AIDS

Acquired immune
deficiency syndrome

WHAT IS AIDS??
AIDS (acquired immune deficiency
syndrome) is the final stage of HIV
disease, which causes severe
damage to the immune system.
This condition progressively
reduces the effectiveness of the
immune system and leaves
individuals susceptible to
oppurtunistic infections and tumors.
2

A case definition of
HIV & AIDS as per
WHO

 A case of HIV infection is defined as

an individual with HIV infection
irrespective of clinical stage
(including severe or stage 4 clinical
disease, also known as AIDS)
confirmed by laboratory criteria
according to country definitions and
requirements.
WHO provides a simplified HIV case
definition designed for reporting and

 Simplified HIV case definitions are

provided based on laboratory criteria
combined with clinical or
immunological criteria.
The clinical staging of HIV-related
disease for adults and children and
the simplified immunological
classification are harmonized to a
universal four-stage system that
includes simplified standardized
descriptors of clinical staging events.

Stage of HIV as per

WHO classification

In Asia, an estimated 4.7

million people were living
with HIV in 2008.
In 2008, an estimated 330
000 people died of AIDSrelated illnesses.
HIV-related mortality in
East Asia continues to
increase.

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Malaysia
First HIV case was reported in 1986
The number of cases continued to increase with the
highest number recorded in 2002 at 6,978 where 28.5
cases per 100,000 populations.
The number and rate of notification continued to
decrease to 13.3 cases per 100,000 populations (3,692
cases) in 2008.

For period between January and June

2009, a total of 1,497 HIV cases were
reported. As of December 2009, there are
87710 persons living with HIV and 13394
20

 Men represent the majority 92% of cumulative HIV

cases while women account for some 8% of this
total.
36% of reported infections are amongst young
people age between 13 to 29 years old.
Amongst men, injecting drug use contributes to
be the main mode of transmission
While women mostly contacted HIV through
heterosexual contact.
Women accounts for almost 20% of the new infections in
2009 as compared to being barely 5% 10 years ago.
21

 The World Health Organization

(WHO) currently classifies
Malaysia as having a
concentrated HIV epidemic
and based on estimations and
projects. HIV in Malaysia will
be increasingly spread
through sexual transmission,
while infections acquired
through injecting drug use are
expected to plateau.
22

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25

The History of
HIV/AIDS
Past
Present
Future

Past history of HIV

HIV was first reported as a new and
distinct clinical disease by the Centers
for Disease Control and Prevention
(CDC) in June 1981. At the time, the
condition did not have a name.
Doctors in San Francisco, Los Angeles
and New York had documented an
unusual cluster of diseases in young
homosexual men.
These diseases, Kaposis sarcoma and
PCP (Pneumocystis carinii pneumonia),
were previously unknown to this group.

History of HIV
All of the subjects were suffering
from general immune deficiency.
Their bodies were vulnerable to rare
opportunistic infections.
The subjects were otherwise
healthy.

The Earliest Known Cases

Five young homosexual men in Los
Angeles were diagnosed with PCP.
26 homosexual men, from both New
York and San Francisco, were
diagnosed with Kaposi Sarcoma.
11 cases of Pneumocystis carinii
pneumonia were documented.

The Earliest Known Cases (contd)

Since all of the first cases of this newly
identified disease involved homosexual
men, researchers initially considered sex
among gay men the route of transmission.
The condition was named GRIDS (GayRelated Immune Deficiency Syndrome).
However, HIV cases were soon reported in
other populations as well.

The Spread to Other Populations

IV drug users
Hemophiliacs
Blood transfusion recipients
Adults from Central Africa
Haitians living in the United States
Infants born to IV drug using
mothers

Initial Focus
Researchers then hypothesized
that because the virus was
primarily affecting homosexual
men and IV drug users, the agent
causing the disease was probably
both blood-borne and sexually
transmitted.

Identifying the Virus

By 1982, research was going on in both
the United States and France to identify
the virus.
In the United States, Dr. Robert C. Gallo of
the National Cancer Institute called the
virus HTLV-III (human T-cell lymphotropic
virus type III).
In France, Dr. Luc Montagnier and his
colleagues at the Pasteur Institute in Paris
called the virus LAV (LymphadenopathyAssociated Virus).

AIDS Researchers
Luc Montagnier and Robert Gallo

Identifying the Virus (contd)

Both groups of researchers were
working on the same virus.
In subsequent years, there was a
dispute as to who discovered the
virus.
In 1983, the disease was said to be
caused by the Human
Immunodeficiency Virus (HIV).
Credit for the discovery was given
jointly to the U.S. team and the French
group.

AIDS
The term AIDS stands for
Acquired Immune Deficiency
Syndrome.
It is the name given to the
condition associated with the HIV
virus.
It replaced the name GRIDS when
it became apparent that the
disease was not just limited to gay
men.

Before the AIDS Era

A review of the medical literature dating
back to the 1950s found 19 cases of what
appear to be AIDS cases.
Meaning? The illnesses fit the CDC
criteria for HIV/AIDS with regards to risk
factors, symptoms and progression.

Before the AIDS Era (contd)

The mean age of patients was 37 years.
More males than females.
Sixteen patients had opportunistic
infections without Kaposi's sarcoma.
The remainder had Kaposi's sarcoma.
Two patients were reported to be
homosexual.
Three others had been living in Africa.
One patient was born in Haiti.
In two instances concurrent or
subsequent opportunistic infection
occurred in family members.
All patients died 1 month to 6 years after

The Case of Robert R.

