1. BORDERNETwork Training on HIV/ AIDS Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A. www.bordernet.eu www.aidshilfe-potsdam.de

2. This presentation arises from the BORDERNETwork project which has received funding from the European Union, in the framework of the Health Program, and co- funding of the Ministry of Environment, Health and Consumer Protection of the Federal State of Brandenburg. The sole responsibility of any use that may be made of the information lies with the authors (SPI, AIDS-Hilfe Potsdam e.V.)

3. Table of Contents Epidemiology Natural Course Diagnostic Therapy Treatment

4. ABBREVIATIONS AND DEFINITIONS AIDSAcquired Immune Deficiency Syndrome HIVHuman Immuno-deficiency Virus RetrovirusesReverse Transcriptase, oncogenic properties Definition: “A virus that replicates by the reverse transcription of a RNA or DNA intermediate. All retro- transcribing viruses utilize the enzyme reverse transcriptase to replicate and may have a DNA- or RNA-based genome.” (Source: http://de.dict.md) Target of virusCD4-Cells (T-helper cells) in organism: CD4 receptor binds to viral gp 120 HAARTHighly active antiretroviral therapy

5. ADULTS AND CHILDREN ESTIMATED TO BE LIVING WITH HIV IN 2010 North America 1.5 million [1.2 million – 2.0 million] Caribbean 240.000 [220.000 – 270.000] Central & South America 1.4 million [1.2 million – 1.6 million] Middle East & North Africa 460.000 [400.000 – 530.000] Sub-Saharan Africa 22.5 million [20.9 million – 24.2 million] Western & Central Europe 820.000 [720.000 – 910.000] Oceania 57.000 [50.000 – 64.000] South & South-East Asia 4.1 million [3.7 million – 4.6 million] East Asia 770.000 [560.000 – 1.0 million] Eastern Europe & Central Asia 1.4 million [1.3 million – 1.6 million] Source: http://www.who.int/entity/hiv/data/2010_globalreport_core_en.ppt Total: 33.3 million [31.4 million – 35.3 million]

6. REGIONAL HIV AND AIDS STATISTICS AND FEATURES 2009 The ranges around the estimates in this table define the boundaries within which the actual numbers lie, based on the best available information. TOTAL 33.3 million [31.4 million – 35.3 million] 2.6 million [2.3 million – 2.8 million] Adults and children newly infected with HIV Adults and children living with HIV Sub-Saharan Africa Middle East and North Africa South- and South-East Asia East Asia Central and South America Caribbean Eastern Europe & Central Asia Western and Central Europe North America Oceania 22.5 million [20.9 million – 24.2 million] 4.1 million [3.7 million – 4.6 million] 1.4 million [1.2 million – 1.6 million] 1.4 million [1.3 million – 1.6 million] 1.5 million [1.2 million – 2.0 million] 1.8 million [1.6 million – 2.0 million] 270. 000 [240. 000 – 320. 000] 92. 000 [70. 000 – 120. 000] 130. 000 [110. 000 – 160. 000] 70. 000 [44. 000 – 130. 000] 460. 000 [400. 000 – 530. 000] 770. 000 [560. 000 – 1.0 million] 240. 000 [220. 000 – 270. 000] 820. 000 [720. 000 – 910. 000] 57. 000 [50. 000 – 64. 000] 75. 000 [61. 000 – 92. 000] 82. 000 [48. 000 – 140. 000] 17. 000 [13. 000 – 21. 000] 31. 000 [23 000 – 40. 000] 4.500 [3.400 – 6.000] 1.8 million [1.6 million – 2.1 million] Adult & child deaths due to AIDS 1.3 million [1.1 million – 1.5 million] 260. 000 [230. 000 – 300. 000] 58. 000 [43. 000 – 70. 000] 76. 000 [60. 000 – 95. 000] 26. 000 [22. 000 – 44. 000] 24. 000 [20. 000 – 27. 000] 36. 000 [25. 000 – 50. 000] 12. 000 [8.500 – 15. 000] 8.500 [6.800 – 19. 000] 1.400 [<1.000 – 2.400] 0.8% [0.7% - 0.8%] Adult prevalence (15 ‒ 49) [%] 5.0% [4.7% – 5.2%] 0.3% [0.3% – 0.3%] 0.5% [0.4% – 0.6%] 0.8% [0.7% – 0.9%] 0.5% [0.4% – 0.7%] 0.2% [0.2% – 0.3%] 0.1% [0.1% – 0.1%] 1.0% [0.9% – 1.1%] 0.2% [0.2% – 0.2%] 0.3% [0.2% – 0.3%] Source: http://www.who.int/entity/hiv/data/2010_globalreport_core_en.ppt

