HIV Infection - A brief note
This web-page is massively out of date, but we've retained it more or less out of
The brilliant identification of the human immunodeficiency virus just
three years after the clinical description of the Acquired Immune Deficiency
Syndrome (AIDS) has unfortunately been marred by scruffy squabbles between
the discoverers, and more recently by certain misguided scientists
(with the help of the ignorant British lay press) questioning the
causal association between HIV and AIDS. The fascinating biology of the
virus has now been rather clearly elucidated, although some details still
remain to be filled in.
HIV is trophic for T lymphocytes, specifically those bearing the T4
receptor, although this receptor alone is not sufficient to allow the
virus entry into T4-bearing cells. Because it is a retrovirus, HIV can
integrate into the genome of the host (using the virus-supplied enzyme
reverse transcriptase). This has tremendous implications for therapy,
as one can never really be sure that, even if we appear to have eliminated
the virus from the host, there is not a single copy lurking somewhere
in some obscure cell, waiting to re-emerge and wreak havoc once more.
The problem is compounded by the lack of proof-reading of viral
transcripts. Normal cells check (proof-read) transcripts, eliminating
mutant nucleic acids, but retroviral copies don't undergo this check,
allowing HIV to mutate at a ferocious rate. This explains why, when an
anti-retroviral drug is given in an attempt to control HIV, resistant
mutants appear literally within days - some mutants are bound to arise
that are resistant to the single drug. It also provides the rationale
for combination therapy, which should hit the virus at several points,
making emergence of resistant mutants less likely.
Unfortunately, in common with many of humanity's most vicious
scourges, HIV is predominantly a disease of the poor and repressed.
The majority of new cases are occurring in sub-Saharan Africa, where
in some areas prevalence may be 30% of the population, but HIV is
still spreading unchecked in other poor countries as well, especially
in Asia. It is perhaps fortunate for researchers into the disease that
the American (and indeed worldwide) homosexual community which initially
seemed to be bearing the brunt of the illess has been so vocal in
drawing attention to HIV, as vast amount of research funds have been
poured into investigating HIV biology and finding therapeutic agents,
but unfortunately all therapies, especially combination therapy is
financially prohibitive for the vast majority of those afflicted with
HIV-1 is a plus sense, single-stranded RNA virus, one of the lentiviruses,
and vaguely related to other human retroviruses such as HTLV-1 (which is
associated with adult T-cell leukaemias, and tropical spastic paraparesis).
The viral core contains the vitally important reverse transcriptase which
makes a DNA transcript of the RNA, as well as structural proteins, the
most prominent of which are p24 (capsid) and p18 (matrix) proteins. Not
content with hijacking the host genome, the virus also sneaks off with
a lipid envelope derived from the host cell, but studded with two
glycoproteins (gp120 and gp41) which are necessary for binding to T4
receptors and entry into host cells. The complex genome contains the
three standard retroviral genes needed for replication (gag, pol and env),
as well as at least six other regulatory genes. Of great significance is
a viral protease, which is necessary to convert some key viral proteins
to active forms.
Unfortunately for humans, T helper lymphocytes are not the only cells
expressing T4 receptors - they are also found on monocytes, macrophages,
and particularly, Langerhans cells in the skin. Even worse, certain central
nervous system cells such as microglia express the receptor, giving the
virus a tropism for the nervous system that practically ensures a long-term
reservoir for the virus, even if it has been eliminated on the other
side of the blood-brain barrier. Early infection of the central nervous
system is thought to occur in many (perhaps most) infected individuals.
HIV progressively incapacitates the immune system by destroying
T-helper cells. This affects every branch of immune system, resulting
in opportunistic infection by a host of bacteria, parasites and viruses,
as well as allowing tumours to proliferate in the affected person. Initial infection
is commonly associated with an "acute viral syndrome" of fever,
lymphadenopathy, pharyngitis and sometimes rash. There may be mild
features of meningeal inflammation. It is at this time that individuals
are perhaps most infective, with up to ten million virions per millilitre
in their peripheral blood. Unfortunately, they initially show no evidence
on antibody testing of HIV, so this highly infective stage might be missed
were they unwise enough to, for example, donate blood after initial
infection. There is a strong suggestion that those individuals who
have the highest initial levels of virus infection progress more rapidly
to immunodeficiency, which will develop within about a quarter to a third
of infected individuals in the first seven years after infection.
Even in asymptomatic individuals however, there is an ongoing and uneasy
balance between the rampant proliferation of the virus and attempts
by the body to maintain immune competence.
