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Preface

The  development of antiviral drugs is still  in its  infancy with rapid changes and  progressive milestones encountered almost daily. By  the  time this book  is  distributed, new  drugs may have already been added. This is particularly true for the anti- retroviral drugs, which seem  to be growing in  number expo- nentially to  the  casual observer trying to  keep  abreast of recent advances in this field. As this book is going to press, the United States Food and  Drug Administration granted acceler- ated approval of Epzicom and  Truvada. Epzicom is  a  fixed- dose combination of the  antiretroviral drugs Ziagen (abacavir sulfate) and  Epivir (lamivudine). Truvada is a fixed-dose com- bination of Emtriva (embricitabine) and  Viread (tenofovir dis- oproxil  fumarate). In  keeping pace  with these advances, the book  will  survey the  latest in  antiretroviral drugs, general antiviral therapies, the  antiviral vaccines, and  immunothera- pies  used for treatment, and  prophylaxis of viral infections.

The book begins with a review of the current state of anti- viral management (therapy and  prophylaxis) and  discussion of the  challenges for the  future. The  second chapter discusses the  major categories as  well as  the  indications, adverse reac- tions, and  drug interactions of each  specific  medication of the

antiretroviral  drugs. Chapter Three delves into  the  treat- ments available for other viral infections, such  as herpes sim- plex  virus, varicella zoster virus, cytomegalovirus, human papilloma virus, chronic viral hepatitis, and  others. The  book then concludes with a discussion of the  vaccines that are  cur- rently available and  being  developed and  gives an overview of the  use  of immunoglobulins and  monoclonal antibodies  for antiviral therapy.

The  last two decades have been  the  most  dynamic in the history of viral infections and  their management. During this time the  eradication of the  epidemic form  of the  most  deadly viral infection known to medicine, smallpox, was  announced. Ironically, this landmark achievement was  followed  almost immediately by the  observation of a new  viral pandemic that currently infects 46 million people, i.e., HIV/AIDS. Within the past decade several new  emerging viral diseases, e.g.,  West Nile  virus, SARS,  avian influenza, etc.,  have challenged our ability to  recognize and  manage these infections. Unfortu- nately, antiviral drugs have been  effective for  only  a  few groups of viruses up  until now.  Most  antiviral drugs do not produce a cure, but  rather allow  control of the  infection. An exception to this observation has  recently been  seen  with the combined use  of pegylated interferon alpha and  ribavirin, which allows virologic  cures for  the  majority of hepatitis  C patients who successfully complete therapy. However, the  lim- itations of antiviral therapy, including the  high  costs  of drugs, make the need  for prevention even more urgent. The most  cost effective means  of prevention are  public  health measures, such  as proper sanitation/clean drinking water, mosquito con- trol,  testing blood/blood  products, not  sharing needles, and safer sex/condom use.  In  addition, vaccines provide the  most effective and  cost-efficient means of preventing infectious dis- eases. The  greatest success story in  medical history was  the eradication of epidemic smallpox, which was  due  to  a  com- bined effort  of public  health measures and  an  effective vac- cine.  For  such   combined efforts to  eradicate other viral diseases, such  as  measles and  polio,  the  challenges are  not only to reach the  susceptible populations but  also to overcome unfounded prejudice against vaccines. At the  same time, new

technologies will lead  to the  development of new  prophylactic vaccines, particularly for infections such  as HIV, human pap- illomaviruses, and   herpes simplex viruses, ushering in  a whole  new set  of arsenals in the  fight against viral infections. It is  my  hope  that Antiviral Agents, Vaccines, and  Immuno- therapies will serve as a valuable tool for the  clinician and  the basic  scientist in  better understanding the  current manage- ment protocols of viral diseases as well as greater possibilities for the  future.

Stephen K. Tyring, MD, PhD,  MBA

The  efforts of Nancy Bell,  PhD,  for all  aspects of the  editing and   production process are  deeply appreciated.  I  wish  to thank my wife, Patricia Lee, MD, for her  support, encourage- ment, and  dedication throughout the  writing and  publication of this book.  In  addition, I wish  to thank my  mentor (and  a pioneer in  antiviral research), Samuel Baron, MD, Professor (and  Chairman Emeritus) of Microbiology/Immunology and Internal Medicine at The University of Texas Medical Branch, Galveston, Texas, for his  guidance, suggestions, and  wisdom over  the  past 25 years. Without such  outstanding people, the publication of Antiviral Agents, Vaccines, and  Immunothera- pies would  not have been  possible.

Introduction

Public health  measures  should always be  the  first line  of defense against  viral infections and   should include clean drinking water, proper sewage disposal, vector  control, testing of blood and  blood products, nonsharing of needles, hand wash- ing and  use  of disposable gloves,  and  safer sex/condom usage/ abstinence (Fig. 1.1). Global  travel has  made the  rapid imple- mentation of these measures paramount. The  rapid spread of the  SARS  (severe acute respiratory  syndrome) corornavirus and  avian influenza are  recent examples of the  problem of viral globalization. In  a similar manner, the  West  Nile  virus and monkeypox virus made their appearance in North America. In  addition, new  viruses are  being  described for  previously recognized diseases, such  as the  role  of human metapneumo- virus as  the  second most  common cause of infant respiratory infections. For viral diseases for which they are  available, vac- cines  can be added to the  list  of measures to prevent viral dis- eases and   should be  used in  combination with the  other interventions. Antiviral drugs, however, can  be considered a

second line of defense against viral infections because they are generally not  viracidal, because they are  much more  expen- sive  than other forms  of intervention, and  because they are usually most  beneficial when used acutely (which limits the time in which the  patient can obtain them).

