HIV Medicine - part 1 pdf

However, it took almost two years until, in 1983,the human immunodeficiency virus type I HIV-1 was defined as the primarycause of the acquired immunodeficiency syndrome Barré-Sinoussi 19

Dirk Albrecht, Borstel

Marcus Altfeld, Boston

Philip Aries, Hamburg

Georg Behrens, Hannover

U Fritz Bredeek, Tucson

Thomas Buhk, Hamburg

Laura Dickinson, Liverpool

Christian Eggers, Linz

Gerd Fätkenheuer, Cologne

Georg Friese, Gießen

Ardeschir Ghofrani, Gießen

Carole Gilling-Smith, London

Katrin Graefe, Hamburg

Christian Hoffmann, Hamburg

Bernd Sebastian Kamps, Paris

Peter Krings, Essen

Christoph Lange, Borstel

Thore Lorenzen, Hamburg

Hermione Lyall, London

Grace A McComsey, Cleveland

Leonie Meemken, Hamburg

Oliver Mittermeier, Hamburg

Fiona Mulcahy, Dublin

Till Neumann, Essen

Tim Niehues, Düsseldorf

Falk Ochsendorf, FrankfurtMario Ostrowski, TorontoWolfgang Preiser, TygerbergAnsgar Rieke, KoblenzJürgen Rockstroh, BonnThorsten Rosenkranz, HamburgAndrea Rubbert, CologneDana A Sachs, Ann ArborBernhard Schaaf, LübeckChristiane Schieferstein, FrankfurtReinhold E Schmidt, HannoverHelmut Schöfer, FrankfurtUlrike Sonnenberg-Schwan, MunichMirko Steinmüller, Gießen

Matthias Stoll, HannoverSusanne Tabrizian, HamburgZahra Toossi, ClevelandMechthild Vocks-Hauck, BerlinBruce D Walker, BostonUlrich A Walker, FreiburgJan-Christian Wasmuth, BonnMichael Weigel, MannheimThomas Weitzel, BerlinEva Wolf, Munich

HIV Medicine 2006 www.HIVMedicine.com

Edited by

Christian Hoffmann Jürgen K Rockstroh Bernd Sebastian Kamps

Flying Publisher

© 2006 by Flying Publisher – Paris, Cagliari, Wuppertal

Proofreading: Emma Raderschadt, M.D.

Cover: Attilio Baghino, www.a4w.it

ISBN: 3-924774-50-1 – ISBN-13: 978-3-924774-50-9

Printed by Druckhaus Süd GmbH & Co KG, D-50968 Cologne, Tel + 49 221 387238

Email: info@druckhaus-sued.de

Preface 2006

As in previous years, all chapters of the 14th edition have been thoroughlyrevised, and new chapters have been added (HIV and Renal Disease, SexualDysfunction in HIV/AIDS) Again, the book is freely available on theInternet That is the way, we firmly believe, that medical textbooks should

be handled in the 21st century

HIV Medicine is now available in Spanish, German, Russian, andPortuguese (www.hivmedicine.com/textbook/lang.htm), and we expecttranslations into further languages This is clearly a challenge for the future,and the authors of HIV Medicine are ready to take the challenge As amatter of fact, the 2007 edition is already under way

The philosophy which governs the publication of HIV Medicine 2006 hasbeen published at www.freemedicalinformation.com

Christian Hoffmann

Jürgen K Rockstroh

Bernd Sebastian Kamps

Hamburg, Bonn, Paris – August 2006

Preface 2003

Hardly any field of medicine has ever undergone a similar stormydevelopment to that of the therapy of HIV infection Little more than 10years passed, between the discovery of the pathogen and the first effectivetreatment! However, there is also hardly a field that is subjected to so manyfast- and short-lived trends What today seems to be statute, is tomorrowoften already surpassed Nevertheless, therapeutical freedom must not beconfused with freedom of choice This book presents the medicalknowledge that is actual today: from December 2002 to January 2003.Because HIV medicine changes so fast, HIV Medicine 2003 will be updatedevery year Additional chapters about opportunistic infections, malignanciesand hepatitis are freely available at our Web site www.HIVMedicine.com.Under certain conditions, the editors and the authors of this book mightagree to remove the copyright on HIV Medicine for all languages exceptEnglish and German You could therefore translate the content of HIVMedicine 2003 into any language and publish it under your own name –without paying a license fee For more details, please seehttp://hivmedicine.com/textbook/cr.htm

Christian Hoffmann and Bernd Sebastian Kamps

Hamburg/Kiel and Paris/Cagliari, January 2003

Partners AIDS Research Center

Massachusetts General Hospital

Sven Philip Aries, M.D.

Max Brauer Allee 45

Phone: + 1 520 628-8287Fax: + 1 520 628-8749fritz@doctor.com

Thomas Buhk, M.D.

Grindelpraxis HamburgGrindelallee 35

D – 20146 HamburgPhone: + 49 40 41 32 420buhk@grindelpraxis.de

Laura Dickinson, BSc

Liverpool HIV PharmacologyGroup

University of LiverpoolBlock H, First Floor

70 Pembroke Place

GB – Liverpool, L69 3GFPhone: + 44 151 794 5565Fax: + 44 151 794 5656Laurad@liverpool.ac.uk

University Hospital Giessen

Department of Internal Medicine

University Hospital Giessen

Department of Internal Medicine

Assisted Conception Unit

Chelsea & Westminster Hospital

Stephen Korsman, M.D.

