Human Immunodeficiency Virus (HIV) And

Acquired Immune Deficiency Syndrome (AIDS)

Jenny Colombo, Pharm.D.
January 1997
Goals and Objectives:
By the end of this lecture the student should be able to:
1. Describe the course of HIV infection.
2. Define AIDS using specific CDC criteria.
3. Discuss the different methods of HIV testing.
4. Identify the various risk factors associated with HIV infection.
5. Discuss the complications of HIV disease.
6. Understand the life-cycle of HIV and the potential target sites for drug activity.
7. Discuss early intervention methods.
8. List laboratory tests used to determine the stage of HIV disease.
9. Identify adverse drug effects and drug interactions for currently approved antiretroviral
agents.
10. Design a rational therapeutic plan based on stage of disease and patient history.

Required Reading:
Applied Therapeutics: The Clinical Use of Drugs. Sixth Edition, 1995
Chapter 68. Human Immunodeficiency Virus (HIV) Infection. Pages 68-1 - 68-48
Pharmacotherapy: A Pathophysiologic Approach. 3rd Edition, 1996
Chapter 117. Principles and Management of the Acquired Immunodeficiency Syndrome. Pages
2353-2386.
Carpenter CCJ, Fischl MA, Hammer SM, Hirsch MS, Jacobsen DM, et al. Antiretroviral Therapy
for HIV Infection in 1996: Recommendations of an International Panel. JAMA 1996;276:146154

I.

Background
In 1981, AIDS was first reported in previously healthy young gay men. It was quickly
recognized that this disease was capable of infecting other high risk group at rates much
faster than anyone could have imagined. As of October 31, 1995, a total of 501,310 cases
of AIDS have been reported to the CDC of these, 62% have resulted in death. Nearly half
of these cases have been reported since 1993. Despite these devastating numbers
significant advances have been made over the past two decades leading to a better
understanding of the immunopathology, epidemiology and clinical manifestations of this
disease. Human immunodeficiency virus (HIV) was identified as the cause of AIDS in
1983. The disease is characterized by the effect of the retrovirus attacking the hosts
cellular immunity resulting in an immunocompromised host and ultimately fatal
complications.

II.

Epidemiology and Trends Cumulative Cases of AIDS

In 1995 the United States reached 500,000 AIDS cases since the start of the epidemic. Of
the cumulative cases 10% were reported during 1981-1987, 41% during 1988-1992 and
49% during 1993 to October 1995.
Changing Rates Determined by Gender, Race and Risk Factor
The proportion of AIDS cases among females increased from 8% of all reported cases to
18% during the period of 1993 to 1995. The proportion of AIDS cases among whites
decreased from 60% to 43%, however, the proportion of blacks and Hispanics increased
from 25% to 38% and from 14% to 18% respectively. The proportion of cases increased
from 17% to 27% among persons who reported injection-drug use. For cases attributed to
heterosexual transmission the proportion increased from 3% to 10% and cases among
men who have sex with men decreased from 64% to 45%
World Health Organization
An estimated 18 million adults and 1.5 million children have been infected with HIV
resulting in 4.5 million AIDS cases worldwide.
MMWR November 24, 1995/Vol.44/No.46

III.

The HIV Life Cycle

Free virus enters the blood during infection

Virus envelope glycoprotein (gp12) attaches to CD4 receptors, primarily found on

the helper T cells, but also recognized on macrophages, B cells and brain cells

The virus sheds its envelope and enters the native cell

The inner core is removed resulting in release of viral RNA

By way of the retroviral reverse transcriptase viral DNA synthesis is initiated

The proviral DNA enters the nuclear cytoplasm and is integrated into the native
cell's DNA

Retroviral synthesis is begun, directed by the cell's infected DNA

New virus cores are assembled

Envelopes enclose the virus core via budding

The complete virus is extruded into the bloodstream

IV.

