III.

Nature of the Disease

A.

Clinical Progression of AIDS

A.1.

Measuring Progression

The progression from the point of HIV infection to the occurrence of one (or more) of the clinical diseases that define AIDS may take six to ten years or longer. The progression to disease in HIV-infected individuals can be monitored using surrogate markers (laboratory data that correlate with disease progression), or clinical end points (illnesses that can occur after a specific degree of immunosuppression has been reached). Surrogate markers for the various stages of HIV disease include the progressive loss of CD4+ T-lymphocytes (CD4+ T-cells), the major white blood cells lost through HIV infection. In general, the lower the patient's CD4+ T-cell count, the more advanced is the degree of immunosuppression. The amount of HIV circulating in the blood is a second surrogate marker. Using sensitive detection techniques, the quantity of HIV in the blood of an untreated individual correlates with the clinical stage of the disease and predicts the rate of disease progression.

A.2.

Acute Retroviral Syndrome

A well-recognized progression of disease occurs in untreated HIV-infected individuals. Within one to three weeks after infection with HIV, many (but not all) individuals experience non-specific flu-like symptoms that may include fever, headache, skin rash, tender lymph nodes, and malaise, lasting approximately one to two weeks. During this phase, termed acute retroviral syndrome or primary HIV infection, HIV reproduces itself to very high levels, circulates through the blood, and establishes infections in tissues throughout the body, especially in the lymph nodes. Patients’ CD4+ cell counts fall briefly but return to near-normal levels as the immune system recognizes the infection and mounts an immune response that reduces HIV replication, albeit incompletely.

A.3.

Asymptomatic Phase

Individuals then enter a prolonged asymptomatic phase that can last ten years or more. During this period, infected individuals usually remain in good health, with levels of CD4+ cells in the low-normal range (750 to 500 cells per cu mm). However, HIV continues to replicate during the asymptomatic phase, causing a progressive destruction of the immune system. Eventually, the immune system declines and patients enter the early symptomatic phase.

A.4.

Symptomatic Phases

The early symptomatic phase can last from only a few months to several years and is characterized by rapidly falling levels of CD4+ cells (500 to 200 cells per cu mm) and non-life-threatening opportunistic infections. From this phase, patients undergo more extensive immune destruction and serious illness that characterize the late symptomatic phase. The late phase again can last from only a few months to years and patients may have CD4+ cell counts below 200 along with AIDS-defining opportunistic conditions. A wasting syndrome of progressive weight loss and debilitating fatigue is observed in a large proportion of untreated patients in this stage. The immune system is now in severe failure, with a CD4+ cell count below 50. In the absence of effective anti-HIV therapy, death from life-threatening AIDS-defining opportunistic infections and cancers is likely to occur within one to two years.

B.

Opportunistic Conditions

Death from AIDS is generally not due to HIV infection itself, but due to opportunistic conditions. These infections and malignancies occur when the immune system can no longer provide protection against agents normally found in the environment. The appearance of any one of more than 20 different opportunistic infections, termed AIDS-defining illnesses, provides the clinical diagnosis of AIDS in HIV-infected individuals.

The most common opportunistic infection seen in AIDS is PCP, caused by a fungus (Pneumocystis carinii), which exists in the airways of all individuals. Bacterial pneumonia (caused by several types of bacteria including Streptococcus and Haemophilus) and tuberculosis (TB: a bacterial respiratory infection caused by Mycobacterium tuberculosis) are also commonly associated with AIDS.

In late-stage AIDS, disseminated infection by Mycobacterium avium intracellulare complex can cause fever, weight loss, anaemia, and diarrhoea. Additional bacterial infections of the gastrointestinal tract (from Salmonella, Campylobacter, Shigella, or other bacteria) commonly cause diarrhoea, weight loss, anorexia (loss of appetite), and fever.

Besides PCP, other fungal infections, or mycoses, are frequently observed in AIDS patients. Oral candidiasis, or thrush (infection of the mouth by the fungus Candida), is seen early in the symptomatic phase in a high proportion of patients. Oesophageal candidiasis (affecting the throat) is a more serious, AIDS-defining illness. Other mycoses include infections with Cryptococcus species, a major cause of meningitis in up to 13 per cent of AIDS patients, and disseminated histoplasmosis, caused by Histoplasma capsulatum, that affects up to 10 per cent of AIDS patients in the south-central United States and South America, but is very rare in the United Kingdom and mainland Europe.

Viral opportunistic infections, especially with members of the herpes virus family, are common in AIDS patients. One herpes family member, cytomegalovirus (CMV), may infect the retina and can result in blindness. Another herpes virus, Epstein-Barr virus, may result in a cancerous transformation of blood cells. Also common are infections with herpes simplex virus types 1 and 2 that result in progressive oral, genital, and perianal lesions.

Neurological problems that may occur among AIDS patients include: HIV encephalopathy (also known as AIDS dementia), caused by direct infection of brain cells by HIV; progressive multifocal leukoencephalopathy, caused by the JC virus; and toxoplasmosis, caused by a protozoal infection, Toxoplasma gondii.

Many AIDS patients develop cancers, the most common being Kaposi’s sarcoma (KS) and B-cell lymphoma. KS is caused by the cancerous transformation of cells in the skin or internal organs, resulting in purple lesions on the skin, lungs, gastrointestinal tract, or elsewhere in the body. A less serious form of KS also occurs among certain non-HIV-infected populations in Africa and the Mediterranean. It is caused by a recently discovered virus, human herpes virus 8 (HHV-8), which appears to be most commonly transmitted in saliva and during sexual contact. KS occurs relatively commonly among HIV-positive homosexual men and Africans but is rare among other HIV-infected people, reflecting the distribution of HHV-8 in different population groups.