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1 HIV/AIDS and Treatment Manado, Indonesia 16 november HIV [e] EDUCATION

2 HIV is a 1. DNA-virus 2. RNA-virus 3. Parasite 0% 0% 0% DNA-virus RNA-virus Parasite

3 HIV HIV is a RNA-virus. HIV is an RNA virus which uses DNA for its replication. A virus is unable to replicate (reproduce) on its own and must first infect a living cell in order to replicate.

4 HIV has to infect living cells in order to replicate What kind of cells? 1. Erythrocytes 2. Lymphocytes 3. Thrombocytes 0% 0% 0% Erythrocytes Lymphocytes Thrombocytes

5 The lifecycle of HIV-1

6 Cellular CD4 receptor Human DNA chromosome CD4 ( T Helper) Cell

7 Reverse transcriptase Cellular CD4 receptor gp41 HIV HIV RNA chromosome Human DNA chromosome CD4 ( T Helper) Cell

8 1. HIV approaches CD4 cell 4. Fusion of cell and virus 2. HIV-CD4 interaction 3. Connection gp41

9 Cellular CD4 receptor HIV RNA chromosome Human DNA chromosome CD4 ( T Helper) Cell

10 Cellular CD4 receptor RNA nucleotides HIV RNA chromosome Human DNA chromosome CD4 ( T Helper) Cell

11 Reverse transcriptase Cellular CD4 receptor RNA nucleotides DNA nucleotides HIV RNA chromosome Human DNA chromosome CD4 ( T Helper) Cell

12 Reverse transcriptase Cellular CD4 receptor HIV RNA chromosome HIV DNA provirus Human DNA chromosome CD4 ( T Helper) Cell

13 Integrase Cellular CD4 receptor Reverse transcriptase HIV RNA chromosome HIV DNA provirus Human DNA chromosome CD4 ( T Helper) Cell

14 Reverse transcriptase Cellular CD4 receptor HIV RNA chromosome HIV DNA provirus Human DNA chromosome CD4 ( T Helper) Cell

15 Cellular CD4 receptor HIV HIV RNA chromosome HIV DNA provirus Human DNA chromosome CD4 ( T Helper) Cell

16 Acute HIV-infection

17 From HIV- exposure at mucosal surface to spreading to organs. How long does it take? minutes 2. 1 day days 4. Three months 0% 0% 0% 0% 10 minutes 1 day 11 days Three months

18 Day 0 Day 0-2 Exposure to HIV at mucosal surface (sex) Virus collected by dendritic cells, carried to lymph node Day 3-11 HIV replicates in CD4 cells, released into blood Day 11 on Kahn JO, Walker BD. N Engl J Med. 1998;339: Virus spreads to other organs

19 29 year old man, no medical history 2 weeks of malaise, myalgia and since a couple days a rash Four weeks ago unprotected sex Complaints of severe fatigue, no weight loss or mouth sores 1week ago his GP gave him antibiotics with no effect Physical exam: temperature of 38.3 C, diffuse adenopathy, maculopapular rash

20 Rash

21 Test results HIV RNA: copies/ml HIV antibody: negative What is your diagnosis? Acute HIV-infection

22 Primary HIV Infection: Signs & Symptoms 80-90% of patients will be symptomatic A mononucleosis-like like illness of non-specific signs and symptoms Signs and symptoms typically begin 1-4 weeks post-exposure Kahn JO, Walker BD. N Engl J Med. 1998;339: Schacker T, et al. Ann Intern Med. 1996;125:

23 Primary HIV Infection: Common Signs & Symptoms fever 86 lethargy 74 myalgias rash headache pharyngitis N = 160 patients with PHI in Geneva, Seattle, and Sydney adenopathy % of patients Vanhems P et al. AIDS 2000; 14:

24 Typical Risk of Unprotected Exposures Estimated Average Per Contact Transmission Risk (%) Shared Needles 0.7% Occupational Needlestick 0.3 % Male to female, vaginal sex 0.2% Female to male, vaginal sex 0.1% Receptive oral sex with male 0.03%

25 How long is your diagnostic window? The current HIV-antibody screening tests are able to recognise almost 99.5 % of HIV infections A. 2 weeks B. 1 month C. 3 months D. 1 year.after primary HIV infection 0% 0% 0% 0% 2 weeks 1 month 3 months 1 year 90

26 How long is your diagnostic window? The current HIV-antibody screening tests are able to recognise almost 99.5% of HIV-infections A. 2 weeks B. 1 month C. 3 months D. 1 year..after primary infection with HIV