Medizinische VirologieTygerberg NHLS / StellenboschUniversity

PO Box 19063, Tygerberg 7505South Africa

Phone: + 27 21 938 9347Fax: + 27 21 938 9361snjk@sun.ac.za

Peter Krings

Klinik für KardiologieWestdeutsches HerzzentrumEssen

Universitätsklinikum EssenHufelandstr 55, 45122 EssenPhone: + 49 201 723 4878Fax.: + 49 201 723 5488Email: peter.krings@uk-essen.de

Christoph Lange, M.D., Ph.D.

Medizinische Klinik desForschungszentrums BorstelParkallee 35

D – 23845 BorstelPhone: + 49 4537 188 0Fax: + 49 4537 188 313clange@fz-borstel.de

Thore Lorenzen, M.D.

ifi InstituteLohmühlenstrasse 5

D – 20099 HamburgPhone: + 49 40 181885 3780Fax: + 49 40 181885 3788lorenzen@ifi-infektiologie.de

Division of Pediatric infectious

Diseases and Rheumatology

Case Western Reserve University

Fiona Mulcahy, M.D., FRCPI

Department of Genito UrinaryMedicine & Infectious Diseases

St James's HospitalJames's Street

EI – Dublin 8Phone: + 353 1 4162590Fax: + 353 1 4103416fmulcahy@stjames.ie

Till Neumann, M.D.

Universitätsklinikum EssenKlinik für KardiologieWestdeutsches HerzzentrumEssen

Zentrum für Innere MedizinHufelandstr 55

D – 45122 EssenPhone: + 49 201 723 4878Fax: + 49 201 723 5401till.neumann@uni-essen.de

Tim Niehues, M.D., Ph.D.

Zentrum für Kinder- undJugendmedizin

Klinik für Kinder-Onkologie,–Hämatologie und –ImmunologieAmbulanz für PädiatrischeImmunologie und RheumatologieHeinrich Heine UniversitätMoorenstr 5

D – 40225 DüsseldorfPhone: + 49 211 811 7647Fax: + 49 211 811 6539niehues@uni-duesseldorf.de

Klinikum Kemperhof Koblenz

II Med Klinik

D – 50924 KölnGermanyPhone: + 49 221 478 5623Fax: + 49 221 478 6459

Dana L Sachs, M.D.

University of MichiganDepartment of Dermatology

1910 Taubman Center

1500 E Medical Center DriveAnn Arbor, Michigan 48109USA

Phone: + 1 734 936 4081dsachs@med.umich.edu

Bernhard Schaaf, M.D.

Universitätsklinikum Holstein

Schleswig-Campus LübeckMedizinische Klinik IIIPneumologie/InfektiologieRatzeburger Allee 160

23538 LübeckTel: + 49 451 500 2344Fax: + 49 451 500 6558schaaf@uni-luebeck.de

Christiane Schieferstein, M.D.

Medizinische Klinik IIUniklinikum FrankfurtTheodor-Stern-Kai 7

D – 60590 Frankfurt am MainPhone: + 49 69 6301 0schieferstein@wildmail.com

Contributors 11

Reinhold E Schmidt, M.D.,

Ph.D.

Abteilung Klinische Immunologie

Zentrum Innere Medizin der

University Hospital Giessen

Department of Internal Medicine

D – 30625 HannoverPhone: + 49 511 532 3637Fax: + 49 511 532 5324stoll.matthias@mh-hannover.de

10900 Euclid AvenueBRB 4th floor

Cleveland, Ohio, USAPhone: + 1 441 06 4984zxt2@po.cwru.edu

Mechthild Vocks-Hauck, M.D.

KIK Berlin-Kuratorium fürImmunschwäche bei KindernFriedbergstr 29

D – 14057 BerlinPhone and Fax: + 49 30 3547421kik@bln.de

Bruce D Walker, M.D., Ph.D.

Partners AIDS Research CenterMassachusetts General HospitalBldg 149, 13th Street, 5th floorCharlestown, MA 02129USA

Phone: + 1 617 724 8332Fax: + 1 617 726 4691bwalker@helix.mgh.harvard.edu

Spandauer Damm 130

D – 14050 BerlinPhone: + 49 30 30116 816Fax: + 49 30 30116 888thomas.weitzel@charite.de

Eva Wolf, Dipl Phys Univ., M.P.H.

