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HIV/AIDS CHALLENGE IN
UGANDA
A REPORT AND PROPOSAL BY A MEDICAL STUDENT FROM
MAKERERE UNIVERSITY
UGANDA
EAST AFRICA
Willington Amutuhaire
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Talk outline
Background
Evolution of the epidemic
History of HIV in Uganda
Epidemiological trends
Routes of transmission
National response
Impact of HIV
Prevention of HIV
HIV testing
HIV treatment
Challenges
Proposal
My Research project
BACKGROUND
GEOGRAPHICAL
LOCATION OF UGANDA
 Uganda lies in subSaharan Africa.
 It is a land locked
country in east Africa
bordering Kenya to the
east, Tanzania and
Rwanda to the south,
Democratic Republic of
Congo to west and
Sudan to the north.
Background
 Covers an area of
236,036 km2 with an
estimated population of
30 million people and
an average population
growth rate of 3.2%
(population secretariat
Uganda 2007).
 Majority of Ugandans
(88%) live in rural areas
where subsistence
agriculture is the source
of food and income.
Ugandan women preparing a meal
(above) and men transporting
matooke (plantain) to the market
(below)
Africa carries 25% of the world’s disease burden;
However she has 3% of the world’s health workers
and 1% of the world’s economic resources.
(Robinson M, Clarke P Lancet 2008)
Patients with liver disease
EVOLUTION OF THE AIDS EPIDEMIC
• The first AIDS cases were
identified in 1982 on the
shores of Lake Victoria in
the southern district of
Rakai.
• Superstitions and
witchcraft characterised
the initial response from
communities.
• The epidemic progressed
very fast to other parts of
the country, initially
concentrating in the
urban and semi-urban
centres.
Lake Victoria
Map of Uganda showing Rakai
district (in red)
HISTORY OF HIV IN UGANDA
In 1982 the first 2 cases
of slim disease were
reported in Rakai.
 In 1983, 17 more cases
of slim were reported.
 In 1984 slim disease
was confirmed as AIDS.
 In 1990 the epidemic
spread from major
towns to rural
populations in Uganda.
 TO DATE-all districts
have reported AIDS.
An HIV/AIDS child at Mulago
Hospital
HIV/AIDS EPIDEMIOLOGICAL TRENDS
IN UGANDA
• Sub-Saharan Africa accounts for 68% of those
living with HIV/AIDS globally (UNAIDS 2007).
• Uganda was among the first hard hit countries
with a prevalence rate of 9% from 1987 to
1988.
• In 1992 the prevalence rate was 18.3% in rural
areas and 30% in the towns.
• From 1993-2002 prevalence rate was 6%.
• The current prevalence rate is 6-8%. Women
8% and 5% in men.
ROUTES OF TRANSMISSION OF HIV IN UGANDA
• Heterosexual transmission accounts for 84%.
• Mother to child transmission accounts for
14%.
• Contaminated blood/blood products, use of
un-sterilised needles and syringes, and use of
un-sterilised instruments all account for 2%.
HIV/AIDS FUNDING IN UGaNDA
• U.S Presidential Emergency plan for AIDS
Relief(PEPFAR) contributes
75%
• The Global fund to fight Malaria,HIV and
Tuberculosis set up by G8 in 2002
• International non governmental organisations
20%
• Government of uganda allocates 5% ($ 30 m) for
HIV/AIDS
• $ 1 is sufficient to buy antiretroviral therapy for
one patient per day but unfortunately majority
of Ugandans can’t afford a dollar per day.
NATIONAL RESPONSE TO HIV/AIDS
• Response confined to Ministry of Health 19821984.
• Disease viewed as witchcraft and later the
disease of the immoral.
• In 1985, the national committee for the
prevention of AIDS was established.
• In the same year, the first AIDS control
program in the country was established.
• In 1987, HIV/AIDS was declared a public health
problem and also a socio-economic disaster
that called for interventions from all sectors.
• AIDS control projects started in 12 ministries.
UGANDA AIDS COMMISSION
• Established in 1992 with the following
objectives;
-prevention of HIV with a focus on children,
youth and gender issues (gender based
violence,).
-mitigating the health and socio-economic
impact of AIDS.
-a national information base for HIV/AIDS.
-capacity building and research in HIV/AIDS.
-planning, monitoring and evaluation
National HIV/AIDS programmes.
The AIDS support organisation(TASO)
• Founded in 1986 by Noerine Kaleeba and 15 colleagues
most of whom have died. With the following objectives
1. Fight discrimination and stigma.
2. Provide counselling services for HIV/AIDS patients and
their families.
3. Complement available medical services (antiretroviral
therapy)
4. Sensitise the public and promote positive attitudes
towards people with HIV/AIDS and their families.
5. Provide material support to clients and their families e.g
food.
6. Build and support community-based efforts initiated to
respond to the AIDS epidemic.
Makerere university HIV/AIDS projects
 Infectious disease institute(IDI)
was opened in 2004 as a
collaboration between Makerere
University and Pfizer. It offers
training, research, prevention,
care and treatment services.