27 Typical Course of Primary HIV HIV RNA 1 mil 100,000 10,000 1, Exposure HIV RNA Symptoms Ab + _ HIV-1 Antibodies Days

28 HIV-markers and disease progression

29 HIV Disease Progression Progression can be monitored by: Clinical markers: HIV/AIDS-related conditions Laboratory markers Increase in blood virus load Decrease in CD4 cell count

30 CD4 Count, Viral Load, and Clinical Course Primary Infection Seroconversion Plasma HIV RNA Plasma RNA Copies CD4 Cells Intermediate Stage AIDS CD4 Cell Count 1, Weeks Up to 12 Years 2-3 Years

31 HIV Infection is characterized by a steady decline in the number of CD4 cells Acute Infection CD4 Cell Count (cells/mm³) 1, Asymptomatic HIV Infection AIDS CD4 cell count high risk of opportunistic infections 4-8 Weeks Up to 12 Years 2-3 Years Time

32 Association between opportunistic infections and CD4 + -lymphocyte count CD4 + -lymphocyte count (cells/µl) Herpes Zoster Tuberculosis Oral candidiasis time Pneumocystis carinii pneumonia Esophageal candidiasis Toxoplasmosis, cryptococcosis Mycobacterium avium complex Cryptosporidiosis, PML

33 Antiretroviral therapy

34 What is antiretroviral therapy? ART Antiretroviral Therapy ARV Antiretroviral cart combination Antiretroviral Therapy HAART Highly Active Antiretroviral Therapy

35 What kind of classes do we have? NRTI s NNRTI s PI s (Entry inhibitors) (Fusion inhibitors) (Integrase inhibitors)

36 Available FDA approved drugs Classes NRTIs NNRTI Protease inhibitors AZT DDI DDC D4T 3TC ABC AZT/3-TC ZT/3TC/ABC TDF FTC 3TC/ABC TDF/FTC NVP Etravirine EFV Fusion inhibitors Enfuvirtide CCR5 antagonist Maraviroc Integrase inhibitor Raltegravir Saquinavir Darunavir Indinavir Nelfinavir Amprenavir Lopinavir/rtv Atazanavir Fosamprenavi Tipranavir

37

38

39

40 PI NRTI NRTI + or (the NRTI backbone ) NNRTI

41 Combination of at least 3 drugs, usually: 2 NRTIs (the NRTI backbone ), plus: 1 NNRTI or 1-2 PIs Therapy with only one or two agents allows HIV to overcome therapy through resistance mutations

42 Goals of HAART Prolong life and improve quality of life Achieve maximal suppression of HIV Low (undetectable) viral load Reverse immune system damage Increase CD 4 -count

43 Initiation of Antiretroviral Therapy: Key Considerations Symptoms & Opportunistic Infections CD4 count Anticipated Adherence - patient readiness

44 CDC A: Asymtomatic Lymphaden. B: Symptomatic C: AIDS defining illness 1 >500 CD4 Deferal treatment start treatment Start treatment CD start treatment Start treatment Start treatment 3 <200 CD4 Start treatment Start treatment Start treatment

45 When to start? DHHS Guidelines 2008 update january

46 Male 28 years, HIV+ CD4 cell count: 150/µl, retrosternal pain 1. Yes 2. No Start HAART? 0% 0% Yes No 90

47 Male 28 years, HIV+ CD4 cell count: 370/µl, retrosternal pain Start HAART? 1. Yes 2. No 0% 0% Yes No 90

48 Male 42 years, HIV+, dry cough since three weeks, breathing frequency 40/min CD4 cell count: 170/µl X-thorax: Start HAART? 1. Yes 2. No 0% 0% Yes No 90

49 Male 42 years, HIV+, dry cough since three weeks, breathing frequency 40/min CD4 cell count: 220/µl X-thorax: Start HAART? 1. Yes 2. No 0% 0% Yes No 90

50 Male 42 years, HIV+, dry cough since three weeks, breathing frequency 40/min, CD4 cell count: 170/µl X-thorax: When to start HAART? 1. Now Weeks 3. 3 months 0% 0% 0% Now 2-8 Weeks 3 months 90

51 Woman 34 years old; HIV+, Unexplained weight loss; 66 kg 46 kg, CD4 cell count: 410/µl Start HAART? 1. Yes 2. No 0% 0% Yes No 90

52 The treatment of patients with symptomatic conditions (CDC B) or an AIDS defining illness (CDC C) should not depend on a CD4 cell count!

53 Pfffffffff finished!

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