3

Acute hepatitis can not be labeled as acute viral hepatitis until an appropriate viral marker is identified. (Table for markers has been included in the section on management of Ac Hepatitis). These must be ordered.

Incidenc of different Viruses.

Overwhelming majority is A & E.In Children it is A which is common and in adults it is E which is common. So first these two shall be tested. If these are negative then HBsAG shall be tested. If HBsAg is negative along with IgM for HAV and HBV then anticore antibodies shall be ordered to rule out window period in Hepatitis B Acute infection.

Window Period.

Sometimes immune system of body is so aggressive that by the time jaundice appears due to damaged hepatocytes, virus has already been cleared from the body. So HBsAg will be negative.e antigen will also be negative. Antibodies against surface antigen and against e antigen appear late. So then acute phase can only be ascribed to HBV if anticore antibodies are positive.

Think of HCV or other viruses only when all above-mentioned markers are negative. AntiHCV antibodies will appear late. PCR for HCV becomes positive withen one week of infection. So this can be ordered to confirm that acute Hepatitis is due to HCV.Acute phase in C is very rare. D virus can be suspected under circumstances where acute on chronic situation in Hepatitis B is suspected. Ig M for D virus can be ordered.

Monitoring of Acute Hepatits against Acute Liver Failure.

Enzyme levels and colour of sclera are not good indicators for prognosis. It is only the Prothrombin Time, which co-relates best with the progress of liver damage. It is affacted at the earliest even before the enzymes are raised. It progresses with the damage. If it keeps on increasing then this is a very poor prognostic indicator inspite of apparently good clinical presentation. To combat the differences in figures of different laboratories, a new parameter or let us say a new way of calculating prothrombin time is now in use. This is the term of

INR = International Normalised Ratio = Actual time divided by the control time of the same Laboratory.

Intervals for repeating investigations.

Enzymes and prothrombin time should be repeated at 1 week, 2 weeks, and 4 weeks and then at 3-6 months.

Vomiting in Acute Hepatitis.

Bilirubin is a very strong stimulant for vomiting centre. So vomiting is always central in origin. As such there is no role of antiacid treatment. Only if some gasteritis is suspected due to some other cause, then these can be uses. Antiemetics can be used. Dextrose 5% infusion can be used.

Chronic Hepatitis.

Symtoms originate from disturbed liver function, obstruction in portal circulation and immune disturbances due to chronic infection. These have been covered in previous interview and journal. Extrahepatic manifestations are more frequent in hepatitis B.This may be due to 3 antigens body is dealing with rather than one as in all other viral infections.

Specific Treatment of Chronic Viral hepatitis.

It is combination therapy of antivirals and Interferon.

Contraindications of Interferon.

Age: 18-60 years in westren world is the limit. It is always relative contraindication. It is being used in children to prevent chronic phase. Older people are also using it, with established Cirrhosis of liver, just to prevent hepatocellular carcinoma.

Diseases.

• Assess life expectancy based upon any concurrent disease.

• Diabetes Mellitus is a relative contraindication.

• Autoimmune diseases like thyroiditis are absolute contraindications. TSH, T3 and T4 must be ordered before initiating interferon. ANA, ANF and other relevant immunological investigation can be done.

• Depression is another absolute contraindication. As this is a frequent side effect. Suicides are on record after use of interferon.

• Neutropenia and thrombocytopenia are also absolute contraindications, unless treated completely.

• Compensation level of Cirrhosis.This must be considered. How much damage has been already done? This can not be reversed. Although it can be used to prevent hepatocellular carcinoma.

Following 3 parameters assesses liver Compensation.

1. Albumin level

2. Platelet counts.

3. Total Bilirubin

Viral Load

Higher the load, greater is going to be the response.

Usually interferon is started at 3.5 million copies.

Genotyping.

Type 2 and 3 respond better than other types. In Pakistan majority of infections fall withen these two types. Other types are not contraindicated. But these require higher doses and for longer duration of period.

ALT Levels

Higher the levels, better is the response. Patients with normal ALT levels respond very poorly to interferon.

Liver Biopsy

Moderate to severe changes in biopsy are a poor prognostic sign. Still it can be used to prevent further damage and to prevent carcinoma.

