Human Immunodeficiency Virus

• Introduction.
• The origins of HIV as a human infection.
• The global spread of HIV infection.
• The global impact of HIV and AIDS.
• The impact of HIV and AIDS in the United Kingdom.
• The three stages of HIV infection.
  • Primary infection.
  • Post-seroconversion - asymptomatic stage.
  • AIDS.
• Oral lesions in HIV infection.
• Diagnosis of HIV infection.
• Management of patients with HIV infection.
• Dental care of HIV positive patients.

Introduction

• Human Immunodeficiency Virus-1 (HIV-1) and HIV-2 are lentiviruses.
  • They are retroviruses that contains all their genetic material as two strands of RNA that have to be converted into DNA by viral reverse transcriptase before the virus can replicate.
  • 'Lenti' = slow, reflecting the long period of time before infection becomes symptomatic.
• HIV-1 and HIV-2 both cause Acquired Immunodeficiency Syndrome (AIDS).
  • HIV-1 has spread rapidly around the world and is much more common than HIV-2.
  • HIV-2 has remained restricted to west Africa, but has also infected significant numbers of people in India.
• HIV-1 and HIV-2 exhibit many common features:
  • For purposes of simplicity, they will be generically referred to as 'HIV' in these pages.
• In 1999 at least 33 million people worldwide were living with either HIV infection or AIDS.
  • This is a lot fewer than for other incurable viral infections (e.g. Hepatitis B: 170 million, Hepatitis C: 300 million).
    • But the impact of HIV is far greater in terms of morbidity and mortality.
  • Currently 95% of HIV infections occur in developing countries.
• No effective vaccines against HIV have yet been produced.
  • In 2000 there were at least 27 different vaccines being tested in clinical trials.
• HIV is of direct relevance to the practice of dentistry as:
  • Appropriate Cross Infection practices will prevent unnecessary spread of HIV infections in the dental surgery.
    • HIV transmission in the dental surgery is most likely to occur via Inoculation Injuries (needlestick or sharps injuries).
    • HIV positive patients can remain clinically well for many years without knowing that they are infected.
  • Oral lesions are common in AIDS and the first clinical suspicion that a patient may be HIV positive can arise during dental treatment.
    • Most oral lesions (except oral warts) regress with anti-retroviral drugs.
    • Development of further oral lesions may indicate that the drugs are starting to become less effective in controlling HIV.
  • The majority of patients who are HIV positive (some of whom will be undiagnosed) can be safely treated in general dental practice.

The Origins of HIV as a Human Infection

• Recent studies concluded that HIV probably arose as a human infection
  • In western central Africa.
  • In the 1930's.
  • As a consequence of transfer from primates.
    • Probably due to the eating of infected meat from:
      • Chimpanzees (HIV1).
      • Sooty Mangabey monkeys (HIV2).
• The clinical illness of AIDS in humans would probably have been apparent within a few years, but was not recognized by Western medicine for several reasons including:
  • It was a new illness.
  • Patients can live with HIV infection for several years before AIDS develops.
  • Only small numbers of patients would have been affected in the early years.
  • Life expectancy amongst the affected communities was already low.
  • Little Western medicine was practiced amongst these communities, especially during, and immediately after the 2nd World War.
• As a consequence, HIV infection spread unrecognized for decades.
• Two factors in particular allowed HIV to spread rapidly around the world.
  • The post-war boom in global travel as airline travel became accessible to millions of people.
  • Increased sexual promiscuity both amongst heterosexuals, but more importantly amongst homosexual men.
    • The 1960s had seen a relaxation of attitudes to sex outside of marriage.
    • 'Bath houses' were established where homosexual men would go and have sex with many different men over a few hours.
• Western medicine began to recognise AIDS in the early 1980's as an illness in sexually promiscuous gay men in the U.S.A..
  • Before the term AIDS was coined, it was initially known as GRID (Gay-Related Immune Deficiency).
    • Some believed that God was punishing homosexuals.
  • One of the first patients to be diagnosed with AIDS was a male homosexual airline pilot who in a short period of time had sex with hundreds of men in a number of cities spread over different continents.
  • With hindsight, it is thought that a Norwegian merchant seaman who visited ports in west Africa was probably the first European to die of AIDS in the 1950s.

