Brain Injuries

Neurocritical care focuses on critically ill patients with primary
or secondary neurological problems. Initially neurocritical care
was developed to manage postoperative neurosurgical patients;
it then expanded to the management of patients with traumatic
brain injury (TBI), intracranial hemorrhage and complications of
subarachnoid hemorrhage, including vasospasm, elevated
intracranial pressure (ICP) and the cardiopulmonary
complications of brain injury (Bamford 1992). The striking
improvements noted in many studies suggest that high-quality
neurocritical care with the delivery of targeted therapeutic
interventions does have an impact, not only on survival, but
importantly also on the quality of survival.
Types of Brain Injuries
Primary brain injuries
Ischemic brain injury: either global, which includes cardiac
arrest or anoxia, or regional ischemic brain injury, which
includes vasospasm, compression of blood vessels or stroke.
Stroke can be classified into ischemic and hemorrhagic strokes.
Ischemic stroke accounts for 80% of all strokes and can be
further classified into thrombotic or embolic stroke; ischemic
40 | Critical Care in Neurology
thrombotic stroke accounts for 77% while ischemic embolic
stroke constitutes the remainder.
Hemorrhagic strokes constitute 10-20% of all strokes, and can
be further classified into two types, the intracerebral
hemorrhage that constitutes up to 75% and the subarachnoid
hemorrhage that makes up the other 25%.
Acute ischemic stroke is the third leading cause of death in
industrialized countries and the most frequent cause of
permanent disability in adults worldwide, so understanding the
pathogenesis of ischemic stroke is mandatory. Despite great
strides in understanding the pathophysiology of cerebral
ischemia, therapeutic options remain limited. Only recombinant
tissue plasminogen activator (rTPA) for thrombolysis is
currently approved for use in the management of acute ischemic
stroke.
However, its use is limited by its short therapeutic window (3-
4.5 hours), complications from the risk of hemorrhage, and the
potential damage from reperfusion injury. Effective stroke
management requires recanalization of the occluded blood
vessels. However, reperfusion can cause neurovascular injury,
leading to cerebral edema, brain hemorrhage, and neuronal
death by apoptosis or necrosis (Hajjar 2011).
Central nervous system (CNS) infections: Acute onset fever
with altered mental status is a problem commonly encountered
by the physician in the emergency setting. “Acute febrile
encephalopathy” is a commonly used term for description of the
altered mental status that either accompanies or follows a short
febrile illness. CNS infections are the most common cause of
nontraumatic disturbed consciousness. The etiologic agents may
be viruses, bacteria, or parasites. Central nervous system
infections are classified into categories beginning with those in
immunocompetent hosts followed by infection with the human
immunodeficiency virus (HIV) and its opportunistic infections.
The viruses responsible for most cases of acute encephalitis in
immunocompetent hosts are herpes viruses, arboviruses, and
enteroviruses. Neurotropic herpes viruses that cause
Brain Injuries | 41
encephalitis predominantly in immunocompetent hosts include
herpes simplex virus 1 (HSV-1) and 2 (HSV-2), human herpes
virus 6 (HHV-6) and 7 (HHV-7), and Epstein-Barr virus (EBV).
Cytomegalovirus (CMV) and varicella-zoster virus (VZV) may in
some situations cause encephalitis in immunocompetent
patients, but more commonly they produce an opportunistic
infection in immunocompromised individuals, such as those
with HIV infection, organ transplant recipients, or other patients
using immunosuppressive drugs. HSV-1 is the most common
cause of severe sporadic viral encephalitis in the United States;
diagnosis has been become more familiar due to the availability
of cerebrospinal fluid (CSF) polymerase chain reaction (PCR)
analysis techniques that allow for rapid, specific, and sensitive
diagnoses. The use of CSF PCR instead of brain biopsy as the
diagnostic standard for HSV encephalitis has expanded
awareness of mild or atypical cases of HSV encephalitis. Adult
encephalitis is caused by 2 viral serotypes, HSV-1 and HSV-2.
Patients with greater than 100 DNA copies/μL HSV in CSF are
more likely than those with fewer copies to have a reduced level
of consciousness, more significant abnormal findings on
neuroimaging, a longer duration of illness, higher mortality, and
more sequelae (Domingues 1997). EBV is almost never cultured
from CSF during infection, and serological testing is
inconclusive, so CSF PCR diagnosis is mandatory.
Semiquantitative PCR analysis of EBV DNA suggests that copy
numbers are significantly higher in patients with active EBV
infection. HHV-6 and -7 can cause exanthema subitum, and
appear to be associated with febrile convulsions, even in the
absence of signs of exanthema subitum. Almost all children
(>90%) with exanthema subitum have HHV-6 or HHV-7 DNA in
CSF. Inflammatory primary brain damage like meningitis and
encephalitis come from pyogenic infections that reach the
intracranial structures in one of two ways - either by
hematogenous spread (infected thrombi or emboli of bacteria) or
by extension from cranial structures (ears, paranasal sinuses,
osteomyelitic foci in the skull, penetrating cranial injuries or
42 | Critical Care in Neurology
congenital sinus tracts). In a good number of cases, infection is
iatrogenic, being introduced in the course of cerebral or spinal
surgery, during the placement of a ventriculoperitoneal shunt or
rarely through a lumbar puncture needle. Nowadays, nosocomial
infections are as frequent as the non-hospital acquired variety.
The reason for altered sensorium in meningitis is postulated to
be the spillage of inflammatory cells to the adjacent brain
parenchyma and the resultant brain edema (Levin 1998).
Compressive brain injury: e.g., tumors and cerebral brain
edema are considered as important causes for impairment of the
level of consciousness. During tumor growth, cerebral tissues
adjacent to the tumor and nearby venules are compressed,
which results in elevation of capillary pressure, particularly in
the cerebral white matter, and there is a change in cerebral
blood flow and consequently intracranial pressure. At that stage
the tumor begins to displace tissue, which eventually leads to
displacement of tissue at a distance from the tumor, resulting in
false localizing signs such as transtentorial herniations,
paradoxical corticospinal signs of Kernohan and Woltman, third
and sixth nerve palsies and secondary hydrocephalus, originally
described in tumor patients.

Delirium

Delirium is a disturbance of consciousness characterized by
acute onset and fluctuating course of inattention accompanied
by either a change in cognition or a perceptual disturbance, so
that a patient’s ability to receive, process, store, and recall
information is impaired.
Delirium, a medical emergency, develops rapidly over a short
period of time, is usually reversible, and is a direct consequence
of a medical condition or a brain insult. Many delirious ICU
patients have recently been comatose, indicating a fluctuation of
mental status. Comatose patients often, but not always, progress
through a period of delirium before recovering to their baseline
mental status.
ICU delirium is a predictor of increased mortality, length of
stay, time on ventilator, costs, re-intubation, long-term cognitive
impairment, and discharge to long-term care facility; it
necessitates special attention, assessment and management.
Delirium assessment is actually an important part of the overall
assessment of consciousness.
Delirium includes three subtypes: hyperactive, hypoactive and
mixed. Hyperactive delirium is characterized by agitation,
restlessness, and attempts to remove tubes and lines. Hypoactive
delirium is characterized by withdrawal, flat affect, apathy,
lethargy, and decreased responsiveness. Mixed delirium is
characterized by fluctuation between the hypoactive and
hyperactive. In ICU patients mixed and hypoactive are the most
common, and are often undiagnosed if routine monitoring is not
implemented. Few ICU patients (less than 5%) experience purely
hyperactive delirium.
The Confusion Assessment Method (CAM) was created in 1990
by Sharon Inouye, and was intended to be a bedside assessment
tool usable by non-psychiatrists to assess for delirium (Inouye
1990). The CAM-ICU is an adaptation of this tool for use in ICU
patients (e.g., critically ill patients on and off the ventilator who
are largely unable to talk).

