1. Clinical Care of HIV, AIDS and Opportunistic Infections
Unit 1:
Natural History of HIV Disease and Overview of Opportunistic Infections
Unit 1 should take approximately 30 minutes to implement:
Step 1: Introduction and Learning Objectives (Slides 1-2) – 1 minutes
Step 2: Definitions (Slides 3-5) – 3 minutes
Step 3: Natural History & OIs (Slides 6-11) – 8 minutes
Step 4: WHO Staging System (Slides 12-13) – 3 minutes
Step 5: CD4 Counts and Differential Diagnosis (Slide 14-17) – 5 minutes
Step 6: Key Points (Slide 18) – 1 minutes
Step 7: Question and Answer (No Slides) – 10 minutes
NOTE: These facilitation notes provide information on timing, items to emphasize, and background information to help the facilitator understand and explain the slide content. These notes are not meant to be read aloud by the speaker.
Clinical Care of HIV, AIDS and Opportunistic Infections

2. Learning Objectives Participants will be able to:
Describe the natural history of HIV and AIDS in adolescents and adults
Use the 2006 WHO clinical staging of HIV
Explain the meaning of ‘opportunistic’ infection or disease
Explain how CD4 lymphocyte count results are used in developing a differential diagnosis
Step 1: Introduction and Learning Objectives (Slides 1-2) – 1 minutes
This course covers HIV-related and opportunistic diseases in adults and adolescents; there is a separate training for care of HIV-infected children.
The discussion of natural history of HIV, the WHO staging system, and meaning of CD4 cell counts applies to adults and adolescents and NOT to children.
ASK participants if they have any questions about the learning objectives before continuing.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

3. Definitions HIV HIV/AIDS Human Immunodeficiency Virus
Two types: HIV-1, HIV-2.
HIV-1 is the cause of the world-wide pandemic
Multiple HIV-1 subtypes or clades
Clades C and A are most common in southern Africa
Clinical meaning - Can refer to persons with asymptomatic infection or symptomatic disease.
HIV/AIDS
Used by MOHSS to describe the epidemic as a whole; WHO is moving away from this term
Step 2: Definitions (Slides 3-5) – 3 minutes
The terms HIV and AIDS can be used with different meanings. This and the next 2 slides define the terms HIV, AIDS, and HIV/AIDS.
HIV is used with a clinical meaning and a virologic meaning. In this course the clinical meaning of HIV includes the full spectrum of HIV disease, from onset of infection to clinical AIDS to death.
HIV is also the name of the virus, Human Immunodeficiency Virus, which causes this syndrome. HIV comes in 2 types (HIV-1 and HIV-2): HIV 1 is the cause of the world wide pandemic and is the important virus in Namibia.
HIV-1 also includes multiple sub-types, also known as clades.
MOHSS uses the phrase HIV/AIDS to refer to the epidemic as a whole. WHO is moving away from using the term “HIV/AIDS”. They advocate using HIV unless specifically referring to AIDS. This is particularly important in the context of prevalence, prevention and testing where using HIV alone makes more sense than using HIV/AIDS.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

4. Definitions (2) AIDS Acquired Immunodeficiency Syndrome
Although used by the public to encompass the whole epidemic, in the clinical sense it refers only to the most severe manifestation of infection with HIV
Defined by the presence of life-threatening AIDS-defining conditions due to HIV-induced severe immunosuppression
Opportunistic infections
Some malignancies
AIDS = Acquired Immunodeficiency Syndrome.
The term is often used to refer to the epidemic as a whole. In this course, the clinical meaning of AIDS to refer to the most severe forms of HIV disease. It is defined by the presence of life-threatening infections due to HIV-induced severe immunosuppression, corresponding to WHO Stage 4 (described in detail in slide ).
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

