1st August 2023

HIV and Infections in Immunocompromised Hosts

HIV Infection

Background

Human immunodeficiency virus (HIV) was first identified in the 1980s. Despite the remarkable progress in treatment and prevention strategies, it remains endemic in many places worldwide, including Eastern Europe, Asia and Sub-Saharan Africa. It is a major cause of morbidity and mortality worldwide and a key global public health concern. The prognosis of HIV has hugely improved since the virus was first identified, and it is now a manageable chronic disease. This is primarily due to the advent of antiretroviral therapy (ART).

Pathophysiology and virology

HIV is a retrovirus. Retroviruses infiltrate the cells of host organisms and use the enzyme reverse transcriptase to transcribe their viral RNA into DNA, which is then incorporated into the host cell genome. Once the virus has ‘taken over’ the host cell, it replicates, creating more HIV-infected cells that proliferate throughout the host organism.

HIV infects CD4 receptor-positive white blood cells. These are T-helper cells which communicate with antigen-presenting cells and are a key part of the cell-mediated immune response. Infection of these cells with HIV, therefore, weakens the immune system.

The amount of HIV-infected cells in the blood is measured as ‘viral load’ – the higher the viral load, the fewer healthy CD4 cells, and the greater burden of disease.

There are two types of HIV – HIV-1 and HIV-2. HIV-1 is the most common, with HIV-2 mainly confined to West Africa. HIV-1 is divided into four distinct strains – group M is by far the most common, with N, O and P much rarer.

Epidemiology

As of 2022, WHO estimates that 37.7 million people are infected with HIV worldwide, with Sub-Saharan Africa most affected.

Advances in treatment mean that survival rates of HIV are increasing, meaning that in countries such as the UK, where treatment is widely available, prevalence has increased whilst mortality decreases – people are living longer with the disease. Undiagnosed HIV (approximately one-quarter of UK cases) is the commonest cause of mortality.

Certain behaviours and conditions increase the risk of contracting HIV, which are as follows:

• Unprotected anal or vaginal sex
• Co-morbid sexually transmitted infections
• The use and sharing of contaminated needles and syringes for injecting intravenous drugs
• Needle stick injuries

HIV is transmitted via bodily fluids, such as blood, breast milk, semen, and vaginal secretions. HIV can also be transmitted vertically (from mother to child, during pregnancy or childbirth). The most common routes of spread are via sexual intercourse and through blood.

When first identified, HIV was thought of as a disease which affected the male homosexual population. In the UK, gay or bisexual men, Black Africans, and people born abroad are the three groups most at risk of HIV. However, heterosexual transmission is the most common cause of infection worldwide.

Prevention

Prevention is a key strategy for managing the rate of HIV infections. Risk factor reduction includes sexual health awareness and the provision of condoms to reduce infection risk, testing and counselling for those diagnosed with risk conditions such as STIs and tuberculosis, needle exchange programmes, and the use of antiretroviral drugs as post-exposure prophylaxis (PEP) for those potentially exposed to HIV.

PEP is offered to people who may have been exposed through sexual contact, needle sharing, or through occupational exposure – and has an evidence basis for reducing the risk of infection if started within 72 hours of potential exposure. Treatment consists of a four week course of dual therapy with the antiretrovirals tenofovir/emtricitabine and raltegravir.

Diagnosis

HIV infection can be symptomatic or asymptomatic and may be detected through screening or following investigation of suspicious clinical features.

Clinical features

Primary HIV infection (or seroconversion illness) refers to the non-specific flu-like illness that may present in the first six months following infection. It generally manifests within the first six weeks when the immune system reacts to the virus and produces antibodies. The common features are fever, sore throat, malaise, lethargy, arthralgia, myalgia, and a maculopapular rash.

Long-term HIV infection may cause constitutional features such as fever, weight loss, night sweats and lymphadenopathy.

HIV may also manifest with the features of associated illnesses as the initial presentations (see Complications section below).

NICE recommends that HIV be suspected in patients presenting with prolonged or recurrent infections, any conditions recognised as complications, unexplained weight loss, unexplained lymphadenopathy, or pyrexia of unknown origin.

Testing

The first line HIV test in the UK is a dual test for the HIV antibody and p24 antigen (HIV viral material). Point-of-care antibody tests can give results within minutes, but should always be followed up by confirmatory serological testing.

There is a roughly six week latency period between the initial infection and the time at which the serological test becomes positive. Therefore, if an individual has been exposed and initially tests negative, repeat tests at this time interval may be indicated. Currently, the window period in which HIV tests may be negative despite the individual being infected is 45 days – therefore, negative tests before this interval may be inaccurate.

All individuals with symptoms suspicious of HIV infection should be tested, and screening tests also offered opportunistically to at-risk individuals, such as men who have sex with men (MSM), female sexual contacts of MSM, sex workers, intravenous drug users, prisoners, people from countries with a high prevalence of HIV, and people reporting sexual contact with individuals from a country with a high prevalence of HIV.

