Combination Therapy of AIDS

247 Pages·2004·12.99 MB·English

by  Erik De Clercq (auth.)

Milestones in Drug Therapy
MDT
Series Editors
Prof. Dr. Michael J. Parnham Prof. Dr. J. Bruinvels
Senior Scientific Advisor Sweelincklaan 75
PLIVA dd NL-3723 JC Bilthoven
Prilaz baruna Filipovica 25 The Netherlands
10000 Zagreb
Croatia
COlllbination Therapy
ofAIDS
Edited by E.D.A. De Clercq and A.-M.I. Vandamme
Springer Basel AG
Editors
Erik D.A. De Clercq / Anne-Mieke 1. Vandamme
Katholieke Universiteit Leuven, Rega Institute
Minderbroedersstraat 10
B-30oo Leuven, Belgium
Advisory Board
J.c. Buckingham (Imperial College School of Medicine, London, UK)
D. de Wied (Rudolf Magnus Institute for Neurosciences, Utrecht, The Netherlands)
F.K. Goodwin (Center on Neuroscience, Washington, USA)
G. Lambrecht (J.W. Goethe Universitiit, Frankfurt, Germany)
Library of Congress Cataloging-in-Publication Data
Combination therapy of AIDS / edited by E.D.A. De Clercq and A.-M.1. Vandamme.
p. ; cm. --(Milestones in drug therapy)
Includes bibliographical references and index.
ISBN 978-3-0348-9604-7 ISBN 978-3-0348-7869-2 (eBook)
DOI 10.1007/978-3-0348-7869-2
1. AIDS (Disease)--Chemotherapy. 2. AIDS (Disease)--Treatment. 3. Chemotherapy,
Combination. 4. Antiviral agents. 1. De Clercq, Erik. II. Vandamme, Anne-Mieke, 1960-
III. Series.
[DNLM: 1. HIV Infections--drug therapy. 2. Anti-HIV Agents--therapeutic use. 3.
Antiretroviral Therapy, Highly-Active. 4. Treatment Outcome. WC 503.2 C7314 2003]
RC606.6.C64 2003
616.97'92061--dc22
2003052372
Bibliographic information published by Die Deutsche Bibliothek
Die Deutsche Bibliothek lists this publication in the Deutsche Nationalbibliografie; detailed biblio
graphic data is available in the internet at http://dnb.ddb.de
ISBN 978-3-0348-9604-7
The publisher and editor can give no guarantee for the information on drug dosage and administration
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The use of registered names, trademarks etc. in this publication, even if not identified as such, does not
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© 2004 Springer Basel AG
Originally published by Birkhauser Verlag in 2004
Softcover reprint ofthe hardcover I st edition 2004
Printed on acid-free paper produced from chlorine-free pulp. TFC
00
Cover illustration: provided by Prof. De CIercq.