Monitoring of Interferon Therapy.

Mainly 3 parameters are checked to see the efficacy and to rule out threatening side effects.

• Platelet counts.

• Neutrophil count

• Enzymes.

These shall be repeated at week 1,week 2 and week 4 initially. PCR shall be repeated after 4 weeks. After 4^th week these can be repeated after 3 months.

If platelet and neutrophil count falls rapidly then stop interferon temporarily. Give some rest. Then start after 2 weeks in lower doses.

Chapter One Available Viral Markers

(Please refer to panel interview for brief summary of structure of Hep B Virus)

Marker (How to order)	Class	For Virus	Shows	Shall be followed by
Ig.M.(AntiHAV IgM) Ig G(AntiHAV Ig G)	Antibody Antibody	A A	Acute infection Life long immunity
HBsAg	Antigen present on the outer wall of Virus B	B	Infection	HBV DNA PCR or E antigen.
HBeAg HBcAg	Part of the Core Of Virus B Antigen	B B	Shows replication of virus Never appears in blood.	HBV DNA PCR for Load Never tested.
IgM anticore antibodies(Anti HBe Ig M) AntiHBc Ig G. Ig G antisurface (AntiHBs) Anti e antibodies	Antibodies against the core antigen These appear when HBsAg disappears. (Anti HBe)	B Immunity against HBV HBV	Even in the absence of HBsAg and Negative PCR for DNA, high titers show acute infection due to HBV. Appears after e antigen dispappears.	Infection is eradicated.Manage.hepatic failure only. Successful vaccination or immunity. Immunity.Seroconversion
AntiHCV	Antibodies against HCV	C	Exposure only to HCV.It is positive in 90 % of HCV infect.65-80 % of positive shall be positive for HCV PCR	HCV PCR. If interferon therapy is planned. Genotyping and load also. (CBC,Platelet )
IgM for Hep E Virus	Antibody against E Virus.	E	Shows acute infection	Essential in pregnancy.
PCR	Polymerase chain reaction	A,B,C,D,E,F	Shows active infection	Determine the load and genotyping.
Alpha Fetoprotien	Tumour Marker	For Carcinoma	Marker for hepatocellular Carcinoma.	Positive in 85 % cases of carcinoma.

Characteristics of Common Viruses

Virus Type	A	B	C	D	E
Family.	Picorna- Viridae	Hepadna- Viridae	Flavi- Viridae	Delta- Viridae.	Caci- Viridae.
Nucleic Acid	RNA	DNA	RNA	RNA	RNA
Mean Incubation period(Days)	30 (15-50 )	80 (28-160)	50 (14-160 )	Variable	40 (15-45 )
Immunity	Life long *	If cured comletely then long lasting.	If cured then long lasting	Yes	yes
Chronic Infection	N0	Yes 10-15 %	Yes 80 %	Yes	No

*10 –15 % cases of Hepatitis A have prolonged or relapsing symptoms over 6-9 months.

Transmission of All viruses.

Virus Type	A	B	C	D	E
Orofaecal	Yes	Possible	No	No	Yes
Sexual	Yes	Yes	Rare	Yes	No
Blood	Rare	Yes	Yes	Yes	No
Perinatal & Skin to Skin	No No	Yes Yes	Rare (5 %) ?	Yes Yes	No No

Transmission of Hepatitis A Orofaecal route does not have to be reminded in Pakistan.It is the sexual route, especially in homosexuals, which needs to be emphasized. All sexual partners are at risk. Paradoxically safe sex has increased the sexual transmission. Probably due to handling of soiled condomes.

It is very resistent to environmental degradation. Infectivity is reduced only to 80 % if stored for 16 weeks below 4 degree C.At room temperature it can survive for months. Virus is excreted in faeces two weeks before symtoms and 1 week after the symptoms when further excretion is stopped by appearance of antibodies in the faeces. Virus also appears in the blood in last week of this period.

