Human immunodeficiency virus

See also the separate Management of HIV in pregnancy and Needlestick injury articles.

What is the human immunodeficiency virus?

Human immunodeficiency virus (HIV) is a lentivirus from the subfamily of retroviruses. It was first identified in 1983.¹

HIV is the causative agent of acquired immunodeficiency syndrome (AIDS).

Types of HIV

HIV I

• Initially named lymphadenopathy-associated virus (LAV).

• It was the third identified in a family of human T-lymphotropic viruses (HTLV-III).

• It was finally renamed as HIV-I.

• HIV I causes the majority of HIV infections worldwide.

HIV II

• In 1985 HIV-II was identified in AIDS patients with West African connections and is uncommon outside that region.¹

• It has also been reported in Portugal, France and increasingly in India and South America.

• An estimated 1-2 million people worldwide have HIV II infection, some of which also have a co-infection with HIV I.²

• Most antiretrovirals were developed to treat HIV I, and there is limited evidence on the optimal antiretroviral therapy for HIV II.³

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. Life expectancy amongst people with HIV who are taking effective ART is now close to that of the general population,⁴ and people taking ART with an undetectable HIV viral load cannot transmit HIV to others.⁵

How common is HIV? (Epidemiology)

In 2022, there were over 39 million people living with HIV worldwide. The numbers of new HIV infections and HIV-related deaths are both falling. The prevalence of HIV varies significantly between countries, and is highest in southern Africa.⁶

In the UK, in 2019 there were estimated to be 105,200 people living with HIV. 94% of them were aware of their HIV status, 92% were being treated for HIV, and 89% were virally suppressed.⁷

There is substantial variation in the prevalence of HIV between different geographical areas, and between different groups of people. London has the highest HIV prevalence in the UK with 5.4 people with diagnosed HIV per 1000 residents, considerably higher than the next highest prevalence region, the North West (2.1 per 1000).⁸ Overall in the UK, HIV prevalence is highest in gay and bisexual men, Black African people, and people who inject drugs, although HIV affects all groups of people.⁷

Rates of new HIV diagnoses in the UK have been falling since the mid-2000s. In 2022, there were 3,805 new HIV diagnoses in England; an increase from 3,118 in 2021, but this was mostly due to an increase in diagnoses in people who were previously diagnosed with HIV abroad, rather than an increase in HIV transmission in England.⁹

As new HIV diagnoses decline, and HIV treatment allows people with HIV to live longer, the overall demographics of people living with HIV are changing, with the proportion of people aged 50 or over increasing.⁷

The number of people diagnosed late decreased from 3,353 in 2009 to 1,883 in 2018 representing a 44% decline over the decade.⁷ Nevertheless, the proportion of late diagnoses in 2018 remained high at 43%. There was substantial variation in sub-populations experiencing late HIV diagnosis rates.

Stages of HIV infection

Groups are those listed in the CDC 1993 classification system.¹⁰

Stage 1: acute primary infection (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.

• Early treatment of HIV substantially improves the prognosis and reduces (or prevents) transmission, so recognising this early phase is 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.

• In the early stages of primary HIV infection, only HIV RNA and p24 antigen are detectable, and HIV antibody tests are negative. ¹¹

• Patients who are diagnosed with seroconversion illness should be referred promptly for specialist assessment and initiation of treatment.

Stage 2: asymptomatic stage

• After seroconversion, virus levels are low, although replication continues slowly.

• CD4 and CD8 lymphocyte levels are normal. This situation may persist for many years.

Stage 3: symptomatic HIV 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

When a person develops certain serious opportunistic infections or diseases - as a result of damage to their immune system from advanced stage 3 HIV infection - they are said to have AIDS.

• Severe immunodeficiency.

• Evidence of life-threatening infections and unusual tumours: see the related separate Complications of HIV infection and HIV and skin disorders articles.

Diagnosis of HIV in adults¹²

Diagnostic tests currently used are usually either:

• Third-generation tests, which detect IgM and IgG antibodies to HIV, or;

• Fourth-generation tests, which detect IgM and IgG antibodies to HIV, and the HIV p24 antigen.