NRTIs: nucleoside reverse transcriptase inhibitors (zidovudine, didanosine, zalcitabine, stavudine,
lamivudine, abacavir, emtricitabine)
NtRTIs: nucleotide reverse transcriptase inhibitors (tenofovir, disoproxil fumarate)
NNRTIs: non-nucleoside reverse transcriptase inhibitors (nevirapine, delaviridine, efavirenz)
Fis: fusion inhibitors (enfuvirtide)
PIs: protease inhibitors (saquinavir, ritonavir, indinavir, nelfinavir, amprenavir, lopinavir,
atazanavir)
ISBN 978-3-0348-9604-7
987654321 www.birkhauser-science.com
v
Contents
Listofcontributors VII
Preface IX
ErikDe Clercq
Anti-HIV agents to be used in drug combinationregimens 1
Deborah Konopnicki andNathan Clumeck
A perspective ofthe history ofHAART 25
Cecile L. Tremblay andMartin S. Hirsch
The basic principles for combination therapy 41
RogerParedes, Bonaventura ClotetandLidia Ruiz
Comparisonofthe efficacy ofHAART: single, dual or
triple-class antiretroviral therapy 53
Michael Kurowski
Pharmacokinetics andpharmacodynamics ofHAART 73
LucPerrin andMarie-Charlotte Bernard
Primary HIV infection: from diagnosis to treatment 87
Marianne Harris andJulio S.G. Montaner
Salvagetherapy 99
Felipe Garda, Joan Joseph andJoseM. Gatell
Structuredtherapy interruptions (STIs): lessons from a
therapeutic strategy 115
BrigitteAutran
Immunereconstitutionin HIV infection 127
Nicole H. Tobin andLisaM. Frenkel
Highly active antiretroviral treatment (HAART) of
pediatric HIV-l infection 141
RoyM. Gulick
Causes ofHIV treatmentfailure 159
VI Contents
ChristopherHoltzerandMike Youle
Economic implicationofHIV-l resistance testing in
overall clinicalcare 195
Charles C.J. Carpenter
Guidelines for antiretroviral therapy 205
Ume L. Abbas andJohn W Mellors
Visions for the future ofantiretroviral therapy 225
Index 239
VII
List of contributors
UmeL. Abbas, University ofPittsburgh, DivisionofInfectious Diseases, Falk
Medical Building, Suite 3-A, 3601 FifthAve, Pittsburgh, PA 15213, USA;
e-mail: [email protected]
Brigitte Autran, Laboratoire d'lmmunologie Cellulaire et Tissulaire, CNRS
UMR 7627, Hopital Pitie-Salpetriere, 47-83, bId de l'hopital, Batiment
CERVI, 75013 Paris, France; e-mail: [email protected]
Marie-Charlotte Bernard, Division of Infectious Diseases and Laboratory of
Virology, Geneva University Hospital, 1211 Geneva 14, Switzerland
Charles c.J. Carpenter, Department of Medicine, The Miriam Hospital, 164
SummitAvenue, Providence, RI 02906, USA; e-mail: [email protected]
Erik De Clercq, Rega Institute for Medical Research, Katholieke Universiteit
Leuven, B-3000 Leuven, Belgium; e-mail: Erik.DeClercq@rega.
kuleuven.ac.be
Bonaventura Clotet, HIV Unit, Hospital Universitari Germans Trias I Pujol,
08916 Barcelona, Spain
Nathan Clumeck, Saint-Pierre University Hospital, Department of Infectious
Diseases, 322 rue Haute, 1000 Brussels, Belgium, e-mail:
[email protected]
Lisa M. Frenkel, University of Washington, Department of Pediatrics and
Laboratory of Medicine, 4800 Sand Point Way, NE, Seattle, WA 98105,
USA; e-mail: [email protected]
Felipe Garcia, Clinic Institute of Infectious Diseases and Immunology,
IDIBAPS, Hospital Clinic, Faculty of Medicine, University of Barcelona,
Villarroel, 170, 08036 Barcelona, Spain; e-mail: [email protected]
Jose M. Gatell, Clinic Institute of Infectious Diseases and Immunology,
IDIBAPS, Hospital Clinic, Faculty of Medicine, University of Barcelona,
Villarroel, 170,08036Barcelona, Spain; e-mail: [email protected]
Roy M. Gulick, Weill Medical College ofCornell University, Cornell Clinical
Trials Unit, 525 East 68th Street, New York, NY 10021, USA; e-mail:
[email protected]
Marianne Harris, British Columbia Centre for Excellence in HIV/AIDS, 667
1081 Burrard Street, Vancouver, BC V6Z lY6, Canada; e-mail:
[email protected]
Martin S. Hirsch, Massachusetts General Hospital, Harvard Medical School,
65 Landsdowne St, Room 419, Cambridge, MA 02139, USA; e-mail:
[email protected]
ChristopherHoltzer, University ofCalifornia, SanFrancisco, Gilead Sciences
