Human Immunodeficiency Virus (HIV)

geekymedics.com/human-immunodeficiency-virus-hiv/

Adrian McGrath

Introduction
The human immunodeficiency virus (HIV) is a species of Lentivirus, a subgroup of the
retrovirus family, that preferentially infects CD4+ T helper lymphocytes, resulting
in the progressive destruction of the immune system and the onset of acquired
immunodeficiency syndrome (AIDS).

Despite the decline in HIV diagnoses seen in the UK during the past several years, HIV
and AIDS remain a huge economic and health burden worldwide.1

This article has been written to provide medical students with the information needed
to achieve the goals set out by the National Institute for Health and Care Excellence
(NICE): identify those at risk of HIV, recognise HIV-related health issues and facilitate
prompt testing and management of patients with HIV.2

Epidemiology
There are two main types of HIV, known as HIV-1 and HIV-2. HIV-1 is the
predominant type found in the UK, whereas HIV-2 is mainly found in West Africa. For
this article, references to HIV will focus on HIV-1 unless specified otherwise.

In recent years, there has been a global decline in new HIV diagnoses of 37% and a
decline in HIV-related deaths of 45%. This change has also been seen in the UK, with
the annual incidence falling from 6,185 in 2014 to 4,363 in 2018.3

Furthermore, the UK has successfully reached the target of diagnosing 90% of HIV
positive people, providing antiretroviral therapy for 90% of those diagnosed, and
achieving viral suppression in 90% of those on treatment. This global ‘90-90-90‘ target
was set by the Joint United Nations Programme on HIV and AIDS (UNAIDS) in 2014.1

The demographic groups most affected by the virus vary. However, in the UK, HIV is
most prevalent among men who have sex with men (MSM) and black-African
2 1/14
heterosexual men and women.2

Aetiology
The life cycle of HIV, its progression to AIDS and the mechanisms by which it causes
disease are well-characterised and a good knowledge of this is useful to understand its
clinical presentation and treatment.

Pathophysiology
The HIV life cycle provides several different targets for pharmaceutical intervention, as
described below and in figure 1.4

1. Binding: viral protein gp120 on the surface of HIV binds host glycoprotein CD4+
and host co-receptor CCR5 or CXCR4. This is blocked by CCR5 antagonists.
2. Fusion: viral protein gp41 penetrates the cell membrane, allowing the fusion of
the virus and cell. This is blocked by cell fusion inhibitors.
3. Reverse transcription: viral reverse transcriptase converts HIV single-
stranded RNA to double-stranded DNA. This is blocked by non-nucleoside reverse
transcriptase inhibitors (NNRTIs) and nucleoside reverse transcriptase inhibitors
(NRTIs).
4. Integration: viral integrase enzymes allows HIV DNA to insert into the host
DNA. This is blocked by integrase inhibitors.
5. Replication: host machinery transcribes and translates new HIV RNA and
polyproteins.
6. Assembly: the new HIV proteins and HIV RNA move to the cell membrane and
assemble the immature, non-infectious virion.
7. Budding: the new HIV virion exits the cell and viral protease cleaves the long
HIV protein chains to form the mature, infectious virion. This is blocked by
protease inhibitors.

2/14
 Figure 1. Illustration depicting the HIV
replication cycle.4

Natural history

Stage 1: Primary HIV infection (seroconversion)

HIV binds to a CD4+ receptor found on the surface of T helper lymphocytes,

monocytes, macrophages and dendritic cells (collectively named CD4+ cells).2

Within one day of its life cycle, the infected CD4+ cell dies and releases large numbers
of new virions which disseminate through the blood to infect more CD4+ cells,
primarily in lymphoid tissue. This period develops within 2-4 weeks after exposure,
during which time there is a high level of viral replication, making the individual highly
infectious.5

The immune response to primary HIV infection (PHI) can cause mild-to-moderate non-
specific symptoms, which is called seroconversion illness. These symptoms are often
described as being similar to flu or infectious mononucleosis and commonly includes
muscle ache, headache and fatigue.5

Stage 2: Chronic HIV infection (asymptomatic infection/clinical latency)

During the second stage, which is also named asymptomatic HIV infection or
clinical latency, the immune response controls the virus, limiting the symptoms despite
a persistent low level of viral replication.

