Human immunodeficiency virus

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

Human immunodeficiency virus (HIV) is a lentivirus from the subfamily of retroviruses. It was first identified in 1983¹ .

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.

• It causes acquired immune deficiency syndrome (AIDS)-related disease in most parts of the world.

HIV II

• In 1985 HIV-II was identified in AIDS patients with West African connections and is uncommon outside that region¹ .

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

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 virus (viral load) predicts progression to late-stage HIV disease.

Epidemiology

After a peak of new HIV diagnoses in the UK in 2014, cases have fallen - from 6,278 in 2014 to 4,453 in 2018² . This decline was particularly marked among gay and bisexual men where diagnoses fell by 35% from 3,480 in 2014, to 2,250 in 2018. The steepest fall was observed among gay and bisexual men (GBM) who are white, born in the UK, aged 25 to 49 and residing in London.

The number of people diagnosed late decreased from 3,353 in 2009 to 1,883 in 2018 representing a 44% decline over the decade² . Nevertheless, the proportion of late diagnoses in 2018 remained high at 43%. There was substantial variation in sub-populations experiencing late HIV diagnosis rates. The highest rates were among black African men (65%), white men who acquired HIV heterosexually (59%), people aged over 50 years (59%) and people who inject drugs (58%).

Globally, at the end of 2018, 37.9 million people were living with HIV worldwide³ . The prevalence of HIV varies widely between regions - the African region is most severely affected with 25.7 million people (more than two thirds of all people living with HIV globally) infected. In 2018, 770,000 people died of HIV-related illness and 1.7 million people were newly infected. Between 2000 and 2018, new HIV infections fell by 37% and owing to more widespread use of ART, HIV-related deaths fell by 45%.

Stages of human immunodeficiency virus infection

Groups are those listed in the CDC 1993 classification system⁴ .

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.

• 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.

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 in adults

Diagnosis 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. Since the US Food and Drug Administration (FDA) approved the first HIV diagnostic test in 1985, four additional 'generations' of antibody tests for HIV have been developed; each improves incrementally on its predecessor(s) in terms of performance and shortening of the window period.

The official nomenclature for HIV testing is currently changing, with classification now based on analytic target instead of generation⁵ . For example, first- and second-generation assays are now referred to as 'IgG sensitive', since they are capable of detecting only IgG. Each category of tests may be further subclassified as point-of-care (POC) or laboratory-based.

Testing recommendations:

HIV testing is recommended for⁶ :

• 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.

• 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 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)⁷ .

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. 38% of infected infants can be detected within the first 48 hours after birth, rising to 96% at four weeks .

1993 Centers for Disease Control (CDC) classification of HIV infection in adults⁸

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 count⁸ .

Monitoring human immunodeficiency virus infection

Monitoring of HIV is usually carried out in specialist clinics using the CD4 lymphocyte cell (CD4) count and viral load⁹ .

• 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

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 now recommended for all patients who have been diagnosed as having HIV infection.

ART should be initiated in all adults living with HIV, regardless of WHO clinical stage and at any CD4 cell count (strong recommendation, moderate-quality evidence)¹⁰ . As a priority, ART should be initiated in all adults with severe or advanced HIV clinical disease (WHO clinical stage 3 or 4) and adults with CD4 count ≤350 cells/mm3 (strong recommendation, moderate-quality evidence).

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 and neurocognitive disorders and that 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 extremely complex. Recent guidance recommends that¹¹ :

• 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

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

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.

• 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 strategies¹² .

• 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 and reduce the chances of opportunistic infection developing. 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 pyridoxine¹³ . 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 months¹⁴ .

• 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

• 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 the 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 ongoing¹⁵ .