Human Immunodeficiency Virus HIV

See also separate articles Management of HIV in Pregnancy and HIV Post-exposure Prophylaxis.

Human immunodeficiency virus (HIV) is a retrovirus that was first identified in 1983^[1].

• Initially named lymphadenopathy-associated virus (LAV), it was the third identified in a family of human T-lymphotropic viruses (HTLV-III) - finally renamed as HIV-I - and causes acquired immune deficiency syndrome (AIDS)-related disease in most parts of the world.
• In 1985 HIV-II was identified in AIDS patients with West African connections and is currently still uncommon outside that region^[1].
• HIV binds to CD4 receptors on helper T-lymphocytes, monocytes, macrophages and neural cells. CD4 cells migrate to the lymphoid tissue where the virus replicates and then infects new CD4-positive cells. As the infection progresses, depletion or impaired function of CD4 cells predisposes to the development of immune dysfunction.
• The success of antiretroviral therapy (ART, formerly highly active retroviral therapy, or HAART) has revolutionised the way we think about HIV infection. Far fewer patients now progress to AIDS, which - due to the stigma surrounding the diagnosis - is increasingly being known as late-stage HIV disease. Both terms are used interchangeably throughout this article, as the term AIDS is still used by some authorities (eg, the Centers for Disease Control and Prevention (CDC) in the USA).
• The number of circulating viruses (viral load) predicts progression to late-stage HIV disease^[2].

Epidemiology

In 2013, a total of 6,000 persons (4,500 men and 1,500 women) were newly diagnosed with HIV in the UK. The number of newly diagnosed heterosexual men and women has dropped over the years from 4,890 in 2004 to 2,490 in 2013) due to fewer diagnoses among people born in sub-Saharan Africa. 76% of infections in men who had sex with men (MSM) were acquired in the UK^[3]. One study suggested that 16% of people newly diagnosed in England, Wales and Northern Ireland acquired their infection 4-6 months before diagnosis^[4]. 19% of new diagnoses of HIV in 2012 were black Africans. Black Africans tend to present late in the infection, suggesting that more could be done to encourage early testing^[5]. Research in 2011 suggested that 48% of people born abroad are likely to have acquired infection in the UK^[6].

107,800 people were estimated to be living with HIV in the UK in 2013. The overall prevalence was 2.8 per 1,000 population aged 15-59 years (1.9 per 1,000 women and 3.7 per 1,000 men). It was estimated that a quarter of people living with HIV were unaware of their infection^[3].

Diagnosis in adults^[7]

• This is based on detecting anti-HIV antibodies in serum. Rapid testing is offered by some sexual health clinics and can produce a result in 20 minutes.
• Acute infection may be detected by the presence of p24 antigen or HIV RNA by polymerase chain reaction (PCR) and precedes the appearance of IgM and IgG. A combination test checking for the presence of HIV antibody and p24 antigen (the so-called 'fourth generation test') is provided by hospital and is very accurate. It takes about four weeks to get the result back.
• HIV counselling is essential both before and after testing.

Stages of human immunodeficiency virus infection

Groups are those listed in the CDC 1993 classification system^[8].

Seroconversion illness

• Occurs between one and six weeks after infection. 20-60% present with symptoms at this time.
• Common symptoms are a glandular fever-type illness with fever, malaise, myalgia, pharyngitis, headaches, diarrhoea, neuralgia or neuropathy, lymphadenopathy and/or a maculopapular rash. Rarely, meningoencephalitis. Acute infection may be asymptomatic.
• As HIV becomes more treatable, so recognising this early phase becomes more important. Although clinical features are similar to infectious mononucleosis, consider HIV seroconversion illness if there are unusual signs - eg, oral candidiasis, recurrent shingles, leukopenia, or CNS signs.
• Although antibody tests are negative, viral p24 antigen and HIV RNA levels are elevated in early infection.
• Patients who are diagnosed with seroconversion illness should be referred promptly for specialist assessment and initiation of treatment.