Scoring and Documentation

Each neurocritical care unit should adopt a special scoring and
documentation system, to be used to assess and document
baseline patient neurological status and status at time of
discharge. These include:
– Vital Signs: BP, temp, pulse, respiration, oximetry
– Pupils: size and reaction to light
– Eye movement: gaze, vergence, individual extraocular
movement and nystagmus
– Mental status: LOC, orientation and speech
– Motor functions: state, power, tone, deep reflexes and
pathological reflexes
– Coordination: gate, upper and lower limbs, if applicable
There are many scales used to assess these functions; each
critical care unit can adopt a set that can be used by its staff.
Tables 3.1, 3.2, and 3.3 show some of the commonly used scales
in clinical practice.
Documentation and Scores | 35
Table 3.1 – Neurological Scales used for assessment of level of
consciousness and mental status
Name and Source Strengths and Weaknesses
Level-of-consciousness scale
Glasgow Coma Scale
(Teasdale 1974, 1979)
Strength: Simple, valid, reliable, for assessment of
level-of-consciousness.
Weaknesses: none observed.
Full Outline
Unresponsiveness – FOUR
Score
(Wijdicks 2005)
Strength: The FOUR score is easy to apply and
provides more neurological details than the
Glasgow scale. This scale is able to detect
conditions such locked-in syndrome and the
vegetative state, which are not detected by the
GCS.
Weaknesses: none observed.
Delirium Scale
Confusion Assessment
Method (CAM)
(Inouye 1990)
Strength: CAM-ICU is an adaptation of the
Confusion Assessment Method (CAM), which was
adapted to be a delirium assessment tool for use in
ICU patients (e.g., critically ill patients on and off
the ventilator who are largely unable to talk).
Weaknesses: none observed.
Richmond Agitation
Sedation Scale (RASS)
(Sessler 2002)
Strength: RASS is logical, easy to administer, and
readily recalled. RASS has high reliability and
validity in medical and surgical, ventilated and
non-ventilated, and sedated and non-sedated
adult ICU patients.
Weaknesses: none observed
Mental status screening
Folstein Mini-Mental State
Examination (Folstein 1975)
Strength: Widely used for screening.
Weaknesses: Several functions with summed
score. May mis-classify patients with aphasia.
Neurobehavioral Cognition
Status Exam (NCSE)
(Kiernan 1987)
Strength: Predicts gain in Barthel Index scores.
Unrelated to age.
Weaknesses: Does not distinguish right from left
hemisphere. No reliability studies in stroke. No
studies of factorial structure. Correlates with
education.
36 | Critical Care in Neurology
Table 3.2 – Neurological Scales used for assessment of stroke deficits
Name and Source Strengths Weaknesses
Measures of disability/activities of daily living (ADL)
Barthel Index
(Mahoney 1965,
Wade 1988)
Widely used for stroke.
Excellent validity and
reliability.
Low sensitivity for high-level
functioning
Functional
Independence
Measure (FIM)
(Granger 1987)
Widely used for stroke.
Measures mobility, ADL,
cognition, functional
communication.
"Ceiling" and "floor" effects
Stroke deficit scales
NIH Stroke Scale
(Brott 1989)
Brief, reliable, can be
administered by nonneurologists
Low sensitivity
Canadian
Neurological Scale
(Cote 1986)
Brief, valid, reliable Some useful measures omitted
Assessment of motor function
Fugl-Meyer
(Fugl-Meyer 1975)
Extensively evaluated
measure. Good validity
and reliability for
assessing sensorimotor
function and balance
Considered too complex and timeconsuming
by many
Motor Assessment
Scale (Poole 1988)
Good, brief assessment of
movement and physical
mobility
Reliability assessed only in stable
patients. Sensitivity not tested
Motricity Index
(Collin 1990)
Brief assessment of motor
function of arm, leg, and
trunk
Sensitivity not tested
Balance assessment
Berg Balance
Assessment
(Berg 1992)
Simple, well established
with stroke patients,
sensitive to change
None observed
Mobility assessment
Rivermead
Mobility Index
(Collen 1991)
Valid, brief, reliable test of
physical mobility
Sensitivity not tested
Documentation and Scores | 37
Name and Source Strengths Weaknesses
Assessment of speech and language functions
Boston Diagnostic
Aphasia
Examination
(Goodglass 1983)
Widely used,
comprehensive, good
standardization data,
sound theoretical
rationale
Long time to administer; half of
patients cannot be classified
Porch Index of
Communicative
Ability (PICA)
(Porch 1981)
Widely used,
comprehensive, careful
test development and
standardization
Long time to administer. Special
training required to administer.
Inadequate sampling of language
other than one word and single
sentences
Western aphasia
Battery (Kertesz
1982)
Widely used,
comprehensive
Long time to administer. "Aphasia
quotients" and "taxonomy" of
aphasia not well validated
Table 3.3 – Neurological Scales used for assessment of health status and
global disabilities
Type Name and
Source
Strengths Weaknesses
Global
disability scale
Rankin Scale
(Rankin 1957,
Bonita 1988,
Van Swieten
1988)
Good for overall
assessment of
disability.
Walking is the only
explicit assessment
criterion. Low
sensitivity
Health status/
quality of life
measures
Medical
Outcomes Study
(MOS) 36 Item
Short-Form
Health Survey
(Ware 1992)
Generic health status
scale SF36 is improved
version of SF20. Brief,
can be self -
administered or
administered by phone
or interview. Widely
used in the US
Possible "floor" effect
in seriously ill patients
(especially for physical
functioning), suggests it
should be
supplemented by an
ADL scale in stroke
patients
Sickness Impact
Profile (SIP)
(Bergner 1981)
Comprehensive and
well-evaluated. Broad
range of items reduces
"floor" or "ceiling"
effects
Time to administer
somewhat long.
Evaluates behavior
rather than subjective
health; needs questions
on well-being,
happiness, and
satisfaction

Brain Death

After exclusion of the previous syndromes, and in the absence
of brain stem reflexes, brain death in deeply comatose patients
should be established through the following criteria:
1. Irreversible coma
2. Absence of brain stem reflexes
3. Absence of spontaneous respiration (Wood 2004)

Locked-in Syndrome

Locked-in syndrome usually results in quadriparesis and the
inability to speak in otherwise cognitively intact individuals.
Patients with locked-in syndrome may be able to communicate
with others through coded messages by blinking or moving their
eyes, which are often not affected by the paralysis. Patients with
locked-in syndrome are conscious and aware with no loss of
cognitive functions. They sometimes can retain proprioception
and sensation throughout their body. Some patients with lockedin
syndrome may have the ability to move some muscles of the
face, and some or all of the extraocular eye muscles. Patients
with locked-in syndrome lack coordination between breathing
and voice that restricts them from producing voluntary sounds,
even though the vocal cords themselves are not paralyzed. In
children, the commonest cause is a stroke of the ventral pons.
Unlike persistent vegetative state, locked-in syndrome is caused
by damage of the lower brain and brainstem without damage to
How to Approach an Unconscious Patient | 31
the upper brain (Leon Carrion 2002). Possible causes of locked-in
syndrome include: traumatic brain injury, diseases of the
circulatory system, overdose of certain drugs, various causes
which lead to damage to the nerve cells, particularly destruction
of the myelin sheath, e.g., central pontine myelinolysis
secondary to rapid correction of hyponatremia and basilar
artery (ischemic or hemorrhagic) stroke.
There is neither a standard treatment for locked-in syndrome,
nor is there a cure, but stimulation of muscle reflexes with
electrodes (NMES) has been known to help patients regain some
muscle function. Assistive computer interface technologies in
combination with eye tracking may be used to help patients
communicate. Direct brain stimulation research developed a
technique that allows locked-in patients to communicate via
sniffing (Leon Carrion 2002). It is extremely rare for any
significant motor function to return and the majority of lockedin
syndrome patients do not regain motor control, but devices
are available to help patients communicate. 90% die within the
first four months after onset. However, some patients continue
to live for much longer periods of time (Bateman 2001).

Permanent Vegetative State 2

Diagnosis
The vegetative state is diagnosed, according to its definition, as
being persistent at least for one month. Based upon class II
evidence and consensus that reflects a high degree of clinical
certainty, the following criteria is standard concerning PVS:
– PVS can be judged to be permanent, at 12 months after
traumatic brain injury in adults and children. Special
attention to signs of awareness should be devoted to
children during the first year after traumatic injury.
– PVS can be judged to be permanent if it lasts more than 3
months, in case of nontraumatic brain injury in both adults
and children.
– The chance for recovery, after these periods, is exceedingly
low and recovery is almost always to a severe disability.
Management
When a patient has been diagnosed as being in a PVS by a
physician skilled in neurological assessment and diagnosis,
physicians have the responsibility of discussing with the family
or surrogates the probability of the patient’s attaining the
various stages of recovery or remaining in a PVS:
– Patients in PVS should receive appropriate medical, nursing,
or home care to maintain their personal dignity and
hygiene.
– Physicians and the family/surrogates must determine
appropriate levels of treatment relative to the
administration or withdrawal of 1) medications and other
commonly ordered treatments; 2) supplemental oxygen and
use of antibiotics; 3) complex organ-sustaining treatments
such as dialysis; 4) administration of blood products; and 5)
artificial hydration and nutrition.
Recovery from PVS can be defined in terms of recovery of
consciousness and function. Recovery of consciousness can be
confirmed when a patient shows reliable signs of awareness of
30 | Critical Care in Neurology
self and their environment, reproducible voluntary behavioral
responses to visual and auditory stimuli, and interaction with
others. Recovery of function occurs when a patient becomes
mobile and is able to communicate, learn, and perform adaptive
skills and self care and participate in recreational or vocational
activities. Using these parameters, recovery of function can be
defined with the Glasgow Outcome Scale.
The life span of adults and children in a PVS proves to be
reduced; for most PVS patients, life expectancy ranges from 2 to
5 years and survival beyond 10 years is unusual. Once PVS is
considered permanent, a “Do not resuscitate (DNR)” order is
appropriate which includes no ventilatory or cardiopulmonary
resuscitation. The decision to implement a DNR order, however,
may be made earlier in the course of the patient’s illness if there
is an advanced directive or agreement by the appropriate
surrogate of the patient and the physicians responsible for the
care of the patient (Plum 2007).

Permanent Vegetative State

Permanent vegetative state (PVS) means an irreversible state of
wakefulness without awareness, associated with sleep-wake
cycles and preserved brainstem functions. There are no reliable
28 | Critical Care in Neurology
set of criteria defining and ensuring diagnosis of PVS in infants
under 3 months old, apart from anencephalics.
There are three major categories of disease in adults and
children that result in PVS, upon which the outcome of PVS
depends:
A. In acute traumatic and nontraumatic brain injury, PVS
usually evolves within 1 month of injury from a state of eyesclosed
coma to a state of wakefulness without awareness with
sleep-wake cycles and preserved brainstem functions.
B. Some degenerative and metabolic disorders of the brain (i.e.,
late stage of dementia of Alzheimer type, end stage of Parkinson
disease, and motor neuron disease, pontine myelinolysis, severe
uncorrected hypoglycaemic coma) inevitably progress toward an
irreversible vegetative state. Patients who are severely impaired
but retain some degree of awareness may lapse briefly into a
vegetative state from the effects of medication, infection,
superimposed illnesses, or decreased fluid and nutritional
intake. Such a temporary encephalopathy must be corrected
before labeling that patient with the diagnosis of PVS.
Consciousness recovery is unlikely if the vegetative state persists
for several months.
C. The third cause is severe developmental malformations of
the nervous system - the developmental vegetative state is a
form of PVS that affects some infants and children with severe
congenital malformations of the nervous system. These children
do not acquire awareness of self or their environment. This
diagnosis can be made at birth only in infants with anencephaly.
For children with other severe malformations who appear
vegetative at birth, observation for 3 to 6 months is
recommended to determine whether these infants acquire
awareness. The majority of such infants who are vegetative at
birth remain vegetative; those who acquire awareness usually
recover only to a severe disability.

General Care of the Comatose Patient

1. Airway protection: adequate oxygenation, ventilation and
prevention of aspiration are the most important goals; most
patients will require endotracheal intubation and frequent
orotracheal suctioning.
2. Intravenous hydration: stuporous patients should receive
nothing by mouth; use only isotonic fluids in these patients to
avoid increasing the size of the cerebral edema or increased
intracranial pressure (ICP).
3. Nutrition: enteral feeds via a small bore nasogastric tube.
4. Skin: the patient must be turned every 1-2 hours to prevent
pressure sores; an inflatable or foam mattress and protective
heel pads may also be beneficial.
5. Eyes: prevent corneal abrasion by taping the eyelids shut or
by applying a lubricant.
6. Bowel care: constipation and gastric stress ulcers should be
avoided.
7. Bladder care: indwelling urinary catheters are a common
source of infection and should be used judiciously; intermittent
catheterization every 6 hours when possible.
8. Joint mobility: passive range of motion daily exercises to
prevent contractures.
9. Deep venous thrombosis prophylaxis: subcutaneous
anticoagulants and external pneumatic compression stockings or
both (Upchurch 1995).
To complete this important critical situation, we will discuss
two other categories, the permanent vegetative state and lockedin
syndrome.