The first cases were reported from Los Angeles (and soon afterwards
from New York) in 1981. Initially homosexual men and intravenous
drug abusers appeared to be the target populations, but we now know
that they represent a small subset of an enormous global population,
most of whom are heterosexual.
Transmission is first and foremost sexual. Certain associations
are common, notably other sexually transmissible diseases (especially
Haemophilus ducreyi [chancroid] in African populations). In homosexual
males, receptive anal intercourse is the major risk factor. Any
exposure to HIV-infected semen or blood is a risk factor, and
a vast number of haemophiliacs and other recipients of blood products
worldwide have acquired the virus. Trans-placental and more importantly,
perinatal infection is extremely common (the risk of infection of the
infant being about 1 in 6, rising to 1 in 3 if the infant is breast
Transmission to health-care workers is well documented, the overall
risk being about 3 per 1000 needle-sticks, but substantially higher if
viral titres are high in the source patient, if visible amounts of blood
are found on the needle, with deep injuries,
or if a hollow-core needle was involved. Rare
infections have been reported with mucosal or even extensive skin
exposure! Up to 40% of documented needlestick injuries were considered
Prevention of HIV
The most important method for preventing HIV transmission is sexual
abstinence or fidelity to one partner. Condoms help with prevention but
failure of condoms to prevent pregnancy is common and similarly
failure to prevent transmission of HIV is possible. The dangers of needle
sharing by IV drug abusers are obvious. Transmission by blood transfusion
should now be rare in developed countries where screening occurs. Health
care workers should observe "universal precautions" to prevent transmission
- any person should be regarded as a potential source of HIV infection.
The following are important:
- All blood, blood products and body fluids should be
- Use gowns, eye protection and masks where splashing of
such fluids is likely;
- Handwashing is mandatory before and after patient contact,
after removing gloves;
- Sharps should be handled with obsessive care and never
manipulated, bent, broken or resheathed
- blood spills: absorb with disposable towel and then
disinfect with 1:10 household bleach;
- Sterilise reusable equipment appropriately (preferably
- Use appropriate devices for CPR;
- avoid patient contact if you as a health care worker
have skin abrasions, lesions or weeping dermatitis;
The development of an HIV vaccine seems years away, and will be
technically extremely difficult to accomplish.
Organ Systems affected by HIV
Each and every organ system in the body may be affected by HIV, often
directly, but even more frequently by opportunistic infections and/or
malignancies. These include:
Commonest by far are Pneumocystic carinii pneumonia, and Mycobacterium
- Pneumocystis carinii pneumonia (PCP) - is common in advanced
HIV infection, often attacking insidiously with progressive dry
cough, fever and dyspnoea. Absence of cough and of shortness of
breath makes PCP unlikely. Although diffuse interstitial infiltration
is common, focal radiological abnormalities may be seen.
- Mycobacterium tuberculosis is particularly common in HIV infected
persons in Africa. This may present early on or later, and if the
HIV infection is advanced, features are less typical, with diffuse
lung involvement and extrapulmonary tuberculosis being common. PCP
- Nontuberculous mycobacterial disease (especially Mycobacterium
avium complex) is fairly common and difficult to treat, in late
HIV disease. M kansasii is seen far less often.
- The incidence of bacterial pneumonias appears to be
- In endemic regions Histoplasmosis and Coccidioidomycosis
are often seen in HIV infected persons; cryptococcal lung infection
may be seen.
- Cytomegalovirus although commonly isolated from lung specimens,
is thought to less often cause clinical lung disease. Look for
- Pulmonary Kaposi's sarcoma is common in advanced HIV disease;
- Interstitial pneumonitis is fairly common, especially in children.
- HIV-1 itself: Early infection is common and may present as
a meningitis, or less commonly as ataxia, myelopathy or
encephalopathy, usually with good recovery. A Guillain-Barre'
like picture may be seen, and chronic demyelinating polyneuropathy
may occur and be disabling. Late infection by HIV
itself is common and debilitating, with progressive dementia
(the "AIDS-dementia complex").
- Cerebral toxoplasmosis is common (depending on baseline
incidence of Toxoplasma in the population) and represents re-activation
of previously acquired Toxoplasma.
