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Antiretroviral Drugs: A Review on its Pharmacokinetic and Pharmacodynamic Profile



Swati Prakash*,
Garima Jain, Prachi Shukla,
V.D. Rangari


Guru Ghasidas Central University, Bilaspur, Chhattisgarh.





































Author for Correspondence:

Swati Prakash

Gu
ru Ghasidas Central University

Bilaspur, Chhattisgarh

Mob. No.
-

07587314204

Email id
-

swati.prakash.0206@gmail.com

ABSTRACT



AIDS is
Acquired Immunodeficiency

Syndrome which begins with
Human Immunodeficiency
V
irus
infection
and is the final stage of
HIV disease. It causes severe damage to the immune
system which makes the body susceptible to opportunistic infections.
The a
cute HIV infe
ct
ion
progresses
over time to asymptomatic infec
tion then
early symptomatic
infection

and finally
AIDS
.
Antiretroviral

Drugs

(ARV)

are

the first line drugs for viral suppression and prevention of
HIV transmission

and so are
consid
ered as life saving drugs. No cure is available for it,
ARVs
suppresses

only viral replication.
Their maximum adherence is essential for HIV infection
management.

Antiretroviral

drugs
are classified into different categories based
on
the
mechanism
of block
ing HIV at various stages of its life cyc
le
as it enters
the host
. The
classes

are NNRTIs,
NRTIs, PIs,

INSTIs and Fusion inhibitors
. In due course of treatment the virus develops
resistance to the single drugs and thus there comes a need for the combinatio
n therapy or
HAART (Highly Active Antiretroviral Therapy). The HAART

has
ability to overcome the
resistance offered by HIV as it contains fixed dose comb
inations of
differe
nt drugs. The
disease,
its prevalence and
the drugs

with the complete pharmacology
are discussed in this review.



Keywords: AIDS, NNRTIs, NRTIs, PIs
, INSTIs
.



























INTRODUCTION



AIDS

Acquired immunodeficiency syndrome is a disease of the human immune system caused by HIV.
It interferes with the functioning of
the
immune system
, making people with AIDS much more
likely to get infections. Transmission of HIV occurs through sexual intercourse, contaminated
blood transfusions, hypodermic needles, exchange between mo
ther and baby during pregnancy
and breastfeeding

[1]
.
At the beginning of 1986, more than 20,000 cases were reported
worldwide. By then India had no reported cases of HIV or

AIDS.

Later in the year, India’s first
cases of HIV were diagnosed among

sex workers

in Chennai, Tamil Nadu.

The contact with the
foreig
n visitors had played a role in the initial infections among the sex workers, and then the
HIV screening centers were set up across the country and there were calls for visitors to be
screened for HIV.

The table below shows the various
programs

launched by

the government

to
cont
r
ol the spread of HIV.



Table 1:

Year

Program

Objectives

1987

National AIDS Control
Program

It regulated activities
as
surveillance, blood
screening
and health education.

1991

Red ribbon became
an International
symbol

for AID awareness

To support AIDS patient.

1992

National AIDS Control Organization
(NACO)

To
overs
ee formulation policies and
control
programs

relating to AIDS

1992

National AIDS Control
Program

(NACP

I
)

HIV

prevention

1999

National AIDS Control
Progra
m

(NACP II)

The prevention of mother to child transm
ission
(PMTCT)
program

and

provision of free
antiretroviral treatment

to AIDS patient.

2006

(NACP III)

To co
-
ordinate the policies



HIV
-

Structure,
P
athogenesis

and
M
anagement

HIV is the lentivirus, of

family retroviridae which causes chronic persistent infection leading to
AIDS with the onset of clinical symptoms. It is a retrovirus w
ith
two major families, HIV
-
1 and
HIV
-
2. Most of the epidemic involves HIV
-
1, HIV
-
2 is a close relative whose distributi
on is
concentrated in western Africa. HIV
-
1 is genetically diverse, with five distinct subfamilies. HIV
-
1 and HIV
-
2 have similar in vitro sensitivity to most
antiretroviral

drugs, although the non
nucleoside reverse transcriptase inhibitors (NNRTIs) are HI
V
-
1
-
specific and have no activity
against HIV
-
2

[2
]
. It is a retrovirus with a small RNA genome of 9300 base pairs. The viral
genome encodes three major open reading frames
-
gag
,
pol

and
env
; f
ig 1.

The
gag

is group
-
specific antigen gene,
pol

is polymerase gene and
env

is
envelope gene. The
gag

encodes a
polyprotein that is processed to release the major structural proteins of the virus,
pol

overlaps gag
and encodes three important enzyme activities reverse transcriptase with RNAase activity,
protease and viral
integrase
, and
env

encodes the large
transmembrane

envelope protein
responsible for cell binding and entry of the virus.
The
small
gene

tat
,
Rev
,
nef
, and
viper

[3]
,


encode regulatory proteins that enhance
virion

production or combat hos
t defenses


Fig

1
:
HIV Structure.