Basic assessments

1. Pupillary functions may be normal if the lesion is rostral to
the midbrain, while if the injury is diffuse, e.g., global cerebral
anoxia or ischemia, the pupillary abnormality is bilateral. Pupil
size is important as midposition (2-5 mm) fixed or irregular
pupils imply a focal midbrain lesion; pinpoint reactive pupils
occur in global hypoxic ischemic insult with pontine damage, or
poisoning with opiates and cholinergic active materials; and
bilateral fixed and dilated pupils can reflect central herniation
or global hypoxic ischemic or poisoning with barbiturates,
scopolamine, and atropine. Unilateral dilated pupil suggests
compression of the third cranial nerve and midbrain, which
necessitates an immediate search for a potentially correctable
abnormality to avoid irreversible injury. In case of post-cardiac
arrest coma, if pupils remain nonreactive for more than 6-8
hours after resuscitation, the prognosis for neurological
recovery is generally guarded (Stevens 2006).
2. Posturing of the body: decorticate posturing (painful stimuli
provoke abnormal flexion of upper limbs) indicates a lesion at
the thalamus or cortical damage; decerebrate posturing (the
arms and legs extend and pronate in response to pain) denotes
that the injury is localized to the midbrain and upper pons; an
injury of the lower brain stem (medulla) leads to flaccid
extremities.
How to Approach an Unconscious Patient | 25
3. Ocular reflexes: assessment of the brainstem and cortical
functions happen through special reflex tests such as the
oculocephalic reflex test (Doll’s eyes test), oculovestibular reflex
test (cold caloric test), nasal tickle, corneal reflex, and the gag
reflex.
4. Vital signs: temperature (rectal is most accurate), blood
pressure, heart rate (pulse), respiratory rate, and oxygen
saturation (Inouye 2006). It is mandatory to evaluate these basic
vital signs quickly and efficiently to gain insight into a patient’s
metabolism, fluid status, heart function, vascular integrity, and
tissue oxygenation status.
5. The respiratory pattern (breathing rhythm) is significant and
should be noted in a comatose patient. Certain stereotypical
patterns of breathing have been identified including Cheyne-
Stokes respiratory pattern, where the patient’s breathing is
described as alternating episodes of hyperventilation and apnea,
a dangerous pattern often seen in pending herniation, extensive
cortical lesions, or brainstem damage. Apneustic breathing is
characterized by sudden pauses of inspiration and is due to
pontine lesion. Ataxic (Biot’s) breathing is an irregular chaotic
pattern and is due to a lesion of the medulla. The first priority in
managing a comatose patient is to stabilize the vital functions,
following the ABC rule (Airway, Breathing, and Circulation).
Once a person in a coma is stable, assessment of the underlying
cause must be done, including imaging (CT scan, CT
angiography, magnetic resonance imaging (MRI), magnetic
resonance angiography (MRA) and magnetic resonance
venography (MRV) if needed ) and special studies, e.g., EEG and
transcranial Doppler.
Coma is a medical emergency, and attention must first be
directed to maintaining the patient’s respiration and circulation
as previously mentioned using intubation and ventilation,
administration of intravenous fluids or blood and other
supportive care as needed. Measurement of electrolytes is a
commonly performed diagnostic procedure, most often sodium
26 | Critical Care in Neurology
and potassium; chloride levels are rarely measured except for
arterial blood gases (Bateman 2001). Once a patient is stable and
no longer in immediate danger, the medical staff should start
parallel work, first investigating the patient to find out any
underlying pathology of his presenting illness, second, managing
the presenting illness symptoms. Infections must be prevented
and a balanced nutrition provided. The nursing staff, to guard
against pressure ulcers, may move the patient every 2–3 hours
from side to side and, depending on the state of consciousness,
sometimes to a chair. Physical therapy may also be used to
prevent contractures and orthopedic deformities that would
limit recovery for those patients who emerge from coma
(Wijdicks 2002).
People may emerge from a coma with a combination of
physical, intellectual and psychological difficulties that need
special attention; recovery usually occurs gradually and some
patients acquire more and more ability to respond, others never
progress beyond very basic responses. Regaining consciousness
is not instant in all comatose patients: in the first days, patients
are only awake for a few minutes, the duration of awake time
gradually increases, until they regain full consciousness. The
coma patient awakens sometimes in a profound state of
confusion, not knowing how they got there and sometimes
suffering from dysarthria, the inability to articulate speech, and
other disabilities. Time is the best general predictor of a chance
of recovery: after 4 months of coma caused by brain damage, the
chance of partial recovery is less than 15%, and the chance of full
recovery is very low (Wijdicks 2002). Coma which lasts seconds
to minutes may result in post-traumatic amnesia (PTA) lasting
from hours to days; recovery occurs over days to weeks. Coma
which lasts hours to days may result in PTA lasting from days to
weeks; its recovery occurs over months. Coma which lasts weeks
may result in PTA that lasts months; recovery occurs over
months.

Diagnosis

In the initial assessment of coma, it is common to judge by
spontaneous actions, response to vocal stimuli and response to
painful stimuli; this is known as the AVPU (alert, vocal stimuli,
painful stimuli, unconscious) scale. The most common scales
used for rapid assessment are:
1. The Glasgow Coma Scale (GCS), which aims to record the
conscious state of a person, in initial as well as continuing
assessment. When a patient is assessed and the resulting score is
either 14 (original scale) or 15 (the more widely used modified or
revised scale), this means ‘normal’; while if a patient is unable to
voluntarily open their eyes, does not have a sleep-wake cycle, is
unresponsive in spite of strong sensory (painful) or verbal
stimuli and who generally scores between 3 to 8 on the Glasgow
Coma Scale, (s)he is considered to be in coma.
2. Pediatric Glasgow Coma Scale: The Pediatric Glasgow Coma
Scale (PGCS) is the equivalent of the Glasgow Coma Scale used to
assess the mental state of adult patients. As with the GCS, the
PGCS comprises three tests: eye, verbal and motor responses.
The three values separately as well as their sum are considered
(Holmes 2005). The lowest possible PGCS is 3 (deep coma or
death) whilst the highest is 15 (fully awake and aware) (Holmes
2005).
Diagnosis of coma is simple; but determining the cause of the
underlying pathology may prove to be challenging. As in those
with deep unconsciousness, there is a risk of asphyxiation as
control over the muscles in the face and throat is diminished, so
those in a coma are typically assessed for airway management,
nasopharyngeal airway or endotracheal intubation to safeguard
the airway (Formisano 2004).
Following the previous assessment patients with impaired
consciousness can be classified according to their degree of
consciousness disturbance into lethargic, stuporous or comatose.
Lethargy resembles sleepiness, except that the patient is
incapable of becoming fully alert; these patients are conversant
24 | Critical Care in Neurology
and attentive but slow to respond, unable to adequately perform
simple concentration tasks such as counting from 20 to 1, or
reciting the months in reverse.
Stupor means incomplete arousal to painful stimuli, little or no
response to verbal commands, the patient may obey commands
temporarily when aroused by noxious stimuli but more often
only by pain.
Coma is the absence of verbal or complex motor responses to
any stimulus (Stevens 2006).

How to Approach an Unconscious Patient

Coma (from the Greek κώμα [ko̞ma], meaning deep sleep) is a
state of unconsciousness lasting more than 6 hours, in which a
person cannot be awakened, fails to respond normally to painful
stimuli, light or sound, lacks a normal sleep-wake cycle and does
not initiate voluntary actions.
All unconscious patients should have neurological
examinations to help determine the site and nature of the lesion,
to monitor progress, and to determine prognosis. Neurological
examination is most useful in the well-oxygenated,
normotensive, normoglycemic patient with no sedation, since
hypoxia, hypotension, hypoglycemia and sedating drugs
profoundly affect the signs elicited. Therefore, immediate
therapeutic intervention is a must to correct aberrations of
hypoxia, hypercarbia and hypoglycemia. Medications recently
taken that cause unconsciousness or delirium must be identified
quickly followed by rapid clinical assessment to detect the form
of coma either with or without lateralizing signs, with or without
signs of meningeal irritation, the pattern of breathing, the size
and reactivity of pupils and ocular movements, the motor
22 | Critical Care in Neurology
response, the airway clearance, the pattern of breathing and
circulation integrity, etc.
Special consideration must be given to neurological causes
which may lead to unconsciousness like status epilepticus (either
convulsive or non-convulsive), locked-in state, persistent
vegetative state and lastly brain stem death. Any disturbances of
thermoregulation must be measured.
Coma may result from a variety of conditions including
intoxication, metabolic abnormalities, central nervous system
diseases, acute neurologic injuries such as stroke, hypoxia or
traumatic injuries including head trauma caused by falls or
vehicle collisions. Looking for the pathogenesis of coma, two
important neurological components must function perfectly that
maintain consciousness. The first is the gray matter covering the
outer layer of the brain and the other is a structure located in
the brainstem called the reticular activating system (RAS or
ARAS), a more primitive structure that is in close connection
with the reticular formation (RF), a critical anatomical structure
needed for maintenance of arousal. It is necessary to investigate
the integrity of the bilateral cerebral cortices and the reticular
activating system (RAS), as a rule. Unilateral hemispheric lesions
do not produce stupor and coma unless they are of a mass
sufficient to compress either the contralateral hemisphere or the
brain stem (Bateman 2001). Metabolic disorders impair
consciousness by diffuse effects on both the reticular formation
and the cerebral cortex. Coma is rarely a permanent state
although less than 10% of patients survive coma without
significant disability (Bateman 2001); for ICU patients with
persistent coma, the outcome is grim.
Maneuvers to be established with an unconscious patient
include cardiopulmonary resuscitation, laboratory
investigations, a radiological examination to recognize brain
edema, as well as any skull, cervical, spinal, chest, and multiple
traumas. Intracranial pressure and neurophysiological
monitoring are important new areas for investigation in the
unconscious patient.