Frozen tissue and serum samples stored at
the University of Arizona were available for
one of these possible early AIDS cases.
The patient was a 15-year-old black male,
named Robert R. from St. Louis, Missouri,
who was hospitalized in 1968.
When admitted, the patient had extensive
swelling of the genitalia and lower
extremities and swelling of the lymph
nodes in his neck.

The Case of Robert R. (contd)

Chlamydia was also found in his body,
indicating that he was sexually active.
During the following year, Robert R.
deteriorated.
He died on May 16, 1969.
Tests done in the mid 1980s found that he
had HIV-antibodies.
The patient had never received a blood
transfusion, nor had he ever traveled
outside of the United States.
Implication: The virus may have been
introduced into the human population long
before the first cases were officially
reported.

HIV and Primates

Soon after AIDS was recognized in humans,
researchers began to report cases of a similar
virus in colonies of monkeys.
The virus, called Simian Immunodeficiency
Virus (SIVsm) was found in African green
monkeys, white-collared monkeys and the
sooty mangabey monkey, among others.
Another strain of the virus, named SIVcpz
was found in chimpanzees.

HIV and Primates (contd)

The SIV virus was found in more than 30
African primate species (ex. red-capped
mangabeys, spot-nosed guenons).
However, the virus was not causing illness
or death to these animals.
The questions then:
Did this simian virus infect humans?
How is it possible?

Primates

From Species to Species

It has been known for some time that
certain viruses can pass between species,
including from animals to humans.
The transfer of disease from animals to
humans is known as zoonosis.
Other examples of zoonosis:
Anthrax
Bubonic plague
Avian Influenza (Bird flu)
Mad-cow disease
SARS

The Contamination of Humans

It is theorized that the virus at
some point crossed species--from
primates to humans.
But how?

Natural Process Theory

This theory proposes that hunters of
chimpanzees contracted the virus as early as the
1940s. (This time frame was arrived at based on
a study done in 2000 using a computer model to
track the evolution of the HIV virus. Margin of
error: 15 years).
The hunters cut themselves while preparing
infected chimpanzee meat.
The virus then mutated into HIV and was passed
along through millions of humans.

Natural Process Theory (contd)

The virus could have also been transferred
to humans through the selling and
consumption of primate bushmeat sold in
African markets, an ongoing practice in
parts of Africa.
Both preparers of the meat and those who
ate it could have easily become infected.

Other Theories
Oral Polio Vaccine theory
Polio vaccine called CHAT was developed in
Africa (Belgian Congo, Rwanda and Urundi)
during the 1950s. The theory is that the
vaccine was produced using the kidney cells
of infected chimps infected with SIV. This then
led to the subsequent infection of humans
with HIV.
This theory was disproved when samples of
the original polio vaccine were analyzed and
no traces of either HIV or SIV were found.
Other tests showed that the kidney cells were
taken from the Asian macaque monkey only,
which has been shown to be incapable of
being infected with either SIV or HIV.

Other Theories (contd)

Contaminated Needle Theory
Healthcare professionals in Africa
during the 1950s used needles on
multiple patients as a way to save
money on syringes.
The virus could have been spread
from one person (ex. a chimp hunter)
to another with relative ease.

Other Theories (contd)

The Colonialism Theory
People across Africa, under colonial rule, were
subjected to harsh conditions in labor camps,
leading to food scarcity, poor sanitation and
poor health.
As a result, SIV could have infiltrated those
camps and taken advantage of the weakened
immune system of the workers.
Additionally:
Workers may have been inoculated with
contaminated needles.
Workers may have become contaminated via
prostitution because many of the camps
employed prostitutes to keep the workers
happy.
Labor camps were set up around the time that
HIV was first believed to have passed into

Other Theories (contd)

The Conspiracy Theory
HIV is a man-made virus and
was designed to be part of a
government biological
warfare program.
The target?
Blacks and gays.

Present History Of
AIDS
91% of people living with HIV in Malaysia are men
In 2008, the number of women living with HIV in
Malaysia increased from 8% to 19%
Everyday 15 Malaysians are diagnosed HIV positive
34% of newly reported cases in Malaysia are in their
twenties
In 20 years, the number of new HIV cases in
Malaysia increased by 88.3%
AIDS has caused the deaths of more than 10,000
Malaysians

Future history of HIV

Integrase inhibitors (raltegravir and elvitegravir)
in advanced development
CXCR4 inhibitors currently in development for
HIV entry blockage
Drugs with a broader spectrum of activity and
less vulnerable to induce resistance
More combination drugs like Atripola (efavirenz,
tenofovir, emtricitabine) so that treatment can
consist of a single pill taken once daily
Making drugs more affordable and available to
more people ($1500/month and
$618,000/lifetime)

Vaccines
Preventative
Subunit Vaccines
Recombinant Vector Vaccines
DNA Vaccines
Therapeutic

56

CLINICAL
PRESENTATION

PRIMARY INFECTION
Symptomatic in 7080% of cases and usually
occurs 26 weeks after exposure.
This coincides with high plasma HIV-RNA levels
and a fall in the CD4 count to 300400
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 .
The appearance of specific anti-HIV antibodies
in serum (seroconversion) takes place later at 3

CLINICAL FEATURES OF PRIMARY

INFECTION
Fever with rash
Night sweating
Pharyngitis with cervical
lymphadenopathy
Mouth sores including yeast
infection(trush)
Myalgia/ Athralgia
Headache
Mucosal ulceration

ASYMPTOMATIC INFECTION
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 more
than 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

MILDLY SYMPTOMATIC DISEASE

( CDC CLASSIFICATION CATEGORY
B DISEASE)
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 710 years, although
subgroups of patients exhibit fast or
slow rates of progression.

