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Human Immuodeficiency Virus 53
Table 2.11 Direct HIV infection effects
Neurological AIDS dementia complex
disease
Eye Retinal cotton wool spots – rarely troublesome
Mucocutaneous Dry, itchy, flaky skin
Haematological Anaemia of chronic disease
Gastrointestinal Anorexia leading to weight loss in advanced disease
Renal Renal impairment
Respiratory Chronic sinusitis and otitis media
Endocrine Reduced adrenal function – infection may precipitate
Cardiac Myocarditis and cardiomyopathy
Sensory polyneuropathy
Autonomic neuropathy causing diarrhoea and postural
hypotension
Aseptic meningitis
Pruritic papular eruption
Aphthous ulceration in the mouth
Neutropenia
Autoimmune thrombocytopenia
HIV enteropathy leading to diarrhoea and malabsorption
Nephrotic syndrome (due to focal glomerulosclerosis)
Lymphoid interstitial pneumonitis – lymphocytic infiltration of the lung, causing dyspnoea and a dry cough
clear adrenal insufficiency
Monitoring
Patients are monitored to assess the progression of the infection and ongoing
treatment. As patient survival has dramatically improved since the availability of ART, so has the recognition of non-AIDS-defining HIV comorbidities,
particularly cardiovascular, renal, metabolic, and bone disease and non-HIVrelated malignancy, all of which require monitoring.
• CD4 lymphocyte count is measured at least biannually but often more
regularly in ART naïve patients or following the initiation of ART. Patients
with counts below 200 cells are at greatest risk of HIV-related pathology,
particularly opportunistic infection.
• Plasma levels of HIV RNA (‘viral load’, measured in copies of RNA per mL)
are a measure of viral replication. The viral load is the best indicator of
long-term prognosis but more immediately reflects the effectiveness of a
chosen ART regimen. A rising viral load in a patient receiving ART suggests
drug failure as a result of poor compliance or emerging resistance.
54 Infectious diseases
Table 2.12 Clinical indicator diseases for adult HIV infection
and testing
Respiratory Bacterial pneumonia
Aspergillosis
Neurology Aseptic meningitis/encephalitis
Cerebral abscess
Space-occupying lesion of unknown cause
Guillain–Barré syndrome
Transverse myelitis
Peripheral neuropathy
Dementia
Leucoencephalopathy
Dermatology Severe or recalcitrant seborrheic dermatitis
Severe or recalcitrant psoriasis
Multidermatomal or recurrent herpes zoster
Gastroenterology Oral candidiasis
Oral hairy leucoplakia
Chronic diarrhoea of unknown cause
Weight loss of unknown cause
Salmonella, shigella or campylobacter
Hepatitis B
Hepatitis C
Oncology Anal cancer or anal intraepithelial dysplasia
Lung cancer
Seminoma
Head and neck cancer
Hodgkin’s lymphoma
Castleman’s disease
Gynaecology Vaginal intraepithelial neoplasia
Cervical intraepithelial neoplasia grade 2 or above
Haematology Any unexplained blood dyscrasia
Thrombocytopenia
Neutropenia
Lymphopenia
Ophthalmology Infective retinal disease including toxoplasmosis and
herpesvirus
Any unexplained retinopathy
Continued
Human Immuodeficiency Virus 55
Table 2.12 Clinical indicator diseases for adult HIV infection
and testing
ENT Lymphadenopathy of unknown cause
Other Mononucleosis-like syndrome
—cont'd
Chronic parotitis
Lymphoepithelial parotid cysts
Pyrexia of unknown origin
Lymphadenopathy of unknown cause
Any sexually transmitted infection
Management
Management involves treatment with antiretroviral drugs, social and psychological care, prevention of opportunistic infections and prevention of
transmission of HIV. Although HIV infection cannot be cured, the advent of
highly active ART has transformed HIV into a chronic controllable condition.
The aims of treatment are to maintain physical and mental health and to
avoid transmission of the virus. It is paramount that the patient is actively
involved in treatment decision making. General health promotion advice on
smoking cessation, alcohol, diet, drug misuse and exercise should be given,
particularly in light of the cardiovascular, metabolic and hepatotoxic risks
associated with ART.