Physical Exam

1. Mental status
Usually we start neurologic examination by assessing the
patient’s mental status (Strub 2000).
A full mental status exam is not necessary in the patient who is
conscious, awake, oriented, and conversant; on the contrary it
must be fully investigated in patients with altered mental status.
Sometimes, we can find no change in mental status; at that
point careful consideration should be given to concerns of
family.
A systematic approach to the assessment of mental status is
helpful in detecting acute as well as any chronic disease, such as
delirious state in a demented patient (Lewis 1995). The CAM
(confusion assessment method) score was developed to assist in
diagnosing delirium in different contexts. CAM assesses four
components: acute onset, inattention, disorganized thinking or
an altered level of consciousness with a fluctuating course. A
‘Mini-Mental Status’ test can also be used but usually is reserved
for patients with suspected cognitive dysfunction as it evaluates
five domains – orientation, registration, attention, recall, and
language (Strub 2000).
2. Cranial nerve (CN) exam
Cranial Nerves II - VIII function testing are of utmost value in the
neurologic assessment in an emergency setting (Monkhouse
2006).
Cranial Nerves II – Optic nerve assessment involves visual
acuity and fields, along with a fundus exam and a swinging
flashlight test. Visual field exam using the confrontation method
is rapid and reliable. Visual loss in one eye suggests a nerve
lesion, i.e., in front of the chiasm; bitemporal hemianopsia
suggests a lesion at the optic chiasm; a quadrant deficit suggests
a lesion in the optic tracts; bilateral visual loss suggests cortical
disease.
Assessment of Patients in Neurological Emergency | 17
Assessment of the optic disc, retinal arteries, and retinal veins
can be done by a fundus exam, to discover papilledema, flame
hemorrhages or sheathing.
Cranial Nerves III, IV, VI – CN III innervates the extraocular
muscles for primarily adduction and vertical gaze. CN III
function is tested in conjunction with IV, which aids in internal
depression via the superior oblique, and VI, which controls
abduction via the lateral rectus. Extraocular muscle function is
tested for diplopia, which requires binocular vision and thus will
resolve when one eye is occluded. Marked nystagmus on lateral
gaze or any nystagmus on vertical gaze is abnormal; vertical
nystagmus is seen in brainstem lesions or intoxication, while
pendular nystagmus is generally a congenital condition.
The pupillary light reflex is mediated via the parasympathetic
nerve fibers running on the outside of CN III. In the swinging
flashlight test a light is shone from one eye to the other; when
the light is shone directly into a normal eye, both eyes constrict
via the direct and the consensual light response.
Pupillary size must be documented. Asymmetry in pupils of less
than 1 mm is not significant. Significant difference in pupil size
suggests nerve compression due to aneurysms or due to cerebral
herniation, in patients with altered mental status.
Bilateral pupillary dilation is seen with prolonged anoxia or
due to drugs (anticholinergics), while bilateral pupillary
constriction is seen with pontine hemorrhage or as the result of
drugs (e.g., opiates, clonidine).
Cranial Nerve V – Individual branch testing of the trigeminal
nerve is unnecessary, as central nervous system lesions affecting
CN V usually involve all three branches.
Cranial Nerve VII – The facial nerve innervates motor
function to the face, and sensory function to the ear canal, as
well as to the anterior two-thirds of the tongue. Central lesions
cause contralateral weakness of the face muscles below the eyes.
Cranial Nerve VIII – The acoustic nerve has a vestibular and a
cochlear component. An easy screening test for hearing defects
is accomplished by speaking in graded volumes to the patient.
18 | Critical Care in Neurology
When vestibular nerve defects are suspected, patients are
assessed for nystagmus, via a past-pointing test and a positive
response to the Nylen-Barany maneuver.
3. Motor exam
Motor system assessment focuses on detecting asymmetric
strength deficits, which may indicate an acute CNS lesion.
Testing motor power can be difficult or impossible in the
uncooperative patient. It is not mandatory to test different
muscle groups but instead just test for the presence of a “drift”.
In diseased patients, the hand and arm on the affected side will
slowly drift or pronate when they try to hold their arm out
horizontally, palms up with eyes closed.
4. Reflexes
For rapid assessment of reflexes, major deep tendon reflexes and
the plantar reflex must be elicited. Major deep tendon reflexes
include the patellar reflex, the Achilles reflex, the biceps reflex,
and the triceps reflex. Response can be graded from 0 (no reflex)
to 4+ (hyperreflexia). Asymmetrical reflexes are the most
important as they are considered pathologic. Many reflexes
indicate upper motor neuron disease; the most commonly
elicited is Babinski’s reflex.
5. Sensory exam
For rapid assessment of the sensory system, pain and light touch
sensations should be done. Testing for other sensory modalities
is reserved for patients with suspected neuropathies or for
further evaluation of sensory complaints.
6. Coordination and balance
Coordination depends on functional integration of the
cerebellum and sensory input from vision, proprioception, and
the vestibular sense. Coordination assessment is an important
part of neurological assessment, as many central lesions may
present only with coordination disturbance, such as cerebellar
infarction, hemorrhage or cerebellar connections insult.
Assessment of Patients in Neurological Emergency | 19
By the end of the examination, you should reach a clinical
diagnosis, which includes answers to the two critical questions,
what is the lesion? and where is the lesion?
7. Neuroanatomical localization
Some knowledge of neuroanatomy is essential for correct
localization. The first step in localizing neurological lesions
should be to determine if it is a central (upper motor neuron)
lesion (i.e., in the brain or spinal cord) versus a peripheral (lower
motor neuron) lesion (i.e., nerve or muscle).
The hallmark of upper motor neuron lesions is hyperreflexia
with or without increased muscle tone. Central (upper motor
neuron) lesions are localized to:
Brain
– Cortical brain (frontal, temporal, parietal, or occipital lobes)
– Subcortical brain structures (corona radiata, internal
capsule, basal ganglia, or thalamus)
– Brainstem (medulla, pons, or midbrain)
– Cerebellum
Spinal cord
– Cervicomedullary junction
– Cervical
– Thoracic
– Upper lumbar
The hallmark of a lower motor neuron (LMN) lesion is
decreased muscle tone, leading to flaccidity and hyporeflexia.
Peripheral LMN lesions are localized to:
– Anterior horn cells
– Nerve root(s)
– Plexus
– Peripheral nerve
– Neuromuscular junction
– Muscle

Assessment of Patients in Neurological Emergency

Care in specialized intensive care units (ICUs) is generally of
higher quality than in general care units. Neurocritical care
focuses on the care of critically ill patients with primary or
secondary neurosurgical and neurological problems and was
initially developed to manage postoperative neurosurgical
patients. It expanded thereafter to the management of patients
with traumatic brain injury (TBI), intracranial hemorrhage and
complications of subarachnoid hemorrhage; including
vasospasm, elevated intracranial pressure (ICP) and the
cardiopulmonary complications of brain injury.
Neurocritical care units have developed to coordinate the
management of critically ill neurological patients in a single
specialized unit, which includes many clinical domains. Care is
provided by a multidisciplinary team trained to recognize and
deal with the unique aspects of the neurological disease
processes, as several treatable neurological disorders are
characterized by imminent risk of severe and irreversible
neurological injury or death if treatment is delayed.
Some diseases need immediate action, so admission to the NICU
is the best solution when there is:
14 | Critical Care in Neurology
1) Impaired level of consciousness.
2) Progressive respiratory impairment or the need for
mechanical ventilation in a neurological patient.
3) Status epilepticus or prolonged seizures.
4) Clinical or Computed Tomographic (CT) evidence of raised
Intracranial Pressure (ICP), whatever the cause (space
occupying lesion, cerebral edema or hemorrhagic
conversion of a cerebral infarct, intracerebral hemorrhage,
etc.)
5) Need for monitoring (for example, level of consciousness,
ICP, continuous electroencephalography (cEEG)), and
6) Need for specific treatments (Baldwin 2010) (e.g.,
neurosurgery, intravenous or arterial thrombolysis).
In the Neurocritical Care unit, patients with primary
neurological diseases such as myasthenia gravis, Guillain-Barré
syndrome, status epilepticus, and stroke have a better outcome
than those patients with secondary neurological diseases. So, we
can conclude that these specialized units have greater
experience in the anticipation, early recognition, and
management of potentially fatal complications.
Early identification of patients at risk of life threatening
neurological illness in order to manage them properly and to
prevent further deterioration is the role of general assessment of
new patients in a neurological emergency. History taking and a
rapid neurological assessment of a specific patient in specialized
neurocritical care units helps answer the question ‘how sick is
this patient?’.
The neurologic screening examination in the emergency
settings focuses primarily on identifying acute, potentially lifethreatening
processes, and secondarily on identifying disorders
that require other opinions, of other specialists.
The importance of urgent neurologic assessment comes from
recent advances in the management of neurologic disorders
needing timely intervention like thrombolysis in acute ischemic
Assessment of Patients in Neurological Emergency | 15
stroke, anticonvulsants for nonconvulsive and subtle generalized
status epilepticus, and plasmapheresis for Guillain-Barré, etc.
It is obvious that interventions can be time-sensitive and can
significantly reduce morbidity and mortality.
A comprehensive neurologic screening assessment can be
accomplished within minutes if performed in an organized and
systematic manner (Goldberg 1987). Neurologic screening
assessment includes six major components of the neurologic
exam, namely:
1) Mental status
2) Cranial nerve exam
3) Motor exam
4) Reflexes
5) Sensory exam
6) Evaluation of coordination and balance.
Based on the chief findings of the screening assessment,
further evaluation or investigations can be then decided upon.

