, China, the Philippines, Indonesia, the Middle East, Africa, parts of South America, and Alaska. The high rates of hepatitis B transmission in these regions are primarily due to perinatal and early childhood infection. Hepatitis B infection is prevalent, affecting 2-7% of the population, in Japan, parts of South America, Eastern and Southern Europe, and parts of Central Asia. The United States, Canada, northern Europe, Australia, and the Southern part of South America have the lowest prevalence of HBV infection, with less than 2% of the population infected.

INDIAN SCENARIO

             About 43 to 45 millions are carrier state out of which 10 to 12 million people having high infectivity. Carrier rate of HBs Ag is 10.87% in Hospital staffs and 5% in general population .

CLINICAL PRESENTATION

Acute HBV infection usually follows an incubation period of 1 to 4 months. Patients then experience non-specific symptoms, such as fatigue, anorexia, nausea, and vomiting, myalgia, low-grade fever, and possible right upper quadrant or midepigastric pain. Jaundice may develop within 10 days of the onset of constitutional symptoms. Laboratory findings are significant for elevations in alanine aminotransferase (ALT), aspartate aminotransferase (AST), and prothrombin time, as well as mild leukopenia with relative lymphocytosis.

In chronic hepatitis B, patient is usually asymptomatic. Alanine Aminotransferase (ALT), Aspartate Aminotransferase (AST), elevations usually reflect the degree of hepatic inflammation. Finally the patient developed cirrhosis of liver and presents with its complication. The most devastating is hepatocellular carcinoma which poses many problem for its management and ultimately patient will die. Markers of hepatic synthesis (prothrombin time, albumin, bilirubin) can become abnormal with development of cirrhosis. Arthralgia and rashes are common presenting signs of HBV infection. Other extrahepatic manifestations are angioneurotic edema, polyarteritis nodosa with systemic vasculitis, glomerulonephritis, papular acrodermatitis, and polyneuropathies.

            The HBV is a small , enveloped virus containing partially double-standard DNA. Diagnosis of HBV infection and determination of HBV status is derived from serologic testing.

TABLE NO. 1

SEROLOGICAL AND BIOCHEMICAL PROFILES OF PATIENTS

WITH VARIOUS STAGES OF HEPATITIS B INFECTION

HBsAg = hepatitis B surface antigen; Anti-HBs = hepatitis B surface antibody; Anti-HBc-IgM = hepatitis core antibody IgM; Anti-HBc-IgG = hepatitis B core antibody IgG; HBeAg = hepatitis B e antigen; HBV = hepatitis B virus.

TREATMENT

Treatment of acute hepatitis B is supportive. Many patients can be managed without hospitalization. However, some require hospital admission, and in rare instances involving fulminant presentation, patients may require liver transplantation.

Currently, main therapeutic options available are interferon-a (IFN-a), larnivudine and recently introduced adefovir. Other new drugs, such as, entecavir, emtricitabine, and immunologic modulators, hold promise for treating chronic HBV infection and are under various stages of development.

INTERFERON - a

Interferon-a exhibits a wide spectrum of antiviral activity, and it has immunomodulating and antiproliferative properties. In hepatitis B, IFN-a works by inhibiting viral RNA pregenomic packaging into core particles and by enhancing the expression of HBsAg on hepatocytes.

Studies have shown IFN-a response to be associated with certain favourable predictive factors, notably high pretreatment ALT levels (at least 2 times the upper normal limit), low pretreatment HBV DNA levels (<100 pg/ml), adult-acquired HBV infection, female gender, and absence of human immunodeficiency virus (HIV) and hepatitis D virus (HDV) infections. The usual dosage for IFN-a is 5 MU/day or 10 MU 3 times/week for 16 weeks. Patients with decompensated liver cirrhosis, uncontrolled depression, or normal liver enzymes should not receive IFN-a.

SAFETY

A flu-like syndrome with fever (38-41°C), fatigue, malaise, headache, chills, and arthralgias can develop in up to 98% of patients within 6 hours after each dose. Since IFN-a is derived from E.coli, it can cause hypersensitivity reactions (frequency < 5%), and it has the potential to exacerbate immunologic responses, including autoimmune thyroiditis. Gastrointestinal effects include anorexia, nausea (50% of patients), and dysgeusia. Depression (6-17%) and irritability (12-16%) are among the most common central nervous system manifestations. Significant cardiovascular effects include hypotension and edema, which occur in 9% of patients. Increases in uric acid levels are seen in 15% of patients. Increased susceptibility to infection is a frequent concern with IFN-a therapy. Possible hematologic toxicities include leukopenia, thrombo-cytopenia, and normochromic, normocytic anemia.

