BORDERNETwork Training on

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


Western & Central Europe

820.000[720.000 – 910.000]

Oceania57.000

[50.000 – 64.000]

South & South-East Asia4.1 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







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]


Adult & child deaths due to AIDS


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


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


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

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