Retransplantation for recurrent HCV cirrhosis

Retransplantation is the only therapeutic option to achieve
long-term survival in patients with decompensated HCV
cirrhosis after LT. Retransplantation for this indication ranges
from 3.6% to 44%. Patient and graft survival rates after
retransplantation are inferior to those after primary LT. HCVinfected
recipients had a significantly lower survival rate
compared to non-HCV-infected patients who underwent
retransplantation at least 90 days after primary LT.
Progression to cirrhosis is faster after retransplantation than
after primary LT, particularly in patients with severe hepatitis C
recurrence (cholestatic hepatitis and graft failure within the first
year) (Carrion 2010). Predictors of poor outcome are: bilirubin
≥10 mg/dL, serum creatinine ≥2 mg/dL, donor age >40, recipient
age >55 and early HCV recurrence (cirrhosis <1 year after LT)
(Wiesner 2003). Thus, the optimal timing to perform elective
retransplantation in HCV patients is a matter of debate.
However, bilirubin and creatinine serum levels are essential for
deciding about retransplantation candidates. Patients with a CTP
score ≥10 or a MELD score >25 have a very high risk of death
after retransplantation.
Outlook
HCV is and will continue to be the most common indication for
LT worldwide and recurrent disease associated with HCV is a
major cause of allograft loss and mortality.
A better understanding of the recipient, donor and viral risk
factors for progressive disease and vigilant post-transplant
monitoring through histologic assessment may guide
management aimed toward reducing the potential for graft
failure as well as helping identify candidates for antiviral
therapy.
Management of recurrent HCV infection following liver transplantation | 89
Antiviral therapy in patients with HCV cirrhosis awaiting LT
should be considered only in selected individuals due to poor
tolerability and limited virologic response. Pre-emptive therapy
is not well tolerated in the post-LT population. Antiviral therapy
with PegIFN/RBV should be considered in transplant recipients
with recurrent HCV infection. Achievement of SVR is associated
with increased allograft and patient survival; however, efficacy
may be limited by poor tolerability, risk of cellular rejection and
risk of alloimmune hepatitis, requirement for dose reductions,
and treatment discontinuation.
Retransplantation is the only therapeutic option to achieve
long-term survival in patients with decompensated cirrhosis
after LT.

Side effects and safety of PegIFN/RBV therapy

The clinical spectrum of AEs is similar to the non-transplant
setting (see chapter 1). Dose reductions are frequent and drug
discontinuation rates are higher than in nontransplant patients.
A major limitation of antiviral therapy is tolerability,
particularly with respect to the hematologic AEs of PegIFN/RBV.
In a recent Cochrane review, up to 87.5% of patients required a
dose reduction and up to 42.9% of patients stopped treatment
Management of recurrent HCV infection following liver transplantation | 87
because of AEs or because of patient's choice to stop it
(Gurusamy 2010). Cytopenias, mood disturbances, and acute
cellular rejection are the most common reasons for dose
reduction or discontinuation (Terrault 2008). The use of growth
factors is required to manage cytopenias (anemia and
neutropenia) in up to 50% of patients, and thus to improve
tolerability. However, there is not enough evidence to support
improvement of SVR with concomitant use of Filgastrim and/or
erythropoietin. Anemia is a common side effect especially in
older LT recipients and with a low BMI (Saab 2007). RBV toxicity
can be of concern in LT recipients with renal dysfunction. Lower
initial RBV dosing, increasing as tolerated, or dosing based on a
nomogram that incorporates renal function (creatinine
clearance) is highly recommended (Watt 2009).
Acute cellular rejection (ACR) and chronic ductopenic rejection
are immune-mediated complications unique to the posttransplant
setting. Acute and chronic rejections are infrequent
complications of antiviral therapy often associated with
concomitant low or negative serum HCV RNA. The reported
incidence of ACR during interferon based therapy ranges from 0
to 35%. It is to be noted that the incidence of ACR in HCV positive
LT recipients treated with combination antiviral therapy for
HCV recurrence does not seem to be higher than that observed
in non treated HCV positive LT recipients (Seltzner 2010).
An autoimmune-like hepatitis (de novo autoimmune hepatitis)
has been reported in LT recipients treated with PegIFN/RBV for
recurrent hepatitis C. In general, these patients have no history
of autoimmune disease, and HCV RNA is undetectable at the time
of the secondary rise in liver enzymes. In HCV infected patients,
it remains controversial whether these cases represent a true
autoimmune (alloimmune) process, as opposed to an atypical
manifestation of recurrent disease or of acute or chronic
allograft rejection. Histologic findings are an essential part in
the differential diagnosis between these entities. Any flare in
liver enzymes in patients treated with antiviral therapy,
particularly in those with undetectable HCV RNA, should raise
88 | Hepatitis C Treatment
the suspicion of these complications and warrant the
performance of a liver biopsy.

Therapy of recurrent hepatitis C after LT

Posttransplant antiviral therapy in recipients with evidence of
biochemical and histological recurrent disease, usually 6 months
after LT, is the mainstay of management. Although a high
number of transplant centers use antiviral therapy, the
treatment is not standardized and is still associated with low
rates of SVR, less than those reported in the non-transplant
setting. The main reasons include high VL post-LT, a higher
frequency of genotype 1 patients, poor tolerability of treatment
after LT, and need for frequent dose reductions.
The combination of PegIFN/RBV is the treatment of choice also
in transplant recipients. The SVR associated with PegIFN/RBV
therapy in predominantly genotype 1 infected populations has
been reported to range from 12% to as high as 50% (Gonzalez
2010). A recent extensive review of 19 prospective and
retrospective clinical studies describing antiviral therapy with
PegIFN/RBV in this population reported a mean SVR of 30.2%
(Berenguer 2008). End of treatment virologic response (EoTR)
was 42.2% (range 17-68%), indicating that relapse was a major
factor in the low SVR rates. Biochemical responses were
registered in 54.8% and histological endpoints were judged to be
too heterogeneous in definition and assessment to provide a
summary estimate. However, it was noted that histological
improvements were generally confined to treated patients who
achieve SVR. Fibrosis has been shown to progress significantly
more in nonresponders to antiviral therapy. Even in the absence
of virological response, the rate of progression of fibrosis was
86 | Hepatitis C Treatment
significantly slowed in patients treated for more than 6 months
(Walter 2009). Using long-term maintenance antiviral therapy
has recently been shown to increase the probability of
biochemical and histological responses, regardless of the timing
of the HCV recurrence (de Martin 2010).
Achievement of SVR in the setting of recurrent HCV following
LT has a major impact on long-term outcomes, including
improved graft and patient survival. Identifying patients with a
greater likelihood of achieving SVR is an important
consideration in the selection of potential treatment candidates
and is a key factor in developing strategies for optimizing
response to therapy.
Predictors of response to therapy identified in different studies
(Terrault 2008, Selzner 2009, Gonzalez 2010, Fukuhara 2010)
were
– Non-1 HCV genotype
– Absence of prior antiviral therapy
– Donor age
– Pretreatment necroinflammatory activity and fibrosis stage
– Concomitant cyclosporine use
– Course completion (the rule of 80/80/80, see chapter 1)
– Low pretreatment HCV RNA (<1 million IU/ml)
– IL28B polymorphism in recipient and donor tissues
– RVR or EVR – that hold the highest predictive values of SVR.
Undetectable VL at 24 weeks of therapy was also noted to
confer a high predictive value (92%) for SVR and prolonged
treatment protocol was suggested in these LT recipients.

Pre-emptive antiviral therapy after LT

Preemptive antiviral therapy started within 2-6 weeks after
transplantation has the advantage of a relatively low VL and the
absence or minimal evidence of histologic recurrence, but is
limited by tolerability, particularly in patients with high MELD
scores pre-transplantation.
Rates of SVR vary from 5% to 39% (Terrault 2008). Better results
were reported in adult-to-adult right lobe live donor LT for HCC
and low MELD scores as well as in planned living donor LT cases
with splenectomy (Sugawara 2010). Dose reductions were
required, more frequently for RBV than interferon, and
treatment discontinuations were highly variable across the
studies, ranging from 0% to 57%.
Two small trials have evaluated the efficacy of PegIFN in this
setting, one of which noted that only 41% of screened transplant
recipients were eligible to begin therapy (Chalasani 2005).
Management of recurrent HCV infection following liver transplantation | 85
Histological benefits in virologic nonresponders have been
demonstrated in a study where only 22% in a group receiving
preemptive therapy progressed vs. 49% of patients not receiving
preemptive therapy (Kuo 2008). However, this prophylactic
approach cannot be used in a considerable proportion of
patients due to initially intense immunosuppression,
pancytopenia, postoperative infections and insufficient recovery
after the surgery.

Prophylactic antiviral therapy in cirrhosis

The main goals of treating cirrhotic patients with antiviral
therapy are to prevent the complications of the disease, to halt
disease progression or allow for the regression of cirrhosis, and
to attain sustained viral clearance in order to prevent
reinfection in the graft in patients undergoing LT.
SVR in patients with Child-Pugh (CP) class A cirrhosis has
improved from 5% with interferon monotherapy to 50% with
pegylated interferon alfa (PegIFN) + ribavirin (RBV) in genotype
1 (Everson 2005).
The safety of combination therapy in cirrhotics is a major
concern. Bone marrow suppression by administration of either
standard or PegIFN alfa leads to significant decrease in all three
lineages of the hematopoietic system (Iacobellis 2008). However,
erythropoietic agents are effective in treating anemia,
preventing RBV dose reduction, improving patients‘ quality of
life, but the effect on SVR is not fully elucidated. Granulocyte
colony-stimulating factor is effective in raising ANC; however,
neutropenic HCV-infected patients on combination treatment
may not experience increased bacterial infections. Eltrombopag,
a new oral thrombopoietin mimetic, may allow combination
treatment in patients with cirrhosis and thrombocytopenia.
Antiviral therapy is commonly deferred in cirrhotics with signs
of liver decompensation, due to even more compelling concerns
over treatment-induced side effects (up to 60%).
There are several studies reporting experience with interferonbased
therapy in pre-transplant patients aiming to prevent
reinfection of the new graft (Alsatie 2007). The largest study
(Everson 2005) included 124 patients with an average CP score of
7.4 and a mean MELD (Model for End Stage Liver Disease – the
currently used allocation system, introduced in 2002 in USA in
order to prioritize patients on the waiting list) score of 11, who
received a low-accelerating-dose regimen. An SVR of 24% was
84 | Hepatitis C Treatment
achieved and 12 of 15 patients who were HCV RNA-negative
before LT remained HCV RNA-negative ≥6 months
postoperatively. The following predictors of response in these
studies were identified: non-1 genotype, CTP class A (genotype 1
only), ability to tolerate full dose and duration of treatment,
lower pretreatment VL, a VL decrease ≥2 log10 at week 4 of
treatment (Alsatie 2007). Premature discontinuation of the
therapy due to side effects was reported in 13-30% and dose
reductions were more frequent.
On the basis of available data, prophylactic antiviral therapy in
this setting to prevent recurrent HCV infection post-LT has a
limited role and may be associated with serious AEs.
Pretransplant therapy, using a low-accelerating dose regimen, is
an important treatment strategy but is applicable to selected
patients only. Prophylactic antiviral therapy should not be
considered in those with high MELD score (≥20) or CTP class B or
C. It is to be noted that up to two-thirds of patients who become
HCV RNA–negative on treatment will be HCV-free posttransplantation.