Inc., FosterCity, CA, USA
VIII Listofcontributors
Joan Joseph, Clinic Institute of Infectious Diseases and Immunology,
IDlliAPS, Hospital Clinic, Faculty of Medicine, University ofBarcelona,
Villarroel, 170,08036Barcelona, Spain; e-mail: [email protected]
Deborah Konopnicki, Saint-Pierre University Hospital, Department of
Infectious Diseases, 322 rue Haute, 1000 Brussels, Belgium; e-mail:
[email protected]
Michael Kurowski, Therapia GmbH, Rubensstrasse 125, 12157 Berlin,
Germany: e-mail: [email protected]
John W. Mellors, University of Pittsburgh, Division of Infectious Diseases,
SchoolofMedicine, ScaifeHall,Suite818, 3550Terrace Street, Pittsburgh,
PA 15261, USA; e-mail: [email protected]
Julio S.G. Montaner, University of British Columbia/St. Paul's Hospital,
British Columbia Centre for Excellence in HIV/AIDS, 667-1081 Burrard
Street,Vancouver, BCV6Z 1Y6, Canada; e-mail:[email protected]
Roger Paredes, HIV Unit, Hospital UniversitariGermansTrias IPujol, 08916
Barcelona, Spain; e-mail: [email protected]
Luc Perrin, Division of Infectious Diseases and Laboratory of Virology,
Geneva University Hospital, 1211 Geneva 14, Switzerland; e-mail:
[email protected]
Lidia Ruiz, mv Unit, Hospital Universitari Germans Trias I Pujol, 08916
Barcelona, Spain; e-mail: [email protected]
Nicole H. Tobin, University of Washington, Department of Pediatrics and
Laboratory of Medicine, 4800 Sand Point Way, NE, Seattle, WA 98105,
USA; e-mail: [email protected]
Cecile L. Tremblay, C.H.U.M., Hopital Hotel-Dieu de Montreal, Pavillon
Jeanne-Mance, Bureau 7-355, 3840, rue Saint-Urbain, Montreal Qc, H2W
1T8, Canada, e-mail: [email protected]
Mike Youle, HIV Clinical Research, Royal Free Centre for HIV Medicine,
Royal Free Hospital, Pond Street, London NW3 2QG, UK; e-mail:
[email protected]
IX
Preface
HIVinfection has been agreaterchallengeto currentmedicine than any other
viraldiseaseofmodemtimes. HIVleadsto apersistentinfectionandthevirus
hasanimmensegeneticflexibility underselectivepressure. Duringitsreplica
tive cycle in patients, HIV accumulates mutations at such a high rate that the
selective pressure inflicted on the immune system, or generated by antiviral
drugs rapidly triggers the appearance ofescape mutants. Currently available
drugs, when used singly, are not capable of suppressing virus replication in
patients to such alevel that the generation ofmutations, from which a variant
resistanttoimmuneattackorantiviraldrugs canbeselected,isprevented.This
is the main reason why combination therapy, usually of three drugs, has
become the standardprocedure for the treatmentofAIDS.
It is obvious that virus eradication will not readily be achievable, so that
drugs have to be taken for aprolongedtime oreven lifelong so as to keep the
viral load as low as possible. Whether the currently used drug combinations
will be able to control virus replication in a particular patient for such a pro
longed period oftime depends on many factors, most ofwhich are addressed
in the differentchapters ofthis book.
The aim of antiviral drug combination therapy for AIDS is ultimately to
restorefull function ofthe immune system.Theexpectedimmunologicalben
efit is one ofthe major determinants driving the decision when to start thera
py.Inprinciple,treatmentshouldbestartedsufficientlyearly,soas nottocom
promise too much immune competence. However, in the past the traditional
drugregimenshavebeencompoundedbyanumberofside-effectswhichoften
caused patients to not adhere to drug intake. Itcould be argued therefore that
therapyshouldnotbe startedtooearly, soas notto weakenmotivationforlife
long compliance in the face ofmore harm from side-effects ofthe drugs than
of the disease itself. Shifting treatment guidelines reflects this difficult bal
ance. In addition, the potency ofthe individual drugs also contributes to the
choice ofthe drugs to be incorporated in thecombinationregimens.