- Cryptococcal meningitis is common;
- Other infective problems include progressive multifocal
leukoencephalopathy, cytomegalovirus encephalitis and polyradiculitis,
and mycobacterial cerebrospinal infections;
- CNS lymphomas (primary or metastatic) are relatively common;
- Stroke (related to 'marantic' endocarditis or coagulopaties)
- Drug complications may affect the nervous system (for example,
DDI causes neuropathy);
- Herpes encephalitis is reported, and zoster is common;
- AZT may cause myopathy.
- Ocular involvement by a variety of associated diseases is
common and often severe. These include retinal microvascular disease
(possibly related to HIV itself), sight-threatening cytomegalovirus
retinitis, and a variety of other disorders.
Gastrointestinal HIV manifestations
AIDS is commonly accompanied by substantial GIT morbidity, including:
- Oral candidiasis, and even severe candida oesophagitis;
- Oral hairy leukoplakia, thought to be due to Ebstein-Barr
virus, and practically pathognomonic of AIDS;
- Oral herpes is often severe;
- Achlorhydria is common;
- Diarrhoea is common in late HIV infection, and a substantial
cause of morbidity (with chronic diarrhoea in 30-60%). Common
causes are Cryptosporidium, Microsporida (especially Enterocytozoon
bieneusi), Mycobacterium avium and cytomegalovirus.
A vast number of other agents have been implicated.
- Tumours (Kaposi's, lymphoma, ..) are common
- "AIDS enteropathy" is poorly characterised but may be
related to HIV itself.
- Liver disease is fairly common, and in some populations
(eg homosexual men, haemophiliacs) viral hepatitis (HBV, HCV) is common.
Haematological & Oncological problems
- Anaemia, thrombocytopaenia and leukopaenia are all common,
resulting from a variety of insults including infections,
side effects of drugs used in HIV treatment, or (in the case
of thrombocytopaenia) possibly even related to early infection
with the virus itself! The latter doesn't necessarily signify
advanced infection, and may be immune mediated or related to
megakaryocyte problems. It may resemble classical"immune thrombocytopaenic
- Kaposi's sarcoma is common, initially presenting with
cutaneous involvement (nonblanching red or violaceous papules),
but often extending to involve viscera. Bacillary angiomatosis
may be confused with Kaposi's and is treatable.
- B-cell lymphoma is common, high-grade and aggressive.
Apart from the frequent electrolyte disorders encountered in advanced
AIDS, a variety of renal diseases is seen, including the specific
entity "HIV-associated nephropathy", which shows focal segmental
glomerulosclerosis as its characteristic lesion. Nephrotic syndrome
is common, followed by rapid progression to florid renal failure,
responding poorly to therapy.
These are common at autopsy but often missed clinically, and include
myocarditis (possibly due to the virus itself), marantic endocarditis,
and pericarditis (for example, tuberculous pericarditis).
Endocrine and Metabolic Disorders
Often clinically silent apart from hypogonadism, endocrine manifestations
are not commonly identified antemortem. In contrast, electrolyte
disturbances are common, and wasting is prevalent and has a major
impact on morbidity and mortality.
A host of rheumatological disorders is seen, ranging from mild arthralgias
and myopathies, to debilitating arthritis, the "painful articular syndrome"
on starting zidovudine, polymyositis, and Reiter's syndrome in
up to 10% of HIV-infected persons with arthritis. Vasculitides and
Sjogren's syndrome also occur.
The skin and AIDS
Cutaneous involvement is common, including a transient roseola-like
rash with initial infection, superficial infections with dermatophytes,
candida and scabies, molluscum contagiosum, papilloma virus infections
including condylomata acuminata, zoster, disseminated herpes simplex,
a variety of cutaneous fungal and mycobacterial infections, bacillary
angiomatosis (Rochalimaea henselae), and of course Kaposi's sarcoma.
The above list is not comprehensive, and newer and more unusual skin
problems continue to be identified.
There are two main components: diagnosis of HIV itself, and diagnosis
of complicating disorders, especially opportunistic infections.
We will here only consider diagnosis of HIV infection itself. This
must always be seen in the clinical context: is there evidence of
immune compromise, and/or opportunistic infection or malignancy?
HIV infection is commonly diagnosed using antibody detection (ELISA
or agglutination). False positives may occur, although currently licenced
ELISAs have over 98% sensitivity and specificity, so confirmation
is most desirable, using for example western blot (immunoblot) techniques,
[Postgrad Med 1995 Nov;98(5):177-180 ], or further specific tests such as competitive ELISA.
All of the above detect antibodies to HIV.
"Third-generation" ELISA assays that can detect anti-viral IgM and
IgA have considerably narrowed the "immunological window".
