25. hiv infection and aids

 The acquired immunodeficiency syndrome (AIDS)
was first recognised in 1981, although the earliest
documented case has been traced to a blood
sample from 1959.
 It is caused by the human immunodeficiency virus
(HIV-1), which has evolved a number of mechanisms
to elude immune control and has thereby prevented
effective control of the epidemic.

 HIV-2 causes a similar illness to HIV-1 but is less
aggressive and restricted mainly to western Africa.
 The origin of HIV is a non-human primate simian
virus which probably passed from chimpanzees to
humans via bush hunters.

 AIDS remains the second leading cause of disease
burden world-wide and the leading cause of death in
Africa, although downward trends in prevalence are
occurring in several countries, partly as a result of
effective prevention measures and partly due to
scaling up of antiretroviral access.

 Highly active retroviral therapy (HAART) with three
or more drugs has improved life expectancy to near
normal in the majority of patients receiving it, with an
80% reduction of mortality since its introduction.

Global epidemic and regional patterns:
 In 2007, the World Health Organization (WHO)
estimated that there were 33.2 million people living
with HIV/AIDS, 2.5 million new infections and 2.1
million deaths.
 The cumulative death toll since the epidemic began
is over 20 million, the vast majority of cases
occurring in sub-Saharan Africa where over 11.4
million children are now orphaned.

 In eight Southern African countries (Botswana, South
Africa, Swaziland, Mozambique, Lesotho, Namibia,
Zaire and Zimbabwe) the prevalence exceeds 15%,
and for many others, such as Cameroon, Central
African Republic and Cote d’Ivoire, it is over 5%.
 Between 2001 and 2007, the steepest increases
have been seen in Asia (> 90%) and Eastern
Europe/Central Asia (150%), predominantly India,
China, Russia and Ukraine.

 In South-east Asia, the epidemic is well developed
but prevalence is falling in Thailand, Cambodia and
Myanmar, although still increasing in Vietnam and
Indonesia.
 In India, the national prevalence is 0.36% (varying
from 0.07% in Uttar Pradesh to 1.13% in Manipur)
and it is estimated that 2.5 million persons were
infected in 2006.
 Given that Asia is home to 60% of the world’s
population, these changes have huge implications.

 Many different cultural, social and behavioural
aspects determine the regional characteristics of HIV
disease.
 Historically, the epidemic in North America and
northern Europe has been in men who have sex with
men (MSM), whereas in southern and Eastern
Europe, Vietnam, Malaysia, Indonesia, North-east
India and China the incidence has been greatest in
injection drug-users.

 In Africa, the Caribbean and much of Southeast Asia
the dominant route of transmission remains
heterosexual and from mother to child.
 However, the epidemic in many nations is changing.
Heterosexual transmission has become a significant
and often dominant route with racial and ethnic
minorities representing an increasing fraction, largely
as a consequence of the influx of migrants from
high-prevalence countries.

 In the European Union (EU) in 2006, more than half
of patients were infected heterosexually, with a
doubling of new cases in the UK over the last 5
years. Additionally, there has been a 50% increase in
reported new diagnoses in MSM, although some of
this may be accounted for by an increased uptake in
testing.

 It is of concern that around 30% of patients are
unaware of their diagnosis and one-quarter of these
present with late disease. This underlies the
importance of having a low threshold to test
individuals, especially when they present with any
condition that has been associated with HIV.

 The economic and demographic impact of HIV
infection in developing countries is profound, as it
affects those at their most economically productive
and fertile age, and is also eroding the health and
economic advances made in the last few decades.
 Although roll-out of drugs and access to care has
improved dramatically recently, less than one-quarter
of patients in many resource-poor countries are able
to access antiretrovirals.

Modes of transmission:
 HIV is present in blood, semen and other body fluids
such as breast milk and saliva.
 Exposure to infected fluid leads to a risk of
contracting infection, which is dependent on the
integrity of the exposed site, the type and volume of
body fluid, and the viral load.
 HIV can enter either as free virus or within cells.

 The modes of spread are sexual (man to man,
heterosexual and oral), parenteral (blood or blood
product recipients, injection drug-users and those
experiencing occupational injury) and vertical.

 The transmission risk after exposure is over 90% for
blood or blood products, 15–40% for the vertical
route, 0.5–1.0% for injection drug use, 0.2–0.5% for
genital mucous membrane spread and under 0.1%
for non-genital mucous membrane spread.

 World-wide, the major route of transmission (> 75%)
is heterosexual.
 About 5–10% of new HIV infections are in children
and more than 90% of these are infected during
pregnancy, birth or breastfeeding.
 The rate of mother-to-child transmission is higher in
developing countries (25–44%) than in industrialised
nations (13–25%).
 Postnatal transmission via breast milk accounts for
some of this increased risk.

 Of those infected vertically, 80% are infected close to
the time of delivery and 20% in utero.
 Around 70% of patients with haemophilia A and 30%
of those with haemophilia B had been infected
through contaminated blood products by the time
HIV antibody screening was adopted in the USA and
Europe in 1985.

 In developed nations, because of routine antibody
screening, the likelihood of acquiring HIV from blood
products is now less than 1:500 000 and arises from
donors in the seroconverting phase of infection.
 However, the WHO estimates that because of the
lack of adequate screening facilities in resource-poor
countries, 5–10% of blood transfusions globally are
with HIV-infected blood.

 There have been approximately 100 definite and 200
possible cases of HIV acquired occupationally in
health-care workers. Such infections are
substantially more frequent in developing nations,
where it is estimated that 40% of syringes/needles
used in injections are reused without sterilisation.

Virology and immunology:
 HIV is a single-stranded RNA retrovirus from the
Lentivirus family.
 After mucosal exposure, HIV is transported to the
lymph nodes via dendritic, CD4 T lymphocytes or
Langerhans cells, where infection becomes
established.
 Dendritic cells express various receptors (e.g. DC–
SIGN) that facilitate capture and transport of HIV-1.

 Free or cell-associated virus is then disseminated
widely through the blood with seeding of ‘sanctuary’
sites (e.g. central nervous system (CNS)) and latent
CD4 cell reservoirs.

 Each mature virion is spherical and has a lipid
membrane lined by a matrix protein that is studded
with glycoprotein (gp) 120 and gp41 spikes
surrounding a cone-shaped protein core.
 This core houses two copies of the single-stranded
RNA genome and viral enzymes.
 The virus infects the CD4 cell in a complicated
sequence of events beginning with engagement of
the viral gp120 and the CD4 cell receptor (stage 1),
which results in a conformational change in gp120.

 This permits interaction with one of two chemokine
co-receptors (CXCR4 or CCR5: stage 2), which is
followed by membrane fusion and cellular entry
involving gp41 (stage 3).
 Monocyte-macrophages, follicular dendritic cells and
microglial cells in the central nervous system also
express the CD4 cell receptor and are permissive to
infection.

 After penetrating the cell and uncoating, a DNA copy
is transcribed from the RNA genome by the reverse
transcriptase (RT) enzyme (stage 4) that is carried
by the infecting virion.
 Reverse transcription is an error-prone process and
multiple mutations arise with ongoing replication
(hence the rapid generation of viral resistance to
drugs).

 This DNA is transported into the nucleus and
integrated randomly within the host cell genome via
integrase enzyme (stage 5).
 Integrated virus is known as proviral DNA.
 On host-cell activation, this DNA copy is used as a
template to transcribe new RNA copies (stage 6),
which are processed and exported from the nucleus,
viral mRNA then being translated into viral peptide
chains (stage 7).