Current clinical tools to evaluate the success ofantiretroviral combination
therapies are still based on viral load, reflecting virus replication, and CD4
count, reflecting the status of the immune system. A new tool has recently
emerged: drugresistancetesting.Itislogicalthatknowledgeofdrugresistance
will help in therapy decisions; however, scientific evidence was only recently
firmly established, so that guidelines now include resistance testing. Other
parameters such as drug level monitoring and drug adherence are considered
very valuable, buthave notbeenevaluated sufficiently thoroughly in prospec
tive studies to warrant theiruse in routine clinicalpractice.
x Preface
In the introduction chapter of the book, Erik De Clercq provides an
overview ofthefourdifferentclasses ofcompounds thatare now availablefor
the treatment ofAIDS, the so-called NRTIs (nucleo~ide reverse transcriptase
inhibitors),NtRTIs (nucleotidereversetranscriptaseinhibitors),NNRTIs (non
nucleoside reverse transcriptase inhibitors) and PIs (protease inhibitors). A
fifth class, that of the virus-cell fusion inhibitors, is represented by a single
compound (enfuvirtide) that has recently been approved and that, together
with the NRTIs, NtRTIs, NNRTIs and PIs, could be included, when available
and desirable, intocombination drugregimens.
How antiviral drug therapy ofAIDS evolved from a single drug (zidovu
dine) therapy in 1987 to what today is commonly referred to as highly!!ctive
!!ntiretroviral therapy (HAART) is chronicled by Deborah Konopnicki and
Nathan Clumeck.
CecileL. Tremblay and Martin S. Hirsch then describe the basicprinciples
for combining different drugs in the treatment ofHIV infection. Simply stat
ed, triple drug combinations do betterthan dual drug combinations, which, in
tum, score better than single drug monotherapy. Roger Paredes, Bonaventura
ClotetandLidiaRuizhaveassesseddifferentforms ofmultiple-drugregimens
from acomparativeviewpoint.
The drug levelsachieved at thesite(s) ofvirus replication areofparamount
importance to predict the efficacy of any drug regimen, and this should
becomeclearfrom thechapterofMichael Kurowski on the pharmacokinetics
and pharmacodynamics ofthe therapeutic regimens used.
LucPerrin andMarie-CharlotteBernarddiscuss HAART treatmentfor pri
mary HIV infection, an indication which today is recommended only within
the scope offormal clinical trials. This chapter is followed by the chapter of
MarianneHarris andJulioS.G. Montaneron salvagetherapyfor which, as for
first-line therapies, sustained immunological and clinical benefit has been
demonstrated only when complete suppression of plasma viral load is
achieved.
Felipe Garcia, Joan Joseph and Jose M. Gatell tell us what to expect from
structural therapy interruptions (STIs) as a strategy to re-activate or reconsti
tuteimmunity, aprovocativeapproachtowards the therapeutic managementof
HIV infections. The kinetics ofimmunereconstitution and the currentlimita
tions thereofare further analyzedby BrigitteAutran.
Specific aspects have to be considered when dealing with HAART in chil
dren infected with HIV-l, and suggestions on how to treat such pediatric
HIV-l infections are proposed by NicoleH. Tobin and LisaM. Frenkel.
Treatment failure continues to occur commonly because of a multitude of
reasons and, when assessing remedies to prevent or overcome treatment fail
ures, discontinuation ofdrug therapy for toxicity, non-adherenceorotherrea
sons mustbedistinguishedfrom virologic,immunologicandclinicaltreatment
failures, as pointedout byRoy M. Gulick.
One ofthe major reasons for treatment failure is the development ofillV
resistance towards the antiretroviral medications. The sensitivity ofHIV-l to