Introduction

Human immunodeficiency virus (HIV) was first identified in 1983. Left untreated, it causes acquired immunodeficiency syndrome (AIDS). In the developed world its spread is relatively limited, and modern treatment means that life expectancy is almost that of non-sufferers. But in the developing world, in Africa and Asia in particular, it is still a growing and widespread problem.
The HIV virus binds to CD4 receptors, which exist on T-cells, monocytes, macrophages and neural cells. Soon after infection, the HIV virus replicates rapidly, but by about 6-8 weeks, the host immune system responds, and thereafter there exists an equilibrium between viral replication and immune response. AIDS develops when the function of the immune system is impaired to such an extent that it can no longer perform its normal functions in fighting off other infections, and is classically defined as a CD4 T-cell count of <200 x 106 / L, although in the UK and Australia, this strict definition is not always used in the presence of AIDS defining infections.
Antiretroviral therapy (ART) has revolutionised treatment and prevents most patients with HIV from progressing to AIDS. As such, some now consider that managing HIV is like managing any other chronic disease. Patients should start ART as soon as possible after diagnosis.
Some countries and facilities now refer to AIDS as “late-stage HIV”. The viral load (number of circulating viruses) can predict the progression to AIDS.
Most patients with HIV require life-long daily antiretroviral drugs to keep the infection under control.

Epidemiology

  • 40 million cases worldwide
  • Incidence – 5m/year
  • Deaths – 3m/year
  • Prevalence of AIDS>3million
    • Most of these cases are in women and children in Africa
  • Types of virus
    • HIV-1 – the most prevalent type in Europe
    • HIV-2 causes a similar disease, but has a longer latency period. Uncommon outside of Africa.
  • UK incidence – 6000/year in 2013, down from 7500 per year in 2005.
    • 75% of cases are in men who have sex with men (MSM)
  • More common in heterosexual individuals than homosexual individuals since 1999.

Transmission

Sexual

75% sexual intercourse
5-7% oral sex
Evidence suggests that circumcision reduces the risk of infection by 60% – however there is some public belief that it provides immunity – it does not!
Risks (per sexual encounter):

  • Anal sex – receiving partner – between 0.1 – 3%
  • Anal sex – active partner – <0.1%
  • Vaginal sex – female – 1 in 100,000
  • Vaginal sex – male – 1 in 200,000
  • Oral sex – less than 1 in 200,000
  • Child birth – 15%
  • Child birth + breast feeding – 25%

Blood products
IV drug use

Needlestick Injury

Vertical transmission

Pathology

HIV is a single stranded RNA retrovirus. The virus is incorporated into a host cell, whereby, the viral enzyme transcriptase will begin transcription of the RNA to DNA. Then, the viral enzyme integrase will integrate the DNA into the host’s.

  • The host cell will then produce viral polypeptides, which are cleaved into functional viral parts by the viral enzyme protease.
  • Finally, complete virions are released by the host cell via budding

Infection of cells – These new virions can now infect new cells. They are capable of entering any cell that expresses the CD4 receptor. The virus will bind to CD4 receptors with the gp120 glycoprotein. Susceptible cells include:

  • CD4+ T cells
  • Macrophages
  • Monocytes
  • Neurons

CD4+ T cells will migrate to lymphoid tissue, and release millions of virons, ready to infect new cells.
As the infection progresses, destruction of CD4+ cells leads to reduced efficacy of the host immune system.  

Clinical features

HIV infection can be divided into stages:

Seroconversion – typically occurs 2-6 weeks after exposure. Is often asymptomatic, but in about 50% of cases there may be a period of fever, malaise, myalgia, pharygnitis and maculopapular rash.

  • This infection often resembles glandular fever (infectious mononucleosis)
  • Consider HIV in any patient with fever, malaise an widespread lymphadenopathy

Asymptomatic infection – typically, after the initial phase, patients enter a long asymptomatic period. This can last for years – typically around 5 years or more.

  • 30% of patients will have a persistent generalized lymphadenopathy (PGL) – where there are lymph nodes 1cm in diameter at >2 extra-inguinal sites. This may last >3 months.