The Global Spread of HIV Infection

• Subsequently, it became clear that AIDS was not a disease restricted to homosexual men, and that spread of HIV occurred via three main routes:
  • Sexual contact:
    • Especially when associated with physical abrasions.
      • Receptive anal sex is an extremely high risk behaviour that is not limited to homosexual men:
        • One study in the U.S.A. reported that 23% of single men and 20% of single women had experienced heterosexual anal intercourse at some point in their life.
        • Vaginal heterosexual intercourse is associated with a lower risk of contracting HIV infection.
    • Oral sex is associated with an extremely low risk of HIV infection.
      • The risk of transmission from unprotected receptive oral sex (no condom) is lower than for receptive anal intercourse using a condom.
  • Blood, blood-derived products and organ transplantation:
    • Blood transfusions not screened for HIV.
    • Factor VIII prepared from HIV infected blood caused AIDS in a large number of haemophiliacs prior to anonymous HIV-screening of blood donors.
  • Sharing of needles (contaminated with blood) amongst people who intravenously injected
    • Recreational drugs such as heroin.
    • Performance enhancing drugs (athletes).
  • Organ or tissue transplantation (e.g. kidney or bone marrow) from an HIV-positive donor could result in transmission to the recipient, but this mode of transfer must be considered extremely rare.
• Maternal-child transmission. Approximately 42% of HIV-infected mothers pass the infection to their children via one of the three following routes:
  • Trans-placental infection in-utero during pregnancy.
  • Infection during vaginal delivery.
  • Infection via breast milk.

• There have been incidences of HIV transmission from health care workers during therapeutic procedures, but these have been rare.
  • A particularly notorious case involved a dentist in Florida who infected a number of his patients, probably deliberately.
  • In 2001, a doctor and 6 health workers in Libya were accused of deliberately infecting 373 children with HIV. The trial is ongoing.
• Identification of HIV infection as the cause of AIDS did not take long after the clinical illness was first described in 1981.
  • HIV-1 and HIV-2 were described in 1983 & 1985 respectively.

• Some influential people still dispute that AIDS is only caused by HIV infection.
  • The most prominent of these is Thabo Mbeke, the President if the Republic of South Africa.
  • President Mbeke's beliefs have had a profound influence on how the AIDS epidemic has been managed in South Africa.

• By the time that AIDS was recognized, HIV infection had already been spread around the world.
  • Developed countries focused on limiting the spread of HIV infection within their own communities.
    • Governments funded massive safer sex campaigns in the 1980s.
  • By comparison, little attention was given to the emerging HIV pandemic in Africa and other developing countries.
    • Education about safe sex remains limited in many parts of the world where HIV infection is common.
      • For example, 50% of women and 35% of men aged 15-19 years old living in Tanzania in 1999 did not know of ways to protect themselves against HIV/AIDS.

   

The Global Impact of HIV and AIDS

• The number of people estimated to be living with HIV/AIDS at the end of 1999 was:
  • Sub-Saharan Africa: 23.3 million.
  • South Asia and South-East Asia: 6 million.
  • Latin America: 1.3 million.
  • North America: 920,000.
  • Western Europe: 620,000.
  • Australasia: 12,000.
• The number of people living with HIV/AIDS is increasing at a dramatic rate.
  • For example, in South Africa about 4.7 million people were HIV positive in 2000, compared to 4.2 million in 1999 (out of a total population of 42 million).
• Within Sub-Saharan Africa, HIV infection is more prevalent in women and the southern countries (e.g. South Africa, Zimbabwe, Botswana and Namibia).
  • For example, 15-25 year old adults living in Botswana in 1999
    • 34% of women had HIV/AIDS.
    • 16% of men had HIV/AIDS.
• The statistics that describe the current extent, and likely expansion of the HIV epidemic involve such large numbers that they can become meaningless.
  • To try and address this problem, a team in South Africa applied the statistics to an imaginary South African town of 4000 people and described the impact that HIV would have on this community in 2000 and 2010. Their findings were as follows:

• HIV infection is mostly spread amongst sexually-active young adults. The consequences of this are devastating on the communities in which they live:
  • This group forms the bulk of the workforce.
    • In some communities the workforce has been decimated with associated economic collapse.
  • A large number of pregnant women are HIV positive:
    • For example, in 2000 24.5% of pregnant women in South Africa were HIV positive.
  • There is a huge impact on the most vulnerable members of these communities (the young and the elderly):
    • Children are being born with HIV contracted from their infected mothers.
    • By 1999 12.1 million children in Sub-Saharan Africa had been orphaned due to HIV.
    • There are fewer young adults to care for the elderly.
• AIDS is the 4th most common cause of death in the World:
  • It is the most common cause of death in Sub-Saharan Africa.
• In countries with adult HIV infection prevalences >10% it is predicted that there will be:
  • An average reduction in life expectancy of 17 years by 2010-2015.
• The full impact of AIDS has yet to be realized.
  • Infection rates are unlikely to drop in the immediate future.
    • Especially in communities who have not adopted safer sex practices despite education campaigns.
  • Although there are drugs that can effectively control HIV infection for many years, delaying the onset of AIDS.
    • These are expensive and available to only a small proportion of patients infected with HIV.

