Antibiotics 2018
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Antibiotics 2018


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effects	of	interferon	therapy	during
treatment,	and	be	vigilant	in	observing	for	emerging	depression.
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39:	Direct-Acting	Anti-hepatitis	C
Agents
Agents:	protease	inhibitors:	simeprevir,
paritaprevir ,	grazoprevir ,	boceprevir,	telaprevir*
NS5A	inhibitors:	daclatasvir,	elbasvir ,	ledipasvir ,
ombitasvir
NS5B	(polymerase)	inhibitors:	sofosbuvir
Non-nucleoside	polymerase	inhibitors:	dasabuvir
Combinations:	paritaprevir/ombitasvir/ritonavir,
* *
* *
*
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Combinations:	paritaprevir/ombitasvir/ritonavir,
grazoprevir/elbasvir,	ledipasvir/sofosbuvir
The	treatment	of	chronic	hepatitis	C	infection	has	undergone	as	big	of	a
revolution	of	therapy	as	HIV	treatment	has\u2014but	instead	of	unfolding	over
three	decades,	it	has	unfolded	over	5	years.
Two	serine	protease	inhibitors	introduced	in	late	2011	(boceprevir,	telaprevir)
heralded	this	new	era\u2014and	quickly	became	obsolete	as	more	potent	and
better-tolerated	agents	have	been	developed.	As	with	HIV	treatment,
treatment	regimens	using	these	drugs	typically	consist	of	multiple	agents	with
different	mechanisms	of	action.	In	contrast	to	HIV	regimens,	the	treatment
duration	for	these	anti-HCV	treatments	is	on	the	order	of	only	3\u20134	months	in
most	patients,	with	cure	rates	ranging	from	80	to	100%.	Compared	to	prior
ribavirin	plus	interferon-based	regimens	for	hepatitis	C,	the	new	drugs	are
much	better	tolerated.	This	revolution	in	therapy	comes	at	a	price\u2014as	in,
actual	cash	money	price.	Currently,	the	price	of	these	drugs	can	be	on	the
order	of	$1,000	per	day.	So,	if	you	are	learning	about	these	drugs	from	this
book\u2014you\u2019re	definitely	not	going	to	be	the	one	who	is	making	the	decision	to
start	therapy	on	a	patient	with	them!	But	everyone	involved	in	the	care	of
these	patients	has	important	roles	to	play	in	ensuring	compliance,	screening
for	drug	interactions,	and	monitoring	for	potential	adverse	effects.
*Only	available	as	a	component	of	a	combination	agent.
Mechanism	of	Action
Along	with	ribavirin,	these	agents	are	considered	to	be	direct-acting	antivirals
(DAAs)\u2014to	distinguish	them	from	the	indirect	anti-HCV	effects	of	interferon.
Their	mechanisms	are	varied;	some	inhibit	proteases,	others	RNA
polymerases	(NS5B	protein\u2014\u201cNS\u201d	stands	for	\u201cnon-structural\u201d),	and	in	the
case	of	the	NS5A	inhibitors\u2014it\u2019s	not	exactly	clear	how	they	work.	Following
the	model	of	the	latest	HIV	therapies,	most	of	the	agents	are	co-formulated
in	fixed	combinations,	which	reduces	the	need	to	select	drugs	with	different
mechanisms	\u201cfrom	the	menu.\u201d
Spectrum
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Spectrum
There	are	at	least	6	HCV	genotypes	that	can	cause	infection	in	humans	and
the	DAAs	differ	in	their	activity	against	each.	Genotype	1	(which	comes	in	1a
and	1b	flavors)	is	the	most	prevalent	in	the	United	States	and	as	such	each
of	the	current	regimens	has	activity	against	these.	Protease	inhibitors	have
potent	activity	against	genotype-1	agents,	but	simeprevir	and	paritaprevir
have	limited	activity	against	other	genotypes.	NS5A	and	NS5B	inhibitors	have
a	broad	spectrum	of	activity	against	various	HCV	genotypes.	Note	that
ritonavir	is	co-formulated	with	ombitasvir	and	paritaprevir	solely	as	a
pharmacokinetic	booster,	not	because	of	any	anti-HCV	activity.
Adverse	Effects
Besides	their	potent	activity,	the	substantially	greater	tolerability	of	these
drugs	relative	to	ribavirin	and	interferon	is	responsible	for	their	having	rapidly
become	the	regimens	of	choice.	Most	agents	are	well	tolerated	and	typically
associated	with	mild	toxicities,	including	nausea,	vomiting,	and	fatigue.
Simeprevir	is	associated	with	photosensitivity	and	thus	patients	should	limit
sun	exposure	and/or	wear	sunscreen	while	taking	this	medication.	Transient
elevations	in	bilirubin	are	frequently	seen	but	do	not	appear	to	be	associated
with	significant	hepatotoxicity.