7. HIV - PANDEMIC Source: www.who.int worldwide about 75 million people were infected 40 million people died off AIDS every day 7.000 new infections and 6.000 people die of AIDS

8. HIV EPIDEMIOLOGY IN GERMANY 2010  People living with HIV/AIDS in Germany (2010): ~ 70.000 people living with HIV/AIDS [ 60.000 - 83.000] ~ 54.000 positive test results [50.000 – 62.000] ~ 29.000 people died off AIDS ~ 40.000 persons get antiretroviral therapy [39.000 – 41.000] 2.918 newly diagnosed HIV infections in 2010 ~ 80% of new infected persons are related to the group of MSM Robert Koch-Institut (RKI): Epidemiologisches Bulletin 46/2010 Robert Koch-Institut (RKI): Epidemiologisches Bulletin 21/2011 URL: http://www.rki.de/cln_226/nn_196658/DE/Content/InfAZ/H/HIVAIDS/hiv__node.html?__nnn=true

9. Transmission ways

10.  Body fluids, which contain a high concentration of HIV: Blood Semen Vaginal secretion Anal secretion Breast milk  Body fluids, which contain a low concentration of HIV and a low infectiosity: Urine Fecal Saliva Sudor Transmission fluids

11.  HIV can be transmitted by Unprotected vaginal intercourse Unprotected anal intercourse Breast feeding and vertical transmission Use of contaminated syringes and needles Blood transfusion  Open wounds and mucous membranes are the gateways for the transmission of HIV. Transmission ways

12. Body fluids (blood, semen, vaginal secretion, anal secretion, breast milk) Open wounds and mucous membranes (vaginal mucous membrane, oral mucosa, bowel mucosa, mucosal of the eyes or the nose ) Pressure and friction (through sexual activities and through rub in the infected material in open wounds or mucous membranes) HIV

13. HIV NATURAL COURSE

14. Clinical Outcome of an Untreated HIV Infection Viral load (HIV RNA copies/ml plasma) 0 3 6 9 12 2 3 4 5 6 7 8 9 10 11 weeksyears 10^7 10^6 10^5 10^4 10^3 10^2 Death AIDS Clinical symptom s Adopted from: Fauci et al Ann Intern Med 1996; 124, 654 – 663; also from unpublished presentation of Prof. Dr. Jürgen Rockstroh on 29.6.2011 in Potsdam

15. CDC Classification System for HIV Clinical Category A without symptoms / acute infection B symptomatic conditions in an HIV- infected C AIDS defined illness

16. CDC Classification System for HIV 1 2 3 CD4 cells more than 500 CD4 cells between 200 - 499 CD4 cells below 200 CD4 Lymphocyte Categories

17. CDC Classification: 3 clinical- (A,B,C) & 3 CD4- categories (1,2,3) CD4 – Cells category Clinical Category A (without symptoms) Clinical Category B (symptoms) Clinical Category C (AIDS-defining illness) 1: > 500A1B1C1 2: 200 – 499A2B2C2 3: < 200A3B3C3

18. AIDS Defined Diseases  Bacterial pneumonia, recurrent (>2 episodes in 12 months)  Candidiasis, esophageal  Cervical carcinoma  Coccidiodomycosis, disseminated or extra pulmonary  Cryptococcosis, extra pulmonary  Cryptosporidiosis, chronic intestinal (>1 month duration)  Cytomegalovirus disease (other than liver, spleen, or nodes)  Encephalopathy, HIV-related  Herpes simplex: chronic ulcers  (>1 month duration), bronchitis, pneumonitis or esophagitis  Histoplasmosis, disseminated or extra pulmonary  Isosporiasis, chronic intestinal (>1 month duration)  Kaposi sarcoma  Lymphoma  fever ≥1 month  Mycobacterium avium complex (MAC),disseminated orextra pulmonary  Mycobacterium tuberculosis  Pneumocystis jiroveci (formerly carinii ) pneumonia (PCP)  Progressive multifocal Leukoencephalopathy (PML)  Salmonella septicemia, recurrent (nontyphoid)  Toxoplasmosis of brain  Wasting syndrome due to HIV