 The precursor polyproteins are then cleaved by the
viral protease enzyme to form new viral structural
proteins and viral enzymes such as the reverse
transcriptase and protease.
 These then migrate to the cell surface and are
assembled using the host cellular apparatus to
produce infectious viral particles.
 These bud from the cell surface, incorporating the
host cell membrane as their own lipid bilayer coat,
and cell lysis occurs (stage 9).

 Once maturation is complete, the new infectious
virus (virion) is then available to infect uninfected
cells and repeat the process.
 All of these processes are enabled by three viral
genes (Gag, Pol and Env ), as well as the products
of six regulatory genes (Vif, Vpr, Vpu, Nef, Tat and
Rev ).
 It has been calculated that each day more than 1010
virions are produced and 109
CD4 cells destroyed.
This represents a daily turnover of 30% of the total
viral burden and 6–7% of the total body CD4 cells.

 A small percentage of T cells (< 0.01%) either
produce small quantities of virus or enter a post-
integration latent phase and represent the main
reservoir of HIV.
 Together with virion-associated immune complexes
bound to follicular dendritic cells, they can refuel
infection if host defences fail or HAART is
discontinued.

 There is ongoing low-level replication within these
cells, even when plasma levels of HIV are below the
level of detection as a result of antiretroviral
treatment.
 They are important as sanctuary sites from antiviral
therapy, as continuing sources of virus (including the
generation of drug-resistant strains) and as eventual
targets for eradication strategies.
 The half-life of the virus is 1–2 hours in plasma, 1.5
days in productively infected CD4 cells and over 12
months in latently infected CD4 cells.

 With time, there is gradual attrition of the CD4 cell
population and, as CD4 cells are pivotal in
orchestrating the immune response, any depletion
renders the body susceptible to opportunistic
infections and oncogenic virus-related tumours.

 The predominant opportunist infections seen in HIV
disease are intracellular parasites (e.g.
Mycobacterium tuberculosis) or pathogens
susceptible to cell-mediated rather than antibody-
mediated immune responses.
 The exact mechanism underlying the CD4 decline is
not fully understood, but it is not restricted to virus-
infected cells and is linked to the height of plasma
viral load.

 Both are monitored closely in patients and used as
measures of disease progression.
 Virus-specific CD8 cytotoxic T lymphocytes develop
rapidly after infection and are crucial in recognising,
binding and lysing infected CD4 cells, thus
controlling HIV replication after infection and the
subsequent rate of disease progression.

 On the basis of DNA sequencing, HIV-1 can be
subdivided into group M (‘major’, world-wide
distribution), group O (‘outlier’, divergent from group
M) and group N (‘non-major and non-outlier’, highly
divergent) types.
 Groups O and N are restricted to West Africa and
may screen weakly positive or negative on routine
antibody testing.

 Group M can be subdivided further into subtypes; 9
are currently recognised (A–K), with numerous
subsubtypes (e.g. A1–A4) and circulating
recombinant forms (e.g. CRF01_AE). Globally,
subtype C (Africa and India) accounts for half of
strains.

 Subtype A (Africa, Asia and Eastern Europe) and
subtype B (Western Europe, the Americas and
Australia) are responsible for approximately 10%
each, and in many countries, more than one subtype
or recombinant exists, or is emerging in restricted
groups (e.g. West Africa, South-east Asia, southern
Europe, and Russia).

 Increased HIV diversity has implications for
diagnostic tests, treatments and vaccine
development. It may also influence transmission
(more frequent with subtype C), disease progression
(faster with subtypes A and D), co-receptor usage
(CXCR4 used early with subtype D) and emergent
resistance patterns (subtype C).
 In Europe, the prevalence of non-B subtypes is
increasing because of migrants ( predominantly from
Africa) and now accounts for a significant proportion
of newly diagnosed infection.

 HIV-2 is an important but separate retrovirus which
has at least five subtypes.
 The virus differs from HIV-1 in that patients have
lower viral loads, slower CD4 decline, lower rates of
vertical transmission and 12-fold lower progression
to AIDS.

Primary infection:
 Primary infection is symptomatic in 70–80% of
cases and usually occurs 2–6 weeks after
exposure.

 Rarely, presentation may be with neurological
features. This coincides with high plasma HIV-RNA
levels and a fall in the CD4 count to 300–400
cells/mm3
, but occasionally to below 200 when
opportunistic infections (e.g. oropharyngeal
candidiasis, Pneumocystis jirovecii pneumonia
(PCP)) may rarely occur.

 Symptomatic recovery parallels the return of the
CD4 count (although this rarely recovers to its
previous value) and fall in the viral load.
 In many patients, the illness is mild and only
identified on retrospective enquiry at later
presentation.

 Diagnosis is made by detecting HIV-RNA in the
serum or by immunoblot assay (which shows
antibodies developing to early proteins).
 The appearance of specific anti-HIV antibodies in
serum (seroconversion) takes place later at 3–12
weeks (median 8 weeks).
 Factors likely to indicate faster disease progression
are the presence and duration of symptoms,
evidence of candidiasis, and neurological
involvement.

 The level of the viral load post-seroconversion
correlates with subsequent progression of disease.
 The differential diagnosis of primary HIV includes
acute Epstein–Barr virus (EBV), cytomegalovirus
(CMV), streptococcal pharyngitis, toxoplasmosis and
secondary syphilis.

Asymptomatic infection:
 Asymptomatic infection (category A disease in the
Centers for Disease Control (CDC) classification)
follows and lasts for a variable period, during which
the infected individual remains well with no evidence
of disease except for the possible presence of
persistent generalised lymphadenopathy (PGL,
defined as enlarged glands at ≥ 2 extra-inguinal
sites).

 At this stage the bulk of virus replication takes place
within lymphoid tissue (e.g. follicular dendritic cells).
 There is sustained viraemia with a decline in CD4
count dependent on the height of the viral load but
usually between 50 and 150 cells/year.

Mildly symptomatic disease:
 Mildly symptomatic disease (CDC classification
category B disease) then develops in the majority,
indicating some impairment of cellular immunity but
which is not AIDS-defining.
 The median interval from infection to the
development of symptoms is around 7–10 years,
although subgroups of patients exhibit ‘fast’ or ‘slow’
rates of progression.

Acquired immunodeficiency syndrome (AIDS):
 AIDS (CDC
classification category C
disease) is defined by
the development of
specified opportunistic
infections, tumours and
presentations.

 Initial HAART is introduced when the CD4 count falls
below 350 cells/mm3
or an AIDS-defining illness
develops.
 Over 85% of cases achieve complete virological
suppression by 3 months, a steady increase in CD4
count and a return to good health.

 Occasionally, patients with low CD4 counts can
experience immune reconstitution disease (IRD).
This indicates either subclinical infection which has
become manifest with HAART, or an enhanced
reaction to dying or dead microorganisms which
results in clinical illness.

Mucocutaneous disease:
 Mucocutaneous
manifestations are
common in HIV and
range from the trivial to
markers of significant
systemic infection.

 Most patients are affected at some point and for
many it is a major problem.
 Dermatological problems may present atypically,
coexist with other pathologies and be harder to
manage than in an HIV-negative patient.
 Type and severity of rash are often dependent upon
the level of CD4 count.
 The presence of either oropharyngeal candidiasis or
oral hairy leucoplakia in a young person is
suggestive of HIV infection.

 Anyone with an unusual rash, especially one
persistent and unresponsive to topical
antifungal/corticosteroid combinations, or in the
presence of severe immune compromise (CD4 < 50
cells/mm3
), merits a skin biopsy for histology and
culture.