HIV symptomatic /indicator diseases:

Oral hairy leukoplakia
Recurrent oropharyngeal candidiasis
Recurrent vaginal candidiasis
Severe PID
Bacillary angiomatosis
Cervical dysplasia
ITP
Weight loss
Chronic diarrhea
Herpes Zoster
Peripheral neuropathy
Low grade fever/ night sweats

AIDS (CDC CLASSIFICATION

CATEGORY C DISEASE)
Defined by the development of
specified opportunistic infections,
tumours and presentations

Central Nervous System

Complication

Primary CNS lymphoma

(PCNSL)
Usually complicate late-stage HIV, occurring in
approximately 5% of AIDS patients and
accounting for 20% of all focal CNS lesions
Tumours are nearly always high-grade, diffuse, Bcell neoplasms and are closely associated with
EBV
Occurs within weeks to months
Presents with seizure, headache, cranial nerve
fidings, altered mental status,
Systemic symptoms including fever, night sweats,
weight loss
Others : diplopia, dysphagia, vertigo, monocular
vision loss, progressive dementia, facial

Progressive multifocal
leucoencephalopathy
(PMFL)

A fatal demyelinating disease caused

by JC papovavirus, occurs in 2-3% of
AIDS patients at very low CD4 counts
Symptoms include weakness, vision
loss, impaired speech, cognitive
deterioration
Lesion affecting the parietal & occipital
lobes can lead to alien hand syndrome
Seizures are uncommon
Diagnosed by presence of DNA of JC

HIV-associated dementia
Occur in late disease
Characterized by global deterioration of
cognitive function, severe psychomotor
retardation, paraparesis, ataxia, urinary &
fecal incontinence
Changes in affect are common, depression or
psychosis may be the predominant future
CSF viral load, lower CD4 count and age are
predictors for HIV-associated dementia
Incidence is decreasing as a result of HAART
Investigations show diffuse cerebral atrophy
with widened sulci and enlarged ventricles on

Cryptococcosis
Caused by cryptococcus neoformans
Common cause of meningitis associated with late-stage
HIV, occurs in 5% of patients
Rarely, non-meningeal (lung, prostate or skin) and
disseminated disease may occur
Present with 2-3 week history of headache, fever,
vomiting, mild confusion
Less common symptoms are seizure, photophobia,
blurred vision
papilloedema is found in 10% but focal features are
rare10% of patients are asymptomatic
Complications are deafness & blindness resulting from
prolonged raised ICP, arachnoiditis & direct
cryptococcal nerve infiltration

Spinal cord, nerve root and

peripheral nerve disease
Vacuolar myelopathy = slowly progressing myelitis
resulting in paraparesis with no sensory level
Hyperaesthesia, pain in the soles of the feet and
paraesthesia are common
Diminished pin-prick, light touch and vibration
sensation, accompanied by loss of ankle reflexes
Polyradiculitis occurs in late-stage HIV
causes rapidly progressive flaccid paraparesis, saddle
anaesthesia, loss of lower limb reflexes and sphincter
dysfunction
Pain in the legs and back is an early symptom
Proximal myopathy
Pain, slowly progressive weakness involving the major
muscle groups, tender muscles and raised creatine

GASTROINTESTINAL
SYSTEM

CYTOMEGALOVIRUS OESOPHAGITIS
AND COLLITIS
Epidemiology:
Reactivation of latent herpes virus
infection
Develops in < 5% of patients
At-risk CD4 count: < 100
cells/mm3
Pathology : Intracellular and
intracytoplasmic owls-eye inclusion
bodies pathognomonic

CLINICAL FEATURES
Presentation
24-wk history
Oesophageal : gradual onset of localised pain on swallowing,
retrosternal pain, dysphagia, fever and weight loss
Colitis: watery diarrhoea often accompanied by blood, colicky
abdominal pain, weight loss and fever
Suspect if:
Oesophageal: empirical fluconazole fails
Colitis: pathogen-negative bloody diarrhoea or thickened dilated
bowel on X-ray
Differential diagnosis:
Oesophageal: Candida, herpes simplex, aphthous ulcers, lymphoma,
KS
Colitis: standard enteric pathogens
Complications
Oesophageal: strictures
Colitis: toxic megacolon, haemorrhage and perforation

INVESTIGATIONS AND
DIAGNOSIS

Endoscopy :
Oesophageal: large shallow erosions/ulcers distally
with inflammation at ulcer edge
Colitis: generalised hyperaemia to segmentalor
confluent shallow or deep ulcers. 20% have disease
proximal to splenic flexure so colonoscopy preferable
Blood: CMV viraemia in high titre
Tissue biopsy:
Evidence of inclusion bodies and CMV
onimmunofluorescence/PCR.
May be seen in the absence of clinical disease

MANAGEMENT
Treatment
Induction: First-line: i.v. ganciclovir or
oral valganciclovir for 3 weeks
Maintenance: valganciclovir
Commence/optimise HAART
Consider stopping CMV therapy when
CD4 > 100 cells/mm3, CMV and HIV
viral loads undetectable, and on
HAART
Prophylaxis: Not recommended;

CRYPTOSPORIDIOSIS
Epidemiology:
Most common species are C.
hominis,C. parvum and C.
meleagridis.
Transmitted through ingestion of
Cryptosporidium ocysts from
animals or contaminated water.
Resistant to standard chlorination
At-risk CD4 count : < 100
cells/mm3

CLINICAL FEATURES OF
CRYPTOSPORIDIOSIS
Presentation:
History is acute or subacute
Large-volume watery stools, vomiting, abdominal pain
and weight loss
Suspect if: Watery stools negative for standard
pathogens
Differential diagnosis: Giardiasis, microsporidiosis
Complications :
Cholera-like illness and malabsorption.
Rarely, acalculous cholecystitis,sclerosing cholangitis,
pancreatitis and
pneumonitis

