AIDS

Preface.




Infection with the human immunodeficiency virus (HIV) and AIDS represents a major challenge to health workers around the world. As of 1st July 1988, 100,410 AIDS cases had been reported to the World Health Organization from 138 countries around the world. An estimated 5 to 10 million persons worldwide are currently infected with HIV. Without a specific means to prevent their developing AIDS, the toll of AIDS cases will rise precipitously during the next five to ten years.



Historical.

AIDS epidemic was first reported in New York and California in 1981, in previously healthy male homosexuals who presented with opportunistic infections and Kaposi’s sarcoma.

The term AIDS was officially adopted in 1982.

The causative retrovirus, called Lymphadenopathy-Associated Virus (LAV), was identified first in 1983 by Montagnier and colleagues in Paris.

Simultaneously, Gallo and colleagues reported isolation from patients of a virus which they called Human T-cell Lymphotropic Virus type III (HTLV-III). Investigations confirmed the identity of LAV and HTLV-III.

By international agreement this virus is referred to now as the Human Immunodeficiency Virus type I (HIV-I).

AIDS was reported in tropical Africa from 1982 onwards while the first (retrospectively recognized) cases in the Americas occurred in 1979. There has been a marked increase in the number of cases reported to the WHO over the years.

Transmission of AIDS in Africa is primarily through heterosexual activity, whereas in America and Europe the main modes of transmission are sexual contact between homosexuals and bisexuals, and sharing of contaminated needles among intravenous drug abusers.



1. Virology and Immunology.



Human Immunodeficiency Virus (HIV-I)

The acquired immunodeficiency syndrome (AIDS) was first recognized in 1981. it has been clearly established that the cause of Aids is a human retrovirus called human immunodeficiency virus – I (HIV-I).

The retroviruses were known long before the emergence of AIDS and HIV-I. many are RNA – containing tumour viruses which cause sarcomas or leukemias in a variety of animals and mammary cancers in mice. The human T-lymphotropic virus (HTLV) group of retroviruses includes HTLV-I which causes a T-cell leukamia in man, a related virus HTLV-II, and HTLV-III which is another name for HIV-I.



HTLV

HTLV, or human T-cell leukaemia virus, either of two viruses now known to cause certain forms of human blood-cell cancer. HTLV-I and HTLV-II were first identified in the late 1970s. They cause cancer by attacking the cells of the immune system known as T lymphocytes, causing the cells to proliferate uncontrollably and to invade various tissues. Both HTLVs are viruses of the retrovirus type, distinguished from other viruses because they code their genetic instructions in RNA instead of DNA molecules (see Nucleic Acids). Another retrovirus in 1983 and 1984 was linked with cases of acquired immune deficiency syndrome, or AIDS, and was tentatively labelled HTLV-III. The virus that causes AIDS is now known as the human immunodeficiency virus, or HIV.



HIV-I

HIV-I, however, does not lead directly to tumour production n but is a member of the lentivirus subgroup of retroviruses also known as slow viruses because they cause chronic infections, which progress slowly over a period of months to years.

HIV-I is a single stranded RNA virus which replicates by using an unique enzyme, reverse transcriptase, to translate its genomic RNA into DNA copy. This DNA is then inserted as a provirus into the host cell DNA, where it may remain latent or be copied again into viral RNA to produce new virus particles.

HIV-I infects T-helper lymphocytes (CD4/OKT4/LEU3a) and also cells of the monocytes / macrophage series, including glial cells of the brain. In fact, monocytes / macrophages have been described as the main reservoirs of HIV-I. Because DNA copies of HIV-I are integrated into host cells, the virus persist throughout the entire life of the infected individual and duplicates itself every time the infected cell multiplies.

HIV-I was first discovered by Barre-Sinoussi, Montagnier and colleagues at the Pasteur Institute in 1983. they called their isolate Lymphadenopathy-associated virus (LAV). Soon therefore, in 1984, Robert Gallo and co-workers, in the USA, described the same virus but called it human T-lymphotropic virus-III (HTLV-III). Recently HIV-I has become the proper name, on the recommendation of the International Committee on nomenclature.

In 1985, another retrovirus of the HIV family was isolated from persons living in West Africa. This virus was called LAV-2 by the French, who found it in patients with AIDS or AIDS-related complex (ARC). The same virus was isolated from healthy West African prostitutes by other workers who called it HTLV-IV. It has been isolated also in Europe and America and appears to be more closely related to simian T-lymphotropic virus-III than to HIV-I. Among isolates of HIV-II, some seem to cause AIDS, while others may not. Like HIV-I, HIV-II infects T4 Lymphocytes. It induces some antibodies that cross react with HIV-I. HIV is seen as mature and budding form in tissue cell line.



The major proteins of HIV-I are its structural proteins enclosed by the gag gene which are recognized on Western blots as 15Kd, 17Kd, 24Kd and 55Kd MW bands, the pol gene proteins of 64Kd and 53Kd MW, and the env gene glycoproteins of 41Kd, 120Kd, and 160Kd MW.



The HIV-II virus induces antibodies that cross react with HIV-I gag proteins but not with the 41Kd env protein.

Remarkable progress has been made in isolating and characterizing these presumably new retroviruses within only a few years of the recognition of AIDS. Indeed, nucleotide sequencing of the genomes of many isolates has already been accomplished. Nevertheless, much remains to be learned. Among the unanswered questions are:

How many different viruses can cause AIDS?

What are the co-factors which lead to active disease?

Which are the important immuno-gens?

Can immunity to these viruses be achieved vaccination?



2. Immunology

It has long been known that HIV cause immune dysfunction resulting mainly from depletion of T4 lymphocytes. The T4 cell among other functions recognizes foreign antigens on infected cells and helps to activate B lymphocytes. The B cell then produce specific antibodies that bind to infected cell and to free organisms bearing the identification antigen, thereby leading to their destruction. The T4 cell also plays a vital role in cell-mediated immunity in killing the infected cells by cytotoxic cells. The T4 cell also influences the activity of monocytes and macrophages which engulf infected cells and foreign particles.

The infection of a T4 cell by HIV beginning when a protein, gp120, on the viral envelop binds to a protein known as CD4 receptor on the surface of the T4 cell.



HIV then merges with the T4 cell and transcribes its RNA genome into double strand DNA. The viral DNA becomes incorporated into the nucleus T4 cell and directs the production of new virion particles.



These virion particles bud from T4 cell membrane and infect other T4 cells.