19. AIDS Indicator Diseases  Sexually transmitted diseases  Malignant Lymphoma  Cervicoplasty or Anadysplasia  Herpes Zoster  Leukopenia  Thrombocytopenia  Dermatides Seborrheic  Symptoms similar to mononucleosis Specific complexes of symptoms and diseases are associated with a HIV infection in an early stage:

20. DIAGNOSTICS

21. HIV DIAGNOSTICS Detection of antibodies Rapid test Screening test (ELISA) Western Blot – confirmation test Viral detection with PCR Qualitative (lowest detection 20 – 50 copies /ml) Quantitative (viral load in copies/ml) Immune status CD4 cells CD4 percentage CD4 /CD8 ration (normal >1)

22. HIV DIAGNOSTICS ELISA - Enzyme Linked Immunoabsorbent Assay  is a direct test for the detection of antibodies  HIV antigens will given on a surface, on which the antibodies can bind  after bonding, the testing serum - which contains potentially HIV antibodies – will be attached: now the antibodies can bind themselves to antigens  The enzyme linked antibodies will given to the antigen-linked antibodies  The reaction of the substances will turn the color on the surface

23. HIV DIAGNOSTICS Western Blot  Verification of antibodies by Western Blot  Dissociation of the virus in its protein components by SDS (sodium dodecyl sulfat)  The protein components will attached to surface of gel and

24. HIV DIAGNOSTICS Window period  Is the time between potential infection and the verifiability of an infection with HIV  Antibodies will be produced a few weeks after the infection  In 80% of all cases the HIV antibodies can be detected after 6 weeks  In 100 % of all cases the HIV antibodies can be detected after 12 weeks  The shift from negative to positive is called seroconversion.

25. HIV DIAGNOSTICS ELISA Screening test Positive result Negative result Western Blot confirmation test ELISA retesting – if test result “negative” is in window period HIV Positive HIV Negative Positive result http://www.hiv-info.de/index.jsp?nodeid=01_4 http://www.hiv-symptome.de/ A good animation of the ELISA process: http://www.sumanasinc.com/webcontent/animations/content/ELISA.html

26. Therapy

27. Therapy of a HIV Infection Adopted from a presentation of: Aids-Hilfe Saar e.V., Gesundheitsamt des Stadtverbandes Saarbrücken, Gesundheitsamt Neunkirchen, Ministerium für Bildung, Kultur und Wissenschaft

28. Therapy Reverse Transcriptase- Inhibitors Protease- Inhibitors Integrase- Inhibitors Entry- Inhibitors  NRTI, N(t)RTI  NNRTI  PI  Attachement – Inhibitors  CCR5 – Inhibitors  Fusion – Inhibitors

29. NRTI (Nucleoside analogue Reverse- Transcriptase- Inhibitors) Emtriva®EmtricitabineFTC Epivir®Lamivudine3TC Retrovir®ZidovudineAZT Videx®DidanosineddI Zerit®Stavudined4T Ziagen®AbacavirABC N(t)RTIViread®TenofovirTDF NRTI - Nucleoside analogue Reverse- Transcriptase- Inhibitors  Are nucleoside analogues, which are similar to natural nucleosides  Intervene into the transcription process, which transcribes the viral RNA genome into DNA  Implementation of nucleoside analogues during the reverse transcriptase leads to an disruption of the new developed DNA helix and of the polymerization/reverse transcriptase

30. NNRTI (Non- Nucleoside Reverse- Transcriptase- Inhibitors) Intelence®EtravirineTMC125 Sustiva®EfavirenzEFV Viramune®NevirapineNVP Edurant®RilpivirineTMC278 NNRTI - Non- Nucleoside Reverse- Transcriptase- Inhibitors  The NNRTIs bind non-competitive on the reverse transcriptase of HIV  Binding close to the bonding site for nucleosides  The catalytic active bonding site will be jammed  Only a few nucleosides can bind, so the polymerization will be decelerated