INVESTIGATIONS AND
DIAGNOSIS

Faeces:
Ocysts by acid-fast stain or
antigen testing on microscopy in
90%. Electron microscopy increases
yield
Other :
Duodenal biopsy if stools negative
ERCP or MRCP if sclerosing
cholangitis possible

MANAGEMENT
Treatment :
Commence/optimise HAART
Some effect with nitazoxanide or
azithromycin and paromomycin
Anti-motility agents
Stop therapy on completion of
treatment course and CD4
restoration > 200 cells/mm3
Prevention/prophylaxis: Boil water
if CD4 < 200 cells/mm3

MYCOBACTERIUM AVIUM
INTRACELLULAR
Epidemiology: Due to
environmental M. avium complex via
GI and respiratory routes
At-risk CD4 count :< 50 cells/mm3
Pathology :
Heavy mycobacterial load with little
inflammatory response on
microscopy.
Reticuloendothelial system bears the
major burden of infection

CLINICAL FEATURES OF MAI

Presentation:
History over weeks to months
Fever, sweats, weight loss, anorexia, chronic diarrhoea
and abdominal pain.
Hepatosplenomegaly and lymphadenopathy
Suspect if: PUO and weight loss with low CD4 count
Differential diagnosis: TB, lymphoma, cryptococcosis,
histoplasmosis, CMV
Complications:
Focal disease: oral ulceration, arthritis/osteomyelitis,
endophthalmitis, pericarditis or pulmonary disease

INVESTIGATIONS AND
DIAGNOSIS
Culture of sterile specimens:
Mycobacterial stain and liquid culture
of blood (> 95% positive) or bone
marrow, liver or duodenal biopsy
Speciation using DNA probes or
conventional tests confirms
mycobacterium as MAI
Culture of non-sterile specimens
Sputum and faeces: not diagnostic
CT: Abdominal lymphadenopathy
Other: Anaemia, leucopenia,

MANAGEMENT
Treatment:
First-line: clarithromycin or azithromycin,ethambutol, rifabutin
Ciprofloxacin or moxifloxacin, andamikacin if treatment failure
or resistance
Commence/optimise HAART
Stop therapy after 12 mths, CD4 restoration to > 100
cells/mm3 and on suppressive HAART
Immune restoration syndrome
Common on starting HAART. Usually focal disease, particularly
lymphadenitis
Prophylaxis
Primary: CD4 < 50 cells/mm3
First-line: azithromycin weekly
Prognosis: 5% mortality

Investigation

Initial assessment
newly diagnosed patients should be
reviewed by HIV clinician within 2
weeks of diagnosis
to determine the stage of infection,
presence of co-morbidities, coinfections, assess overall physical,
mental and sexual health

Screening test
1. ELISA- shortly after infection, IgM
antibodies to HIV first appear,
followed IgG weeks to months later.
Newly infected people have
detectable IgG levels by 6 months
(window period)
2. Rapid tests->Dot Blot and Latex
Agglutination
3. Simple tests->Particle
Agglutination test

Baseline investigation

3. Immunology
- Lymphocytes subsets- CD4 cell count
4. Virology
- HIV antibody IgG (confirmatory test)-> ELISA, Western blot
(window period is upto 3 months/mean 6 weeks from initial
infection)
- HIV viral load->HIV RNA
- Viral p24 antigen-> detectable shortly after infection but usually
disappeared by 8-10 weeks after exposure (marker of recent
infection)
- Hepatitis A IgG
- Hepatitis B surface antigen and full profile
- Hepatitis C antibody
* Standard anti-HIV IgG
antibody tests cannot be used
<18 months age, because
maternal antibodies maybe
detected
therefore, PCR and virus
culture are used in children
born to infected mothers.

5. Microbiology
- Screen for sexually transmitted infections
(TB, Hep B, CMV, toxoplasmosis, syphilis,
varicella)
6. Other
- Cervical cytology-> TRO infection of HPV
that may cause cervical carcinoma
- CXR-> TRO pulmonary complication (TB,
pneumonia etc)
- Fracture risk assessment

Management

Aim
To maintain physical and mental
health
To improve the quality of life,
To increase survival rates
To restore and improve immune
function
To avoid onward transmission of the
virus
To provide appropriate palliative

GOALS OF ART THERAPY (WHO)

Table 1: Goals of Antiretroviral Therapy

Maximal and durable suppression of viral replication

(measured by viral load assays)
Restoration and/or preservation of immune function
Reduced HIV-related morbidity and mortality
Improved quality of life
Limitation of the likelihood of viral resistance to preserve
future treatment option

Global performance of ART

Antiretroviral
Agents

Reverse Transcriptase
Inhibitors
1. Nucleoside/nucleotide analogues.
MOA :
They inhibit the synthesis of DNA by
reverse transcription and also act as
DNA chain terminators. NRTIs need to
be phosphorylated intracellularly for
activity to occur.
ADR :
2. mitochondrial toxicity a consequence of
their effect on the human mitochondrial
DNA polymerase.
3. Lactic acidosis

 Zidovudine (ZDV), previously known as

azidothymidine (AZT)
It is a thymidine analogue, when it is
phosphorylated inside HIV-infected cell,
inhibits reverse transcriptase in preference
to cellular DNA polymerase.
recommended when the CD4+ counts are
below 200/uL , 500-600mg per day in 2 or
3 divided doses of Zidovudine is given
(250mg b.i.d. or 200mg t.i.d).
Side effects : Headache ; Nausea ;
Diarrhoea ; Myalgia ; Anorexia ; Vomiting ;
Malaise ; Fatigue ; Macrocytosis ;
Anaemia ; Neutropenia ; Proximal
myopathy ; Encephalomyelopathy ;
Hepatotoxicity ; Nail pigmentation

Didanosine
It is a purine nucleoside analogue.
The intreacellular conversion of
didanosine triphosphate competes
with ATP for incorporation in viral
DNA , inhibits HIV reverse
transriptase and terminates proviral
DNA
Dosage : 200mg BD (>60 kg body
weight ) or 125mg (<50kg body
weight) 1 hour before or 2 hour after
meal.