Though the individual is not displaying symptoms, they are infectious. Although the
timeline may vary between individuals, this asymptomatic stage can continue for 10-15
years, with symptoms only presenting when the host’s ability to replenish CD4+ cells
5 3/14
wanes. 5

Stage 3: Acquired immunodeficiency syndrome (AIDS)

When the persistent HIV infection compromises the ability of the immune system to
replenish CD4+ cells, the CD4+ cell count drops below 200 cells/µL, which is
sufficient for a diagnosis of AIDS.2

At this advanced stage, the ability of the immune system to combat infection is severely
compromised and the infected individual will become susceptible to opportunistic
infection and malignancy. Such AIDS-defining illnesses and AIDS-related
complications can be found below.

If left untreated, AIDS will cause death within around 20 months. 5

Transmission
As with all infectious disease, understanding the mechanisms of transmission is crucial
to breaking the chain and curtailing the spread of HIV.

HIV spreads from HIV-positive individuals through infected bodily fluids, most
commonly through anal or vaginal intercourse. An estimated 75% of cases worldwide
are transmitted through sexual activity (vaginal, anal and oral), which highlights the
importance of promoting safe sexual practice in preventing the spread of HIV.2

Other mechanisms include vertical transmission (from an infected mother to child

during pregnancy, childbirth or breastfeeding), and inoculation (via contaminated
needles, blood/blood products and occupational exposure).2

It should be noted that HIV cannot be spread through social interactions such as
shaking hands and kissing, nor can it be spread by a vector (such as insects). In
addition, oral transmission is rare and typically associated with concurrent oral
pathology.2

Risk factors
A thorough clinical history should be taken of the patient’s presenting symptoms
alongside their risk factors for HIV infection.

Demographic groups that are considered high risk for HIV infection include: 2

Men who have sex with men (MSM)

Female sexual contacts of MSM
Those originating from areas with a high prevalence of HIV
Those in current or former serodiscordant relationships (in which a HIV-negative
individual is partnered with a HIV-positive individual)

4/14
Lifestyle and social risk factors include:

Intravenous drug use

Occupational exposure (such as accidental needlestick injury)
Sexual risk factors such as unprotected anal or vaginal sex with one or multiple
partners, and having another sexually transmitted infection such as hepatitis B or
hepatitis C.2

Furthermore, a thorough medical history should also be taken to identify the possibility
that the patient may have received an unsafe blood transfusion or transplant.

Clinical features
This section provides information on what should be considered when suspecting HIV
infection, including what information should be gathered from the clinical history and
what signs and symptoms may present in the context of both primary and long-
standing HIV infection.

Clinical features of primary HIV infection (seroconversion)

Seroconversion illness develops in over 60% of patients in the primary stage of HIV
infection.

As the common symptoms are non-specific, UK national guidelines for HIV testing
recommend HIV testing should be administered to patients presenting with glandular
fever-like symptoms, fever of unknown origin, lymphadenopathy and unexplained
weight loss, unexplained neutropenia, anaemia and thrombocytopenia.3

Typical symptoms of primary HIV infection (seroconversion) include:

Fever (80%)
Malaise (68%)
Arthralgia (54%)
Loss of appetite (54%)
Maculopapular rash (51%)
Myalgia (49%)
Pharyngitis (44%)
Oral ulcer (37%)
Weight loss >2.5kg (32%)

Clinical features of longstanding HIV infection

HIV should be considered in patients who have experienced one or more of the
following symptoms in the past 3 years, or if a single symptom is severe or resistant to
treatment.

5/14
Table 1. An overview of the clinical features of longstanding HIV infection.