The Impact of HIV and AIDS in the United Kingdom

• Compared to other parts of the world including parts of Europe (prevalence rates are 6 times higher in Spain), the U.K. has had few cases of HIV infection.
  • However, the number of cases is rising as safe sex practices are followed less rigorously.
    • The number of new U.K. cases of HIV infection was 7% higher in 2000 compared to 1999.
• In the U.K. between 1982 and 1999:
  • 37,875 cases of HIV infection were recorded.
  • 22% of these were a consequence of heterosexual sex.
• Within the U.K. there is great regional variation in prevalence rates.
  • >70% of all cases have been in London or the surrounding areas.
  • Rates amongst gay men are greater in London than elsewhere in the U.K.
  • Rates amongst intravenous drug abusers are higher in Edinburgh than London.
• In Leeds between 1982 and 1999:
  • 474 cases of HIV infection were recorded.
    • 25% of these were a consequence of heterosexual sex.
    • 107 went on to develop AIDS, of which 82 had died by 1999.
• In recent years, there has been an increase in the number of cases of HIV infection contracted via heterosexual sex.
  • Of 2868 new cases of HIV infection recorded in the U.K. in 2000
    • 1315 (45.8%) were transmitted via heterosexual sex.
    • 1096 (38.2%) were transmitted via male homosexual sex.
  • Of the 20 new cases of HIV infection recorded in Leeds in 1999:
    • 13 (65%) were transmitted by heterosexual sex.
• Although the U.K. has had relatively few cases of HIV infection compared to other parts of the world, it has had a significant social and economic impact:
  • HIV infection has mostly occurred in young adults.
  • HIV infection is associated with considerable social stigma.
  • The health care costs are high.
  • HIV infection cannot be cured.

The 3 Stages of HIV Infection

1. Primary HIV Infection

• The risk of HIV transmission is largely dependent upon direct transfer of infected secretions (e.g. semen) or blood that include high copy numbers of HIV.
  • HIV is much less infective than many other viral infections such as hepatitis B.
  • Genital secretions and blood have the highest HIV copy numbers per ml and pose the greatest risk of transmission.
  • Breast milk also has high HIV copy numbers, and may be a potential source of transmission between mother and child, although the risk is lower compared to that associated with either genital secretions or blood.
  • Cerebrospinal fluid also contains high HIV copy numbers, but is unlikely to be the cause of HIV transmission.
  • Saliva, tears, sweat, urine or faeces have low copy numbers of HIV and pose a low risk of transmission.
• HIV infection spreads rapidly from the point of inoculation and:
  • Many CD4 positive T-lymphocytes (T-helper cells) are infected.
  • Some macrophages become infected.
• In the first few weeks there is massive HIV replication that results in:
  • A marked viraemia (e.g. 5000 infectious HIV particles per ml) at which stage:
    • The patient is highly infectious.
    • Antibodies against HIV have yet been formed, so an HIV test would be negative.
  • Dissemination of HIV infection throughout the lymphoid tissue and many other cell types.
    • As many as 250 billion cells may become infected at this time.
• Within a few weeks a specific immune response against HIV controls the viraemia and copy numbers of HIV drop dramatically.
  • CD4 positive lymphocyte numbers, which have been reduced by HIV viral replication, return to normal.
  • Seroconversion occurs and antibodies against HIV antigens are produced for the first time, and persist thereafter.
  • Although the viraemia ends, HIV is not eliminated from the body.
  • The infectious risk to others diminishes with resolution of the viraemia, but is still present.
• Clinical symptoms experienced during the primary phase of infection are extremely variable.
  • In many patients this phase is subclinical and they are free of symptoms.
  • Others, perhaps up to 50% experience a Glandular Fever-Like Syndrome.
    • During the acute phase the severity of symptoms varies from patient to patient.
      • There may be little more than a mild flu-like illness.
    • Symptoms may include
      • Sore throat.
      • Fever.
      • Lymphadenopathy (tender, enlarged lymph nodes).
      • General malaise.
      • Headache.
      • Muscle aching.
      • Erythematous rash involving the trunk.
    • Most of the symptoms subside in a few weeks
      • But, lymphadenopathy and general malaise do persist for several months in some patients.
  • A small proportion of patients become clinically immunocompromised at this stage (due to HIV replication killing large numbers of CD4 positive cells) and may present with:
    • Minor infections such as oral or vaginal thrush, or herpes.
    • AIDS-defining opportunistic infections such as oesophageal candidiasis or pneumocystis pneumonia.

