The acquired immunodeficiency syndrome (AIDS) was first described in 1981 in Los Angeles, and over the following few years the cause was identified and named the human immunodeficiency virus (HIV). It is now thought that HIV species evolved from viruses found in non-human primates, the initial inter species transmission taking place probably in the first half of the 20th century.
Since 1981 physicians have gained considerable experience in treating patients with HIV and AIDS. Almost 20 antiretroviral drugs in four classes have been developed and in the West, deaths from AIDS have fallen significantly since the mid-1990s. Despite the optimism that these advances have brought, HIV is still incurable and the number of people infected continues to increase. The efforts of the many groups working to develop an effective vaccine have so far been fruitless.
In the UK HIV is usually managed by genitourinary medicine and infectious disease physicians, although GPs are increasingly being encouraged to take a more active role.
Virology and immunology of HIV/AIDS
Lymphocytes are white blood cells integral to the functioning of the immune system. The main role of B-lymphocytes is the production of antibodies against foreign organisms (humoral immunity). T-lymphocytes predominantly deal with cell-mediated immunity and their main functions are exerted using the T-cell receptor. The subtypes of T-lymphocytes are named according to the proteins expressed on their surface. One such subtype expresses a membrane protein which functions as a co-receptor to the T-cell receptor. This protein is called the CD4 antigen.
Although CD4 is found on other cells, including Langerhan’s and glial cells, the term ‘CD4 cell’ is usually taken as meaning a CD4+ lymphocyte. These CD4 cells (also called T helper cells) have several important functions including the activation of B-lymphocytes and macrophages.
HIV-infected CD4+ cells die, although the actual mechanism of death is surprisingly poorly understood. In the early stages of infection, billions of T helper cells are destroyed each day and billions more are made. Ultimately, though, the body cannot keep up the pace and the number of T helper cells declines. This manifests as an increasing chance of acquiring infections with viruses, intracellular bacteria, fungi and protozoa. A variety of cancers, mostly virally mediated, also become more common.
HIV-1 and HIV-2 are part of the retroviridae family. They are RNA viruses and rely on the enzyme reverse transcriptase to incorporate their genetic material into the host genome.
When discussing HIV infection we usually are referring to infection with HIV-1. HIV-2 is associated with lower viral loads and is thought to be less easily transmitted and less pathogenic than HIV-1. It is found mostly in West African countries.
Transmission of HIV/AIDS
HIV is present in blood and other body fluids including semen and vaginal secretions. The risk of transmission varies enormously with the nature of the risk event (see Table Approximate risk of transmission from a person with HIV).
Table Approximate risk of transmission from a person with HIV [modified from British Association for Sexual Health and HIV (BASHH) guideline for the administration of post-exposure prophylaxis following sexual exposure to HIV]
|Type of exposure||Estimated risk of HIV transmission per exposure|
|Blood transfusion (one unit)||90-100%|
|Receptive anal intercourse||0.1-3.0%|
|Receptive vaginal intercourse||0.1-0.2%|
|Insertive vaginal intercourse||0.03-0.09%|
|Insertive anal intercourse||0.06%|
|Receptive oral sex (fellatio)||0-0.04%|
|Sharing injecting equipment||0.67%|
|Vaginal delivery (no treatment)||5-20%|
|Breast feeding (no treatment)||10-15%|
|Vaginal delivery, on treatment with undetectable viral load||<1%|
|Mucous membrane exposure||0.006-0.5%|
|NB. no transmissions have been identified following exposure of intact skin to blood, tears, saliva, sweat or urine.|
Numerous factors can increase the risk of transmissibility of the virus. In early HIV infection, the viral load can be extremely high (millions of virions per millilitre compared to tens of thousands once someone has had the infection for a year or so). Therefore, the above transmission estimates can be increased by a factor of 10 if the source patient had recently acquired the infection. Of course, they are also less likely to know they are infected.
