The Human Immunodeficiency Virus (HIV) is a retrovirus that infects cells of the human immune system. The eventual destruction of these cells leads to immune system failure and can cause Acquired Immune Deficiency Syndrome (AIDS). AIDS is defined as HIV infection alongside an AIDS defining illness.
Two types of the HIV virus exist; HIV-1 and HIV-2. HIV-2 is a notably rarer form and primarily found in west Africa, and so the rest of these notes focus on HIV-1
HIV is a single stranded RNA retrovirus. After entering the blood, it binds to T cells (and other tissues) in the body via the CD4 receptors, using the gp120 molecule on the HIV. Through binding with a coreceptor on the T cell (CCR5 or less commonly CXCR4), it is then able to enter the cell. Once inside the cell reverse transcriptase converts the HIV RNA into proviral DNA. This inserts itself into the DNA of the host cell through an integrase enzyme, allowing replication of the HIV RNA and proteins when the cell’s DNA is read. These proteins then assemble in the cell. This process is especially ‘faulty’ resulting in variations of the HIV as it happens - producing resistance to the immune response of the host and treatment.
With transmission via the mucosal route, the HIV is initially taken up by dendritic cells. These these move to the local lymph nodes, as they would normally. This allows transmission of the HIV to the lymph nodes either attached to the cell, intact within the cell, or having actually infected the cell. In the lymph nodes, the virus is then brought directly into the environment where it can infect its desired target cells - the CD4 T cells. The CD4 molecule is present on helper T cells, dendritic cells and macrophages, which are all therefore vulnerable to the effects of the virus.
The impact of the disease occurs due to loss of the CD4+ lymphocytes. This may be due to cell destruction during virus reproduction, or as part of the host’s immune response against the virus (and thus the CD4+ cells). There also appears to be a significant number (perhaps the majority) of CD4+ cells which are caught in the crossfire of the inflammatory response in infected cells and are destroyed even without being infected themselves. CD4+ cells are a key component of cell-mediated immunity. Once their numbers drop, cell mediated immunity is notably impaired and opportunistic infections and malignancy proliferate. The normal CD4+ count is around 750/microL, with a threshold of < 200/microL being key for infections.
This can occurs through several mechanisms where there is transmission of bodily fluids.
Blood to blood
Sexual transmission is the most common method. The highest risk is that which causes mucosal trauma i.e. intercourse. Anal receptive intercourse poses the highest risk. Oral sex is lower risk, but not zero, and may be increased by open sores.
Blood to blood may be from needle sharing as part of IV drug use. Needlestick injuries may be another concerning route for clinicians but is relatively rare. The risk of needle transmission appears to be about 1 in 300 without post exposure prophylaxis. Risk factors include hollow needles and puncture of vessels. Transmission via blood transfusion is now incredibly low due to screening programmes.
Maternal to foetal infection can occur through several mechanisms:
In breast milk
Transmission can be notably reduced by maternal treatment and careful management of the perinatal and postnatal period.
The period of highest risk of someone transmitting the disease is probably during the initial infection stage where there is a significant peak in the viral load.
HIV infection has a typical clinical progression. These can generally be divided into 4 stages:
Persistent generalised lymphadenopathy
Symptomatic HIV infection
Acute seroconversion This occurs in the first 1-4 weeks after infection. There is rapid spread of the virus within the cells of the immune system. This causes an initial rise in viral load and a reduction in T cells. This phase is characterised by general systemic features of a flu-like or glandular fever-like picture. This may include:
It will usually last for a few days, up to 2 weeks.
Asymptomatic Infection At this stage the immune system response to the virus gain control against the proliferation of the virus. The viral load reduces and there is some recovery of T-cell numbers. This latent period can then last for several years, with a highly variable time frame (2-15 years) Whilst infections ar not characteristic of this stage as with later stages, some chronic diseases (particularly tuberculosis) may progress. The persistence of the infection is due to the virus’s ability to ‘hide’ within certain cells in the body that make it difficult for the immune response to have an effect. There may be significant weight loss during this stage.
Persistent Generalised Lymphadenopathy This is defined as lymph nodes of greater than 1cm in size at two extrainguinal sites persisting for more than three months without an alternative cause.
Symptomatic HIV infection At this stage, T-cell numbers have continued to fall steadily. The ability of the immune system to function begins to fail. This stage of HIV infection is characterised by the development of infections and neoplastic disease. AIDS is the presence of and AIDS defining illness in a patient with HIV infection, and occurs at this stage of the illness. However, there may be an increased susceptibility to infections that occurs, which are not AIDS defining in nature.
AIDS defining illnesses include:
Pneumocystis jiroveci pneumonitis (PJP)
Mycoplasma avium complex
Recurrent bacterial infections
Cervical and anal neoplasm
Other infections that may occur which are not AIDS defining:
Persistent or repeated candidiasis (oral or vaginal)
Herpes zoster infections
There can also be other effects on the body from HIV infection, other that that related to immune suppression. Some of this may relate to the direct effects of the virus on the cells of the body, or other pathological processes not fully understood (perhaps related to the immunosuppression).
Increase cardiovascular risk is well recognised in these patients
Atherosclerotic processes appear to be expedited (HIV or treatment related)
Other features may include pericarditis, cardiomyopathy
HIV associated nephropathy
Increased impact of the viral hepatitides
Vitamin D deficiency
The revised CDC AIDS surveillance case definition is the most widespread staging categorisation. A - Initial seroconversion, asymptomatic infection, or lymphadenopathy B - Symptomatic disease other than AIDS defining conditions C- AIDS defining conditions
There is also a staging (1-3) based on the CD4 count (see below). The condition of AIDS is identified by patients with either a class C clinical condition or a class 3 CD4 count.