Pathogenesis
HIV can infect a variety of cells. However, the helper T cells have been most widely
recognized as the main target of attack. The CD4 positive T lymphocytes are
progressively depleted by HIV infection. These cells are a key component to the part of
the immune system that is primarily responsible for controlling invasion by intracellular
pathogens. As a patients CD4 falls the likelihood of developing an opportunistic infection
is increased. HIV may also attach itself to the CD4 receptors of monocytes and
macrophages, the effect of monocyte-macrophage infection is not well understood. Once
in the macrophage HIV remains undetected and may replicate freely. Thus, the
macrophage may serve as a reservoir for HIV. Macrophages may also be responsible for
introducing HIV to the brain potentially causing AIDS-related dementia. HIV may also
infect bone marrow cells resulting in a pancytopenia that is often seen in AIDS patients.

V.

Modes of Transmission
o

Sexual Contact
1.

Homosexual, bisexual and heterosexual

2.

multiple sexual partners, receptive anal intercourse, presence of ulcers

have been suggested as risk factors

3.

appropriate use of latex condoms is > 90% protective

Blood or Blood Product Exposure

1.

Injection Drug Use: sharing of infected needles

2.

Blood Transfusions: incidence has been decreased with the

implementation of blood product screening.

3.

Health Care Providers: inadvertent needle stick or exposure during high

risk procedures; incidence is extremely low; the benefit of post-exposure
AZT therapy has never been proven, nonetheless this is one non-approved
AZT indication.

Maternal-Infant Transmission: may occur in utero, during delivery, or through

breast feeding - approximately 1/3 of infants born to untreated HIV (+) mothers
are infected with HIV. AZT has recently been shown to decrease the rate of
transmission from 25.5% to 8.3%. This has lead to the indication of AZT during
pregnancy.

B. Definitions and Classification of HIV Infection

o

HIV Infection - defined as seroconversion documented by the presence of HIV

antibodies (ELISA, Western Blot Test). Can also be determined by the presence of
p24 antigen or by viral culture.

AIDS - CDC Case Definition

1982 - patients with opportunistic infections without evidence of an
immunodeficient state or patients < 60 years old diagnosed with Kaposi's
Sarcoma. (prior to availability of HIV testing)

1984-1985 - development of serologic testing

1986 - CDC defined a classification system
1987 - CDC expanded its definition of AIDS to include other AIDS related
conditions such as HIV encephalopathy and wasting syndrome
1992 - CDC revises the classification system and expands the case definition for
AIDS to include other AIDS related conditions such as pulmonary tuberculosis,
invasive cervical cancer and recurrent bacterial pneumonia (2 episodes/year). In
addition, the definition of AIDS was expanded to include all HIV infected persons
who have less than 200 CD4+ T-lymphocytes/ml or a CD4+ T-lymphocyte
percent of total lymphocytes less than 14%.
o

Classification According to AIDS Surveillance Case Definition:1993

A
CD4 cell categories

1)>500/cu mm (greater than

or equal to 29%)
2)200-499/cu mm (14-28%)
3)<200/cu mm (<14%)

Clinical Categories
B

C*

Asymptomatic, or PGL or PGL or

acute HIV infection

Symptomatic** (Not A
or C)

AIDS indicator
condition (1987)

A1

B1

- C1 -

A2
- A3 -

B2
- B3 -

- C2 - C3 -

*All patients in categories A3, B3, and C 1-3 are reported as AIDS, based on the AIDS-indicator
conditions and /or a CD4 cell count <200/mm3. AIDS indicator conditions include three new
entries: recurrent bacterial pneumonia, invasive cervical cancer, and pulmonary tuberculosis.
** Symptomatic conditions not included in Category C that are a) attributed to HIV infection or
indicative of a defect in cell-mediated immunity, or b) considered to have a clinical course or
management that is complicated by HIV infection. Examples of B conditions include but are not
limited to bacillary angiomatosis; thrush; vulvovaginal candidasis that is persistent, frequent, or
poorly responsive to therapy; cervical dysplasia (moderate or severe); cervical carcinoma in situ;
constitutional symptoms such as fever (38.5 C) or diarrhea > 1 month; oral hairy leukoplakia;
Herpes zoster involving two episodes or >1 dermatome; ITP; listeriosis; PID (especially if
complicated by a tubo-ovarian abscess); and peripheral neuropathy.

C.

D. Serologic Testing/Staging of Disease

o

HIV Antibody Assays

1.

