Control

Blood banks today routinely screen donors for HBsAg using a sensitive enzyme immunoassay or radioimmunoassay. This has almost eliminated post-

transfusion hepatitis B. Intravenous drug users should be the target of educational campaigns to reduce the extreme risk of transmission that accompanies needle sharing. Some countries such as Australia have established programs for free distribution of disposable sterile syringes and needles to registered drug users. Sexual transmission is obviously difficult to address, other than by general education advocating moderation, monogamy, screening of sexual partners for HBsAg, and so on. Partners of known carriers should be vaccinated and encouraged to avoid contact with the carrier's blood or other secretions, for example, by using condoms, covering skin sores or abrasions, and eschewing the sharing of toothbrushes, razors, eating utensils, etc. Perinatal transmission to newborn infants of carrier mothers can be minimized by inoculation at birth with both hepatitis B vaccine and hepatitis B immune globulin.

Prevention of infection in health care workers and their patients is based on vaccination and universal precautions in the ward, theater, and laboratory founded on the presumption that any patient may be infectious. Barrier techniques include wearing of gloves, gowns, masks, and eyeglasses to prevent exposure to blood in high-risk situations, such as during invasive procedures, avoidance of mouth-pipetting and of eating or smoking while working, meticulous hand washing routines, careful attention to the disposal of blood and body fluids and to cleaning up blood spills with appropriate chemical disinfectants fsuch as 2% glutaratdehyde, 0.5% (5000 ppm available chlorine) sodium hypochlorite, or 1-5% formalin|, special precautions in disposal of used needles, the use of disposable equipment wherever possible, and appropriate procedures for the sterilization of reusable equipment. These approaches to aseptic technique and sterilization of equipment should apply equally to dentists, acupuncturists, tattooists, etc.

Passive Immunization

Hepatitis B immune globulin, obtained by plasmapheresis of subjects with high titers of anti-HBs, is effective for postexposure prophylaxis of hepatitis B, for example, in unvaccinated people who have been recently exposed to infection with HBsAg positive blood in needle-stick accidents or in newborn infants born to HBsAg positive mothers. However, it is most efficacious when used in conjunction with vaccination (active-passive prophylaxis).

Vaccines

Paradoxically, an effective vaccine against hepatitis B was produced and licensed in 1981 even though the virus has not yet been reliably cultured in vitro. Such high concentrations of HBsAg can be found in the sera of human carriers that this prototype vaccine was prepared simply by purifying 22 nm HBsAg particles directly from this source, followed by chemical treatment to inactivate any accompanying HBV or other contaminating virus. This "plasma-derived" vaccine is still being produced and is widely used, particularly in developing countries where the need is greatest, but it has progressively been replaced by the world's first genetically engineered human vaccine.

In the mid-1980s the HBsAg gene, cloned into a plasmid, was used to transfect the yeast Saccharomyces ccrevisiae, and the nonglycosylated form ol HBsAg particle produced was extracted and purified for use as a vaccine. Like the plasma-derived vaccine, the recombinant vaccine is adsorbed with the adjuvant aluminum hydroxide, stored cold but not frozen, and administered by intramuscular injection into the deltoid in a course of three doses, separated by 1 month then 5 months, respectively. There are no side effects other than an occasional (5-20%) sore arm, and protective levels of neutralizing antibody are elicited in over 90% of recipients (95% of neonates). Of the nonresponders, only half seroconvert following a second full course, suggesting the absence of an appropriate immune response gene. Renal dialysis patients and immunodeficient or elderly recipients also respond subop-timally. Protection studies demonstrate that immunity in immunocompetent vaccinees remains solid for a decade or so, and that those who do become infected during this period generally develop an anamnestic anti-HBs response as well as an anti-HBc response and do not progress to chronicity. Nevertheless, longer term studies may reveal that a booster dose of vaccine is desirable after about 10 years.

Recombinant HBsAg vaccines are continually being refined. First, inclusion of the nucleotide sequence encoding pre-SI and pre-S2 in the cloned gene construct enhances the immunogenicity of the resultant protein particles. Second, HBsAg produced by mammalian cell lines such as CHO are glycosylated normally and thus more closely resemble the natural human product. Third, encapsulation of HBsAg in a polyglycan or other matrix may enhance immunogenicity by creating a depot from which antigen is released slowly or in pulses. Finally, the HBsAg gene has been incorporated into live vaccinia virus or adenovirus recombinants and demonstrated to confer protection.