Antiretroviral drugs available in the UK (Table 2.13) continue to evolve
and improve. Increased potency, reduced toxicity, greater convenience
of formulation, and availability of compounds with different mechanisms
of action, coupled with a better understanding of drug resistance, have
combined to improve HIV clinical and virological outcomes. Regularly updated
treatment guidelines are produced in the UK by the British HIV Association
(BHIVA) and in the USA by the Department of Health and Human Services
(DHHS).
Treatment regimens are complicated and require a long-term commitment
to high levels of adherence. A combination of clinical assessment and
laboratory marker data, including viral load and CD4 counts, together with
individual circumstances, should guide therapeutic decision making.
Treatment is initiated with a combination of drugs started simultaneously. The
preferred starting regimen is two nucleoside/nucleotide reverse transcriptase
inhibitors plus one of a ritonavir-boosted protease inhibitor, a non-nucleoside
transcriptase inhibitor or an integrase inhibitor. The goal is to suppress
the viral load to an undetectable level (<50 copies/mL) within 3–6
months of starting therapy. Patients may need to change therapy because
of drug resistance or intolerance/adverse drug reactions. Adverse drug
reactions are relatively common. Many antiretroviral drugs have significant
Table 2.13 Antiretroviral drugs commonly used in clinical practice
Drug class Drugs Mechanism of action Comments
Nucleoside and nucleotide
reverse transcriptase
inhibitors (NRTIs)
Non-nucleoside reverse
transcriptase inhibitors
(NNRTIs)
Tenofovir, abacavir,
lamivudine,
emtricitabine
Efavirenz, nevirapine*,
etravirine, rilpivirine
Inhibit synthesis of DNA by
reverse transcription and also
act as DNA chain terminators.
Usually, two drugs of this class
are combined to provide the
‘backbone’ of an ART regimen
Bind directly to and inhibit
reverse transcriptase
Tenofovir is associated with renal dysfunction
Abacavir is associated with hypersensitivity reactions in at-risk
individuals (HLA-B*5701)
Abacavir plus lamivudine should only be used when baseline VL
is <100 000 copies/mL
The combination of tenofovir plus emtricitabine is a preferred
first-line regimen in most regions
Efavirenz can cause central nervous system toxicity (usually
time-limited)
Nevirapine can cause severe hepatotoxicity in patients with
higher CD4 cell counts (>250 cells/mm3 for women and
>400 cells/mm3 for men)
Rilpivirine should be used only when baseline VL is <100 000
copies/mL
Etravine is given twice daily and has generally been used as a
second-line regimen
56 Infectious diseases
Table 2.13 Antiretroviral drugs commonly used in clinical practice
Integrase inhibitors or
integrase strand transfer
inhibitors (INSTIs)
Protease inhibitors
Raltegravir,
dolutegravir,
elvitegravir
Fosamprenavir,
atazanavir, darunavir,
lopinavir, saquinavir
(ritonavir)
Prevents insertion of HIV DNA
into the human genome
Act competitively on HIV
aspartyl protease enzyme,
which is involved in production
of functional viral proteins and
enzymes
CCR5 inhibitors
Maraviroc Blocks the CCR5 chemokine
co-receptor
Fusion inhibitors
Enfuvirtide Inhibits fusion of HIV with
target cell
Modified from Volberding, P. A. & Deeks, S. G. (2010). Antiretroviral therapy and management of HIV infection. Lancet, 376, 49–62.
*Some drugs, such as zidovudine, stavudine and nevirapine, are generally used in low-income countries because of cost considerations. These are not recommended as preferred
agents in resource-rich regions in view of their potential toxic effects. HLA, human leucocyte antigen; VL, viral load.
Integrase inhibitors are generally well tolerated and have fewer
adverse effects than other ARV classes
Raltegravir is taken twice daily
Elvitegravir requires boosting by cobicistat
Most protease inhibitors are extensively metabolized by the
cytochrome P450 3 A system; ritonavir is generally given at
low doses (100–200 mg per day) to inhibit P450 and boost the
co-administered protease inhibitors
Most protease inhibitors are associated with hyperlipidaemia
and other metabolic abnormalities such as insulin resistance
Long-term protease inhibitor exposure has been associated
with increased risk of cardiovascular disease
Maraviroc is active only in patients who do not have virions
that use CXCR4 for cell entry. A specialized assay is therefore
needed to screen for co-receptor tropism. By contrast with
other ARVs, maraviroc binds to a host rather than a viral target
Enfuvirtide must be given subcutaneously twice daily and is
very expensive; generally used only in patients who have no
other therapeutic options
Human Immuodeficiency Virus 57
58 Infectious diseases
interactions with other classes of compounds and when commencing any
new medication in a patient receiving ART it is highly recommended that
these be considered. Comprehensive interaction data are available at http://
www.hiv-druginteractions.org.