   

2. Post-Seroconversion - Asymptomatic Stage

• The second phase is entered once a specific immune response against HIV has been mounted and has controlled the initial viraemia.
  • This phase is asymptomatic.
• The duration of the second phase is usually at least a year and can be over 10 years.
  • The mean length is shorter in Sub-Saharan Africa than in Europe and North America.
    • The reasons for this are not entirely clear, but malnutrition is probably an important factor.
  • A small proportion of patients appear to remain in this asymptomatic stage indefinitely (at least 20 years so far).
    • These fortunate people have been intensively investigated as they may hold the key to finding effective treatments and even a cure for HIV infection.
• Although the patient is asymptomatic, HIV replication is continuing insidiously
  • The patient is an infection risk to others.
  • The CD4 positive lymphocyte counts drop progressively.
  • The HIV copy number rises progressively.

3. AIDS

• AIDS is currently defined as an illness characterised by one or more indicator illnesses.
  • The indicator illnesses have changed over the years from those included in the original list formulated by the CDC (Centers for Disease Control).
  • The current list can be found in the British Medical Journal 2001; 322: 1226.
• AIDS can be diagnosed in the absence of laboratory proof of HIV infection (either the test has not been done or the results are inconclusive) if:

• Another cause for immune deficiency cannot be identified.

• Many patients do not know that they are HIV positive until they become clinically immunocompromised and are diagnosed with AIDS.
• Progression from primary infection to AIDS takes 5-8 years in the majority of HIV positive people living in developed countries.
• Clinical symptoms are particularly associated with
  • CD4 positive lymphocyte counts below 200/microlitre, and especially below 100 (normal 500-2000).
  • An increase in viral load.
• The direct effects of HIV infection on cells (such as those in the brain) and immunosuppression due to HIV infection causes a wide range of clinical illnesses including:
  • Opportunistic infections:
    • Fungal infections such as Oesophageal Candidiasis.
    • Viral infections such as disseminated CMV infection.
    • Bacterial infections such as Necrotising Ulcerative Periodontitis.
    • Other infections such as Pneumocystis carinii pneumonia.
  • Neoplasms
    • Particularly Non-Hodgkin's Lymphoma and Kaposi's Sarcoma, both of which are associated with viral infections (EBV and HHV8 respectively).
  • Dementia.
• The majority of patients with advanced HIV infection have oral lesions.

Oral Lesions in HIV infection

• Oral lesions were recognized in the earliest descriptions of HIV disease.
• It subsequently became apparent that oral lesions had important relationships to:
  • Immune status.
  • HIV viral load.
  • Progression and stage of HIV disease.
• For example, oral candidiasis and Hairy Leukoplakia correlate with:
  • Low CD4 counts (a marker of immune suppression)
  • High HIV viral load.
  • The clinical severity of HIV infection.
• Mucosal lesions are often the earliest clinical indication that a patient has HIV infection.
  • Accordingly, a patient with undiagnosed HIV infection may present to the dental team.
  • Early diagnosis is important in optimising overall management.
• A wide range of different oral mucosal lesions have been described.
  • A good summary of these remains 'Classification and diagnostic criteria for oral lesions in HIV infection'.
    • Journal of Oral Pathology and Medicine 1993; 22: 289-291.
      • This short paper was distributed in the lecture. Read it.
      • Group 1 lesions that are strongly associated with HIV infection include:
        • Candidiasis
          • Erythmatous candidiasis.
          • Pseudomembranous candidiasis.
        • Hairy Leukoplakia.
        • Kaposi's Sarcoma.
        • Non-Hodgkin's Lymphoma.
        • Periodontal Disease.
          • Linear Gingival Erythema
          • Necrotising (Ulcerative) Gingivitis.
          • Necrotising (Ulcerative) Periodontitis.
  • Also look at HIVdent: (www.HIVDENT.org/main.htm)
    • This is a very good web site aimed at dentists that includes:
      • Brief descriptions of the oral manifestations of HIV infection.
      • Accompanying photographs.
      • Advice about treament planning and provision of dental care.
• HAART has a major impact on oral lesions due to HIV infection and is considered below.
• Tobacco smoking is associated with an increase in oral lesions (except Recurrent Oral Aphthous Ulceration).
  • Candidosis and HIV-periodontal disease are likley to be more exagerated in smokers.
• In contrast to other oro-facial lesions, salivary gland enlargement with associated xerostomia and CD8 positive lymphocyte infiltration is a good prognostic sign:
  • Progression to end-stage AIDS tends to be delayed in these patients.