Specific skin conditions:
a. Fungal infections:
 Early HIV-associated skin diseases include xerosis
with pruritus, seborrhoeic dermatitis, and an itchy
folliculitic rash which may be fungal (Malassezia
furfur), staphylococcal or eosinophilic in aetiology.

 Dermatophyte infection affecting skin (feet, body and
face) and nails is also common, and may be
extensive and difficult to treat.
 Seborrhoeic dermatitis is very common in HIV and is
present in up to 80% of patients with AIDS; severity
increases as the CD4 count falls.

 It presents as dry scaly red patches on the face
(typically on the cheeks, in the nasolabial folds,
around the eyebrows, behind the ears and on the
scalp).
 The cause is multifactorial but M. furfur is important.
It responds well to a combined topical
antifungal/steroid.

b. Viral infections:
 The major viral infections affecting the skin are
herpes simplex, varicella zoster (VZV), human
papillomavirus (HPV) and molluscum contagiosum.

Herpes simplex (type 1 or 2):
 This may affect the lips,
mouth and skin or
anogenital area and is
seen in 20% of cases.
 In later-stage HIV, the
lesions are usually
chronic, extensive, harder
to treat and recurrent.
 Persistent and severe
anogenital ulceration is
usually herpetic and a
marker for underlying HIV.

VZV:
 This usually presents with a dermatomal vesicular
rash on an erythematous base, and may be the first
clue to a diagnosis of HIV infection.
 It can occur at any stage but is more frequent with
failing immunity.
 In patients with a CD4 count < 100 cells/mm3
, the
rash may be more severe, multidermatomal,
persistent or recurrent, or may become
disseminated.

 Involvement of the trigeminal nerve, scarring on
recovery and associated motor defects are probably
also more common.
 Diagnosis of herpetic infection can be confirmed by
culture, smear preparations showing characteristic
inclusion bodies, electron microscopy or biopsy.

 Treatment should be given for all cases of active
disease, irrespective of the time since onset of rash.
 In patients with severe mucocutaneous herpes
simplex or herpes zoster which is disseminated,
multidermatomal, ophthalmic or very dense, or when
the CD4 count is < 200 cells/mm3
, parenteral
aciclovir must be used.

HPV infection:
 This is frequent amongst HIV patients and is usually
anogenital; disease may be extensive and very
difficult to manage.
 Warts on the hands and feet (especially periungual)
are also common and may attain considerable size,
requiring surgery.
 Occasionally, myriads of flat-topped papules occur
over the body and face.
 Both oncogenic (16, 18, 31, 33) and non-oncogenic
(6, 11) genotypes are found.
 There is often improvement on HAART.

Molluscum contagiosum:
 This is an epidermal poxvirus infection.
 It is found in approximately 10% of AIDS patients.
 The lesions are usually 2–5 mm diameter papules
with a central umbilicus and most frequently affect
the face, neck, scalp and genital region.
 Lesions may become widespread and attain a large
size (giant mollusca).
 Treatment is with curettage or cryotherapy, and with
improvement in CD4 counts, lesions usually
disappear.

c. Bacterial and parasitic infections:
 Bacterial infections include Staphylococcus aureus
(folliculitis, cellulitis and abscesses), bacillary
angiomatosis and syphilis (primary and secondary).
 Bacillary angiomatosis is a bacterial infection due to
the cat-scratch bacillus, Bartonella henselae.
 Skin lesions range from solitary superficial reddish-
purple lesions resembling Kaposi’s sarcoma or
pyogenic granuloma, to multiple subcutaneous
nodules or even hyperpigmented plaques.
 Lesions are painful and may bleed or ulcerate.

 The infection may become disseminated with fevers,
lymphadenopathy and hepatosplenomegaly.
 Diagnosis is made by biopsy of a lesion and
Warthin–Starry silver staining which reveals
aggregates of bacilli.
 Treatment with doxycycline or azithromycin is
effective.

 In HIV, scabies (due to the mite Sarcoptes scabiei)
may cause intensely pruritic, encrusted papules
affecting most areas. Classically, the interdigital web
spaces, wrists, periumbilical area, buttock and sides
of the feet are involved.
 Commonly in HIV the infestation may be heavy, the
rash hyperkeratotic (Norwegian scabies) and the
patient highly infectious. Uniquely, the face and neck
are often affected.

 Rarely, cutaneous disease may be a manifestation of
mycobacterial infection (tuberculosis or an atypical
mycobacterium) or disseminated fungal infection.
 Papular pruritic eruption is an itchy symmetrical rash
affecting the extremities and resulting in hyper-
/hypopigmentation. It is seen mainly in those from
sub-Saharan Africa where it is the most common
skin manifestation of HIV, and is highly indicative of
HIV when present.
 Topical steroids, emollients and antihistamines are
useful but response is variable.

Specific oral conditions:
a. Candidiasis:
 Candida infection in HIV is almost exclusively
mucosal, affecting nearly all patients with CD4
counts < 200 cells/mm3
.
 In early disease, it is nearly always caused by C.
albicans.
 Pseudomembranous candidiasis describes white
patches on the buccal mucosa that can be
scraped off to reveal a red raw surface. The
tongue, palate and pharynx may also be
involved.

 Less common is erythematous candidiasis; patients
present with a sore mouth, reddened mucosa and a
smooth shiny tongue.
 Hypertrophic candidiasis (leucoplakia-like lesions
which do not scrape off but respond to antifungal
treatment) and angular cheilitis may also be present.

 Diagnosis is clinical but it is important to perform a
mouth swill for culture, speciation and sensitivities in
patients unresponsive to fluconazole or other azole
drugs. The cause is usually C. albicans.
 Prophylaxis is not recommended and therapeutic
courses of azoles should be given with each attack.

 Oesophageal infection
may coexist, although
no oropharyngeal
candidiasis is visible in
up to 30%.
 Up to 80% of patients
with pain on swallowing
have Candida
oesophagitis with
pseudomembranous
plaques visible on
barium swallow and
endoscopy.

 The pain is usually associated with dysphagia and,
when untreated, leads to weight loss.
 Treatment is with an oral azole drug, usually
fluconazole.
 Where azole-resistant candida is present,
caspofungin or amphotericin can be used.

b. Oral hairy leucoplakia:
 Oral hairy leucoplakia appears as corrugated white
plaques running vertically on the side of the tongue,
and is virtually pathognomonic of HIV disease in the
context of HIV risk factors.
 It is usually asymptomatic and does not require
treatment.
 The aetiology is closely associated with EBV.
 High-dose aciclovir or valaciclovir is sometimes
effective in eradicating the infection but relapse often
follows cessation of treatment.
c. Kaposi’s sarcoma.

Gastrointestinal disease:
 Pain on swallowing, weight loss and
chronic diarrhoea are common presenting
features of later-stage HIV.
 A range of opportunistic organisms and
HIV-related tumours may be responsible.

Specific conditions:
a. Cytomegalovirus
(CMV):
 Gastrointestinal
CMV is now
infrequent and is
only seen if the
CD4 count is < 100
cells/mm3
(usually
< 50).

 It may cause disease throughout the entire
gastrointestinal tract, including the liver and biliary
tree, but most commonly affects the oesophagus,
where it accounts for 10–20% of disease, and the
colon.

b. Cryptosporidium and Microsporidium:
 Cryptosporidium is a
highly contagious
zoonotic protozoal
enteric pathogen that
infects a wide range of
animals.

 Microsporidia are water-borne zoonoses, of which
four main species infect humans: Encephalitozoon
bieneusi, E. hellem, E cuniculi and E. intestinalis.
 They are intracellular spore-forming protozoa which
cause a mild inflammatory infiltrate and are carried
by a wide range of animals, birds and fish.