The mechanism from the entry of HIV to the release of
new virions occurs as follows
[4
]
:

1. Binding of the HIV to

CD4+ cell receptors present on
cytoplasm. 2. Entry of virus in the
cytoplasm. 3.
Uncoating

of virus to release reverse transcriptase, protease, and integrase enzymes
along with viral RNA. 4. Reverse transcriptase makes
a double stranded DNA copy

of
the viral
RNA
. 5. DNA copy enters the nucleus and integrates with host DNA forming
provirus
. 6.
T
ranscription of
provirus
. 7. Translation by host
ribosomes
. 8. Protease action in the formation of
polypeptides. 9. Assembly and Budding. 10. Formation of new virions.




Fig

2
:

HIV replication cycle
[5
]
.


T
he management of AIDS deals with
the use of
ARVs.

HAART is more effective in HIV
treatment
. The American National Institutes of Health and other organizations
recommend

antiretroviral

treat
ment to all patients with AIDS.


Antiretroviral

Drugs

AIDS is one of the most destructiv
e pandemics in recorded history.
ARVs
prevents

HIV
multiplication
in the body, which helps people infected with HIV live longer and healthier lives.
Antiretroviral therapy (ART) reduces the risk of
HIV
transmission
but cannot cure
it
[6
]
. The
ARVs
only
prevents

the infection of
susceptible cells but cannot cure the cells that already
harbor HIV. The available antiretroviral drug
s
are

classified as follows:


Table 2:



Drug Class

Generic Name

Brand
name

Manufacturer

FDA
approval
date

1. Non
-
Nucleoside
Reverse Transcriptase Inhibitors (NNRTIs)


Nevirapine

(
NVP)

Veramine

Boehringer

Ingelheim

21 June 1996

Delavirdine

(
DLV)

Rescriptor

Pfizer

4 April 1997

Efavirenz

(
EFV)

Sustiva

Bristol
-
Myers Squibb

17 September
1998

Etravirine

(
ETR)

Intelence

Tibotec

18 January
2008

Rilpivirine

(RPV)

Edurant

Janssen
Pharmaceuticals Inc.

20 May 2011

2. Nucleoside Reverse Transcriptase Inhibitors (NRTIs)


Abacavir

(ABC)

Ziagen

GlaxoSmithKline

17 Dec 1998

Didanosine

(ddl)

Videx

Bristol
-
Myers Squibb

9 Oct 1991

Emtricitabine

(FTC)

Emtriva

Gilead Sciences

2 July 2003

Lamivudine

(3TC)

Epivir

Glaxo SmithKline

17 Nov 1995

Stavudine

(d4T)

Zerit

Bristol
-
Myers Squibb

24 June 1994

Tenofovir

(TDF)

Viread

Gilead Sciences

26 Oct 2001

Zidovudine

(ZDV,AZT)

Retrovir

Glaxo SmithKline

19 March
1987

3. Protease Inhibitors (PIs)


Atazanavir

(ATV)

Reyataz

Bristol
-
Myers Squibb

20 June 2003

Darunavir

(DRV)

Prezista

Janssen
Pharmaceuticals Inc.

23 June 2006

Fosamprenavir

(FPV)

Lexiva

Glaxo SmithKline

20 Oct 2003

Indinavir

(IDV)

Crixivan

Merck

13 March
1996

Nelfinavir

(NFV)

Viracept

Agouroun
Pharmaceuticals

14 March
1997

Ritonavir

(RTV)

Norvir

Abott Laboratories

1 March 1996

Saquinavir

(SQV)

Invirase

Hoffmann
-
La Roche

6 Dec 1995

Tipranavir

(TPV)

Aptivus

Boehringer Ingelheim

20 June 2005

4. Fusion Inhibitors


Enfuvirtide (T
-
20)

Fuzeon

Hoffmann
-
La Roche,
Trimeris

13 March
2003

5. CCR5 Antagonists


Maraviroc

(MVC)

Selzentry

Pfizer

6 Aug 2007

6. Integrase Inhibitors


Raltegravir

(RAL)

Isentress

Merck

12

Oct 2007

7. Fixed Dose Combinations


Abacavir, Lamivudine

Epzicom

Glaxo SmithKline

2 Aug 2004

Abacavir,
Lamivudine,Zidovudine

Trizivir

Glaxo SmithKline

14 Nov 2000



Efavirenz,

Emtricitabine,
Tenofovir DF

Atripla

Bristol
-
Myers Squibb,
Gilead Sciences

12 July 2006

Elvitegravir,
Cobicistat,
Emtricitabine,
Tenofovir DF

Stribild

Gilead Sciences

27 Aug 2012

Emtricitabine,

Rilpivirine,Tenofovir
DF

Complera

Gilead Sciences

10 Aug 2011

Emtricitabine,

Tenofovir DF

Truvada

Gilead Sciences

2 Aug 2004

Lamivudine,
Zidovudine

Combivir

Glaxo SmithKline

27 Sept 1997

Lopinavir, Ritonavir

Kaletra

Abott Labs

15 Sept 2000


Antiretroviral

therapy

The Standard antiretroviral therapy (ART) consists of the combination of at least three ARV
s
to
maximally suppress

the replicating HIV virus and stop progression of HIV disease. The primary
goa
ls of ART

are maximal and durable suppression of viral load to undetectable levels (HIV
-
1
RNA levels>
50 copies/ml), restoration and preservation of immunological functions, reducing
risk of clinical progression and ultimately improving the quality of life and reducing HIV related
morbidity and mortality.