MUC Research GmbHKarlsplatz 8

D – 80335 MunichPhone: + 49 89 558 70 30Fax: + 49 89 550 39 41

Content

1 Introduction 23

Transmission routes 23

Natural history 25

CDC classification system 26

Epidemiology 28

Conclusion 29

References 29

2 Acute HIV-1 Infection 33

Introduction 33

Immunological and virological events during acute HIV-1 infection 33

Signs and symptoms 35

Diagnosis 35

Treatment 37

References 37

3 HIV Testing 41

How to test 41

HIV antibody diagnosis 42

When to test 49

Problem: The "diagnostic window" 50

Direct detection of HIV 51

Test results 52

Special case: Babies born to HIV-infected mothers 53

Special case: Needlestick injury or other occupational HIV exposure 54

Special case: Screening of blood donations 55

What is relevant in practice? 56

Useful Internet sources relating to HIV testing 57

References 58

4 Pathogenesis of HIV-1 Infection 61

1 The structure of HIV-1 62

2 The HIV replication cycle 66

3 HIV and the immune system 74

References 82

5 ART 2006 89

1 Perspective 89

2 Overview of antiretroviral agents 94

3 ART 2006/2007: The horizon and beyond 130

4 Goals and principles of therapy 162

14 Content

5 When to start HAART 184

6 Which HAART to start with? 199

7 When to change HAART 224

8 How to change HAART 231

9 Salvage therapy 238

10 When to stop HAART 253

11 Monitoring 267

6 Management of Side Effects 279

Gastrointestinal side effects 279

Hepatotoxicity 281

Pancreatitis 284

Renal problems 284

CNS disorders 286

Peripheral polyneuropathy 287

Haematological changes 288

Allergic reactions 289

Lactic acidosis 290

Avascular necrosis 292

Osteopenia/osteoporosis 292

Increased bleeding episodes in hemophiliacs 293

Specific side effects 293

References 294

7 Lipodystrophy Syndrome 301

Background 301

Clinical manifestation 301

HAART, lipodystrophy syndrome and cardiovascular risk 303

Pathogenesis 304

Diagnosis 307

Therapy 309

References 313

8 Mitochondrial Toxicity of Nucleoside Analogs 317

Introduction 317

Pathogenesis of mitochondrial toxicity 317

Clinical manifestations 318

Monitoring and diagnosis 322

Treatment and prophylaxis of mitochondrial toxicity 323

References 326

Content 15

9 HIV Resistance Testing 331

Assays for resistance testing 331

Background 333

Interpretation of genotypic resistance profiles 336

Summary 344

Resistance tables 346

References 349

10 Pregnancy and HIV 357

HIV therapy in pregnancy 357

References 370

11 Antiretroviral Therapy in Children 375

Characteristics of HIV infection in childhood 375

Diagnosis of HIV infection < 18 months of age 379

Diagnosis of HIV infection > 18 months of age 379

When to initiate antiretroviral therapy 379

General considerations for treatment of HIV-infected children 382

Strategy 383

Classes of antiretrovirals 384

Drug interaction 388

Monitoring of therapy efficacy and therapy failure 388

Change of therapy 388

Supportive therapy and prophylaxis 389

Conclusion 389

References 390

12 Opportunistic Infections (OIs) 395

OIs in the HAART era 395

Pneumocystis pneumonia (PCP) 398

Cerebral toxoplasmosis 406

CMV retinitis 412

Candidiasis 418

Tuberculosis 422

Interaction of HIV and MTB 422

Clinical manifestations 423

Diagnosis 424

Therapy 426

Atypical mycobacteriosis (MAC) 436

Herpes simplex 440

Herpes zoster 443

Progressive multifocal leukoencephalopathy 446

16 Content

Bacterial pneumonia 450

Cryptosporidiosis 453

Cryptococcosis 456

Salmonella septicemia 460

Immune reconstitution inflammatory syndrome (IRIS) 462

Wasting syndrome 468

Rare OIs 471

13 Kaposi’s Sarcoma 481

Signs, symptoms and diagnosis 481

Prognosis and staging 483

Treatment 484

Local therapy 484

Chemotherapy 485

Immunotherapy 487

Monitoring and follow-up care 487

References 488

14 Malignant Lymphomas 491

Systemic non-Hodgkin lymphomas (NHL) 492

Primary CNS lymphoma 503

Hodgkin’s disease (HD) 506

Multicentric Castleman's Disease (MCD) 508

15 The New HIV Patient 515

The initial interview 515

The laboratory 516

The examination 517

16 Vaccinations and HIV 519

General considerations 519

Vaccinations in HIV-infected children 520

Postexposure prophylaxis 521

Practical approach to vaccinations 521

Details on individual vaccines 522

17 Traveling with HIV 533

Travel preparations 533

Antiretroviral therapy (ART) 533

General precautions 534

Vaccinations 534

Malaria prophylaxis 535

Entry regulations and travel insurance 535

Special risks 536

Content 17

Medical problems after traveling 539

References 539

Links 540

18 HIV and HBV/HCV Coinfections 541

HIV and HCV Coinfection 541

HIV and HBV coinfection 554

19 GBV-C Infection 565

Is GBV-C a friendly virus? 565

Does the knowledge about GBV-C have any practical use? 567

Proposed pathomechanisms 568

References 569

20 HIV and Renal Function 571

Clinical manifestation/diagnosis of nephropathy 571

Routine tests for renal impairment 572

HIV-associated nephropathy (HIV-AN) 572

Post-infectious glomerulonephritis 573

Principles of therapy of glomerulonephritis 573

Renal safety of antiretroviral therapy 574

Nephroprotection 577

Estimating the GFR 578