Most STIs can facilitate transmission of HIV. The main effect is from ulcerating conditions such as herpes, syphilis and chancroid. For example, people who have HSV-2 are twice as likely to transmit or acquire HIV. Other STIs including gonorrhoea, chlamydia and trichomoniasis have also been shown to contribute to transmission, and non-transmissible conditions such as bacterial vaginosis and vaginal candidiasis also appear to be cofactors.
Globally, vaginal intercourse is the main route of HIV transmission. In the UK in 1987 this accounted for only 6% of the total number of HIV diagnoses. This proportion has increased, and in 2003, 65% of newly diagnosed people were thought to have acquired their infection by heterosexual sex (presumed to be largely vaginal sex). About 80% of these people acquired their infection outside the UK, mostly in Africa. Most UK-acquired infections are in men who have sex with men. In Eastern Europe and parts of South East Asia, the main method of transmission is injecting drug use.
Stages of HIV infection
Signs and symptoms of HIV infection vary according to the degree of immunodeficiency. The stage of HIV infection can be classified using the Centers for Disease Control (CDC) system (see Table CDC classification system). This uses clinical conditions associated with HIV and the CD4 cell count. However, it is important to note that many of the conditions that are more common in people with HIV are due to chronic B cell stimulation rather than CD4 depletion.
The World Health Organisation also has a classification system. Their system is designed to be used without the benefit of laboratory data: only clinical markers are used.
Table CDC classification system
|CD4 cell count||Clinical category|
In Europe, categories Cl-3 are AIDS defining. In the US the definition is extended to include categories A3 and B3.
Clinical category A
Most people in CDC category A are asymptomatic and this stage can last for months or years. Indeed, a small proportion of people are long-term non-progressors and never become significantly immunocompromised.
Category A presentations include:
Seroconversion illness (the production of antibodies against HIV). Fever and rash are the commonest symptoms of seroconversion. Other symptoms include joint pain, oral ulceration, weight loss, muscle pain and fatigue. Seroconversion can mimic glandular fever and can give a false-positive monospot test. About 25% of people have an asymptomatic seroconversion. Viral titres in the blood and genital secretions are very high during the seroconversion illness and people are highly infectious. HIV seronconversion should be considered in all people presenting with a glandular-fever-like illness since missing the diagnosis at this stage has serious implications for the further spread of the virus.
Persistent generalized lymphadenopathy.
Clinical category B
Category B includes symptomatic infection in an adult where the condition is thought to be attributed to HIV infection. It includes all symptomatic conditions except those in category C.
Category B presentations include, but are not limited to:
• Constitutional symptoms such as fever > 38.5°C or diarrhoea lasting longer than 1 month.
• Thrombocytopenia. This is thought to be due to reduced production and immune destruction of platelets. It often responds to antiretrovirals.
• Bacillary angiomatosis (also called cat scratch disease) is caused by Bartonella henselae and B. quintana. Symptoms include fever and a painful rash.
• Shingles (caused by reactivation of varicella zoster) is more common in HIV-positive individuals and is frequently a presentation of previously undiagnosed HIV infection. Atypical presentations such as multidermatomal involvement and a generalized rash over the limbs or trunk may occur.
Infection with Campylobacter and Clostridium difficile and viral gastroenteritis are common and can occur with any CD4 cell count. Entamoeba and giardia also occur more commonly in HIV, irrespective of cell count. Salmonella occurs with lower CD4 cell counts and recurrent salmonella bacteraemia is category C.
• Sinusitis is common in HIV, particularly with decreasing cell counts. It should be treated for several weeks to prevent recurrence. Pseudomonas may also be a pathogen in this condition.
• Oropharyngeal and recurrent vulvovaginal candidiasis.
• Seborrhoeic dermatitis and various forms of folliculitis are common.
Oral hairy leucoplakia is commonly seen with a CD4 count below 250 or so. Usually presents as white ridges on the lateral sides of the tongue. It is caused by the Epstein Barr Virus and does not usually need treatment.
Clinical category C
These conditions are AIDS defining and include but are not limited to:
• Kaposi’s sarcoma. Caused by human herpes virus 8. Usually first becomes apparent as a spreading purplish spot on the skin, but can involve any part of the body including the gastrointestinal tract and other internal organs.