Enzyme-Linked Immunosorbent Assay (ELISA)

Measures serum anti-HIV-1 antibodies. This test is widely used because it
is inexpensive, rapid and well suited for large numbers of samples.
However, it has the potential to produce false positive reactions due to
nonspecific binding of antibodies present in samples from subjects
exposed to other infections or vaccines. If positive, this test must be
followed by a confirmatory test.

2.

Western Blot
This test has become the principle method of confirming HIV-1 infection.
The Western Blot also measures anti-HIV-1 antibodies and is capable of
identifying specific HIV-1 antigens that are present. This test is reserved as
a confirmatory test because it is slow, labor intensive and costly.

Tests That Measure HIV Virus or Viral Components

1.

Viral Culture - cultures are capable of measuring the relative amount of

virus within the cells or the mount of free virus in the plasma. Although
cultures are a direct method of measuring viral load they are extremely
expensive, labor intensive and not yet used widely in practice.

2.

Viral load: Polymerase Chain Reaction (PCR) (Roche) - this technique

can amplify target DNA existing in very small amounts through a series of
binary replicative cycles. This procedure can also be applied to RNA. PCR
is extremely sensitive which poses both a strength and a weakness. PCR
can be used early to detect disease even before a serologic response and it
can also be used successfully to quantitate HIV as a relative measure of
viral load. Another method for measuring viral load is Branched DNA
(Chiron). These techniques differ in sensitivity; thus; measurements are
not interchangeable. These tests are expensive and timely; however, they
are rapidly gaining wide use by clinicians in determining disease
progression and therapeutic efficacy or failure.

3.

p24 Antigen - this assay measures the amount of free viral protein (p24)
present in the plasma. This protein may be in the plasma at all stages, but
it is most prevalent during the time of initial seroconversion and again
later in the course of more advanced disease. This test is widely used in
clinical practice, however, because it is an indirect way of measuring viral
load it has very little value in determining progression of disease or
efficacy of antiretroviral agents.

Surrogate Markers
CD4
Surrogate markers are widely used in practice to determine the stage and
progression of disease. The CD4 count is the most commonly used marker in
clinical practice. The CD4 is widely used as an indicator for therapeutic
interventions including initiation of antiretroviral therapy and prophylaxis of
opportunistic infections (e.g. PCP, MAC). The CD4 can vary widely from time to
time and can be affected by time of day or the presence of an acute infection.
Although, still widely used this marker is quickly losing its value in clinical
practice.
Another marker is the CD4% (< 50%) which tends to vary less. In addition the
CD4:CD8 ratio (normal >1) is decreased with disease progression.
Absolute CD4 count = total WBC X % lymphocyte X CD4 %
Corresponding CD4 counts to CD%:
CD4 cell count
> 500
200-500
< 200

%CD4
> 29%
14-28%
<14%

Viral Load
This is the best marker for predicting disease progression. A consensus panel
recommends using viral load in all patients to guide initiation of therapy, changes
in therapy and drug resistance.
E.
A. Clinical Course of HIV Infection
HIV infection is a progressive disease. Typically the patients progress from acute
infection to an asymptomatic stage through a progressive lymphadenopathy and finally to
full blown AIDS. The time course varies widely from patient to patient, but the average
life-expectancy from time of seroconversion is estimated to be 10 years.
Stages of HIV Disease

1.

Viral transmission

2.

Acute retroviral syndrome

3.

Seroconversion

4.

Clinical latent period with or without persistent generalized

lymphadenopathy (PGL)

5.

Early symptomatic HIV infection (AIDS-Related Complex)

6.

AIDS as defined by the CDC

Correlation of HIV Complications with CD4 Cell Count

CD4 cell count*

Infections

Non-infections**

>500/mm3

Acute retroviral syndrome

Candidal vaginitis

Persistent generalized
Lymphadenopathy(PGL)

200-500/mm3

Pneumococcal and other

Bacterial pneumonia
Pulmonary TB
Herpes zoster
Thrush
Candidal esophagitis
Cryptosporidiosis,
Self-limited

<200/mm3

P.carinii pneumonia
Disseminated/chronic
Herpes simplex
Toxoplasmosis
Cryptococcosis
Disseminated histoplasmosis
And coccidioidomycosis
Cryptosporidiosis, chronic
Microsporidiosis
Miliary/extrapulmonary TB
Disseminated CMV
Disseminated M. avium complex

<50/mm3

Guillain-Barre syndrome
Polymyositis
Aseptic meningitis
Cervical intraepithelial
Neoplasia
Cervical cancer
Kaposi sarcoma
B-cell lymphoma
Anemia
Mononeuritis multiplex
Idiopathic
Thrombocytopenic
Purpura
Wasting
Peripheral neuropathy
HIV-associated
Dementia
CNS lymphoma
Cardiomyopathy

* Most complications occur with increased frequency at lower CD4 counts; lymphomas may occur
at any CD4 counts, but are most frequent with counts <200/mm3.

