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BORDERNETwork Training on. HIV/ AIDS. Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A. www.bordernet.eu. www.aidshilfe-potsdam.de. - PowerPoint PPT Presentation
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BORDERNETwork Training on
HIV/ AIDS Dr. med. Wolfgang Güthoff / Alexander Leffers, M.A.
www.bordernet.euwww.aidshilfe-potsdam.de
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.)
Table of Contents
Epidemiology
Natural Course
Diagnostic
Therapy
Treatment
ABBREVIATIONS AND DEFINITIONS
AIDS Acquired Immune Deficiency Syndrome
HIV Human Immuno-deficiency Virus
Retroviruses Reverse Transcriptase, oncogenic propertiesDefinition: “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 virus CD4-Cells (T-helper cells) in organism:CD4 receptor binds to viral gp 120
HAART Highly active antiretroviral therapy
ADULTS AND CHILDREN ESTIMATEDTO BE LIVING WITH HIV IN 2010
North America1.5 million
[1.2 million – 2.0 million]
Caribbean240.000
[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 Africa22.5 million
[20.9 million – 24.2 million]
Western & Central Europe
820.000[720.000 – 910.000]
Oceania57.000
[50.000 – 64.000]
South & South-East Asia4.1 million
[3.7 million – 4.6 million]
East Asia770.000
[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]
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
HIV - PANDEMIC
Source: www.who.int
worldwide about 75 million people were
infected
40 million people died
off AIDS
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
Transmission ways
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
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
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 )
Pressure and friction(through sexual activities and through
rub in the infected material in open wounds or mucous membranes)
HIV
HIV NATURAL COURSE
Clinical Outcome of an Untreated HIV Infection
Vira
l loa
d (H
IV R
NA
copi
es/m
l pla
sma)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 150
100
200
300
400
500
600
700
800
900
1000
1100
1200
10
210
410
610
810
1010C
D4
lym
phoc
ytes
(cel
ls/m
m3)
Primary infection
Acute retroviral syndrom
Clinical latency
0 3 6 9 12 2 3 4 5 6 7 8 9 10 11weeks years
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
CDC Classification System for HIV
Clinical Categor
y
A without
symptoms / acute
infection
Bsymptomatic conditions in
an HIV- infected
CAIDS
defined illness
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
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: > 500 A1 B1 C1
2: 200 – 499 A2 B2 C2
3: < 200 A3 B3 C3
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
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:
DIAGNOSTICS
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)
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
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
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.
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_4http://www.hiv-symptome.de/A good animation of the ELISA process: http://www.sumanasinc.com/webcontent/animations/content/ELISA.html
Therapy
Therapy of a HIV Infection
RNA DNAreverse transcriptase
Virus-RNA
gp 120 CD4
translation intoviral proteins
translation
nucleus
1 Docking2 Entry3 Desintegration of viral envelope4 Translation of viral information5 Integration in cell core6 Transcription (messenger-RNA, Viral-RNA)7 Cutting viral particles to shape8 Composition of the virus9 Exit of new viruses10 Maturation
10integrase
1
24
6 7 8
95
3
mRNAchromosomes-
DNA
Adopted from a presentation of: Aids-Hilfe Saar e.V., Gesundheitsamt des Stadtverbandes Saarbrücken, Gesundheitsamt Neunkirchen, Ministerium für Bildung, Kultur und Wissenschaft
Therapy
Reverse Transcriptase- Inhibitors
Protease- Inhibitors
Integrase- Inhibitors
Entry- Inhibitors
NRTI, N(t)RTI NNRTI
PI
Attachement – Inhibitors CCR5 – Inhibitors Fusion – Inhibitors
NRTI (Nucleoside analogue Reverse- Transcriptase- Inhibitors)
Emtriva® Emtricitabine FTCEpivir® Lamivudine 3TCRetrovir® Zidovudine AZTVidex® Didanosine ddIZerit® Stavudine d4TZiagen® Abacavir ABC
N(t)RTI Viread® Tenofovir TDFNRTI - 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
NNRTI (Non- Nucleoside Reverse- Transcriptase- Inhibitors)
Intelence® Etravirine TMC125Sustiva® Efavirenz EFVViramune® Nevirapine NVPEdurant® Rilpivirine TMC278
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
PI (Protease- Inhibitors)
Aptivus® Tipranavir TPVCrixivan® Indinavir IDVInvirase® Saquinavir SQVKaletra® Lopinavir + Ritonavir LPV/rNorvir® Ritonavir RTVPrezista® Darunavir DRVReyataz® Atazanavir ATVTelzir® Fosamprenavir FPVViracept® Nelfinavir NFV
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
INI (Integrase- Inhibitors) Isentress® Raltegravir MK-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
EI (Entry- Inhibitors)Fuzeon® Enfuvirtide ENF T20Celsentri® Maraviroc MVC
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
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
ANTIRETROVIRAL DRUGS COMBINATIONS
• AZT / 3TCCombivir®
• AZT / 3TZ / ABCTrizivir®
• ABC / 3TCKivexa®
• TDF / FTCTruvada®
• TDF / FTC / EFVAtripla®
• TDF / FTC / TMC278Eviplera®
CYTOCHROM P 450 3A4BOOSTED 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
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
ANTIRETROVIRAL THERAPYGOALS OF ART
Source: New York State Departement of Health AIDS Institute: www.hivguidelines.orgURL: 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
ANTIRETROVIRAL THERAPYBENEFITS AND RISKS OF ART
Source: New York State Departement of Health AIDS Institute: www.hivguidelines.orgURL: http://www.hivguidelines.org/clinical-guidelines/adults/antiretroviral-therapy/ (September 2011).
Benefits Risks
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
ANTIRETROVIRAL THERAPYWHEN TO START?
European AIDS Clinical Society : Guidelines. Clinical Management and Treatment of HIV infected Adults in Europe. 2010URL: 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
ANTIRETROVIRAL THERAPYWHEN 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 riskEuropean AIDS Clinical Society : Guidelines. Clinical Management and Treatment of HIV infected Adults in Europe. 2010URL: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/1_treatment_of_hiv_infected_adults.pdf
ANTIRETROVIRAL THERAPYWHEN 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. 2010URL: http://www.europeanaidsclinicalsociety.org/images/stories/EACS-Pdf/1_treatment_of_hiv_infected_adults.pdf
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
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
Efavirenz
Nevirapine
Atazanavir/r
Lopinavir/rSaquinavir/r
Raltegravir
+
recommended
alternative
Tenofovir + LamivudineZidovudine + LamivudineDidanosine + LamivudineorDidanosine+ Emtricitabine
EACS - Guidelines
EACS Guidelines (Version 6, 10/2011), p.13
Tenofovir + Emtricitabine
Column A Column BNNRTI NRTI
Ritonavir boosted PI
Darunavir/r
Fosamprenavir/rINI
CCR5-/EIMaraviroc
Abacavir + Lamivudine Tenofovir + Emtricitabine
Abacavir + Lamivudine Tenofovir + Emtricitabine
Efavirenz**Nevirapin***
Atazanavir/rDarunavir/rLopinavir/r
Fosamprenavir/rSaquinavir/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