2. Learning Objectives
• By the end of the session you will
understand
– Burden of HIV in South Sudan
– How HIV may be acquired
– Natural history of HIV infection in Adults/
children
– Challenges with providing Adult/ pediatric HIV
services
– Strategies to over come these challenges
3. History of HIV
• Virus officially named “Human Immunodeficiency
Virus” in 1986
• International Committee on Taxonomy of Viruses
selected a name based on two most important
properties of the virus:
– HIV infects only human beings
– HIV induces a profound immunodeficiency characterized
by depletion of the T-helper cells, which today are
referred to as the CD4 cells
4. Introduction
• HIV and AIDS is a major cause of morbidity and
mortality in Africa.
• Of the estimated RSS total population of 10.9 million
as of 2014, about 2.6% of adults aged 15-49 years are
infected with HIV
• HIV prevalence by geographical region ranging from
0.3% in Northern Bar El Ghazal to 6.8% in Western
Equatorial.
• Mother to child transmission of HIV accounts for up
to 90% of childhood infections.
5. Introduction contd…
• An estimated 14,000 children are living with HIV in
South Sudan
• Currently in South Sudan, only about 10% of
estimated number of children who are HIV infected
are on ARV therapy.
• Majority of Adult infections are acquired through
heterosexual transmission.
• Number of PLHIV – 193,000
• Annual AIDS Deaths – 13,000
• New infection- 15,000
7. Human Immunodeficiency Virus
• HIV-1 and HIV-2 belong to the Lentivirus group of
Retroviridae family
• HIV contains RNA and uses reverse transcriptase to
make DNA, which gets incorporated into the host
cell (provirus)
• HIV consists of a cylindrical centre surrounded by a
sphere-shaped lipid envelope. The centre consists
of two single strands of RNA
8. Molecular Epidemiology of HIV
• HIV-1 has a global distribution while HIV-2 is limited
to West Africa
• HIV-1 has been further divided into groups and
subtypes
11. The Normal immune System
• Protects the body from disease
• Consists of lymphoid organs and tissues that
produce lymphocytes and immune molecules
– T-lymphocytes are responsible for cellular immunity
• Play role in defence against viral, fungal, and bacterial
infections
– B-lymphocytes recognize specific antigen targets and
secrete specific antibodies
12. The Normal Immune System (2)
• Composed of two systems
– Innate immunity
– Adaptive immunity
• Common cells of the immune system include CD4
cells, CD8 cells and macrophages
• CD4 receptors are found on:
– Helper T-lymphocytes
– Macrophages
– Dendritic cells, stem cells and Langerhans cells
13. Mechanism of infection
• HIV-1 targets CD4 molecule on T-helper
• Other cells infected by HIV-1 include macrophages and
glial cells
• HIV binds to the CD4 cells in the presence of chemokine
co-receptors (CCR5 and CXCR4) on the host cell to allow
entry
• The viral envelope is shed and its contents are released
into the host cell cytoplasm.
14. B Cell
Helper T Cell
Macrophage
Infected
CD4
Cytotoxic T Cell
Killed
CD4
KEY
HIV particle
Helper T Cell
Cytotoxic T Cell
B Cell
Macrophage
Cell nucleus
Cell receptor
HIV antibodies
(antibody secreting cell)
(CD8)
Role of CD4 Cells
(CD4)
15.
16. Mechanism of infection
• HIV RNA is transcribed by reverse transcriptase to a
double stranded DNA
• It is then integrated into host DNA by integrase and
resides as a provirus
• On activation, the proviral DNA is transcribed into
mRNA by host enzyme RNA polymerase to begin
replication
• The mRNA is then translated into viral proteins
which assemble and “bud-off” from the host cell
membrane.
