Reverse Transcriptase Inhibitors in HIV/AIDS Therapy

536 Pages·2006·7.87 MB·English

by  David K. Stammers

Reverse Transcriptase Inhibitors
in HIV/AIDS Therapy
I
n f e c t i o u s . D i s e a s e
SERIES EDITOR: Vassil St. Georgiev
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Reverse Transcriptase Inhibitors in HIV/AIDS Therapy,edited byGail
Skowron,MDand Richard Ogden,PPPhDD, 2006
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PPPharmDandKeith A. Rodvold, PPPharmDD,2001
I n f e c t i o u s . D i s e a s e
Reverse Transcriptase
Inhibitors
in HIV/AIDS Therapy
Edited by
Gail Skowron,
MD
Chief, Division of Infectious Diseases
Roger Williams Medical Center, Providence, RI
Boston University School of Medicine, Boston, MA
Richard Ogden,
PhD
Pfizer Inc., San Diego, CA
Foreword by
Joep M. A. Lange, MD, PhD
Professor of Medicine
Center for Poverty-Related Communicable Diseases
Academic Medical Center, University of Amsterdam
Amsterdam, The Netherlands
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Library of Congress Cataloging-in-Publication Data
Reverse transcriptase inhibitors in HIV/AIDS therapy /edited by GailSkowron, Richard Ogden ;
foreword by Joep M. A. Lange.
p. ; cm. -- (Infectious disease)
Includes bibliographical references and index.
ISBN 1-58829-649-0 (alk. paper)
1. AIDS (Disease)--Chemotherapy. 2. HIV infections--Chemotherapy. 3. Reverse transcriptase--
Inhibitors--Therapeutic use. 4. Antiretroviral agents. [DNLM: 1. Acquired Immunodeficiency
Syndrome--drug therapy. 2. HIV Infections--drug therapy. 3. Reverse Transcriptase Inhibitors--
therapeutic use. WC 503.2 R452 2006] I. Skowron, Gail. II. Ogden, Richard C., 1953- III. Series:
Infectious disease (Totowa, N.J.)
RC606.7.R48 2006
616.97'92061--dc22
2005033190
Foreword
Although nucleoside analog reverse transcriptase inhibitors (NRTIs) were
the first active antiretroviral agents that made it to the market–zidovudine, as
early as 1987, less than four years after the discovery of HIV as the causative
agent of AIDS–they remain a mainstay of anti-HIV therapy: the “backbone” of
most highly active antiretroviral therapy (HAART) regimens still consists of a
combination of two NRTIs or the nucleotide.
The dramatic impact that the introduction of HAART in the mid-1990s has
had on HIV-related morbidity and mortality in the developed world is one of
the success stories of modern medicine, a success story that was initially almost
exclusively ascribed to the introduction of HIV protease inhibitors (PIs), but
that to a greater extent was a consequence of the introduction of molecular
techniques, such as PCR, to measure plasma HIV-1 load. The ability to quantify
the HIV load led to the elucidation of HIV dynamics and an understanding of
the necessity to suppress HIV replication to near minimal levels with a
combination of drugs with nonoverlapping drug resistance patterns. When
these principles were applied for the first time in the INCAS study, which used
a non-nucleoside RT-inhibitor (NNRTI) instead of a PI as the third drug or
“anchor drug” in a HAART regimen, NNRTIs—which were initially discarded
because of rapid loss of activity due to the rapid development of viral drug
resistance—were resurrected as a valuable antiretroviral drug class. In fact,
most first line HAART regimens are now NNRTI- and not PI-based.
With all the excitement about drugs in development with new antiviral
targets, such as HIV entry and proviral integration in the host genome, it is
easy to forget the simple fact that most current first-line HAART regimens rely
exclusively on inhibition of RT, albeit by two different mechanisms.
Combinations of two N(t)RTIs and an NNRTI have proven to be exceptionally
successful, from the perspectives of efficacy, tolerance, and ease of use.
Who would have predicted this in the early 1990s? Then, NNRTIs were cast
aside because of the aforementioned low genetic barrier against resistance
development, and NRTIs were considered by many to be useless drugs because
of the outcomes of the ill-conceived and misinterpreted Concorde and
ACTG155 studies.
Because they can be manufactured at low cost and can be coformulated,
NRTI/NNRTI combinations have also become the dominant regimens used in
the scale up of antiretroviral therapy in resource-poor settings.
The characterizations “timely” and “relevant” thus very much apply to this
book, which covers all aspects of NRTIs, N(t)RTIs and NNRTIs, including
v
vi Foreword
drug discovery, pharmacology, development of viral drug resistance, toxicity,
and prevention of mother-to-child transmission of HIV. In recognition of the
global distribution of HIV and the current momentum to increase access to
antiretrovirals in resource-poor settings, and much to my satisfaction,Reverse
Transcriptase Inhibitors in HIV/AIDS Therapy also dedicates a chapter to HIV
therapies in the developing world, coauthored by my oldest African friend and
collaborator Elly Katabira.
