Human Immunodeficiency Virus



HUMAN IMMUNODEFICIENCY VIRUS (HIV)

Introduction

Acquired immune deficiency syndrome (AIDS) is a severe, life-threatening disease that represents the late clinical stage of infection with human immunodeficiency virus (HIV).

Human immunodeficiency virus (HIV) medicine is a very specialized field and expert advice should ways be sought regarding the management of HIV/ AIDS patients.

These guidelines describe general principles only.

The Origin of HIV

Clinically apparent human immunodeficiency virus (HIV) infection first was recognized in 1981 in homosexual men in New York City who presented with evidence of a profound acquired immune deficiency syndrome (AIDS).

For many years scientists theorized as to the origins of HIV and how it appeared in the human population, most believing that HIV originated in other primates.

Then in 1999, an international team of researchers reported that they had discovered the origins of HIV-1, the predominant strain of HIV in the developed world. A subspecies of chimpanzees native to west equatorial Africa had been identified as the original source of the virus. The researchers believe that HIV-1 was introduced into the human population when hunters became exposed to infected blood. 3

Epidemiology

● Occurrence is worldwide. There were 40 million people living with HIV/AIDS by the end of 2001 and in 2000 three million people died from HIV-related illnesses.

The vast majority of HIV infections occur in developing countries.

● For the period 1983 to 2003 there was a cumulative total of 4680 HIV diagnoses in Victoria. This represents about 21% of Australia’s total. Males accounted for 94% of the diagnoses.

Pathophysiology

Organism

● Human immunodeficiency virus (HIV) types 1 and 2 are a member of family retroviridae.

Immunopathology

HIV results in chronic infection of immune cells that express the antigen CD4+, to which the virus attaches and gains entry to the cell.

A DNA copy of the viral RNA genome is then produced by the viral enzyme reverse transcriptase, (retroviruses are distinguished by this ability).

This DNA “pro-virus” then integrates into the host’s DNA where it codes for continuing viral production. Ongoing replication of the virus eventually leads to the death of the cell.

Cells expressing the CD4+ antigen include:

● Monocytes/ macrophages

● Helper lymphocytes.

Infection of the helper lymphocytes leads to a relentless depletion of these cells, which play a major role in the body’s cell mediated immunity.

Immune dysfunction is typically not clinically apparent some years following initial infection because CD4+ lymphocytes are usually present initially in numbers that greatly exceed requirements. As numbers of these cells reduce with time to critical levels, malignancies and opportunistic infections begin to occur.

Transmission

HIV can be transmitted from an infected person by:

1. Sexual exposure:

● Sexual exposure to infected semen, vaginal fluids and other infected body fluids during unprotected sexual intercourse with an infected person. This includes oral sex.

2. Inoculation from biological tissues, icluding:

● Inoculation with infected blood transfusions.

● Blood products transfusions.

● Transplantation of infected organs such as bone grafts or other tissues,

● Artificial insemination with infected semen.

3. Vertical:

● Mother to fetus via placental transfer

● Interventions that decrease the risk of vertical transmission from an infected woman to her child include antiretroviral therapy during pregnancy and caesarean section. With these interventions the risk of mother to child transmission is less than 5%. If there is no intervention, the risk of mother to child HIV transmission has been estimated to be 20–45%.

4. Breastfeeding:

● Breastfeeding of an uninfected infant by an HIV positive mother.

5. Sharps injuries:

● Sharps injuries including needle stick injuries or other exposure to blood and body fluids.

● The overall rate of seroconversion following a needle stick injury involving HIV infected blood is said to be less than 0.5%, however this is dependent on the type of needle stick injury (deep versus shallow) and the viral load of the infected person.

Incubation Period

● The period from infection to the primary seroconversion illness is three to eight weeks.

● The period from infection to development of anti-HIV antibodies is three weeks to three months.

● The interval from HIV infection to the diagnosis of AIDS ranges from about nine months to 20 years or longer, with a median of 12 years.

● There is a group of people with a more rapid onset of disease who develop AIDS within three to five years of infection.

● Treatment with antiretroviral drugs and disease specific prophylaxis has resulted in an 80% reduction in AIDS-associated illnesses.