 Makerere University Walter Reed
Project. A collaboration between
Makerere & Walter Reed institute
of research (U.S Army) in HIV
Vaccine development
 Makerere - Mbarara Universities
joint AIDS programme (MJAP)
collaboration in Study of Effects of
Antiretroviral therapy, teaching of
service providers
IDI building (above) and Makerere
main building (below)
• Joint clinical research centre
(JCRC)
Founded in 1990 as a joint
project of the Ministries of
Health, Defence and
Makerere University.
Early on, 70% of HIV
patients received their
Antiretroviral therapy from
JCRC.
• Baylor College of Medicine
Children foundation, cares
for children infected or
exposed to HIV, teaching
and research
• Makerere-Johns Hopkins
University research
collaboration in Prevention
of Mother to Child HIV
Transmission
Baylor college of medicine (above)
and JCRC ART clinic launch below
Trends in the prevalence of AIDS in Uganda
3 phases:
Phase 1: Rapid spread and
increase in prevalence from
1982-1991.
Phase 2: Dramatic decline in
prevalence
From 1992-2000 during which
period, HIV prevalence fell
drastically from 15% in rural
areas and over 30% in cities to
around 5% in 2001.
Phase 3: Stabilisation of
prevalence rate at 6-7% from
2002-2005.
Phase 4: HIV prevalence rate may
be increasing again?
Reasons for Change in Trends
Phase 1
 Lack of knowledge about the
disease
 Lack of treatment
Phase 2
 Death
 Decline in new infections due to
behavioural change (ABC) and
the sheer scale of HIV epidemic
Phase 3
 Free HIV drugs.HIV is no longer
an immediate death sentence
Phase 4: Economic crisis, NGOs have
cut funding and some HIV centres
IMPACT OF AIDS ON UGANDA
1. Death of approximately
one million people since
the beginning of the
epidemic.
2. Reduced life expectancy
from 54.1 to 42.6 years.
3. One million orphans left
behind (child headed
homes).
4. Depleted labour force,
reduced agricultural
output and food security.
5. Weakened health sector.
An HIV/AIDS lady at her home(above)
and a child headed family(below)
6. Increased poverty at the household level
7. Stigma and discrimination at all levels of
society
8. Increased school drop-outs due to lack of
school fees and also to care for the sick
“If someone in Uganda tells you they have not
been affected by HIV/AIDS, then they are
lying”
HIV prevention in Uganda
Uganda has always been
cited as an example of
success in a continent
facing a severe AIDS
crisis.
The approach Uganda
used has been based on
ABC.
A- Abstinence
B- Be faithful to your
partner(zero grazing)
C- Condom use
C-?Circumcision
A message on HIV prevention on a
school compound (above) and an HIV
sensitisation talk (below)
Prevention of Mother To Child
Transmission (PMTCT)
 Started in 2000 in a small
number of Antenatal
clinics. The programme
includes;
1. Voluntary counselling and
testing (VCT) for mothers
attending ANC.
2. Treatment of mothers
and children following
positive diagnosis.
 Currently 80% of pregnant
mothers receive PMTCT.
A pregnant mother receiving PMTCT
services at a health centre in
Kampala, the capital city of Uganda
HIV testing
 Uganda was the first to
open Voluntary Counselling
& Testing (VCT) clinic in SubSaharan Africa.
 In 1999 VCT started in
resource limited areas.
 In 2007 VCT was available
in 45% of health facilities.
 Currently Routine
Counselling & Testing (RCT)
is done to everyone who
comes to a health facility
unless they choose to opt
out.
People lining up to test for HIV
 80% of Ugandans remain
in Kampala city suburb
unaware of their HIV status.
HIV treatment in Uganda
 Uganda was among the first
countries in Africa to
distribute life saving
Antiretroviral therapy
(ARVs) in 1998.
 In June 2004, free ARV
medication for people living
with HIV was started.
 Only 30% of people needing
ARVs receive them due to
lack of sufficient supply.
 95% of ARVs funded by the
U.S. through Presidential
Emergency Plan For AIDS
Relief (PEPFAR) and Global
fund
HIV patients waiting for ARVs at
Infectious disease institute Makerere
University
Number of active ART sites in Uganda: 20032008
350
331
305
Number of Health units
300
?
250
207
184
200
150
110
100
50
26
0
2003
2004
2005
2006
Year
Ministry of Health - Uganda
2007
2008
009
Common Opportunistic infections
• TB. Uganda is 15th
among the 22 TB High
Burden Countries
(HBCs). High association
of TB & HIV (40-50% TB
are HIV+).
• Kaposi Sarcoma(48.9 of
cancers in men and
17.9 in women)
• Cryptococcus
Meningitis(10-30%)
• Pneumocysts Carinii
neumonia(16.5%)
• Candidaisis(80-90%)
Cutaneous KS(above) and Oral
Candidiasis(below)
Mulago Hospital
Ashinaga Uganda - Caring for AIDS
Patients
• Started in 2000 with the
president, Museveni, as
its patron.
• Supports 1300 orphans
• Education for AIDS
orphans
• Offers emotional and
psychological support
• HIV prevention through
counselling and
community education
Challenges
• HIV prevalence is high among the married, this
increases transmission to children.