Diagnosis of HIV is done in two main ways:
Nucleic acid amplification
Detection of antibodies to HIV is a sensitive and specific test for the disease. Antibodies will be detectable except during the first few weeks after infection.
Testing for the p24 antigen can also be performed. These tests are initially done using ELISA (enzyme linked immunosorbent assays), but a repeat with Western Blot technique may be done (when suspicion of false positive).
Nucleic acid amplification can be used in cases of clinical suspicion but with negative initial testing e.g. early after infection. Combined testing may be performed.
Other investigations may be useful in this condition:
FBC - assessment for cytopenias. CD4 count
Important laboratory information about HIV includes:
The CD4 count is calculated by analysing the percentage of WBCs that are CD4 lymphocytes. Staging of the levels and therefore the disease (CDC AIDS surveillance case definition) can be useful:
The viral load denotes the replication rate of the HIV. After initial infection, this will often settle at a ‘set point’ that is stable in that patient. In general, the higher this set point the more rapid the CD4 count drop. With effective treatment this can drop to undetectable levels.
Antiretroviral drugs are given as combinations of 3 or 3 different agents. This is because of the high mutation rate discussed above, which would give the chance to select out resistant strains of the virus if just one drug class was given.
Fusion inhibitors These prevent the binding of the HIV virus gp120 and gp41 molecules with the CD4 molecule on the T cells.
CCR5 antagonists As the CCR5 molecule is an important cofactor for HIV binding and fusion, antagonism of it is another way to prevent entry into the T cell.
NRTI E.g. abacavir, lamivudine, tenofovir. This blocks the enzymatic step needed for the virus to convert the viral RNA into proviral DNA. They work by imitating a DNA nucleoside, but halting the attachment of further molecules, thus preventing translation. They should be used with caution in patients with hepatic dysfunction (including coexisting hepatitis infection). Side effects include GI disturbance, cytopenias, and an increased risk of CVS disease.
NNRTIs E.g. efavirenz, etravirine. These also target the step of reverse transcription, but act by blocking the reverse transcriptase enzyme itself. Side effects include rashes (including Stevens Johnson syndrome), and severe hepatitis.
Integrase inhibitors These block the action of the integrase enzyme that inserts the proviral DNA into the T cell DNA chain. This is an important mechanism of action, as insertion of this DNA is a factor in triggering cell apoptosis and therefore causing loss of T cells.
Protease Inhibitor These act on the protease that break up the manufactured polypeptides that have been produced by the hijacking of the cell protein synthesis mechanisms. If this step is blocked, these polypeptides can’t be assembled into new viruses.
HAART This stands for highly active antiretroviral therapy. This references the fact that now multiple drugs are given together to minimise the risk of resistance developing, and so the drugs remain highly active (unlike previously when resistance could fairly rapidly develop to a single agent). This is now the standard treatment approach.
Treatment is now generally started/advised in all patients with HIV infections, regardless of the stage. Previous guidance weighed up the drawbacks of treatment in patients with early asymptomatic disease, but it appears that even this early stage can result in a worse outcome e.g. non AIDS related illnesses. They should also be started in cases of AIDS defining illness or severe bacterial infection when the CD4 count is below 200/microL, even before diagnosis.
In many cases, this is available as a single pill, aiding compliance. Side effects have also markedly improved with newer therapies.
It is important to note that these drugs have multiple interactions, which can make the management of these patients challenging when acutely unwell. This is a very useful resource from the University of Liverpool: https://www.hiv-druginteractions.org/checker The British HIV association have also produced helpful guidelines (and a useful app.) https://www.bhiva.org/
There has been a significant improvement in disease outcome when it is effectively treated (much of this now relating to healthcare provision). Patients with HIV can now be considered to have an essentially normal life expectancy. Indeed, there may be a health benefit derived from the regular medical care that accompanies ART, which has manifested as an improved life expectancy in some data.
The infective complications are now much reduced, and it is primarily the malignancy complications that are seen in patients with HIV. Otherwise, healthcare interactions are related to unrelated pathology, or complications of treatment (now also much reduced). However, this is all very much dependent on patients receiving the optimum medical care. This requires an appropriately early presentation/detection of the condition, continued engagement with healthcare, and an appropriate response to treatment (this being at least partly impacted by the previous points and additional individual patient/viral factors).
Without treatment, life expectancy is described as 10 years. There is some variation in host response (of a genetic and viral basis) that impacts on this, with some patients being highly resistant to progression, and others very sensitive.
NICE recommend screening of high risk patient groups. This includes groups in areas with an incidence of 2 per 1,000 or higher (common in many major city areas). More details are available here: https://www.nice.org.uk/guidance/ng60
Consent & Ethics
This has been raised as a concern regarding the investigation and management of HIV, especially in the critically ill population. This is because there remains a significant stigma attached to the disease, despite the massive improvements in care. Regarding testing, it is advised that it be treated the same as any other investigation. That is, appropriate consent is obtained, and strict medical confidentiality adhered to. Similarly, in emergency conditions (and unable to provide consent) appropriate investigation may proceed as with other investigations. Divulging a diagnosis is more complicated in this setting, and this should conform strongly with confidentiality guidance. The patient should be allowed to receive the diagnosis and decide on subsequent divulgange. Specialist GUM or ID guidance can be useful here.