Smallpox is presumably one of the most attractive pathogens to a potential bioterrorist because it meets the twin criteria of high transmissibility and high mortality. In addition, survivors are left with disfiguring sequelae. Historically drugs were tried both for treatment of smallpox and for prophylaxis of contacts but rarely in well-controlled clinical trials. Post-exposure prophylaxis with vaccinia immune globulin (VIG) demonstrated a modest anecdotal benefit when given to close contacts of smallpox patients along with revaccination, yet this scenario is not altogether relevant when an ever-increasing portion of the population has not received even a primary vaccination, and supplies of VIG are limited (454-456).

In 1963, post-exposure prophylaxis with marboran (N-methylisatin jS-thiosemicarba-zone) (194) was hailed as "the most significant

(194) Methisazone (Marboran)

advance in smallpox control since the days of JENNER." (457). However, this influential study was seriously flawed by current standards because most subjects were successfully vaccinated in infancy and revaccinated before receiving therapy. In addition, the study

groups were not randomized and subject compliance with the dosing schedule was not adequately ascertained (458). This last point is especially relevant because marboran caused severe nausea and vomiting in approximately one-half of treated subjects. Other investigators conducted a well-designed post-exposure prophylaxis study of a similar thiosemicarba-zone (4-bromo-3-methylisothiazole-5-carbox-aldehyde thiosemicarbazone, M&B 7714) in India (459). Enrollees were limited to those without previous vaccination before their contact with an index case of smallpox. Although there was a small decrease seen in the incidence of smallpox in the treated group, there was no decrease in mortality of those who acquired smallpox. The authors concluded that post-exposure treatment was not appropriate for routine use as the benefit was small and the drug poorly tolerated — 52%of those in the treatment group refused to complete their treatment course.

On the basis of encouraging data in animal models of poxvirus infections, a controlled clinical trial was undertaken in India to evaluate the treatment of smallpox with M&B 7714, the thiosemicarbazone described above that showed a small amount of benefit as a prophylactic agent. Unfortunately, this compound showed no therapeutic benefit in patients with or without prior vaccination (460).

Other antiviral agents were studied in small trials. An initial uncontrolled treatment study in Bangladesh of nine patients with cy-tosine arabinoside reported that eight survived compared with an expected 45% mortality in this area (461). This report was quickly followed by two randomized hospital-based controlled studies in Ethiopia and Bangladesh that showed no benefit for treatment (462, 463). The observation in one study that three treated patients who seemed to be improving died late in the course of infection is worrisome in view of cytosine arabinoside's immunosuppressive activity (463) .Adenosine arabi-was also studied in Bangladesh in a small double-blind placebo-controlled trial, and no differences were found between placebo and Ara-A treated groups in mortality, fever days, or duration of days of virus isolation.

Another historically important medical need was for prophylaxis and treatment of complicationsfor vaccination for smallpox. Although vaccination is undeniably effective, it is a live vaccine and not sufficiently attenuated to prevent its unwanted replication in people with impaired immune systems. There are four complications of vaccination that are considered serious. Three of these involve viral replication and should potentially be responsive to antiviral therapy. These are as follows. (1) progressive vaccinia in which the original vaccination lesion gradually extends rather than resolves and new lesions appear at noncontiguous sites. This is almost always fatal. (2) Eczema vaccinatum in which lesions appear on previously normal as well as eczem-atous areas of skin. The prognosis is correlated with the extent of skin involved. (3)Generalized vaccinia, a generalized skin eruption, has a good prognosis. The fourth serious complication is post-vaccinial encephalitis and is thought to result from immunpathology rather than viral replication. In the absence of treatment progressive vaccinia is usually fatal (458), and the U.S. mortality rate for eczema vaccinatum in very young children was ap-

proximated as 33%. Fortunately treatment B C with VIG seems to significantly improve sur- B o vival to about 93%, although complication B p rates are too low to conduct controlled clinical B a trials (455.458). B s:

Historical data on complication rates from B v the past will probably not be reliable predictors of future rates, should any government undertake the vaccination of large segments of the population to deter or ameliorate the consequences of a potential terrorist use of smallpox. The world's population has changed dramaticallv since the middle of the 20th cen- B tury. Immunocompromised individuals com- B ei prise a much larger proportion of the overall population as a result of advances in transplantation and cancer treatment as well as the B in global devastation caused by HIV. In addition, B aj the incidence of atopic dermatitis has dramat- B re ically increased in recent decades. As supplies B in of VIG are very limited, it may be as or even B tr more important to identify an effective chemo- B therapeutic agent for the treatment of vac- B cinia complications as for the treatment of B rn smallpox. Fortunately, because the viruses are B th

closely related, most antiviral agents with activity against one of these viruses is likely to also inhibit the other.

New preclinical data support use of cidofo-vir (195) for both treatment of smallpox and of

(195) Cidofovir

(195) Cidofovir treatment of complications of vaccination. Accordingly, the Department of Health and Human Services has prepared and sponsored Investigational New Drugs (INDs) for both potential indications.

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