The severe depletion of T4 cells seen patients with AIDS is difficult to explain sol on the basis of destruction of a few infected T4 cells during replication of HIV in them. In the laboratory, other likely mechanisms of T4 cell destruction have been identified: syncytia formation, antiviral activities of cytotoxic antibodies and cells, and cytokines produced monocytes and macrophages. Syncytia develop after a single infected T4 cell produces gp 120 on its cell surface and this viral protein has high affinity for CD4 receptors on uninfected cells. Thus, uninfected T4 cells can bind to infected T4 cell forming a syncytium which cannot function and dies.



In the second possible mechanism cytotoxic antibodies and cells destroy any cells which exhibit free virus gp 120 on their surfaces. Thus, even uninfected T4 cells which have free gp 120 on their surface are susceptible. The third possible mechanism involves cytokines produced by infected monocytes, macrophages and other tissues dendritic cells present in the skin, mucos membranes, liver, spleen and brain.



B cell function in HIV disease patients is also impaired. Polyclonal B cell activation has been shown as a major feature of B cell dysfunction. In spite of high levels of antibodies in these patients, the role of these antibodies is not known. Besides B cell, T4 cell and macrophage dysfunction, the natural killer cell activity is also reducing in these patients. Whatever may be the mechanism of depletion of T4 cells it seriously impairs the ability of the immune system to fight against virus, fungi, parasites and certain bacteria, including myco-bacteria. It is generally recognized that as T4 cell count falls below 400 chronic infections of the skin and mucous membranes set in and as the count falls further, systemic infections appear.



3. Serology

Evidence of HIV-I infection may be gained by isolating the virus, by demonstrating antibodies to it or by detecting viral antigens. Anti-HIV antibodies usually become detectable between three weeks to three months after exposure to HIV-I.

For serological tests, antigen can be prepared from HIV-I grown in cell lines and purified, or prepared synthetically by genetic engineering. The serologic tests which are used for diagnostic purposes are:

1. Agglutination

2. ELISA (enzyme-linked immuno-sorbent assay)

• Quantum spectrophotometer II used to read optical density of ELISA test.

• Anti-globulin ELISA tests for detection of anti-HIV antibodies. Various shades of brown colour indicate a positive test which means that the victim is infected by HIV.

3. Immuno-blotting

4. Immuno-fluorescence.

5. Hypersensitivity skin tests

Known antigen Result

1. PPD +

2. Candidin -

3. Trichophytin -

4. Tetanus -

5. Mumps -

6.



ELISAs use an enzyme conjugated to give a colour reaction between specifically bound HIV-I antigen and antibodies to it. Since HIV-I serologic test were licensed in 1985, they have been used in many countries throughout the world. Although the early tests were sensitive, they were not very specific. Subsequent ELISA tests have been developed which use purified HIV-I virus or genetically engineered HIV-I antigens which have high sensitivity and specificity.

The choice of a serologic test should be based on its availability, cost, specificity, sensitivity, simplicity, and the other possible infections in the environment that may cause cross-reactions.

Currently, the most widely used confirmatory tests are the western blot and ELISA using genetically produced HIV-I antigens.

Detection of various classes of immuno-globulins is also widely used. The IgM anti-HIV response is of particular interest as appearance of IgM slightly precedes the IgG response. Detection of individual immunoglobulin classes is of particular interest in babies, because IgM does not cross the placenta and when present it is made by the baby, whereas IgG from the mother crosses the placenta. Thus IgM anti-HIV antibodies in a young baby might indicate that the baby has been infected, although the tests are not commercially available and methodology is cumbersome. Presence of IgG may only mean that the mother was infected. However, if IgG antibodies persist in the baby past 15 months age, the baby is infected.

Tests have also been developed to detect HIV-I antigens e.g. HIV core antigen (p24). These tests are of particular importance detecting early infection when HIV antibodies are not detectable because they are absent or present in low concentration. Isolation of HIV is very demanding; it required technical expertise and a sophisticate laboratory so it is seldom used as a diagnostic procedure. Simple tests are being developed for laboratories with inadequate facilities for ELISA or radio-immunoassay.



4. Epidemiology of AIDS



Epidemiologic studies indicate that transmission of HIV-I IN AFRICA AND Haiti is primarily by heterosexual intercourse as indicated by the 1:1 sex ratio of HIV infections. Between 80% and 90% of those infected are in the most sexually active age group (20 – 40 years) and have had multiple sexual partners. There has been some evidence that genital ulcer disease might facilitate transmission of HIV.

Other modes of transmission are by blood and blood products (as seen in hemophiliacs), and by congenital r perinatal transmission from mother to child. This has important implications for family size and population structure in thee tropics where more than half of infected adults are women of child – bearing age.

Homosexuality and intravenous drug abuse are rarely acknowledged by Africans and these probably are not significant modes of transmission for HIV in Africa. The pattern of HIV –I transmission in the tropical parts of South America, Asia and Oceania has not been established because of the small number of cases that have occurred to date. HIV is not transmitted by casual no venereal contact or by blood sucking arthropods. Transmission via infected needles, scarification instruments, infected organ transplants, and artificial insemination is possible, but its extent is not known. Transmission through breast milk seems to have an insignificant role.

Although HIV- II has been identified in Gambia, Guinea Bissau, Senegal and the Ivory Coast, there is no evidence of this virus as yet in East and Central Africa.

Under –reporting of AIDS cases in Africa is common and laboratory confirmation for the diagnosis is not widely available. This makes it difficult to present a clear picture of its epidemiology. However, clinical criteria can be used to diagnose HIV – related disease in Africa



Manifestations and AIDS



5. Spectrum of HIV-related Disease.



HIV related diseases have a clinical spectrum ranging from asymptomatic infection to the full-blown picture of AIDS.

All systems of the body may be affected either singly or in combination.

AIDS patients lose the ability to immunologically defend themselves against many infectious agents. Current evidence indicates that progressive immunodeficiency will cause death in most of those infected with HIV –I.

In the northern hemisphere a few patients who acquire HIV infection experience an acute viremic febrile illness, similar to infection mononucleosis with or without acute encephalitis, before seroconversion occurs. Such acute-onset illnesses are very rarely recognized in the tropics and possibly misdiagnosed as malaria. However, many patients who appear to have early infections have experienced minor symptoms including lymph node enlargement for several months.

After an incubation period of months or years, HIV-infected persons develop opportunist infections as evidence of deteriorating immune competence. Abnormal neurologic signs may also be detected, although symptoms are uncommon. Once this stage has been reached periods of reasonable well-being alternate with acute or chronic infections. The clinical features are listed below in order of frequency of occurrence and might be as a direct consequence of HIV or due to opportunists/tumours occurring as a result of immunosuppression:



1. Weight loss.

2. Persistent generalized Lymphadenopathy.

3. Chronic cough.

4. Recurrent fever.

5. Multidermatomal herpes zoster.

6. Recurrent diarrhoes.

7. Candidiasis.

8. Aggressive Kaposi’s sarcoma.



There is a slow loss of vitality and weight with increasingly frequent and serious bouts illness which interfere with work and social life. This stage may last several years but progressive inexorably to life-threatening infections and tumours which lead to death.

