Antiviral Agents, Vaccines and Immunotherapies

438 Pages·2004·7.7 MB·English

by  Stephen Tyring

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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
iii
iv Preface
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
Preface v
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

Acknowledgements
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.
vii

Contents
Chapter 1. Introduction .................................................. 1
References .... 22
Chapter 2. Antiretroviral Drugs to Treat Human
Immunodeficiency Virus Infections ...... 25
Introduction .... 25
Human Immunodeficiency Virus .... 27
Nucleoside Reverse Transcriptase Inhibitors .... 39
Zidovudine [AZT] (Retrovir) .... 39
Didanosine[ddI] (Videx) .... 42
Stavudine [d4T] (Zerit) .... 44
Zalcitabine [ddc] (Hivid) .... 46
Lamivudine [3TC] (Epivir) .... 48
Abacavir [ABC] (Ziagen) .... 50
Emtricitabine (Emtriva, Coviracil, FTC) .... 52
Non-Nucleoside Reverse Transcriptase Inhibitors .... 53
Nevirapine [NVP] (Viramune) .... 54
Delavirdine [DLV] (Rescriptor) .... 56
Efavirenz [EFV] (Sustiva) .... 59
Nucleotide Reverse Transcriptase Inhibitors .... 62
Tenofovir Disproxil Fumerate (Viread) .... 62
ix
x Contents
HIV Protease Inhibitors .... 65
Saquinavir [SQV] (Invirase: Hard Gel;
Fortovase: Soft Gel) .... 67
Ritonavir [RTV] (Norvir) .... 68
Indinavir [IDV] (Crixivan) .... 71
Nelfinavir [NFV] (Viracept) .... 75
Amprenavir [APV] (Agenerase) .... 77
Fosamprenavir (Lexiva, GW 433908) .... 80
Atazanavir (Reyataz, BMS-232632) .... 83
Lopinavir + Ritonavir [ABT-378/r] (Kaletra) .... 84
Fusion Inhibitors .... 85
Enfuvirtide (ENF, T-20, Pentasufide, Fuzeon) .... 86
Investigational Drugs .... 88
Conclusion .... 89
References .... 90
Chapter 3. General (Non-Antiretroviral)
Antiviral Drugs.......................................... 123
Introduction .... 123
Viral Infections Other than HIV .... 126
Herpes Simplex Virus (HSV-1 and -2) .... 126
Varicella Zoster Virus (VZV) .... 131
Epstein-Barr Virus (EBV) .... 132
Cytomegalovirus (CMV) .... 133
Human Herpesvirus 8 (HHV-8) .... 135
Human Papillomavirus (HPV) .... 135
Molluscum Contagiosum Virus (MCV)
and other Poxviruses .... 137
Hepatitus B Virus (HBV)/Hepatitus C Virus (HCV) .... 139
Influenza Virus .... 140
Respiratory Syncytial Virus (RSV) .... 142
Rhinovirus .... 142
Nucleoside Analogs .... 143
Acyclovir .... 143
Valacyclovir .... 154
Famciclovir .... 160
Penciclovir .... 166
Ganciclovir .... 169
Valganciclovir .... 174
Ribavirin .... 178