There was a need for the combination therapy
becaus
e of the
incomplete inhibition of virus replication or due to the development of viral resistance to
monotherapy
.
Resistance to the
antiretroviral

drug appears due to mutation in reverse
transcriptase (RT) coding region of the
pol

gene
of HIV
-
1

[7
]
.

The factors that distinguish one
ART regimen from other are simplicity, toxicity and cost
[8
]
. A regimen contains three or more
anti
-
HIV medications from at least two different drug classes
.
It contains tw
o NRTIs along with
one NNRTI/
PI

(boosted with RTV
)
/ INSTI or a CCR5 antagonist.
The backbone in this drug
regimen is formed by the NRTIs
[9
]
. The virus is being attacked at different steps of its life cycle,
by
combining

drugs with synergistic effect. This treatment is known as highly active
antiretrovira
l therapy (HAART), and it reduces the patient's viral load to below detectable levels
for prolonged periods. The selection of the appropriate combination of the antir
etroviral drugs is
based on:
avoidi
ng the use of two agents of same nucleoside analog,
avoiding overlapping
toxicities, genotypic and phenotypic cha
racteristics of
viruses
,
patient factors such as disease
sympt
oms and concurrent illness,
ease of adherence to a frequently co
mplex administration
regimen
[10
]
. HIV patients having detectable vir
al loads (1,000

5,000 copies/
ml
) and/or evidence
of immunologic dysfunction (CD4+ T
-
lymphocyte count < 500/mm
3
) should be given a potent
combination of antiretroviral drugs as stated above. The drugs should be selected with a view
toward

maximizing adheren
ce and minimizing drug
-
drug interactions and side effects. If a
regimen is failing in
patients

due to non

adherence, a new regimen should be chosen using at
least two new medications to which viral strain
s are likely to be sensitive
[11
]
.


Nonnucleoside Re
verse Transcriptase Inhibitors (NNRTIs)

This category consists of chemically
and structurally
diverse compounds which are non
-
competitive inhibitors of the
HIV
-
1
RT enzyme and bind at its
allosteric

site

[12
]
. RT enzyme,
called as RNA
-
directed DNA
polymerase, is encod
ed from the genetic material of
retroviruses. It


catalyzes the transcription of retrovirus RNA
into DNA
.

This catalyzed transcription is the
reverse process of normal cellular transcription of DNA into RNA, hence is the name reverse
tra
nscriptase and retrovirus. RT inhibitors are used as potent antiretroviral drugs. The drugs in
this category are Nevirapine, Dela
viridine, Efavirenz, Etravirine

and Rilpivirine

of which
Nevirapine and Delavirdine, have been formally li
censed for clinical u
se and
others are under
preclin
ical or clinical development
[13
]
.


Mode of Action

The
NNRTIs
act by directly inhibiting the HIV
-
1 RT e
nzyme in the hydrophobic pocket
in
reversible and non
-
competitive manner resulting into its
denaturation
. This leads to
slow down
the rate of polymerization caused

by
RT enzyme. These drugs specifically inhibit HIV
-
1 RT to a
great extent, but their efficacy is impaired by
the rapid emergence

of mutations
[14
]
. NNRTIs ar
e
extensively metabolized in
the liver

through cytochrome P450 leading to
pharmacokinetic

interactions w
ith the compounds utilizing
same metabolic pathway, particularly PIs
.


Table 3:

Drug name

Chemical Formula

Structure

Nevirapine

11
-
cyclopropyl
-
4
-
methyl
-
5, 11
-
dihydro
-
6H
-

dipyrido
[3,2
-
b:2′,3′
-
e][1,4]diazepin
-
6
-
one


Delaviridine

N
-
[2
-
({4
-
[3
-
(propan
-
2
-
ylamino) pyridin
-
2
-
yl]
piperazin
-
1
-
yl} carbonyl)
-
1H
-
indol
-
5
-
yl]
methanesulfonamide



Nevirapine
(NVP)

It is t
he first approved member of
NNRTIs.
It
is a dip
yridodiazepinone NNRTI with
potent
activity against HIV
-
1 (t
able 3
)
.
It is used in pregnancy to prevent vertical transmission at an oral
d
ose of 200 mg to mother at labo
r and 2mg/kg oral dose to neo
nate within 3 days after birth.

Pharmacokin
etics

It is well absorbed orally
at a dose of 400mg once or twice daily
. I
ts bioavailability is

more than
90% which

is

not altered by food or antacids
[15
]
.
Its plasma protein binding is 60%.

The drug
readily crosses
placenta and has been found in breast milk, a

feature that has encouraged use of
NVP for prevention of mother to
child transmission of HIV
.
It is an enzyme inducer and
is
metabolized
in
liver. The plasma half l
ife is reached in 45 hrs and

e
xcretion occurs by renal
route.