AIDS related complex (ARC) – aka – symptomatic infectionthis is a set of prodromal symptoms that precedes the onset of AIDS. It can include:

  • Opportunistic infection (e.g. candidal infection, herpes etc)
  • Night sweats
  • High temp
  • Diarrhoea

AIDS

  • There is marked immunodeficiency
  • In the US –  defined as a CD4 count <200 x 106 / L. In Australia and the UK typically defined more a clinical syndrome. The list of “AIDS defining infections” is long, but in the presence of known HIV, the occurrence of these infections can be said to confirm AIDS. The list includes things such as:
    • Candidiasis of respiratory tract or oesophagus
    • Chronic HSV
    • Disseminated TB
    • Toxoplasmosis of the brain
    • Recurrent Salmonella
    • Pneomocystis jiroveci pneumonia
    • Lymphoma of the brain
    • Invasive cervical cancer
  • It takes on average about 10 years to develop, but can be seen as early as 2 years or as late as 20 years later

Diagnosis

HIV antibody testing is typically a 2-step process. The antigen-antibody (ELISA) test is used a screening test, and if positive, diagnosis is confirmed by a secondary test (e.g. Western Blot test).

  • Antigen-antibody (ELISA) test becomes positive 2-6 weeks after infection
  • Current guidelines recommend a repeat test after 3 months if the initial test is negative to confirm the negative result
  • The Western blot test is used to confirm the diagnosis. It detects HIV antibodies.
    • Combined positive ELISA and Western blot is 99.9% accurate

Other tests associated with HIV:

  • P24 antigen – present in the blood in the first 3 months of infection. Usually levels drop by the time IgG and IgM are produced (3 months). Levels rise again as immunodeficiency develops. Due to its variability it is not often useful in diagnosis
  • CD4 T lymphocyte count – Used to measure immune function. A normal result is >500. A result of <200 is used by some centres as a definition of AIDS.
  • HIV RNA (viral load) – can also be detected using PCR techniques during the early stages of the infection
    • Used to monitor progress and effectiveness of treatment (See below)
  • IgG and IgM – levels detectable after 3 months. Fall as immunodeficiency develops (try looking for P24).
  • HIV point of care testing – OraQuick(R) – is a method of detecting HIV antibodies in saliva. Fast and easy – results in 10-20 minutes, but high false positive rate 

HIV and TBoften co-exist, and can be a real problem.

  • 30-50% of those with AIDS also have TB
  • Mantoux test can be negative even in positive patients
  • TB presentation is often atypical
  • AFB (Acid-fast bacilli) Smear – may be negative, or have very few cells. Important to culture for sensitivities.
  • All HIV positive patients should be regularly monitored for TB. Some recommend the use of isoniazid as prophylaxis in HIV positive patients.
Once diagnosis is confirmed, patients should also be tested for:
  • Hepatitis B
  • Hepatitis C
  • HIV type and resistance assay
  • Consider testing for:
    • TB
    • Toxoplasmosis
    • CMV
    • Syphilis
    • Full STI screen

Monitoring

The following should be measured every 3 months:

HIV RNA levels (viral load)strongly predicts the progression to AIDS, regardless of the CD4 count!

  • Patients can be ‘staged’ according to HIV RNA levels, e.g.:
  • Those in the lowest quartile have an 8% chance of progressing to AIDS in 5 years, compared to 62% of those in the highest quartile.

CD4 count

  • In the developing world, this test may be too expsenive. A total lymphocytes count may be adequate
  • Total lymphocytes = 1400, then CD4 roughly =200
  • This is accurate enough for predicting HIV progression

Management

Sensitive and sympathetic discussion is typically appropriate in the first consultation(s) after diagnosis. In asymptomatic patients in particular, try to avoid technical discussions about treatment regimens.

  • Provide printed fact sheets
  • Discuss issues around HIV transmission and contact tracing
  • Consider referral to psychology

ART – antiretroviral therapy (formerly known as HAART – highly active anti-retroviral therapy) is the mainstay of medical treatment.

  • In the developed world, this is the mainstay of treatment. There is not one specific recommended regimen – essentially all regimens are experimental combinations of anti-retroviral drugs
  • ART aims to reduce the rate of viral replication below detectable levels. This does not mean that replication is not occurring!
  • ART should be part of a holistic care approach.
  • It is a combination of two Nuceloside analogue reverse transcriptase inhibitors (NRTI’s), PLUS
    • Either; a Protease Inhibitor (PI),
    • Or; a non-nucleoside reverse transcriptase inhibitor (NNRTI)

 

Principles of therapy

Typically 3+ drugs are used in combination
Start treatment as early as possible – i.e. before CD4 count <200, ideally as soon as diagnosis is confirmed.

