S. M. Wasim Jafri  ( Department of Medicine, The Aga Khan University Hospital, Karachi. )

About 60-70% of patients infected with HBV (Hepatitis B virus) do not manifest clinical illness, but rather develop antibody and per­manent immunity¹. For each case of Acute Hepatitis B, there are 2 or 3 cases of subclinical infection (Figure².

5-10% of adults infected with HBV develop HBSAg carrier state and chronic infection, manifested by the persistence of HBSAg and virus in serum and HBV DNA in liver³. When infection with HBV occurs in childhood during first few months of life, chronic HBSAg carrier state often results⁴. There are about 200 million carriers worldwide of HBV and it is the main cause of chronic liver disease⁵. The high risk groups in­clude homosexuals, drug addicts, patients who receive multiple blood transfusions such as hemo­philiacs and uraemics in haemodialysis centres. The persistence of hepatitis B virus may lead to the development of chronic active hepatitis, cirrhosis and bepatocellular carcinoma. Chronic Active Hepatitis is progressive in 20-70% of cases⁶ and the 5 year mortality may be as high as 50%⁷. It is very important indeed to institute treatment as early as possible in all infected patients in ordcr to reduce morbidity and mortality and also for pati­ents with chronic persistent hepatitis which was considered as a benign disease but is now proven to progress to chronic active hepatitis and cir­rhosis. Aldershville et al⁸ reported in 1982 progres­sion in patients with chronic persistent hepatitis, to chronic active hepatitis or cirrhosis in 5 of 14 patients with continued viral replication, compa­red with one of nine in whom viral replication had stopped and only 2 of 28 with chronic persistent hepatitis unrelated to hepatitis B virus infection. If the hepatitis Be antigen (HBeAg) a marker of ac­tive viral replication disappears from the serum and antibody against it is found, the patient usual­ly enters remission⁹. Some patients who have anti HBe show continued activity of infection histologi­cally, which could be due to auto immune reaction, superimposed Delta infection or continued re­plication of HBV which can be detected by the presence of hepatitis B DNA (Deoxyribonucleic acid) in serum. Patients who show active disease on biopsy specimens or show hepatitis B virus DNA in the serum or, in the absence of this investigation, if HBeAg and DNA polymerase is present, may be considered for treatment¹⁰. Since integrated viral sequences may be related to the development of hepatocellular carcinoma with the passage of time, treatment ideally should also aim at preventing in­tegration and this would necessitate treatment as early as possible. Antiviral agents and interferons, either alone or in combination have been tried in several studies to identify the best treatment pro­spects for this infection. Infection acquired in neonatal life differs from early childhood or adult acquired infections, in addition homosexuals often exhibit secondary immunodeficiency state due to coincidental viral infections and behave different­ly.

Adenine arabinoside is poorly water soluble and had to be administered intravenously whereas the monophosphate derivative (AraAMP) is high­lywater soluble and therefore can be administered intramuscularly. Bassendine and colleagues¹¹ showed definite benefits of Adenine Arabinoside therapy in HBSAg positive chronic liver disease in a controlled study with a significant effect on the rate of seroconversion from HBeAg to antibody. Majority of patients in this study acquired infec­tion during childhood or adult life and there was no identification of heterosexuals or homosexuals. In a randomised study Hoofnagle and associates¹² showed a significantly increased rate of FIBe an­tigen to antibody seroconversion observed at 1-year after one month therapy but 2 to 4 responders subsequently showed reactivation of virus; but in a different study Weller et al¹³ showed a sig­nificant rate of clearance of HBeAg with no evi­dence of viral replication. Trepo¹⁴ reported from. France in a randomised placebo controlled study that repeated courses of Ara-Amp could convert 70% of patients with HBeAg to anti HBe. Homo­sexuals HBV carriers are noticeably non respo­nders to a single course of Ara Amp, whereas in the heterosexuals infected in adults life response rates upto 45% can be obtained^15,16. This respo­nse rate is significantly different when judged against spontaneous seroconversion rate of 5-15% reported in several studies. The action of Ara A and Ara AMP (Mono­phosphate Derivative) is to inhibit the synthesis of HBV nucleic acid by acting as a faulty substrate¹⁸, thus preventing DNA transcription. The long term benefits depend on recovery of the host immuhe response for continued inhibition of viral replica­tion. During the 4 week period of treatment with Ara A or Ara AMP viral replication is inhibited and on stopping therapy, the host immune res­ponse is rapidly restored which results in lysis and elimination of infected cells. This would result in elevation of transaminases which is always seen after cessation of treatment if good therapeutic response is to be achieved. Patients who are in­fected in neonatal life may be tolerant of the virus, and homosexual patients who have a secondary immune deficiency do not respond¹⁵.