18. Major Steps in HIV Lifecycle
1. HIV attaches to CD4 cell
2. Releases RNA and enzymes
3. Enzyme Reverse Transcriptase makes a DNA copy of
viral RNA
4. New viral DNA integrated into CD4 cell nucleus using
enzyme integrase
5. New viral components produced, using cell’s
“machinery”
6. These are assembled together using enzyme protease
7. These are released as new viruses
20. Natural History of HIV Infection in
Adults
• HIV-1 infection has the following phases:
– Viral transmission
– Primary HIV infection
– Sero-conversion
– Clinical latent period
– Early symptomatic HIV infection
– AIDS and severe HIV infection
21. Primary Infection
• During this phase, a person may experience non-
specific ‘flu-like’ symptoms
• These symptoms do not lead directly to the
diagnosis of HIV infection and may not be present
in all patients, but commonly include:
– Fever
– Fatigue
– Pharyngitis
– Lymphadenopathy
– Rash
22. Primary Infection contd…
• Pathogenesis of Primary Infection:
– Initial infection of CD4 T-lymphocytes and
macrophages with receptors at site of exposure
– Dissemination of infection to lymph nodes
– Burst of viral replication results in intense viraemia
– Development of humoral immunity (HIV-specific
antibodies)
– Response by cellular immunity (HIV-specific CD4 and
CD8 cells)
23. Symptomatic Phase
• Presentation depends on
viral load and CD4 count
• At CD4 cell counts over
500 cells/µl, PLHIV may
develop complications
found in the general
population:
– Malaria
– Bacterial pneumonia
– Tuberculosis
– Minor skin conditions
• At CD4 counts between
200 and 500 cells/µl, other
conditions, or
opportunistic infections,
begin to appear:
– Pulmonary Tuberculosis
(current)
– Oral or vaginal
candidiasis
– Herpes zoster
24. Symptomatic Phase contd..
• The late symptomatic phase is characterized by
patients having a CD4 cell count less than 250
cells/µl and conditions such as:
– Wasting syndrome
– Oesophageal candidiasis
– Atypical and extra-pulmonary TB
– Pneumocystis pneumonia
– Recurrent, invasive herpes simplex virus infections
25. Severe HIV Infection and AIDS
• This phase is characterized by patients
having a CD4 cell count less than 50 cells/µl
and conditions such as:
– Cryptococcal meningitis
– Cryptosporidiosis
– Toxoplasmosis of the brain
– HIV encephalopathy (PML/dementia)
– CMV retinitis
26. • CD4 Count is an indicator of immune
system status (distance to the cliff)
• Viral Load is an indicator of the amount
of virus in the blood (speed of the train)
27. Natural history of HIV infection in
Children
• Absolute CD4+ count in children varies with age and
is generally higher in healthy children than in adults
• Normal absolute CD4+ counts slowly decline to adult
levels by 6 years
• CD4+% does not change with age;
28. Natural history of HIV infection in
Children
• Risk of AIDS or death rises as CD4+ cell % falls to <25 in
infants, <20 from 1-3 years and <15 thereafter
• Prognosis is poorer in infants than in older children.
29. Changes in Viral load and CD4 in
HIV-infected Adults and Children
• VL trend in perinatally infected infants differs
from that in adults and children >5 years:
• In Infants:
– VL levels are low at birth
– Increases to levels >100,000 to millions of copies/ml
by 2 months of age
– Remain at same level
throughout first year of life
– Decline slowly over the next
few years to a “set point”.
30. Factors predicting disease progression
• Infant factors:
– Infecting viral dose (maternal VL)
– Infection before 4 months of life
– Infant peak viraemia
– Rapid decline in CD4+
– Clinical AIDS
– p24 antigenaemia.
31. CHER: Early ART during the first months of
life decreases the risk of AIDS/death
Violari et al, NEJM 2008
Early treatment before immunologic decline or
disease progression decreases mortality by 76%
32. Modes of HIV Transmission
• Sexual Contact: Unprotected sexual contact with infected
partner(s)
– Male-to-female; female-to-male; male-to-male; female
to female (rare)
• Parenteral: Contact with HIV-infected blood products
– Blood transfusion; intravenous drug use (IDU) through
needle sharing; needle-stick accidents; unsterilized
sharp objects
33. Modes of HIV transmission
• Perinatal: Mother-to-child transmission
– In utero; during labour and delivery; through
breastfeeding
– Accounts for >90% of transmission in children
– Prolonged breastfeeding and mixed feeding are
key factors responsible for higher transmission
rates in Africa
– Without intervention overall transmission rate is
30-40%.
34. Transmission through Sexual
Contact
• Heterosexual and male-to-male transmission of
HIV most common
• Receptive sexual partner at higher risk than
insertive partner
35. Transmission through Sexual
Contact contd..
• Male-to-female transmission is more common than
female-to-male transmission
– Biological factors
– Social factors
– Teenage girls exceptionally vulnerable due to
immature reproductive system
37. Challenges of Pediatric & Adult HIV
• Challenges related to prevention of mother to child
transmission
• Accessibility of PMTCT and Paediatric HIV/AIDS
services
• Availability of effective PMTCT and Paediatric HIV/AIDS
interventions (EID services)
• Challenges of chronicity of the disease
• Provision of life long counselling and support services
• Psychosocial issues
• Cost of care
38. Challenges of Pediatric & Adult HIV cont’d
• Challenges to the health care system
• Increased burden on an already overstretched healthcare
system.