 Both Cryptosporidium and Microsporidium complete
their life cycle in a single host.
 Together they account for 10–20% of cases of
diarrhoea in HIV patients. This may vary from a mild
illness to severe diarrhoea, and may be complicated
by malabsorption and biliary disease.
 Encephalitis, sinusitis, and ocular and disseminated
infection may rarely occur with E. intestinalis.

 Diagnosis is usually
made by stool
microscopy, although
duodenal biopsy is
occasionally necessary.

 Electron microscopy is essential for speciation of
microsporidia.
 Although treatment for cryptosporidiosis and
microsporidiosis (albendazole ± itraconazole for E.
intestinalis and nitazoxanide or fumagillin for E.
bieneusi) may be effective, reconstitution of the
immune system with HAART is the most important
component of treatment and offers the best chance
of cure.

c. Other infections:
 Isospora (Africa and Latin America) and Cyclospora
(Asia) cause watery diarrhoea, weight loss and
malabsorption akin to Cryptosporidium, accounting
overall for 2–4% of cases in the UK. Diagnosis is by
stool microscopy and treatment for both is co-
trimoxazole.
 Giardia, Entamoeba histolytica, adenovirus and
bacterial overgrowth also occur more frequently in
HIV patients.
 Of the standard enteric pathogens, Salmonella is
important because of the increased probability of
bacteraemia and recurrent disease.

d. Mycobacterium avium intracellulare (MAI):
 Until the introduction of
HAART and primary
prophylaxis,
disseminated MAI
occurred in up to 35%
of all patients.

 Like other opportunistic infections, the incidence has
now fallen but it remains a problem in late-stage
AIDS, especially those cases that are newly
diagnosed.
 Patients present with fever and weight loss.
 Combination antibacterial therapy is essential to
prevent resistance, but reconstitution of the immune
system with HAART is necessary for cure.

Liver disease:
Hepatitis B and hepatitis C:
 The importance of hepatitis B and C co-
infection is increasingly recognised.
 For both HBV and HCV, co-infection is
associated with higher HBV or HCV viral
loads, accelerated natural progression to
cirrhosis (5–8 years after infection), an
increased rate of hepatoma and higher
mortality.

Hepatitis B:
 The majority of those with HIV have evidence of
HBV exposure.
 HBV carriage rate depends on the mode of
acquisition, place of birth and ethnic group (reflecting
vertical transmission), immunisation history (although
response rates are lower in HIV patients) and
likelihood of immune clearance after infection.

 Although HBV co-infected patients have more
aggressive disease, the immunosuppression seen in
more advanced HIV affords some protection
because hepatic damage is immune-mediated.
 Treatment with antivirals should be considered for all
patients who have active viral replication (HBVeAg-
positive or HBV-DNA > 2000 U/mL) and/or evidence
of inflammation, fibrosis or scarring on liver biopsy.

 When the CD4 is ≥ 500 cells/mm3
and in the
absence of cirrhosis, pegylated interferon or adefovir
can be considered. Otherwise, antivirals should
ordinarily be used.
 A combination of either tamivudine (3TC) or
emtricitabine (FTC) with tenofovir and an additional
anti-HIV drug provides effective anti-HIV and anti-
HBV treatment.

 A flare of hepatitis may be associated with improved
immune function consequent to HAART or
interruption of therapy and rebound HIV viraemia.
 All patients should be immunised against HAV.

Hepatitis C:
 Most patients with HCV have acquired their infection
from injection drug use but increasingly acute
infection is being seen in MSM.
 The major determinant of co-infection rate is the
mode of acquisition: > 80% for haemophiliacs, 70–
80% for injection drug-users, 10–15% for MSM and
3–5% for heterosexuals.
 Only 15–20% of patients ever clear their initial
infection, but this rate is higher in females, those with
higher CD4 counts, and those with raised
transaminases.

 Response to 12 months’ combination therapy with
pegylated α-interferon and weight-based ribavirin is
dependent on the HCV genotype (approximately
65% with genotypes 2 or 3 as opposed to
approximately 27% with other genotypes), HCV viral
load, CD4 count and the presence of cirrhosis; those
acutely infected also have an improved response
rate.
 HIV treatment is usually initiated first to optimise the
CD4 count to ≥ 350 cells/mm3
.

 Because of interactions with ribavirin, some
nucleotide reverse transcriptase inhibitors (ZDV,
didanosine (ddI) and possibly abacavir) should be
avoided if HAART is being co-administered.
 Therapy may be associated with a flare of hepatitis
because of improved immune responsiveness.
 All patients should be screened for HBV and HAV,
and immunised if not protected.

Respiratory disease:
 Many patients with HIV will develop pulmonary
disease at some time.
 Several factors influence the likely cause, including
CD4 count, ethnicity, age, risk group, prophylactic
history and geographical location.
 The history is vital in discriminating acute bacterial
pneumonia (rapid onset, pleuritic chest pain, rigors)
from Pneumocystis jirovecii pneumonia (subacute
onset, breathlessness, dry cough), a common
differential in later-stage disease.

 The chest X-ray is also important in distinguishing
presenting syndromes.

a. Pneumocystis
jirovecii:
 Pneumocystis jirovecii
(previously carinii)
pneumonia (PCP) was
the first major indicator
disease for HIV at the
beginning of the
epidemic, and still
accounts for 25% of
AIDS-defining illness.

 The incidence of PCP has fallen dramatically with
HAART and primary prophylaxis.
 Presentation is with fever, breathlessness, and dry
cough, and other markers of HIV (e.g. oropharyngeal
candidiasis or mucocutaneous herpes simplex) may
be present.

 The chest X-ray is usually
typical, but 20% are
atypical with unilateral
infiltration, upper lobe
disease (often when on
inhaled pentamidine
prophylaxis), focal
consolidation, cavitation
or nodular shadows.
 Clinical and radiological
deterioration within the
first 48 hours of treatment
is not uncommon.

b. Mycobacterium tuberculosis:
 Tuberculosis (TB) is the most common global
infection, affecting up to one-third of the estimated 40
million HIV patients.

 Estimated annual new case and death rates (8
million and 2 million respectively) are expected to
continue to rise inexorably.
 In some countries up to 30% of patients presenting
with TB are co-infected with HIV.
 Presentation is invariably with fever, weight loss and
site-specific symptoms (pulmonary, meningeal,
pericardial, etc.).

 Diagnosis may be
difficult, as smear-
positive rates are
reduced in pulmonary
TB, and chest X-ray
appearances may be
atypical with less
cavitation.

 Standard quadruple therapy is curative in the
majority, with mortality often being attributable to
other disseminated bacterial infections (e.g.
Salmonella and pneumococcus).
 If compliance is likely to be a problem, daily or thrice-
weekly directly observed therapy (DOT) should be
considered.

 Multidrug-resistant TB (MDRTB) presents a serious
clinical and public health problem in many areas of
the world (e.g. Eastern Europe, South Africa).
 In addition, extensively drug-resistant TB (XDRTB)
has now been reported from South Africa, where it
has become a significant problem, and also in small
numbers from over 100 countries.
 Treatment often entails hospital admission and 6–7
drug combinations.

c. Bacterial infections:
 Bacterial pneumonia is a common cause of morbidity
and mortality in HIV.
 The incidence, severity, likelihood of bacteraemia
and recurrent pneumonia, and mortality rate are all
increased compared to non-HIV-infected patients.
 Susceptibility to particular respiratory pathogens is
influenced by risk group, level of immune depletion,
age and presence of neutropenia.