Transmission of Hepatitis B in different Zones

It depends on the percentage of the population affacted (endemicity) in the area. Dominant route is different in low, intermediate and high endemic areas. Pakistan has been placed in the area of high to intermediate endemicity zone. In much of the developing world, (sub-Saharan Africa, most of Asia, and the Pacific), most people become infected with HBV during childhood, and 8% to 10% of people in the general population become chronically infected. In these regions liver cancer caused by HBV figures among the first three causes death by cancer in men.

Young children who become infected with HBV are the most likely to develop chronic infection. About 90% of infants infected during the first year of life and 30% to 50% of children infected between 1 to 4 years of age develop chronic infection. The risk of death from HBV-related liver cancer or cirrhosis is approximately 25% for persons who become chronically infected during childhood.

Perinatal Transmission

This is one of the most efficient and serious modes of HBV transmission. Transmission occurs from mothers who ar positive for surface antigen HbsAg and the hepatitis B ‘e’ antigen (HBeAg). 90 % of these women are chronic carriers for HBV.70 – 90 % chance of transmission to infants. Almost all of these become chronic carrier themselves. Women suffering from acute infections may also transmit infection to newborn.

Transmission from Chid to Child. Horizontal Transmission.

It is also one of the most serious and efficient modes of HBV transmission. It is responsible for the majority of HBV infection and carriers. Skin lesions such as imptigo, Scabies, Abrasions, and infected insect bites play an important role. Although relative importance has not be determined. These lesions provide a route for the virus to leave the body of infectitious children and a route into the body of susceptible children with whom they have skin to skin contact such as playing together or sharing the same furniture.

Different Zones and associated transmission of Hep B

Zones	Carrier rate in population	Exposure of Population to Hep B shown by serology	Major route of transmission	Availability of Vaccination Efficacy of vaccination= 95 %
High endemicity (Pakistan)	10-15 %	50-95 %	Perinatal. Skin to Skin. Lack of sterlization.	99.5 % population Can not afford. Incidence is rising.
Low Endemicity (Western World)	2-5 %	30-50 %	Sexual activities and i/v drug use in young adulthood	Free availability to all. Eradication is approaching

Pregnancy and Lactation versus Viral Hepatitis.

HEV is notorious regarding pregnancy. It is more common than HAV in adults. So in pregnant women it is supposed to be more prevalent than HAV.Mortality is greater with Hepatitis E in pregnancy than with other viruses, especially in third trimester. Positive Ig M for HEV can label acute hepatitis as E .It may sensitize physicians towards extra nursing care considering the higher mortality rate in this type of hepatitis. There is no specific treatment available against E.Even Immunoglobulin is protective. From rarer causes of Hepatitis, D virus needs separate mention, as it is not covered in following table. It follows all features of Hepatitis B.

Featurs	Hepatitis C	Hepatitis B
Transmission Blood or its products. Transfusion. I/V and parenteral routes. Sexual Route	Yes.Major transmission route. Take perfect measures against transmission. Yes. In monogamous couples, risk of transmission to healthy partner is negligible. They do not need any precaustion. Persons with multiple partners shall adopt safe sex measures against the possibility of transmission.	Yes.Along with veritcal and skin to skin contact this is still a major route. Take all possible measures. Yes. HBeAg positive person can transmit it to the other partner. Adopt safe sex.
Vertical Transmission	Very Rare.Less than 5 %.Only in mothers with high levels of viraemia	Mothers with HBeAg positive or HBV PCR positive almost certainly transmit it to babies.90 % rate. All of these become carriers for life.25-30 % develop Cirrhosis and/or Carcinoma.
Pregnancy	Not contraindicated.	Couples shall have informed choice.
Mode of Delivery	Does not influence transmission.	Does not influence transmission.
Breast Feeding	Allowed.	Not allowed
IVF	Insufficient data	Same.
Screening	All pregnant mothers. All babies born to anti HCV positive mothers at 5 years.	All pregnant mothers. All babies born to HBeAg mothers.
Diagnosis	All AntiHCV positive patients should repeat Anti HCV with latest Eliza 3 or 4 technique. All such positive persons shall have HCV PCR.This will diagnose acute as well as chronic hepatits C patients. Patients with negative PCR are totally cured. No risk.	All HBsAg positive patients shall have HBeAg and/or HBV PCR.If positive, only then these are infectious and need further management.
Vaccination.	No vaccination present	All infants shall be vaccinated on first day of life irrespective of the status of the mother. Total three doses at intervals of one month. Dose 10 units. All family members of HBeAg positive mother shall have HBsAg.All negative persons shall be vaccinated by the same schedule. Adult Dose = 20 units.
Immuno-globulin	Not available	Shall be given to all newborns to HBeAg. (Expensive). In addition to vaccine.
Treatment during pregnancy	Ribavirin is teratogenic.Contraindicated.Patiets already on ribavirin shall protect against pregnancy untill 6 months after stopping the treatment. Use of Interferon is controversial. Patients already on it can continue it. Growth of baby can be affacted.	Same about interferon. Lamivudine can be with held.
Risk to the Molhters	No additional risk due to pregnancy.	Same
Risk to infants.	Abortions Premature labour Intrauterine demise (IUD) No foetal anomalies.	Abortions Premature Labour. IUD. No Foetal anomalies.
Prognosis of Hepatitis affacted by Prenancy.	No	No