AIDS was defined in 1982 and 1983 by description of its end-stage diseases. The transition from pre –AIDS to AIDS may led difficult to identify or may depend upon the availability of diagnostic tests. On progressive disease interferes with a patient functions in the family and community, return to sustained normal health never occurs. The appears to be the natural history of the diseases as seen in the developing and the develop world.

In children the course of the disease accelerated. In adults intercurrent infection such as tuberculosis and sexually transmitting disease may precipitate or accelerate to progression of immunodeficiency.

A clinical diagnosis of AIDS in main according to the criteria below. The symptoms and signs of the AIDS- related complex (ARC) are due to a partial loss of cell-medical immunity. From the available evidence, some progression of the disease in unidirectional from ARC to AIDS. It may be useful in the future to separate the clinical features of the primary to HIV infections from symptoms and signs related to opportunistic infections.



CDC/WHO case definition for AIDS, 1988



A case of AIDS is defined as an illness characterized by one or more of the following ‘indicator’ diseases, with or without laboratory evidence of HIV infection:



1. Without laboratory evidence for HIV infection



If laboratory tests for HIV are not performed or give inconclusive results and the patient has no other cause of immunodeficiency, then any disease listed below indicates AIDS if it is diagnosed by a definitive method.



(a) Candidiasis of the oesophagus, trachea, bronchi, or lungs

(b) Cryptococcosis, extrapulmonary

(c) Cryptosporidiosis with diarrhea persisting for more than 1 month

(d) Cytomegalovirus disease of an organ other than liver, spleen, or lymph nodes persisting for more than1 month

(e) Herpes simplex virus infection causing mucocutaneous ulcer that persists for more than1 month; or bronchitis, pneumonitis, or oesophagitis of any duration

(f) Kaposi’ sarcoma affecting a patient under 60 years of age.

(g) Lymphoma of the brain (primary) affecting a patient under 60 years of age.

(h) Lymphoid interstitial pneumonia and/or pulmonary lymphoid hyperplasia affecting a child under 13 years of age.

(i) Mycobacterium avium complex or M. Kansasii disease, disseminated (at a site other than or in addition to the lungs, skin, or cervical hilar lymph nodes)

(j) Pneumocystis carinii pneumonia

(k) Progressive multifocal leucoencephalopathy

(l) Toxoplasmosis of the brain affecting a person more than one month of age



2. With laboratory evidence for HIV infection



Regardless of the presence of other causes of immunodeficiency, laboratory evidence of HIV infection together with any disease listed above or below in diagnostic of AIDS.



a. Bacterial infection, multiple or recurrent, including septicaemia, pneumonia and meningitis.

b. Disseminated coccidiomycosis.

c. HIV encephalopathy.

d. Disseminated histoplasmoss.

e. Isosporiasis with diarrhea persisting for more than one month.

f. Kaposi’s sarcoma at any age

g. Lymphoma of the brain at any age

h. Non-Hodgkin’s lymphoma of B-cell or unknown immunological phenotype.

i. Any mycobacterial disease caused by mycobacteria other than M. tuberculosis

j. Disease caused by M. tuberculosis, extrapulmonary.

k. HIV wasting syndrome (‘SLIM’ disease).

l. Recurrent septicaemia by nontyphoid Salmonella.



Although CDC/WHO case definition is the ‘gold standard’ for diagnosis of AIDS, the laboratory diagnosis of pathogens in most clinical case-definition used in some African countries might be useful elsewhere in the tropics and is given below:



DEFINITION – Adult AIDS



A case of AIDS in an adult is defined as a patient with no known underlying cause of cellular immunodeficiency who presents with at least two of the major signs associated with at least on minor sign:



Major signs

Weight loss of > 10% of body weight in 1 month.

Chronic diarrhea > 1 month.

Prolonged fever > 1 month (intermittent or constant).



Minor signs

Persistent cough > 1 month.

Generalized Lymphadenopathy.

Herpes zoster.

Persistent fatigue night sweats.



DEFINITION – Paediatric AIDS



Paediatric AIDS is suspected in an infant or child (under 13 years of age)presenting with at least two major signs associated with at least

Two minor signs in the absence of known causes of immunodeficiency:



Major signs

recurrent fever> 1 month

recurrent oropharyngeal Candidiasis

recurrent pulmonary infections



Minor signs

chronic diarrhea> 1 month

weight loss or abnormally slow growth

generalized Lymphadenopathy

persistent cough > 1 month

Extrapulmonary tuberculosis

Pneumocystis carinii pneumonia

confirmed maternal HIV infection



6. Persistent Generalised Lymphadenopathy



PGL caused by HIV is common in the tropics as elsewhere in seropositive persons who are otherwise symptom- free. These enlarged lymph nodes are 1 to 2cm in diameter, discrete, numerous, regular, symmetrical around the sagittal plane and persist for at least 3 months. Usually occipital nodes are noticed first by the patient. Awareness of the enlarged lymph nodes causes anxiety, particularly if they fluctuate in size and cause discomfort. There are no signs of opportunist infections, and haematologic investigations may show no abnormality other than mild lymphopoenia. Oropharyngeal lymphoid tissue commonly becomes hyperplasic to produce tonsillar enlargement comparable to the hypertrophy seen in adolescent children who have recently started school:

When lymph nodes enlarge asymmetrically, or to an average size in excess of 2cm, a biopsy may be indicated to exclude tuberculous adenitis or lymphoma (asymmetrical) or Kaposi’s sarcoma (symmetrical)

When lymph nodes enlarge asymmetrically,

Histological examination of persistently enlarged nodes (without secondary pathology) shows marked follicular hyperplasia with an intact network of follicular dendritic cells, increased numbers of macrophages and lymphocytes and in some patients, increased vascularity. As the disease progresses, the Lymphadenopathy may disappear. In some cases cytotoxic drugs may precipitate full-blown AIDS with diarrhea, fever and a variety of opportunistic infections.



Differential diagnoses:

Cervical lymph node enlargement may be due to carcinomas of the head and neck. Nasopharyngeal carcinoma often presents with bilateral deeply fixed nodes in the upper jugular chains, but without symptoms to draw attention to the primary tumour.

Secondary syphilis is an important cause of generalized lymphadenopathy and should be exclude by serologic tests. Infectious mononucleosis and sarcoidosis are both exceptionally rare in Africa, so neither is likely to account for generalized node enlargement.