Asymptomatic infection
After seroconversion, virus levels are low, although replication continues slowly. CD4 and CD8 lymphocyte levels are normal. This situation may persist for many years.

Persistent generalised lymphadenopathy (PGL)

• Defined as nodes >1 cm in diameter at two extra-inguinal sites, persisting for three months or longer, not due to any other cause.
• Biopsy is not recommended, unless an alternative diagnosis needs to be excluded, as features are nonspecific.

Symptomatic infection

• Nonspecific constitutional symptoms develop: fever, night sweats, diarrhoea, weight loss.
• There may also be minor opportunistic infections - eg, oral candida, oral hairy leukoplakia, herpes zoster, recurrent herpes simplex, seborrhoeic dermatitis, tinea infections.
• This collection of symptoms and signs is referred to as the AIDS-related complex (ARC) and is regarded as a prodrome to AIDS.

AIDS

• Severe immunodeficiency.
• Evidence of life-threatening infections and unusual tumours: see related separate articles Complications of HIV Infection and HIV and Skin Disorders.

Investigations in adults

• Detection of HIV antibody: enzyme-linked immunosorbent assay (ELISA), Western blot.
• Assessment of viral load; detection of virus or viral antigen: HIV RNA or branched DNA (bDNA) assay.
• FBC: anaemia, thrombocytopenia, lymphocytopenia with reduced CD4 cell count.
• Raised ESR.
• Assessment of other infections: eg, tuberculosis, hepatitis B, cytomegalovirus (CMV), toxoplasma, syphilis, varicella.
• Screening for co-existing sexually transmitted infections (STIs).
• Baseline CXR and cervical smear.
• It may be appropriate to screen for glucose-6-phosphate dehydrogenase (G6PD) deficiency in appropriate racial groups (some drug treatments can cause haemolysis in these patients)^[9].

Investigation in children

Standard anti-HIV IgG antibody tests cannot be used before 18 months of age, as maternal antibodies may be detected. HIV DNA PCR and virus culture are the best investigations in children born to infected mothers^[10]. 38% of infected infants can be detected within the first 48 hours after birth, rising to 96% at four weeks^[11].

1993 Centers for Disease Control and Prevention classification of HIV infection in adults^[12]

The initial assessment should also 'stage' the disease. The most widely used staging system is the 1993 revision of the CDC's AIDS Surveillance Case Definition for Adolescents and Adults. According to this system, individuals are assigned a stage according to both a CD4 cell count category and a clinical one (eg, 'A1' or 'C2'). The CD4 cell count categories are as follows:

• CD4 count greater than or equal to 500 cells/mm³ or 29%.
• CD4 count equal to 200-499 cells/mm³ or 14%-28%.
• CD4 count less than 200 cells/mm³ or less than 14%.

Clinical categories

Category A

• Documented HIV infection, asymptomatic, including persistent generalised lymphadenopathy (PGL) - a condition in which HIV continues to produce chronic painless swellings in the lymph nodes during the latency period - or acute HIV infection.

Category B

• Symptomatic disease, conditions not listed in clinical Category C, including conditions that are:
• Attributed to HIV infection or indicative of a defect in cell-mediated immunity; or
• Considered to have a clinical course or management that is complicated by HIV infection.

• Conditions such as: bacillary angiomatosis, persistent or recurrent oral or vaginal candidiasis, moderate-to-severe cervical dysplasia; constitutional symptoms such as fever (38.5°C) or diarrhoea for over one month, oral hairy leukoplakia, herpes zoster (>1 episode or >1 dermatome), idiopathic thrombocytopenic purpura (ITP), listeriosis, pelvic inflammatory disease and peripheral neuropathy.

Category C

• AIDS indicator condition (see below): once a Category C condition has occurred, the individual remains in Category C.

Any individual with stage A3, B3, C1, C2 or C3 infection has AIDS by the CDC definitions.

The World Health Organization (WHO) has produced a staging system for children, based on infection status, clinical status and CD4 count^[12].