• Inadequate access, low uptake and utilisation of PMTCT and
Paediatric HIV and AIDS services.
• Limited Human resources to manage PMTCT and
Paediatric HIV and AIDS
• Issues around infant feeding and nutrition
• Poor integration, inadequate linkages and weak referral
system.
• Weak Logistic Management Information System (LMIS)
39. Challenges of Pediatric & Adult HIV cont’d
• Societal challenges
• Loss of productive age group
• Increasing number of orphans and vulnerable
children
• Stigma, discrimination and cultural barriers to
effective care and treatment.
40. Challenges of Pediatric & Adult HIV cont’d
• HIV infection poses a number of challenges to the
patients, the mother/caregivers, the family, the
community and the nation as a whole
• These challenges are identified so that plans can be
made to reduce the overall impact of HIV and AIDS in
patients
INTRODUCE the module.
TELL participants that in order to effectively control HIV/AIDS it is important that we have basic understanding of the nature of the virus and the mechanisms by which it is transmitted. This session provides a very detailed insight into the history, epidemiology and molecular biology of the virus, information that will form useful background for the course.
EXPLAIN that knowing the structure of HIV helps to understand how the virus interacts with the human immune system. The structure and interaction of the virus with the immune system also is important in understanding how medicines work to suppress the virus.
EXPLAIN that the 2 sub-types of the virus also vary in their biological characteristics. The rate of transmission is higher and progression to disease is faster in HIV-1 than in HIV-2.
EXPLAIN that HIV-1 has been classified into three major groups, the group M (major), N (non-M, non-O) and group O (Outlier). The group M virus has been further classified into at least nine different subtypes (A, B, C, D, F, G, H, J, K). Recombination of the virus subtypes is a well known phenomenon. Recombination occurs when an individual is super-infected or co-infected with two or more subtypes of HIV-1. HIV-2 is classified into 5 subtypes, A to E and recombinant forms have not yet been identified.
POINT OUT the various parts of the virus on the slide as you explain the following:
HIV consists of a cylindrical centre surrounded by a sphere-shaped lipid envelope. The centre consists of two single strands of RNA.
HIV uses an enzyme reverse transcriptase to make DNA (from RNA) which gets incorporated into the host cell (as provirus)
HIV-1 viral particles have a diameter of 100 nm and are surrounded by a lipoprotein membrane. Each viral particle contains 72 glycoprotein complexes, which are integrated into this lipid membrane, and are each composed of trimers of an external glycoprotein, gp120, and a transmembrane spanning protein, gp41.
Once in the cell, the RNA genome is converted to double-stranded DNA by reverse transcriptase enzyme.
In this process, the integrated provirus becomes a DNA version of HIV that gets incorporated into the host cell.
The next slide describes HIV replication in more detail.
If necessary, REMIND participants that:
RNA stands for ribonucleic acid. HIV is transmitted into the cell enveloped in RNA.
DNA stands for deoxyribonucleic acid and is the genetic material inside human cells.
REVIEW: The immune system refers to the mechanisms by which the body prevents invasion of the body by pathogenic organisms as well as those mechanism that prevent spontaneous developments of neoplasms.
ASK for a volunteer to explain the basic mechanisms of how the immune system works. EXPLAIN that for the purpose of this course, the focus will be on the cells mentioned in the slide.
EXPLAIN to participants that CD4 is a 58 kDa monomeric glycoprotein on the cell surface of about 60% of T-lymphocytes, on T-cell precursors within the bone marrow and thymus, and on monocytes and macrophages, eosinophils, dendritic cells and microglial cells of the central nervous system, langerhans, and stem cells.
EXPLAIN to participants that CD4 is a primary and necessary receptor for HIV-1, HIV-2 entry into the cells.
EXPLAIN:
Innate immunity is the immunity that a person has as part of his or her biological makeup. It does not arise as the result of exposure to an illness, nor from a vaccine. A person is born with innate immunity.
Adaptive immunity, also known as acquired immunity, is the ever evolving immunity that the body develops in response to illness and infection. Vaccines can also serve to promote adaptive immunity. Adaptive immunity leads to the development of “memory” cells.
EXPLAIN that CD4 cells (also known as helper T cells) coordinate the functions of the adaptive immune system and are one of the first cells to respond to infection. Macrophages are cells that engulf and digest cellular debris and pathogens, and stimulate lymphocytes and other immune cells to respond to pathogens.
EXPLAIN the role of CD4 cells in relation to HIV as outlined in this diagram:
The macrophage engulfs the HIV particle and presents it to the CD4 cell, stimulating the CD4 cell to respond to the infection in two ways
When the HIV particle enters the CD4 cell, the CD4 cell sends out a warning signal to other immune cells, primarily the B Lymphocyte and other killer (cytotoxic) cells, including the cytotoxic T-lymphocyte.
