Contributing Authors Marcus Altfeld – Boston Georg Behrens – Melbourne Mario Ostrowski – Toronto Andrea Rubbert – Köln Christiane Schieferstein – Frankfurt Reinhold E. Schmidt – Hannover Bruce D. Walker – Boston Eva Wolf – München HIV Medicine 2003 www.HIVMedicine.com Edited by Christian Hoffmann and Bernd Sebastian Kamps Flying Publisher 3 Editors Christian Hoffmann, M.D. University of Schleswig Holstein Infectious Diseases Outpatient Clinic Kiel Chemnitzstr. 33 24116 Kiel, Germany Fax: + 49 431 1697 1273 www.HIVMedicine.com www.SARSReference.com Bernd Sebastian Kamps, M.D. Flying Publisher Rue Saulnier 75009 Paris France www.FlyingPublisher.com HIV Medicine is an ever-changing field. The editors and authors of HIV Medicine 2003 have made every effort to provide information that is accurate and complete as of the date of publication. However, in view of the rapid changes occurring in medical science, HIV prevention and policy, as well as the possibility of human error, this site may contain technical inaccuracies, typographical or other errors. Readers are advised to check the product information currently provided by the manufacturer of each drug to be administered to verify the recommended dose, the method and duration of administration, and contraindications. It is the responsibility of the treating physician who relies on experience and knowledge about the patient to determine dosages and the best treatment for the patient. The information contained herein is provided "as is" and without warranty of any kind. The contributors to this site, including Flying Publisher and AmedeoGroup, disclaim responsibility for any errors or omissions or for results obtained from the use of information contained herein. © 2003 by Flying Publisher – Paris, Cagliari, Wuppertal, Sevilla Assistant Editors: Nyasha Bakare, Dianne Lydtin Design: Attilio Baghino, www.a4w.it ISBN: 3-924774-37-4 4 Preface Hardly any field of medicine has ever undergone a similar stormy development to that of the therapy of HIV infection. Little more than 10 years passed, between the discovery of the pathogen and the first effective treatment! However, there is also hardly a field that is subjected to so many fast- and short- lived trends. What today seems to be statute, is tomorrow often already surpassed. Nevertheless, therapeutical freedom must not be confused with freedom of choice. This book presents the medical knowledge that is actual today: from December 2002 to January 2003. Because HIV medicine changes so fast, HIV Medicine 2003 will be updated every year. Additional chapters about opportunistic infections, malignancies and hepatitis are freely available at our Web site www.HIVMedicine.com. Under certain conditions, the editors and the authors of this book might agree to remove the copyright on HIV Medicine for all languages except English and German. You could therefore translate the content of HIV Medicine 2003 into any language and publish it under your own name – without paying a license fee. For more details, please see http://hivmedicine.com/textbook/cr.htm. Christian Hoffmann and Bernd Sebastian Kamps Hamburg/Kiel and Paris/Cagliari, January 2003 5 Contributing Authors Marcus Altfeld, M.D. Partners AIDS Research Center Massachusetts General Hospital Bldg. 149, 13th Street, 5th floor Charlestown, MA 02129 USA Tel: 617-724-2461 Fax: 617-726-5411 [email protected] Georg Behrens, M.D. Immunolgy Division Walter And Eliza Hall Institute of Medical Research PO Royal Melbourne Hospital Parkville, 3050, Victoria Australia Fax: 61-3-9347-0852 [email protected] Mario Ostrowski, M.D. Clinical Sciences Division University of Toronto Medical Sciences Building, Rm 6271 1 King's College Circle Toronto, ON M5S 1A8 Canada Tel: 416-946-5805 FAX: 416-978-8765 E-mail: [email protected] 6 Contributing Authors Andrea Rubbert, M.D. Medizinische Klinik I Universitätsklinik Köln Joseph-Stelzmann Str 9 50924 Köln Germany Tel +49 221-478-5623 Fax: +49 221-478-6459 Christiane Schieferstein, M.D. Medizinische Klinik II Uniklinikum Frankfurt Theodor-Stern-Kai 7 60590 Frankfurt am Main Germany Tel: +49 69-6301-0 [email protected] Reinhold E. Schmidt, M.D., Ph.D. Abteilung Klinische Immunologie Zentrum Innere Medizin der Medizinischen Hochschule Hannover Carl-Neuberg-Straße 1 30625 Hannover Germany Tel: +49 511-532-6656 Fax: +49 511-532-9067 [email protected] Contributing Authors 7 Bruce D. Walker, M.D., Ph.D. Partners AIDS Research Center Massachusetts General Hospital Bldg. 149, 13th Street, 5th floor Charlestown, MA 02129 USA Tel: 001 617-724-8332 Fax: 001 617-726-4691 [email protected] Eva Wolf, Dipl. Phys. Univ., M.P.H. MUC Research GmbH Karlsplatz 8 80335 München Germany Tel: +49 89 - 558 70 30 Fax: +49 89 - 550 39 41 Contents 11 Contents Chapter 1: Pathogenesis of HIV-1 Infection 15 Introduction 15 The Structure of HIV-1 17 The HIV Replication Cycle 21 HIV and the Immune System 31 References 41 Chapter 2: Acute HIV-1 Infection 47 Introduction 47 Signs and Symptoms 47 Diagnosis 48 Treatment 50 References 51 Chapter 3: HIV Therapy 2003 53 