INTERFERONS
Interferons consist of a group of secretory proteins and glycoproteins that are produced by human cells following an approprilte stimula­tion¹⁹. The interferons’ antiviral, antiproliferative and immunomodulatory effects could be benefi­cial in a variety of clinical conditions. The effec­tiveness of alpha, beta and gamma interferons (IFN) are currently being evaluated in the treat­ment of chronic HBV infection. As the production of interferons is relatively easy through the recom­binent DNA techniques and lymphoblastoid cell system several clinical trials are under study re­garding its usefulness in a number of diseases. Greenberg and collegues²⁰ demonstrated in 1976 the effectiveness in inhibiting viral replica­tion by using leucocyte IFN in HBSAg positive CAH (Chronic active hepatitis). Scullard and as­sociates²¹ showed a response of 25% in an uncon­trolled study when IFN was administered for prolonged periods upto 6 months. Lymphoblastoid interferon IFN is the mix­ture of alpha interferons. Courses of alpha inter­feron given thrice weekly in doses of about 5 x 10 u/ml for 3 months favoUrably inhibit viral replica­tion without significant toxicity²². The response was better in women and, unlike Adenine Arabinoside, both homosexuals as well as heterosexuals can respond. It was further noticed in other trials that Chinese were not good responders perhaps because the infection happened at birth. Further trials showed that increasing the dose or duration of treatment the response was not sig­nificantly altered^23,24. A hepatitis like illness occurs in some patients in the third month and is followed in most by seroconversion from I-rBeAg to anti HBe²⁵. Further work needs to be done before ef­ficacy of Beta and Gamma interferons could be es­tablished. Kingham and associates²⁶ published in 1978 the use of human fibroblast interferon (IFN­B) on hepatitis BVDNA in chronic active hepatitis claiming some success. It doesn’t cause significant leukopenia which is an advantage over alpha IFN. Interferons inhibit viral protein synthesis and are immunostimulatory. It possibly enhances the host immune system which then destroys infected hepatocytes and this may result in long term im­provement by inhibiting viral replication.
CLINICAL TOXICITY OF INTERFERONS
Acute symptoms include fever, chills, hea­dache, malaise, myalgias, anorexia, fatigue and nausea. Weight loss may also be present. Other significant side effects include paresthesias, con­fusion, electro-encephalographic abnormalities, arrhythmias, hyper and hypotension, syncope, co­agulation defects, thyroid dysfunctions, electrolyte imbalances and azotemia. Taste disturbances and elevation of trans­aminases may be encountered. Anaemia, granulocytopema, lymphopenia and throm bocy­topenia maybe serious enough to necessitate ces­sation of therapy. Combination therapy with IFN and Ara A produces synergism and improvement in serocon­version but the incidence of side effects also in­crease significantly therefore this mode of treatment is unacceptable at present.
PREDNISONE WITHDRAWAL AND ANTI VIRAL AGENT
Scullard and associates²⁷, Rakela et al²⁸ and Weller²⁹ reported in 3 different studies that sud­den withdrawal of corticosteroids may be as­sociated with an increase in transaminases and clearance of HBV.A significant response was seen by Ometa et al³⁰ when 9 of 14 patients who were treated with steroid withdrawal, followed by Ara A or IFN, responded whereas only 1 of 25 on anti-viral agents alone showed seroconversion. The majority of these patients were thought to be in­fected at birth. In 1985 Perillo³¹ reported that after corticosteroid withdrawal followed by Ara-Amp, 73% of the patients treated in this fashionshowed disappearance of HBV DNA polymerase fromthe sera. Most of these patients were adults. These two studies clearly demonstrate the efficacy of this mode of treatment on both the childhood infected or adult infected patients. However, corticoster­oids withdrawal may precipitate fulminant hep­atitis or hepatic decompensation specially in cirrhotics and should be avoided in this group. It has been further shown that anti-viral treatment may produce long term inhibition of viral replication, but HBS antigenemia persist³². Seroconversion from HBe antigen to antibody is beneficial as it reduces hepatic inflammatory response. If treatment is instituted within 12 to 24 months of infection, successful inhibition of viral replication may also result in clearance of HBS Ag and would prevent the development of cirrhosis and reduce the risk of development of hepatocel­lular carcinoma.