Monitoring human immunodeficiency virus infection

• Clinical assessment.
• Monitoring the CD4 count.
• Plasma HIV RNA levels strongly predict progression to AIDS and death but the CD4 count may be sufficient in the later stages in resource-poor countries^[13].
• Clinical benefit from anti-HIV agents depends not only on improving the CD4 count but also from decreasing HIV RNA. Optimal viral suppression is defined generally as a viral load persistently below the level of detection (HIV RNA <20 to 75 copies/mL, depending on the assay used). This is now possible with combination therapy^[14].

Management^[15]

People with HIV infection (and their families) need a great deal of support, as well as monitoring and drug treatment for the patient. Management also includes the treatment of any specific complications of HIV infection. See separate article Managing HIV-positive Individuals in Primary Care.

The following guidance is taken from the British HIV Association (BHIVA) guidelines.

Antiretroviral therapy is now recommended for all patients who have been diagnosed as having HIV infection^[16].

It is also recommended for those patients who have either have a serious bacterial infection or an AIDS-defining infection, who have a CD4 count of <200 cells/mm^3.

Co-existing viral hepatitis^[18]

The treatment of HIV in patients with co-existing viral hepatitis is extremely complex. Recent guidance recommends that:

• ART choice should take into consideration pre-existing liver disease but ART should not be delayed because of a risk of drug-induced liver injury.
• ART should be used with close monitoring in patients with end-stage liver disease and consideration given to performing plasma level monitoring of ART agents.
• Some agents should be used differently in patients with co-existing viral hepatitis - see guidelines.
• Innovative agents have been developed for patients with co-existing hepatitis C and new treatments are being approved on a regular basis.

Drug treatment^[16]

ART may cause lipodystrophy syndrome which includes fat redistribution, insulin resistance and dyslipidaemia.

• Preferred initial therapy is usually three drugs: efavirenz plus tenofovir or abacavir, plus lamivudine or emtricitabine.
• Other drugs are used in particular circumstances (see treatment guidelines).

Other measures^{[15, 19]}

Immunise against hepatitis B, pneumococcal disease and Haemophilus influenzae type b (and possibly influenza and hepatitis A). Because of immunosuppression, HIV patients should not receive BCG vaccination, yellow fever, oral typhoid or live oral polio immunisations.

Chemoprophylaxis

Chemoprophylaxis is used to prevent infection in HIV-positive patients^{[19, 20, 21]}.

• Primary chemoprophylaxis is used when the CD4 lymphocyte count drops below a certain level, making opportunistic infection likely.
• Secondary chemoprophylaxis is used to prevent the recurrence of an infection that has already occurred.

Primary prevention

• Early disease (WHO stages 1-3). The type of infection will depend on local disease prevalence. The advent of ART has dramatically reduced the risk of developing AIDS (increasingly being known as late-stage HIV disease). Some idea of UK prevalence can be obtained from statistics of diseases which indicate possible development of late-stage HIV disease (so-called 'indicator diseases'). UK data commonly feature pneumocystis pneumonia (PCP), tuberculosis (TB), atypical mycoplasma, candidiasis, CMV and toxoplasma. Recent years have seen TB overtake PCP as the most common indicator disease. Globally, the important infections are TB, pneumococcal pneumonia, shingles, malaria, staphylococcal skin infections and septicaemia. Of these, TB is the most prevalent and WHO is encouraging international collaboration on joint prevention/treatment strategies^[22].
  
• Late disease (WHO stage 4 - equivalent to AIDS). Common recurring infections are pneumocystis, cryptococcus, toxoplasma and TB.

Antiretroviral therapy (ART)^{[19, 23]}

Antiretroviral drugs are now available to inhibit the replication of HIV. This helps to prolong life, restore the patient's immune system to something approaching normal activity and reduce the chances of opportunistic infection developing. Combinations of three or more drugs are given to lessen the possibility of resistance.

See separate article Antiretroviral Agents for more details.

Prevention of HIV-related opportunistic infections^{[19, 24, 25, 26]}

Where there is no prevalent UK policy, the WHO or American policy is adopted.