In response to the infection, the cytotoxic T cell responds to the infected CD4 cell, either killing it or engulfing it (which essentially destroys it as well); B cells respond by making and secreting antibodies that bind to antigens and make them more susceptible to phagocytosis (a major mechanism used to remove pathogens and cellular debris).
EMPHASIZE that the antibodies produced by B cells in response to HIV are NOT effective in destroying HIV, whereas they are with other infections. These antibodies are useful in helping clinicians to detect HIV infection, though.
Update this picture:
REFER participants to Handout 1.2: HIV Lifecycle, so that they can follow along with the slide, and also get more detail about the process.
ASK participants if they have any questions.
Image Source: Federal Ministry of Health Nigeria National Guideline for HIV and AIDS Treatment and Care in Adolescents and Adults, May 2007
EXPLAIN these steps to participants. You can refer to the diagram on the next slide as you describe each step.
EXPLAIN that HIV uses the CD4 cell like a factory to reproduce more of itself. The host CD4 cell gets destroyed during this process.
PRESENT the graphic and explain to participants the different stages that a patient with HIV goes through. Use the analogy of a traveler who starts a journey (starting at point zero) and goes through different parts to reach the end.
EXPLAIN that initially there is a 2-4 week period of intense viral replication before the onset of an immune response and clinical illness.
Acute illness lasts about 1-2 weeks and is often not recognized (flu-like syndrome).
Clinical manifestations resolve as antibodies to the virus become detectable in serum.
Patients then enter a stage of asymptomatic infection lasting months to years.
The viral load is stable until late in the disease.
CD4 are being constantly destroyed by HIV and replaced by the immune system.
REFER participants to Handout 1.3: Typical Course of HIV Infection.
HIGHLIGHT that this diagram assumes that the patient does not receive antiretroviral therapy. Thus, he/she goes through all the stages, from primary infection to latent stage to symptomatic stage until AIDS and death.
REFER to the graph on the previous slide as you discuss the various phases of HIV infection further.
DISCUSS:
Normal adult CD4 count reference ranges vary by laboratory; however, ranges are generally within 500 -1500/mm3.
The constant exposure to a number of other pathogens in sub-Saharan Africa may result in an overall less healthy immune system with which to fight HIV infection.
EXPLAIN that primary HIV infection can be recognized in infants, children, adolescents and adults. It can be asymptomatic or be associated with features of an acute retroviral syndrome of variable severity in about 70% of HIV-infected persons.
EXPLAIN that the clinical latency period may occur with or without persistent generalized lymphadenopathy (PGL).
EXPLAIN to participants that the period of early HIV disease extends from sero-conversion to an asymptomatic, or latent, phase for a variable period through to symptomatic and advanced AIDS as the CD4 count decreases and viral load increases.
EXPLAIN that the most common symptoms for this stage include: Fever, lymphadenopathy, sore throat, mucocutaneous lesions, myalgia/arthralgia, diarrhoea, headache, nausea/vomiting, and weight loss.
EXPLAIN that after HIV-1 exposure, initial virus replication and spread occur in the lymphoid organs, and systemic dissemination of HIV-1 is reflected by the peak of plasma viraemia. A clinical syndrome of varying severity is associated with this phase of primary HIV-1 infection in up to 70% of HIV-1 infected persons.
Down regulation of viraemia during the transition from the primary to the early chronic phase coincides with the appearance of HIV-1 specific cytotoxic T-lymphocytes and with the progressive resolution of the clinical syndrome.
The long phase of clinical latency is associated with active virus replication, particularly in the lymphoid tissue. During the clinically latent period, CD4+ T-lymphocyte counts slowly decrease as does the HIV-specific immune response. When CD4+ T-lymphocytes decrease below 200,000 cells/ml (i.e. when overt AIDS occurs), the clinical picture is characterized by severe constitutional symptoms and by the possible development of OIs and neoplasms.
REMIND participants that HIV has several targets including dendritic cells, macrophages, and CD4+ T cells.
EXPLAIN to participants that HIV specific immune responses include the emergence of virus-specific CD8+ cytotoxic T-lymphocytes.
If necessary, EXPLAIN to participants that viraemia means that there is virus in the blood.
EXPLAIN to participants that although PLHIV may develop complications found in the general population, they may experience these complications more frequently than would someone with a healthier immune system.
EXPLAIN that another term for this phase is mild immunodeficiency.
EXPLAIN to participants that approximately 10% of patients develop an AIDS-defining diagnosis even when their CD4 count is above 250/mm3.