HIV – I (LAV 1).

AIDS – Is caused by human retrovirus called Human Immune-defiance Virus I (HIV).

1. Retroviruses – are RNA containing tumour Viruses that cause sarcomas or Leukemia’s in animals. (Mammary cancer in mice).

2. Lentivirus –



HTLV – Is Human T-Lympholropic Virus (HTLV).

HTLV I – is a group of retroviruses which caused T-Cell Leukemia in human.

 ALL (Acute Lymphoblastic Leukemia ALL).

 LAV (Lymphadenopathy-associated Virus) it isolated name of HIV-1.

 HTLV-1 to HTLV-IV They have called as HIV-I.



HIV-I.

1. Is a single stranded RNA virus which replicate by using a unique enzyme reverse transcriptase to translate its genomic RNA into a DNA copy.

2. This DNA inserted as provirus into host cell DNA, where it remain latent or be copied again into viral RNA to produce new virus particles.

HIV – I

1. Infects T-helper lymphocytes (CD4/OKT4/LEU3a) and also cells of the monocyte / macrophage genes, including glial cells of the brain.

2. Monocyte / macrophages have been described as the main reservoirs of HIV-I. Because DNA copies of HIV-I are integrated into host cells, the virus persists throughout the entire life of the infected individual and duplicates itself every time the infected cell multiplies.



HIV – II



HIV – III



HIV – IV (LAV-2).



AIDS

Acquired Immune Deficiency Syndrome



1. Introduction.

Acquired Immune Deficiency Syndrome (AIDS), a clinical syndrome (a group of various illnesses that together characterize a disease) resulting from damage to the immune system caused by infection with the human immunodeficiency virus (HIV).

In HIV-infected individuals, there is a gradual loss of immune cells (called CD4+ T-lymphocytes) and immune function. The mechanisms by which HIV causes this immune deficiency are still not completely understood, although direct infection of CD4+ T-lymphocytes by HIV certainly plays a role. The loss of immune function, if untreated, results eventually in the development of opportunistic diseases caused by common infections that do not present a threat to healthy individuals, including fungal, bacterial, protozoal, and viral diseases, as well as by malignancies that appear to be associated with immune dysregulation. In the absence of treatment, it generally takes six to ten years from the point of infection to develop AIDS, although the rate of disease progression may vary substantially from person to person.



In the early 1980s deaths by opportunistic infections, previously observed mainly in transplant recipients receiving immunosuppressive therapy, were recognized in otherwise healthy homosexual men. In 1983, Luc Montagnier and scientists at the Pasteur Institute in Paris isolated what appeared to be a new human retrovirus from the lymph node of a man at risk of developing AIDS. Almost simultaneously, both Robert Gallo’s group at the National Cancer Institute (NCI), and a group headed by Jay Levy at the University of California, San Francisco, isolated a retrovirus from AIDS patients and from people who had had sexual contact with AIDS patients. All three groups had isolated what is now known as HIV—the aetiological (causative) agent of AIDS.

2. Detection and Diagnosis.

With the identification of HIV in 1983 came the opportunity to develop a method of specific detection. The screening tests now in widespread use by blood banks, plasma centres, reference laboratories, private clinics, and health departments analyse a sample of blood for the presence of antibodies produced by the immune system in response to infection with HIV. Separate serological tests were developed to detect HIV-1 and HIV-2, owing to the major differences in the protein components of these two related viruses. There are also different sub-types (or "clades") of HIV-1 and HIV-2, reflecting the different evolutionary paths that the viruses have taken in specific geographical locations. As new sub-types of HIV are identified from around the world, they too will need to be evaluated for detection by these tests.There is a brief “window period” (normally four to eight weeks) after exposure to HIV during which standard screening tests are unable to detect the presence of HIV because the immune system has not had enough time to make antibodies against HIV. During this period, other methods that use amplification techniques (such as polymerase chain reaction) to detect the genetic material of the virus itself, rather than antibodies against it, may be able to determine whether an individual is infected with HIV.

A person who receives a positive test result for HIV infection is often described as HIV-positive. Being HIV-positive does not necessarily imply that a person also has AIDS. A person can be infected with HIV for a long period—greater than ten years—without developing any of the clinical illnesses that constitute a diagnosis of AIDS.

The Centers for Disease Control and Prevention in Atlanta, Georgia, established an authoritative definition for the diagnosis of AIDS: in an HIV-positive individual, the CD4+ cell count must be below 200 cells per cu mm of blood, or there must be the clinical appearance of a specific opportunistic condition that is considered AIDS-defining, from a long list that includes Pneumocystis carinii pneumonia (PCP), oesophageal candidiasis (thrush), pulmonary tuberculosis, and invasive cervical carcinoma. In Europe, however, a CD4+ cell count below 200 is not in itself grounds for the diagnosis of AIDS; HIV-positive people must have an AIDS-defining opportunistic illness to be diagnosed with AIDS.



3. Nature of the Disease.



A. Clinical Progression of AIDS.



A1. 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.

A2. 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.

A3. 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.

A4. Symptomatic Phase.

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.

4. Cause of AIDS.

A. Human Immunodeficiency Virus (HIV).

The aetiological agent of AIDS is HIV, a human retrovirus. HIV is closely related to viruses that cause similar immunodeficiency diseases in a range of animal species. Its origin in humans is widely accepted to have resulted from cross-species transfer of a simian immunodeficiency virus (SIV) from the chimpanzee, Pan troglodytes troglodytes, in central Africa, probably centuries ago. Changing social mores and urbanization are believed to have provided the conditions necessary for the emergence of HIV as a pandemic during the latter decades of the 20th century.

HIV is an enveloped virus, meaning that the viral genetic material is surrounded by a lipid membrane derived from the host cell. HIV enters susceptible cells by the fusion of its envelope glycoproteins gp120 and gp41 with specific molecules in the lipid membrane of certain cells, allowing the viral genetic material to enter the cell and eventually replicate, leading to cell death. The most important cellular receptor is CD4, a surface molecule important for normal immune interaction, but other co-receptors called CCR5 and CXCR4 are also important. Inherited genetic factors affect the extent to which an individual’s cells express these co-receptors, which in turn may affect their susceptibility to infection with HIV, or their rate of disease progression if they do become infected.

Any human cell that expresses the necessary receptor molecules is a potential target for HIV infection. However, the cells that are most affected during HIV infection are white blood cells that express high levels of the CD4 molecule, and are therefore referred to as “CD4-positive (CD4+) T-cells”. HIV replication in CD4+ T-cells can directly kill them or they may be killed or rendered dysfunctional by indirect means without ever being infected with HIV.