A prototype successful vaccine was  the  use  of vaccinia to eliminate  epidemic smallpox from  the  world.  Starting with Jenner’s use  of cowpox  to prevent smallpox in  1797  through the  last epidemic case  of smallpox, treated  in  1977,  this accomplishment could easily be considered the  single greatest achievement in  medical history. Even in  the  20th century, hundreds of millions of persons died  from  smallpox and  hun- dreds of millions more  suffered marked morbidity, such  as blindness. Thus, by  extrapolation into  the  21st  century and beyond, an infinite number of lives and  dollars will have been saved by this landmark event. It is  important to  remember that no antiviral drug was approved for smallpox and  that the elimination of this deadly disease was accomplished via public health measures plus  an effective vaccine.

For  the  150 years after Jenner, only  one other viral vac- cine was developed—the rabies vaccine by Pasteur in 1885. In the  50 years between 1945  and  1995,  however, 11 more  vac- cines  were  approved (Fig. 1.2). Although the  rotavirus vaccine

Dates for smallpox and  rabies vaccines are  for the  first published results of vaccine usage. Remaining dates are  for FDA approval of vaccine.

Fig. 1.2 Timeline of virus vaccine development.

was  approved by  the  U.S.  Food  and   Drug Administration (FDA) in 1998, it was taken off the  market after a few months due  to a relatively small but  statistically significant increase in  the  number of infants developing intussusception. There- fore,  the  medical-legal environment  in  the  United States forced  the  removal of a  vaccine from  the  market that could have saved millions of infants around the  world  from dying  of diarrhea. Hopefully, potentially safer versions of the  rotavirus vaccine, currently  being  tested, will  be  available in  a  few years. It may  be asked whether the  smallpox vaccine, i.e., vac- cinia, would  have reached the  market and  saved hundreds of millions of lives  and  billions of dollars if it had  been  required to pass the  extremely rigorous standards of the  21th century.

Although vaccinia has  not  been  routinely administered (and  not  available) to the  public  for more  than 20 years, it is now  being  offered  to certain populations considered to be at high  risk in the  event that the  smallpox virus is used for bio- terrorism. In contrast to other available vaccines, there is the potential for morbidity, and  even mortality, with vaccinia. This potential, however, is  very  low  if the  vaccinated population does  not  include immunosuppressed  individuals or  persons with certain skin  conditions, such  as  atopic dermatitis, that compromise the  epidermal barrier. Potentially safer alterna- tives to  live  vaccinia for  smallpox vaccination, however, are being  studied in clinical trials.

Other marked success stories with vaccines include those to prevent poliomyelitis and  to prevent measles. Polio vaccines (plus  public   health measures) have eliminated polio  from North America and  from  most  of the  remainder of the  world. Unfortunately, the  goal  of global  elimination of polio  by the beginning of the  21st  century has  not been  met,  primarily due to  the  difficulty of reaching susceptible individuals in  a  few war-torn parts of the  world.  Although the  distinct advantage exists of polio  having an  effective oral  vaccine, polio  has proven more  difficult to  eradicate than smallpox because of the  numerous subclinical infections (1). The  measles vaccine has  been  almost as  successful as  the  polio  vaccine in  the United States, considering that  fewer  than 100  cases have been  reported annually in this country for the  past few years.

In many parts of the world, however, measles is a major source of mortality as  well  as  morbidity. Approximately 36  million cases of measles occurred globally in 2003. More than one mil- lion  children die  of measles annually, mostly in Third World countries where there is  marked malnutrition and  lack  of vaccines.

Biological criteria  that  are  essential for a  disease to be considered a reasonable candidate for global  elimination are as follows:

• The  disease is  specifically human,  with no  animal reservoir.

• The  disease is  acute, self-limiting, and  infectious for other persons for  about only  a  week  (two  exceptions exist: inclusion body  encephalitis and  subacute scle- rosing panencephalitis).

• An effective method of intervention exists, e.g., a vac- cine (2).

Measles, like  smallpox, meets these criteria, but  measles appears more  difficult to eradicate, partly because it is more infectious than smallpox. Also, there is a period of vulnerabil- ity  between passive immunity due  to  maternal antibodies (and  concomitant resistance to measles vaccination) and  the age  of 12  months, the  youngest age  at which the  vaccine is known to be effective.

Because measles vaccine is usually given  along  with the rubella and  mumps vaccines, these viral diseases should be candidates for  eradication as  well.  This  possibility is  espe- cially  important because of the  severity of congenital rubella. The  difficulty in diagnosis of rubella (and  mumps) makes the surveillance of the  eradication of these viruses more  difficult. Because measles is the  most  infectious of the  three diseases and  the  clinical manifestations are  most  easily recognized, a good surveillance system for measles potentially can  serve as an  effective marker for surveillance of rubella and  mumps in judging the  efficacy  of vaccination campaigns.

Hepatitis B is also a specifically human pathogen and  the vaccine is  safe  and  effective. Indeed, hepatitis  B produces extensive morbidity and  mortality  worldwide. Unlike other viruses that are  reasonable candidates for global  eradication, hepatitis B is a disease in which many persons become  chron- ically  infected early in life and  become  persistent or recurrent excretors of the  virus. Therefore, surveillance becomes much more  difficult and  would  involve  large numbers of people  who are  infected but  are  not ill.