• Non-Hodgkin’s lymphoma.
• Tuberculosis (tuberculosis). In HIV this is usually the result of reactivation of a primary infection. The rate of co-infection varies geographically, being very high in Sub-Saharan Africa. People found to have tuberculosis should be offered an HIV test.
• Infection with Mycobacterium avium and Mycobacterium intracellulare are usually grouped together as Mycobacterium avium complex (MAC). Infection is common in AIDS patients with cell counts less than 100. Any organ may be affected.
• Oesophageal candidiasis. This can present with heartburn and dysphagia.
• Herpes simplex ulceration persisting for more than a month.
• Pneumocystis pneumonia (PCP). This is caused by Pneumocystis jiroveci not P. carinii as previously thought. Pneumocystis pneumonia usually presents with a dry cough, fever and progressive breathlessness. The chest X-ray may be normal and CT imaging may be required. The diagnosis is usually made by performing immunofluorescent microscopy on material obtained by bronchoscopy or on induced sputum. Most cases occur in those who have CD4 cell counts of <200 mm3, so people with a CD4 count below this figure are advised to take prophylactic antibiotics.
• Cerebral toxoplasmosis. This is caused by Toxoplasma gondii, which is acquired from undercooked meat or cat faeces. People may present with headache, seizures, hemiparesis or altered mental state. Typical ring-enhancing lesions are seen on CT or MRI. These may be multiple and are seen in the basal ganglia and cortex.
• Chronic intestinal Cryptosporidiumparvum infection (>1 month). The parasite lives in the gut wall and infection may be primary or reactivation of latent infection. Diarrhoea, abdominal pain and cramps are common.
• Cytomegalovirus (CMV) reactivation. The average CD4 cell count at the time people develop their first episode of CMV disease is below 30. CMV retinitis may be asymptomatic therefore screening is essential. Encephalopathy and pulmonary and neurological manifestations can occur.
• Cryptococcosis. Cryptococcus neoformans is a yeast found in soil. Symptoms are associated with a CD4 count less than 100. Initial infection through the lungs can then spread through the bloodstream to any organ. Meningitis is a common presentation. Skin lesions similar to molluscum contagiosum are also seen.
• Progressive multifocal leucoencephalopathy (PML). This is caused by JC virus, which infects the oligodendrocytes. It causes progressive ataxia, paralysis and cognitive impairment. The typical MRI appearance is of diffuse hypodense fluffy lesions which do not enhance with contrast.
• HlV-associated dementia (HAD) is more frequently an AIDS-defining diagnosis in older individuals. In those HIV-positive patients without AIDS, cognitive impairment rises with age.
• Wasting is a common symptom of HIV and can occur at any stage of infection. Technically it refers to loss of 10% of body weight in the absence of an active infection or identifiable cause.
Diagnosis of HIV/AIDS
Many patients come into contact with medical services without a diagnosis being made, and partially because of these missed opportunities, 29% of people with HIV in the UK are unaware that they have the infection. HIV should be considered in anyone who falls into a risk group. A brief risk assessment and tailored pretest discussion takes little time and testing should be performed more widely.
An ‘HIV test’ usually involves 3-4 sub-tests, which are usually antibody based. Most people do not develop antibodies until approximately 6 weeks after infection and this ‘window period’ can be up to 3 months. However, modern ‘fourth generation’ tests include a test for an HIV antigen; using such a test -50% of infected patients would get a positive test at a month, -95% at 2 months and 100% at 3 months. It is therefore essential to know which test your lab uses before discussing test results with a patient. If someone has been given post-exposure prophylaxis following a needle-stick injury or sexual assault, the window period can be as long as 6 months.
False positives are rare but may occur in autoimmune disease and post-immunization. False negatives are usually due to the window period but may occur in agammaglobulinaemia; however, even in this situation a fourth generation test would still be positive.