** Some conditions listed as "Non-infections" are probably associated with transmissible

microbes: lymphomas, cervical cancer, CIN and Kaposi sarcoma.

B. Management of HIV Disease

Early detection of HIV is essential in order to decrease the rate of transmission. It is also
critical to identify potentially preventable conditions such as tuberculosis, pneumococcal
pneumonia, syphilis, etc. Additionally, early initiation of antiretroviral therapy may
improve quality of life and survival.
Early Intervention

1.

Disease detection:

PPD skin test

2.

3.

serologic testing for other diseases (e.g. Toxoplasmosis, Syphilis,

Hepatitis)

pap smear

Baseline Laboratory Tests

Can help determine hematologic, renal and hepatic status. particularly
useful prior to instituting therapy and to detect underlying diseases or
complications of HIV.

CBC

chemistries

G-6-PD level

CD4/CD4%

Viral load

Immunizations
Immunization is a very important part of early management in HIVinfected patients. In general, symptomatic patients have a suboptimal
response to vaccines. Therefore, all vaccines should be given as early in
the course of HIV as possible. For the most part, HIV-infected patients
should not receive live virus or live bacteria vaccines.
Influenza: annual vaccination is recommended
Pneumococcal: consider revaccination every 6 years
Haemophilus B Influenza: Use is controversial
Hepatitis B: recommended in patients with no evidence of
exposure
Tetanus-Diphtheria: recommended every 10 years
MMR: can be considered (live virus vaccine)

2.

Approaches for Antiretroviral Therapy

1.

Monotherapy: no longer recommended due to poor efficacy and rapid

development of resistance.

2.

Combination Therapy (two vs three agents vs four): combination therapy

is standard of care. The decision on whether to use 2, 3 or 4 drugs depends
on stage of disease (viral load, CD4), drug tolerance, prior antiretroviral

use, concomitant drugs, compliance and insurance. The Optimal

combination varies from patient to patient.

3.

Alternating Regimens

4.

Sequential Therapy

Potential Sites of Actions

Potential Benefits of Antiretroviral Therapy

1.

prolong survival

2.

slow disease progression

3.

improve quality of life and functional status

4.

reduce incidence and severity opportunistic diseases

Potential Problems with Antiretroviral Therapy

1.

resistance

2.

toxicities

3.

cost

4.

drug-interactions
Monitoring

1.

Viral Load: obtain 2 baseline measurements at least 2 weeks apart, then at

1 month after start or change of therapy. A change of at lease 0.5 log (3
fold) is considered significant. An ideal viral load is < 5000 copies/ml.
Patients with viral loads &GE 100,000 copies/ml have a poor prognosis.

2.

CD4/CD4%: obtain 1 baseline reading with viral load, then repeat every 3
months or hand in hand with viral loads.

3.

Opportunistic Infections

4.

Other HIV Complications (ie. wasting syndrome, Kaposis sarcoma,

Lymphoma)

Antiretroviral Agents

1.

Reverse Transcriptase Inhibitors:

Nucleoside Analogue:

ZIDOVUDINE (AZT, Retrovir) 100mg capsules

INDICATIONS: AIDS, asymptomatic HIV with CD4 < 500, CD4 >
500 controversial. Should no longer be used as monotherapy. Good
combinations include: AZT/3TC, AZT/ddI, AZT/D4T, AZT/DDC,
AZT/Nevirapine plus or minus a protease inhibitor.