Pharmacodynamics

Resistance
:
The specific mutations associated with resistance to NNRTIs correlate with amino
acid changes

in the pocket where
NNRTI drug preferentially binds. NVP
is not effective against
HIV
-
2
because the pocket of the HIV
-
2
RT
has a different structure, which provid
es intrinsic
resistance to the NNRTI class
[16
]
. Resistance to NVP develops rapidly if viral replication is not
completely suppressed
[
1
7
]
. The most common mutations observed after its treatment are Y181C
and K103N
[18
]
.
It is
also asso
ciated with mutations at codons
100, 106, 108, 188, and 190, but
either the K103N or Y181C mutation is sufficient to produce treatment failure
[19
]
. NNRTIs
exhibit the phenomenon of cross
-
resistance.

Adverse Effects:

Hypersensitivity syndrome and rash acco
mpanied by f
ever, general malaise,
fatigue,
arthralgias, blisters,

conjunctivitis, facial edema, eosinophilia, granulocytopenia,


lymphadenopathy

and
renal dysfunction.
Stevens
Johnson syndrome, toxic epidermal n
ecrolysis
and
hepato
toxic
ity.


Drug
interactions:

The
antitubercular drug Rifampicin
lowers NVP levels
and thus
both

drugs
should not be

co
-
administered.
I
t is
cytochrome P4
50 isoenzymes CYP3A4 and CYP2B6

inducer
, and so
i
t reduces the levels of
co
-
administered drugs
Clarithromycin, Ketocona
zole,
Methadone and forms of hormonal contraceptive besides
the
ARVs
Efavirenz, Indinavir,
Lopinavir, Nelfinavir and Saquinavir
.


Delavirdine

(DLV
)

It is
available
as the mesylate prodrug

(t
able 3
)
.

It was appr
oved by the U.S. FDA
in 1997. Its
efficacy is
lower than ot
her NNRTIs, especially EFV

so it is not recommended in the early
therapy of disease.
It exhibits cross resistance
with other NNRTIs.

It
binds t
o HIV
-
1
RT and
t
he
DLV
-
RT

complex

so formed

is stabilized by hydrogen bonding
[2
0
]
.

Pharmacokinetic
s

D
LV

is absorbed rapidly after oral administration
and
its dose is 400mg t
hrice
d
aily
.
The
bioavai
lability is more than 85% and
plasma protein binding is 98%. It is metabolized in liver by
CYP3A4 and CYP2D6 cytochrome enzymes.
It is cytochrome CYP3A4 enzym
e inhibitor.
The
plasma half life is reached in 5.8 hrs and the excretion occurs by renal (51%) and fecal (44%)
route
s
.

Pharmacodynamics

Resistance:

The K103N or Y181C is gene is
observed as the initial mutation

responsible for
early DLV failure
. D
LV

resi
stance is also associated wit
h mutations at codons 106, 188
and 236

but either the K103N or Y181C mutation is sufficient to produce treatment failure.


Adverse Effects:

Rash, hepatitis, f
atigue, headache, nausea
, gastrointestinal complaints,
increases in
transaminase level.

Rash occurs between 7
-
15 days after initiating treatment and
occurs more commonly in patients with CD4+ counts less than 100 cells/mm
3
.


Drug interactions:
It
CYP3A4 inhibitor
and so
should not
be
co
-
administe
red with drugs
including

Am
prenavir, Fosamprenavir, Simvastatin, Lovastatin, Rifampin, Rifabutin,
Rifapentine, St John's wort, Astemizole, Midazolam, T
riazolam and
ergot medications for acid
reflux.


Nucleoside Reverse Transcriptase Inhibitors

(NRTIs)

This category
comprises
a large

group of riboside analogues i.
e., nucleosides or nucleotides
which
are competitive and potent inh
ibitors of the RT enzyme of HIV
-
1.The drugs in this
category are Abacavir, Didanosine, Embricitabine, Lamivudine, Stavudine, Zidovudine and
Tenofovir
[2
1
]
.


Mode of Action

The drugs in this category are prodrugs which lack a 3’
-
hydroxyl group and are activated by cell
kinases to form phosphorylated derivatives. These formed derivatives competitively inhibit RT
enzyme and act as chain terminators by
getting
inc
orporat
ed

into the viral DNA chain via virus
transcriptase. The nucleotide analogues do not require bioactivation by the kinases to act.


Table 4:

Drug name

Chemical Formula

Structure



Abacavir

{(1S,4R)
-
4
-
[2
-
amino
-
6
-
(cyclopropylamino)
-
9H
-
purin
-
9
-
yl]cyclopent
-
2
-
en
-
1
-
yl}methanol


Lamivudine

4
-
amino
-
1
-
[(2R,5S)
-
2
-
(hydroxymethyl)
-
1,3
-
oxathiolan
-
5
-
yl]
-
1,2
-
dihydropyrimidin
-
2
-
one



Abacavir (ABC)

It is a
n

only approved antiretroviral which is a guano
sine analogue and is so far proved to be
better than other NRTIs. T
he phosphorylation of ABC
first takes place by adeno
sine
phosphotransferase and
then by cellular kinases
to di
-

and triphosphates. Carbovir triphosphate
terminates the elongation of provira
l DNA by getting incorporated into nascent DNA by RT.