5. Definitions (3) 2006 WHO definitions
Advanced HIV infection (most relevant for patient management)
WHO Clinical Stage 3 or 4 OR
CD4 count < 350 cells/mm3
AIDS
WHO Clinical Stage 4
CD4 count < 200 cells/mm3
The 2006 WHO Guideline (see ref below) states that for surveillance, advanced HIV disease includes any clinical stage 3 & 4 disease or any clinical stage and <350mm3.
AIDS is defined as a clinical diagnosis (presumptive or definitive) in HIV confirmed infection of any stage 4 condition OR immunological criteria in adults and children ≥5yo with CD4<200 or <15% (children months <20%; children <12 months 25%) – “severe” HIV-associated immunodeficiency. AIDS case reporting for surveillance is no longer required if HIV infection or advanced HIV infection is reported.
AIDS case definitions first developed in 1982 were primarily designed as an epidemiological tool for surveillance purposes. Various revisions over the next two decades led to inclusion of clinical and laboratory criteria to the surveillance definitions. WHO introduced a clinical case definition for surveillance in 1985, and revised this in 1986 and 1994 to include serological testing for HIV. ‘AIDS’ as a term has also been used to describe the various clinical syndromes, specific opportunistic infections or malignancies that occur with HIV infection and signal those in whom advanced HIV infection has occurred. There has been confusion between surveillance definitions and clinical staging definitions. These guidelines seek to harmonize both. In the present context of scaling up ART the purpose of surveillance is to monitor the burden of advanced HIV disease and allow estimates of the number of people who require or may shortly require ART. Including a CD4 threshold in surveillance definitions specifies the level at which advanced HIV related immunosuppression is deemed to have occurred and from which intervention with ART is immediately or soon needed to offset disease progression. For surveillance purposes once the clinical OR immunological trigger event has occurred the patient should be captured only once in surveillance data, regardless of ART or other treatment interventions or outcomes.
From 2005 INTERIM WHO CLINICAL STAGING OF HIV/AIDS AND HIV/AIDS CASE DEFINITIONS FOR SURVEILLANCE (AFRICAN REGION)
2006 CASE DEFINITIONS OF HIV FOR SURVEILLANCE AND REVISED CLINICAL STAGING AND IMMUNOLOGICAL CLASSIFICATION OF HIV-RELATED DISEASE IN ADULTS AND CHILDREN
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

6. Question 1
How long do people live after they acquire HIV infection, without HAART?
How long does it take for a person with HIV to develop AIDS?
Step 3: Natural History & OIs (Slides 6-11) 8 minutes
Begin the discussion of HIV natural history by asking the participants these 2 questions. Anticipate and accept a range of answers. (There is no definite answer for Namibia, but the next slides will provide some answers to these questions.)
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

7. CD4 Count, Viral Load and Clinical Course of Untreated HIV Infection in Adults
CD4 Cells
4-8 Weeks
5-10 Years to AIDS
CD4 Cell Count
1,000
500
Intermediate Stage
AIDS
Primary Infection
Sero-conversion
Survival with AIDS 1 year
200 1 10
100
10,000
100,000
1,000,000
10,000,000
Plasma HIV RNA
Refer to Handout 1.1 in the Participant Handbook.
This is a very important slide to review. This should be familiar to participants who have attended the ART course.
This is the overview of natural history showing the median progression and survival, and typical changes in plasma HIV RNA PCR (viral load) and CD4 counts over time, in adults and adolescents with HIV. In developed countries, the time from onset of HIV infection to the first AIDS defining illness like PCP was around 10 years prior to HAART. Survival after a first AIDS defining illness like PCP was 11 months, or about 1 year, again without HAART. So the natural history was thought to be about 11 years from acquisition of infection to death, when individual opportunistic infections were treated but without antiretroviral therapy and without opportunistic infection prophylaxis. The time was shorter for older persons, and longer for adolescents and adults under age 40.
HIV grows within, and destroys CD4 lymphocytes (a type of white blood cell). The reduction of CD4 lymphocytes is the main cause of reduced immunity (reduced ability to fight other infections) in persons with HIV. The lower the CD4 count, the more severe the immunosuppression.
The red dotted line shows the amount of HIV in the plasma portion of blood during infection measured by PCR (viral load). It reaches very high levels in the first weeks of infection, sometimes associated with an illness called Primary or Acute Retroviral Syndrome (fever, lymphadenopathy, rash, oral ulcers, etc). After a few months the immune response lowers the viral load to a level where it remains relatively stable for years (the “set point”). As immunity fails, the viral load typically rises again with advanced disease.
The green solid line shows the CD4 count over time. Here it starts at a normal level over 1000, has a short drop during acute retroviral syndrome, then falls gradually over years. When the CD4 count falls below 500, mild immunosuppression begins, below 200 is severe immunosuppression with a high risk of AIDS defining illnesses. The CD4 categories will be reviewed in greater detail in upcoming slides.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