Conditions due to immunodeficiency
Immunodeficiency allows the development of opportunistic infections.
These are diseases caused by organisms that are not usually considered
pathogenic, unusual presentations of known pathogens, or the occurrence
of tumours that have an oncogenic viral aetiology. Susceptibility increases as
the patient becomes more immunosuppressed. When patients are profoundly
immunocompromised (CD4 count <100 cells/mm3), disseminated infections
with organisms of very low virulence such as M. avium-intracellulare and
Cryptosporidium are able to establish themselves. Long-term secondary
chemoprophylaxis for previously life-threatening infections may not be
necessary when ART maintains the CD4 count above 200 cells/mm3 and the
viral load is low.
Fungi
Pneumocystis jiroveci (formerly P. carinii) causes pneumonia in immunocompromised patients, usually when CD4 count <200 cells/mm3. There is
an insidious onset of breathlessness, specifically exertional dyspnoea, a
non-productive cough, fever and malaise. The chest X-ray may be normal
or show bilateral perihilar interstitial infiltrates, which can progress to more
diffuse shadowing. Pneumothorax may complicate P. jiroveci pneumonia.
High-resolution CT scans of the chest are abnormal even if there is little on
the chest X-ray. Histoplasmosis can produce a similar appearance. Definitive
diagnosis is made by PCR amplification of the fungal DNA from induced sputum or bronchoalveolar lavage. Treatment depends on severity assessment
and is usually with co-trimoxazole. Treatment should not be delayed if clinical suspicion is high. High-dose corticosteroids reduce mortality in severe
cases. Long-term prophylaxis, usually with oral co-trimoxazole, is required in
patients whose CD4 count remains below 200 cells/mm3 despite ART.
Cryptococcus neoformans most commonly causes meningitis in HIV
patients. There is an insidious onset of fever and headache. Nausea, vomiting
and impaired consciousness may suggest raised intracranial pressure.
Diagnosis is made by demonstration of the cryptococcal antigen in serum.
CSF microscopy with Indian ink staining shows the organisms directly, and
culture of the organism from CSF and/or blood is possible. A CT scan is
performed before the lumbar puncture to exclude a space-occupying lesion.
Treatment is with intravenous amphotericin B ± flucytosine or fluconazole.
Serial lumbar punctures may be necessary to reduce intracranial pressure.
Candida infection (usually Candida albicans) presents as creamy plaques
in the mouth, vulvovaginal region and oesophagus (producing odynophagia
and dysphagia). Treatment is with fluconazole (preferred if Candida is
Human Immuodeficiency Virus 59
disseminated) or other azoles. Disseminated infection with Aspergillus
fumigatus occurs in advanced HIV infection. Treatment is with voriconazole
or liposomal amphotericin B.
Protozoal infections
Toxoplasma gondii most commonly causes cerebral abscesses in immunocompromised HIV-infected patients. Clinical features include focal
neurological signs, fits, fever, headache and confusion. Toxoplasma infec-
tion in immunocompromised patients is usually caused by reactivation of
previous infection and diagnosis is made on the basis of positive Toxoplasma
serology. Multiple ring-enhancing lesions in the brain on contrast-enhanced
CT or MRI are characteristic. Treatment is with anticonvulsants and a combination of pyrimethamine, sulfadiazine and folinic acid for at least 6 weeks.
Lifelong maintenance is required to prevent relapse unless the CD4 count
can be restored by ART. The differential diagnosis of multiple ring-enhancing
central nervous system (CNS) lesions in these patients includes lymphoma,
mycobacterial (e.g. tuberculoma), progressive multifocal leucoencephalopathy or focal cryptococcal infection.
Cryptosporidium species (parvum and hominis) cause self-limiting watery
diarrhoea and abdominal cramps in immunocompetent individuals and a
severe chronic watery diarrhoea in HIV patients, in whom it also causes
sclerosing cholangitis. Diagnosis is made by demonstrating cysts on stool
microscopy or on small bowel biopsy specimens obtained at endoscopy.