Specific verbal consent must be given for an HIV test, and a patient cannot be tested without their consent. Permission to disclose positive test results to other healthcare professionals – such as a patient’s GP – must also be specifically sought and can be refused.

Management

Antiretroviral therapy

The first line treatment for established HIV infection is antiretroviral therapy (ART). ART directly targets the underlying pathophysiology by limiting viral replication and has drastically changed the management of HIV. The goal of treatment is to reduce viral load to undetectable levels.

There are five classes of ART drugs, which are categorised by their mechanism. Examples are listed in the table below, along with common side effects, and the most frequently used drugs highlighted in bold.

Due to the tendency of the HIV virus to mutate, drug resistance is high, so ART is typically given as combination therapy of three or more drugs to reduce resistance. Typically, regimens consist of two nucleoside reverse transcriptase inhibitors (NRTI), with either a non-nucleoside reverse transcriptase inhibitor (NNRTI) or a protease inhibitor (PI). Integrase inhibitors (II) and entry inhibitors (EI) are newer drugs with less long-term evidence available in regard to side effects. They are more expensive than the first line treatments, so they are generally reserved for resistant infections.

Current guidance states that ART should be started as soon as the infection is confirmed, as early treatment is a key positive prognostic factor.

Table 1: Classes and side effects of antiretroviral therapy (ART)

Monitoring

Disease monitoring consists of CD4 count and HIV viral load. The two are linked – a falling CD4 count is associated with a rising HIV viral load and is indicative of disease progression. A falling CD4 count may also suggest a lack of treatment adherence.

Monitoring blood tests for patients on ART include FBC, U&Es, LFTs, lipid profiles and glucose levels to assess for toxicity. Regular reviews of therapeutic compliance and monitoring for the development of any complications is also indicated, with specialist services available to facilitate this.

Patients with CD4 counts below 200 are most at risk of opportunistic infections (see AIDS and Other Complications).

Patient education and support

HIV is a chronic illness that has the potential to cause significant morbidity and a variety of complications, and remains associated with social stigma. As such, education and support are crucial aspects of management. Specialist services exist nationwide, through which patients can access specialist medical care, but also support groups and other forms of psychosocial input to help them live with their disease.

It is crucial that patients with HIV are educated on the risk of infections and fully immunised. Patients with HIV should also not receive live attenuated vaccines. Information on sexual health, and in particular, barrier methods of contraception to reduce transmission risk, is key.

HIV and Pregnancy

ART is the first line treatment for pregnant women with HIV, and the risk of vertical transmission correlates directly with viral load, which means ART is the single most important intervention for reducing the risk of vertical transmission. If a woman is on effective ART, then vaginal delivery is preferred to a C-section.

In the UK, breastfeeding is not recommended due to the risk of transmission. However, breastfeeding is preferred in the developing world due to the other benefits it provides.

Babies born to HIV-positive mothers should receive four weeks of treatment with zidovudine (AZT) postpartum.

AIDS and Other Complications of HIV

AIDS

Without treatment, HIV progresses to acquired immunodeficiency syndrome (AIDS). AIDS is defined as either an HIV positive patient with a CD4 count of less than 20 or developing an AIDS-defining illness in the context of HIV infection.

When a patient is diagnosed with AIDS, management of the underlying HIV infection with antiretroviral therapy (ART) should continue, alongside specific and supportive treatment of any associated complications. There is no cure for AIDS – treatment aims to slow the disease progression, minimise complications, and provide symptom relief. Palliative care input may be required, especially in the final stages of the illness.

ART is the single greatest intervention which prevents the progression of HIV into AIDS.

AIDS-defining illnesses

The following conditions, if they occur in the context of an HIV positive patient, are diagnostic of AIDS. 

Table 2: AIDS-defining illnesses

Malignancies Associated with HIV

The three cancers most closely associated with HIV are Kaposi’s sarcoma, non-Hodgkin’s lymphoma, and cervical cancer –all of which are AIDS-defining illnesses. HIV patients are also at increased risk of liver and anal cancer and Hodgkin’s lymphoma.

Kaposi’s sarcoma

A type of skin tumour which originates from vascular and lymphatic endothelial skin layers. There is a strong aetiological association with herpesvirus type 8 (HHV-8).

It presents as characteristically purplish flat or nodular lesions. The form associated with HIV causes a severe presentation, with widespread lesions of the skin and oral cavity, as well as visceral disease in the bowel and lungs.

Skin and lymph node disease can be treated with localised radiotherapy, and systemic chemotherapy is given for disseminated disease. ART can also lead to the regression of lesions.

An example of limited Kaposi’s sarcoma, affecting the tip of a patient’s nose

Image Source: Wikimedia Commons (2018). Kaposi’sSarcoma, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Kaposi%27sSarcoma.jpg (Accessed: 12 July 2023).