Management of recurrent HCV infection following liver transplantation

Natural history of recurrent HCV infection after
liver transplantation
Chronic hepatitis C (CHC) is a worldwide health problem and,
despite a decline in the incidence of new HCV infections, the
prevalence of cirrhosis and the incidence of its complications
will not peak until the year 2040 (Davis 2003). CHC has become
the leading indication for both cadaveric and living donor liver
transplantation (LT), accounting for approximately 50% of cases
in the United States, Europe and Japan.
Demand does not slow down because of the constant increase
of the number of patients with HCV end-stage liver disease
(ESLD) and HCH.
Unfortunately, HCV infection invariably recurs after LT and the
natural course of the disease is accelerated compared to the nontransplant
setting. The influence of HCV infection on allograft
histology is highly variable, but at least 50% of recipients
develop histological evidence of recurrent disease within 1 year
80 | Hepatitis C Treatment
post-transplant. The progression of fibrosis occurs at a rate 1.4
times faster when compared to progression of fibrosis in the
non-transplant population (Mohsen 2003).
The estimated rate of allograft cirrhosis reaches 30% at 5 years
of follow-up, leading to increasing incidence of
retransplantation in HCV recipients. After the diagnosis of
cirrhosis, the decompensation risk appears to be accelerated
(17% and 42% at 6 and 12 months, respectively). Patient survival
is also significantly decreased: 66% and 30% at 1 and 5 years,
respectively (Berenguer 2000). HCV infection-associated
allograft injury is incriminated as the most common cause of
both death (28-39%) and graft failure (~40%) among transplant
recipients (Charlton 2004). Retransplantation represents the last
option for these patients in the context of increasing demands
for LT.
Many factors such as donor and host characteristics, virologic
features and immunosuppression have been shown to influence
the progression of post-transplant liver disease.
Viral factors. As early as the first week postoperatively, the
HCV RNA level increases 10- to 20-fold and plateaus at 1 month,
with higher levels noted in those with more severe recurrent
hepatitis (Berenguer 2001). However, the role of HCV RNA levels
in determining severity of HCV recurrence remains
controversial. The single exception is the well-proven
relationship between very high VL and occurrence of cholestatic
hepatitis (~2-5% of patients). Other viral factors that may
influence the severity of the recurrence are difficult-to-treat
viral genotype (1 and 4) and the quasi-species.
Recipient factors. Increasing age of the recipient (>50 years)
and female sex, as well as non-Caucasian (Afro-American, Asian)
have a more aggressive recurrence (Belli 2007). Thus, a
combination of a liver from an old donor with an old recipient
should be avoided. Presence of a necroinflammatory score ≥2 in
the explants was shown to be a predictor of progressive fibrosis.
Also, the HLA donor-recipient matching was associated with a
Management of recurrent HCV infection following liver transplantation | 81
more severe HCV recurrence, although overall graft survival was
not influenced (Langrehr 2006).
Donor factors. Evidence suggests the following donor factors
to be associated with negative outcome in HCV-infected LT
recipients: donor age, donor fat content (>30%) and ischemic
time. Older donor age (≥50 years) was an independent predictor
for HCV related cirrhosis after 5 years and reduced graft survival
in several studies (Iacob 2007, Samonakis 2005). Prolonged warm
ischemia time (begins as the liver is secured in place and extends
until reperfusion with recipient blood starts) represents a higher
risk for a severe histological recurrence; this risk increases by
13% for each hour increase of cold ischemia time (time elapsed
between removal and cooling of the donor liver and extends
until the donor liver is rewarmed during implantation). Recent
studies have demonstrated that living-related LT is not a risk
factor for severe HCV recurrence. The HCV histological
recurrence rate was 58% after 4 months, 90% at 1 year and 100%
after 2 years in patients transplanted with a living donor
compared to 71% at 4 months, 94% at 1 year and 95%,
respectively, after 2 years in deceased donor LT (Guo 2006).
Clinical factors. A number of potentially modifiable posttransplant
factors have also been associated with increased
severity of HCV recurrence and poorer patient and graft survival
such as immunosuppression, acute rejection episodes treated
with bolus corticosteroids or T-lymphocyte depleting agents,
cytomegalovirus or herpes simplex 6 virus infection, metabolic
syndrome or insulin resistance.
Much emphasis has been placed on the different
immunosuppressive regimens and their changes during the
last 20 years. CHC is more aggressive in LT recipients than in
immuno-competent patients. However, a sudden change in the
degree of immunosuppression, rather than the absolute amount
of immunosuppression, is deleterious for HCV-infected
recipients.
Regarding the calcineurin inhibitors (CNI), most of the studies
suggest that there is no significant difference between
82 | Hepatitis C Treatment
tacrolimus and cyclosporine with respect to their impact on
histologically diagnosed HCV recurrence and graft or patient
survival (Iacob 2007, Berenguer 2007). Cyclosporine has a strong
in vitro suppressive effect on HCV replication (Watashi 2003).
Several clinical although relatively small studies suggested a
higher sustained virologic response (SVR) in HCV LT patients
receiving cyclosporine and interferon therapy.
The cornerstone of immunosuppressive agents, the
corticosteroids, slowly tapered off over a long time, may prevent
progression to severe forms of recurrent disease (Iacob 2007,
Brillanti 2002). In contrast, the boluses of methylprednisolone
(MP) used for acute rejection episodes were deleterious to the
HCV-related graft survival. Outcome of HCV-positive patients
who received multiple pulses of MP is significantly worse than
that in patients with a single pulse therapy (Bahra 2005). High
levels of viremia can determine an HCV-cytopathic mechanism
involved in the allograft injury. Currently, steroid-free
immunosuppression regimens are preferred in HCV recipients.
Actual data for mycophenolate mofetil (MMF), a morpholino
ester prodrug of mycophenolic acid (MPA), favor its use in
recurrent hepatitis C. MPA is a selective, noncompetitive,
reversible inhibitor of inosine monophosphate dehydrogenase
(IMPD), a key enzyme in the biosynthetic pathway of the guanine
nucleotides. It is also a potent inhibitor of both B and T cell
proliferation. MMF in combination with CNI taper showed a
positive effect on fibrosis progression, graft inflammation and
ALT levels (Lake 2009, Iacob 2007). Less data are available for
azathioprine, but its inclusion in the maintenance regimen was
associated with survival advantage.
The potential antifibrotic and antiviral benefit of mTOR
(mammalian target of rapamycin) inhibitors after LT in HCV
positive patients awaits further investigation in prospective
randomized controlled trials. Sirolimus, a macrolide isolated
from Streptomyces hygroscopius reduces TGF-β and procollagen,
inhibits hepatic stellate cell proliferation and may have an
inhibitory action on HCV replication through phosphorylation of
Management of recurrent HCV infection following liver transplantation | 83
signal transducers and activators of transcription (STAT-1)
(Matsumoto 2009).

What does the future hold?

In the near future, trials of SoC plus STAT-C will be initiated in
difficult-to-treat populations (patients with advanced liver
disease, cirrhosis, recipients of liver transplantation or patients
with major comorbidities such as HIV coinfection). It remains to
be seen if there are safer regimens with less drug interactions,
especially with antiretroviral drugs (Seden 2010). As shown in
chapter 1, race is an important determinant of the therapy
response; as a consequence new HCV therapies should be also
studied in Asian, Afro-american and Latino populations in order
to fully characterize their efficacy and safety.
The predictive value of on-treatment viral kinetics will require
re-evaluation for the DAAs and their combinations. Although
evaluation of SVR at 6 months after treatment completion will
remain the gold standard for treatment success, there is growing
evidence indicating that SVR at 12 weeks after treatment
completion may be enough to predict long-term viral clearance.
Searching for new antiviral therapies | 75
Preliminary data show that DAAs induce a more rapid decline in
the VL than the one seen with PegIFN/RBV.
Table 4.3 – The most promising new therapeutical options for CHC
(as of June 2011) *
Category Mechanism Example Manufacturer Phase
BI201335 Boehringer III
TMC435 Medivir/Tibotec III
GS-9256, -9451 Gilead II
Danoprevir Intermune/Roche II
Vaniprevir Merck II
NS3/NS4A
protease
inhibitors
ACH-1625 Achillon Pharm. II
ABT 450 Abbott/Enanta II
BMS-650032 Bristol-Myers Squibb IIa
Mericitabine Roche/Pharmaset II
PSI-7977 Pharmaset II
IDX 184 Idenix II
NS5B polymerase
inhibitors,
nucleoside
analogs
Filibuvir Pfizer II
GS-9190 Gilead II
VX 222 Vertex II
ABT 333, -072 Abbott II
Setrobuvir Anadys Pharm. II
NS5B polymerase
inhibitors,
non-nucleoside
analogs
BMS-790052 Bristol-Myers Squibb II
ABT 267 Abbott II
AZD 7295 AstraZeneca II
Direct-acting
antivirals
NS5A inhibitors
Cyclophilins
inhibitors
Alisporivir Novartis/Debiopharm III
MBL-HCV1
human
monoclonal
antibody
The University of
Massachusetts Medical
School
Virus entry II
inhibitors
ITX 5061 iTherX II
Host
targeting
agents
Bavituximab Peregrine Pharm. II
* For more information, see http://hcvdrugs.com and the manufacturers' web
sites presented at the end of the chapter.
76 | Hepatitis C Treatment
Resistance testing is likely to become a part of the treatment
algorithm with the introduction of DAAs. Extensive knowledge of
the impact of these mutations on the phenotypic characteristics
and on the replicative fitness of the viral population will be
important (Kuntzen 2008) in order to tailor therapeutic decisions
for the management of the HCV infected patient.
It is expected that the HIV model of development of highly
active combined therapies, consisting of at least 3 drugs with
different mechanisms of action will be reproduced for HCV, in an
attempt to obtain effective interferon-free regimens. With such
combinations, HCV may become the first chronic viral infection
to be cured. While sufficient suppression of HIV RNA and HBV
DNA can only be achieved by long-term administration of potent
antiviral drugs, HCV RNA may be completely eradicated from the
infected individual after a limited duration of treatment. This is
foreseeable due to the fact that, unlike HIV (that replicates
through a proviral DNA subsequently integrated into the
lymphocytes nucleus), or HBV (that replicates through a cccDNA
that may integrate into the hepatocyte nucleus), HCV replication
is entirely intra-cytoplasmic and is not accompanied by the
establishment of extrahepatic reservoirs. In a viral kinetic model
for the pharmacokinetics of telaprevir, a rapid decrease in the
second slope of viral decline was found, four fold higher than
with standard interferon therapy. According to these data, a
combination triple therapy administered for 7-10 weeks might
be sufficient to eradicate the virus in fully compliant patients
(Guejd 2011). Patients who ultimately fail to clear the virus with
combination STAT-C regimens may still have improvements in
liver histology that can be further sustained by introduction of a
separate group of anti-fibrotic agents.