Advice about pregnancy in our society shall be given with a humate attitude. Careless wording, overenthiusiatic pressing of the point may ruin the life of partner women from Hep B.Whole family of husband and all other concerned may not be sympathetic to the patient. At the most what can happen is the transmission to the neonate. Immunoglobulin plus vaccination at birth can block this. Actual problem remains of management of the patient herself.

Management of Acute Hepatitis

1. Find a virus for each case. Essential.

2. Monitor with Prothrombin time for prognosis.

.

Two important aspects.

Acute Viral Hepatitis can be labelled for different viruses using following table.

Virus	Marker	Becomes Positive
A	Ig M for the given virus	During incubation period
B	HBsAg Ig M anticore antibodies	During incubation period If HBsAg is negative.(To cover the window period)
C	AntiHCV HCV PCR	6 weeks to 6 months 1 week
D	Ig M for this virus Always include HBsAg	During incubation period. (It can not survive without HBV infection)
E	Ig M for E	During incubation period.

Virus	Period of Infectivity
A	2 weeks before and one week after juandice appear.
B	2 weeks before jaundice appears, until HBsAg becomes negative.
C	One week after exposure to till HCV PCR is –Ve.
E	Incubation Period.2-9 weeks.

Other biochemical or haematological abnormalities seen in acute hepatitis

• Leucopenia is common (<5×109/l in 10% of patients)

• Anaemia and thrombocytopenia

• Immunoglobulin titres may be raised

Acute Liver Failure (Onset of encephalopathy 8 weeks after symtoms or 2 weeks after the onset of jaundice) Early recognition with the help of prothrombin time and immediate admission in ICU can avert almost all the mortality attached with Acute hepatitis. In all pregnant patients Ig M for E virus shall be immediately ordred so that high-risk patients can be given proper nursing care.

Chronic Viral Hepatitis

Important Aspects.

• Essentials of diagnosis

• Differential Diagnosis

• Tools of Diagnosis/monitoring of therapy.

• Specific Antiviral Therapy

Differential Diagnosis

• Alcohalic Liver Disease.

• Autoimmune Hepatitis.

• Drugs induced hepatitis

• Any Systemic Disease.

• Hemochromotosis.

• Wilson’s Disease

Interferon

• Used after ruling out contraindications.

• 70 % patients tolerate inspite of side effects.15 % have no side effects.15 % discontinue due to side effects.

• Dose varies very widely patient to patient, virus to virus, physician to physician. It is 3 to 10 millions on alternate days or even daily for 6-12 monhts.

• Interferons of longer duration are expected in the market soon.

Essentials of Diagnosis.

• PCR for the virus must be positive.

• Inflammatory changes in the liver for more than 6 months.

(Shown by Liver Biopsy, USG, or History of rise in liver enzymes).

• Rule out any other chronic liver disease

Tools for Diagnosis and monitoring

Of Therapies.

• Ultrasonograpy picks up cirrhotic changes very late.when USG is positive cirrhosis is quite advanced.

• Liver Enzymes can not quantifiy cirrhosis.

• Liver Biospy is the only reliable method to quantify the changes.