Some  viral diseases that have effective vaccines are  less likely  to be eradicated because of animal reserves. Therefore, control is more  reasonable than eradication. In the  case of yel- low fever, mosquito control is extremely important and  proved very  effective even  before   the   vaccine became available. Another important factor in the  control of yellow  fever  is the fact  that monkeys constitute a jungle reservoir of this virus. Likewise, intervention in the  spread of rabies involves control and  containment of animal reservoirs.

In  general, the  risk / benefit ratio of approved vaccines is extremely favorable. In fact, the  chance of major morbidity (or mortality) from  these vaccines is on the  order of a millionfold less  than that of the  diseases they are  designed to  protect against.  Many persons in  industrialized  countries have reached adulthood in recent decades without knowing anyone who  has  suffered from  measles, rubella, hepatitis B or polio. Thus, they sometimes do not believe there is sufficient justifi- cation to have their children vaccinated. Moreover, unfounded claims have surfaced linking the  measles/mumps/rubella (MMR) vaccine to autism as well as the  hepatitis B vaccine to certain autoimmune diseases. Extensive investigations by such  independent agencies as  the  FDA  and  the  Centers for Disease Control and  Prevention (CDC), however, have demon- strated that there is no cause-and-effect relationship between these vaccines and  the  alleged diseases. Likewise, in  some Third World  countries, some  persons refuse government- sponsored vaccination programs because they fear  that politi- cians do not  have their interests in mind. For  example, some groups believe that vaccine is a form of population control and that it might make them sterile.

While  many persons do not  become  vaccinated because they do not  feel  they are  at risk, this false  sense of security becomes even  more  complicated when vaccines to  prevent sexually transmitted  diseases (STDs)  and  parental consent are  involved. Currently, only  one  vaccine to prevent an  STD is available—the hepatitis B vaccine. Because hepatitis B can also  be  transmitted by  nonsexual routes, however, it is  not perceived by  the  public  as  an  STD  vaccine. The  safety and efficacy  of vaccines to prevent herpes simplex virus (HSV)-2 and   human  papillomavirus (HPV)-16 indicate that  these vaccines could  be marketed by the  end  of the  decade (3,4). If these vaccines are  not  given  before  a  girl  becomes sexually active, the  chance that they would  benefit her  is  markedly decreased. On  the  other hand, convincing the  parents that their daughter will  need  a  vaccine against an  STD  is  often difficult. The  medical need   for  vaccination against  HPV-16—prevention of cervical cancer—is obvious  to the  medical community.

The added difficulty that advocates of this vaccine face is that this relationship between HPV  and  cervical cancer is unknown to most  of the  lay public.

Although the  benefits of vaccination over  therapy are numerous, many persons do not  become  vaccinated for  one reason or another and  there are  vaccines against only 13 viral diseases. Sometimes the cost of the vaccine is cited as a reason not  to  vaccinate. The  cost  of not  vaccinating, however, is almost always greater than the  cost of vaccinating.

In the past three years there have been eight major short- ages  of vaccines. In the  2003–2004 “flu” season, the  shortage of influenza vaccine resulted from the early start of the influenza outbreak as well as the  severity of the  infections. In fact, influ- enza vaccines have been  in short supply for three of the  past four  years. Since  the  beginning of 2000,  there have also  been shortages of vaccines for varicella and  measles as  well as  for such  bacterial diseases as diphtheria and  tetanus. A report by the  Institute of Medicine (IOM),  a  branch of the  National Academy of Sciences, noted that there has  been  a steady ero- sion  in  the  number of vaccine producers over  the  past three decades. In  the  1970s, there were  25 vaccine makers, but  in 2004  there are  only five manufacturers. Most  of the  decline is due  to slim  profit margins and  legislative and  liability issues. Due to such  small number of producers, shortages can develop quickly as  a result of manufacturing problems or underesti- mating the  expected demand.

Approximately 150 million people  are  considered at high risk for  influenza in  the  United States, especially children, persons over 50 years of age and  those suffering from  chronic diseases. One  of the  big uncertainties in forecasting demand for  vaccines is  that only  70  million to  80  million people  are vaccinated annually, leaving a large number who might panic and   seek   vaccination once  a  severe outbreak  begins, as occurred during the  2003–2004 season.

Although vaccines have been  available for  influenza viruses for a number of years, these viruses also  mutate rap- idly  or undergo antigenic drift. Therefore, development of an effective vaccine each  year usually has  limited benefit for sub- sequent years. Because time is  needed for  development and manufacture of the  appropriate influenza vaccine at the beginning of each  “flu” season and  approximately two  weeks are  needed for optimal immunity after receiving the  vaccine, each  year vaccine manufacturers  must make an  educated “guess” regarding the appropriate strain of virus for which the vaccine must be made. Even more  difficult is the  task of deter- mining the  quantity of vaccine to manufacture.

Distribution is often  a problem with influenza vaccines, because some states are  usually hit  worse  than others. Trans- ferring vaccines between states is  a  moderate problem, but during the  2003–2004 influenza season, there was  a nation- wide  shortage which necessitated the  United States to  buy influenza vaccine from other countries.

Four anti-influenza medications are  available for  those persons who do not receive the  vaccine or if the  vaccine strain is  significantly different than  the  infecting strain. These agents include amantadine, ramantadine, oseltamivir, and zanamivir. Whereas some  studies suggest that such  agents may  help  protect a person from  the  symptoms of influenza if started before  or soon after exposure to the virus, most  clinical investigators have confirmed that these drugs can shorten the duration of symptoms of influenza if they are  initiated within the  first one to two days  of the  first symptom.