Emergence of drug resistant mutations

High levels of baseline drug resistance mutations in the NS3
protease or NS5B polymerase were identified in a significant
number of viral isolates from treatment-naive patients.
Moreover, there seem to be differences between HCV
genotypes/subtypes in terms of the frequencies of baseline
mutations and natural polymorphisms which can translate into
distinct susceptibility to DAAs. An overlap of immune escape and
drug resistance profiles has also been reported (Gaudieri 2009).
74 | Hepatitis C Treatment
The majority of DAAs have a low genetic barrier to resistance,
with the possible exception of nucleoside analogs inhibitors of
HCV polymerase.
There is broad cross resistance between drugs in the same
class, as has been shown for the two approved PIs, telaprevir and
boceprevir. Possible exceptions are the non-nucleoside
inhibitors of HCV polymerase that might be administered in
additive or synergistic combinations. The majority of patients
with virologic breakthrough during triple therapy with PIs
presented high-level resistant variants, these emerged more
frequently in the HCV genotype 1a patients (Kuntzen 2008);
predominant mutations were V36M and R155K compared to
A156T in genotype 1b. There is no information regarding the
possible archiving of drug resistant mutants in cellular
sanctuaries, as is the case for HIV. Emergence of resistance may
be limited by optimized pharmacokinetics of the DAAs and by
their use in combinations.

Host cyclophilins inhibitors

Another interesting therapeutic approach is directed at host
factors important in the viral life cycle. The most promising
target are cyclophilins, a family of highly conserved cellular
peptidyl-prolyl isomerases (PPIase) involved in many cellular
processes such as protein folding and trafficking. Cyclophilin
inhibitors block the interaction of cyclophilins with HCV
proteins and hence the formation of a functional viral
replication complex. Currently, several non-immunosuppressive
cyclosporin analogs are being tested. The most potent seems to
be Alisporivir (Debio-025), tested in both HCV monoinfected
and HIV/HCV coinfected patients with promising results. The
combination of Debio 025 and PegIFN-ɑ2a showed a significant
VL reduction after 28 days in patients infected with genotypes 1,
3 and 4 (Flisiak 2009). Such host protein-targeting compounds
have the advantage of higher genetic barriers to resistance and
could be instrumental in future IFN-free regimens (Table 4.3).

NS5A inhibitors

NS5A is a membrane-associated phosphoprotein involved in
both the formation of the replication complex and in the virus
assembly. The most potent HCV NS5A inhibitor reported to date
Searching for new antiviral therapies | 73
is BMS-790052, currently in phase II clinical trial in combination
with SoC. It was also used in combination with a protease
inhibitor (BMS-650032) for retreatment of previous nonresponders
to SoC with good results, but only in association with
PegIFN/RBV. Exclusion of SoC from the therapeutic regimen
resulted in high rates of viral breakthrough through week 12.

HCV polymerase inhibitors

The HCV NS5B enzyme is an RNA-dependent RNA polymerase
essential for viral replication. As the enzyme is highly conserved
across all HCV genotypes, the inhibitors are expected to have
pan-genotypic activity. The structure of NS5B, like many other
viral polymerases (HIV reverse transcriptase included),
resembles the shape of a hand consisting of finger, thumb and
palm domains. There are two major classes of polymerase
inhibitors: nucleoside analogs and non-nucleoside analogs. The
enzyme has a catalytic site for nucleoside binding and at least
four other sites to which a non-nucleoside molecule could bind
and cause allosteric alteration. Inhibitors of NS5B polymerase
have advanced to the phase II of clinical development. These
agents have demonstrated potent antiviral efficacy, achieving
multi-log reductions in HCV RNA with short-term treatment.
Searching for new antiviral therapies | 71
Nucleoside analogs target the catalytic sites of the enzyme by
competing with natural substrates and, once incorporated, act as
chain terminators stopping the further extension of viral RNA
nascent strand. This drug class is considered to have the
broadest genotypic coverage as well as a high resistance barrier.
This is due to the fact that mutations at the active site also affect
the viral polymerase fitness.
Several early developed compounds were discontinued because
of high toxicity (gastrointestinal or neutropenia related,
respectively).
The current most advanced compound in development is the
nucleoside analog mericitabine (R7128), an investigational
nucleoside inhibitor of NS5B HCV polymerase with antiviral
activity against HCV genotypes 1-6. The compound is a prodrug
of an oral cytidine nucleoside analog (PSI-6130). A phase IIb trial
in therapy-naive patients with genotype 1 or 4 HCV infection
demonstrated that a combination of mericitabine and
PegIFN/RBV achieves high rates of both rapid and complete
early virologic responses. Mericitabine has a safety profile
similar to SoC and, importantly, does not seem to be associated
with treatment-emergent viral breakthrough or resistance. The
combination of this NS5B polymerase inhibitor with an NS3
protease inhibitor (Danoprevir, R7227), administered without
additional PegIFN/RBV, for 14 days in treatment-naive, genotype
1-infected patients, demonstrated sustained viral suppression,
absence of PI resistant mutations and acceptable safety and
tolerability (INFORM 1 trial). The combination is associated with
a lower risk of relapse during SoC.
There are several others compounds in early stages of clinical
development, that are designed to achieve higher concentrations
of the active substance in the liver, reducing systemic exposure
and limiting the potential side effects.
The non-nucleoside polymerase inhibitors are a very
promising class of molecules, because they target multiple
distinct domains on the NS5B polymerase, acting through
72 | Hepatitis C Treatment
allosteric inhibition. HCV polymerase has at least four allosteric
binding pockets for nonnucleosidic inhibitors, unlike the HIV
reverse transcriptase where there is only a single one. Therefore,
if patients do not respond to one non-nucleoside inhibitor, there
is enough differentiation between the binding sites to allow the
use of a different drug within the class. Several non-nucleoside
HCV polymerase inhibitors are in clinical development. Most of
these investigational agents are active only against HCV
genotypes 1a and 1b and show a relatively high rate of
resistance, as well as an increased frequency of specific sideeffects.
These observations suggest that their use could be
limited to combination with other DAAs (Table 4.2). Such an
approach was investigated for a low potent non-nucleoside
polymerase inhibitor (tegobuvir, formerly known as GS-9190) in
combination with a protease inhibitor (GS-9256) in treatmentnaive
G1 HCV patients. The combination alone, without SoC was
not effective due to virologic rebound and selection of dual
resistance mutations that existed before treatment. Addition of
RBV alone significantly reduced the virologic breakthrough
rates.
Table 4.2 – Combinations of DAAs tested with or without PegIFN/RBV
Company DAA combination Phase
Vertex Telaprevir (PI*) + VX-222 (NNI†) II
Boehringer Ingelheim BI 201335 (PI) + BI 207127 (NNI) IIb
Bristol-Myers-Squibb BMS-650032 (PI)
+ BMS-790052 (NS5A inhibitor) II
Gilead GS-9256 (PI) + GS-9190 (NNI) II
Hoffmann-La Roche Danoprevir (R7227) (PI) + R7128 (NI‡) I
* PI: protease inhibitor
† NNI: non-nucleoside (polymerase) inhibitor
‡ NI: nucleoside (polymerase) inhibitor

Other investigational HCV PIs

A series of additional PIs are in development and preliminary
studies confirm their superior antiviral effectiveness in
combined triple therapy over the SoC in treatment-naive
patients. Unlike telaprevir or boceprevir, which are active only
on genotypes 1 and 2 and have to be dosed three times a day,
investigational second-generation PIs, mainly non-covalent
inhibitors of the NS3/4A, seem to be active against different HCV
genotypes, as well as against resistant HCV variants previously
selected by other PIs. Also, they have a longer half-life which
enables more convenient once-daily dosing. In addition, they
may provide improved safety and efficacy as well as shortened
treatment duration for a higher proportion of patients. An
example is BI 201335, a once-daily HCV NS3/4A protease
inhibitor optimised to target genotype-1 HCV, with strong in
vitro activity also against GTs 4-6. Phase II studies showed
BI 201335 to have strong efficacy, with overall SVR rates
70 | Hepatitis C Treatment
reaching 83% in GT1 patients at once-daily dosages of 240 mg (in
combination with PegINF+RBV). BI 201335 is now in phase III
trials in combination with PegINF+RBV and in phase II as part of
the interferon-free combination with the polymerase inhibitor,
BI 207127, in genotype-1 HCV patients.
Other notable examples are MK-5172, a competitive inhibitor
of HCV NS3/4A protease that has demonstrated in vitro activity
against genotypes 1b, 2a, 2b, and 3a, and proved to be active in
vivo against genotypes 1 and 3; and TMC435 (that can also be
administered once-daily), active in therapy-naive patients with
HCV G4 infection. Moreover, TMC435 antiviral activity was
similar, irrespective of the IL28B genotype. Some compounds,
such as Danoprevir (formerly R7227/ITMN-191) are being
studied in combination with low-dose ritonavir (a pharmacologic
booster used for HIV protease inhibitors) in order to improve
pharmacokinetics, without increasing toxicity. Whether such
complex therapies have the potential to minimize the risk of
viral breakthrough and the selection of resistance mutations,
remains to be evaluated.