The viral load measured by PCR detects the concentration of HIV present in body fluid (usually blood). This can usually be detected from 48 hours after exposure. It can be of diagnostic use in testing for seroconversion illness when the enzyme-linked immunosorbent assay (ELISA) test may still be negative; however, false-positive results can occur. It is more commonly used in quantifying the burden of virus present in those who are known to have HIV infection and assessing response to treatment.
CD4 and CD8 lymphocyte counts are used to assess the immune function. The rate of decline of CD4 cells (normal range CD4 500-1400 cells/mm3) correlates with progression of HIV. The percentage of lymphocytes which are CD4 cells is another useful marker. In addition, the ratio of CD4:CD8 cells can give useful information about the stage of the disease. A low ratio implying late disease.
Treatment of HIV/AIDS
Antiretrovirals have been available since the late 1980s, but it was the introduction of new classes of drugs in the late 1990s that has led to significantly prolonged survival. Combination treatment with these agents has been given the catchy although slightly over-optimistic acronym HA ART (highly active antiretro viral therapy).
The four main classes of drugs are:
1. nucleoside analogue reverse transcriptase inhibitors (NRTIs)
2. non-nucleoside analogue reverse transcriptase inhibitors (NNRTIs)
3. protease inhibitors (PIs)
4. fusion inhibitors.
Although effective in combination, resistance can rapidly occur if an inadequate regimen is prescribed or if the patient is incompletely adherent to a regimen. Adherence can be difficult; some drugs need repeated doses through the day while others have to be taken either with food or on an empty stomach.
Antiretrovirals have numerous side effects, including metabolic, haematological and gastrointestinal symptoms. Some side effects can be disfiguring, in particular lipoatrophy (the loss of subcutaneous fat from the face and limbs). Because of these side effects and the need for close monitoring, antiretrovirals should only be prescribed under specialist supervision.
There are conflicting views with respect to using HAART during seroconversion illness. The rationale of early treatment is that the immune system may better respond to HIV infection; this has to be balanced with the potential side effects of the drugs.
There is also a public health case for starting early treatment and reducing transmission during a period when viral titres are high. In view of the lack of a consensus, treatment should only be started in primary HIV infection when people have severe symptoms.
Current recommendations in the UK are to start treatment when the CD4 count is 200-350 cells/ml3. First-line treatment should be with two NRTIs and either a NNRTI or a PI.
Prophylaxis against opportunistic infections includes:
• PCP prophylaxis for those with a CD4 cell count <200 cells/ml. Co-trimoxazole is most commonly used. This also is protective prophylaxis against Toxoplasma gondii.
• Cytomegalovirus prophylaxis with valgancyclovir for those who have a CD cell count <50 cells/mm.
• US guidelines recommend prophylaxis against mycobacterium avium intracellulare (MAI) when CD4 cell count <50 cells/mm.
Immunodeficient individuals may not have a good response to vaccination, and in the face of a falling CD4 count, vaccinations should be undertaken soon after diagnosis. Immunoglobulin may be given if protection is required following exposure to some organisms. The HIV viral load may increase following vaccination, although it is unclear if this has any clinical significance.
Apart from MMR, live vaccines should be avoided in all patients with HIV infection, even in those who are asymptomatic; these include BCG, cholera (live oral) and typhoid (live oral).
All HIV-positive individuals should be given pneumococcal, hepatitis B and influenza vaccines. Tetanus and hepatitis A vaccine is recommended for injecting drug user (IDU). Other vaccines may be required for overseas travel such as rabies, meningococcal A and C, and Japanese encephalitis.
Overseas travel for those with HIV
Certain countries completely prohibit the entry of HIV-infected individuals, although this is now uncommon. It is important to check the individual country’s legislation. Advice should be given to reduce risk of food- and vector-borne infections. Adequate supplies of drugs should be taken in hand luggage to avoid problems if checked-in luggage goes missing.
Antenatal screening should be offered to all pregnant women. If a woman is HIV positive, antiretrovirals can be given, the aim being to reduce the viral load to undetectable levels by the time of delivery.