Public Health Considerations
THE COMMITTEE CONSIDERED HOW an antiviral drug could be applied in the field to further the goal of global polio eradication. The committee recognizes that a drug that inhibits poliovirus replication in vivo has the potential to be used for prevention of infection or for treatment of infected patients. Because the challenges to polio eradication in the immediate post-OPV era are different from those in the more distant future, more than 3years after OPV cessation (Aylward and Cochi 2004), each of these timeframes is considered individually. The utility of antiviral drugs for the treatment of chronic shedders, the potential sources of iVDPV, is addressed separately.
Production of a drug that prevents infection or reduces viral shedding among those who are infected would be the major goal of an antiviral drug development program in support of global polio eradication. A drug designed for prevention of infection would require an oral formulation that is safe, effective, affordable, and unlikely to induce transmission of resistant polioviruses. An ideal prophylactic drug would require only one, or at most two doses per day for optimal compliance. Its use would be limited to distribution by public health authorities in the event of an outbreak of wild type poliovirus or vaccine-derived poliovirus (VDPV) infection. When given to all who are at risk of infection as the sole strategy, an antiviral agent given to those with current (but unidentified) poliovirus infection might prevent paralytic disease in recipients and reduce the risk of transmission of the outbreak strain to susceptible contacts. However, the committee concludes
that it is most likely that an antiviral drug would be used as a supplement to vaccination in order to prevent infection.
In the first 2-3 years after OPV cessation, response to outbreaks of cVDPV is expected to consist of comprehensive, regional mOPV distribution (Aylward and Cochi 2004). Because the immune response to a live vaccine depends on replication of the vaccine virus in the gastrointestinal tract, concomitant administration of a potent antiviral drug would interfere with the induction of immunity. Therefore, when OPV is used for outbreak control, the role of an antiviral drug might be quite limited. If sufficiently safe and inexpensive, such a drug might be used by public health authorities to control spread of live polioviruses—both the virulent outbreak virus and OPV viruses—in unaffected areas that surround the outbreak zone. The drug supply would need to be very large and the logistics of distributing the drug would be complex, potentially draining resources from the areas affected by the outbreak.
The risk of an outbreak of cVDPV more than 3 years after OPV cessation is thought to be low (Duintjer Tebbens et al. 2005), but the consequences could be severe, in that the number of susceptible children would by then be substantial. It is during the period more than 3 years after OPV cessation that the committee concludes that an antiviral drug may be most useful. If such an outbreak occurs and it is undesirable to reintroduce live poliovirus to control it, IPV could be used as an alternative. IPV is safe and carries no risk either of VAPP or of initiating a cVDPV chain of transmission. However IPV does not induce a mucosal immune response and thus is less effective in interrupting transmission of polioviruses. By itself, IPV may not induce immunity quickly enough to stop an outbreak. Use of an antiviral drug in conjunction with IPV would protect vaccine recipients from poliovirus infection until IPV-induced immunity can be assured. Virtually all studies with the currently available IPV vaccines confirm that at least two doses are required to achieve seroconversion in more than half the vaccinees. Actual seroconversion rates vary, not only with the number of doses, but also with the interval between doses and with age (Sormunen et al. 2004; Simoes et al. 1985). Simoes et al. showed that IPV containing 40, 8, and 30 D antigen units for serotypes 1, 2, and 3, respectively, induced seroconversion rates of 96%, 80%, and 96% 4 weeks after the second dose, if two IPV doses were administered a month apart (Simoes et al. 1985). These rates are slightly lower than rates observed after a 2-month dose interval but it is likely that the shortest effective interval between IPV doses would be chosen for purposes of outbreak control.
To be effective in supplementing an outbreak response with IPV, a polio antiviral drug would have to exhibit the following characteristics:
Extreme safety—especially for young children because the drug would be given to young IPV recipients and taken daily for 4-6 weeks.
