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BORDERNETwork Training on

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

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BORDERNETwork Training on

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  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 HAART Highly active antiretroviral therapy

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

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

  7. HIV - PANDEMIC Source: www.who.int

  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. Transmission fluids • 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

  11. Transmission ways • 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.

  12. Transmission ways 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 ) HIV Pressure and friction (through sexual activities and through rub in the infected material in open wounds or mucous membranes)

  13. HIV NATURAL COURSE

  14. Clinical Outcome of an Untreated HIV Infection 10^7 10^6 10^5 10^4 10^3 10^2 Death Viral load (HIV RNA copies/ml plasma) AIDS Clinical symptoms 0 3 6 9 12 2 3 4 5 6 7 8 9 10 11 weeksyears 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

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

  17. CDC Classification: 3 clinical- (A,B,C) & 3 CD4- categories (1,2,3)

  18. AIDS Defined Diseases • 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 • 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

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

  20. DIAGNOSTICS

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

  22. HIV DIAGNOSTICS • ELISA - Enzyme Linked ImmunoabsorbentAssay • 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 Western Blot confirmation test HIV Positive Positive result Positive result ELISA Screening test ELISA retesting – if test result “negative” is in window period Negative result HIV Negative 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 CD4 gp 120 reverse transcriptase 2 DNA RNA 4 10 3 integrase 5 nucleus 1 9 chromosomes- DNA mRNA Virus-RNA 8 1 Docking 2 Entry 3 Desintegration of viral envelope 4 Translation of viral information 5 Integration in cell core 6 Transcription (messenger-RNA, Viral-RNA) 7 Cutting viral particles to shape 8 Composition of the virus 9 Exit of new viruses 10 Maturation 6 7 translation translation into viral proteins 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 • NRTI, N(t)RTI • NNRTI Protease- Inhibitors • PI Integrase- Inhibitors Entry- Inhibitors • Attachement – Inhibitors • CCR5 – Inhibitors • Fusion – Inhibitors

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

  35. ANTIRETROVIRAL DRUGS COMBINATIONS

  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).

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

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

  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. ADDITIONAL CRITERIA FOR STARTING ART • Pregnancy • Age >50 years • Hepatitis B • Hepatitis C • High cardiovascular risk (Farninghamrisk > 20%/10 Years) • Decreasing of CD4 cell rate • Plasma viraemia > 100.000 copies/mL • Reduction of infectiosity 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.

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

  46. German-Austrian Guidelines for antiretroviral therapy of HIV-1-infection Efavirenz** Choice of substances NNRTI Nevirapin*** Atazanavir/r Tenofovir + Emtricitabine Darunavir/r PI/r Abacavir + Lamivudine* + Lopinavir/r Tenofovir + Lamivudine Fosamprenavir/r Saquinavir/r Raltegravir INI recommended * onlyfor HLA-B*5701-negative; Cave: eventuallyincreasedcardiovascularrisk, virologicalinferirior ** not recommend during pregnancy and for women with desire to have children *** Cave: increased Hepatotoxicity for women with CD4+-cells >250 and for men with >400/µL alternative 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

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