Non-Approved Indications: prevent maternal transmission, postexposure prophylaxis, AIDS dementia and HIV-Related
thrombocytopenia.
Dose: 200mg TID (minimum effective dose: 300mg/day) or
300mg BID
Absorption- 60% bioavailability
Distribution- 34-38% plasma protein binding widely distributed
penetrates CSF
Elimination/Metabolism- 75% hepatic metabolism and 25% renal
elimination; Serum half-life is approximately 1.1 hour in normal
renal function; Intracellular half-life is 3 hours
Renal Disease- dose should be adjusted for patients with
severe renal dysfunction (CrCl < 10ml/min) to half dose.
Specific guidelines are not available.
Adverse Drug Reactions:
1.

Subjective: GI intolerance, insomnia, myalgias,malaise and

headaches. GI intolerance may improve by administration
with food. Patients complain of these side-effects in the
first 1-4 weeks of therapy and most improve with continued
treatment.

2.

Hematologic Toxicity: is both disease stage and dosedependent. Anemia occurs in 29% of AIDS patients and
only in 2% of asymptomatic HIV patients. Neutropenia
occurs in 37% of AIDS patients and in only 1% of
asymptomatic HIV patients. Management includes
reducing the dose of AZT, discontinuing AZT and
substituting with other agent or treatment with epogen or
neupogen. The latter is extremely costly and should only be
considered when the first two options are not acceptable.

3.

Macrocytosis: occurs in most patients within the first four

weeks of therapy and can be used as an indicator of
compliance.

4.

Others: myopathy, myositis, nail bed pigmentation,

hepatitis (increases in transaminase levels), rash, fever

DIDANOSINE (DDI, Videx) 25mg, 50mg, 100mg Tablets;

167mg, 250mg, 375mg buffered powder packets
INDICATIONS: originally indicated for patients with advanced
HIV infection intolerant of AZT and for patients not responding to
AZT. More recent data suggests that DDI may be considered as
potential first-line therapy or earlier post AZT therapy. Good
combinations include: AZT/DDI, DDI/Nevirapine, DDI/D4T plus
or minus protease inhibitor. Although not recommended DDI may
be considered as monotherapy in patients who do not tolerate any
other antiretrovirals.
Dose: based on body weight
> 60kg 200mg BID for patients(TWO 100mg Tabs)
< 60kg 125mg BID for patients(ONE each 100 & 25mg)
*

Must take TWO tablets in order to get the full benefit of the
buffer system needed for absorption. On empty stomach.
Absorption- 40% bioavailable in the tablet form and 30% in the
powder form. DDI is acid labile so that oral preparations contain
buffer to promote absorption.
Distribution- variable volume of distribution, 20% of plasma
concentrations detected in CSF
Elimination- Renal clearance accounts for approximately 36% of
the administered dose, however, the exact fate of the metabolized
DDI is unknown. The plasma half-life is approximately 1.5 hours
and the intracellular half-life has been reported in the range of 12
to 24 hours.
Renal or Hepatic failure- appear to be associated with higher
toxicity and dose reductions should be considered, however, there
are no guidelines available.
Adverse Drug Reactions:
1.

Peripheral neuropathies: with pain and/or paresthesias in

extremities related to cumulative dose occurs in 5-12% of
patients. May be reversible in most cases provided DDI is

discontinued promptly. If DDI is continued despite

symptoms of neuropathy the patients may experience
persistent, debilitating pain.

2.

2.

Pancreatitis: has been related to total cumulative dose,

preexisting pancreatic disease, alcoholism, advanced stage
HIV disease and concurrent medications that cause
pancreatitis. It has been reported in 5-9% of patients and is
fatal in 6% of those with pancreatitis. Consider reducing
dose or discontinuing therapy if serum amylase is > 1.5-2X
upper limit of normal.

3.

Gastrointestinal: (nausea, vomiting, diarrhea) may be

related to buffer system and taste.

4.

Other: rash, hepatitis, hyperuricemia

ZALCITABINE (DDC, Hivid) 0.375mg, 0.75mg

INDICATIONS: originally approved for use in combination with
AZT only. Combinations of AZT/DDC/Protease inhibitor are
effective. Other DDC combinations have not be studied.
Dose: 0.75mg TID
Absorption- 85% bioavailable
Distribution- <4% protein binding. CSF penetration is
approximately 20% of serum levels.
Elimination - mostly excreted unchanged, cleared predominantly
by the kidney. Half-life is 1-2 hours.
Adverse Drug Reactions: DDC is associated with peripheral
neuropathies, oral ulcerations, anorexia, nausea, vomiting,
headache, fever, rash and fatigue. Pancreatitis and ototoxicity have
also been reported.