CD4+ T-cells are critical in the normal immune system because they help other types of immune cells recognize and respond to invading organisms. Therefore, as CD4+ T-cells are specifically targeted and lost during HIV infection (a hallmark feature of AIDS), no help is available for immune responses. General immune system failure occurs and permits the opportunistic infections and cancers that characterize the clinical picture of AIDS.

While it is agreed that HIV is the virus that causes AIDS, and that HIV replication can directly kill CD4+ T-cells, the large variation among patients in the time of progression to AIDS indicates that other factors can influence the course of disease. Several inherited genetic factors have been shown to influence an individual's susceptibility to acquiring HIV and, once infected, to HIV-induced immune damage. Other factors that may influence the rate of disease progression remain unclear, but may include the nature of the infected person’s immune response to HIV, and perhaps certain viral co-infections. However, it is very clear that HIV must be present for the development of AIDS.

B. Modes of Transmission

HIV can be transmitted by either homosexual or heterosexual contact with an infected person and these routes represent the majority of transmissions. Present in the sexual secretions of both men and women, HIV gains access to the bloodstream of the uninfected partner by infecting cells in mucous membranes or via small abrasions that occur as a consequence of intercourse. HIV is also spread by sharing injecting equipment, most commonly done by those abusing drugs, and this results in a direct exposure to the blood from an infected individual.

HIV transmission through medical transfusions or blood-clotting factors is now extremely rare because of extensive screening of the blood supply. HIV can also be transmitted from an infected mother (either before giving birth, during labour, or through breastfeeding), but only about 30 per cent of babies born to untreated HIV-infected mothers are actually infected, and the use of antiviral medications by the mother and the newborn child can reduce this risk almost to zero.

Although these routes of HIV transmission are well established, public fear still exists concerning the potential for transmission by other means. There is no evidence that HIV can be transmitted through the air or by biting insects. If this were the case, the pattern of HIV infections would be dramatically different from what has been observed and cases of AIDS would be reported more frequently in individuals with no identifiable risk for infection (now only a very small percentage of reported cases).

Although HIV is a very fragile virus and does not survive well when exposed to the environment (for example, drying of HIV-infected fluids rapidly reduces their infectiousness almost to zero), fear also exists for HIV transmission by casual contact in a household, school, workplace, or food-service setting. No documented cases of HIV transmission by casual contact with, or even kissing, an infected individual have been identified. However, practices that increase the likelihood of blood contact, such as sharing toothbrushes or razors, should be avoided.

Public fear has also persisted regarding HIV transmission from infected health-care workers, because of a case of transmission from a dentist to several patients. This now appears to be an extremely rare and isolated case of transmission and, in general, infected health-care workers pose no risk to their patients. There is no risk of HIV transmission while donating blood.

C. Epidemiology.

By the end of 2002, 42 million adults and children were estimated to be living with HIV, of whom 5 million were believed to have become infected during 2002. A total of about 25 million people were estimated to have died from AIDS since the start of the pandemic. The epidemiology (incidence and distribution) of AIDS is an evolving picture. Initially in the United States, HIV infection was mainly concentrated in the homosexual community, where widespread transmission occurred because of unprotected anal intercourse, and in haemophiliacs and people receiving other blood products. HIV infection became established among IV drug users, who in turn infected their heterosexual partners. African-American communities in the United States have relatively high rates of HIV infection among both heterosexuals and homosexuals; although they represent only an estimated 12 per cent of the US population, they make up 34 per cent of all US AIDS cases.

C1. Epidemiology in the USA and UK.

By the end of December 2001, over 807,000 adults and over 9,000 children had been diagnosed with AIDS in the United States, and over 174,000 people had been reported to have HIV infection (but not AIDS) in the 36 areas that have confidential HIV reporting systems. Approximately 40,000 Americans are estimated to be newly infected with HIV each year. Among adults and adolescents, three HIV exposure categories continue to account for nearly all cases of AIDS in the United States: homosexual contact (46 per cent); injection-drug use (25 per cent); and heterosexual contact with a person who is in a high-risk group or has HIV (11 per cent). The vast majority of AIDS cases among children have resulted from mother-to-baby HIV transmission. Thanks to effective screening, HIV transmission by blood products is now rare, constituting 1 per cent of cases during the entire course of the epidemic.

By the end of September 2002, 18,972 cases of AIDS had been reported in the United Kingdom, of whom 14,910 (79 per cent) had died. Including these AIDS cases, a total of 52,666 cases of HIV infection had been reported. Sex between men remains the commonest exposure category, accounting for 54 per cent of all cases of HIV reported to date, although in every year since 1999, a greater proportion of newly detected cases has been attributed to heterosexual contact than to homosexual contact. In the United Kingdom, most cases of HIV infection attributed to sex between men and women reflect exposure to HIV while abroad, especially in Africa.

C2. Epidemiology in the Developing World.

On a global scale, AIDS continues a frightful expansion. Over 25 million people are estimated to have died from AIDS worldwide by the end of 2002. At that time, 29.4 million individuals in sub-Saharan Africa were estimated to be living with HIV/AIDS, representing 8.8 per cent of all adults. Of the estimated 5 million people who acquired new HIV infection during 2002, 3.5 million lived in sub-Saharan Africa, and over 75 per cent of the 3.1 million adults and children who died due to AIDS during 2002 also lived in sub-Saharan Africa. In four sub-Saharan African countries, more than 30 per cent of the adult population is now infected: Botswana (38.8 per cent), Lesotho (31 per cent), Swaziland (33.4 per cent), and Zimbabwe (33.7 per cent).

There are an additional 6 million infected individuals living in South and South East Asia, and 1.5 million in Latin America. Infection rates are currently rising fastest in Eastern Europe and Central Asia, where over one fifth of the estimated 1.2 million HIV-positive people acquired the virus during 2002 alone. There are also rapidly growing epidemics in China, with 1 million HIV-positive people, and in India with 4 million.

5. Treatment.

By the end of 2002, 16 antiretroviral drugs had been approved for use in the treatment of HIV infection. From the late 1980s until the mid-1990s, the available drugs were generally used one at a time in sequence, but their effects were disappointingly short-lived. Greater success has been achieved by using them in combination regimens, which can significantly delay the onset of opportunistic infections and prolong life. Current guidelines for the use of antiretroviral drugs advise that they should be used in combinations of three or more drugs. These potent regimens, known as highly active antiretroviral therapy (HAART) regimens, have had dramatic effects in reducing rates of AIDS-related illness and death. Their effects can be monitored by measuring the amount of HIV in the blood, known as the viral load. An effective regimen should rapidly suppress the viral load to a level so low that it cannot be detected by the most sensitive tests available. However, this profound viral suppression certainly does not mean that the virus has been eradicated and the patient is cured; HIV persists at very low levels in the blood and tissues such as the lymph nodes, and if therapy is stopped, the viral load rapidly rebounds. Although successful viral suppression does appear to reduce the infectiousness of infected individuals, it does not eliminate it and cases of HIV transmission from individuals with suppressed viral load do occur.