LAMIVUDINE

A dideoxynucleoside reverse transcriptase inhibitor, Lamivudine inhibits viral DNA replication. In HBV infection, Lamivudine functions by inhibiting replication of the virus and reducing the viral load. Some evidence suggests that it may enhance T-cell responses. Lamivudine 100~mg/day suppressed HBV DNA in 96-98% of patients. When Lamivudine was discontinued, HBV DNA became detectable again in more than 80% of patients. Sustained clearance of HBV DNA and HBeAg was achieved in only 20% of patients or less. In patients who achieved seroconversion with Lamivudine, the response usually was sustained.

The best predictor of HBeAg seroconversion was ALT level. In patients whose ALT levels were at least 5 times the upper limit of normal at the start of treatment, the HBeAg seroconversion rate was 64%. In contrast, the seroconversion rate was 26% for patients with ALT levels between 2 and 5 times the upper limit of normal, and less than 5% in patients with slightly elevated to normal ALT levels. Cirrhosis and HBV DNA levels showed only borderline associations. Therefore, patients with active , chronic HBV infection benefit most from Lamivudine therapy.

SAFETY

Lamivudine is very well tolerated by most patients. Studies show that most common side effects, including malaise, fatigue, nausea, and vomiting, occur equally in placebo and Lamivudine groups. It is safe to administer in patients with decompensated liver disease, and it lacks significant drug interactions or serious side effects,

Hepatitis B Virus Resistance

Lamivudine has a serious drawback: With prolonged therapy, it may cause the emergence of a mutant, drug-resistant strain of HBV. This strain has a mutation in a nucleoside binding site designated the YMDD motif. The mutation typically emerges within 8-9 months of Lamivudine therapy; the rate of mutation correlates with the length of treatment. As the mutant strain replicates, patients develop detectable levels of HBV DNA, although HBV DNA is usually below pretreatment levels.

ADEFOVIR

Adefovir dipivoxil shows particular promise for treatment of chronic hepatitis B. It is an acyclic analogue of deoxyadenosine monophosphate (dAMP) that precludes dAMP incorporation into HBV DNA, thus inhibiting viral DNA replication. It may stimulate natural killer cells and immune responsiveness through endogenous IFN-a production.

A multicentre double-blind trial investigated the effects of Adefovir 10 mg/day and 30 mg/day versus placebo in 515 HBeAg-positive patients, again with promising results. Patients treated with Adefovir showed a mean -3.5 log₁₀ reduction of HBV DNA levels compared with those who received placebo. Moreover, 42% of patients who received Adefovir had normalized ALT levels, compared with 16% in the placebo group. Patients in the Adefovir 30-mg/day dosage arm displayed a higher frequency of mild renal abnormalities than their counterparts in the other treatment groups. No resistance emerged after 2 years of continuous Adefovir administration.

An important distinction of Adefovir is that it has demonstrated activity against Lamivudine-resistant HBV strains, both in vitro and in vivo. In a phase II trial, continuous Adefovir treatment for 24 weeks did not induce resistance. The benefits of adding Adefovir to the treatment regimen of patients previously receiving Lamivudine were assessed in a trial involving patients with hepatitis B with the YMDD mutant strain of HBV. Addition of Adefovir resulted in a median HBV DNA decrease of 3.9 log₁₀ from baseline and a median ALT decrease by a factor of 0.6 from baseline. The combination was well tolerated at 24 weeks, according to a report at 52 weeks.

Efficacy of Adefovir was also seen in patients coinfected with HIV, decompensated liver disease patients and in those awaiting or post-liver transplantation. No resistant mutants to Adefovir were reported from various ongoing trials after administration of Adefovir up to 2 years.

ENTECAVIR

             This agent shows promise for treatment of chronic Hepatitis B. In vitro trial ENTECAVIR is 30 times more  potent than Lamivudine. Entecavir given for 4 weeks produced  significant  reduction  of HBV DNA.

            No major side effects were noted except headache & fatigue. Entecavir is currently in phase III trial.

EMTRICITABINE

            The necleotide analogue emtricitabine (FTC) as been found to suppress replication of Woodchuck HBV in vivo and its efficacy was comparable to Lamivudine in animal models.