Fourth-generation laboratory testing of venous blood is recommended as the first-line investigation. Point-of-care tests, which are largely third-generation, are also available and give rapid results. Self-testing and self-sampling is also becoming more widely available, which should make HIV testing more acceptable and accessible.

Clinicians and patients should be aware of the 'window period' of HIV tests, ie the length of time between contracting HIV and the test becoming positive. These are:

• Fourth-generation laboratory tests: 45 days.

• Third-generation laboratory tests: 60 days.

• Point of care tests: 90 days.

HIV tests can be done 'early' within these window periods (as a positive result is still useful), but should be repeated at an appropriate interval after a potential HIV exposure, if negative.

Acute infection may be detected by the presence of p24 antigen or HIV RNA by polymerase chain reaction (PCR), which precede the appearance of IgM and IgG.

Molecular assays (for HIV RNA or proviral DNA) are not currently recommended for routine HIV diagnosis, but are useful in cases of diagnostic uncertainty (eg, primary HIV infection).

All clinicians should be capable of offering HIV testing. Lengthy pre-test discussions are not required. Patients should be informed that they are being tested for HIV, that testing is voluntary, and be told how the results will be managed. Further information may be provided, but this should be tailored to the circumstances (ie the indication for testing, the setting, and the wishes of the person being offered the test).

The use of opt-out consent, whereby patients are informed that they will be tested for HIV automatically unless they actively decline, is increasingly common.

Testing recommendations:

HIV testing is recommended for:¹²

• People belonging to groups at increased risk of exposure to HIV, including men who have sex with men (MSM) and the female sexual partners of those men, black Africans, people who inject drugs (PWID), sex workers, prisoners, trans women and people from countries with high HIV seroprevalence and their sexual partners. An annual test is recommended for PWID, sex workers and MSM, and more frequently for those reporting higher risk behaviours or those also belonging to other groups.

• People attending health services whose users have an associated risk of HIV, including sexual health services, tuberculosis (TB), hepatitis and lymphoma clinics, antenatal clinics, termination of pregnancy services and addiction and substance misuse services.

• All people presenting with symptoms and/or signs consistent with an HIV indicator condition. This includes AIDS-defining conditions (conditions which indicate AIDS in people living with HIV), and conditions where the prevalence of undiagnosed HIV is at least 1 in 1000. These are:

  • Sexually-transmitted infections.

  • Malignant lymphoma.

  • Kaposi's sarcoma.

  • Anal cancers or dysplasia.

  • Cervical cancer or dysplasia.

  • Herpes zoster (shingles).

  • Tuberculosis infection.

  • Disseminated or extrapulmonary Mycobacterium infections.

  • Cytomegalovirus retinitis.

  • Persistent herpes simplex ulcers (>1 month), or herpes simplex bronchitis or pneumonitis.

  • Progressive multifocal leukoencephalopathy.

  • Cerebral toxoplasmosis.

  • Cryptosporidiosis diarrhoea.

  • Extrapulmonary cryptococcosis.

  • Disseminated or extrapulmonary histoplasmosis.

  • Disseminated or extrapulmonary coccidioidomycosis.

  • Disseminated talaromycosis.

  • Hepatitis A infection.

  • Hepatitis B or C infection.

  • Unexplained lymphadenopathy.

  • An infectious mononucleosis-like illness.

  • Community-acquired pneumonia.

  • Unexplained leukocytopenias or thrombocytopenias lasting 4 weeks or longer.

  • Seborrhoeic dermatitis.

  • Peripheral neuropathies.

  • Severe or atypical psoriasis.

  • Mononeuritis.

  • Unexplained weight loss.

  • Unexplained oral candidiasis.

  • Unexplained fever.

  • Candidaemia.

  • Visceral leishmaniasis.

  • Primary lung cancers.

  • Invasive pneumococcal disease.

  • Oral hairy leukoplakia.

  • Guillain-Barré syndrome.

  • Subcortical dementia.

  • Multiple sclerosis-like diseases.

  • Unexplained chronic diarrhoea.