Dosage of antiretrovirals in renal insufficiency 578

OIs and renal insufficiency 579

References 581

21 HIV-associated Skin and Mucocutaneous Diseases 585

Introduction 585

Dermatological examination and therapy in HIV-infected patients 587

HAART: Influence on (muco-) cutaneous diseases 589

Conclusions 590

Most frequent HIV-associated skin diseases 591

Skin and mucocutaneous disease related to antiretroviral drugs 601

References 603

22 HIV and Sexually Transmitted Diseases 611

Syphilis 611

Gonorrhea 613

Chlamydia infection 615

Chancroid 616

Condylomata acuminata 617

18 Content

23 HIV and Cardiac Diseases 619

Coronary artery disease (CHD) 619

Congestive heart failure 621

Pericardial effusion 623

Cardiac arrhythmias 623

Valvular heart disease 624

Further cardiac manifestations 624

References 625

24 HIV-associated Pulmonary Hypertension 629

Etiology, pathogenesis, classification 629

Diagnosis 630

Therapy 631

Conclusion for clinicians 636

References and Internet addresses 636

25 HIV and Pulmonary Diseases 639

Anamnesis 640

Pulmonary complications 642

References 645

26 HIV-1 associated Encephalopathy and Myelopathy 647

HIV encephalopathy 647

HIV-associated myelopathy 651

References 652

27 Neuromuscular Diseases 655

Polyneuropathy and polyradiculopathy 655

Myopathy 663

28 HIV and Psychiatric Disorders 667

Major depression 667

Psychotic disorders 673

Acute treatment in psychiatric emergency 676

References 677

29 Sexual Dysfunction in HIV/AIDS 679

Introduction 679

Definitions 679

Etiology of sexual dysfunction in HIV/AIDS 679

Ongoing research 681

Diagnosis of sexual dysfunction 681

Therapy for sexual dysfunction 682

30 HIV and Wish for Parenthood 687

Introduction 687

Content 19

Pre-conceptual counseling 689

Male HIV infection 689

Female HIV infection 690

HIV infection of both partners 691

Psychosocial aspects 692

The future 692

References 694

31 Post-Exposure Prophylaxis (PEP) 697

Transmission 697

Transmission risk 697

Effectiveness and limitations of PEP 698

When is PEP indicated? 699

Potential risks of PEP 699

Initial interventions 700

Initiation of PEP 701

Management of PEP 703

References 703

32 Drug Profiles 706

3TC – Lamivudine 706

Abacavir (ABC) 707

Acyclovir 709

Amphotericin B 709

Amprenavir 711

Atazanavir 712

Atovaquone 713

Azithromycin 714

AZT – Zidovudine 715

Cidofovir 717

Clarithromycin 718

Clindamycin 719

Combivir™ 719

Co-trimoxazole 720

d4T – Stavudine 721

Dapsone 722

Daunorubicin, liposomal 723

ddC – Zalcitabine 724

ddI – Didanosine 725

Delavirdine 726

Doxorubicin (liposomal) 727

20 Content

Efavirenz 728

Emtricitabine (FTC) 730

Erythropoietin 731

Ethambutol 731

Fluconazole 733

Fosamprenavir 734

Foscarnet 735

Ganciclovir 736

G-CSF 737

Indinavir 738

Interferon alfa 2a/2b 739

Interleukin-2 740

Isoniazid (INH) 741

Itraconazole 742

Kivexa™ (USA: Epzicom™) 743

Lopinavir 744

Nelfinavir 745

Nevirapine 746

Pentamidine 748

Pyrimethamine 749

Ribavirin 750

Rifabutin 752

Rifampin (or rifampicin) 753

Ritonavir 754

Saquinavir 756

Sulfadiazine 757

T-20 (Enfuvirtide) 758

Tenofovir 759

Tipranavir 761

Trizivir™ 762

Truvada™ 763

Valganciclovir 764

Voriconazole 765

33 Drug-Drug Interactions 767

Part 1

Basics

22

1 Introduction

Bernd Sebastian Kamps and Christian Hoffmann

The first reports of homosexual patients suffering from previously rare diseasessuch as pneumocystis pneumonia and Kaposi’s sarcoma were published in May

1981 (Centers for Disease Control 1981a, 1981b, 1981c) It soon became clear thatthe new disease affected other population groups as well, when the first cases werereported in injecting drug users However, it took almost two years until, in 1983,the human immunodeficiency virus type I (HIV-1) was defined as the primarycause of the acquired immunodeficiency syndrome (Barré-Sinoussi 1983, Broder

dra-In the following 800 pages, we present a comprehensive overview of the treatment

of HIV infection and its complications As in previous years, all chapters have beenthoroughly revised, and most parts of the book were available on the Internet(www.HIVMedicine.com) months before they were printed here The philosophythat governs the publication of HIV Medicine 2006 has recently been published atwww.freemedicalinformation.com We firmly believe that that is the way medicaltextbooks should be handled in the 21st century

Transmission routes

There are several ways in which someone can become infected with HIV Thesetransmission routes are well defined (see also Chapter “Post-Exposure Prophy-laxis”) HIV infection can be transmitted through:

• unprotected sexual intercourse with an infected partner;

• injection or transfusion of contaminated blood or blood products (infectionthrough artificial insemination, skin grafts and organ transplants is alsopossible);

• sharing unsterilized injection equipment that has been previously used bysomeone who is infected;

• maternofetal transmission (during pregnancy, at birth, and through feeding)

breast-Occupational infections of healthcare or laboratory workers may occur; however, a