  • Advise the patient that regimens are complex, and require strict adherence
  • Monitor Viral load and CD4 count regularly.
  • Ideally, viral load will be undetectable after 4 months of HAART
  • If viral load is apparently erratic, consider poor adherence
  • If viral load remains high despite treatment, change the regimen

Exact treatment regimens vary locally. Involve a specialist (sexual health physician) as soon as the diagnosis is made. Below is an overview of some of the classes of medications used.

NRTI’s – e.g. Zidovudine, Didanosine, Lamivudine, Emtricitabine, Tenofovir, Abacavir

  • Side effect are not particularly pleasant, and include:
  • Anaemia, leucopaenia, GI disturbance, rashes, myalgia, neuropathies, pancreatitis.
  • CI’s: LFT disturbance, Hepatomegaly, lactic acidosis, breast feeding, anaemia. Monitor for liver problems and amylase.

Protease Inhibitors – e.g. Indinavir, Ritonavir, Saquinavir, Lopinavir

  • Slow the viral spread, prolong the asymptomatic stage of the disease
  • Metabolized y cytochrome P450 system – so can cause drug interactions
  • Can cause metabolic syndrome (insulin resistance, hyperglycaemia, dyslipidaemia)
  • Side effects: Taste disturbance, rash, pruritus (itch), hyperpigmentation, alopecia, parasthesia, myalgia, headache, dizziness, pancreatitis, anaemia, abnormal LFTs.

NNRTI’s e.g. Nevirapine, Efavirenz

  • Again, involved with cytochrome P450
  • Resistance occurs quickly
  • Side effects
  • Hepatitis, dizziness, avoid in pregnancy.

Prevention

PEP – post-exposure prophylaxis – anti HIV drugs can be taken as prophylaxis, if taken within 72 hours of exposure to HIV. This exposure could be in the form of sexual contact (including oral, vaginal, anal), or blood products contact.
Needlestick injuries
  • Risk of HIV infection is <0.5%
    • Tests for HIV antibodies should be done at 3,6 and 8 months to check for seroconversion
  •  Risk of Hep B infection is about 30%
  • Make it bleed!
    • But do not suck, or put in bleech
  • Get the details of the ‘donor’
  • Report to occupational health ASAP
  • Store blood samples from both parties (onset required for the ‘donor’ blood)
  • Check risk
    • Related to the donor CD4 level and viral load
  • Consider prophylaxis
    • Low risk – may not be needed
    • High risk – zidovudine – 250mg / 12h + lamivudine 150mg / 12h + indinavir 800mg / 8hr, all PO
    • Do a pregnancy test before starting on prophylaxis!
    • There have been about 100 cases worldwide, and 5 in the UK, of a healthcare working contracting HIV from a patient – it is rare
Prevention of vertical transmission

15% risk of vertical transmission (higher in Africa)
Methods of prevention of vertical transmission:
All HIV positive mothers should 

  • Take anti-retrovirals – nevirapine is recommended. If on another agent before pregnancy, switch to this once pregnant
  • Consider Caesarian
  • Usually elective caesarean at 38 weeks
  • Vaginal delivery is a RF – if twins, the first twin is at greater risk of vertical transmission
  • Abstain from breast feeding
  • If all the above measures are adhered to, risk of transmission is about 2%.
  • Have tests for genital infection at booking and at 28 weeks

Counseling for HIV testing

It is very important to remember that before you perform an HIV test you need to tell the patient about the implications of a positive result. You should:
Determine the level of risk (e.g. unprotected sex, number of partners, sex overseas)
Discuss the benefits of knowing if test is positive:

  • Protect partner
  • Reduce risk of vertical transmission
  • Get treatment

Ask about major concerns e.g.:

  • Telling partner / friends
  • Job
  • Mortgage (if can’t work)
  • Confidentiality
  • You don’t have an obligation to inform the partner as this would break confidentiality. Encourage patient to discuss these issues with partner – offer them to invite partner along to surgery if this would help.
  • However – if the patient refuses to tell their partner, you should consult GUM specialists / MDU / MPS to discuss the cases. In some instances it may be acceptable to break confidentiality to inform those at risk.

Post-term counseling

  • Again discuss effects on family, job, telling partner / friends
  • Emphasize methods to reduce exposure.
  • Long-term counseling – may involve making plans for death, e.g.
    • Making a will
    • Housing
    • Employment
    • Care of children
    • Involvement of GP, palliative care services, and HIV experts

References

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