ART and immune restoration is associated with resolution of symptoms.
Treatment is otherwise symptomatic. Paromomycin and nitazoxanide have a
limited effect on diarrhoea.
Microsporidia infection (Enterocytozoon bieneusi and Septata intestinalis)
cause diarrhoea. Diagnosis is made by demonstrating spores in the stools.
Treatment is with ART and albendazole.
Leishmaniasis in HIV-infected patients occurs as in any immunocompetent
host with either visceral (weight loss, fever, hepatosplenomegaly),
mucocutaneous or cutaneous disease. In Europe most cases are cutaneous.
Diagnosis is by parasitological or histological confirmation and may require
splenic, bone marrow or skin biopsy. Visceral disease is treated with
liposomal amphotericin B.
Viruses
Cytomegalovirus. Cytomegalovirus (CMV) causes retinitis, colitis,
oesophageal ulceration, encephalitis, pneumonitis, polyradiculopathy and
adrenalitis. Retinitis presents with floaters, loss of visual acuity and orbital
pain, usually in a patient with CD4 count <100 cells/mm3. The diagnosis is
made on fundoscopy, which shows a characteristic appearance of the retina
with haemorrhages and exudate. Colitis presents with bloody diarrhoea
and abdominal pain. Diagnosis is made by demonstrating characteristic
‘cytomegalic cells’ (large cells containing an intranuclear inclusion and
60 Infectious diseases
sometimes intracytoplasmic inclusions) on pathology examination of mucosal
biopsy specimens. CMV DNA via PCR can be detected in peripheral blood but
high titres do not always correlate with clinical infection and it is best used to
monitor treatment response. Treatment of CMV infection is with intravenous
ganciclovir, foscarnet or oral valganciclovir. Reactivation occurs in CMV
retinitis and oral or topical ganciclovir is given long term, unless immune
competence can be restored with ART.
Herpes virus. Primary infection with herpes simplex virus causes genital
and oral ulceration, and systemic infection. Varicella zoster occurs at any
stage of HIV infection, but may be more aggressive and longer lasting than in
immunocompetent patients. Treatment is with aciclovir. Human herpesvirus
8 is associated with Kaposi’s sarcoma (see below). EBV causes oral hairy
leucoplakia, presenting as a pale, ridged lesion on the side of the tongue.
EBV is also associated with primary cerebral lymphoma and non-Hodgkin’s
lymphoma (see below).
Human papilloma virus. Human papilloma virus (HPV) produces genital
and plantar warts. HPV infection is associated with the more rapid
development of squamous cell cancer of the cervix and anal cancer.
Polyomavirus. Infection with polyomavirus (JC virus) causes progressive
multifocal leucoencephalopathy, which presents with intellectual impairment
and often hemiparesis and aphasia.
Hepatitis virus B and C. Because of the comparable routes of
transmission of hepatitis viruses and HIV, co-infection is common, particularly
in drug users and those infected by blood products. Hepatitis B does not
seem to influence the natural history of HIV, though there is a reduced rate
of clearance of the hepatitis B e antigen in co-infected patients and thus
the risk of developing chronic infection is increased. Hepatitis C, however,
is associated with a more rapid progression of HIV infection, and the
progression of hepatitis C is more likely and more rapid.
Bacterial infection
Bacterial infection may present early in HIV infection and it is often disseminated and frequently recurs. Mycobacterium tuberculosis can cause disease
at all stages of HIV infection, but extrapulmonary tuberculosis (TB) is more
common with advanced disease. M. tuberculosis infection usually responds
well to standard treatment regimens, although the duration of therapy may
be extended, especially in extrapulmonary infection. Treatment of TB in HIV
co-infected patients presents specific challenges, particularly with regard to
drug interactions and multidrug resistance (p. 526), and requires input from
a specialist physician.
Mycobacterium avium-intracellulare (MAI) occurs only in the later
stages of HIV infection when patients are profoundly immunosuppressed
(CD4 count <50 cells/mm3). Clinical features include fever, anorexia,
weight loss, diarrhoea and anaemia with bone marrow involvement. MAI is
typically resistant to standard anti-tuberculous therapies. A combination of
Human Immuodeficiency Virus 61
ethambutol, rifabutin and clarithromycin reduces the burden of organisms and
provides symptomatic benefit. Other infections include Strep. pneumoniae, H.
influenzae, staphylococcal skin infection and salmonella.