CLEVUDINE

            The agent is a potent HBV replication inhibitor in vitro. Clevudine was well tolerated by eight subjects followed for 6 weeks. These promising results emerged from the early stages of an ongoing 24 weeks phase I – III trial.

L-DEOXYTHYMIDINE

Suppression of HBV DNA appears to be dose related, with the most suppression occurring at higher dosages. No significant toxicities have been identified in woodchucks or humans. A phase Ml dose-escalation trial has shown promising results.

FAMCICLOVIR

It is guanosine nucleoside analogue that is that active against Herpes viruses but has limited activity against HBV. Famciciovir was found effective in small open -label trials. However, its benefits failed to reach statistical significance when compared with placebo in two large, phase III trials.

GANICICLOVIR

Gancidovir is an aminopurine compound active against Herpes viruses, including Cytomegalovirus and Hepadnaviruses. It competitively inhibits HBV polymerasemyelotoxicity and the modest antiviral potency of Ganciclovir may limit its use in HBV infection.

LOBUCAVIR

A guanosine nucleoside analogue, suppresses replication of both wild type and YMDD mutant HBV. Unfortunately, its long-term safety is questionable, due to potential proneoplastic properties.

IMMUNOLOGIC MODULATORS

1. Theradigm-HBV. This therapeutic vaccine consists of HBV core antigen peptide, a T-helper peptide, and two palmitic acid molecules that further enhance immunogenicity. Larger trials are necessary to determine whether theradigm-HBV holds clinical promise.

2.      Thymosin-a-1. This thymic extract stimulates cytotoxic T cell activity. The agent yielded promising results in a preliminary pilot study, but its efficacy was not supported by a larger trial. Further evaluation of thymosin -a-1 as a single agent  or in combination is warranted.

RECENT RESEARCHES

§                      Tenofovir and Lamivudine Combination Therapy for 96 week in HIV and HBV Co-infected patients effective.

§                      Pegasys study published in New England journal of Medicine. This study compares pegasys, (peginteferon alpha-2a), to Lamivudine in patients with hepatitis B antigen (HBe Ag) negative chronic hepatitis B and finds it is more effective.

Preventing Vertical Transmission of hepatitis B

Approximately 350 trillion people worldwide are chronically infected with hepatitis B virus (HBV), and over 1 million die each year.   Given the worldwide  importance of chronic  HBV,  it  is  imperative that vertical transmission , a major route of infection, be halted. Perinatal transmission of HBV results from exposure of fetal mucous membranes to infectious maternal blood or body fluids.

§         Adefovir Dipivoxil and Tenofovir are highly efficacious therapies in HBV patients with Lamivudine resistance.

§         Hbe Ag – ve chrome HBV : better response to pegy a - 2a than to LAM.

§         HBe AG – ve : 4 years treatment with LAM promising results.

PLANT DERIVED

            Mab to HBV surface Antigen may provide treatment  alternative. June 23, 2004 – Japanese scientists have successfully used transgenic tabocco cells produce the human monoclonal antibody (Mab) to hepatitis B virus (HBV) surface antigen (Hbs Ag).

HIV – HBV CO-INFECTION

            Co-infection with HBV is an increasing in patients with HIV. French pilot study published in October 1 , 2004 in clinical infectious diseases shows promising results with Tenofovir/Lamivudine combination therapy for 96 weeks , which results in sustained antiviral activity against wild type of HBV strain in HIV infected patients.

THERAPEUTIC APPROACHES IN CHILDHOOD CHRONIC HBV INFECTION

            Three forms of therapy are licensed, which are IFN - a, Lamivudie & Adefovir. Lamivudine is well tolerated upto one year with seroconversion rate of 15-20% in children however the resistant limits the benefit of monotherapy.

MANAGEMENT OF HBV TREATMENT SIDE EFFECTS

Almost everyone who uses conventional or pegy Interferon or Lamivudine or Adefovir notices side effects which are as follows:

1.      Fever : Manage by lukewarm water sponging (not by cold/hot water)

2.      Diarrhoea: Immodium or bulking agents like Metamucil or psylium bran may be given.

3.      Depression : Treat with anti-depressants.

4.      Headache: Take rest, avoid physical exertion

5.      Tooth decay & gum disease : Regular dental checkup & oral hygiene.

6.      Anxiety : Meditation to avoid.

7.      Weight Loss: Foods with high calories to be taken

8.      Drink pleanty of fluids like (water, fruit juices before and after injection of INF.)

PREVENTION