Oral administration—in liquid form because it must be available for infants and young children.
Once, or at most twice, daily dosing—to encourage compliance.
Stability—to allow production and stockpiling before outbreaks occur.
High activity against all poliovirus types—specifically,
—In uninfected patients to prevent infection or markedly reduce virus shedding if infected.
—In already infected patients to reduce infection to a level where the likelihood of transmission to susceptible contacts is very low and, ideally, to prevent progression to the central nervous system (CNS). Halting the progression of the disease once it has reached the CNS may not be possible.
Of course, the success of an antiviral drug strategy will also depend on factors unrelated to the agent’s pharmacological properties, efficacy, and safety. These include the cost of the drug, the expense of distribution, the ability to identify the target population and distribute the drug in a timely manner, and compliance among those who are given the drug. Therefore an antiviral program will require not only design, manufacture, and testing of an antiviral, but also detailed plans that include criteria for employment of the drug, a distribution strategy, and innovative ways of enhancing compliance.
It is not possible to ignore the ease with which RNA viruses such as poliovirus develop resistance. In a setting in which a drug and a virus co-exist for any amount of time—for example, when a drug is given continuously to control a chronic viral infection, such as HIV—the development of resistance is virtually certain. In the prophylactic setting described above, it is anticipated that the great majority of recipients will not be infected with poliovirus at all; in these patients, the drug will not be exerting selective pressure on the virus. In patients who are already infected (but asymptomatic) when they receive the drug, it will be important that the drug work quickly enough for the patient to be unlikely to pass on the virus (if it is passed on, it might come under selective pressure in successive patients, increasing the chances of developing resistance).
Although development of a drug with therapeutic efficacy would not be the main objective of an antiviral development program to aid eradication of poliomyelitis, it is possible, if not likely, that a prophylactic drug would have the potential to ameliorate disease or reduce the risk of developing disease in persons infected with poliovirus. An antiviral drug, if available, would probably be given to patients who had acute paralytic poliomyelitis in the hope of favorably altering the natural course of neurological disease, although it is unlikely that true therapeutic efficacy could ever be measured with confidence. A therapeutic drug might also have both personal and public health benefits when made available to treat immunodeficient persons known to be persistently infected with live poliovirus. The number of such chronic shedders is thought to be extremely small; fewer than 30 have ever been identified and only 3 are known to be alive now (Halsey et al. 2004). All 3 of these patients live in developed countries that have replaced or will someday replace OPV with IPV. If the number of chronic shedders turns out to be higher than now expected, especially in poor countries, they could become a source of live virus in countries that cease vaccination and a treatment that could reduce or eliminate shedding would provide a significant public health benefit.
It is recognized that the difficulty of identifying all chronic virus shedders, particularly in developing countries, may impede this application of an antiviral drug. With so few patients, it would be virtually impossible to complete a well-designed clinical trial to demonstrate clinical benefit for either acutely infected or chronically infected persons. Long-term use of the drug in chronic shedders could theoretically lead to development of resistant virus. Therefore, it would be ideal to have more than one antiviral drug available, so that combination therapy could be used to discourage the emergence of resistance in patients who might take the drugs for extended periods. Because of the very small number of such patients, the difficulty of demonstrating the efficacy of such a compound and the likelihood that drugs that would be effective for prophylactic use in normal populations might not be as effective in the immunocompromised, the committee does not recommend that effort be concentrated on developing drugs to cure chronic shedders. However, it is anticipated that any antiviral drugs developed for prophylaxis may also have some efficacy in this small patient population.
If, as currently planned, universal vaccination with OPV is discontinued, it would be extremely useful and may, in fact, be essential to
have additional tools to control outbreaks of poliomyelitis in an increasingly susceptible world. The availability of an antiviral drug that either prevents infection altogether or decreases shedding of the virus to levels that prevent transmission would give the public health community much-needed flexibility in reacting to post-vaccination outbreaks.