The high cost of multi-drug combination therapy regimens has placed strain on the health services—even in developed countries such as the United Kingdom—and has to date rendered them almost entirely inaccessible for the developing world where most cases of HIV infection occur. At a time when they need more resources to combat HIV, African governments are paying four times more in external debt payments than they currently spend on health and education. In recent years, pressurized by the mounting toll of HIV in the developing world, legal actions, and activist campaigns, a number of pharmaceutical companies have made anti-HIV drugs available to developing countries at or below the price they cost to produce, but nevertheless, fewer than 4 per cent of people in need of antiretroviral treatment in low- and middle-income countries were receiving the drugs at the end of 2001.

Zidovudine

Zidovudine, formerly known as AZT from its synthetic chemical name, azidothymidine, the drug most commonly used in the treatment of HIV (human immunodeficiency virus) infection. Zidovudine is the international non-proprietory name of the drug; Retrovir is its brand name. A laboratory at the United States National Institutes of Health discovered in 1985 that zidovudine inhibited the replication of HIV by interfering with the process of reverse transcription, which is necessary for the production of new virus particles. Zidovudine was shown by clinical trials in 1986 to be effective at improving survival in patients with AIDS (Acquired Immune Deficiency Syndrome) and has since then been licensed as the first-choice treatment for HIV infection in North America, Europe, and Australia. Subsequent studies have defined the benefits of zidovudine more clearly. The drug appears temporarily to delay the progression of disease and death in people who have HIV infection with symptoms, but does not significantly delay the development of AIDS in HIV-positive people without symptoms.

Zidovudine is increasingly prescribed as part of a combination of antiviral drugs, and a recent international study conducted in Britain and the United States showed that this approach results in greatly enhanced survival when compared with zidovudine treatment alone.

Zidovudine appears to have a significant protective effect against HIV-related brain disease and dementia. This is due to the ease with which the drug crosses the blood-brain barrier, a quality not shared by other anti-HIV drugs that have come into use subsequently.

Zidovudine causes serious side-effects, however, such as anaemia and muscle wasting, especially if used at doses above 1,000 mg a day for long periods, and treatment with zidovudine alone stimulates the emergence in patients of HIV strains that are resistant to the drug. It appears that resistance emerges most quickly in individuals with very high levels of virus in their blood, such as those who have already been diagnosed with AIDS; the development of resistance appears to be connected to the clinical decline of the patient. Zidovudine resistance emerges less rapidly when it is used in combination with other antiviral drugs. For example, the derivative 3TC (non-proprietory name Iamivudine) has been used in combination with zidovudine in a recent European study, and showed that the effects of the drugs combination on CD4 T-lymphocyte cell counts were sustained for two years in the 26 patients for whom data was available.



Contributed By:

Keith Alcorn



A. Reverse Transcriptase Inhibitors.

The development of antiviral drugs to attack HIV has targeted specific stages in the viral replication cycle. One such target is the requirement for HIV to undergo reverse transcription (the conversion of viral genomic RNA into DNA) at an early stage of infecting a host cell; this is a process unique to retroviruses and performed by the viral enzyme, reverse transcriptase (RT).

Nine of the approved anti-HIV agents are RT inhibitors. There are three different classes of RT inhibitors. The nucleoside analogue RT inhibitors (NRTIs) work as “DNA chain terminators”. That is, because each appears to be a normal nucleotide base (the building blocks of DNA), the RT enzyme mistakenly inserts the drug into the growing viral DNA chain. However, unlike normal nucleotide bases, the drugs cannot be further elongated (no additional DNA bases can be added once the drug is inserted) and therefore viral DNA synthesis is terminated. Nucleotide reverse transcriptase inhibitors (NtRTIs) are closely related to NRTIs. The non-nucleoside reverse transcriptase inhibitors (NNRTIs) have a different mode of action; they are thought to inhibit RT by binding to the enzyme.

In the United States and Europe alike, six NRTIs have been approved for use: zidovudine (also known as ZDV or AZT and made by GlaxoSmithKline with the brand name Retrovir), didanosine (ddI or Videx, from Bristol-Myers Squibb), zalcitabine (ddC or Hivid, from Roche), stavudine (d4T or Zerit, from Bristol-Myers Squibb), lamivudine (3TC or Epivir, from GlaxoSmithKline), and abacavir (Ziagen, from GlaxoSmithKline). Two formulations that combine more than one NRTI in a single pill are also available: coformulated zidovudine plus lamivudine (Combivir), and coformulated zidovudine, lamivudine, and abacavir (Trizivir), both manufactured by GlaxoSmithKline. In addition, the NtRTI tenofovir (Viread, from Gilead) has been approved.

In the United States, three NNRTIs have been approved: nevirapine (Viramune, from Boehringer-Ingelheim), delavirdine (Rescriptor, from Pfizer), and efavirenz (Sustiva or Stocrin, marketed by Bristol-Myers Squibb in some countries and by Merck in others); nevirapine and efavirenz have also been approved in Europe. A number of additional NRTIs and NNRTIs are under development.

B. Protease Inhibitors.

The second major class of anti-HIV drugs is the protease inhibitors. These are drugs that specifically interfere with the action of the HIV protease enzyme. Protease is employed at a later stage of the viral replication cycle, when new virus particles are being produced within an HIV-infected cell. The protein from which the core and envelope of the new particles will be formed is initially synthesized in a long strip, which has to be cut up by protease into smaller functional proteins. When the protease enzyme is inhibited, an HIV-infected cell can only produce immature, non-infectious viral progeny. In the United States and Europe, six protease inhibitors are licensed: saquinavir (available in two formulations, Fortovase or Invirase, from Roche), indinavir (Crixivan, from Merck Sharp & Dohme), ritonavir (Norvir, from Abbott), nelfinavir (Viracept, from Pfizer), amprenavir (Agenerase, from GlaxoSmithKline), and a combination pill containing lopinavir and ritonavir (Kaletra, from Abbott). Additional protease inhibitors are under development.