Reservoir

● Humans.

Period of Communicability

● All antibody positive persons carry the HIV virus.

● Infectivity is presumed to be life long.

● Successful therapy with antiretroviral drugs can lower the viral load in blood and semen to undetectable levels and reduce infectivity.

Susceptibility and Resistance

● Everyone is susceptible to infection.

● The presence of other sexually transmitted infections, especially those with skin or mucosal ulceration, may increase susceptibility.

Clinical Features

The 1993 CDC Classification for HIV/ AIDS:

| | |

| |CLINICAL CATEGORY |

| | | | |

|CD4 Cell Count |A |B |C |

| | | | |

|≥ 500/ mm 3 |A1 |B1 |C1 |

| | | | |

|200-499/ mm 3 |A2 |B2 |C2 |

| | | | |

|< 200/ mm 3 |A3 |B3 |C3 |

Patients who have clinical category C conditions or who have a CD4 count that is less than 200 are classified as having AIDS.

See appendix 1 below for a table that demonstrates the relationship of the CD4 count to the development of clinical disease.

Therefore AIDS patients will be classified as C1, 2, 3 or A3, and B3.

Clinical Category A

This group includes:

1. Acute primary (seroconversion) HIV illness

2. Asymptomatic (latent) HIV infection.

3. Persistent generalized lymphadenopathy.

Acute primary (seroconversion) HIV illness

1. Acute seroconversion:

● This generally occurs within 2-4 weeks of primary contact with the HIV virus.

● Many cases will be very mild or asymptomatic.

● The illness itself is non-specific with constitutional symptoms which may include, fever, myalgias, arthralgias, anorexia, malaise and lethargy. Lymphadenopathy and mild splenomegaly may occur. A non-specific rash may also occur. It is often described as an infectious mononucleosis type illness.

● The illness may last 2-3 weeks.

2. Occasionally a neurological syndrome may present: 4

● Meningo-encephalitis.

● Neuropathies.

● Guillain Barre syndrome.

Asymptomatic (latent) HIV infection.

● Infected persons may then be free of clinical signs or symptoms for months to 10 years or sometimes even longer than this.

● During this period there is usually a progressive decline in the CD4 count.

Persistent generalized lymphadenopathy.

● Some patients who are otherwise asymptomatic may develop persistent generalized lymphadenopathy (PGL).

● Some definitions have described PGL as two or more nodes of greater than one centimetre persisting for greater than 3 months.

Clinical Category B

These patients have symptoms but they are not those which would be classified as group A or group C clinical disease.

The predominant clinical features in this group include:

1. Persistent non-specific constitutional symptoms:

● Lasting for greater than one month.

● Fever (>38 5 )

● Diarrhoea

● Weight loss, (> 10% body weight).

2. A range of muco-cutaneous conditions, including:

● Oropharyngeal candidiasis, (excluding esophageal involvement)

● Oral leukoplakia

● Vulvovaginal candidiasis (persistent, recurrent or refractory)

● Cervical dysplasia (moderate or severe)/cervical carcinoma in situ

● Vasculitis.

● Herpes zoster (shingles), involving ≥2 episodes or ≥1 dermatome

● Atypically severe and generalized skin disorders of xeroderma, molluscum contagiosum or seborrheic dermatitis

3. Idiopathic thrombocytopenic purpura.

4. Peripheral neuropathies.

Clinical Category C

There is a large range of AIDS-defining illnesses.

These include:

Neurological

● Progressive HIV encephalopathy.

Infective

1. Bacterial

● Recurrent bacterial pneumonia, (≥2 episodes in 12 months)

● Tuberculosis or other mycobacterium

2. Viral

● Chronic herpes simplex infection

● Cytomegalovirus infection, this causes eye disease in particular

3. Fungal

● Candidiasis of the bronchi, trachea, or lungs

● Esophageal candidiasis.

● Cryptococcus neoformans, which may result in meningitis.

4. Protozoal

● Toxoplasmosis of the brain.

● Pneumocystis carinii pneumonia (PCP), this is one of the most common opportunistic infections in HIV patients.