Fairly recently, nucleic-acid-based
assays have emerged: these allow for detection in the newborn (who may
have maternal antibodies that confuse the issue), characterisation of
strains, and monitoring of response to therapy.
[See Gurtler L: Lancet 1996 348(9021) pp176-179 ] Polymerase chain reaction
is commonly used.
p24 core antigen assay is also available, but is
far less sensitive in detecting HIV infection than is nucleic-acid based
amplification [e.g. Sitnik & Pinho: Mem Inst Oswaldo Cruz 1998 May;93(3):411-415 ]
Newer ELISAs for antigen detection, for example the
enzyme-linked amplified sorbent test (ELAST), can detect down to
the equivalent of 330-1000 RNA copies/ml of blood. [Goldschmidt PL et al,
Clin Diagn Lab Immunol : Jul 1998 5(4) pp513-518 ]
New "fourth-generation" ELISAs have also been developed that allow for
simultaneous detection of HIV antigens and antibodies! [ Weber et al,
J Clin Microbiol : Aug 1998 36(8) pp 2235-2239 ]
Note that EDTA blood is best suited for quantification of plasma
Prophylaxis after needle-stick injury
The risk of infection after percutaneous HIV exposure is about 0.3% (95%
confidence interval 0.2 - 0.5%). Putting this in perspective, this is
similar in magnitude to the risk after a single episode of receptive
anal intercourse with an HIV positive male. Transmission to health-care
workers has been documented even with undetectable levels of virus in
the source patient, suggesting that one should give post-exposure
prophylaxis (PEP) wherever
risk of HIV transmission exists. Zidovudine monotherapy confers about
80% protection against infection; current recommendations are that
at least two drugs be given (and possibly 'triple therapy' where the
risk is extreme). [ See MMWR May 15 1998 47 RR-7 pp1-33 ]
Median time to seroconversion is 46 days, but median time to
symptoms compatible with primary infection is only 25 days. Rarely,
seroconversion may be delayed by up to 12 months or more, but it is
usually in under six months, if it is going to occur.
In summary, the following regimen is probably acceptable:
- Wash the wound site; DO NOT apply caustics..
- Assess risk rapidly - when in doubt, start PEP.
- Start post-exposure prophylaxis as soon as possible, ideally
within half an hour;
A recent MMWR report suggests determining an "exposure code":
- if no blood or other potentially infectious material,
OR intact skin with small volumes, probably don't need to
- if small volume mucosal contact, "EC1";
- if large volume mucosal or superficial scratch, "EC2",
- if large-bore hollow needle, deep puncture, visible
blood on device, or needle was in artery or vein, i.e.
large exposure, "EC3"
- Once have EC status, determine HIV status code ("SC"):
- If HIV negative, no PEP needed;
- If positive AND asymptomatic AND high CD4, "SC1"
- If positive and high titre exposure, "SC2"
- if unknown, "SC unknown";
- THEN, if EC1 AND SC1, possibly don't give PEP
- IF EC1 + SC2, consider basic regimen
- IF EC2 and SC1, recommend basic regimen
- If EC2 and SC2, recommend expanded regimen
- If EC3, recommend expanded regimen.
- Basic Regimen:
Use zidovudine (a nucleoside reverse transcriptase inhibitor=NRTI)
600mg/day (divided into 2 or 3 doses);
AND another "NRTI": preferably lamivudine (3TC) 150mg BD
OR possibly didanosine (ddI)
or zalcitabine. The combination of ZDV + 3TC (Combivir) is available
and given as 1 tablet BD (300mg ZDV + 150mg 3TC per tablet).
- Expanded regimen:
With high-risk exposure, add a protease inhibitor(PI) such as indinavir 800mg 8 hourly
OR nelfinavir 750mg 8 hourly. (If saquinavir is used, use the soft-gel
formulation in the large dose of 1200mg TDS = 6 pills TDS).
- Compliance for four weeks is vital. This may be a problem
as side-effects are common, especially GIT side effects.
- Be aware of drug interactions and side-effects, notably:
- nelfinavir and ritonavir interfere with OC effectiveness,
necessitating additional contraceptive measures;
- Protease inhibitors may exacerbate diabetes mellitus,
or possibly even cause it;
- indinavir may cause renal calculi if over 1.5 litres/day
of fluid is not taken;
- Diarrhoea with NRTIs and protease inhibitors;
- Nausea, vomiting, malaise, headache and insomnia;
- Rarely: haemolysis, hepatitis and pancytopaenia.