Many vaccines, such  as  those for tetanus and  varicella, have only a single supplier in the  U.S. market. The  influenza vaccine, including the  recently available nasal spray, has  only three manufacturers. At least for some vaccines, stockpiling is one  solution to  reducing shortages, but  the  CDC  notes that only  three vaccines (of the  10 vaccines targeted for stockpil- ing)  were  stockpiled in  2002.  The  vaccines that were  stock- piled  were  for  measles, mumps, and   rubella, but  a  small amount of polio vaccine is also in storage.

Stockpiling, however, is expensive and  the  CDC has  been conservative about developing stockpiles to  minimize the financial risk. Because of seasonal strain variations, the  influ- enza vaccine cannot be stockpiled.

One reason for manufacturers’ decreased interest in vac- cines  is the  fact  that the  U.S. government buys  slightly more than 50%  of the  vaccines in  the  United States and  keeps prices low, primarily through the  Vaccines for Children pro- gram run by  the  CDC.  Because the  influenza  vaccines are given  to  many more  adults than children, the  government buys  a lower percentage of these vaccines. The CDC negotiates a discounted price  with the  manufacturer under the  Vaccines for Children program. Then it allocates to each  state a credit balance, which states can  use  to buy  vaccines from  the  man- ufacturer at the  discounted price. The  program offers  free vaccines to  uninsured children under 18  years of age  or  to those eligible for Medicaid or care from federally funded qual- ified health centers.

The IOM reports that health-care providers such  as phy- sicians and  clinics  face  unusual  difficulties in  carrying out vaccination programs and  notes that “reimbursements for vaccines and  administrative fees barely cover the  costs  of vac- cine purchase. In many cases, providers lose money  on immu- nization.” In  addition, the  cost  of immunizing children and vulnerable adults is escalating rapidly, as new, expensive rec- ommended vaccines are  FDA-approved. The  cost of immuniz- ing children (adjusted for inflation) has  risen to $385 per child in  2001  from  $10  per  child  in  1975,  and  may  triple to more than $1000  per  child  by 2020.

The  IOM concluded that the  price  squeeze, coupled with a heavy regulatory burden, has  discouraged investment and driven drug companies out  of the  vaccine business. In  addi- tion,  the  manufacture of most  vaccines involves the  complex transformation of live  organisms into  pure, active, safe,  and stable vaccines. Many vaccines must remain in a narrow tem- perature range during storage and  delivery, called the  cold chain. In  addition, each  lot  must be  tested and  approved before  release.

One possible attractive and  potentially inexpensive alter- native to vaccination by injection is the ingestion of transgenic plants  expressing recombinant vaccine immunogens. Such edible plants can be grown locally and  easily distributed with- out  special training  or  equipment. For  example, the  full- length HPV-L1 protein has  been  expressed and  localized to the  nuclei of potatoes. The  plant-expressed L1 self-assembles into  VLPs  (Virus-Like Particles) with immunological proper- ties  comparable to those of native HPV virions. In mice, inges- tion  of the  transgenic potatoes induced a  humoral response similar to that induced by parenteral administration of HPV- L1 VLPs  (5). Thus, the  potential exists for  such  vaccines to become  available for use  in resource-poor areas of the  world, where most  cervical cancer is found.

There is  also  the  problem of legal  liability. Supposedly, manufacturers are  protected from  lawsuits regarding pediat- ric vaccines, but  plaintiffs’ attorneys have found  ways  around that insulation.

All  available vaccines are  prophylactic; there are  no approved viral vaccines that are  therapeutic once  symptoms develop. Some  vaccines, however, can  be  effective if given shortly after exposure to the  virus, although it is always pref- erable to  administer the  vaccine before  exposure to  assure that  sufficient immunity develops. Vaccination after symp- toms  of a disease are  manifested is rarely effective. This  strat- egy,  however, has   been  studied for  the  therapy of human immunodeficiency virus (HIV),  herpes simplex virus (HSV) and  human papillomavirus (HPV)  diseases, but  with limited success. A possible exception is  the  varicella zoster virus (VZV) vaccine, which is  normally given  to  prevent primary varicella (i.e.,  chickenpox). This  vaccine is  currently being studied to determine whether it can be given  to older  individ- uals to prevent the  reemergence of this virus in  the  form  of shingles. Preliminary evidence is encouraging thus far.

Although therapeutic viral vaccines are  not yet available, certain antiviral drugs can  help  prevent infection (Fig. 1.2). The first routine use of an antiviral drug to help  prevent infec- tion  was  the  administration of antiretroviral agents to preg- nant HIV-seropositive women to help  reduce transmission of HIV  to  their infants before  delivery. It is  logical  to  consider that similar use  of antiretroviral agents should reduce sexual transmission of HIV  as  well.  In  fact,  investigators have reported a 60% per partnership reduction in risk of HIV infec- tion  following the  widespread use  of highly active antiretrovi- ral  therapy (HAART)  by  HIV-seropositive persons in  San Francisco. Unfortunately, however, study participants  dou- bled  their rate of unprotected receptive anal intercourse, which offset  the  beneficial effects   of HAART  (6). Another potential means of preventing infection following occupational exposure to  HIV  is  postexposure prophylaxis (PEP). After occupational exposure to blood, empirical treatment with two or more  antiretroviral drugs not  part of the  source patient’s current regimen (i.e.,  PEP) should be provided unless infor- mation such  as  HIV  test results in  the  source patient  or  a detailed description of the  exposure indicate that PEP is not necessary. A third drug, such  as a protease inhibitor, is a rec- ommended addition to  the  regimen if other factors such  as deep  puncture, high  viral load, etc., suggest an  increased risk of HIV. The  source patient should be evaluated to determine the  probability of HIV infection (in accordance with state and local laws and  policies). The use of a quick  HIV test can reduce the  time needed to rule out  HIV  infection to a few hours or less.  A useful resource for discussing treatment options and obtaining  advice regarding  the   management of  adverse effects  of drugs is the  U.S. National Clinicians’ Post-Exposure Prophylaxis Hotline (PEPline, 888-448-4911).