Vaccination strategies differ from country to country. In populous areas of the world where the HBsAg carrier rate is high the top priority must be to interrupt the chain of perinatal and early horizontal transmission by vaccinating all infants at birth. For convenience, the course of injections should be synchronized with those for diphtheria/pertussis/tetanus and/or with oral poliovaccine, and should become an integral part of the Expanded Programme of Immunization (EPI), Pilot programs have been conducted in several developing countries since the late 1980s. Finance is the major impediment to implementation on a world scale.

The strategy of universal immunization of newborn infants should be the aim of all countries, but current policy in most of the developed world where the HBsAg carrier rate is less than 1% is to target only high-risk groups in the community (Table 22-3). Several of these cohorts are notoriously difficult to access, and the experience in the United States has been that the incidence of HBV has actually increased in spite of strenuous efforts to implement this policy. Moreover, the cost of locating and testing for HBsAg carriage approaches that of the vaccine. As a result, health authorities in the United States and elsewhere have recently been lobbying for funding to support a policy of universal vaccination of all children. A number of manufacturers are developing "pentavalent" vaccines against diphtheria, pertussis, tetanus, Haemophilus influenzae type B, and hepatitis B, for administration to infants at

Table 22-3

Priority Candidates for Hepatitis 13 Vaccine m Developed ¡Countries1'

Newborn babies born of HBsAg positive mothers'1 and of immigrants from countries of high HBV prevalence1

Sexual and close household contacts of HBV carriers

Needle-stick injuries from HBV carriers

Parenteral drug abusers

I lomosexually active men

Heterosexual!}1 promiscuous persons including prostitutes and those with sexually transmitted disease

Hemophiliacs, hemodialysis patients, or others requiring frequent transfusions or blood products

Clients and staff of homes for the developmentally disabled and other custodial institutions, such as prisons

Health care and public safety workers potentially exposed to human blood''

Immigrants and ethnic minorities from countries of high HBV prevalence1

International travelers to HBV endemic areas who anticipate close or sexual contact with the local population

" Based on Recommendations of the Immunization Practices Advisory Committee, Centers for Disease Control (1990) Protection against viral hepatitis Morbidity Mortality IAkekly Report 39, RR-2

'' Identified by screening of pregnant women

1 Immigrants and refugees from East Asia, Africa, etc., should ideally be screened for HBV markers, if an HBV cairier is detected, all members of the family (as well as all subsequent newborn infants) should be vaccinated Vaccinate students undergoing professional training.

birth, 1-2 months, and 6-18 months of age, in lieu of the currently popular DPT schedule of 2, 4, 6, and 15 months.

Chemotherapy

Theoretically, any of the several enzymatic functions of the HBV polymerase offer tempting targets for che moth era peutic attack. In practice, however, inhibitors of reverse transcriptase (such as AZT) have proved to be ineffective, as have inhibitors of DNA polymerase (such as acyclovir and adenine ar-abinoside), with the exception of ganciclovir, especially in combination with phosphonoformate (foscarnet), which has recently been reported to reduce HBV replication in chronic carriers following liver transplantation. The newer nucleoside analogs penciclovir and its oral form, famciclovir, have also been reported to inhibit HBV DNA replication in vitro and in vivo. An alternative approach is to inhibit the generation and processing of the main transcriptional template, the viral supercoiled DNA, using compounds known to interfere with DNA topology. The DNA gyrase inhibitor nalidixic acid, a well-characterized oral antibacterial antibiotic, blocks viral replication at this level and has displayed efficacy against duck hepatitis virus in vitro and in vivo.

Interferons (see Chapter 16) have an established place in the treatment of chronic hepatitis B but have been generally disappointing. Their efficacy seems to be largely limited to a particular cohort of patients with chronic active hepatitis in the window between the high and low replicafive phases. In this subset, which represents only a small minority of the HBV carriers worldwide, a 6-monfh conrsc of interferon a, 5-10 million units injected three times a week, brings about a response in up to 50% of cases, but there is often a relapse after cessation of therapy. The naturally occurring human immunomodulatory thymic hormone and interferon inducer thymosin a-1 appears to have a similar effect and is being tested for synergism with other anti-HBV chemotherapeutic agents.

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