8. Natural History High Viral Load: Rapid Progressor
Normal
CD4 cells
> 500
High Viral Load
Remind participants the HIV grows within, and destroys CD4 lymphocytes. The rate of CD4 decline, and the rate at which disease progresses in an infected individual, depends mostly on the HIV viral load. In some persons their immune system cannot limit the growth of HIV at all.
This shows rapid progression in persons who maintain high viral loads so they become immunosuppressed, ill, and die, within a few years of infection. This accounts for about 5% of HIV+ adults and adolescents.
CD4 cells
< 200
AIDS
Infection
2-3 years
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

9. Natural History Low Viral Load: Long-Term Non-Progressor
Normal
Infection
10 years
CD4 cells
> 500
Low Viral Load
This shows the lack of progression over 10 years in a long term non-progressor. The immune system of these persons keeps HIV growth at very low levels. These persons remain healthy with very low viral loads and normal CD4 counts over at least 7-10 years without therapy. This accounts for about 5% of HIV+ adults and adolescents.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

10. Question 2
What is the meaning of ‘opportunistic’ infection or disease?
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

11. Opportunistic Disease or Infection
Strict meaning:
An infection or disease that occurs only in persons with weakened immune systems
Common meaning:
Any one of a number of infections or diseases that occur often in persons with HIV or AIDS
Also in the strict sense, an opportunistic disease or infection would only occur in a person with a damaged immune system, and does not occur in healthy persons. However, In the context of the HIV epidemic, these terms are used to describe conditions that occur in persons with HIV or AIDS. Bacterial pneumonia may occur in anyone, for example, but is more frequent and more severe in persons with HIV-associated immunosuppression. This course includes HIV-related conditions in this broad sense.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

12. Training on Clinical Care of HIV, AIDS and Opportunistic Infections
Step 4: WHO Clinical Staging and Immunologic Classification System (Slides 12-13) – 3 minutes
This slide illustrates the revised, 2006 WHO clinical staging of HIV/AIDS in adults and adolescents.
Refer participants to Handout 1.2 in the Participant Handbook for a clearer version of this table.
The first level describes Primary HIV Infection, when a person acquires HIV infection. Remember that the viral load is very high, and the CD4 count may decrease. These patients may have no symptoms or may have an illness with fever, lymphadenopathy, rash, oral ulcers, and other features.
Clinical stage 1 includes persons with ongoing HIV infection but either no symptoms or only several areas of enlarged lymph nodes: persistent generalized lymphadenopathy.
Clinical stage 2 includes minor conditions especially of the skin and oral cavity.
Clinical stage 3 includes more serious conditions, but many are conditions that may occur in persons without HIV: such as tuberculosis and bacterial pneumonia. Oral candidiasis is unusual in persons with normal immunity, and oral hairy leukoplakia almost never occurs without HIV infection. Notice that stage III includes weight loss of more than 10%, chronic fever, or chronic diarrhea, but NOT the combination of weight loss with fever or diarrhea.
Stage 4 includes AIDS-defining conditions. Most of these do not occur in persons with normal immune systems, like cryptococcal meningitis or Pneumocystis pneumonia, and are true opportunistic diseases. However, some may occur in persons with normal immunity and without HIV, such as extra-pulmonary TB. A new diagnosis has been added to clinical stage 4: Symptomatic HIV-associated nephropathy or symptomatic HIV-associated cardiomyopathy.
HIV wasting syndrome is by definition:
Unexplained involuntary weight loss (>10% baseline body weight), with obvious wasting or BMI<18.5 PLUS
Unexplained chronic diarrhoea (loose or watery stools 3 or more times daily) reported for > 1 month OR
Reports of fever or night sweats for >1 month without other cause and lack of response to antibiotics or antimalarial agents; malaria must be excluded in malarious areas
Table source: World Health Organization. WHO Case Definitions of HIV for Surveillance and Revised Clinical Staging and Immunological Classification of HIV-Related Disease in Adults and Children,
Training on Clinical Care of HIV, AIDS and Opportunistic Infections
WHO,

13. Natural History: WHO Immunological Classification of HIV Infection
No significant immunosuppression
CD4 cells
> 500
CD4 cells
Mild
immunosuppression
Advanced immuno-suppression
This graph shows the gradual decrease in CD4 counts over the years of HIV infection, and the associated decrease in immune function over time.
Remind participants not to confuse these levels of immunosuppression with the WHO Clinical Staging system. Often people in clinical stage 1 will have CD4 counts >500, those with the mild skin and oral conditions of stage 2 will have counts of , those with moderate conditions will have counts between 350 and 200, and those with AIDS defining conditions will usually have CD4 counts less than 200. The 4 WHO clinical stages often correspond to specific categories of CD4 count, however, there are also many exceptions. When diagnosing a new illness, it is helpful to know the patient’s CD4 count and medical history, in order to know what illnesses that person is more susceptible to, but patients can get infections with CD4 counts which fall outside the usual ranges. Clinical evidence should take precedence over CD4 counts when making a diagnosis.
CD4 cells
Severe immuno-suppression
CD4 cells
< 200
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