A patient with AIDS who presented via general dental practice. A. The dentist was concerned about the rapid alveolar bone loss and gingival recession that had not responded to oral hygiene therapy. B. A smooth-surfaced wart was present on the buccal mucosa. C & D. A small purple lesion on the dorsum of the tongue was a Kaposi's sarcoma. More obvious Kaposi's sarcomas involved the hard palate. Abundant Candida was cultured from the saliva.

E. Examination of the skin identified further Kaposi's sarcomas. In addition, the patient had been receiving treatment for a number of warts involving the hands, but there had been little response to treatment.

Diagnosis of HIV Infection

• Clinical signs and symptoms may raise the possibility that someone is HIV positive.
  • However, remember that there may be other causes for similar clinical lesions:
    • Glandular Fever-Like Syndromes during seroconversion.
    • Patients may be immunocompromised for other reasons.
• The history may indicate that the patient belongs to a high risk group for transmission of Blood-borne Viruses including HIV:
  • The relevant questions are considered in the Inoculation Injuries page.
• However, the diagnosis needs to be confirmed by detection of:
  • HIV antibodies:
    • Only positive following seroconversion.
    • Assays of antibodies raised against HIV form the basis to what has become generically known as an 'AIDS test'.
  • HIV RNA:
    • Assays that estimate of the viral load are:
      • Usually only undertaken when HIV antibodies are present.
      • Important in the determination of:
        • Timing of, and response to treatment.
        • How infective a patient is (low titre, low infection risk).
• HIV testing should only be undertaken by someone with the appropriate training to counsel the patient.
• If you see a patient who you suspect may have undiagnosed HIV infection, a prompt referral should be made to an Oral Medicine Unit for further assessment in the near future.

Management of Patients with HIV Infection

• HIV infection cannot be cured.
• However, a great deal can be done to support patients with HIV infection and improve their quality of life.
  • In the U.K. services are well-developed, but this is not the case for the majority of patients with HIV infection.

HAART

• The development of HAART (Highly Active Anti-Retroviral Therapy) has had a major impact on the management of AIDS by slowing the progression to AIDS. Of relevance to dentistry:
  • Many oral lesions regress.
    • Although oral warts tend to increase in number and severity.
  • Side effects can include:
    • Dry mouth.
    • Increased melanin pigmentation of oral mucosa - this can be unsightly.
    • Perioral dysaesthesia.
• HAART can suppress HIV replication for many years allowing the patient to live a relatively normal life free from the symptoms of AIDS.
  • Many systemic lesions regress and others, such as Non-Hodgkin's Lymphoma, are less likely to develop.
  • HPV infections increase and there is an increased risk of cervical cancer in women.
• Although effective, HAART ultimately fails and HIV replication returns to high levels.

• Development of new oral lesions is associated with failure of HAART.

• HAART has only been available for a few years and is evolving all the time as new drugs become available, so the long term benefits and side effects remain unknown.
• Drugs that suppress HIV in different ways are included together. For example, these include:
  • Reverse transcriptase inhibitors (e.g. AZT) that prevent reverse transcription of HIV RNA.
  • Protease inhibitors that prevent cleavage of newly synthesized HIV proteins.
    • This cleavage is essential for HIV replication.
• The potential benefits of HAART are considerable, but:
  • It is expensive (unavailable to most patients with HIV around the globe).
  • It can be associated with poor compliance (too many tablets to take every day).
  • The side effects can be severe.
  • HIV resistance is becoming more common.
  • It ultimately fails in most patients.

Dental Care of HIV Positive Patients

• The realization that patients can be HIV positive, yet clinically well, drove the adoption of current cross infection measures used in dental practice in the United Kingdom.
• The majority of patients who are HIV positive can be treated safely in general dental practice. Have a look at HIVdent.
  • These patients should not be discriminated against.
    • It is unethical to refuse to treat patients soley because they are HIV positive.
    • It is also illogical as some HIV patients:
      • Have not been diagnosed as being HIV positive.
      • Will not declare to you that they are HIV positive.
  • In the dental surgery, the risk of transmission to the dental team is negligible in the absence of Inoculation Injuries.
    • Know what to do if an Inoculation Injury occurs.
  • The dental team form a very important part of the overall team caring for patients who are HIV positive:
    • It is essential that good oral health is established whilst the patient is in the asymptomatic phase prior to development of AIDS.
• The oral care of patients with AIDS is often more complex:
  • Appropriate referral is then warranted, although it may still be possible to provide dental treatment in the general dental practice after an expert opinion has been obtained.

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