1. Perspective 53 2. Overview of Antiretroviral Drugs 61 3. Goals and Principles of Therapy 120 4. When to Start HAART 146 5. How to Start with HAART 163 6. When to Change HAART 194 7. How to Change HAART 199 8. Salvage Therapy 204 9. When to Stop HAART 215 10. Monitoring 230 Chapter 4: Management of Side Effects 247 Gastrointestinal Side Effects 248 CNS Disorders 249 Peripheral Polyneuropathy 250 Hoffmann, Kamps, et al. 12 Contents Renal Problems 250 Hepatotoxicity 251 Anemia, Leukopenia 252 Allergies 253 Pancreatitis 256 Avascular Necrosis 257 Osteopenia/Osteoporosis 258 Lipodystrophy, Dyslipidemia 259 Hyperglycemia, Diabetes mellitus 259 Increased Bleeding Episodes in Hemophiliacs 260 References 260 Chapter 5: The Lipodystrophy Syndrome 263 Background 263 Clinical Manifestation 263 HAART, Lipodystrophy Syndrome and Cardiovascular Risk 267 Pathogenesis 268 Diagnosis 272 Therapy 275 References 280 Chapter 6: HIV Resistance Testing 285 Assays for Resistance Testing 285 Background 287 Interpretation of Genotypic Resistance Profiles 289 Summary 296 References 301 Chapter 7: Drug Profiles 307 Abacavir (ABC) 307 Amprenavir (APV) 309 HIV Medicine 2003 – www.HIVMedicine.com Contents 13 Atazanavir (AZV) 312 Combivir® 314 Delavirdine (DLV) 314 Didanosine (ddI) 316 Efavirenz (EFV) 318 Emtricitabin (FTC) 320 Indinavir (IDV) 321 Lamivudine (3TC) 324 Lopinavir (LPV) 326 Nelfinavir (NFV) 329 Nevirapine (NVP) 330 Ritonavir (RTV) 334 Saquinavir (SQV) 337 Stavudine (d4T) 339 T-20 (Enfuvirtide) 341 Tenofovir (TDF) 343 Tipranavir 345 Trizivir® 346 Zalcitabine (ddC) 348 Zidovudine (AZT) 349 Hoffmann, Kamps, et al. 14 Contents HIV Medicine 2003 – www.HIVMedicine.com Introduction 15 Chapter 1: Pathogenesis of HIV-1 Infection Andrea Rubbert and Mario Ostrowski Introduction Since the initial description of the human immunodeficiency virus type I (HIV-1) in 1983 (1,2) and HIV-2 in 1986 (3), these two viruses have been identified for almost 20 years as the pri- mary cause of the acquired immunodeficiency syndrome (AIDS). As HIV-1 is the major cause of AIDS in the world to- day, our discussion will be primarily limited to HIV-1 infection. Worldwide, the number of HIV-1 infected persons exceeds 40 million, the majority of whom live in the developing countries of Asia, sub-Saharan Africa and South America. The introduction of protease inhibitors and non-nucleoside re- verse transcriptase inhibitors (NNRTI) to antiretroviral treat- ment regimens in 1995 began the era of highly active antiretro- viral therapy (HAART), and resulted in dramatic improvements in the mortality and morbidity of HIV disease, as determined by a decreased incidence of opportunistic infections, tumors, and deaths. Despite all the therapeutic advantages achieved during the last decade, including the development of highly active antiretroviral therapy ("HAART"), once an individual has be- come infected, eradication of the virus still remains impossible. In addition, new problems relating to the short- and long-term toxicity of drug treatments and the occurrence of resistance mutations in both circulating and transmitted viruses are emerging. In most countries in South East Asia and Africa, the incidence and prevalence of HIV-1 infection continues to in- crease and surpass that of Europe and North America. However, due to the high costs of drug regimens and the lack of a healthcare infrastructure in these developing countries, the Hoffmann, Kamps, et al. 16 Pathogenesis of HIV-1 Infection widespread use of HAART is currently not feasible. The further course of the HIV-1 pandemic therefore mainly depends on how and to what degree the developing countries with a high HIV-1 prevalence are able to take advantage of the medical progress achieved in Europe and North America, and whether an effective prophylactic vaccine might become available in the near future. An understanding of the immunopathogenesis of HIV-1 infec- tion is a major prerequisite for rationally improving therapeutic strategies, developing immunotherapeutics and prophylactic vaccines. As in other virus infections, the individual course of HIV-1 infection depends on both host and viral factors. The course of infection with HIV-1 in HIV-infected humans may vary dramatically, even though the primary infections arose from the same source (4). In some individuals with a long-term nonprogressive HIV-1 infection (i.e. lack of decline in CD4 counts, or chronic infection for at least seven years without the development of AIDS), a defective virion was identified (5). Thus, infection with a defective virus, or one which has a poor capacity to replicate, may prolong the clinical course of HIV-1 infection. However, in most individuals HIV-1 infection is characterized by a replication competent virus with a high turn-over of virions produced daily. Host factors may also deter-mine whether or not an HIV-1 infected individual will rapidly develop clinically overt immunodeficiency or whether this individual may belong to the group of long-term nonprogressors, who represent about 5% of all infected patients.