31. PI (Protease- Inhibitors) Aptivus®TipranavirTPV Crixivan®IndinavirIDV Invirase®SaquinavirSQV Kaletra®Lopinavir + RitonavirLPV/r Norvir®RitonavirRTV Prezista®DarunavirDRV Reyataz®AtazanavirATV Telzir®FosamprenavirFPV Viracept®NelfinavirNFV PI - Protease Inhibitors  are molecules which inhibit the function of proteases  Protease inhibitors bind directly in the catalytic center of the protease and prevent their activity

32. INI (Integrase- Inhibitors)Isentress®RaltegravirMK-0518 INI - Integrase Inhibitors  HIV integrase is important for the integration of viral DNA into the host DNA of the cell core  The integrase Inhibitor prevents the docking and binding of the of the viral DNA on the host DNA

33. EI (Entry- Inhibitors) Fuzeon®EnfuvirtideENF T20 Celsentri®MaravirocMVC EI - Entry Inhibitors  Inhibit the entry of the virus in the DNA of the host  Entry inhibitors inhibiting three processes: The binding of HIV on the CD4 receptor The binding of co receptors The fusion of virus and host cell

34. Simplification of HIV Therapy 1996 - 2006 1996: d4T/3TC/IDV, 10 pills, TID 2002: ZDV/3TC/EFV, 3 pills, BID 1998: ZDV/3TC/EFZ, 5 pills, BID 2004: TVD or EPZ /EFV, 2 pills, QD 2006: ATRIPLA, 1 pill, QD

35. ANTIRETROVIRAL DRUGS COMBINATIONS AZT / 3TC Combivir® AZT / 3TZ / ABC Trizivir® ABC / 3TC Kivexa® TDF / FTC Truvada® TDF / FTC / EFV Atripla® TDF / FTC / TMC278 Eviplera®

36. CYTOCHROM P 450 3A4 BOOSTED PROTEASE INHIBITORS  First pass metabolism of PIs by Cytochrom P 450 enzyme system can cause rapid declines in there plasma concentration  Ritonavir inhibits this metabolic activity, already in a mini dose (100mg)  In combination with a second PI a high plasma concentration can be reached and maintained, because the enzyme system is inhibited  Most PIs are given in combination with Ritonavir Advantages: Higher blood concentrations, less pills, better long term effect, no early drug resistance

37. HAART - HIV TREATMENT HAART - when to start?  If AIDS is diagnosed in a very progressive stage, treatment is also possible, but there are difficult conditions to manage the therapy of opportunistic infections in combination with HAART Our aim: HIV infection should be diagnosed before HAART has to be started

38. ANTIRETROVIRAL THERAPY GOALS OF ART Source: New York State Departement of Health AIDS Institute: www.hivguidelines.org URL: http://www.hivguidelines.org/clinical-guidelines/adults/antiretroviral-therapy/ (September 2011). Maximal suppression of viral replication Restoration / preservation of immune system Reducing HIV related morbidity and mortality Improving quality of life Prevention of viral resistance / drug resistance

39. ANTIRETROVIRAL THERAPY BENEFITS AND RISKS OF ART Source: New York State Departement of Health AIDS Institute: www.hivguidelines.org URL: http://www.hivguidelines.org/clinical-guidelines/adults/antiretroviral-therapy/ (September 2011). BenefitsRisks  Restoration or preservation of immune function  Decreasing of viral transmission  Improvement of health  Prolongation of life  Suppression of viral replication  Adverse effects of medication  Drug toxicities  Development of drug resistances and limitation of treatment options

40. ANTIRETROVIRAL THERAPY WHEN TO START? European AIDS Clinical Society : Guidelines. Clinical Management and Treatment of HIV infected Adults in Europe. 2010 URL: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/1_treatment_of_hiv_infected_adults.pdf Symptomatic:  If OI, CD4 < 200 or CDC 3: initiate as soon as possible