HLA
-
B*5701 screening should be performed prior to

the

initiation of ABC
because adverse
events occur due to this genetically mediated gene, and if
found to be
positive then
ABC should
not be
administered
.

Pharm
acokinetics


Its route of administration is oral
. The introduced dose of
ABC was 300
mg

twice daily
, but

now

the approved dose
has changed to 600mg qid

because the carbovir triphosphate accumulates
inside the cell and
has a reported elimi
nation half
life of up to 21 hours
[2
2
]
. Its bioavailability is
86% an
d plasma protein binding is 56%
.

It is metabolized in liver by alcohol dehydrogenase and
the plasma half life is reached in 3
-
6 hrs. The excretion occurs by renal route.

Pharmacodynamics

Resistance:

The resistance to
ABC
is associated with four specific codon substitutions K65R,
L74V, Y115
F
and M184V
[2
3
]
. The Y115F mutation is associated uniquely with

ABC
. The L74V
mutation is assoc
iated with cross
-
resistance to Didanosin
e and Zalcitabine
, the
K65R
mutation
provides cross
resist
ance to all nucleosides except Z
idovudine.

Adverse Effects:

Hypersensitivity syndrome
characterized by f
ever, abdominal pain, malaise,
fatigue, gastrointestinal complaints and maculopapular rash. Respiratory complaints
as dyspnea,
cough and pharyngitis
.

Cardiovascular and m
usculoskeletal co
mplaints
.

Drug interactions
: It is not associated with significant pharmacokinetic drug
interaction
s, b
ut
large dose

of ethanol (0.7 g/kg) increases

the
plasma
concentration of ABC
by 41% and prolongs
the elimination half
-
life by 26% due to competition for alcohol dehydrogenase

[24
]
.


Lamivudine (3TC)

It is a cytosine analogue and is chemically active against HIV
-
1, HIV
-
2 and HBV.
It
enters cells
by passive diffusion and
undergoes phosphorylation
by deoxycytidine kinase and nucle
oside
diphosphate kinase enzyme

to yield lamivudine 5
-
triphosphate, which i
s the active anabolite
[
25
]
.The intracellular triphosphate acts as a competitive inhibitor of
RT
and is incorporated into
HIV
DNA to cause chain termination. 3TC
has low affinity for human DNA polymerases and so
exerts low toxicity to the host.

Pharmacokinetic
s

It is
absorbed orally. The approved dose
of 3TC
is 300mg
once
d
aily

[26
]
. Its bioavailability is
86% which is not affected by
the presence of
food. The plasma protein binding i
s 35% and it
freely crosses
placenta. It is metabolized in liver
and
p
las
ma half life is reached in 3
-
6 hrs. The
excretion occurs by renal route.

Pharmacodynamics



Resistance:

The resistance to
3TC
occurs with a single mutation in the HBV

DNA polymerase
gene. It
consists of a methion
ine to
valine substitution (M2041V) in the
active site of the
enzyme.
HIV/HBV coinfected patients develop resistance to
it
even a
fter 4 years of treatment in
up to

90% cases. However, virologic benefits persist
s

in some treated patients harboring
3TC
-
resis
tant HBV,
possibly because the mutated virus has substantially reduced replicative capacity
[27
]
.

Adverse Effects:

It is one of the least toxic
ARVs
with fewer side
effects. At hig
her doses
neutropenia, headache

and nausea

occur
.

Drug Interactions:

It
is synergistic with many nucleoside analogs in vitro
[
2
8
]
,

[
29
]
.
Trimethoprim
-
sulfamethoxazole increases
its

plasma AUC by 43% through inhibition of renal
tubular secretion
[3
0
]
.


Protease Inhibitors

(PIs)

An aspartic protease enzyme is encoded by HIV
which is involved in the production of structural
proteins and enzymes required for the

virus growth.
It
is responsible for the maturation of new
viral particles so formed.
Structurally it
is a homodimer consisting

of two 99 amino acid
monomers,
each monomer contributes an aspartic acid residue that is essential for
the
catalysis
[3
1
]
. The drugs in this category include Atazanavir,
Fosamprenavir
, Ritonavir, Darunavir,
Indinavir, Nelfinavir, Saquina
vir and Tipranavir.

Mode of Action

HIV PIs are pep
tide like chemicals that competitively inhibit the action of virus aspartyl protease
enzyme.
These drugs prevent proteolytic cleavage of HIV
gag

and
pol

polyproteins that include
essential structural and enzymatic components of the virus. This prevent
s the

metamorphosis of
HIV viral

particles into their mature infectious forms
[3
2
]
.