14. Question 3
How can you use CD4 lymphocyte count results in developing a differential diagnosis?
Step 5: CD4 Counts and Differential Diagnosis (Slide 14-17) – 5 minutes
ASK participants, “How can you use CD4 lymphocyte count results in developing a differential diagnosis?”
If they don’t know the answer, move ahead to the next slide. This is meant as an introduction to the idea of using the CD4 cell count result in helping to make a diagnosis.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

15. Relation Between CD4 Count and Types of Pathogens
CD4 cells
> 500
Usual pathogens
Usual pathogens;
disease more frequent or severe
CD4 cells
Opportunistic pathogens
Remind participants that different CD4 counts indicate different degrees of immunosuppression, and susceptibility to different types of organisms.
As the CD4 count falls below 500, persons can become ill with the usual organisms that can cause disease in healthy people, but the illnesses are more frequent and more severe.
As the CD4 counts fall below 200, persons become susceptible to true opportunistic pathogens that do not cause disease in healthy people, in addition to all the usual pathogens.
With CD4 counts below 50, extremely low, persons become susceptible to a group of conditions that are even more extreme.
CD4 cells
< 200
‘Severe’
opportunistic pathogens
CD4 cells
< 50
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

16. Examples of Pulmonary Pathogens
CD4 cell count
Pathogen
Examples
> 500
Usual
Bacterial pneumonia TB
More frequent
More severe
200-50
Opportunistic
Pneumocystis
< 50
MOTT or TB
CMV
Kaposi’s Sarcoma
Here is an example of the range of pathogens that cause lung disease based on CD4 cell count.
Persons with counts above 200 can get the bacterial pneumonia or TB, as can anyone. However, persons with counts below 500, and especially below 350, are much more likely to get these conditions than healthy persons. With counts below 200 Pneumocystis pneumonia and other opportunists join the list of possible diseases. Below CD4 counts of 50, extreme pathogens join the list of possibilities, such as mycobacteria other than tuberculosis (MOTT), CMV (a severe viral infection), or Kaposi’s sarcoma may occur in the lung.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

17. Distribution of HIV Infected Persons and Levels of Immunosuppression
Stage 1
Stage 2
Stage 3
Stage 4
AIDS
Advanced
immunosuppression
No significant
Mild
This famous pyramid illustrates the proportion of persons with HIV in the population with various degrees of immunosuppression.
Most people with HIV are in clinical stage 1, feel fine, and have no symptoms. They are an invisible part of the epidemic, unless they have lymphadenopathy or have an HIV test.
Those in Stage 2 or 3 may come to medical attention because of their minor or moderate conditions, but still need an HIV test to be properly diagnosed.
Those in stage 4 have the severe conditions that define AIDS, and are the most visible part, although the smallest part, of the epidemic. It is often obvious that they are severely ill, but an HIV test should be done to confirm the diagnosis.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections

18. Key Points
Persons with HIV may have normal immune function, or varying degrees of immunodeficiency
Knowledge of the degree of immunodeficiency in an HIV+ person helps determine which infections or diseases are most likely
The CD4 lymphocyte count, if available, helps determine the degree of immunodeficiency
Staging of HIV disease is based on clinical factors, not CD4 counts
Step 6: Key Points (Slide 18) – 1 minutes
Key Points serve as a tool for summarizing and reviewing the main ideas that were discussed in the unit. Summarize the presentation and review the Key Points.
Step 7: Question and Answer (No Slides) – 10 minutes
Spend 10 minutes answering participant questions about natural history and opportunistic infections.
Collect the questions first, and then answer the most important, avoid repetition, and postpone questions referring to topics to be covered later in the course.
Questions that cannot be answered at the time, or are not immediately relevant, should be written on flip chart paper and answered later (this is often called the ‘parking lot’).
If there are more questions than time allows, remind participants that questions can be asked informally of faculty throughout the day, at breaks, or during the daily review sessions.
Training on Clinical Care of HIV, AIDS and Opportunistic Infections