System Symptom/ sign

Constitutional Fever/sweats

Weight loss

Lymphadenopathy (especially if >3 months, occurring in 2 or

more extra-inguinal sites)

Haematology Unexplained neutropenia

Unexplained anaemia

Unexplained thrombocytopenia

Respiratory Cough

Breathlessness

Infection with pneumocystis jirovecii, tuberculosis, bacterial

pneumonia

Neurological Confusion

Personality change

Seizures

Focal neurological symptoms

Oral Conditions Candidiasis (figure 2)

Aphthous ulcers

Hairy leukoplakia (figure 3)

Gingivitis

Dental abscess

Gastrointestinal Oesophageal candidiasis

Diarrhoea

Dermatological Dark purple/brown skin lesions (Kaposi’s sarcoma) (figure 4)

Fungal skin and nail infection

Pityriasis versicolor

Shingles

Warts
6/14
 Genito-urinary Candidiasis

Herpes simplex

Warts

Malignancy Dark purple/brown intradermal skin lesions

Clinical features of AIDS

AIDS can be defined as the development of one or more AIDS-defining illnesses in
the presence of HIV infection or by a CD4+ count <200 cells/µL. 2

A non-exhaustive list of AIDS-defining illnesses include:

Pneumocystis pneumonia (pneumocystis jirovecii)

Kaposi’s sarcoma
Cryptococcal meningitis
Cerebral toxoplasmosis
Cerebral lymphoma
Cytomegalovirus retinitis
Non-Hodgkin’s lymphoma
Oesophageal candidiasis
Tuberculosis
Primary central nervous system lymphoma

Figure 2. Oral
candidiasis in a
HIV-positive
patient. 6

7/14
 Figure 3. Oral
hairy
leukoplakia
(OHL) caused
by secondary
Epstein-Barr
virus infection
in a HIV-
positive
patient. 7

Figure 4.
Kaposi’s
sarcoma
affecting the
medial side of a
HIV-positive
patient’s right
heel.8

Investigations
NICE recommends testing patients who belong to at-risk groups, those presenting with
another sexually transmitted infection, new patients at a GP practice in an area of high
prevalence, as part of routine antenatal care, and for those who request it.

Clinical judgement and patient discussion should dictate when and where HIV testing
is performed. Those suffering from symptoms indicative of a serious HIV-related
condition should be admitted for urgent specialist assessment, with HIV testing
being a priority.

In other cases, testing may be done in primary care, sexual health clinics, or appropriate
HIV charities, depending on appropriate need and patient preference. Generally, results
are available within 72 hours in primary care, on the same day in genitourinary
medicine clinics, and under one-hour in specialist charities.2

There are two main methods for HIV testing:

Laboratory-based tests on patient venipuncture samples (largely 4 th generation

tests)
rd 8/14
 Point of care tests (largely 3 rd generation tests).

The most used assay is the 4th generation HIV test, which detects the presence of
HIV IgM and IgG antibodies as well as the viral p24 antigen. A positive result
necessitates a second sample for confirmation and a negative test result 4 weeks after
exposure may be reassuring, but still requires a repeat test at 12 weeks post-exposure to
definitively exclude HIV infection.

The 3rd generation test is employed in point of care tests and self-testing, in which
samples are taken from a finger prick or mouth swab. These tests detect HIV IgM and
IgG antibodies with increased sensitivity during early seroconversion and results can be
ready in under an hour.

This test is more likely to have false positives, so a positive result should be confirmed
with laboratory tests (quantitative PCR to measure viral load). A negative result
should be considered in the context of a 90-day window period; for exposures within
this period, a second test is required to exclude HIV infection.2

Pre-test and post-test counselling

According to UK HIV testing guidelines, lengthy pre-test counselling is not required
unless requested. However, the patient should always be made aware of what is being
tested, the benefits of testing and details of how the results will be given and their
implication.3

Pre-test counselling should aim to determine the level of risk (travel history, sexual
history, intravenous drug use etc.) and explore the benefits and difficulties of the test.
Benefits of the test will include anxiety reduction and the ability to begin future
planning, including how to avoid transmitting to others.

Difficulties may include dealing with a positive diagnosis, the potential effect on
employment and difficulties associated with disclosure and social stigma. 3

Post-test counselling should preferably be face-to-face, especially if the patient has

mental health issues, is at risk of suicide and is younger than 16 years of age.
Counselling should aim to review the test result and promote risk-minimising
behaviours.