• Viral clearance is certain if PCR is negative one year after stopping the therapy.

• Bilirubin, Albumin, platelet count, and prothrombin time estimate liver function.

• Interferon/Ribavirin therapy is monitored by clinical symptoms (for side effects), and estimating Hb, TLC, DLC and platelet count at intervals of 0,1,2,4, 12 weeks. Then at the end of therapy.

Ribavirin therapy is monitored by estimating Hb, TLC, DLC and platelet count at 0,1,2,4 12 weeks.

• Lamivudine is specific antiviral agent being used for Hep B in doses of 100 mgs daily. Well tolerated.

• Ribavirin is used for Hep C.Severe Anaemia is the main side effect.

• It is almost certain that new and more effective therapies are going to emerge withen few years. You may elect to wait.

Chapter Two Hepatitis D, E, F and G Viruses.

Hepatitis D Virus.

It is an incomplete circular RNA virus. It can exist only in the presence of HBV.It needs outer covering from HBV provided by HBsAg.Without this it can not replicate.

It is transmitted along the same routes as HBV.Blood contact; sexual trasmission and vertical routes, all have been documented. It can produce co-infection with HBV if transmitted together. It produces a self-limiting acute hepatitis. If it is superadded to already existing chronic Hepatitis B, it can induce rapidly progressing worsening of chronic hepatitis B.It shall always come in mind when a stable patient of ch. Hep B starts going rapidly downhill.

Ig M antibodies can detect acute infection. PCR for HDV also is available.

Interferon has been shown to be only marginally effective if used in higher doses.

Vaccine is available for people who are at risk. For example patients suffering from Ch Hep B or C.People who are at risk of receiving blood or blood products, unscreened for this virus can also be vaccinated.

Hepatitis E Virus.

Hepatitis E virus (HEV), the major etiologic agent of enterically transmitted non-A, non-B hepatitis worldwide, is a spherical, non-enveloped, single stranded RNA virus that is approximately 32 to 34 nm in diameter.

• Transmitted by orofaecal and sexual routes.

• Produces an acute self limiting illness similar to hepatitis A.

• Common in developing world only. In adults it is more common than Hep A.

• High mortality in third trimester of pregnancy.

• Incubation period is two to nine weeks.

• HEV PCR is available for diagnosis. Although Ig M antibodies can also detect acute infection.

• Immunoglobulin has no role in protection. No effective treatment exists.

• No vaccination is available for this.

Hepatitis F Virus.

Only few cases have been defined in France.Different characteristics are being defined.

Hepatitis G Virus (HGV) or TT Virus.

It was first defined in the serum of a 34 years old surgeon, Mr GB, who was suffering from hepatitis. From his serum it is still being transmitted in monkeys over many years. It is an RNA virus from the family of Flaviridae.It shares many RNA sequances with Hep C virus.

In routine screening of population it is more common than Hep C.It is detected in 1.6 % of population screened. Hepatitis C is present only in 1 % of population. It is yet to be ascertained that what type of illness it is producing. Uptill now even this is not sure whether it can replicate in liver cells. Its detection may be a co-incidence only or it may be causing some other illness. It is detected in 0.3 % of community acquired Hepatitis.In 2 % of all blood transfusion transmitted cases where no other causitive agent is isolated, this is detected.

It can survive for years. RNA can be detected by PCR over many years. When it is cleared from serum only then antibodies against this virus appear in the serum. No important chronic sequellae have been ascribed to it.

Immediae Protection to the Contacts

Immunoglobulin is highly effective in rendering immediate protection against the infection.90 % of the contacts using immunoglobulin are protected against the possibility of infection due to present contact. It shall be combined with active vaccination against A and B where appropriate. Immonoglobulin has no negative effect on development of immunity. Immunoglobulin is effective if used 2 weeks or withen one week of exposure.

Chapter Three Chronic viral hepatitis

Important considerations.

• Exclude other Liver diseases by following investigation.

1. Serum Ferritin levels, Autoantibodies/Immunoglobulins & serology for viruses.

• Diagnosis. (Incidental detection of abnormal liver function or viral marker, symtoms of impaired liver function and complication of cirrhsis of Liver). Covered in last issue.