3. STAVUDINE (D4T, Zerit) 15mg, 20mg, 30mg, 40mg

INDICATIONS: Initially approved for patients who are intolerant

of other nucleoside analogues as last line therapy. May be
considered as monotherapy for in patients who do not tolerate
other antiretroviral agents. Good combinations include: AZT/d4T,
ddI/d4T, 3TC/d4T plus or minus protease inhibitors. Caution with
ddI due to overlapping side-effects.
Dose: Based on body weight
>60 kg 40mg BID
<60 kg 30mg BID
Adverse Drug Reactions: D4T is more commonly associated with
peripheral neuropathies. It is otherwise well tolerated. Pancreatitis
has been reported.

LAMIVUDINE (3TC, Epivir) 150mg

Approved in 1995 for use in combination with AZT. Widely used

in combination with AZT or d4T plus or minus a protease inhibitor
Dose: 150mg BID

Non-Nucleosides:

NEVIRAPINE (Viramune) approved in August 1996

Dose: 200mg daily x 2 weeks; then 200mg BID

pharmacokinetics: rapidly absorbed and metabolized by the liver.
interactions: interacts with drugs metabolized by Cytochrome P450
(potent inducer)
side-effects: rash(30%), nausea, diarrhea, increased LFTs, fever
indications: Should never be used alone due to rapid development
of resistance. Combination with 2 nucleoside analogs appears to
work best (ie. AZT/DDC). Concomitant use with protease

inhibitors currently not recommended due to decreased levels of

protease inhibitors leading to sub-therapeutic levels.

DELAVIRDINE (investigational)

b. Protease Inhibitors
HIV protease is an enzyme required for the cleavage of viral polyprotein
precursors into individual functional proteins found in infectious HIV.
Protease inhibitors bind to the protease activity site and inhibit the activity
of this enzyme. This prevents cleavage of these polyproteins and produces
immature noninfectious viral particles. These agents have recently been
shown to be the most potent antiretroviral agents available. However, they
are associated with numerous problems. These agents must always be used
in combination ( 3-drug combination appears to be most effective) due to
rapid development of resistance. Therapeutic serum levels must be
maintained in order to delay drug resistance, thus, full compliance is
extremely important. These agents are all metabolized by the cytochrome
p-450 system and are associated with numerous significant drug
interactions. Cross-resistance is common among these agents.
Gastrointestinal side-effects are common. Finally, these agents are
extremely expensive.

SAQUINAVIR (Invirase-Roche)

dose: 600mg TID with meals

side-effects: nausea, diarrhea, headaches
drug-interactions: Rifampin and rifabutin significantly decrease
AUC of saquinavir; ketoconazole increases AUC and Cmax of
saquinavir.

INDINAVIR (Crixivan-Merck)

dose: 800mg TID on empty stomach

side-effects: hyperbilirubinemia, nephrolithiasis, GI
drug-interactions: Indinavir and didanosine should be
administered at least one hour apart on an empty stomach because
the gastric buffering property may interfere with the absorption of
indinavir. Rifabutin dose should be decreased when used
concurrently and indinavir dose should be decreased when used

concurrently with ketoconazole. Co-administration of rifampin and

indinavir should be avoided if possible. Indinavir may compete
with metabolism of terfenadine, astemizole, cisapride, triazolam,
and midazolam and create potential for serious and/or lifethreatening events. Indinavir should not be administered
concurrently with any of these agents.

RITONAVIR (Abbott)

dose: 600mg BID (dose escalation recommended)

side-effects: nausea, diarrhea, circumoral paresthesias
drug-interactions: Ritonavir has a very high affinity for several
cytochrome P-450 enzymes and is metabolized by the same
enzyme system, there are significant drug interactions with this
agent. The following drugs should not be coadministered with
ritonavir: amiodarone, astemizole, bepridil, bupropion, cisapride,
clozapine, encainide, flecainide, meperidine, piroxicam,
propafenone, propoxyphene, quinidine, rifabutin, terfenadine,
alprazolam, clorazepate, diazepam, estazolam, flurazepam,
midazolam, triazolam, zolpidem.