1995 study estimated that although 600,000 to 800,000 needlestick injuries curred among healthcare workers every year in the USA, occupational infectionwas not frequent The risk of occupational HIV transmission from contaminatedneedles to healthcare workers was found to be 0.3 % in case series performed prior

oc-to the availability of potent ART

24 Introduction

There are sometimes concerns that there may be alternative routes of HIV

transmis-sion It must be explicitly stated that HIV is NOT transmitted by mosquitoes, flies, fleas, bees, or wasps HIV is NOT transmitted through casual every day contact No

case of HIV infection has been documented to arise from contact with non-bloodysaliva or tears Since HIV is not transmitted by saliva, it is not possible to contract itthrough sharing a glass, a fork, a sandwich, or fruit (Friedland 1986, Castro 1988,Friedland 1990) In the opinion of leading experts, exposure of intact skin to HIV-contaminated body fluids (e.g blood) is not sufficient to transfer the virus

Sexual intercourse

Unprotected sexual intercourse is the most important transmission route of HIVinfection worldwide Although receptive anal sex is estimated to produce the high-est risk of infection, infection after a single insertive contact has also been de-scribed The presence of other sexually transmitted diseases markedly increases therisk of becoming infected with HIV

The lower the viral load, the less infectious the patient A prospective study of 415HIV-discordant couples in Uganda showed that of 90 new infections occurring over

a period of up to 30 months, none was from an infected partner with a viral loadbelow 1,500 copies/ml The risk of infection increased with every log of viral load

by a factor of 2.45 (Quinn 2000) It should be noted that the levels of viral load inblood and other body fluids do not always correlate with one another Thus, indi-vidual risk remains difficult to estimate In addition, HIV-infected patients are notprotected from superinfection with new viral strains

The higher the viral load, the more infectious the patient This is especially true forpatients during acute HIV infection During acute HIV-1 infection, the virus repli-cates extensively in the absence of any detectable adaptive immune response,reaching levels of over 100 million copies of HIV-1 RNA/ml (see Chapter “AcuteHIV-1 infection”)

Intravenous drug use

Sharing unsterilized injection equipment that has been previously used by someonewho is infected is an important route of HIV transmission in many countries with ahigh prevalence of intravenous drug users In contrast to the accidental needlestickinjury (see also Chapter “Post-Exposure Prophylaxis”), the risk of transmissionthrough sharing injection equipment is far higher: the intravenous drug user ensuresthe proper positioning of the needle by aspiration of blood

In Western countries, perinatal (vertical) HIV infection has become rare since theintroduction of antiretroviral transmission prophylaxis and elective cesarean sec-tion For more details, see Chapter “Pregnancy and HIV”

Natural history 25

Injection or transfusion of contaminated blood products

In most Western countries, administration or transfusion of HIV-contaminatedblood or blood products has become a rare event With current testing methods (fordetails see also Chapter “HIV Testing”), the risk of acquiring HIV from a unit oftransfused blood is about 1:1,000,000 However, while Western European coun-tries, the United States, Australia, Canada, and Japan have strict and mandatoryscreening of donated blood for HIV, not all countries do

Figure 1: CD4+ T-cell count and viral load during HIV infection.

After the acute infection, equilibrium between viral replication and the host immuneresponse is usually reached, and many infected individuals may have no clinicalmanifestations of HIV infection for years Even in the absence of antiretroviraltreatment, this period of clinical latency may last 8-10 years or more However, the

In this situation, the level of 200 CD4+ T-cells/µl is an important cut-off, belowwhich the risk of many AIDS-defining illnesses increases, among them several op-portunistic infections and certain neoplasms (see Table 1) Above 200 CD4+ T-cells/µl, most AIDS-defining illnesses are rare events (see also Chapter “AIDS”).However, the course of infection may vary dramatically, and in some cases, theprogression to AIDS occurs rapidly Host factors mainly determine whether or not

an HIV-infected individual rapidly develops clinically overt immunodeficiency, orwhether this individual belongs to the group of long-term non-progressors, whorepresent about 5 % of all infected patients (for details, see “Pathogenesis of HIV-1Infection”)

CDC classification system

The most widely accepted classification system of HIV infection, initially published

by the U.S Centers for Disease Control and Prevention (CDC) in 1986, is based oncertain conditions associated with HIV infection (see Table 1) This classificationsystem was intended for use in conducting public health surveillance and it hasbeen a useful epidemiological tool for many years In 1993, the CDC classificationwas revised (CDC 1993b) Since then, the clinical definition of AIDS has been ex-panded in the USA (not in Europe) to include HIV-infected patients with a CD4+T-cell count of less than 200 cells/µl or less than 14 % of all lymphocytes, even inthe absence of the listed conditions

Thus, the current CDC classification categorizes persons on the basis of clinicalconditions and CD4+ T-lymphocyte counts There are three clinical categories (A,

B, C – see Table 1) and three CD4+ T-lymphocyte categories (1, 2, 3 – see Table2) For example, a patient with oropharyngeal candidiasis and a CD4+ T-cell count

of 250/µl would be classified as B2; someone with asymptomatic infection and aCD4+ T-cell count of 550/µl would be in category A1 Categorization of the CD4+T-cells should be based on the lowest accurate CD4+ T-cell count (“CD4 nadir”)and not on the most recent one