The  guidelines for  nonoccupational HIV  postexposure prophylaxis (NPEP) are  less well defined, but  a registry exists at http://www.hivpepregistry.org. The  NPEP should never be given  as a substitute for primary prevention, i.e., reduction of risky behavior. When prevention efforts have failed (e.g., con- dom  breakage) or  were  not  possible (e.g.,  sexual assault), NPEP can be an important second line of defense. Ideally, PEP or NPEP should be started within one hour, but at least within 72 hours, of exposure.

An early limitation in  knowing who  should receive pos- texposure prophylaxis was  the  fact  that traditional labora- tory  tests for  HIV  took  days  or  weeks to  produce results. In November, 2002, the  OraQuick Rapid HIV-1 test was approved. Although the test only took 20 minutes, it required whole blood. In December, 2003, the Uni-Gold test was FDA-approved as the first rapid-test product for  testing blood  serum, plasma and whole  blood.  This  test, which takes only  10 minutes, had already been  approved by  the  World  Health Organization (WHO)  for HIV  testing in Africa.  Preapproval testing demon- strated that the  Uni-Gold test was  100% accurate in detecting known HIV-positive specimens and  99.7% accurate for confirm- ing negative specimens. On March 25, 2004, the  FDA approved the  first rapid test for HIV in oral  fluids. Therefore, these tests will guide physicians in the  use of postexposure prophylaxis as well  as  in the  use  of antiretroviral agents in HIV-seropositive pregnant women to prevent transmission of the  virus.

The  first FDA-approved use  of an  antiviral agent to reduce sexual transmission of a virus came  in 2003 when val- acyclovir was  approved to reduce the  risk of transmission of genital herpes. This  reduction was  suspected based on  the marked decline in  asymptomatic viral shedding of HSV-2  in persons taking  nucleoside analogs (acyclovir, famciclovir or valacyclovir) (7). In the  study that led to FDA approval, 1484 immunocompetent, heterosexual, monogamous couples were enrolled: one person with clinically symptomatic genital HSV-2 and  one HSV-2 seronegative partner. The partners with HSV-2 infection were  randomly assigned to receive either 500 mg of valacyclovir once daily  or placebo for eight months. Both  part- ners were  counseled on safer sex and  were  offered  condoms at each visit. The susceptible partners were closely monitored for signs or symptoms of genital herpes as well as for seroconver- sion. The study demonstrated that daily  use of valacyclovir by the  source partner resulted in a 77% reduction in clinical gen- ital  herpes and  a 48% reduction in  HSV-2  seroconversion in the  susceptible partner (8). Thus, valacyclovir was  capable of reducing transmission of genital herpes with safer sex  coun- seling and  condom  use.

There is little data to support the  use  of antiherpes med- ication as a “morning after pill.” Although nucleoside analogs used for  herpes treatment are  generally very  safe,  they all require activation by viral thymidine kinase. Therefore, if a person is  not  already  infected with a  herpes virus, it is unlikely that the  nucleoside analog would  be active and  thus able  to prevent infection.

Although there is only one vaccine to prevent a herpesvi- rus  infection—the varicella vaccine—numerous agents  are available to  treat HSV-1,  HSV-2,  VZV, and  cytomegalovirus (CMV).  Interferon-alpha  (IFN-a) was  approved to  treat Kaposi’s  sarcoma before  the  etiology  was  found  to be HHV-8. Therefore, IFN-a alpha is  not  technically approved to  treat HHV-8,  but  it is clear that part of its  mechanism of action is antiviral. Systemic use of such nucleoside analogs as acyclovir, famciclovir, and  valacyclovir can be safe and  effective for acute therapy of herpes labialis, herpes genitalis, primary varicella, or herpes zoster. Suppressive daily  use  of these agents is also safe  and  effective for  preventing most  outbreaks of herpes labialis or herpes genitalis. Topical  acyclovir and  penciclovir are  approved for therapy of herpes labialis and  are  very  safe, but  they are  minimally effective. Trifluridine is available for optical use  only. Although originally proposed to have antivi- ral  properties, n-docosanol was approved as a nonprescription drug to  treat herpes labialis. A number of agents are  now available to treat cytomegalovirus (CMV) infections, primarily in immunocompromised patients. These drugs include ganci- clovir, valganciclovir, foscarnet,  cidofovir, and  fomivirsen. In general, agents used to treat herpes simplex viruses and  vari- cella  virus are  safe  and  effective, but  usually only benefit the patient while  the  drug is being  taken. Antiviral drugs used for therapy of CMV infections, on the  other hand, can  have dose- limiting toxicities, primarily renal, and  should be reserved for those patients for whom  there is a documented indication.

Acyclovir-resistant HSV-1,  HSV-2,  or VZV is usually the result of a mutation or a deficiency of viral thymidine kinase (TK),  the   enzyme necessary  to  phosphorylate acyclovir. Because famciclovir, penciclovir, and  valacyclovir also must be activated by TK, acyclovir resistance usually translates into resistance to all  members of this class  of nucleoside analogs. Foscarnet is FDA-approved for therapy of acyclovir-resistant HSV and  is frequently used for acyclovir-resistant VZV infec- tions. Although not  FDA-approved for  this indication, cido- fovir is also  recommended by the  CDC for acyclovir-resistant HSV and  VZV infections.