Sofosbuvir	is	rarely	associated	with	symptomatic	episodes	of	bradycardia,
but	almost	all	of	these	occurred	in	the	context	of	patients	receiving
concomitant	amiodarone.
Elbasvir/grazoprevir	and	ombitasvir/paritaprevir/ritonavir	have	been
associated	with	hepatic	decompensation	in	some	patients,	particularly	those
with	pre-existing	cirrhosis.	Close	monitoring	of	ALT	is	indicated,	with
treatment	interruption	recommended	for	substantial	asymptomatic	elevations
(e.g.,	>10-fold	of	upper	limit	of	normal)	or	lower	elevations	that	are
associated	with	symptoms	of	hepatitis	(e.g.,	jaundice,	nausea,	vomiting,
abdominal	pain).
Important	Facts
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Important	Facts
These	agents	have	LOTS	of	drug	interactions,	and	given	the	high
prevalence	of	HIV\u2013HCV	coinfection,	interactions	with	antiretrovirals	are	a
major	issue.	The	interactions	are	mediated	through	cytochrome	P450
metabolism,	as	well	as	by	interference	with	transporters	like	P-
glycoprotein	or	the	organic	anion	transporters.	The	Website
http://www.hep-druginteractions.org	is	an	excellent	resource	for
assessing	drug	interactions	of	DAAs	with	a	wide	spectrum	of	agents,
including	antiretrovirals.
Administration	with	food	can	be	an	important	consideration	for	some	of
these	agents:	simeprevir,	ombitasivir/paritaprevir/ritonavir,	and	dasabuvir
are	recommended	to	be	administered	with	food.	Also,	the	presence	of
gastric	acidity	is	important	for	the	absorption	of	ledipasvir;	thus,	patients
who	receive	the	ledipasvir/sofosbuvir	combination	should	avoid	acid-
suppressing	agents	or	carefully	time	their	administration	with	respect	to
ledipasvir/sofosbuvir.
For	some	genotypes	and	patient	populations	(e.g.,	cirrhotic	patients),
addition	of	ribavirin	or	pegylated	interferon	to	the	DAA	regimen	is	still
recommended.
Resistance	to	these	agents	does	emerge	during	therapy	and	seems	to
correlate	with	failure	to	eradicate	HCV.	The	genetic	barrier	for	resistance
emergence	is	lowest	with	dasabuvir,	the	NS5A	inhibitors,	and	simeprevir
and	higher	with	the	other	protease	inhibitors	and	sofosbuvir.	The	clinical
significance	of	resistance	mutations	to	DAAs	is	less	well	established	than
for	HIV	antiretrovirals.	Thus,	testing	for	the	presence	of	resistance
mutations	is	recommended	before	initiating	therapy	only	in	selected
patients,	including	those	with	prior	exposure	to	DAAs	and	some	patients
with	cirrhosis.
What	They\u2019re	Good	For
These	drugs	are	used	in	the	treatment	of	patients	with	chronic	HCV	infection,
where	they	are	typically	associated	with	a	high	rate	of	cure.
Don\u2019t	Forget!
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Don\u2019t	Forget!
These	drugs	represent	a	true	breakthrough	in	treating	HCV,	but	the	drugs	are
expensive	(meaning	they	may	only	get	one	shot	at	therapy)	and	drug
interactions	are	problematic,	so	patients	need	all	the	help	they	can	get	to
make	sure	they	get	the	most	out	of	their	treatment	course.
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40:	Ribavirin
Agent:	ribavirin
Ribavirin	is	an	antiviral	agent	that	is	active	against	many	different	types	of
viruses,	though	it	is	used	primarily	for	the	treatment	of	HCV	and	respiratory
syncytial	virus	(RSV)	infection.	The	addition	of	ribavirin	to	some	other	agents
for	HCV	treatment	increases	both	the	effectiveness	and	toxicity	of	treatment.
Mechanism	of	Action
The	mechanism	of	action	of	ribavirin	is	not	well	characterized,	but	it	is	a
nucleoside	analogue	of	guanosine	that	is	phosphorylated	into	its	active	form
inside	cells.	Technically	it	is	a	direct-acting	anti-HCV	antiviral	like	those
discussed	in	Chapter	39,	but	is	generally	considered	separately	from	those
agents.
Spectrum
Well-characterized	activity	has	been	described	for	HCV	and	RSV,	though
ribavirin	has	some	activity	against	other	viruses	as	well	including	influenza
and	adenovirus.
Adverse	Effects
The	main	adverse	effect	of	ribavirin	is	haemolytic	anemia.	This	effect	is	dose-
related,	dose-limiting,	and	may	be	severe.	Interferons,	which	are	often
administered	with	oral	ribavirin	for	treatment	of	HCV,	can	exacerbate	this
effect