May the book enlighten, inspire, and guide those involved in antiviral drug
discovery, and those involved in the care and treatment of persons living with
a virus that is not only killing individuals on a massive scale, but also fueling a
global tuberculosis epidemic and threatening the survival of whole societies.
Joep M. A. Lange,MDDD,PPPhD
Professor of Medicine
Center for Poverty-Related
Communicable Diseases
Academic Medical Center
University of Amsterdam
Amsterdam, The Netherlands
Preface
Inhibitors of nucleic acid biosynthesis have had a long and varied history as
therapeutic agents. They have frequently provided the backbone of therapy in a
wide variety of proliferative disorders ranging from infectious diseases to
cancer. Because of the specialized and highly evolved synthetic chemistry in
this area, the many analogs of nucleosides, nucleotides, and their biosynthetic
precursors have found use as tools for basic research. It is not surprising that,
upon discovery of the etiology of AIDS about twenty years ago—it is a
syndrome associated with infection with a retrovirus—nucleoside analogs with
potential antiviral activity against the virally encoded RNA-dependent DNA
polymerase (reverse transcriptase) were among the first compounds to be
screened.
Reverse Transcriptase Inhibitors in HIV/AIDS Therapy covers the discovery
and development of this class of drugs and others inhibiting the same viral
target from a therapeutic perspective. As the vanguard agents with efficacy in
this disease, these nucleoside analogs were also the first to manifest the
toxicities and resistance associated with chronic administration and inadequate
single-agent potency. Nevertheless, they have retained their position as the
backbone of therapy in the vast majority of newly treated and treatment-
experienced patients. The discovery of several unrelated chemical classes of
inhibitors, all binding to the same target, has meant for many patients that viral
reverse transcriptase is the sole target for highly active drug combination
therapy.
Human cells express many polymerases involved in essential functions.
Therefore, there is every expectation that nonselective viral polymerase
inhibitors would possess inescapable mechanism-based toxicities. The HIV
reverse transcriptase, however, has no human counterpart, giving reason to
believe that a wider safety margin might be achievable. This is still a
challenging area of research.
The early chapters describe the role of reverse transcriptase in the viral life
cycle and structural work that has led to a greater understanding of mechanism
and resistance. The discovery and development of six nucleoside analogs are
described in the next chapters. Among these are drugs representing milestones
in treatment history, such as the benefit of combination therapy, as well as
milestones in pharmaceutical manufacturing, such as coformulation. The
inescapable topics of toxicities and resistance to this class are described in
subsequent chapters.
vii
viii Preface
The non-nucleoside reverse transcriptase inhibitors are described in a similar
fashion in general terms, and two chapters discuss these agents with respect to
pharmacokinetics and comparative clinical efficacy. New reverse transcriptase
inhibitors in all classes in various stages of development are described in one
chapter and the impact of the approved agents on treatment in general and on
vertical transmission in the developing world are dealt with in the final chapters.
Gail Skowron,MD
Richard Ogden,PPPhD
Contents
Foreword
Joep M. A. Lange, MD, PhD .................................................................v
Preface ............................................................................................vii
Contributors ....................................................................................xi
1 Structural Studies on HIV Reverse Transcriptase
Related to Drug Discovery
David K. Stammers, PhD and Jingshan Ren, PhD.........................1
2 Zidovudine, Lamivudine, and Abacavir
Monica Carten, MD and Harold Kessler, MD .............................33
3 Stavudine, Didanosine, and Zalcitabine
Gail Skowron, MDD, Sapna Chowdhry, MDD,
and Michael R. Stevens, PharmD...............................................77
4 Emtricitabine
Gail Skowron, MDD, Jeffrey Bratberg, PharmD, BCPSS,
and Rudi Pauwels, PhD ...........................................................133
5 Nucleotide Analogs
Craig J. Hoesley, MD ....................................................................157
6 Resistance to Nucleoside and Nucleotide Reverse
Transcriptase Inhibitors
Nancy Shulman, MD and Mark Winters, MS...........................179
7 Pharmacokinetics of Reverse Transcriptase Inhibitors
Patrick Hoggard, PhD, Stephen Kewn, PhD,
Saye Khoo, MDD, PhDD, and David Back, PhD...........................209
8 Peripheral Neuropathy Associated With Nucleoside
Reverse Transcriptase Inhibitor Therapy
Bruce A. Cohen, MD and Russell Bartt, MD..............................237
ix