Over  100 types of HPV have been  described. These infec- tions cause either benign or malignant lesions of the  skin  or mucous membranes.  Benign lesions can  be  treated with cytodestructive measures or with surgery, but  often  recur due to latent or subclinical HPV in clinically normal-appearing tis- sues. Oncogenic HPV  can  result in  neoplasia such  as  squa- mous   cell  carcinoma, especially in  the   cervix   and   other anogenital tissues. Cervical cancer is the second most  common cause of cancer death of women worldwide. Regular  Pap smears have reduced cervical cancer in  most  industrialized countries by  the  detection of abnormal cytology  and  subse- quent cytodestructive/surgical intervention. The  sensitivity and  specificity of Pap  smears have increased in  recent years due  to the  concomitant use  of HPV  typing. Therapy of benign and  dysplastic lesions due  to HPV  has  improved during the past decade due  to  the  use  of immune response modifiers (IRMs),  such  as imiquimod. Our  understanding of the  mecha- nism of action of imiquimod is partly based on the  activities of IFN-a, the  first antiviral agent approved for therapy of HPV infections. Interferon-alpha  has  antiviral  action, modulates the  immune system, is  antiproliferative, causes phenotypic reversion, downregulates oncogenes, and  upregulates antion- cogenes. Exogenous interferon  was  effective but  had  many negative features, such  as the  necessity of administration via injection, as  well  as  systemic side  effects. Imiquimod stimu- lates the  production of many TH1  cytokines in  addition to IFN-a. Thus it has  potential to be more  effective than exoge- nous  IFN. In addition, imiquimod is applied topically and  has no  systemic side  effects. Use  of IRMs  as  monotherapy, or in combination with traditional treatment,  has  led  to  marked clearances and  has  significantly reduced the  recurrence rate of these lesions. The  clinical effect  of IRMs  originates from cytokine-induced activation of the  immune system. This  is the initial event in  an  immunological cascade resulting  in  the stimulation of the  innate  immune response and   the  cell- medicated pathway of acquired immunity. This  immune mod- ification mediates the  indirect antiviral, antiproliferative, and antitumor activity of imiquimod in vivo.

Whereas VLP vaccines against  oncogenic HPV  will prob- ably  be  available before  the  end  of this decade (4), much remains to  be  learned about how  HPV  causes cancer. The oncogenic HPV  is  considered necessary but  not  sufficient to result in  a  carcinoma. The  role  of cofactors such  as  helper viruses, immunity, cigarette smoking, diet,  and  genetics are under active investigation. A better understanding of these factors should lead  to better prevention and  management of HPV infections (9).

Respiratory syncytial virus (RSV) is a common childhood infection, but  no vaccine is yet  available. Ribavirin, however, is  an  approved therapy and  is  administered to  the  affected patient via  an  aerosol. In  addition, a  monoclonal antibody, palivizumab, is widely  used to prevent RSV infections in high- risk infants.

Approximately 46  million HIV-seropositive persons are estimated by the  WHO to be living  in the  world  at the  begin- ning  of 2004.  Another 16,000 people  acquire the  virus every day,  and  millions of orphans have lost  one or both  parents to the  virus. Over one-third of the  adult populations of some sub- Saharan countries are  infected and  unable to work,  resulting in  collapsed economies. Therefore, the  need  for  a  safe  and effective vaccine to prevent HIV  infection is paramount. The results of the  first phase-III vaccine trial to prevent HIV, how- ever, failed to show  efficacy. The reasons for the  failure of this recombinant gp120  vaccine are  not  completely understood, but  possible explanations include its inability to induce cellu- lar immunity to the  virus, although it did induce antibodies to gp120. General problems with developing an effective vaccine against HIV are  the  ability for the  virus to mutate rapidly and the  existence of many clades of HIV  throughout the  world.  A number of more  antigenic vaccines are  being  developed that involve   recombinant HIV  proteins being   associated with attenuated carrier viruses such  as  adenovirus, vaccinia, or canarypox.

Antiretroviral agents are  now  available to block  replica- tion  of HIV at three different steps: 1) fusion of the  virus and target cell; 2) reverse transcription; and  3) assembly of viral proteins. There are  three types of reverse transcriptase inhibi- tors:  1) nucleoside inhibitors (e.g., zidovudine, lamivudine, zal- citabine, didanosine, stavudine, abacavir, and  emtricitabine);

2) nucleotide inhibitors (e.g.,  tenofovir); and  3) nonnucleo- side  inhibitors (e.g.,  nevirapine, efavirenz, and  delavirdine). Protease inhibitors interfere with viral assembly and  include saquinavir, ritonavir, indinavir, lopinavir, nelfinavir, ampre- navir, fosamprenavir, and  atazanavir. The  newest class  of medication to be approved is the  fusions inhibitors (e.g., enfu- virtide). When used in  certain combinations, these agents compose   highly active antiretroviral  therapy  (HAART). Although HAART  has  resulted in marked reductions in mor- bidity and  mortality in those industrialized areas of the  world where patients or  third-party payers can  afford  the  cost  of approximately $20,000 per year to treat one patient, most  HIV- seropositive persons live  in Third World  countries. Therefore, approximately 99% of the  world’s AIDS patients cannot afford HAART. Although some of these persons have received medica- tion  through donations from  pharmaceutical companies, WHO activities, and  inexpensive generic substitutes,  distribution remains a problem. Most  of the  antiretroviral drugs have toxi- cities (e.g.,  gastrointestinal,  hepatic, neurologic, pancreatic, etc.)  in some  individuals, while  other persons have developed mutant HIV stains that do not  respond to these agents. Phar- macogenetic laboratory tests, such  as  with single-nucleotide polymorphisms (SNPs), now allow  many of these mutations to be detected before  the  patient initiates therapy, thus allowing alternative treatments (10).