Severe widespread cutaneous Kaposi’s sarcoma

Image Source: Wikimedia Commons (2008). Kaposi’s sarcoma before, Licensed under a creative commons licence. Available for free at: https://commons.wikimedia.org/wiki/File:Kaposi%27s_sarcoma_before.jpg (Accessed: 12 July 2023).

Non-Hodgkin’s lymphoma

Large B-cell type lymphoma is the most common lymphoma in HIV patients. Epstein-Barr virus (EBV) is strongly implicated in aetiology in HIV patients.

Typically, lymphoma in HIV patients is very aggressive and frequently causes extranodal disease in the brain, lung, and gastrointestinal tract, with severe systemic ‘B’ symptoms (i.e. fatigue, weight loss, night sweats).

Treatment is with aggressive chemotherapy –there is a poor response rate, and the prognosis is poor for HIV-related lymphoma.

Cervical cancer

Women with HIV are at significantly increased risk of cervical cancer, especially caused by human papillomavirus (HPV). Colposcopy is offered to patients with a cervix at diagnosis, and annual smear tests are subsequently indicated.

Other Complications of HIV

Neurological complications

AIDS-dementia complex (ADC) is a type of dementia seen in HIV patients and commonly associated with cerebellar features. Clinical presentation can range from mild memory impairment to severe cognitive decline and personality change, and psychotic features may be seen. Diagnosis is supported by MRI head scans showing white matter lesions and encephalopathic features on EEG.

HIV is also associated with sensory neuropathies, which typically cause an intensely painful symmetrical sensory neuropathy of the feet, which may progress to the upper limbs. HIV is also associated with autonomic neuropathy, which mainly presents with postural hypotension and diarrhoea.

Haematological complications

Haematological complications are more frequent as HIV progresses and are associated with a falling CD4 count. Associated conditions include lymphopenia, anaemia (classically normocytic and normochromic), neutropenia, thrombocytopenia, and pancytopenia.

Metabolic and endocrine complications

Adrenal gland dysfunction and testosterone deficiency are associated with HIV.

Osteopenia, osteoporosis and avascular necrosis are all associated with HIV, with ART also implicated in the aetiology.

Cardiovascular complications

Lipid dysfunction is associated with ART, meaning HIV patients are more at risk of cardiovascular disease as a therapeutic side effect. Data also suggests that ischaemic heart disease is more common in untreated HIV patients, and there is a risk independent of treatment side effects.

Cardiomyopathy and myocarditis are also associated with HIV.

Renal complications

Renal disease in HIV is known as HIV-associated nephropathy (HIVAN). Nephrotic syndrome secondary to focal segmental glomerulosclerosis is the most common renal disease in HIV. It causes a severe, progressive illness, and dialysis is often indicated. HIVAN is most common in male patients and patients with African-American heritage.

Opportunistic Infections

The immunocompromised state of many HIV patients means they are vulnerable to various opportunistic infections. These are AIDS-defining illnesses, and many are listed in Table 2 above.

A useful way to consider these infections is the risk in relation to CD4 count, which is summarised in the following table.

Table 3: CD4 count with associated conditions

The key opportunistic infections are covered in greater detail in the Common Infections in Immunocompromised Hosts section.

Common Infections in Immunocompromised Hosts

Causes of Immunocompromisation

Immunocompromisation, or immunodeficiency, refers to a state in which the ability of a person’s immune system to combat disease is either diminished or absent. It is most often secondary (Table 4). Primary immunodeficiency is rare and due to congenital developmental defects or genetic abnormalities present from birth (Table 5).

Immunocompromised patients are more likely to be severely affected by common pathogens and more vulnerable to certain pathogens that rarely cause illness in patients with fully-functioning immune systems, i.e. opportunistic infections. Many of these are associated with HIV, as explained in the previous section.

Selected causes of acquired immunodeficiency

Table 4: Selected causes of acquired immunodeficiency

Selected causes of primary immunodeficiency

Table 5: Selected causes of primary immunodeficiency

Bacterial Infections

Viral Infections

 Other Types of Infections

 Infections in Organ Transplant Patients

In order to reduce the risk of graft rejection, patients who receive organ transplants are generally prescribed strong immunosuppressive drugs. This leads to immunocompromise and means special consideration should be given to the risk of opportunistic infections in organ transplant patients. This is most commonly considered in the context of renal transplant patients.

Bacterial infections are generally seen in the first month post-transplantation, whereas in the weeks-months after, cytomegalovirus (CMV) is relatively frequent. Prophylaxis with valganciclovir may be given against CMV, although the evidence basis is unclear.

Routine prophylaxis is also indicated in renal transplant patients against Pneumocytis jirovecii and oral candidiasis with co-trimoxazole and nystatin, respectively.