41. ANTIRETROVIRAL THERAPY WHEN TO START ? Asymptomatic:  CD4 < 500: recommendations of American Guidelines; discussion of starting ART with CD4 <500 in Germany/Austria in progress (2012)  CD4 < 350: treatment recommended.  CD4 350-500: Treatment recommended if Hepatitis C coinfection, Hepatitis B coinfection requiring therapy, HIV-associated nephropathy or other specific organ deficiency, age > 50, pregnancy or malignancy. Treatment should be considered for viral load (VL) > 105 c/ml or high cardiovascular risk European AIDS Clinical Society : Guidelines. Clinical Management and Treatment of HIV infected Adults in Europe. 2010 URL: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/1_treatment_of_hiv_infected_adults.pdf

42. ANTIRETROVIRAL THERAPY WHEN TO START? A-symptomatic:  CD4 > 500: Treatment should generally be deferred, independently of plasma HIV RNA; closer follow-up of CD4 if VL > 105 c/ml Treatment can be offered if presence of the above co-morbidities (see CD4 350-500)  Regardless of CD4 count or VL CD4 and Plasma HIV RNA, treatment can be offered on an individual basis, especially if patient is seeking and ready for ARV therapy and/or for any personal reasoning including being part of a zero-discordant relationship as part of risk reduction. European AIDS Clinical Society : Guidelines. Clinical Management and Treatment of HIV infected Adults in Europe. 2010 URL: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/1_treatment_of_hiv_infected_adults.pdf

43. Deutsche AIDS-Gesellschaft e.V. (DAIG) & Österreichische AIDS Gesellschaft: Deutsch-Österreichische Leitlinien zur antiretroviralen Therapie der HIV-1-Infektion (2010); URL: http://www.daignet.de/site-content/hiv-therapie/leitlinien-1/Leitlinien_28-05-2010_V_late.pdf.  Pregnancy  Age >50 years  Hepatitis B  Hepatitis C  High cardiovascular risk (Farningham risk > 20%/10 Years)  Decreasing of CD4 cell rate  Plasma viraemia > 100.000 copies/mL  Reduction of infectiosity ADDITIONAL CRITERIA FOR STARTING ART

44. HAART - HIV TREATMENT Resistance testing:  Genotypic testing and subtype determination recommended, ideally at the time of HIV diagnosis, otherwise before initiation of firstline regimen. If genotypic testing is not available, a ritonavir-boosted PI should be included in the first-line regimen Additional remarks:  Before starting treatment, the VL and CD4 count should be repeated to obtain a baseline  Time should be taken to prepare the patient, in order to optimize compliance and adherence

45. Efavirenz Nevirapine Atazanavir/r Lopinavir/r Saquinavir/r Raltegravir + recommended alternative Tenofovir + Lamivudine Zidovudine + Lamivudine Didanosine + Lamivudine or Didanosine+ Emtricitabine EACS - Guidelines EACS Guidelines (Version 6, 10/2011), p.13 Tenofovir + Emtricitabine Column A Column B NNRTINRTI Ritonavir boosted PI Darunavir/r Fosamprenavir/r INI CCR5-/EI Maraviroc Abacavir + Lamivudine Tenofovir + Emtricitabine

46. Efavirenz** Nevirapin*** Atazanavir/r Darunavir/r Lopinavir/r Fosamprenavir/r Saquinavir/r Raltegravir NNRTI PI/r INI + recommended alternative * only for HLA-B*5701-negative; Cave: eventually increased cardiovascular risk, virological inferirior *** Cave: increased Hepatotoxicity for women with CD4+-cells >250 and for men with >400/µL Choice of substances ** not recommend during pregnancy and for women with desire to have children Tenofovir + Emtricitabine Abacavir + Lamivudine* Tenofovir + Lamivudine German-Austrian Guidelines for antiretroviral therapy of HIV-1-infection Deutsche AIDS-Gesellschaft e.V. (DAIG) & Österreichische AIDS Gesellschaft: Deutsch-Österreichische Leitlinien zur antiretroviralen Therapie der HIV-1-Infektion (2010) URL: http://www.daignet.de/site-content/hiv-therapie/leitlinien-1/Leitlinien_28-05-2010_V_late.pdf