The  most  important limitation of HAART,  however, is that it does  not  provide a cure. Although some  persons may have viral loads  below  detectable levels  for many years, dis- continuation of HAART will result in reappearance of HIV in the system. Another major limitation to HAART, in addition to antiviral resistance, is noncompliance. The  reason that com- pliance is difficult for many patients is that HAART  requires a lifetime commitment and  often  necessitates daily  ingestion of multiple medications, avoidance of certain foods, and  con- stant awareness of the  potential of negative interactions with other medications. An unexpected consequence of the  success of HAART  is  that  many high-risk individuals have become complacent about AIDS. Because they know of the  availability of HAART and  do not see large numbers of AIDS patients suf- fering horrible deaths due  to HIV in industrialized countries, many younger individuals are  returning to unprotected sex, intravenous drugs, etc.

With  more  than 20 antiretroviral drugs currently avail- able  and  many more  in clinical trials, many questions remain to be answered, such  as

• What is the  best  combination of antiretroviral agents?

• When is the  best  time to start therapy?

• What is the  optimal sequence in which to use the  anti- retroviral agents?

• What parameters should be used to define the  success or failure of HAART?

Whereas the best  antiretroviral agents usually depend on mul- tiple factors, such  as the  HIV strain  involved and  the  individ- ual  patient’s potential for adverse reactions to a given  drug, it was recently confirmed that the efficacy of antiretroviral drugs depends on  how  they are  combined (11).  Robbins et  al.  (12) determined that the  combination of zidovudine, lamivudine, and  efavirenz was  superior to  other antiretroviral  combina- tions used in the study. This combination not only works longer and  better, but  is also easier to take and  suppresses HIV more quickly. In previous studies, a combination of three antiretro- viral drugs was  superior to two  agents, and  a combination of two  agents was  better than one.  Shafer et  al.  (13)  reported, however, that a four-drug regimen was not significantly differ- ent  from two consecutive three-drug regimens.

The  best  time to initiate therapy depends on many fac- tors   and   is  currently  debated among HIV  experts. Until recently, the  standard of care  was  to start therapy at a low- plasma HIV RNA level and when the CD4 cell count decreased to below 500/mm3. In 2004, however, most  clinicians are  advo- cating initiation of therapy when the  CD4  cell  count falls below  350/mm3  or if the  plasma HIV  RNA level  raises above

55,000 copies/ml. If symptoms of HIV and/or an opportunistic infection develop, however, therapy should be initiated before these laboratory landmarks are  reached. Another factor is patients’ potential to be compliant with the medication. If they are  not  prepared to  adhere to  therapy, drug resistance can develop. In fact, some studies suggest that missing even 5% of antiretroviral medication can hasten drug resistance. In vitro resistance testing of the  virus and  pharmacogenetics can help prevent the  use  of antiretrovirals that may  be resisted. New classes of medication, such  as  the    fusion inhibitors, have allowed new  regimens to be initiated, if resistance develops. Although new drugs are rapidly appearing on the market, new classes of drugs are  developed more  slowly. These new catego- ries  of antiretroviral  agents include viral adsorption inhibi- tors, viral entry inhibitors, viral assembly and  disassembly inhibitors, integrase inhibitors, and  inhibitors of viral mRNA transcription (transactivation) processes (14).

The  most  important criteria for successful antiretroviral therapy are  the  clinical parameters of reductions in morbidity and  mortality. Improvements in morbidity may  be measured by reductions in opportunistic infections or lessened drug tox- icities. Laboratory changes, such   as  increasing CD4  cell counts and /or  decreasing viral loads, usually correlate with clinical improvements.

While  the  treatment of hepatitis A is symptomatic, a safe and  effective vaccine exists and  is recommended for persons at high  risk for this virus. The risk of hepatitis A is dependent on the  quality of food preparation procedures and  on the  sanitary habits of food  service workers. Many persons are  therefore unaware of their risk of hepatitis A. This  fact  became obvious when 555 persons became ill with hepatitis A and  three died in November, 2003,  after ingesting green onions at a restau- rant in Pennsylvania (15).

The vaccine to prevent hepatitis B was  the  first recombi- nant vaccine and  is recommended for health care personnel as well  as  for anyone at high  risk for infection with this virus. Because of the  severe health  consequences of hepatitis  B infection, it is now  given  to neonates as  part of their recom- mended  childhood vaccines (www.cdc.gov/nip). A series of three injections is needed for vaccination against hepatitis B, and  a  series of two  injections is  needed for  hepatitis A. For persons who  have not  been  vaccinated against either virus, however, a simpler alternative to five injections is to receive the  combination of vaccines against both  viruses, which only requires three shots. Approved therapies  for  hepatitis  B include interferon alpha, lamivudine, and  adefovir, although a number of other treatments are  under study.