• Assessment of Liver damage. (T.Bilirubin level. Albumin, Prothrombin time, Liver Biopsy and ultrasound examination of liver and abdomen). Covered in last issue.

• Assessment of whether to give or not to give Interferon. (Discussed under the management of HBsAG Positive and AntiHCV positive patients.)

• Management of complications of impaired liver function and Cirrhosis of Liver.Discussed in last issue

• Screening and then appropriate advice to contacts.

Chapter Four. Chronic Hepatitis B

Natural Features of Hepatitis B Virus.

HBV is a double-stranded DNA virus .The HBV genome has four genes: with specific messages.pol, encodes for the viral DNA-polymerase env, for envelope protein pre-core, pre-core protein (which is processed to viral capsid) and X, that respectively encodes protein X. The function of protein X is not clear but it may be involved in the activation of host cell genes and the development of cancer.

Factors influencing the disease

• Out come is different according to the age at which infection occurs.

• Young children rarely develop symptomatic infection with jaundice but 25 % of children infected below the age of 7 will become carriers. Younger the child more likelihood of this.

• After the age of 7 children exhibit the pattern of adults.5 to 10 % becoming carriers.

So practical implication is this. If children are vaccinated before the age of seven, or more appropriatley withen 48 hours after birth, and even if duration of protection (of vaccine against infection) is seven years Children will be protected in most vulnerable period against infection and so major reduction in HBV transmission.

Natural Course of disease.

1. An infected person may die of fulminant hepatitis withen days or weeks of clinical onset of disease.

2. He may recover after syptomatic or asymptomatic acute infection with life long immunity.

3. He may develop a chronic carrier state, a persistent infection that usually lasts for life, without any long-term implications other than posing a threat to others.

4. Chronic viral Hepatitis.Immune recognization of virus leading to an effort to clear the virus. Persistent immune process leads to ongoing necroinflammatory changes throughout liver. Immune system usually fails to clear the virus but may continue slow damage untill whole liver is consumed.

5. From here patient may further progress to Cirrhosis of liver or carcinoma. Primary Liver cancer caused by HBV infection is one of the top three causes of cancer death in much of Africa, Asia, and the pacific Basin.Hepatocellular carcinoma may appear before the Cirrhosis.Alpha fetoprotien picks up 85 % of the cases.

Age at the time of infection is major factor in determining

The outcome of HBV infection.

Pancreatitis, Myocarditis etc.accompanying Hepatitis.

Rarely, patients with acute hepatitis B infection present with acute pancreatitis. Up to 30% of patients have raised amylase activity, and postmortem examinations in-patients with fulminant hepatitis B show histological changes of pancreatitis in up to 50%. Myocarditis, pericarditis, pleural effusion, aplastic anaemia, encephalitis, and polyneuritis have all been reported in-patients with hepatitis.

Phases of infection with hepatitis B virus.

Replicative/Non Replicative Phases.

Chronic infection with HBV can be either "replicative" or "non-replicative." Only HBV DNA PCR or detection of e antigen (HBeAg) can decide whether virus is replicating or not.

• If it is not replicating specific antiviral treatment and Interferon shall be withheld irrespective of liver enzymes or liver biospy or ultrasound examination. HBsAg and HBV DNA PCR is to be repeated if enzymes go up.

• Patients with chronic hepatitis B and "replicative" infection defined by the presence of detectable HBeAg have a generally worse prognosis and a greater chance of developing cirrhosis and/or hepatocellular carcinoma than those without HBeAg develop. In rare strains of HBV with mutations in the pre-core gene, "replicative" infection can occur in the absence of detectable serum HBeAg.

Chronic hepatitis B virus infection can be thought of as occurring in phases dependent on the degree of immune response to the virus. If a person is infected when the immune response is "immature," there is little or no response to the hepatitis B virus. The concentrations of hepatitis B viral DNA in serum are very high; the hepatocytes contain abundant viral particles (surface antigen and core antigen. Liver Biospy showing glassy appearance of cells,) but little or no ongoing hepatocyte death is seen on liver biopsy because of the defective immune response. Over some years the degree of immune recognition usually increases. At this stage the concentration of viral DNA tends to fall and liver biopsy shows increasing inflammation in the liver. Two outcomes are then possible, either the immune response is adequate or the virus is inactivated and removed from the system or the attempt at removal results in extensive fibrosis, distortion of the normal liver architecture, and eventually death from the complications of cirrhosis.