 There is a 150-fold greater risk of pneumococcal
pneumonia in advanced HIV, when it is the cause of
40% of all pneumonias in which a pathogen is
identified, and 70% of those with bacteraemia.
 Pseudomonas (5%) and Nocardia infections are
more likely in later-stage disease.
 Legionella is also found more frequently.
 Chest X-ray appearances may be atypical.
 Infection usually responds to standard antibiotic
therapy.

Nervous system and eye disease:
 Disease of the central
and peripheral nervous
system is common in
HIV.
 It may be a direct
consequence of HIV
infection or an indirect
result of CD4 cell
depletion.

a. Toxoplasma gondii:
 Toxoplasma infection
results in a mild or
subclinical illness in
immunocompetent
individuals, with the
formation of latent
tissue cysts that persist
for life.

 The infection rate, as judged by seroconversion, is
0.5–1% per year.
 In advanced HIV, reactivation of these cysts may
occur with the development of cerebral
toxoplasmosis.
 Despite the characteristic findings on imaging, it is
often impossible to distinguish Toxoplasma
encephalitis from primary CNS lymphoma.

 However, the response to a trial of anti-Toxoplasma
therapy is usually diagnostic, with clinical
improvement within 1 week in 50% and 2 weeks in
90%; shrinkage of lesions on MRI is usual by 2–4
weeks.

b. Progressive multifocal leucoencephalopathy
(PML):
 PML is a demyelinating
disease caused by the
JC papovavirus; it
occurs at very low CD4
counts.
 Seroprevalence studies
demonstrate that up to
90% of young adults
have been exposed to
JC virus, most infections
occurring in childhood.

 A combination of
characteristic
appearances on MRI
and positive JC virus in
CSF is diagnostic.
 No specific treatment
exists and prognosis
remains poor despite
HAART.

c. Primary CNS lymphoma (PCNSL):
 PCNSLs are high-grade, diffuse, B-cell lymphomas
which usually complicate late-stage HIV (CD4 < 50
cells/mm3
).
 They occur in approximately 5% of AIDS patients
and account for 20% of all focal CNS lesions.
 The history is 2–8 weeks of headache, focal features
and sometimes confusion; seizures occur in 15% but
fever is absent.

 Characteristically, imaging demonstrates a large,
single, homogeneously enhancing periventricular
lesion with mild to moderate surrounding oedema
and mass effect.
 Multiple lesions may occur on MRI but a solitary
lesion is four times more likely to be PCNSL than
Toxoplasma.
 The presence of EBV-DNA in the CSF has a high
sensitivity and specificity for PCNSL.

 Biopsy is definitive, but carries a small risk of
morbidity and may be non-diagnostic in up to one-
third.
 Failure to improve clinically or on scanning with a
trial of anti-Toxoplasma therapy after 2–4 weeks is
consistent with PCNSL and is an indication for brain
biopsy.
 Treatment can be tried with HAART and high-dose
methotrexate, but the prognosis is poor.

d. Other focal brain disease:
 M. tuberculosis, Cryptococcus neoformans and
Treponema pallidum predominantly affect the
meninges but can produce mass lesions with focal
neurology.
 A less frequent cause of focal disease is CMV, which
presents with a subacute history of progressive
disorientation, withdrawal, apathy, cranial nerve
palsies and nystagmus. Bilateral enhancing
periventricular changes on MRI are characteristic
and retinitis is present in over half. Diagnosis is
made by identifying CMV-DNA in the CSF.

e. HIV-associated encephalopathy:
 HIV is a neurotropic virus and infects the CNS early
during infection.
 Aseptic meningitis or encephalitis may occur at
seroconversion, and minor cognitive defects such as
mental slowness and poor memory may develop as
the disease progresses.
 The incidence has fallen dramatically as a result of
HAART.

 Dementia occurs in late disease and is characterised
by global deterioration of cognitive function, severe
psychomotor retardation, paraparesis, ataxia, and
urinary and faecal incontinence.
 Changes in affect are common, and depression or
psychosis may be the predominant feature.
 Higher plasma and CSF HIV viral load, lower CD4
count and age are predictors.

 Investigations show diffuse cerebral atrophy with
widened sulci and enlarged ventricles on imaging,
and a raised protein in the CSF.
 Combination therapy using agents providing optimal
CNS penetration may slow or even reverse the
progression of HIV-associated dementia.
 Appropriate psychotropic medication may also be
necessary.

f. Cryptococcosis:
 Cryptococcus
neoformans is the most
important cause of
meningitis associated
with late-stage HIV and
occurs in up to 5% of
patients, who usually
present with a 2–3-
week history of
headache, fever,
vomiting and mild
confusion.

 Neck stiffness is present in less than 25% of
patients, and around 10% are asymptomatic.
 Diagnosis is made by CSF antigen detection and
culture.
 Between 10% and 20% of patients require treatment
for raised intracranial pressure with repeated lumbar
punctures, a lumbar drain or shunting.

g. Spinal cord, nerve root and peripheral nerve
disease:
 A variety of neuropathies occur in HIV infection.
 At seroconversion, Guillain–Barré syndrome,
transverse myelitis, facial palsy, brachial neuritis,
polyradiculitis and peripheral neuropathy have all
rarely been described.

 Vacuolar myelopathy is a slowly progressive myelitis
resulting in paraparesis with no sensory level.
 Ataxia and incontinence occur in advanced cases.
 The CSF may show a raised protein but is frequently
normal; MRI of the spine is normal, and the
diagnosis is by exclusion of other causes.

 A predominantly distal HIV-related sensory
neuropathy of the lower limbs affects up to 30% of
patients.
 It is associated with a lower CD4 (usually < 200
cells/mm3
), higher viral load, older age and wasting,
and results from axonal degeneration.
 Hyperaesthesia, pain in the soles of the feet and
paraesthesia, with diminished pin-prick, light touch
and vibration sensation, and loss of ankle reflexes
(75%) are typical.

 The nucleoside reverse transcriptase inhibitor (NRTI)
drugs, especially d4T and didanosine (ddI), can
produce an identical picture but this remits if the
offending agent is withdrawn early.
 Treatment is often difficult, although amitriptyline,
lamotrigine and topical capsaicin cream may help
symptoms.
 HAART has minimal effect on halting or reversing
the process.

 Polyradiculitis occurs in late-stage HIV (CD4 count <
50 cells/mm3
) and is nearly always a result of CMV.
 It causes rapidly progressive flaccid paraparesis,
saddle anaesthesia, absent reflexes and sphincter
dysfunction. Pain in the legs and back is an early
symptom.
 Nerve root involvement on nerve conduction studies,
a neutrophil CSF pleocytosis and the presence of
CMV-DNA demonstrated by PCR confirm the
diagnosis.
 Despite treatment, functional recovery may not
occur.

 Lastly, proximal myopathy can result from HIV, when
it may occur at any stage, or rarely from zidovudine
(ZDV) (< 1% of patients).

g. Psychiatric disease:
 Significant psychiatric morbidity is not uncommon.
 Anxiety and mood disturbance may be caused by
pre-test issues such as worries about being infected
and disclosure, receiving a positive result (e.g.
confidentiality, discrimination and stigmatisation),
concerns about life expectancy, or facing up to
death.
 Mild cognitive dysfunction is a common occurrence
in later-stage disease and usually improves with
HAART.

 Disorders of mental state may also result from drugs
directly (e.g. depression with efavirenz) or indirectly
(e.g. those affecting sexual dysfunction).
 Psychiatric morbidity is a major risk factor for poor
compliance with drug treatment, which is a critical
component of HAART management.

i. Retinitis:
 Since the advent of
HAART, there has been
a 90% fall in the
incidence of CMV
infections.
 Patients usually present
with field defects and
well-demarcated areas
of retinal disease.