Triple therapy

Triple therapy with a PI was shown to almost double the
success rate in treatment-naive patients infected with HCV
genotype 1 from 38-44% obtained with SoC to 63-75% (Poordad
2011). The increase in SVR rate is even higher in previous
nonresponders-from 17-21% with SoC to 59-66% with triple
therapy (Bacon 2011). Nevertheless, the addition of a new agent
to an existing treatment regimen will pose substantial challenges
in terms of drug interactions and adherence, due to the
associated side effects and risk of resistance emergence.
Maximizing tolerance of future PIs based regimens will be
extremely important to achieve optimal treatment outcomes.
Telaprevir (Incivek™, Vertex Pharmaceuticals) was approved
by FDA for treatment of genotype 1 CHC in adult naive patients
with compensated liver disease, including cirrhosis, and in prior
null responders, partial responders, and relapsers, only in
combination with PegIFN/RBV.
Preliminary studies have demonstrated that 14 days
monotherapy, while inducing a VL median decline of more than
4.4 log10 units in patients with CHC G1 infection, was limited by
the appearance of resistance mutation as early as 4-7 days after
initiation. Interestingly, the mutations were subsequently
suppressed by administration of PegIFN/RBV. Consequently,
telaprevir was administered in combination with PegIFN/RBV
Searching for new antiviral therapies | 67
for 12 weeks, followed by SoC therapy alone for another 24 - 48
weeks. The recommended dose of Incivek is 750 mg orally 3
times a day.
Several phase II and III studies have assessed the efficacy and
safety of telaprevir in treatment naive G1 patients, concluding
that triple therapy yields a higher rate of SVR than current SoC
and lower rates of relapse. The SVR for patients treated with
Incivek across all studies, and across all patient groups, was
between 20 and 45% higher than the current SoC (Hézode 2009,
McHutchison 2009). RBV was shown to be an essential part of the
therapeutic regimen, playing a critical role both in achieving
superior RVR and SVR and in reducing the rates of virologic
breakthrough due to drug resistance.
The results of a response-guided therapy (RGT) study,
ILLUMINATE (Sherman 2010) support a shorter course of
treatment (from 48 to 24 weeks) for rapidly responsive naivepatients.
Sixty percent of previously untreated patients achieved
an EVR and received only 24 weeks of treatment. The SVR for
these patients was 90%. In order to identify patients who may
benefit from shorter duration of therapy, a new predictor of
treatment response was proposed: extended RVR (eRVR),
defined as undetectable HCV RNA at week 4 and 12. Among
patients who achieved an eRVR, rates of SVR were comparable
between those treated for a total duration of 24 or 48 weeks (92%
vs. 88%, respectively). Among those who did not achieve eRVR,
but continued treatment for 48 weeks, the SVR rate was lower,
but still significant (64%). More recent studies have evaluated
the use of triple therapy including telaprevir as a retreatment
option for nonresponders and relapsers to previous SoC therapy,
demonstrating synergistic effects in viral reduction and
decreased emergence of resistance. SVR rates were higher
among patients who previously experienced relapse versus
nonresponders (McHutchison 2010).
Rashes, pruritus, anemia and nausea were the most commonly
reported AEs with the use of telaprevir. AEs rates resulting in
treatment withdrawal were about 10% higher in telaprevir arms
68 | Hepatitis C Treatment
vs PegIFN/RBV, the most severe being rash, that resolved with
discontinuation of therapy. Serious skin reactions, including
Drug Rash with Eosinophilia and Systemic Symptoms (DRESS)
and Stevens-Johnson Syndrome were reported in less than 1% of
subjects who received telaprevir combination treatment
compared to none who received PegIFN/RBV alone. A sequential
discontinuation of drugs was proposed for the management of
moderate or severe rash.
Boceprevir (Victrelis™, Merck) is another potent HCV NS3 PI
with antiviral activity against genotype 1 HCV. Boceprevir is FDA
approved for the treatment of CHC genotype 1 infection, in
combination with PegIFN/RBV, in patients aged 18 years of age
and older with compensated liver disease, including cirrhosis,
who are previously untreated or who have failed previous
interferon and ribavirin therapy. Boceprevir is administered
orally, at a dose of 800 mg three times daily.
The safety and efficacy of triple therapy with oral boceprevir
plus PegIFN/RBV vs PegIFN/RBV alone were demonstrated in a
phase III registration trial for treatment-naive patients, SPRINT-
2 (Poordad 2011) and in previously partial responders and
relapsers to SoC (RESPOND-2) (Bacon 2011). Boceprevir, in
combination with PegIFN/RBV has not been studied in patients
documented to be historical null responders (less than 2 log10
HCV RNA decline by treatment week 12) during prior therapy
with PegIFN/RBV.
The treatment strategy is different from telaprevir, Boceprevir
being administered in triple combination therapy for 24-44
weeks only after a 4 weeks lead-in phase with PegIFN/RBV alone.
Therefore, RVR was defined as undetectable HCV RNA at week 4
of boceprevir-containing therapy (meaning week 8 of all
therapy, including the lead-in period). In theory, a lead-in phase
may provide the additional advantage of reducing viral
replication and, consequently, the rate of resistance emergence.
However in phase III clinical trials, patients with poor response
to PegIFN/RBV, defined as <1 log10 decline after 4 weeks lead-in,
had a higher incidence of resistance mutations. Nevertheless, the
Searching for new antiviral therapies | 69
virologic response at the end of the lead-in phase is highly
predictive for the final outcome of therapy. Substantially higher
SVR rates are obtained in patients showing more than 1 log10
decline in HCV RNA at this time point. Even in patients with a
poor response to interferon, addition of boceprevir can generate
a SVR in up to 34% of the patients. This is an important
information, arguing for the utility of a lead-in phase in the
previously treated nonresponders or relapsers. For naive
patients, the lead-in period can further serve to test both
compliance and tolerability before exposure to PIs.
The most commonly reported AEs with boceprevir were anemia
(almost twice as many boceprevir recipients had Hb levels <9.5
mg/ml compared to controls) and dysgeusia (more than twice as
often in boceprevir recipients than in controls). Serious AEs were
reported in 11% of patients receiving boceprevir in combination
with PegIFN/RBV compared with 8% of patients receiving
PegIFN/RBV alone. The most common reason for dose reduction
in the trials was anemia.

Protease inhibitors (PIs)

A clear understanding of the key sites of action for the newer
antiviral compounds in development is of outmost importance.
HCV is a positive-sense single-stranded RNA virus, meaning that
its genome can function directly as a template for viral protein
synthesis. Consequently, after entering into hepatocytes, HCV
starts its replication by direct translation of the genome into a
large polypeptide that is further processed by the virus NS3
protease. This enzyme has dual activity of serine protease and of
helicase (unwinding the single-strand viral RNA). Together with
the NS4A cofactor, the NS3 protease is responsible for
proteolytic cleavage of its downstream nonstructural proteins
that in turn are critical in forming the replicative complex from
which viral synthesis occurs. Additionally, NS3 protease may
directly impair host IFN responses through the inhibition of
phosphorylation of IFN regulatory factor-3, and administration
of PIs may restore interferon responsiveness.
66 | Hepatitis C Treatment
Both FDA-approved PIs – Telaprevir and Boceprevir – are
peptidomimetic PIs that bind reversibly and block the protease
catalytic site.
However, monotherapy with PIs is not an option, due to
early emergence of resistance. Minor resistant populations
preexist at baseline in all HCV-infected patients and are rapidly
selected with PIs monotherapy. Therefore, boceprevir and
telaprevir still require a platform of PegIFN/RBV. When
administered in this triple therapy combination, each of the two
PIs substantially increases the rates of SVR in both treatmentnaive
and treatment-experienced patients

Direct-Acting Antivirals (DAAs)

Direct-acting antivirals (DAAs), also known as “specifically
targeted antiviral therapy for hepatitis C” (STAT-C), are the most
important new therapeutical options for CHC. In May 2011, two
HCV protease inhibitors Telaprevir (Incivek™) and Boceprevir
(Victrelis™) have been approved by the FDA. For the first time,
we have now drugs with specific anti-HCV activity. Several other
DAAs are at various stages of clinical development, the most
advanced being alternative protease inhibitors and nucleoside
and non-nucleoside polymerase inhibitors. Other tentative
approaches include inhibitors of host cyclophilins, alphaglucosidase
inhibitors, oligonucleotides and immune modulators
(Soriano 2009).

Alternative RBV formulation

Optimal RBV dosages are essential in achieving a SVR.
Maintenance of RBV in the therapeutic regimen has been proven
to have an important additive effect in the overall success rate,
leading to both increased RVR and reduced rates of relapses (as
demonstrated by the PROVE-2 trial).
As described in chapter 1, the main impediment in the
administration of high-dose RBV is the dose-dependent
development of hemolytic anemia. Although the addition of
epoetin alfa has been useful in maintaining the highest possible
RBV doses, new RBV-replacement compounds, with an improved
side effects profile, are investigated.
Taribavirin – formerly known as viramidine – (Valeant
Pharmaceuticals International/Kadmon Pharmaceuticals LLC), is
a prodrug of RBV, converted in the active form by adenosine
deaminase. This nucleoside analog was studied for the treatment
of CHC, due to the lower frequency of anemia, a benefit
registered especially within the first 12 weeks of treatment, the
period in which maintenance of the dose of RBV has been shown
to be the most critical. The major conversion site of taribavirin is
in the liver, enabling drug concentration in this location. Due to
its lower uptake in red blood cells, taribavirin causes
significantly less hemolytic anemia compared to RBV. While this
effect was confirmed in several clinical studies, the rates of SVR
were lower with taribavirin.
In two phase III studies, taribavirin failed to prove
noninferiority compared to RBV (SVR rates were 38% and 40%
with taribavirin vs. 52% and 55% with RBV in the VISER 1 and
VISER 2 trials, respectively), even if taribavirin caused lower
rates of severe anemia (5% vs 24%). Suboptimal dosing of
taribavirin (Marcellin 2010) seems to be the explanation, as
recent studies with weight-based dosing of taribavirin confirmed
reduced rates of anemia (7%-15% vs. 24% with RBV), while
acquiring comparable SVR rates and lower relapse rates than
RBV. Whether taribavirin will have a role in the future
Searching for new antiviral therapies | 65
combination therapies including DAAs (most of which are also
associated with a certain degree of anemia) remains to be seen.