EXPLAIN atypical and extra-pulmonary TB further. According to the WHO staging book, these types of TB mean “Disseminated non-tuberculous mycobacterial infection and Extrapulmonary tuberculosis.”
EXPLAIN that another term for this phase is severe immunodeficiency.
COMPARE HIV disease progression to a train moving toward a cliff with a break in the train track.
The CD4 count can be compared to the DISTANCE between the present status (asymptomatic/mild disease) and the cliff (AIDS). The greater the distance (higher CD4 count), the more distance left to the cliff, and “catastrophe.”
The viral load can be compared to the SPEED of the train. If the speed (VL) is high, the train will travel faster to the cliff and crash, even if there are still many CD4 left.
ASK participants “What are some factors that affect HIV progression?”
ALLOW time for participants to respond.
RECORD their answers on flip chart.
In children ≤5 years CD4+% is preferred parameter for monitoring disease progression.
VL trend in perinatally infected infants differs from that in adults and children >5 years:
In Infants:
VL levels are low at birth
Increases to levels >100,000 to millions of copies/ml by 2 months of age
Remain at same level throughout first year of life
Decline slowly over the next few years to a
“set point”.
This graph is from the CHER study which looked at starting ART immediately infant had a positive test or waiting gin until they met immunologic criteria to start ART (CD4 fell < 25%) or clinical criteria ( WHO stage III or IV)
Antiretroviral therapy initiated during the first 7 weeks of life reduced early mortality from 16% to 4% as compared to initiating treatment according to a threshold CD4 percentage ( 25%) or clinical progression of HIV disease. This is a relative reduction of 76%
EXPLAIN to participants that sexual transmission is the predominant mode of HIV transmission worldwide.
EXPLAIN that heterosexual and male-to-male transmission are the most common ways in which HIV is passed through unprotected sexual contact. Although it is physiologically possible for female-to-female transmission to occur, to date, it is rare.
EXPLAIN that heterosexual and male to male transmission are the most common ways in which HIV is passed through unprotected sexual contact. Although it is physiologically possible for female-to-female transmission to occur, to date it is rare.
ASK, “Why do you think a receptive partner is more at risk than the insertive partner?”
Potential answers include:
In penile-vaginal sex, women are more likely to become infected with HIV than men because of the structure of the genital tract.
In penile-anal sex, the receptive partner is more likely to become infected with HIV owing to the structure of the rectal mucosa.
Tears and/or sores may facilitate HIV virus in semen to enter the body.
Male-to-Male Sexual Transmission
Men who have sex with men are rarely acknowledged in Africa.
The risk of infection is dependent on whether the index is a receptive or insertive partner.
The anal mucosa is thinner than the vaginal mucosa and is more liable to tear during intercourse.
Factors Which Promote Male- to-Female Transmission
HIV concentration in semen and pre-ejaculatory fluid is higher than that in vaginal fluid
Genital ulcer diseases are hidden in females but are exposed in males
Lacerations, sores, or vaginal irritation/inflammation can increase likelihood of virus entering the body.
The rules that govern sex in Africa do not permit women to negotiate for safer sex.
Economic poverty has forced many women into commercial sex work or other sex for favour situations.
Increased Biological Predisposition of the Teenage Girl
The mucosal lining of the vagina in the young girl is thinner than in mature women; it is a less efficient barrier to HIV and is more prone to tearing than the thicker, multi-layered mucosa of the mature genital tract.
Vagina and cervical mucus which can offer physical and immunological barriers against HIV is less profuse in adolescent girls.
ASK participants the question on the slide.
RECORD participants responses on the flip chart. ASK participants to explain what they mean if it is not clear. ELABORATE on responses to clarify how it drives the HIV epidemic.
Responses could include the following:
Population Mobility: Global economy involves population mobility, with HIV/AIDS following routes of commerce; Displacement due to war/conflict, or natural disasters
Health System Insufficiencies
Cultural Factors: Traditions, beliefs and practices affect understanding of health and disease, as well as acceptance of conventional medical treatment; Cultural norms create barriers which prevent people, and especially women, from taking precautions (for instance, pressure to breastfeed may expose more infants); Spousal inheritance; Pressure to bear children and/or religious beliefs inhibit condom promotion and use
Knowledge/Stigma Factors: Denial prevents acknowledgment of risk; Stigma; People may feel isolated and rejected which prevents risk reduction efforts and care-seeking
Poverty: Lack of access to information needed to understand and prevent HIV; Poor nutritional status; Commercial sex for income; Reduced access to health care services
THANK participants for their responses and move on to the next slide.