  • Unexplained chronic renal impairment.

• People accessing healthcare in areas with high (>2/1,000; if undergoing venepuncture) and extremely high (>5/1,000; all attendees) HIV seroprevalence.

• Sexual partners of an individual diagnosed with HIV.

Investigations in adults¹³

As discussed above, a fourth generation (antibody and antigen) test on venous blood is recommended as the initial investigation in most situations where HIV testing is required.

For people with newly-diagnosed HIV, the following baseline investigations should be conducted in specialist care:

• Confirmation of HIV-1 or -2 status.

• Tests for primary HIV infection.

• HIV-1 plasma viral load.

• HIV-1 drug-resistance testing.

• CD4+ T cell counts.

• Hepatitis A, B, and C serology.

• A full STI screen, including syphilis serology.

• Measles and varicella antibodies (according to vaccination and infection history).

• FBC, renal profile, LFTs, and bone profile.

• Dipstick urinalysis, and urine protein:creatinine ratio if protein positive in the urine dipstick.

• Cervical cytology, in women who have not had this in the last 12 months.

• Rubella serology, in women of child-bearing potential with no history of previous testing or vaccination.

Additional investigations at presentation include:

• HLA-B*57:01 testing if abacavir therapy is being considered.

• Viral tropism testing if a CCR5 inhibitor is being considered.

• Cardiovascular risk assessment using QRISK for patients over 40 years or age.

• Fracture risk assessment, using RAX, for patients over 50 years of age, post-menopausal women, or other patients at high risk of osteoporosis.

• Interferon-gamma release assay, as per the BHIVA tuberculosis guidelines.

• Tests for parasitic infections, in patients with persistent eosinophilia and a relevant travel history.

Investigation in children¹⁴

Vertical transmission of HIV (from mother to child) is now rare in the UK, due to high uptake of HIV screening in antenatal care, and the availability of effective interventions to prevent HIV transmission.

HIV antibody tests are non-diagnostic in infants under the age of eighteen months, as maternal HIV antibodies may still be detectable up to this point. Positive HIV antibodies in infants are therefore a marker of perinatal HIV exposure, but not necessarily HIV infection.

Molecular diagnostic tests (for HIV DNA or RNA) are therefore used in infants of mothers with HIV to detect HIV infection.

In children of mothers with HIV, HIV antibody testing should be repeated at 22-24 months of age. At this point, they should 'serorevert' - test negative - as maternal HIV antibodies have disappeared. A positive test at this point indicates HIV infection in the child - rarely, late postnatal transmission can occur.

1993 Centers for Disease Control (CDC) classification of HIV infection in adults¹⁵

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.

AIDS-defining conditions in adults

The World Health Organization (WHO) has produced a staging system for children, based on infection status, clinical status and CD4 count.¹⁵

Monitoring HIV

Monitoring of HIV is usually carried out in specialist clinics using the CD4 lymphocyte cell (CD4) count and viral load.¹⁶

• CD4 count:

  • The CD4 count reflects the degree of immunosuppression in people infected with HIV - see Table 1 for further information.

  • In a healthy person not infected with HIV, the CD4 count is usually greater than 500 cells per microlitre - some people may have naturally lower counts.

  • People with CD4 counts below 200 cells per microlitre are most at risk of HIV-related opportunistic infections and cancers. If treatment is started at CD4 counts above 500 cells per microlitre, rather than later, prognosis is improved.

• Viral load:

  • Viral load reflects rates of viral replication and is measured using a PCR test.

  • A rising viral load may indicate non-adherence to ART, resistance to one or more antiretroviral drugs, or an interaction with another medication.

  • Viral load ranges from undetectable (less than 20-50 copies of viral genome/mL blood) to over a million copies/mL.

  • The degree of viral replication is linked to the rate of CD4 decline and therefore disease progression - when viral load is suppressed through ART, CD4 counts recover and risk of HIV-related opportunistic infections and cancers declines.

Management of HIV¹⁷

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.

ART is recommended for all people who are living with HIV infection.