Patients should always be informed if their test is negative, and they should be made
aware of the detection window period and the potential need for repeated testing. For
positive test results, patients should be reassured that effective treatment can prevent
illness and further transmission. 3

Management

9/14
There is currently no cure for HIV, and management focusses on early initiation of
antiretroviral therapy (ART) which aims to suppress viral replication to the point
where it is undetectable and cannot be transmitted.

In addition, opportunistic infections should be treated appropriately and acute

symptoms of AIDS (as previously discussed) necessitate hospital admission.

Antiretroviral therapy
HIV is highly mutagenic and can quickly develop drug resistance, so ART is
comprised of a minimum of 3 different drugs to target different parts of the HIV life
cycle.

The regimen of choice contains a backbone of two nucleoside reverse

transcriptase inhibitors (classically tenofovir disoproxil and emtricitabine)
combined with either an integrase inhibitor, a non-nucleoside reverse
transcriptase inhibitor or a boosted protease inhibitor.9

Table 2. An overview of antiretroviral therapy for HIV.

Drug Class Drug Name

Nucleoside reverse transcriptase inhibitor Emtricitabine

Tenofovir disoproxil
fumarate

Abacavir

Lamivudine

Non-nucleoside reverse transcriptase Efavirenz

inhibitor
Nevirapine

Rilpivirine

Protease inhibitor Atazanavir

Darunavir

Ritonavir

Integrase inhibitor Dolutegravir

Elvitegravir

Raltegravir

CCR5 antagonist Maraviroc

Fusion inhibitor Enfuvirtide

10/14
If a patient continues to deteriorate (clinically or as represented by a raised viral load or
decreased CD4+ count), their regimen may be changed according to previous response
to treatment, tolerability, and drug interactions.

Adverse effects of antiretroviral therapy can be serious or life-threatening, but

medication should not be stopped without specialist advice.

Potential adverse effects include hypersensitivity, mood/behaviour/sleep changes,

hyperlipidaemia, lipodystrophy, renal impairment, hepatic toxicity, peripheral
neuropathy, bone marrow suppression and pancreatitis.

Pre-exposure prophylaxis
Adults at high risk of HIV may benefit from pre-exposure prophylaxis (PrEP),
which is a combination of emtricitabine with tenofovir disoproxil that is taken
daily prior to exposure to the virus to reduce the risk of HIV acquisition. Tenofovir
disproxil may be used alone for HIV-negative individuals when emtricitabine is
contraindicated.9

At-risk groups who should be offered PrEP include men or transgender individuals who
have sex with men and HIV-negative sexual partners of HIV-positive individuals with a
detectable or unknown viral load.

Post-exposure prophylaxis
Occupational and sexual exposure to HIV is a medical emergency that requires prompt
treatment with a course of post-exposure prophylaxis (PEP).

PEP is a course of emtricitabine, tenofovir disoproxil and raltegravir which

should be initiated as soon as possible (no later than 72 hours following exposure) and
continued for 28 days.10

PEP is not recommended for human bites or community needlestick injuries unless the
donor is known to be highly viral or high risk.2

Patient support and HIV monitoring

Patients diagnosed with HIV will require advice and support, as well as close
monitoring of their CD4+ levels to follow disease progression.

Advice should be given regarding appropriate HIV specialist services, HIV charities and
local services for safer intravenous drug use, if appropriate. In addition, patients should
be supported to minimise the risk of transmission through the discussion of safer sexual
practices and adherence to medication.

Pregnant women should be assured that adherence to medication drastically reduces

the risk of transmission to their children, and patients should be made aware of the
British HIV Association’s endorsement of the ‘Undetectable=Untransmittable
11/14
(U=U)’ consensus: a HIV-positive individual with sustained undetectable levels of HIV
in their blood cannot transmit the virus to their sexual partners.10

For HIV-positive individuals, their progress should be monitored every 3-6 months for
early disease and every 2-3 months in late disease. This should include assessment for
opportunistic infection, viral load (PCR test for HIV RNA) and CD4+ count.

An increased viral load indicates increased viral replication which may be caused by
non-adherence to medication or viral drug resistance. CD4+ count is particularly useful
to determine the degree of immunocompromise and risk of opportunistic disease; a
CD4+ count >500 cells/µL represents little risk, whereas a count of <200 cells/µL is
sufficient for a diagnosis of AIDS and associated risk of HIV-related cancer and illness. 2

Prognosis
Life expectancy for those living with HIV is lower than the general population but has
lengthened over time as the effectiveness and tolerability of ART has been improved.