- ZVD + 3TC appears safe in pregnant women. We don't know about PIs.
- Counsel the health-care worker;
- Report the incident, including date, time, details of exposure,
details of source, and of couselling, post-exposure management and
follow-up. Follow-up testing should be done at least at 6 weeks,
12 weeks, and 6 months. Monitor for PEP toxicity.
- Also follow up & manage risk of other agents such as
hepatitis B and C;
- Read the full MMWR report, and keep up to date with new
developments in post-exposure prophylaxis.
Treatment of HIV infection
The mainstay of therapy is use of combinations of expensive agents. Three
(or more) agents acting in different ways are combined to try and reduce
serum viral load to undetectable levels (which means, using current
technology, about 100 or fewer virions per millilitre of blood). Unfortunately,
prior use of single agents predisposes to viral resistance. Current
guidelines for treatment of early HIV infection recommend the use
of three drugs (two nucleoside reverse transcriptase inhibitors and
a protease inhibitor) [ MMWR 1997 46 RR-5 pp43-82 ]
Available agents include:
- Nucleoside reverse transcriptase inhibitors:
- zidovudine (Retrovir*) 600mg - 1200mg/day, divided.
( bone marrow suppression, nausea, headache, fatigue )
- lamivudine (3TC = Epivir*) 150mg BD < headache, abdominal pain, diarrhoea,..pancreatitis )
- zalcitabine (DDC = Hivid*) 0.75mg TDS
( stomatitis, peripheral neuropathy )
- didanosine (DDI = Videx*) 200mg BD, dep on body wt.
( pancreatitis, peripheral neuropathy, nausea & diarrhoea )
- stavudine (d4T = Zerit*) 40mg BD, dep on body wt.
( peripheral neuropathy )
- non-nucleoside reverse transcriptase inhibitors:
- nevirapine (Viramune*) 200mg daily for 2/52, then 200mg BD
( rash .. Stevens-Johnson sydrome, fever, nausea,
headache, abnormal liver function tests )
- Delavirdine (Rescriptor*) 400mg TDS.
( as for nevirapine )
- HIV protease inhibitors
- indinavir (IDV = Crixivan*) 800mg 8 hourly
( nephrolithiasis, nausea, headache, indirect
hyperbilirubinaemia, abnormal liver function tests,
- saquinavir (soft or hard-gel formulations differ,
Invirase* or Fortovase*)
( as for other PIs )
- ritonavir (Norvir*) 600mg BD, starting from 300mg BD;
( nausea,vomiting & diarrhoea, altered taste,
hyperlipidaemia, diabetes, abnormal liver function tests.. )
- nelfinavir (Viracept*) 750mg TDS
( diarroea, failure of oral contraceptives )
- A variety of experimental agents:
- Interferon alpha
- antisense oligodeoxynucleotides
- Agents that boost immune function
- and more...
Prevention of opportunistic infection is extremely important.
- Pneumocystis carinii prophylaxis is vital, especially
with CD4 counts under 200/ml; Sulphamethoxazole + trimethoprim
is still the best prophylaxis, but is especially toxic in
these patients, with rashes and bone marrow suppression.
- Some advocate rifabutin for Mycobacterium avium prophylaxis
with CD4 counts under 100/ml.
- In areas where tuberculosis is rife, it makes sense to
aggressively pursue the diagnosis and treatment of Mycobacterium
tuberculosis. The first placebo-controlled trial of INH prophylaxis
showed its efficacy [ Pape JW et al Lancet 1993 342 pp268-72].
A subsequent trial [ Whalen CC : NEJM 1997 337 pp801-8] confirmed this,
showing similar protection with INH and with combined regimens.
Daily INH for six months reduced the risk of tuberculosis by 67%,
although it may not have helped much in anergic subjects.
Halsey et al [ Lancet : 14 Mar 1998 351(9105) pp786-792 ]
showed that bi-weekly INH for six months, or INH+rifampicin for two
months are "equally effective"
in preventing tuberculosis activation in HIV positive patients with
positive PPDs. Incidence of tuberculosis at 36 months was 5 percent.
This virus, originally found in West Africa and now spreading worldwide
is only 40-50% similar (on a genomic basis) to HIV-1 but it causes
similar clinical disease. HIV-2 appears to be less agressively pathogenic
that HIV-1 causing immunosuppression over a longer period of time.
Most of the registered tests for HIV-1 detect this virus with greater
or lesser efficiency, but few seem to approach 100% sensitivity!