Assessment of chronic hepatitis B infection.

Patients positive for hepatitis B surface antigen with no evidence of viral replication, normal liver enzyme activity, and normal appearance on liver ultrasonography require no further investigation. Such patients have a low risk of developing symptomatic liver disease or hepatocellular carcinoma. Reactivation of B virus replication can occur, and patients should therefore have yearly serological and liver enzyme tests.

. Patients with repeatedly normal alanine transaminase activity and high concentrations of viral DNA are extremely unlikely to have advanced liver disease, and biopsy is not always required at this stage.

Treatmentof Chronic Hepatitis B.

Interferon alfa

This remains the mainstay of treatment. The optimal dose and duration of interferon for hepatitis B is somewhat contentious, but most clinicians use 5 million units three times a week for four to six months. Overall, the probability of response (that is, stopping viral replication) to interferon therapy is around 40%. Few patients lose all markers of infection with hepatitis B, and surface antigen usually remains in the serum. Successful treatment with interferon produces a sustained improvement in liver histology and reduces the risk of developing end stage liver disease. The risk of hepatocellular carcinoma is also probably reduced but is not abolished in those who remain positive for hepatitis B surface antigen.

Lamivudine

It is a nucleoside analogue that is a potent inhibitor of hepatitis B viral DNA

Replication. It has a good safety profile and has been widely tested in-patients with chronic hepatitis B virus infection. In long term trials almost all treated patients showed prompt and sustained inhibition of viral DNA replication, with about 17% becoming e antigen negative when treatment was continued for 12 months. There was an associated improvement of inflammation and a reduction in progression of fibrosis on liver biopsy. Side effects are generally mild. Combination therapy with interferon and lamivudine has been found recently to have additional benefit. Dose is usually between 25 mgs to 100 mgs /day. Duration depends upon the response of the patient.

ADVERSE DRUG REACTIONS Occasional: headache, nausea, diarrhea, abdominal pain and insomnia. Rare cases of lactic Acidosis. No clinically pertinent drug interactions.

Combination therapies including more than Lamivudine.

These include lamivudine, famciclovir, and penciclovir. Lamivudine inhibits

The virally encoded enzyme reverses transcriptase and prevents translation of an RNA

Pre-genome to a complementary DNA molecule whereas famciclovir and

Penciclovir inhibit the elongation of the viral DNA molecular chain and inhibit viral

DNA polymerase. From what we know about the importance of the immunologic

Response in the treatment of chronic hepatitis B, however, one may be

Cautiously optimistic about using drugs which are only able to reduce viral

Proliferation, particularly in individuals with mild hepatitis in whom stimulation of

The immune response may be required.

Because immunologic reactivity to HBV appears to be a critical determinant of response, it is reasonable to assume that a combination of an immunomodulatory

Agent with an antiviral might be a more efficacious approach to the treatment of

Chronic hepatitis B.

It is easy to imagine that other immunomodulatory approaches might also be

Adjunctive to antiviral therapy such as interferon or nucleoside analogues (see

Below). This interest in combination therapy has lead to a phase III study in the U.S.,

Canada, and Europe in which interferon (as a prototypical immunomodulatory drug)

Is used in combination with lamivudine to treat patients who have failed to respond

To interferon alone. As interferon seems to be a modest and unpredictable

Immunoregulatory agent, however, the search is on for other therapeutic agents

Which can be used to stimulate immunologic response against the virus. One of the

Approaches involves the use of a core peptide vaccine which is a construct

Consisting of an immunodominant epitope (HBcAg 18-27), bound to part of the

Tetanus-toxoid molecule, and 2 palmitic acid residues. This vaccine has been

Shown to induce a dose related core specific CTL in healthy volunteers and in some

Individuals with chronic hepatitis B.7

Another therapy which holds promise is the use of recombinant human IL-12 which

Is stimulatory to Th1 cells. This has been shown in the transgenic mouse model to

Suppress HBV gene expression; increase CTL and natural killer cell production.