Table 5:

Drug name

Chemical Formula

Structure

Atazanavir

(3S,8S,9S,12S)
-
3,12
-
Bis(1,1
-
dimethylethyl)
-
8hydroxy
-
4,11
-
dioxo
-
9
-
(phenylmethyl)
-
6
-
[[4
-
(2
-
pyridinyl)phenyl]methyl]
-
2,5,6,10,13penta
azatetradecanedioic acid dimethyl ester


Ritonavir

1,3
-
thiazol
-
5
-
ylmethyl N
-
[(2S,3S,5S)
-
3
-
hydroxy
-
5
-
[(2S)
-
3
-
methyl
-
2
-
{[meth
yl({[2
-
(propan
-
2
-
yl)
-
1,3
-
thiazol4yl]methyl})carbamoyl]amino}butanamido]
-
1,6
-
diphenylhexan
-
2
-
yl]carbamate.



Atazanavir

(ATV)

It
is an azapeptide
PI (t
able 4
)
, having
a C2
symmetric chemical structure that is active against
both HIV
-
1 and HIV
-
2
[3
3
]
. AZT was a product of rational drug design based on the X
-
ray crystal
structure of a peptide
-
enzyme complex
[3
4
]
. It is t
he first PI approved for once
daily dosing
without causing lipodystroph
y and elevated cholesterol side
ef
fects. It may also not be cro
ss
resistant with other PIs. The boosting of
ATV
with

RTV
produces higher plasma levels of A
TV
,
which gives higher efficacy but it should be used only in specific situations and as a main
tenance
strategy. The unboosted
ATV
should not be considered

an optimal choice for treating HIV naive
patients and
for administration to
pregnant women. Clinical data indicate that
switching to
unboosted ATV based regimens is a feasible option to control and prevent toxicity events in


patients with sustained undete
ctable HIV RNA
and
without previous virological failure or HIV
drug re
sistance associated mutations, especially those patients
who cannot tolerate
RTV

[
35
]
. It
reversibly binds to the active site of HIV protease enzyme and thus prevent
s

polypeptide
process
ing and virus maturation.

Pharmacokinetic
s

A
TV

is rapidly absorbed after oral administration with peak
plasma
concentrations reaching after
2 hours of dosing.
Its absorption gets a
ffected by the type of food, a light meal in
creases the
AUC and vice versa.
The dose of ATV is 400mg
once
d
aily

and its bioavailibilty is 60
-
68% with
86% plasma protein binding. Hepatic metabolism occurs which is CYP3A4 mediated. The half
life is reached in 6.5 hrs and excretion occu
rs via fecal and

renal routes.
Absorption may be pH
-
dependent because proton pump inhibitors reduce
its
concentrations after oral dosing. It is poorly
water soluble
. It

is a substrate of bot
h hepatic metabolizing enzymes, c
ytochrome 450 (CYP3A)
and intestinal drug efflux
pump P
-

glycoprotein (Pgp) and so have low oral bioavailability
[
36
]
.

Pharmacodynamics

Resistance:

The ATV resistance mutation occurs at HIV protease codon 50. Patients isolated
with this mutation are still susceptible to get inhibit
ion by other PIs
. Sensitivity to
ATV
is
affected by various primary and secondary mutations that accumulate in patients who have failed
other HIV
PIs
[37
]
.

Adverse Effects:

Jaundice due to u
nconjugated hyperbilirubinemia
, diarrhea,
nausea
,

lower
ing

of
fasting triglyceride

and cholesterol concentrations

occurs
.

Cardiovascular disease,
n
eprotoxicity and rash.

Drug interactions:

ATV

is meta
bolized by CYP3A4 enzyme, so
concomitant administration of
inducers of
this enzyme is contraindicated. It

is
CYP3A4
inhibitor so
the

plasma concentration
of
other CYP3A4 substrates

is altered
. It does not inhibit ot
her CYP isoforms. Efavirenz 600
mg
once
d
aily

reduces its AUC by 75% and T
enofovir decreases its concentrations by 25%
[38
]
. R
TV

significantly increases the AUC of ATV and re
duces its systemic clearance. R
TV 100
mg
qid

increases the

ATV 300mg qid

steady
state AUC by 2.5 times and increases the C
min

6.5 times.
Proton pump inhibitors reduce
its
concentrations with the concomitant administration. Thus H
2

blockers should be avoi
ded

in patients receiving ATV.

Lipid lowering agents, ergot derivatives,
neuroleptics and St. John’s wort should not be
co
-
administered
.


Ritonavir

(RTV)

R
TV

is a pepti
domimetic PI which complements the C2
symmetry of the
active site

of the
enzym
e

(t
able 4
)
.

It is active against both HIV
-
1 and HIV
-
2 but may show less activity against
the latter. It is frequently prescribed with HAART, not for its antiviral action, but because it
inhibits the same host enzyme which metabolizes the other protease inhibitors
, in

turn leading to

higher plasma concentrations of the latter drugs. It therefore increases the bioavailability of

concurrently administered drugs by inhibition

of drug transporters and/or CYP3A enzymes
[
3
9
]
.

This helps
the
clinician in
improving
the
clinical efficacy and lowering
the frequency

and dose of

drugs. The monotherapy with one
RTV

boosted
PI
offe
rs several potential advantages

such as
avoiding long
term toxicity associated with nucleoside/nucleotide analog,
reducing costs,
preventing drug dr
ug interactions
and preserving future treatment options
[4
0
]
.