 Macular disease is rare but constitutes the most
sight-threatening feature.
 Diagnosis is usually clinical.
 Treatment needs to be prompt, as the leading edge
will progressively advance; no recovery of vision
occurs in affected areas.
 Some patients may develop immune recovery uveitis
in response to HAART, with intra-ocular
inflammation, macular oedema and cataract
formation that requires prompt treatment with oral
and intra-ocular corticosteroids to prevent visual
loss.

Miscellaneous conditions:
Haematological conditions:
 Disorders of all three major cell lines may occur
in HIV and are most frequent in later-stage
disease (anaemia 70%, leucopenia 50% and
thrombocytopenia 40%), when pancytopenia
may also be seen.

 Numerous causes for anaemia exist, including
marrow infiltration with opportunistic infections (MAI
or TB) or neoplasms (non-Hodgkin lymphoma); bone
marrow suppression from drugs (ZDV) or as a direct
effect of HIV; and chronic blood loss (Kaposi’s
sarcoma) or malabsorption (chronic protozoal
infections) in gastrointestinal tract disease.
 Haemolytic anaemia is uncommon but is seen with
lymphoma.

 Leucopenia is usually seen in the context of marrow
infiltration, as above, or drug toxicity (e.g. ZDV, co-
trimoxazole, ganciclovir).
 Lymphopenia (< 1.0 × 109
/L) is a good marker of
HIV.

 Thrombocytopenia may appear early (5–10%) and
be the first indicator of HIV, or in later-stage disease.
Its behaviour is very similar to idiopathic
thrombocytopenic purpura, with detectable platelet
antibodies and short-lived response to intravenous
immunoglobulin. However, the treatment of choice is
HAART.

Renal, cardiac and endocrine conditions:
 With the advent of HAART, opportunistic infections
have declined substantially, and non-HIV-related
illnesses of the cardiovascular, liver and renal
systems have emerged as more important causes of
morbidity and mortality.

 Acute renal failure may be associated with acute
infection or medication-related nephrotoxicity; this
usually resolves with appropriate management.
 HIV-associated nephropathy (HIVAN) is the most
important cause of chronic renal failure and is seen
most frequently in patients of African descent and
those with low CD4 counts.
 Other important HIV-associated renal diseases
include HIV immune complex kidney diseases and
thrombotic microangiopathy.

 Several drugs used in HIV management are also
associated with renal disease, including indinavir
(causes renal stones), tenofovir, pentamidine,
cidofovir and co-trimoxazole.
 HIVAN usually presents with nephrotic syndrome,
chronic renal failure or a combination of both.
 With the overall improvement in life expectancy,
conditions such as diabetes mellitus, hypertension
and vascular disease add to the burden of chronic
kidney disease.

 HAART has some effect in slowing progression of
renal disease.
 Doses of NRTIs must be adjusted according to
creatinine clearance.
 Those who progress to end-stage renal disease
while receiving HAART may be eligible for renal
transplant.

 With increasing life expectancy, cardiac disease has
become important.
 Although HIV-related dilated cardiomyopathy can be
detected in 25–40% of AIDS patients, symptomatic
heart disease is rare (3–6%) and zidovudine-induced
cardiomyopathy rarely seen.

 Nevertheless, patients on certain antiretrovirals (e.g.
protease inhibitors, abacavir and ddI) and those with
CD4 counts < 350 cells/mm3
not taking HAART have
increased rates of coronary artery disease.
 Moreover, there is a small but additional effect of
drug-induced hyperlipidaemia with protease
inhibitors and stavudine.

 Patients with fatigue and low CD4 counts should be
screened for hypoadrenalism, which is seen in up to
one-quarter of patients, and hypogonadism.
 Hypopituitarism has also been described

HIV-related cancers:
 Malignancies in HIV can be divided into AIDS-
defining and non-AIDS-defining cancers.
 AIDS-defining cancers are characterised by a strong
inverse association with CD4 count, which is also
seen but to a lesser extent in many of the non-AIDS
malignancies.
 Kaposi’s sarcoma and non-Hodgkin lymphoma are
the most important AIDS-defining malignancies, with
anal cancer and Hodgkin disease becoming
increasingly important non-AIDS-defining
malignancies.

a. Kaposi’s
sarcoma (KS):
 Together with PCP,
KS has become a
hallmark of AIDS; it
is due to the herpes
virus HHV-8.

 Prior to HIV, KS was a rare tumour
restricted to elderly Mediterranean or
Jewish males, immunosuppressed
transplant recipients, and children and
young adults in sub-Saharan Africa.

 Typical presentation is with raised non-pruritic
papules, often found incidentally on examination in a
newly diagnosed patient.
 As the disease progresses, the skin lesions become
more numerous and larger.
 Visceral disease occurs in only 10% at presentation.
 With the widespread use of HAART, which is also the
mainstay of treatment, there has been a 70% fall in
incidence.

 Primary-effusion lymphoma (< 2% of cases of non-
Hodgkin lymphoma) and multicentric Castleman’s
disease, which is a rare lymphoproliferative disorder
affecting mainly HIV patients who present with
anaemia, fevers and multifocal lymphadenopathy,
are other HHV-8-associated conditions seen rarely
with HIV.

b. HIV-associated lymphoma:
 In the majority of
patients, non-Hodgkin
lymphoma (NHL)
represents a late
manifestation of HIV,
with risk increasing as
CD4 count falls.

 The risk is > 50-fold greater than in HIV-negative
individuals, with a lifetime risk of developing NHL of
5–10%.
 Over the last 10 years, the incidence of NHL has
fallen by > 40% but has increased as a proportion of
AIDS-defining illnesses.

 By comparison, the incidence of Hodgkin disease
(HD) has a definite but less marked association with
HIV (10–20-fold greater than in HIV-negative
individuals) and CD4 count fall.
 For both, extranodal and advanced presentation is
more likely, with the majority having B symptoms.
 Histologically, HD is more likely to show mixed
cellularity or lymphocyte-depleted subtypes, as
opposed to nodular sclerosis; a high percentage
stain EBV-positive.

 After diagnosis of NHL or Hodgkin lymphoma, a
staging evaluation is required.
 For both, HAART therapy is associated with
improved overall response, disease-free survival and
complete remission rates, so its introduction should
not be delayed.
 Multi-agent chemotherapy is the mainstay of
treatment but intrathecal chemoprophylaxis, support
of bone marrow reserves and prevention of infection
are also key elements.

 Additional rituximab may improve response,
depending on tumour cell markers.
 More intensive regimens are required for Burkitt’s
lymphoma.
 For HD, first-line treatment is as standard.
 Use of HAART with chemotherapy is safe, although
drugs that have overlapping side-effects with
cytotoxics should be avoided (e.g. ZDV and marrow
suppression).
 Following chemotherapy, it may take up to 1 year for
the CD4 count to return to pre-treatment levels.

c. Other non-AIDS-defining cancers:
 HIV-infected patients have a greater risk of
developing anogenital (vulval/vaginal, anal, penile)
and in situ cervical cancer (cervical intra-epithelial
neoplasia (CIN) III), all of which are closely
associated with HPV co-infection.
 This is more frequently observed in HIV (60% of
females; 90% of males), including the most
oncogenic genotypes (HPV-16, 18, 31, 33, 35).

 Patients are more likely to have multiple genotypes
which persist with time, and to progress more rapidly
from dysplasia to in situ cancer.
 Both a higher viral load and a lower CD4 count are
associated with higher co-infection rates.

 Invasive cervical cancer is an AIDS-defining
diagnosis, although it is unrelated to CD4 count and
the risk is much lower than that for KS and NHL; by
contrast, CIN is more common and more likely to
recur. Disease tends to present late and is more
aggressive.
 Annual cervical smears should be taken from all HIV-
infected women.