• TB - this is 30-50 times more likely to develop in HIV-positive patients than in those who do not have the virus. WHO guidance recommends that the decision to prescribe isoniazid preventative therapy (IPT) can be based on a symptom algorithm. It is no longer necessary to perform tuberculin skin tests or CXRs before isoniazid is instituted. These guidelines have been slow to percolate through the developed world but have been rapidly adopted in resource-poor countries:
  • The WHO guidelines have been adapted by individual countries to suit available resources. For example, in South Africa (where TB is the most common opportunistic infection and most patients will have a positive skin test) guidelines state that tuberculin skin testing should be offered 'where necessary'^[27].
  • In the UK, the success of ART has made the routine use of IPT unnecessary for the indigenous population. 
• Pneumocystis jirovecii pneumonia - UK recommendations are to offer co-trimoxazole to all patients with a CD count below 200/mm³ or with a history of oral candidiasis, a CD4 T-cell percentage of all lymphocytes <14%, or a previous AIDS-defining illness. Discontinue if CD count remains above 200/mm³ for 3-6 months.
• Bacterial pneumonia - offer pneumococcal vaccine to all patients with a CD count above 200/mm³ who have not had vaccine within five years.
• Mycobacterium avium-intracellulare (MIA) - BHIVA recommends azithromycin for individuals with CD4 counts <50 cells/μL. Patients receiving ART can stop prophylaxis once the CD4 count rises above 50 cells/μL and the viral load is <50 copies per ml for at least three months. Clarithromycin is sometimes used as an alternative.
• Toxoplasma - offer co-trimoxazole for toxoplasma-positive patients with counts below 100/mm³ or test at regular intervals. Dapsone plus pyrimethamine can be used in cases of co-trimoxazole allergy.
• Varicella zoster - if susceptible (no history of chickenpox, shingles, or detectable antibody), offer varicella immune globulin within 96 hours of exposure.
• CMV and herpes simplex - primary prophylaxis is not routinely offered in the UK.
• Microsporidiosis, cryptosporidiosis - there is no known prophylaxis available.
• The combined influenza/swine flu vaccine is routinely offered in the UK to all individuals living with HIV, especially those with a CD count below 200/mm³.

Secondary prevention

• CMV - use ganciclovir to prevent retinitis. Long-acting drug-release intravitreous implants have been shown to be cost-effective.
• Herpes simplex - may require temporary daily suppressive treatment with oral aciclovir. There are limited safety data for famciclovir and valaciclovir.
• Oral candidiasis - may require suppressive treatment with an antifungal agent.
• Salmonella - long-term therapy may be required to prevent septicaemia - ciprofloxacin is the first choice.
• Toxoplasma - give co-trimoxazole to prevent relapse (pyrimethamine plus dapsone if allergic); discontinue if the CD4 cell count increases above 200/mm³ and is sustained for at least six months. Resume if the count subsequently falls below 200/mm³.

Preventing human immunodeficiency virus spread^{[15, 28]}

• Promote lifelong safer sex, barrier contraception and reduction in the number of partners. Videos, followed by interactive discussions, are one way to double the use of condoms. Another way is the 100% condom programme involving distribution of condoms to brothels, with enforcement programmes enabling monitoring and encouraging of condom use at any sex establishment. Such programmes are estimated to have prevented 2 million HIV infections in Thailand.
• Warn heterosexuals about the dangers of sexual tourism/multiple sexual partners.
• Tell drug users not to share needles. Use needle exchange schemes.
• Vigorous control of other STIs can reduce HIV incidence by 40%.
• Strengthen awareness of clinics for STIs.
• Reduce unnecessary blood transfusions.
• Encourage pregnant women to have HIV tests.
• Post-exposure prophylaxis after occupational and sexual exposure also helps to limit HIV spread. See separate HIV Post-exposure Prophylaxis article for more details.
• Pre-exposure prophylaxis is being explored by the WHO in a number of at-risk groups (eg, serodiscordant couples) and trials are ongoing^[29].