For children less than 13 years of age, there is a modified and revised classificationsystem for HIV infection (see chapter “Antiretroviral Therapy in Children”) Itshould also be noted that, besides the CDC classification, the World Health Organi-zation (WHO) has also published a staging system for HIV infection The WHOclassification is an approach for use in resource-limited settings and is widely used

in Africa and Asia

CDC classification system 27

Table 1 Clinical categories of the CDC classification system in HIV-infected persons

Category A

Asymptomatic HIV infection

Acute (primary) HIV infection with

accom-panying illness or history of acute HIV

infection

Persistent generalized lymphadenopathy

Category B

Symptomatic conditions* that are not

in-cluded among conditions listed in clinical

Category C Examples include, but are not

limited to:

Bacillary angiomatosis

Candidiasis, oropharyngeal (thrush)

Candidiasis, vulvovaginal; persistent,

frequent, or poorly responsive to therapy

Cervical dysplasia (moderate or

se-vere)/cervical carcinoma in situ

Constitutional symptoms, such as fever

(38.5° C) or diarrhea lasting longer than

1 month

Hairy leukoplakia, oral

Herpes zoster (shingles), involving at least

two distinct episodes or more than one

dermatome

Idiopathic thrombocytopenic purpura

Listeriosis

Pelvic inflammatory disease, particularly if

complicated by tubo-ovarian abscess

Peripheral neuropathy

Category C - AIDS-defining illnesses** Candidiasis of bronchi, trachea, or lungs Candidiasis, esophageal

Cervical cancer, invasive*

Coccidioidomycosis, disseminated or pulmonary

extra-Cryptococcosis, extrapulmonary Cryptosporidiosis, chronic intestinal (greater than 1 month's duration)

Cytomegalovirus disease (other than liver, spleen, or nodes)

Cytomegalovirus retinitis (with loss of vision) Encephalopathy, HIV-related

Herpes simplex: chronic ulcer(s) (greater than 1 month's duration); or bronchitis, pneumonitis, or esophagitis

Histoplasmosis, disseminated or monary

extrapul-Isosporiasis, chronic intestinal (greater than

1 month's duration) Kaposi's sarcoma Lymphoma, Burkitt's (or equivalent term) Lymphoma, immunoblastic (or equivalent) Lymphoma, primary, of brain

Mycobacterium avium complex or M sii, disseminated or extrapulmonary Mycobacterium tuberculosis, any site (pul- monary or extrapulmonary)

kansa-Mycobacterium, other species or fied species, disseminated or extrapulmo- nary

unidenti-Pneumocystis pneumonia Pneumonia, recurrent*

Progressive multifocal leukoencephalopathy Salmonella septicemia, recurrent

Toxoplasmosis of brain Wasting syndrome due to HIV

* These conditions must meet at least one of the following criteria: a) the conditions are uted to HIV infection or are indicative of a defect in cell-mediated immunity; or b) the conditions are considered by physicians to have a clinical course or to require management that is com- plicated by HIV infection.

attrib-** Once a Category C condition has occurred, the person will remain in Category C.

it provides the most recent estimates of the epidemic’s scope and explores newtrends in the epidemic’s evolution It can be found at the Websitehttp://www.unaids.org/ Table 1 provides an overview of the devastating situation

of the HIV pandemic

Table 3: The AIDS epidemic**

HIV-infected adults and chil- dren

HIV prevalence among adults (%)

New infections per day Daily deathsfrom AIDS

Subsaharian

South and

Southeast Asia 7,400,000 0.7 2,700 1,300Eastern Europe

and Central Asia 1,600,000 0.9 740 170

Conclusion 29

Conclusion

HIV cannot be transmitted as easily as the influenza virus Compared to other viraldiseases, the prevention of HIV infection is therefore easier In rich countries, indi-viduals who don’t want to be infected with HIV may protect themselves and avoidHIV infection The same people will not be able to avoid the influenza virus of thenext pandemia

HIV infection has become a treatable disease – at least in countries that can affordwidespread health coverage The following chapters describe how patients should

be managed in these countries

Outside these havens of material well-being, things have not changed since theearly years of the HIV epidemic 25 years ago Many people live in a world where

no medical progress seems to have been made This is a shameful situation, andfuture generations will hopefully do better than we did

4 Barre-Sinoussi F, Chermann JC, Rey F, et al Isolation of a T-lymphotropic retrovirus from a patient at risk for AIDS Science 1983, 220: 868-71 http://amedeo.com/lit.php?id=6189183

5 Bobat R, Moodley D, Coutsoudis A, Coovadia H, Gouws E The early natural history of vertically transmitted HIV-1 infection in African children from Durban, South Africa Ann Trop Paediatr 1998,, 18: 187-96 http://amedeo.com/lit.php?id=9924555

6 Bowen PA 2nd, Lobel SA, Caruana RJ, et al Transmission of HIV by transplantation: clinical aspects and time course analysis of viral antigenemia and antibody production Ann Intern Med 1988, 108: 46-8 http://amedeo.com/lit.php?id=3276264