C. Drug Resistance.

One problem with all anti-HIV drugs produced to date is the development of viral resistance. HIV's replication process is relatively imprecise, resulting in the steady production of mutant variants of the virus, some of which are resistant to the effects of specific anti-HIV agents, meaning that they are able to replicate and cause immune damage despite the presence of the drug. The selective pressure exerted by treatment drugs means that within treated people these drug-resistant strains have a survival advantage over “wild-type” drug-sensitive strains, and over time they will replace the drug-sensitive strains as the dominant type of circulating virus. In such a patient the viral load starts to rise, reflecting increased rates of viral replication, and the disease course may revert towards that seen in untreated patients, with a falling CD4+ cell count and an increased risk of opportunistic conditions.

The appropriate therapeutic response is to change the treatment regimen to a different antiviral drug combination. However, the similarities between drugs in the same class mean that HIV that has become resistant to one NRTI may be cross-resistant to other NRTIs that the patient has not yet taken, and likewise within the NNRTI and protease inhibitor classes, thus limiting the patient's subsequent options for effective treatment. An important priority for companies developing new RT inhibitors or protease inhibitors is, therefore, to try to create agents that retain efficacy against HIV strains that have developed resistance to the agents that are already in use.

The development of resistance can be delayed or prevented by the use of potent HAART regimens. These combinations rapidly suppress viral replication to very low levels, thus preventing the evolution of mutant variants. To maximize the chances of a successful and durable response to antiretroviral therapy patients have to maintain very high rates of adherence to their drugs' dosing schedule, since missed doses allow the virus to replicate and thus provide it with the opportunity to develop resistance to the treatment regimen.

D. Experimental Classes of Anti-HIV Drugs.

The best hope of avoiding the problem of cross-resistance is to create entirely new classes of anti-HIV drugs. One such class currently in development consists of agents that may bind either to gp120 or to the cellular receptors to which gp120 attaches itself, thus interfering with the processes of viral binding, fusion, and infection of susceptible human cells. Enfuvirtide (also known as T-20 or Fuzeon, from Trimeris and Roche) is the first fusion inhibitor that has been shown to be effective among patients with extensive prior use of current antiretrovirals, and is expected to be approved for use during 2003.

Intensive research is under way into agents designed to inhibit HIV's integrase enzyme. Integrase enables HIV to incorporate its genetic material into the DFNA of a host cell, a vital step in the viral life cycle.

AIDS activists have campaigned vigorously for early access to experimental therapies for HIV. Community-based organizations such as NAM in the United Kingdom, or AIDS Treatment News and Project Inform in the United States, provide accessible information about new treatments and trials, helping individuals reach informed decisions about their options. Many infected people are willing to participate in clinical trials in the hope that experimental drugs may prove effective. Drug companies often provide pre-approval access to promising therapies through expanded access schemes and, in the United Kingdom, “named patient basis” prescribing.

E. Gene Therapy.

Gene therapy is also being studied as a potential treatment for HIV-infected people. One approach uses small molecules called anti-sense oligonucleotides, which bind to the viral RNA strand, preventing it from acting as a template for viral proteins. Another antiviral strategy uses molecules called ribozymes that can detect specific parts of HIV's RNA within infected cells and splice it, rendering it inactive.

Other researchers are using gene therapy to insert a gene into immune cells taken from infected people, either to boost the cellular immune response against HIV or to protect the CD4+ cells from infection. This is called adoptive cell therapy. The main problems with all these gene therapy approaches are delivering the new genes into cells, and ensuring that the altered cells are not identified as "foreign" and attacked by the host immune system.

F. Immune-Based Therapies.

It has become increasingly clear that the immune system is able to contribute significantly to the control of HIV in certain individuals. So-called long-term non-progressors, who are able to live with HIV for many years without signs of significant immune damage, tend to have strong and persistent immune responses that specifically target HIV. In most patients, however, initially strong HIV-specific immune responses rapidly wane. Several new approaches to therapy are designed to try to elicit and preserve HIV-specific immune responses in patients who lack them. There is preliminary evidence that starting antiviral therapy very promptly after initial infection may help to preserve HIV-specific immunity, and in some cases such individuals may be able to stop antiviral therapy and maintain very low levels of HIV replication. Other experimental strategies to try to generate HIV-specific immune responses include immunizations with therapeutic vaccines containing HIV antigens.

The drug interleukin-2 is being evaluated in large controlled studies. It stimulates the production of CD4+ T-cells, resulting in substantial increases in the patient's CD4+ cell count. The on-going studies are designed to see whether these artificially generated CD4+ cells provide effective immunologic protection against HIV-related conditions.

G. Preventing and Treating Opportunistic Conditions.

Use of potent antiretroviral regimens is now viewed as the best way to prevent HIV-infected patients from developing opportunistic conditions. Prior to the widespread use of HAART, however, many of the improvements in the quality and quantity of life among people with HIV resulted from better prophylactic (preventative) antimicrobial drugs to prevent or treat HIV-related opportunistic infections. Use of prophylaxis meant that many HIV-infected people did not now develop an AIDS-defining illness until they had reached an advanced stage of immune suppression. At present, most cases of HIV-related diseases occur in patients who have not received antiretroviral therapy, either by choice or because they were unaware that they were HIV-infected, or in those for whom antiretroviral therapy is no longer effective due to the development of viral resistance. In these patients, HIV-related diseases are treated with specific drugs, such as antibiotics for PCP, anti-fungal drugs for infections such as Cryptococcus, or antiviral drugs for CMV infections.

H. Emerging Complications: Drug Toxicity and Viral Hepatitis.

The advent of effective anti-HIV therapy has led to dramatic changes in the pattern of illnesses experienced by people with HIV. As the use of HAART regimens has become commonplace in the developed world, it has prevented or reversed damage to the immune systems of many HIV-infected people, so they are not at risk from the classic opportunistic conditions observed among immuno-suppressed individuals. Many people who previously had to take prophylactic antimicrobial drugs to prevent the occurrence of HIV-related diseases have been able to discontinue those treatments and rely solely on anti-HIV drugs to maintain their immunologic function.

As opportunistic conditions have declined as causes of morbidity and mortality, treatment-related toxicities have increased in importance. HAART combinations can cause a relatively high rate of side-effects, including liver or kidney problems, nerve damage, nausea and vomiting, rashes, metabolic abnormalities including elevated levels of cholesterol and triglycerides, and disfiguring changes in the distribution of body fat. Most side-effects are not life threatening, however, and for individuals at significant risk of HIV-related disease the benefits of treatment far outweigh the costs in terms of toxicities. However, the risk/benefit equation is less clear-cut for individuals who have acquired HIV relatively recently and are unlikely to be at substantial risk of HIV-related complications for many years. For this reason, guidelines on the use of anti-HIV drugs recommend that they should generally be deferred until the patient's CD4+ cell count has declined to between 200 and 350 and they are at significant risk of developing AIDS-related conditions in the near future.