 The incidence of anal cancer is increasing (37-fold
for men and 6.8-fold for women), particularly for
MSM. Most are squamous cell carcinomas and tend
to be advanced at presentation; treatment is with
chemo- and radiotherapy. Survival rate is around
50% at 2 years.

 Management of HIV involves both treatment of
the virus and prevention of opportunistic
infections.

The aims of HIV treatment are to:
A. reduce the viral load to an undetectable level for as
long as possible
B. improve the CD4 count to > 200 cells/mL so that
severe HIV-related disease is unlikely
C. improve the quantity and quality of life without
unacceptable drug-related side-effects or lifestyle
alteration
D. reduce transmission.

 The principle of combining drugs serves to provide
additive antiviral activity with a reduction in the
emergence of viral resistance. This is known as
highly active antiretroviral therapy (HAART) and is
the cornerstone of management.

Drugs:
a. Nucleoside reverse transcriptase inhibitors
(NRTIs):
 The drugs in this class are zidovudine (ZDV),
didanosine (ddI), lamivudine (3TC), stavudine
(d4T), abacavir and emtricitabine (FTC), which
have been developed sequentially.

 The NRTIs act through intracellular phosphorylation
to the triphosphate form and incorporation into the
DNA, where they inhibit further lengthening of the
complementary strand to the viral RNA template.
 Each drug specifically competes with a natural
nucleoside (e.g. ZDV with thymidine).
 CNS penetration is good with all NRTIs, and ZDV
has been demonstrated to be of benefit in AIDS
dementia.

 Tenofovir is a nucleotide drug which only requires
two phosphorylation steps to the triphosphate form.
Its activity and characteristics are similar to the
NRTIs.
 The inclusion of two NRTIs, or one NRTI and
tenofovir, remains the cornerstone of HAART.

 Resistance occurs to all NRTIs unless they are part
of a maximally suppressive HAART regimen;
resistance to 3TC and FTC is rapid and high-level.
 Occasionally, certain single mutations in the viral
reverse transcriptase may result in broad resistance
to several or all of the NRTIs and tenofovir. These
can be selected out by combining drugs that have
overlapping resistance profiles and a low genetic
barrier to resistance.

 Early side-effects are uncommon with current
recommended NRTIs.
 Abacavir can result in a hypersensitivity reaction in
3% of patients with rash, fever and an influenza-like
illness, but this only occurs in those with the genetic
allele HLAB57*01; this can be screened for prior to
use of abacavir and the drug avoided if it is present.

 Abacavir also appears to be associated with a small
risk of coronary heart disease, and tenofovir with
bone demineralisation and rarely renal tubular
toxicity. They should be avoided if possible in those
with existing cardiovascular risk factors or renal
impairment respectively.

 ZDV is occasionally used (mainly during pregnancy),
which can result in nausea and macrocytic anaemia.
 In resource-poor countries, ZDV and d4T are
important first-line drugs.

 However, lipoatrophy
(fat loss from the face,
limbs and buttocks) is a
frequent long-term
complication, and
peripheral neuropathy
and lactic acidosis (ddI
and d4T) may occur
due to inhibition of
mitochondrial DNA
synthesis.

b. Protease inhibitors (PIs):
 The first PI developed was saquinavir followed by
indinavir, ritonavir, lopinavir and tipranavir; more
recently, atazanavir, fosamprenavir and darunavir
have become available.
 Currently used PIs should always be boosted by low-
dose ritonavir, which is a potent inhibitor of liver
metabolism.

 This increases drug exposure, thereby prolonging
the PI’s half-life, allowing reduction in pill burden and
dosing frequency and so optimising adherence. It
also limits the development of resistance.
 Pis prevent post-translational cleavage of
polypeptides into functional virus proteins.
 When they are given with two NRTIs, the
combination controls viral replication in plasma and
tissues, and allows reconstitution of the immune
system.

 Early and late side-
effects are common.
 PI use has been linked
with fat accumulation
which is characterised
by central adiposity and
localised collections
(buffalo hump,
peripheral lipomatosis,
and breast enlargement
in women).

 In addition, their use may be associated with
hyperlipidaemia (mainly total cholesterol and
triglyceride), and abnormal glucose tolerance; this is
less marked for atazanavir and darunavir.
 An increased risk of myocardial infarction has been
linked to certain PIs that is not explained by
dyslipidaemia.
 Individual PI side-effects include diarrhoea
(lopinavir), renal stones (indinavir),
hyperbilirubinaemia (atazanavir) and rash (
fosamprenavir and darunavir).

 PIs are metabolised by the P450 cytochrome system
(mainly the CYP3A4 isoenzyme), giving rise to the
potential for multiple drug interactions.
 Commonly used drugs that interact with PIs (in
particular ritonavir) are rifampicin, midazolam and
simvastatin.
 Monitoring plasma levels and dose adjustments may
be necessary to optimise the antiviral effect and
reduce toxicity.

c. Non-nucleoside reverse transcriptase inhibitors
(NNRTIs):
 There are two main NNRTIs used in drug-naïve
patients (nevirapine and efavirenz) and one in drug-
experienced (etravirine).
 Activity is through inhibiting reverse transcriptase by
binding near to the active enzyme site.

 NNRTIs do not require intracellular activation and
are not active against HIV-1 subtype O or HIV-2.
 All have good bioavailability and, for efavirenz and
nevirapine, low daily tablet number and apparent
freedom from long-term side-effects.
 Hypersensitivity rash and hepatitis are the major
class-specific side-effects.
 The rash is usually mild and self-limiting but
Stevens–Johnson syndrome may occur (0.3% with
nevirapine, 0.1% with efavirenz).

 Similarly, hepatitis occurs more frequently with
nevirapine, when it is gender- and CD4 count-
dependent (11% in women with CD4 counts of > 250
cells/mm3
), and may be fulminant. Hence its use is
restricted to CD4 count thresholds of 250 cells/mm3
for women and 400 cells/mm3
for men.

 CNS side-effects, including dizziness, vivid dreams,
insomnia, somnolence and poor concentration, are
described in half the patients treated with efavirenz.
These usually resolve by 2–4 weeks and are only
sufficiently severe to require discontinuation in 2–
5%.

 The major disadvantage of efavirenz and nevirapine
is the rapid development of resistance in patients
with virological failure, although they usually remain
susceptible to etravirine. This is commonly used in
combination with boosted darunavir and/or an
integrase or entry inhibitor in patients with triple-
class treatment failure.
 Nevirapine and efavirenz reduce methadone levels
by approximately 50% and may precipitate opiate
withdrawal.

d. Entry inhibitors:
 Currently, two classes of entry inhibitor exist: those
that interfere with fusion by binding to gp41 (e.g.
enfuvirtide) and those that bind to the CCR5 co-
receptor blocking attachment of the virus (e.g.
maraviroc). Both are given twice daily and used in
patients with advanced disease and few other
options.

 However, enfuvirtide has to be injected
subcutaneously, and maraviroc can only be used in
patients whose virus is CCR5-tropic (only 50% of
patients with advanced disease).
 Together with boosted darunavir, etravirine and
raltegravir, these drugs have transformed the
management of patients with triple-class failure or
resistant virus.

 In these highly treatment-experienced patients, it is
imperative to use two and preferably three active
agents in the new regimen.
 Because 95% of patients with early disease harbour
CCR5-tropic virus, maraviroc has also been
evaluated as a drug option for treatment-naïve
patients.

e. Integrase inhibitors:
 This class of drug inhibits the third and final step of
proviral DNA integration: that of strand transfer.
 Raltegravir is the first in this class and has shown
high potency in heavily experienced patients
irrespective of existing resistance, subtype and
tropism. It is primarily metabolised by glucuronidation
and therefore is not affected by co-administration
with other antiviral drugs and has no major side-
effects.