DELIA HEPAITILS AND ITS TKEATMENT
PROSPECTS
The hepatitis Delta virus is an incomplete RNAvirus which produces disease inpatients who are hepatitis surface antigen positive. This is a highly pathogenic virus and is responsible for both acute and chronic liver disease³³. Hepatitis Delta virus infection in patients with chronic hepatitis B is associatedwith a more rapid progression to cir­rhosis compared with hepatitis B surface antigen carriers with chronic hepatitis and no evidence of HDV infection³⁴. The incidence ofHDV infection in HBSAg positive carriers is 12.3% to 51% reported in different series from Italy^34,35. This high degree of prevalence of HDV certainly war­rants treatment programmes to eliminate the delta virus. Lymphoblastoid human alpha interferon does inhibit delta virus replication and in some cases this effect is long lasting. Further trials need to be conducted to prove the definite efficacy of this agent.
NON-A NON-B HEPATITIS AND PROSPECTS OF ITS TREATMENT
Albert and associates reported in 1987 from Mayo Clinic the benefits of corticosteroid therapy in achieving sustained remission in severe hepatitis B surface antigen negative chronic active hep­atitis³⁶. Twenty four of 66 patients (36%) sus­tained remission for at least 5 years (mean 11 ± 0.6 yr) after initial therapy and 42(64%) relapsed and were retreated; of the 42 patients who re­lapsed 9 (21%) ultimately entered a sustained re­mission after retreatment. Remission for at least 5 years was possible in 33 of 66 patients (50%). The usefulness of alpha interferon in the treatment of NANB was demonstrated by Thomson and col­leagues³⁷; Non-A Non-B hepatitis is commonly the cause of hepatitis following transfusion of blood and its products as HB surface antigen screening is commonly used on donated blood 5-15% of post transfusion hepatitis is caused by an unidentified virus NANB. NANB hepatitis occurs after infusion of fibrinogen, factor VIII, factor IX concentrates and cryoprecipitates and has been reported after IV gammaglobulin in hypogam maglobulinaemic patients. NANB hepatitis com­monly progresses to chronic active hepatitis and cirrhosis. Steroids and acyclovir therapies have been unsuccessful in the treatment of post-trans­fusion hepatitis. The success that Thomson and as­sociates have shown is quite promising in the treatment of short incubation period NANB hepatitis. Further trials will be very helpful as evI­dence is accumulating that NANB hepatitis is quite prevalent in our country with all its sequelae and complications.

Chronic infection as a result of neonatal ex­posure is the most difficult to treat. Interferons have no value, the carrier status is the result of im­munologic tolerance to part of the antigenic struc­ture of the virus. Carrier status in adults may be the result of defect in IFN production on ad­ministration of deficient IFN, lysis of infected cells would result in elimination of the virus. Upto 60% of Northern European patients respond to lymph­oblastoid IFN with clearance of HBV DNA and HBeAg. Some of the non responders have a coexisting deficiency of gamma interferon and as­sociated HTV III infection. In these patients com­bined alpha and gamma IFN treatment may be effective. Ara-AMP was found to be non-effective in treating patients infected in neonatal life and ho­mosexual group of adult carriers; however, a single course of Ara-AMP proved to be effective in 45% of adult heterosexual carriers, IFN because of im­munostimulatory effect is beneficial for both ho­znosexual and heterosexual patients. Neither Ara AMP, nor IFN are found to be effective in carriers resulting neonatal infection. Steroid withdrawal followed by anti-viral therapy maybe the only hope of treating these patients at present or early vac­cination of these infants who are predisposed to this infection from their hepatitis B surface antigen positive mothers would be most beneficial.

I would like to acknowledge the services of Ms Rozina and Mr. Saleem for typing this article.

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