Co-infection with viral hepatitis, especially hepatitis C virus (HCV), is a growing problem among HIV-infected patients. Compared with HIV-negative persons who are infected with HCV, patients who have both HIV and HCV typically experience more rapid and more severe liver damage. Treating HIV does not of itself ameliorate hepatitis co-infection, and some anti-HIV drugs cause increased rates of liver toxicities in co-infected patients. A sizeable proportion of deaths among HIV-infected patients is now attributable to end-stage liver disease caused by viral hepatitis, even among patients whose HIV infection is well-controlled by anti-HIV therapy.

6. Prevention and Education.

A. Vaccines.

Efforts are under way to develop an effective vaccine for HIV that could be either protective (preventing infection if an immunized person is exposed) or therapeutic (slowing immune destruction or prolonging survival in people who are already infected).

Most of the current experimental vaccines consist of one or more of HIV's structural proteins, such as the core protein p24 or the outer “envelope” proteins gp120 and gp160, used in combination with an adjuvant to boost the immune response.

Trials to date have been largely discouraging. Studies of several different therapeutic vaccines have found that some are immunogenic (they stimulate immune responses) but all have failed to show any effects on disease progression or survival rates. Ongoing studies are exploring whether the use of therapeutic vaccines combined with HAART may be more effective than current treatment strategies that use HAART alone.

Researchers working on preventive vaccines face a range of technical problems, including the difficulty of producing a vaccine that might offer protection against the range of HIV sub-types (or clades) found around the world, and HIV's ability to mutate rapidly so that its surface proteins are no longer recognized by the body's immune response. An effective vaccine would need to protect the individual against infection when exposed to either free HIV particles or HIV-infected cells, and to stimulate effective immune responses when the virus enters the body through the blood (such as during injecting drug use or occupational exposure) or across mucous membranes (such as during sexual intercourse).

The first large-scale efficacy trial of a protective HIV vaccine, AIDSVAX from VaxGen, is due to report its findings in 2003. Scientists have disagreed strongly over whether the vaccine, which is comprised of genetically engineered versions of the gp120 protein found on the surface of HIV, is likely to be effective. Several other large-scale preliminary studies of protective vaccine candidates are under way in high-risk populations such as gay and bisexual men, and in areas of the world with high incidence of HIV infection, such as Thailand, Brazil, and India. Some studies are evaluating a strategy known as "prime-boost", in which an initial immunization with one type of HIV vaccine is followed by a different type of vaccine, to try to stimulate different parts of the immune system. Although there have been promising results from animal tests of this approach, it will be many years before results of human studies are available.

B. Prevention.

HIV infection and AIDS are considered by many to be completely preventable, because the routes of HIV transmission are so well documented. It is clear that a reliable protective vaccine will not be available for many years. In the absence of a vaccine, the only means of preventing the spread of infection is to avoid personal behaviours that carry a risk of transmission. This has been the focus of AIDS education campaigns throughout the world.

B1. Safe Sex.

Globally, the most common route of HIV transmission is through unprotected anal or vaginal intercourse. The risk can be eliminated by avoiding intercourse, or minimized by using a condom or "female condom", since HIV cannot pass through an intact latex barrier.

HIV transmission through oral sex is possible but rare, and AIDS organizations in most countries do not routinely recommend condom use for this activity.

Many safer sex campaigns have been conducted to encourage the general public and the groups most at risk from HIV to avoid unprotected sex. However, research on health promotion repeatedly shows that the simple provision of information is usually not in itself sufficient to lead to behaviour changes. That may require additional factors; for example, campaigns are more likely to succeed if they present acceptable and achievable options, and are reinforced by peer pressure in favour of certain forms of behaviour and against others.

The most successful safer sex campaigns were those conducted by and for urban gay communities in the 1980s, where the reduction in unprotected anal intercourse has been identified as the greatest health-related behaviour change ever achieved.

B2. Preventing Drugs-Related Infection.

HIV transmission through drug-injecting equipment can be prevented by avoiding injecting drug use or by only using sterile equipment. Needle-exchange programmes have been introduced in many countries to minimize HIV transmission among drug users. In the United States such schemes are controversial as some regard them as condoning illegal drug use, but studies consistently show that needle exchanges are effective, leading to a lower incidence of HIV infection among injecting drug users.

B3. Heat Treatment of Donated Blood.

In the early years of the epidemic, many cases of HIV transmission occurred through contaminated blood products and transfusions; the introduction of screening and heat treatment procedures means that infection through these routes is now extremely unlikely.

B4. AIDS Awareness Campaigns.

Prevention efforts to promote sexual awareness through sex education in schools have faced opposition from certain groups in society on the unfounded grounds that these efforts promote sexual promiscuity among young adults. Approaches such as requiring HIV-infected individuals (or their doctors) to disclose their HIV status to sexual partners, or mandating HIV testing at the time of marriage or pregnancy, have been criticized on the grounds that they may discourage HIV-infected individuals from coming forward for HIV testing. In these cases, issues of individual rights and personal privacy have to be weighed against their possible role in controlling the spread of HIV.

In recent years there has been intense debate about the proper allocation of AIDS education funds. In many countries, HIV transmission still occurs primarily among definable population groups and their sexual partners, yet the majority of resources have been spent on campaigns targeted at the general population rather than at the groups most at risk. In the United Kingdom, the Department of Health has recognized these criticisms and since the mid-1990s has stressed the importance of directing campaigns at gay and bisexual men and injection-drug users.

Prevention efforts through public awareness have been propelled by community-based organizations, such as the Terrence Higgins Trust in Britain, that provide current information to HIV-infected and at-risk individuals. Public figures and celebrities who are themselves HIV-infected or have died from AIDS, including Earvin "Magic" Johnson, Rock Hudson, and Freddie Mercury, have given a recognizable face to AIDS for society to come to terms with the enormity of the pandemic. In memory of those individuals who died from AIDS, especially in its early years, a giant quilt was made in 1986 by the US-based NAMES Project, where each panel of the quilt was in memory of an individual AIDS death.

In the United States, the government has also attempted to assist HIV-infected individuals through legislation and additional community funding measures. In 1990, HIV-infected individuals were included in the Americans with Disabilities Act so that it became illegal to discriminate against such individuals for jobs, housing, and other social benefits. A community funding programme to major US cities designed to assist the daily lives of individuals living with AIDS was established. There are currently no equivalent provisions made by central government in the United Kingdom and local health authorities and local councils may offer help to AIDS patients according to their own separate funding and policy provisions.