Early initiation and strict adherence to ART is key. Poor adherence can result in drug
resistance and failure to control the virus, resulting in a steady decline in CD4+ cells
and the onset of constitutional symptoms, malignancy, and opportunistic infection.
Suppression of the virus is achieved within 3-6 months of ART initiation. 2

Complications
As a result of HIV infection and AIDS, the host immune system is severely
compromised, increasing the risk of developing a wide range of opportunistic
infections which can cause severe health complications and death.

Table 3. An overview of the complications of HIV infection and AIDS.

System Illness Description

Respiratory Pneumonia Pneumocystis carinii

Most common life-threatening

opportunistic infection in AIDS

Tuberculosis

Gastrointestinal Oral/oesophageal Candida infection

candidiasis

Hepatomegaly Viral hepatitis or drug cause

Chronic diarrhoea Variety of bacteria

Perianal disease HSV ulceration

12/14
 Neurological Meningoencephalitis Transient, associated with acute HIV

Toxoplasmosis Toxoplasma gondii

Eye CMV retinitis

Dermatology Kaposi’s sarcoma

Key points
Human immunodeficiency virus (HIV) infects the immune system and results in
acquired immunodeficiency syndrome (AIDS).
Despite a decline in HIV diagnoses in the UK and worldwide, it remains a large
economic and health burden.
High-risk groups include: men who have sex with men (MSM), female sexual
contacts of MSM, black-African heterosexual men and women, HIV-negative
individuals in serodiscordant relationships, and those with occupational exposure.
Primary HIV infection can present with seroconversion illness within 2-4
weeks of exposure, symptoms can include fever, fatigue, maculopapular rash and
lymphadenopathy.
Long-standing HIV infection can present with a diverse range of symptoms
resulting from an impaired immune system, opportunistic infection and
malignancy.
AIDS is diagnosed by a CD4+ count <200 cells/µL, or the presence of one or more
AIDS-defining illnesses.
HIV testing uses combinations of serological testing, antigen detection and viral
load measurement.
HIV has no cure, and treatment centres upon a combination of antiretrovirals
to suppress viral replication.
Adherence is key to effective treatment and should be emphasised along with
lifestyle and risk factor modification.
HIV-positive patients should be monitored every 3-6 months in early disease and
2-3 months in late disease, to assess for opportunistic infection, changes in viral
load and CD4+ count.
Life-expectancy is lower for HIV-positive individuals but is significantly improved
with early initiation and strict adherence to antiretroviral therapy.
Complications are caused by the destruction of the immune system resulting
in opportunistic infection, malignancy and death.

Reviewer

Dr Steven Laird

Consultant Physician in Infectious Diseases

13/14
Editor

Dr Chris Jefferies

References
1. Avert (2019) HIV and AIDS in the United Kingdom. Available from: [LINK]
2. National Institute for Health and Care Excellence (2018) HIV infection and AIDS.
Available from [LINK]
3. British HIV Association (2020) BHIVA/BASHH/BIA Adult HIV Testing
Guidelines 2020. Available from [LINK]
4. National Institute of Allergy and Infectious Disease (2010) HIV Replication Cycle.
License: [CC-BY]. Available from [LINK]
5. AIDSinfo (2019) The Stages of HIV Infection. Available from: [LINK]
6. CDC, Sol Silverman, Jr.(1999) Candidiasis in HIV infection. License: [Public
domain]. Available from [LINK]
7. CDC, J.S. Greenspan, Sol Silverman, Jr.(1987) Oral hairy leukoplakia in HIV
infection. License: [Public domain]. Available from: [LINK]
8. CDC (1986) Kaposi’s Sarcoma. License: [Public domain]. Available from: [LINK]
9. Joint Formulary Committee (2020) British National Formulary- HIV Infection.
Available from: [LINK]
10. British HIV Association (2018) BHIVA Encourages Universal Promotion of
Undetectable=Untransmittable (U=U). Available from: [LINK]

14/14