● Cryptosporidiosis

Malignancies

1. Kaposi’s sarcoma

2. Lymphomas.

HIV wasting Syndrome

Wasting syndrome due to HIV is defined as

● Weight loss >10% of baseline body weight

Associated with either:

● Chronic diarrhea (≥2 loose stools per day ≥1 month)

● Chronic weakness

● Documented fever ≥1 month

Investigations

Diagnostic tests

1. FBE:

● Look for lymphopenia.

● Reduction in the lymphocyte CD4 count

2. Serology:

● Detection of HIV antibody by the ELISA screening test. IgM is produced as well as IgG however IgG is more reliable in the screening for HIV and this is the one that is used. Neither the IgG nor IgM are protective.

● IgG in most cases becomes detectable within 3 months.

● If IgG is detected the result is usually then confirmed by Western blot analysis which involves the detection of antibodies direction toward specific HIV viral antigens. The most commonly detected antibody being that which is directed against the p24 antigen.

3. Viral antigen:

● Detection of the viral p24 antigen in serum is done by an EIA (enzyme immuno-assay) test.

● The level of viral load provides an indication of the infectivity of the patient.

(From Australian Family Physician vol 20 no 6 June 1991)

4. PCR:

● PCR tests can be done to detect pro-viral DNA sequences, but these are not routinely done nor are they routinely necessary.

5. Viral cultures:

● This is only necessary in certain special clinical situations.

The above graph shows the natural history of untreated cases of HIV infection. There is a relentless attrition of CD4 cells with a corresponding increase in viral load.

Explanation, counselling and consent:

● Note that when testing any patient for HIV it is very important to include a discussion on the risk profile the patient has (by which many could be reassured) and the meaning of what a positive or negative result would mean.

● It is important also to get specific consent for HIV testing.

Further tests

CXR

● In particular, to look for evidence of infection or malignancy

CT Scan

● This will be indicated in patients being investigated for progressive HIV encephalopathy.

● Metastatic disease or other malignancy such as lymphoma.

● The ring enhancing lesion characteristic if toxoplasmosis.

Esophagoscopy/ Bronchoscopy

● This may be done to define the extent of an oropharyngeal candidiasis. Esophageal involvement or tracheal or bronchial involvement are AIDS defining conditions.

Management

Management issues include:

● Acute seroconversion illness.

● Anti-retroviral treatment

● Treatment of specific AIDS illnesses

● HIV and pregnancy

● Post exposure prophylaxis.

● Education

● Counseling and support

Acute seroconversion illness:

● In acute HIV infection, treatment is appropriate on theoretical grounds but is of unproven clinical benefit based on current published evidence.

● The decision to treat at this stage will be made by a specialist in HIV medicine. 2

Anti-retroviral treatment:

The following is provided for general information only. Antiretroviral therapy continues to evolve. It should only be prescribed by specialists in HIV medicine.

Initiation of treatment will depend on a wide range of factors including:

● The presence or absence of symptoms

● The CD4 count

● The viral load

● Patient profile factors/ co-morbidities.

The recommendations for initiation of antiretroviral therapy are summarised in the table below from the Therapeutic guidelines 2006.

In general the following principles apply:

● Symptomatic HIV infection (including HIV-associated opportunistic infections, malignancies, central nervous system disease, thrombocytopenia) - all patients should be treated.

● Asymptomatic HIV infection - all patients with a CD4 cell count less than 200 per microlitre should be treated.

● Treatment is usually deferred if the CD4 cell count is greater than 350 per microlitre.

● Patients with a CD4 cell count between 200 and 350 per microlitre should also be treated, although the exact time to initiate antiretroviral therapy in the latter group will be influenced by factors such as short-term risk of disease progression, tolerability and long-term toxicity of the antiretroviral regimen, and the patient’s willingness to maintain a high level of adherence to lifelong therapy.

| | | | |

|Clinical condition |CD4 cell count |HIV viral load |Recommendation |

|Symptomatic |Any value |Any value |Treat |

|Asymptomatic |200/microlitre but ≤350/microlitre |Any value |Offer therapy |

|Asymptomatic |>350/microlitre |≥100 000 copies/mL |Discuss with patient, may defer therapy |

|Asymptomatic |>350/microlitre | ................
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