7 Broder S, Gallo RC A pathogenic retrovirus (HTLV-III) linked to AIDS N Engl J Med 1984, 7.

311:1292-8 Burger H, Weiser B, Robinson WS, et al Transmission of lymphadenopathy-associated virus/human

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9 Calzavara L, Burchell AN, Major C, et al Increases in HIV incidence among men who have sex with men undergoing repeat diagnostic HIV testing in Ontario, Canada AIDS 2002, 16: 1655-61 http://amedeo.com/lit.php?id=12172087

10 Castro KG, Lieb S, Jaffe HW, et al Transmission of HIV in Belle Glade, Florida: lessons for other communities in the United States Science 1988, 239: 193-7 http://amedeo.com/lit.php?id=3336781

11 Centers for Disease Control (1981c) Follow-up on Kaposi's sarcoma and Pneumocystis pneumonia MMWR Morb Mortal Wkly Rep 1981, 30: 409-10.

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homo-13 Centers for Disease Control (1981a) Pneumocystis pneumonia Los Angeles MMWR Morb Mortal Wkly Rep 1981, 30: 250-2 Volltext: http://hiv.net/link.php?id=144

14 Centers for Disease Control (1982a) epidemiologic notes and reports persistent, generalized adenopathy among homosexual males MMWR Morb Mortal Wkly Rep 1982, 31: 249.

lymph-http://hiv.net/link.php?id=145

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51 Kamradt T, Niese D, Brackmann HH, et al Heterosexual transmission of HIV in hemophiliacs Klin Wochenschr 1990, 68:1203-7 http://amedeo.com/lit.php?id=1981245

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Introduction 33

2 Acute HIV-1 Infection

Marcus Altfeld and Bruce D Walker

Introduction

Acute HIV-1 infection presents in 40 – 90 % of cases as a transient symptomaticillness, associated with high levels of HIV-1 replication and an expansive virus-specific immune response With 14,000 new cases per day worldwide, it is an im-portant differential diagnosis in cases of fever of unknown origin, maculopapularrash and lymphadenopathy

The diagnosis of acute infection is missed in the majority of cases, as other viralillnesses (“flu”) are often assumed to be the cause of the symptoms, and there are

no HIV-1-specific antibodies detectable at this early stage of infection The sis therefore requires a high degree of clinical suspicion, based on clinical symp-toms and history of exposure, in addition to specific laboratory tests (detection ofHIV-1 RNA or p24 antigen and negative HIV-1 antibodies) confirming the diagno-sis

diagno-An accurate early diagnosis of acute HIV-1 infection is important, as infection ofsexual partners can be prevented and patients may benefit from therapy at this earlystage of infection (see below)

Immunological and virological events during acute HIV-1 infection

During acute HIV-1 infection, the virus replicates extensively in the absence of anydetectable adaptive immune response, reaching levels of over 100 million copiesHIV-1 RNA/ml It is during this initial cycle of viral replication that importantpathogenic processes are thought to occur These include the seeding of virus to arange of tissue reservoirs and the destruction of CD4+ T-lymphocytes, in particularwithin the lymphoid tissues of the gut The very high levels of HIV-1 viremia arenormally short-lived, indicating that the host is able to generate an immune re-sponse that controls viral replication Over the following weeks, viremia declines

by several orders of magnitude before reaching a viral setpoint This setpoint, lowing resolution of the acute infection, is a strong predictor of long-term diseaseprogression rates (Mellors 1995)

fol-Several factors can influence viral replication during acute infection and the lishment of a viral setpoint These include the fitness of the infecting virus, hostgenetic factors and host immune responses While antibodies against HIV-1 withneutralizing capacities are rarely detectable during primary HIV-1 infection, anumber of studies have demonstrated a crucial role of HIV-1-specific cellular im-mune responses for the initial control of viral replication during this stage of infec-tion A massive, oligoclonal expansion of CD8+ T-cell responses has been de-scribed during acute HIV-1 infection (Pantaleo 1994), and the appearance of HIV-1-specific CD8+ T cells has been temporally associated with the initial decline ofviremia (Koup 1994, Borrow 1994) These CD8+ T-cells have the ability to elimi-

estab-34 Acute HIV-1 Infection

nate HIV-1-infected cells directly by MHC class I-restricted cytolysis or indirectly

by producing cytokines, chemokines or other soluble factors, thus curtailing thegeneration of new viral progeny (Yang 1997) The biological relevance of HIV-1-specific cytotoxic T cells (CTL) in acute HIV-1 infection was highlighted in recentin-vivo studies demonstrating a dramatic rise of SIV viremia and an acceleratedclinical disease progress in macaques after the artificial depletion of CD8+ T-cells(Schmitz 1999, Jin 1999) Additional evidence for the antiviral pressure of HIV-1-specific CTLs during primary HIV-1 infection has been provided by the rapid se-lection of viral species with CTL epitope mutations that were detected within a fewweeks after HIV-1 and SIV infection in humans and rhesus macaques, respectively(Allen 2000, O’Connor 2002, Price 1997)

During acute HIV-1 infection, the number of CD4+ T-cells decline, occasionally tolevels that allow the development of opportunistic infections at that time (Gupta