• Religious leaders preach against condom use.
• Some religious groups discourage use of
antiretroviral therapy and encourage patients to
concentrate on prayers.
• 95% of ART is donor funded.
• Political instability especially in northern Uganda.
• Limited resources for research about HIV in Uganda.
• Corruption: Global fund suspended funding in 2005
due to financial mismanagemant.
• Economic crisis. Reduced funding by international
organisationsS
Proposal
Collaboration between Universities in Africa
and U.S.A both in research and student
exchange programs is necessary, particularly
in basic science research in HIV where little
basic research has been done in Africa
To establish a basic HIV/AIDS research centre
in Africa in future.
To accelerate basic reseach to deveop new
and more effective antiretroviral drugs that
are affordable to HIV/AIDS patients.
Research Project
BACKGROUND:
HIV –ASSOCIATED METABOLIC
SYNDROME
The introduction of highly active antiretroviral therapy
(HAART) has drastically improved the life expectancy
of patients with acquired immunodeficiency
syndrome (AIDS), by reducing infection-related
mortality. There has, however, been an increasing
adverse events,such as metabolic derangements,
related to HAART, especially with regimens
containing protease inhibitors. These metabolic
complications include insulin resistance, diabetes
mellitus, dyslipidemia and lipodystrophy. All of these
complications are associated with increased risk for
atherosclerosis and cardiovascular disease
Background: A Role of Tat in HIV associated metabolic
syndrome
The etiology of human immunodeficiency virus (HIV)-associated
metabolic syndrome appears to be multifactorial. Other than
the anti-viral drugs, HIV-1 infection itself, including virally
encoded molecule, Tat (Transactivator of transcription), has
been proposed as a major contributor to the development of
these pathologic changes and/or the vulnerability of patients
to the adverse effects of HAART.
The Human immunodeficiency virus type 1 (HIV 1) Tat protein is
also a major viral transactivator required for HIV replication.
Nonetheless, neither the approach nor the management of
the HIV patient with metabolic syndrome has been
established
BACKGROUND: Sirt1 and Tat in HIV infection
Sirt1 is NAD+-dependent deacetylase and the closest mammalian
homologue of the yeast longevity gene, Sir2 (silent information
regulator 2). Sirt1 plays important roles in metabolism, as well as
DNA repair, transcriptional regulation and apoptosis. Sirt1
deacetylates a variety of substrates, including p53, PPAR-γ, FOXOs
and NF-κB. Importantly, activation of Sirt1 improves insulin
sensitivity and ameliorates obesity-induced diabetes in mice. The
clinical trial is under way to evaluate the efficacy and safety of Sirt1
activator in patients with type 2 diabetes.
A previous study has shown that Tat binds to the catalytic domain of
Sirt1 and inhibits the deacetylase activity of Sirt1 and that Sirt1
deacetylates Tat and inhibits the function of Tat
Sirt1
Tat
In HIV1 Infection:
Sirt1
activity
Insulin resistance
Tat
Promotion of HIV replication,
aggravation of HIV related symptoms
A Novel Drug candidate Compound A can block the
inhibition of Sirt1 by Tat and can inhibit Tat activity
by enhancing Sirt1 –mediated deacetylation of Tat.
Compound A
Sirt1 activity
Tat
activity
AIM: To identify a compound which can block the
binding of Tat to Sirt1
METHODS: Cos-7 cells were co-transfected with HA-Tat
and Flag-Sirt1; the cells were then treated with
different concentrations of compound A
Protein expression of Sirt1 and Tat was assayed by
western blotting using Anti-Flag antibody and AntiHA antibody
The effect of Compound A on Sirt1 activity and Sirt1-Tat
interaction was determined by western blotting
using Anti-acetyl lysine antibody and
immunoprecipitation using Anti-flag antibody
respectively
Immunoprecipitation with Anti-Flag antibody of cell-lysate co
transfected with Sirt1-Flag and Tat-HA
IgG heavy chain
IgG light chain
HA-Tat
RESULTS:Western blotting with
a) Anti-Flag antibody
Flag-Sirt1
1
2
3
4
b) Ant-HA antibody
HA-Tat
1
2
3
4
Compound A reduced acetylation of Tat presumably by
increasing Sirt1 mediated deacetylation in TSA –treated cells
Acetylated
Tat
Compound A
TSA(0.3uM) -
+
+
+
KEY FINDINGS:
1. Compound A decreased Tat acetylation in a
dose dependent manner in TSA treated cells.
2. Compound A blocked the binding of Tat to
sirt1.
DISCUSSION: Compound A and its derivatives
which can block the binding of of Tat to Sirt1
while reducing the acetylation of Tat may be
a potential drug candidate to prevent and/
treat HIV infection and HIV –related
metabolic syndrome by inhibiting Tat activity
while activating Sirt1.
Acknowlegement
1.Endocrine society for the sponsorship
2.My mentor: Prof Masao Kaneki
3.Faculty of Medicine Makerere University
Thank you for listening
Welcome to Kampala, Capital city of Uganda