The drug regimen
of a single
PI
result
s

in both viral
resistance and
cross
resistance to other
PIs. Therefore
combination therapy

includ
ing
the

PIs
, is the standard of care. This type of therapy

has potential
to both prolong the effectiveness of treatment and alter the efficacy of drugs in the regimen.




It binds reversibly to the active site
of viral

protease enzyme
and

blocks it. This

prevents the
polypeptide processing and subsequent virus matu
ration. The

noninfectious

virus particles are
produced in the presence of
RTV.

Pharmacokinetic
s

RTV
is absorbed
orally and rapidly which is slightly affected by the presenc
e of food. Its dose
is
600mg
twice
d
aily

and its bioavailability is 74
-
75%
[
4
1
]
. It
s protein binding is 98
-

99% which is
m
ainly to α
-
1
acid glycoprotein

a
nd half
life is 3
-
5 hours. Its metabolism mainly occurs
by
CYP3A4 and to a lesser extent by CYP2D6.

The elimination of RTV

and its metabolites occurs
mainly through feces. The drug eliminated in urine is about 3%

(unchanged form) whereas in
feces it is 86%.

Pharmacodynamics

Resistance:

The primary
RTV
resistance mutat
ion occurs at protease codon 82

or 84. Additional
mutation
s associated with increasing resistance occur at co
dons 20, 32, 46, 54, 63, 71, 8
4 and 90.
The multiple mutation

leads to
its
increased resistance.

Adverse Effects:

G
astrointestinal disturbances, nausea, vomiting, diar
rhea, anorexia, abdominal
pain
and tas
te perversion.
These side eff
ects are dose
dependent and occ
ur rarely with low doses.
Peripheral
,

perioral paresthesias

and
lipodystrophy

[42]
. D
ose

dependent elevations in serum total
cholesterol and triglyceri
des
.

Drug interactions:

It is potent
CYP3A4
inhibitor

and so
increases
plasma concentration and
prolongs

elimination of many drugs. The list

includes Amiodarone, Propafenone, Ergot
derivatives, Pimozide, Triazolam and Midazolam,
so they should not be co
-
administered.

It is

weak
CYP2D6 inhibitor
. Pot
ent CYP3A4 inducers as Rifampin
lower its

concentrations and so
should be avoided or doses should be adjusted.
Its
interaction with F
luticasone
[4
3
]

and inhaled
B
udesonide
[
4
4
]

leads to cushing syndrome in HIV patients. The capsule and solution
formulation
s of
RTV
s
hould not be administered with Disulfiram or M
etronidazole because they
contain alcohol. It is a moderate in
ducer of CYP3A4, glucuronosyl S
-
transferase
an
d other
hepatic enzymes and so concentration of some drugs decreases

in
its presence
. It

red
uces the
ethinyl estradiol
AUC by 40%

probably because of time and concentration dependent induction
of metabolic enzymes by RTV
,
so
alternative forms of contraception should be used
[4
5
]
.

The
multiple doses
of RTV

have altered its own pharmacokinetics

[46]
.

Fusion Inhibitors

These are also known as Entry inhibitors
. When the HIV virion enters the cell, it uses the CD4
co
-
receptor and Chemokine (Ck) receptor CXCR4 or CCR5 as the binding sites to facilitate its
entry into the
DNA of the host
cell
.
Enfuvirtide and Maraviroc are the agents belonging to this
class.

Mode of Action

The fusion inhibitor
interferes with entry of
virus into the host cell
. Enfuvirtide

binds to

the HIV
envelope glycoprotein gp41

and
Maraviroc
binds to the CCR5 co
-
receptor
. Th
is interferes with
the binding, fusion

and entry of HIV virion to the

human cell. By blocking this step

in HIV's
replication cycle, the
s
e

agent
s retard

the progress
ion from HIV infection to AIDS.


Enfuvirtide

(T
-
20)

It is a large synthetic HIV
derive
d peptide which has potent
activity against HIV
-
1 form

only
. It
is expensive to manufacture and must be administered by subcutaneous injection twice daily.
Thus cost and route of administration limit
s

its use. It has a unique mechanism of action and

high


v
iral target specificity. In
clinical trials
it
has been shown to exhibit both high efficacy and

low
toxicity. It is a 36
amino
acid synthetic peptide whose sequence is derived from a part of the
transmembrane gp41 region of HIV
-
1
. Chemically it is known Ac
etyl
-
YTSLIHSLIEESQNQ
QEKNEQELLELDKWASLWNWF
-
amide
.
Its structure is given as follows:


Pharmacokine
tic
s

It is the only approved antiretroviral drug that must be taken subcutaneously. It is well absorbed
from the gastrointestinal tract and reaches peak
plasma concentrations within 5 hours. Its
bioavailability is

40
-
45% withou
t food, which is increased with
high fat meal in
intravenous
dose. The bioavailability of subcutaneous
T
-
20
is 84%
[
4
7
]
. The protein binding is 92% mainly to
albumin. Its
metabolism
occurs via hepatic route b
y cytochrome CYP3A4 and CYP2B6. T
he
half
-
life is reached in 3.8 hours.