Treatment:
The naïve patient:
 The decision to start therapy is a major one; it is
influenced by several factors but predominantly
by the CD4 count.
 The risk of HIV-related disease with opportunistic
infection and malignancy increases, treatment is
less effective and side-effects are more common
when the CD4 count is < 200 cells/mm3
.

 Prior to commencing treatment, all patients should
have hepatitis B and C status checked, along with
HIV viral resistance (5–10% incidence of primary
resistance in the UK and Europe) and HLA-B*5701
tests (if abacavir is being considered an option).

 With careful and appropriate choice of HAART, over
80% of patients have an undetectable viral load (VL)
(i.e. < 50 copies/mL) at 4–6 months.

 The factors that reduce the probability of achieving
prolonged viral suppression include low CD4 count
(< 50 cells/mm3
) and high VL (> 100 000 copies/mL),
poor adherence, pre-existing or emergent
resistance, and drug interaction or toxicity.

 The presence of active opportunistic infection or
other HIV-related disease should not delay the
introduction of HAART, which usually should be
commenced as soon as the patient’s condition has
stabilised.

The drug-experienced patient:
 A change in antiretroviral therapy may be necessary
because of drug side-effects (early or late),
difficulties in adherence or virological failure (defined
as detectable VL despite treatment).
 In a patient with a previously undetectable VL,
treatment failure is indicated by viral rebound.
 With increasing time on a failing regimen, the VL
rises towards baseline levels, resistance mounts, the
CD4 count falls and clinical progression occurs.

 In essence, most early failures are related to
adherence difficulties (sometimes resulting from
toxicity) and most late failures are a result of
virological resistance.
 A resistance test should always be obtained before
switching drugs, with a new active regimen being
introduced as soon as possible and guided by this
result. Account should also be taken of prior drug
exposure.

 In certain situations, therapeutic drug monitoring
may be helpful in confirming that virological failure is
not related to inadequate PI or NNRTI levels.
 The new combination should include a minimum of
two fully active new agents.
 Occasionally, HAART must be stopped because of
life-threatening drug toxicity or overriding medical
problems where predicted drug interactions will
occur.

 In this situation, the prolonged half-life of the
NNRTIs should be covered by substitution of a PI
or continuation of the other components of
HAART for 2 weeks.

 Treatment interruption is associated with an
increased risk of progression and non-HIV-related
complications.

Special situations:
Children:
 The general principles of management are
the same as those for adults, although the
CD4 percentage is a more accurate marker of
immunological health until 5 years of age.
 All infants should receive PCP prophylaxis
and commence HAART, irrespective of CD4
count or VL.

CD4 counts (cells/mm3
) and CD4 percentage
thresholds to initiate HAART are:
A. < 1000 cells and/or < 25% at 1–2 years
B. < 500 cells and/or < 20% at 3–4 years
C. < 350 cells and/or < 15% if above 5 years and in
any child with advanced clinical disease.

 It should also be considered in those with a VL >
100000 copies/mL.
 After 1 year of age, PCP prophylaxis should be given
to children until they are 5 with a CD4 percentage of
< 15%, and then at the same CD4 levels as for
adults.
 Not all antiretroviral drugs are available in a suitable
formulation for children, e.g. suspension, powder,
crushable tablet or a capsule that can be opened.

 First-line preferred choices include boosted lopinavir,
nevirapine (< 3 years) and efavirenz (> 3 years) with
two NRTIs.
 Coordinated, comprehensive, family-centred
systems of care are necessary to support the child
and parents and to optimise compliance with
medications.

Maternal HIV:
 All pregnant women should routinely be
recommended for HIV testing at an early stage in
pregnancy, with rapid tests considered for those
presenting in or just after labour.
 Pre-HAART, the rate of mother-to-child transmission
was 26% with rates being influenced by several
factors

 The likelihood of transmission at delivery is
decreased to the order of 8% with single-dose
nevirapine to mother and child, 6–8% for ZDV alone,
< 1% for ZDV and caesarean section, and < 1% for
HAART and planned vaginal delivery when the viral
load is < 50 copies/mL.

 Single-dose nevirapine is used in resource-poor
nations, but in the absence of other drugs is
associated with a 30–50% chance of NNRTI
resistance in mother and infected child.
 Mothers should formula-feed their babies exclusively.
 Screening for HIV in the baby by proviral DNA
should be performed at birth (not on cord blood), 6
weeks and 3 months. If negative, vertical
transmission has not occurred.

 In discordant couples (i.e. only one partner is HIV-
positive) who desire a family, self-insemination of the
partner’s semen is recommended to protect the
uninfected male and sperm-washing is
recommended to protect the uninfected female
partner.

Post-exposure prophylaxis:
 Post-exposure prophylaxis with combination therapy
(boosted lopinavir, tenofovir and FTC) is
recommended when the risk is deemed to be
significant after a careful risk assessment, in both
occupational and non-occupational settings.
 The first dose should be given as soon as possible,
preferably within 6–8 hours.
 However, protection is not absolute and
seroconversion may occur.

 Non-occupational settings include condom breakage
in HIV-serodiscordant partners, victims of rape, and
sharps-related home exposures in families of
injection drug-users or HIV patients.
 Many individuals experience side-effects and only
half complete the recommended 4 weeks of therapy.

Prevention of opportunistic infection:
 Patients should be immunised with hepatitis A and
hepatitis B vaccines if there is no evidence of
naturally acquired infection.
 HBV surface antibody levels need to be monitored
and boosters given when < 100 U/mL.
 Pneumococcal vaccine (every 3–5 years) and
influenza vaccine (annually) should be given to all
patients.

 Response to all immunisations is lower when the
CD4 count is < 200 cells/mm3, although some
protection is afforded.
 Live attenuated vaccines (BCG, oral polio) should be
avoided or restricted to those with high CD4 counts
(yellow fever).
 Nevertheless, MMR (measles/mumps/rubella)
vaccine is safe and can be given

 Prophylaxis against infection is another vital aspect
of management.
 Primary prophylaxis is to prevent the initial disease
occurring, and secondary to prevent recurrence of
infection.
 Primary prophylaxis is introduced at specified CD4
counts at which there is a risk of infection.

 Secondary prophylaxis is started after successful
treatment of the opportunistic infection, usually with
the same drug(s) that was used to treat it, but at
lower doses.
 Drugs can usually be stopped when the CD4
threshold at which primary prophylaxis is introduced
is reached.

Prevention of HIV:
 HIV vaccine development is slow.
 An effective, safe and cheap vaccine would radically
alter the future global epidemic of HIV.
 Despite advances in the understanding of HIV
pathogenesis and immunology, prototype HIV-1
vaccine candidates aimed at eliciting humoral and
cellular immune responses have so far failed.

 Challenges include the extensive subtype and
sequence diversity of HIV, the early establishment of
reservoirs, the lack of a safe attenuated virus, the
lack of a small animal model, and the inability of
vaccines to generate protection across different viral
strains.

 The United Nations’ aim is universal access to
comprehensive prevention programmes, treatment,
care and support by 2010. To achieve this, access to
HIV testing needs to be widened, and strategies are
required to protect the HIV non-infected person (e.g.
promoting consistent condom use, improved STI
management, male circumcision), for effective
mother-to-child prevention programmes, and for
scaling up of antiretroviral drug access.

25. hiv infection and aids

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