 Lamivudine
It is deoxycytidine analogue which
phosphorylated intracellularly and
inhibits reverse transcriptase . The
incorporation results in chain
termination.
However point mutation in reverse
transcriptase results in rapid
resistance.
Dose : 150mg BD
ADR: headache , fatigue , nausea ,
anorexia , abdominal pain .

Combination therapy :
1. Zidovudine and Didanosine
2. Zidovudine and Zalcitabine
3. Zidovudine and Lamivudine

2. Non-nucleoside analogues.
MOA :
They interfere with reverse transcriptase
by direct binding to the enzyme
without need of intracellular
phosphorylation. They widely
disseminated throughout the body and
have a long half-life. NNRTIs affect
cytochrome P450.
However , they are ineffective against HIV2. The level of cross-resistance across
the class is very high.
ADR :
Rashes and elevation of liver enzymes.
A second-generation NNRTI, etravirine, has
now been developed with activity
against viruses resistant to other
compounds of the NNRTI class.

Efavirenz
Dose : 600mg OD on empty stomach
ADR : headache , rashes , dizziness ,
insomnia , neuropsychiatric
symptoms
Nevirapine
Dose : 200mg/day to 200mg BD
ADR : rashes , nausea,vomiting ,
fever , rise in liver enzymes ,
hepatoxicity
Avoid rifampicin ( enzyme inducers)

Protease inhibitors (PIs)

MOA :
These act competitively on the HIV aspartyl
protease enzyme, which is involved in the
production of functional viral proteins, and
enzymes. As a consequence, viral maturation is
impaired and immature dysfunctional viral
particles are produced.
Cross-resistance occurs across the PI group,
which can make it difficult to use the drugs
sequentially.
ADR:
Abnormalities of fat metabolism and control of
blood sugar, deterioration in clotting function in
people with haemophilia.
Second generation Pis (e.g. daruna- vir,
tipranavir) with activity against viruses resistant
the first generation drugs are now available.

Indinavir
Dose : 800 mg + 100 mg ritonavir BD Take With food.
ADR : Nephrolithiasis, hyperbilirubinaemia, alopecia,
headache, hyperlipidaemia, lipodystrophy
Lopinavir/ritonavir
Dose : 400mg + 100 mg ritonavir BD , take with food.
ADR : GI intolerance, nausea, vomiting and diarrhea .
Hyperlipidaemia, lipodystrophy
Ritonavir
Dose : 600 mg orally BD
ADR : GI intolerance, nausea, vomiting, diarrhoea, perioral paraesthesia, hyperlipidaemia, lipodystrophy, metallic
taste
Saquinavir
Dose : 1000 mg +
100 mg ritonavir BD orally
ADR : GI intolerance, nausea, diarrhoea, headache,
hyperlipidaemia, lipodystrophy

Fusion inhibitors
Enfurvitide
MOA : It is an injectable peptide
derivedfrom HIV gp41 that inhibits
gp41-mediated fusion of HIV with the
target cell. It is synergistic with NRTIs
and PIs.
Dose : 90mg (1mL) BD by
s.c.injection
ADR : Reaction at the injection site.
Hypersensitivity

Co-receptor blockers
Maraviroc
MOA : a chemokine receptor
antagonist which blocks the cellular
CCR5 receptor entry by CCR5 tropic
strains of HIV.
Dose : 150600 mg BD , metabolized
by cytochrome P450
ADR : Hepatotoxicity, pyrexia, rash,
hypotension

Integrase inhibitors
Act as a selective inhibitor of HIV
integrase, which blocks viral
replication by preventing insertion of
HIV DNA into the human DNA
genome.
Raltegravir
Dose : 400 mg (1 tablet)BD .
ADR : Diarrhoea,nausea,
headache,myopathy and

Management of
Opportunistic
Infections

1. Pneumocystis carinii
pneumonia (PCP)
It is a common in HIV infected individuals. It is the first
indicator of the development of AIDS in most of the
cases. Usually CD4+ T- lymphoeyte counts of less then
200/uL or a CD4+/CD8+ ratio of less then 20%.
Symptoms :
dry cough of more then 5 days
fever
Dyspnea
Physical examination shows minimal signs. In advanced
infection will include acute breathlessness, cyanosis
and presence of respiratory rales. The chest X-ray may
be normal.

Investigations:
Tracheal secretions for Pneumocytis carinii collected by induction of sputum production with
inhaled 3% saline. or bronchial lavage or by
bronchoscopy and lung biopsy.
Arterial Blood gases - this may indicate oxygen
desaturation
Management :
In moderate to severe infections it is advisable to
hospitalize the patient.
oral cotrimoxazole, 4 tablets 6 hourly for 14 days
if not acutely ill.
Intravenous cotrimoxazole, 20 mg trimethoprim
and 100 mg sulphamethoxazole/kg/day (diluted
1:25 in 0.9% saline or 5% dextrose) for 14 days for
severe infection
ADR : nausea, fever, rashes, which may lead to
Steven-Johnson's syndrome, raised liver enzymes,
bone marrow suppression, and hyponatremia.
Short course of steroids can be used together with
the cotrimoxazole. Prednisolone is used when the
pA02 is less then 70 mm.Hg.