Hepatitis C is a major cause of morbidity and  mortality in many parts of the  world  and  infections are  increasing rapidly. Unfortunately, because of the  rapid mutation rate of this virus, vaccine development is progressing relatively slowly.  Therapy for hepatitis C was  only  moderately effective with interferon alpha monotherapy, but improved with the addition of ribavirin. Most  recently, clinical and  virological results have been  signifi- cantly better with pegylated interferon combined with ribavirin.

Other hepatitis viruses (i.e., D, E, and  G) have no specific antiviral therapies or  vaccines. The  first line  of defense against all  these viruses, including those for which a vaccine is available, continues to be good public  health procedures.

Although antiviral drugs and  vaccines are  widely  used, the   third classification of medical intervention—passive immunity via  immunoglobulins—is generally less  common. Immunoglobulins (IG) are  difficult to produce in large qualti- ties, have the  potential of microbial contamination, and  have only  transient benefits. In  certain cases, the  use  of IGs  has largely been  replaced by specific  vaccines that provide lifelong immunity (e.g.,  hepatitis A vaccine). Virus-specific IGs  are given to unvaccinated persons exposed to hepatitis B or rabies. Varicella-zoster IG  (VZIG)  is  given  to  susceptible persons exposed to varicella who have a high risk for complications (e.g., immunocompromised patients and  neonates). Cytomegalovirus IG is administered to seronegative transplant recipients of an organ from  a CMV-positive donor. Vaccinia IG is indicated for the therapy of eczema vaccinatum, but this IG is in very limited supply.  Nonspecific IG is given  to unvaccinated, high-risk per- sons  exposed to  measles, hepatitis A, rubella, or  varicella (if VZIG is not available). Perhaps the  most  widely  used IG is the specific  monoclonal antibody against  respiratory  syncytical virus, which is used as  prophylaxis in  high-risk infants (e.g., those with bronchopulmonary dysplasia or prematurity).

Although approval of agents against other families of viruses (e.g., rhinoviruses) is expected in the near future, most advances are  being  made in antiretroviral drugs. Today,  one- half  of all  antiviral agents are  antiretrovirals, but  greater understanding of how to interfere with replication of retrovi- ruses will aid  in the  development of antiviral agents against other families of viruses.

Vaccines for a number of emerging viral diseases are  in development and  include vaccines for West  Nile  virus, Ebola virus, and  the  coronavirus responsible for severe acute respira- tory  syndrome (SARS).  Development of a Dengue vaccine is a particular  challenge because a person with antibodies to one strain of Dengue usually develops more  severe clinical manifes- tations when subsequently exposed to a different strain. The analogous situation could arise if the antibodies to the first strain originated from vaccination. Therefore, the  ideal vaccine against Dengue would  elicit  antibodies to all four common strains.

Development of future antiviral agents and  vaccines will require enhanced knowledge of viral immunology and  phar- macogenetics. Studies that led  to the  first safe  and  effective herpes simplex vaccine revealed at least two surprises:

1.   Neither studies of circulating antibodies to the  recom- binant gD2 glycoproteins nor investigations of periph- eral blood  mononuclear cells  in  vaccinees  were predictive of the  clinical efficacy  of the  vaccine; and

2.   Women seronegative for HSV-1  and  HSV-2  were  pro- tected by the  vaccine, but  men  were  not (3).

Because of the fact that in over two centuries of vaccine develop- ment, there have been  no previous reports of one gender being protected by a vaccine that did  not  protect the  other, current studies involving the herpes simplex vaccine are focusing on the component of immunity that may  play  a greater role in protect- ing a woman against an  STD than a man, i.e., mucosal immu- nity. In  addition to  understanding this component of viral immunity, development of future vaccines and  antiviral agents will need  to focus on persons’ genetic ability to respond, i.e., on the  field  of pharmacogenetics. Just as  some  persons are  more susceptible to infection than others, some individuals are  genet- ically  more  able  to  respond to  prophylaxis or  therapy than others. One  method used to distinguish the  smallest possible genetic differences between individuals and  thus identify those who  could  best  benefit from  a drug or a vaccine is the  SNP. Alternatively, SNPs can also be used to determine who will suf- fer an  adverse effect of a drug, as is already being  done  in HIV therapy. For example, SNPs are used to detect the 5% of the pop- ulation who  inherit a predisposition to a potentially fatal side effect of abacavir. Ultimately, future vaccines and  drugs may  be designed for a specific  patient and  against a specific  virus.

The  future development of drugs and  vaccines, however, will  be  increasingly  expensive. According to  one  study, the average investment required to get one drug approved by the FDA and  marketed in the  United States has  risen to approxi- mately $1.7 billion if one extrapolates from spending by phar- maceutical companies on the  various stages of research and development during the  2000–2002 period. This  figure is an increase from $1.1 billion from 1995–2000, when clinical trials cost  less  and  drug companies were  more  productive in  drug discovery. A 2001 study, however, placed the  cost of bringing a new  drug to  market at $802  million, but  this study did  not include such  commercialization costs  as preparing marketing materials. For every  13 drugs that start out in animal testing, only one reached the  market in 2003–2004, in contrast to one in eight during the  1995–2000 period.

In  summary, public  health measures should remain the first line  of defense against viral diseases, and  should be com- bined with antiviral vaccines when available. Antiviral drugs and   passive immunity with IGs  provide a  second line  of defense, but  are  usually more  expensive than  vaccines and public  health measures, and  provide shorter duration of pro- tection. Although many more  antiviral drugs will  become available in the  21st  century, the  greatest need  is for safe  and effective vaccines against  HIV,  HPV,  HSV,  Dengue, rotavi- ruses, Ebola, West  Nile  virus, SARS, coronavirus, etc. (16).

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