1993, Vento 1993) Even though the CD4+ T-cell count rebounds with the tion of primary infection, it rarely returns to baseline levels in the absence ofantiretroviral therapy In addition to the decline in CD4+ T-cell counts, qualitativeimpairments of CD4+ T-cell function are perhaps the most characteristic abnor-malities detected in HIV-1 infection The impairment of HIV-1-specific CD4+ T-cell function occurs very early in acute infection (Rosenberg 1997, Altfeld 2001,Lichterfeld 2004), potentially due to the preferential infection of virus-specificCD4+ T-cells by the virus (Douek 2002) This is followed by a functional impair-ment of CD4+ T-cell responses to other recall antigens, as well as a reduced re-sponsiveness to novel antigens (Lange 2003) The impairment of HIV-1-specificCD4+ T-helper cell function in acute HIV-1 infection subsequently results in afunctional impairment of HIV-1-specific CD8+ T-cells (Lichterfeld 2004)

resolu-In addition to host immune responses, host genetic factors play an important role inboth susceptibility and resistance to HIV-1 infection and speed of disease progres-sion following infection The most important of these is a deletion in the majorcoreceptor for entry of HIV-1 into CD4+ T-cells, a chemokine receptor calledCCR5 (Samson 1996) Homozygotes for this 32 base pair deletion (CCR5delta32)

do not express the receptor at the cell-surface and can only be infected with HIVstrains that are able to use other coreceptors, such as CXCR4 Thus, althoughCCR5delta32 homozygotic individuals show a significant degree of resistance toHIV-1 infection (Samson 1996), a number of cases of infection with CXCR4-usingHIV-1 strains have been described (O’Brien 1997, Biti 1997) Heterozygotes for thedeletion exhibit significant lower viral setpoints and slower progression to AIDS Inaddition to mutations in the chemokine receptor genes, a number of HLA class Ialleles have been described to be associated with both, lower viral setpoints andslower disease progression, including HLA-B27 and -B57 (O’Brien 2001, Kaslow1996) Recent studies demonstrated that individuals expressing HLA-B57 presentedsignificantly less frequently with symptomatic acute HIV-1 infection and exhibited

a better control of viral replication following acute infection (Altfeld 2003) Thesedata demonstrate that host genetic factors can influence the clinical manifestations

of acute HIV-1 infection and have an important impact on subsequent viral points and the speed of disease progression

set-36 Acute HIV-1 Infection

In one study (Hecht 2002), all assays for HIV-1 RNA that were tested (branchedchain DNA, PCR and GenProbe) had a sensitivity of 100 %, but occasionally (in 2– 5 % of cases) led to false positive results False positive results from these testsare usually below 2,000 copies HIV-1 RNA per ml plasma, and therefore far belowthe high titers of viral load normally seen during acute HIV-1 infection (in our ownstudies on average 13 x 106 copies HIV-1 RNA/ml with a range of 0.25 – 95.5 x 106copies HIV-1 RNA/ml) Repetition of the assay for HIV-1 RNA from the samesample with the same test led to a negative result in all false positive cases Meas-urement of HIV-1 RNA from duplicate samples therefore results in a sensitivity of

100 % with 100 % specificity In contrast, detection of p24 antigen has a sensitivity

of only 79 % with a specificity of 99.5 – 99.96 % The diagnosis of acute HVI-1infection must be subsequently confirmed with a positive HIV-1 antibody test (se-roconversion) within the following weeks

During acute HIV-1 infection, there is frequently a marked decrease of CD4+ T-cellcount, which later increases again, but usually does not normalize to the initial le-vels In contrast, the CD8+ T-cell count rises initially, which may result in aCD4/CD8 ratio of < 1 Infectious mononucleosis is the most important differentialdiagnosis Hepatitis, influenza, toxoplasmosis, syphilis and side effects of medica-tions may also be considered

Figure 1: Algorithm for the diagnosis of acute HIV-1 infection

In summary, the most important step in the diagnosis of acute HIV-1 infection is toinclude it in the differential diagnosis The clinical suspicion of an acute HIV-1infection then merely requires performance of an HIV-1 antibody test and possibly

First pilot studies in patients who were treated during acute HIV-1 infection andsubsequently went through structured treatment interruptions show that the HIV-1-specific immune response could be boosted in these patients (Rosenberg 2000).Most patients were subsequently able to discontinue therapy and experienced atleast temporal control of viral replication, with viral set points remaining below5,000 copies/ml for more than 3 years in some patients However, in the majority ofindividuals in this study (Kaufmann 2004), as well as in other studies assessing vi-ral control following treated primary infection (Markowitz 1999), viral load re-bounded during longer follow-up, requiring the initiation of therapy.

The long-term clinical benefit of early initiation of therapy has not been strated yet It is also not known how long the period between acute infection andinitiation of therapy can be without losing immunological, virological and clinicalbenefit In view of all these unanswered questions, patients with acute HIV-1 infec-tion should be treated in controlled clinical trials (Yeni 2002) If this is not possible,the option of standard first-line treatment should be offered and discussed It is im-portant during counseling to clearly indicate the lack of definitive data on clinicalbenefit of early initiation of antiretroviral therapy and to address the risks of antiret-roviral therapy and treatment interruptions, including drug toxicity, development ofresistance, acute retroviral syndrome during viral rebound and HIV-1 transmissionand superinfection during treatment interruptions

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38 Acute HIV-1 Infection

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