Other drugs:
1. A combination of dapsone and trimethoprim
2. Clindamycin 600-900 mg 6 hourly with
primaquine 15-30 mg 6 hourly
3. Atovaquone 750 mg 3 times a day given orally.
Second line therapy:
When fail to respond to cotrimoxazole, or develop
adverse reactions
1. Intravenous or inhaled pentamidine isethionate
, 4mg/kg/day in 250mls of dextrose 5% by slow
infusion for 14-21 days.
Intravenous pentamidine is not usually used
because may form sterile abcesses when
extravasation of the drug occurs. Inhaled
pentamidine has no effect on systemic
pneumocystosis , only have effect towards lung
tissues.
ADR : hypoglycemia, abscess formation, hepatitis,
renal failure, and bone marrow suppression.

PCP Prophylaxis
Start when the CD4+ T-lymphocyte
counts of below 200/uL
trimethoprim/suphamethoxazole
(cotrimoxazole) 2-tables 3 times a
week
Other drugs that can be used in the
PCP prophylaxis :
1. Dapsone 100mg. daily or
2. Fansider 1 tab weekly

2. Toxoplasmosis
The most common infection affecting the central
nervous system in HIV-infected patient.
Presentation : headache, fever, confusion, and
convulsions.
Physical examination may reveal minimal signs,
patient may show focal neurological signs.
Investigations :
CT scan of the brain may show a single or multiple
hypodense lesions with ring enhancement.
MRI of the brain is more sensitive
The findings suggest a primary brain Iymphoma or
toxoplasma infection in the brain. Give antitoxoplasmosis therapy for 2 weeks then a repeat CT
scan.if the lesion decreased in size , extend the
therapy for 6 weeks. The presence of persistent
hypodense areas in the brain tissue may suggest
Iymphoma.

The recommended therapy is:

sulphadiazine 4gm daily (or 150mg/kg/day)
orally + pyrimethamine 25 - 50 mg /day, (or
50mg. Ioading dose followed by 25 mg/day) (or 4
tabs stat, followed by 2 tabs daily for 6 weeks), +
Folinic acid 5 - 10 mg daily, orally for 3 - 6
weeks.
ADR : bone marrow suppression. Require follow
up as recurrence of toxoplasmosis can occur
OR
Pyrimethamine 50 - 100mg/day + clindamycin
2.4 - 4.8gm/day or
pyrimethamine 50 - 100mg/day + clarithromycin
2gm/day
Prophylaxis :
trimethoprim + sulphamethoxazole + dapsone +
pyrimethamine, or
sulphadiazine + pyrimethamine

3. Fungal Infections
The most common fungal infection in AIDS
patients :
oral/esophageal candidiasis,
cryptococcal meningitis
invasive aspergillosis (complication) . Seen
when CD4 + T-Iymphocyte counts are
below 100/uL.
Antifungal Agents : triazole , itraconazole
and fluconazole shown to be effective.

I. Aspergillosis in AIDS patients:

can present as allergic aspergillosis,
aspergillomas (fungus balls) in the
lungs, superficial (ears, eyes, skin)
aspergillosis, chronic necrotising
pulmonary aspergillosis and
invasive aspergillosis with
pulmonary involvement (90-95%)
and extrapulmonary dissemination
(25%) like ulcerative
trancheobronchitis
Diagnosis is by biopsy and culture.
common species are Aspergillus
fumigatus and A flavus.

Invasive Aspergillosis:
Predisposing factors : prior episode of
Pneumocystis carinii pneumonia in AIDS
patients, neutropenia, organ and bone
marrow transplantation, hematologic
malignancies, chronic granulomatous
disease, corticosteroid therapy , use of
marijuana.
Invasive pulmonary aspergillosis can be
divided into
(1) acute invasive, and
(2) chronic invasive types.
The clinical manifestations of invasive
pulmonary aspergillosis includes:

Complaints :
(1) unremitting fever and new
pulmonary infiltrates in spite of
broad-spectum antibiotic therapy,
(2) dyspnoea,
(3) non productive cough,
(4) sudden pleuritic pain, fever,
tachycardia and sometimes with a
pleural rub, may mimic pulmonary
embolism,
(5) hemoptysis,
(6) night sweats.

Treatments:
Triazole, itraconazole can be given
initially at 200mg bd, and
subsequently reduce to l00mg bd for
2-5 months.
In disseminated aspergillosis,
advisable to prolong the therapy for
12 months.

II. Candida
Common species : Candida albicans.
Symptoms : In the early stages of the progression to AIDS,
the patient may complain of painful lesions in the
mouth, subsequently becoming worsen with burning
pain in the throat during swallowing (oro-pharyngeal
candidiasis) Oroeosophageal candidiasis is a
recognised AIDS-defining illness. At this stage the
CD4+ T-lymphocyte count would be below 400/uL.
Candida can also affect other organs like the gut, liver,
central nervous systems and the respiratory system.
Treatment :
1. Nystatin suspension - 100,000 IU 6 hourly given as a
gargle.
2.
Short term use of ketoconazole, itraconazole or
fluconazole can be given for 2 weeks (oral or
oropharyngeal candidiasis ) ; 4 weeks for
oropharyngeal or esophageal candidiasis Longterm
therapy with ketoconazole is not advisable because of
the hepatic and endocrine toxicities.
3. For persistent oral or oropharyngeal candidiasis,
fluconazole or itraconazole can be given 100 - 200 mg

4. Cryptococcal
Infections
Common when CD4+ T cell counts
are less then 100/uL.
Causative organism : Cryptococcus
neoformans var neoformans and var
gatti.
The infection is probably well
established in the lungs and other
viscera before disseminating to the
brain and meninges.