Neoplasia
The most common tumours are Kaposi’s sarcoma and non-Hodgkin’s lymphoma. The incidence of all HIV-related malignancies has fallen dramatically
since the introduction of ART.
• Kaposi’s sarcoma is a vascular tumour that appears as red-purple,
raised, well-circumscribed lesions on the skin, hard palate, conjunctivae,
and in the gastrointestinal tract. The lungs and lymph nodes may also
be involved. Human herpesvirus 8 is implicated in the pathogenesis.
Localized disease is treated with radiotherapy; systemic disease is
treated with chemotherapy. Initiation of ART may cause regression of
lesions and prevent new ones emerging.
• Non-Hodgkin’s lymphoma occurs in the brain, gut and lung.
• Squamous cell carcinoma of the cervix and anus is associated with HIV.
Infection with oncogenic strains of HPV has a causal association with
invasive cancer.
• Non-HIV-related malignancy is more common in people living with HIV.
Prevention and control
• The risk of HIV transmission following a needle-stick injury involving
contaminated blood is reduced by using combination ART. Occupational
Health and local HIV specialists must be involved. Prophylaxis should be
started as soon as possible after exposure following risk assessment.
• Pregnant HIV-positive women should receive ART to reduce the risk
of vertical transmission. For patients not adequately treated with ART,
delivery by caesarean section dramatically reduces perinatal infection
but access to these interventions is limited in resource-poor countries.
In the UK, guidance suggests that infants with mothers known to be HIV
positive should be exclusively formula fed.
• The use of condoms reduces sexual transmission of HIV. Male
circumcision protects those individuals against infection with HIV
and also other sexually transmitted infections, such as syphilis and
gonorrhoea.
• People who inject recreational drugs should not share needles;
some areas provide free sterile needles as part of needle exchange
programmes.
Prognosis
The rate of progression among patients infected with HIV varies greatly. The
introduction of ART has resulted in a dramatic decrease in mortality and
opportunistic infections in patients with HIV who now lead long and productive lives while managing a chronic health condition.
62 Infectious diseases
THERAPEUTICS
Antimicrobial agents are natural or synthetic chemical substances that
suppress the growth of, or destroy, microorganisms including bacteria,
fungi and viruses. Antimicrobial treatment must be started immediately
in patients with life-threatening infection using ‘blind therapy’ based
on the likely causative organisms and system involved. Treatment must
then be adjusted later based on antimicrobial susceptibility data from
specimens (e.g. pus, blood, foreign bodies) sent before or coinciding
with start of treatment. Treatment should be prescribed for the shortest
course likely to be effective and agents selected to minimize collateral
damage and side effects. Antimicrobials should always be prescribed
in accordance with local policies, formularies and guidelines. Such
antimicrobial stewardship is of paramount importance in reducing
the use of broad-spectrum antibiotics, particularly those associated
with C. difficile infection, and minimizing the ongoing emergence of
resistant organisms to allow infection to be treated successfully for
future generations.
Antibacterials
β-Lactam antibacterials
Mechanism of action
The β-lactam antibacterials inhibit synthesis of the peptidoglycan layer of the
cell wall, which surrounds certain bacteria and is essential for their survival.
Indications
Benzylpenicillin (penicillin G) is effective for many streptococcal and
meningococcal infections, leptospirosis and treatment of Lyme disease.
Phenoxymethylpenicillin (penicillin V) has a similar antibacterial spectrum
to benzylpenicillin but it should not be used for serious infections because
gut absorption is unpredictable. Flucloxacillin is effective for infections due to β-lactamase-producing staphylococci (most staphylococci
are resistant to benzylpenicillin because they produce penicillinases).
Ampicillin is principally indicated for the treatment of exacerbations of
chronic bronchitis and middle ear infections. Amoxicillin is derived from
ampicillin and has a similar antibacterial spectrum. It is better absorbed
than ampicillin when given by mouth. Co-amoxiclav consists of amoxicillin with the β-lactamase inhibitor clavulanic acid, which extends the
spectrum of activity of amoxicillin. Piperacillin is an extended spectrum
β-lactam antibiotic. It is usually used together with a β-lactamase
inhibitor such as tazobactam. The combination has activity against many
Gram-positive and Gram-negative pathogens and anaerobes including
Pseudomonas aeruginosa.