The dose is 600mg
once
d
aily
.

The drug should be taken initially
on an empty stomach at bedtime to
lower the
side effects. The excretion occurs by fecal and
re
nal route. The major route of elimination for
T
-
20
has not been determined. It is an enzyme
inducer.

Pharmacodynamics

Resistance
:

HIV can develop resistance to this drug through specific mutations in the
T
-
20
binding domain of gp41

[48
]
. The most common
mutations involve a V38A or N43D substitution.
A va
riety of different mutations are reported

in the amino acid region 36

45 each conferring a
distinct level of r
esistance or susceptibility to it
. Single amino acid substitutions in this region are
most comm
on and cause variable degrees

of susceptibility loss. It exhibits a 5
-
10 fold reduction
in its susceptibility
[49
]
. Single amino
acid substitutions
confer up to 450 times res
istance in vitro,
although high
level
resistance is associated with two or more am
ino acid changes.

Adverse Effects
:

I
njection
site reactions

like nodules or cysts
. P
ain, erythema,

lymphadenop
athy,
pneumonia
hypersensitivity reactions like
macu
lopapular
rash on
chest and
abdomen

[50
]
.
It suppresses the interleukin
-
12 production in vitro

by more than 90% at
concentrations equal to or less than those requir
e
inhibiting

HIV replication
[51
]
. Flu like

symptoms,
headac
he, dizziness, mood alteration and
gastrointestinal

effects.

Drug interactions:

It
is not metabolized to a significant extent
and is not known to alter the
concentrations of any
co
-
administered

drugs.


Integrase

Strand Transfer

Inhibitors

(INSTIs)

Integrase is a viral enzyme

responsible for inserting
viral genome into the DNA of host cell.
I
ntegration is a vital step in
the retroviral replication and so
block
ing it can
prevent

HIV

replication
. Since these inhibitors target a distinct step in the retroviral life cycle they may be


taken in combination with other types of anti
-
HIV drugs to minimize the adaptation by virus.
T
hey are also useful in salvage therapy for patients whose virus has mutated and acquired
resistance to other drugs. The first integrase inhibitor approved in this category by U.S. FDA is
Raltegravir. The other drug in this category is Elvitegravir under p
hase 3 clinical trials and is
highly selective. MK
-
2048 is a second generation integrase inhibitor under clinical development.

Mode of Action

The drugs in this class block the action of integrase
enzyme
preve
nting

vira
l replication in the
host cell.


Raltegravir

(RAL)

T
he first approved drug in this class which is active against HIV
-
1. It was initially approved for
those individuals who
developed
resistan
ce

to other HAART drugs. But later on, the FDA
granted expanded approval
to it
for use in all patients. It is
a
substi
tuted naphthyridine derivative.

Chemically it is
4
-
[N
-
(4
-
Fluorobenzyl) carbamoyl]
-
1
-
methyl
-
2
-
[1
-
methyl
-
1
-
(5
-
methyl
-
1,3,4
-
oxadiazol
-
2
-
ylcarboxamido)ethyl]
-
6
-
oxo
-
1,6
-
dihydropyrimidin
-
5
-
olate
. Its structure is as
follows
:


Pharmacokinetics

RAL is absorbed

rapidly after oral administration

with a bioavailability of 32%.
Its
bioavailability is enhanced
and rate of absorption is reduced
with
h
igh fat meal
.

The doses
prescribed for RAL are 200, 400 and 600mg

twice
d
aily
.
The plasma protein binding is 83%.
Its
metabolism

occurs by hepatic ro
ute via glucoronidation and half
life is reached in 9 hours.
Its
clearance
in human beings
occurs by metabolism via UGT1A1
mediated glucuronidation.
Pharmacodynamic
s

Resistance:

The mutations Q148K, E138A and
G140A

are reported for it
. Additional mutation
s
were acquired with the higher doses
. The resistant mutations
such as G118R, R263K and S153Y
have been

recently identified through in
vitr
o selection studies with second
generat
ion integrase
strand
-
transfer inhibitors (INSTIs)
[5
2
]
. There are two distinct pathways of resistance, one
involving amino acid residue 148 (Q148H, Q148K, or Q148R) and the other involving N
155H.
These mutations confer 10
-
25
fold

decreased susceptibility
to

it
. Additional secondary mutations
such as L74M, E92Q, T97A
, E138K, G140S, V151I, G163G/R
and D232D/N may also be
present in
RAL
virologic failures.

Adverse Effects
:

D
iarrhea, nausea
,
abdominal

pain,
up
per respiratory tract infection,
nasoph
aryngitis,
headache, dizziness,
ins
omnia,
lipodystrophy,
elevated
serum glucose levels,
h
epatitis,
skin and hypersensitivity reactions

including Steven
-
Johnson syndrome and toxic
epidermal necrosis
.

Increase in creatinine kinase, myopathy and rhabdomylosis.

Drug Inte
raction
s:

The

UGT1A1 inhibitors increase the plasma concentration
of RAL

whereas
medications like
ATV, Phenobarbital and P
henytoin
decreases
its level.






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