I.
Cryptococcal meningitis:
Symptoms : fever, headaches, meningeal signs, altered mental
status, cranial nerve palsies, motor abnormalities, cerebellar
signs and occassional fits.
Diagnosis : lumbar puncture, collecting the cerebrospinal fluid
(CSF) for microscopic examination looking for the spores
under India ink staining and culturing for the organism. ;
cryptococcal antigen titres on the CSF specimen.
II. Pulmonary Cryptococcal Infection:
The respiratory infection is usually asymptomatic and accidentally
found during a chest radiological examination;
Symptoms : chronic cough, weight loss, low grade fever,
hemoptysis, dyspnoea, night sweats and malaise.
Diagnosis : sputum culture on Sabouraud's agar medium and on
histology.
III.

Less common are infections in the skin, bone, genitourinary

tract, Iymphnodes, liver, spleen, and adrenals.

Treatment:
The gold standard treatment for
cryptococcal meningitis :
Intravenous amphotericin B
0.4mg/kg/day, with flucytosine 100200mg/kg/day orally or I/V infusion in
divided doses, can be given in the initial
phase until the CSF cultures become
negative then triazoles like fluconazole
200- 400mg daily can be used to continue
therapy for at least 6-8 weeks.
Lifelong maintenance therapy with
fluconazole 200mg daily is recommended
as the relapse rate is high in crytococcal

DOSES AND DRUG

REGIMENTS

Summarized
recommendations on
when to start treatment

(from Malaysian Consensus of Antiretroviral Treatment,

SEVERE SYMPTOMS

Factors to consider when

selecting an initial regimen
1. Co morbidity (e.g.
cardiovascular, liver diseases, viral
hepatitis status, psychiatric
disease, renal disease, TB)
2. Patient compliance and
convenience
3. Potential drug adverse effect
4. Potential drug interaction with
other meds

How to stop/interrupt
NNRTI
It has low genetic barrier to
resistance with long half lifes. NNRti
half life is approx. 40 160 hrs.
compared to NRTi (0.5 17 hrs.)
Abruptly stopping regimen with
Nevirapine (NVP) or Efavirenz (EFV)
causes periods of NNRTI
monotherapy and subsequently,
NNRTI resistance

Treatment Failure

WHO definitions of clinical, immunological and virological

failure for the decision to switch ART regimens

Failure

Definition
Adults and adolescents
New or recurrent clinical
event indicating severe
immunodeficiency (WHO
clinical stage 4 condition)a
after 6 months of
effective treatment

Clinical
failure

Children
New or recurrent clinical
event indicating
advanced or severe
immunodefiency (WHO
clinical stage 3 and 4
clinical condition with

Comments

The condition must be

differentiated from
immune reconstitution
inflammatory
syndrome occurring
after initiating ART
For adults, certain
WHO clinical stage 3
conditions (pulmonary
TB and severe
bacterial infections)
may also indicate
treatment failure

Adults and adolescents

CD4 count falls to the baseline
(or below) or
Persistent CD4 levels below
100 cells/mm3

Immunologi
cal failure

Without concomitant or
recent infection to cause a
transient decline in the CD4
cell count

A systematic review found

that current WHO clinical
and immunological criteria
have low sensitivity and
positive predictive value for
identifying individuals with
virological failure (182). The
predicted value would be
expected to be even lower
Children
with earlier ART initiation
Younger than 5 years
and treatment failure at
Persistent CD4 levels below 200 higher CD4 cell counts.
cells/mm3 or <10%
There is currently no
Older than 5 years
proposed alternative
Persistent CD4 levels below 100 definition of treatment
cells/mm3
failure and no validated
alternative definition of
immunological failure

The optimal
threshold for
defining virological
failure and the
need for switching
ART regimen has
not been
Plasma viral load
determined
above 1000 copies/ ml
An individual must
based on two
be taking ART for
Virologic
consecutive viral load
al failure
at least 6 months
measurements after 3
before it can be
months, with
determined that a
adherence support
regimen has failed
Assessment of viral
load using DBS and

Second line regime

EXPERIENCED PATIENTS
limited therapy or second
line failure

Treatment goal is to maintain CD4 above

200, viral load of up to 200 000 copies/ml
It has been shown that continuing a
failing regime rather than stopping it
is beneficial provided that patients havent
developed any other side effects to the
drugs, and he is clinically well
Consult with an Infectious Disease
specialist/physician for managing this
patients.

HIV Vaccines

Why a vaccine in HIV?

-Best long term hope for controlling
the AIDS pandemic
-800,000 900,000 infected in the
U.S.
-40,000 newly infected each year in
U.S.
-Globally, 14,000 infected every day
-Each minute, 6 people under 25 are
infected
-Over 40,000,000 infected
worldwide

An effective vaccine could have a MAJOR

Impact on the future prognosis

iavi.org

An effective vaccine must get around

the strategies HIV uses to evade the immune system
This allows T cells to recognize HIV infected
cells,
for example, and even internal proteins
like reverse transcriptase can serve as antigens

What type of vaccine?