ART should be started immediately in people with primary HIV infection, and within 2 weeks of beginning antimicrobial treatment in people presenting with an AIDS-defining infection, or a severe bacterial infection and CD4 count below 200.

Otherwise, ART should be offered to all people newly diagnosed with HIV within 2-4 weeks of diagnosis. It can also be started immediately upon HIV diagnosis, if the patient wishes to, and there are no clinical contraindications.

Earlier initiation of ART results in reduced mortality, morbidity and HIV transmission outcomes. Increasing evidence from systematic reviews and cohort analyses also indicates that untreated HIV infection may be associated with the development of several non-AIDS-defining conditions, including:

• Cardiovascular.

• Kidney and liver disease

• Several types of cancer.

• Neurocognitive disorders.

Initiating ART earlier reduces such events and improves survival.

Co-existing viral hepatitis

The treatment of HIV in patients with co-existing viral hepatitis is complex. Recent guidance recommends that:¹⁸

• People with hepatitis B and HIV co-infection should be offered anti-HBV ART, specifically ART regimes that contain TDF or TAF as first-line.

• People with hepatitis C and HIV co-infection should be offered direct-acting antiviral (DAA) treatment alongside ART; however, many of these agents interact, and interactions should be carefully checked prior to initiating DAAs.

Drug treatment

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

• Preferred initial therapy is usually three drugs - see the BHIVA guidelines for details on options.¹⁷

Other measures¹⁹

People with HIV should be offered hepatitis B vaccination, annual influenza vaccination, pneumococcal vaccination, and other routine vaccinations.

Most live attenuated vaccines can still be used in people with HIV, as long as they have a CD4 count greater than 200. The BCG vaccine for tuberculosis and live attenuated typhoid vaccine should be avoided.

Chemoprophylaxis

Chemoprophylaxis is used to prevent infection in HIV-positive patients.

• 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), 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.²⁰

• Late disease (WHO stage 4 - equivalent to AIDS). Common recurring infections are pneumocystis, cryptococcus, toxoplasma and TB.

Antiretroviral therapy (ART)

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, reduce the chances of opportunistic infection developing, and prevent onward transmission. Combinations of three or more drugs are given to lessen the possibility of resistance.

See the separate Antiretroviral agents article for more details.

Prevention of HIV-related opportunistic infections

• TB - this is 30-50 times more likely to develop in HIV-positive patients than in those who do not have the virus. BHIVA recommends treatment for latent TB with six months of isoniazid plus pyridoxine; or three months of isoniazid plus rifampicin plus pyridoxine²¹ . Where isoniazid mono-resistant isolates are identified, a regimen of daily rifampicin, ethambutol, levofloxacin and pyrazinamide for six months is recommended.

• 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.²²

• 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.

• All people living with HIV should be offered an annual influenza vaccine.

• People living with HIV should also receive Covid vaccinations. At the time of writing, they were considered an 'at-risk' group eligible to receive Covid vaccine boosters in the UK.²³

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 HIV spread

• Achieving a sustained undetectable viral load on ART eliminates the risk of spreading HIV to sexual partners.⁵

  • Early diagnosis of HIV and provision of ART is therefore critical to reducing, and eventually eliminating, HIV transmission. This involves widespread testing to identify people living with undiagnosed HIV.

• Pre-exposure prophylaxis (PrEP) can be taken by HIV-negative people, and provides a high level of protection against HIV infection. It does not prevent against pregnancy or other sexually-transmitted infections, and should be used in combination with other preventative infections.¹⁸

  • PrEP usually involves a combination of two antiretroviral drugs; there is a risk of HIV viral resistance if used by someone with HIV infection. People taking PrEP should be offered regular HIV tests, with a switch to triple-drug ART as soon as possible if there are signs of primary HIV infection or a positive HIV test.¹⁸

  • Provision and use of PrEP is another key component of the strategy to eliminate HIV transmission.⁷

• Other methods for reducing HIV transmission include promoting 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.

• People who inject drugs should avoid sharing needles, and should use needle exchange schemes.

• Post-exposure prophylaxis after occupational and sexual exposure also helps to limit HIV spread. See the separate Needlestick injury article for more details.