Early clinical trials are underway with this agent.

Finally, HBV-specific DNA mediated immunization has been put forth as a potential

Therapeutic approach. It is likely that these immunomodulatory agents will be most useful when combined with drugs that are capable of blocking viral replication.

Simplified Classification of Therapeutic Approaches to Hepatitis B:

Chapter Five Chronic Hepatitis C

More people are going to be killed worldwide by hepatitis C than AIDS in next 10-15 years. Up to 300 million people have chronic hepatitis C infection worldwide?

Structure of Hepatitis C

HCV is a positive, single-stranded RNA virus. The genome is approximately 10,000 nucleotides and encodes a single polyprotein of about 3,000 amino acids. Several different genotypes of HCV with slightly different genomic sequences have since been identified that correlate with differences in prognosis and response to treatment.

Important facts about Chronic Viral Hepatits C

Consensus on dosage of Interferon and duration of therapy is lacking. Very wide variations. FDA of USA accepts the following figures.

• Upto 80 % of patients exposed to hep C virus can go into chronic phase. Chronic phase does not mean cirrhosis. Only 10-20 % of patients with chronic phase develops cirrhosis over a period of approximately 20 years.

• Males suffer more aggressice disease. They respond comparatively less than females to combination therapy.

• More than 30-40 % of patients of chronic hepatitis C can have normal ALTS.Only 60-70 % patients have persistently raised ALT.Even these can have variations.

• Patients who go into normal phase of ALT with chronic disease can have normal enzymes for upto one year before there is another phase of rise. So long term follow up is required.

• FDA does not recommend Interferon below 18 and above 60 years of age.

• They’re 6 genotypes of HCV and atleast 90 subtypes. Type 1 has substancialy lower response to interferon. But this is no reason to deny these patients this treatment.

• Alcohal intake changes ALT levels and has negative effect on the disease. So manage this before thinking of specific antiviral therapy. Behaviour must remain normal for at least 6 months before thinking of interferon.

• ALT level variation in this infection is quite wide, as activity of virus is diminishing and exaggerating. So only persistently raised ALT shall be considered for antiviral therapy.

• Patients with persistently normal levels of ALT are not candidates for Interferon therapy, independent of other factors. Therapy may itself cause inflammatory changes and rises in levels. These are least likely to respond.

• Higher the viral load, less likely to respond.

• 3 million units of interferon on alternate days for one year will bring ALT levels to normal in 50 % of treated patients. Out of these 33 % will have HCV PCR also negative. One year after stopping the therapy 50 % of these will relapse. So true rate of cure is 15-25 %. In such cases even histology improves.

• Combination therapy of Interferon and Ribavirin has brought the response rate to near 50 % even after counting the relapsing.

• Non responders are less likely to respond to increased duration or higher dose.

• Responders usually show improvement in ALT and viral load withen 3 months. Patients who show no improvement are most likely going to be non-responders. Interferon may be stopped.

Natural Course of Hepatitis C Infection.

• Generaly slowly progressive.

• 15 % of infected recover spontaneously.

• 25 % of infected have asymptomatic illness with persistently normal SGPT levels and benign hisotological lesions. So 40 % recover or have benign outcome.

• Majority of patients with chemical markers has only mild to mederate necro-inflamatory lesions and minimal fibrosis. Most of these will not succumb to liver disease. Majority will live out their life span.

• About 20 % chronic hepatitis C will develop Cirrhosis of Liver and die with the complications of Cirrhosis, in the absence of liver transplant.

• Hepatocellular Carcinoma.1-4 % /year in-patients of Cirrhosis.This risk supports the necessity of regular monitoring by ultrasonography and alphafetoprotein in patients of established or suspected Cirrhosis.Development of Carcinoma is rare in patients with Chronic Hepatitis but not Cirrhosis.

The other way of looking at the clinical problems caused by Hepatitis C is as below.

Hepatitis C is responsible for

• 40 % of all cases of endstage Cirrhosis

• 60 % of Hepatocellular Carcinoma

• 30 % of Liver transplants

The main factors associated with increased risk of progressive liver disease are

• age