Preventative vs. Therapeutic
Multiple vaccines may be needed
Preventative vaccine could stop the
spread of HIV but can not cure
someone who is already infected.
Therapeutic vaccine could be used to
treat individuals with HIV
What works to prevent HIV infection
may not necessarily work in
individuals who are already infected

Challenges in developing a
vaccine
HIV continually mutates and

There are many possible

HIV Vaccine Approaches

amil Sapinoro, University of Rochester Medical Center

Protein subunit
Synthetic peptide
Naked DNA
Inactivated Virus
Live-attenuated
Virus
Live-vectored Vaccine

To begin we need to
ask some key questions

What should vaccine elicit?

Neutralizing antibodies
to kill free virus

OR

T cell response to
kill infected cells

OR BOTH?

Types of Vaccines
1)Peptide Epitopes
Status: In Phase I trials
Advantages: Simple and inexpensive to prepare;
probably safe
Disadvantages: Can accommodate limited amount of HIV
genetic material; stability challenges
Ex: HIV peptides

2)DNA
Status: In Phase I trials
Advantages: Simple and inexpensive to prepare
Disadvantages: Some worry that integration of HIV
genes into human cells could harm patients (no current
evidence of this); current vaccines elicit modest immune
responses
Ex: Naked DNA containing one or more HIV genes

5) Recombinant Viral Proteins

Status: In Phase II and Phase III trials
Advantages: Safe and simple to
prepare
Disadvantages: Vaccine-elicited
antibodies have failed to recognize HIV
from patients
Ex: Viral surface proteins (i.e. gp120)
6)Pseudovirions
Status: Close to Phase I trials
Advantages: Present HIV surface and
internal proteins in a relatively natural
conformation
Disadvantages: Difficult to produce
7)Replicons
Status: Close to Phase I trials

3)Live vectors
Status: In Phase I trials
Advantages: Simple and inexpensive to
prepare; probably safe
Disadvantages: Can accommodate limited
amount of HIV genetic material; stability
challenges
Ex: Live bacterial vectors (harmless bacteria
with genes to produce HIV proteins)
4) Combination of Elements
Status: In Phase II Trials
Advantages: Should stimulate both arms of
immune response
Disadvantages: Current combinations elicit
modest immune responses
Ex: pure gp120 protein plus canarypox vector

5)AIDSVAX Phase III Trial

Produced by VaxGen
Phase III in U.S. and Thailand
Bivalent vaccine composed of
gp120 proteins from HIV-1 subtypes
B and E
Proven safe and effective for
stimulating antibody production
against B and E (most common in
Thailand)

Mother-to-Child
Transmission
2535% of HIV positive pregnant
mothers will pass HIV to their
newborns
In the absence of breastfeeding:
30% of transmission in utero
70% of transmission during the
delivery
Meta-analysis showed 14%
154
transmission with breastfeeding

Risk Factors for Mother-toChild Transmission

Viral load (HIV-RNA level)

Genital tract viral load
CD4 cell count
Clinical stage of HIV
Unprotected sex with multiple
partners
Smoking cigarettes
Substance abuse
Vitamin A deficiency

STDs and other coinfections

Antiretroviral agents
Preterm delivery
Placental disruption
Invasive fetal monitoring
Duration of membrane
rupture
Vaginal delivery vs. cesarean
section
Breastfeeding

Interventions to Reduce
Mother-to-Child
Transmission

HIV testing in pregnancy

Antenatal care
Antiretroviral agents
Obstetric interventions

Avoid amniotomy
Avoid procedures: Forceps/vacuum
extractor, scalp electrode, scalp blood
sampling
Restrict episiotomy
Elective cesarean section
Remember infection prevention practices

Newborn feeding: Breastmilk vs.

HIV Testing during

Pregnancy
Advantages:
Possible treatment of mother
Reduce risk of mother-to-child
transmission
Future family planning issues
Precautions against further spread
If negative, advise about HIV prevention

Counseling is important!

Antenatal Care
Most HIV-infected women will be asymptomatic
Watch for signs/symptoms of AIDS and
pregnancy-related complications
Unless complication develops, no need to
increase number of visits
Treat STDs and other coinfections
Counsel against unprotected intercourse
Avoid invasive procedures and external cephalic
version
Give antiretroviral agents, if available
Counsel about nutrition

Antiretrovirals
Zidovudine (ZDV):
Long course
Short course

Nevirapine
ZDV/lamivudine (ZDV/3TC)

Intrapartum vs. Postpartum Regimens for

HIV-Infected Women in Labor with No Prior
Antiretroviral Therapy
Drug Regimen

Maternal Intrapartum

Newborn Postpartum

Nevirapine

One oral dose at onset of

labor

One oral dose at age 4872 hours

(if mother received nevirapine < 1
hour before delivery, newborn
given oral nevirapine as soon as
possible after birth and at 4872
hours)

ZDV/3TC

ZDV orally at onset of labor ZDV orally every 12 hours

followed by dose orally
AND
every 3 hours until delivery
3TC orally every 12 hours for 7
AND
days
3TC orally at onset of
labor, followed by dose
orally every 12 hours

Intrapartum vs. Postpartum Regimens for

HIV-Infected Women in Labor with No Prior
Antiretroviral Therapy (contd.)
Drug Regimen

Maternal Intrapartum

Newborn Postpartum

ZDV

IV bolus, followed by
continuous infusion of every
hour until delivery

Orally every 6 hours for 6

weeks

ZDV and
Nevirapine

IV bolus, then continuous

infusion until delivery
AND
Nevirapine single oral dose at
onset of labor

Orally every 6 hours for 6

weeks
AND
Nevirapine single oral dose
at age 4872 hours

Obstetric Procedures
Because of increased fetal exposure to
infected maternal blood and
secretions, increased transmission
may come from:
Amniotomy
Fetal scalp electrode/sampling
Forceps/vacuum extractor
Episiotomy
Vaginal tears