TreatmentUpdate 207 - CATIE

TreatmentUpdate 207 Vol.27,No.2
February 2015

Available online at
www.catie.ca/en/treatmentupdate

Contents I  HEPATITIS C VIRUS

I  HEPATITIS C VIRUS A. About some terms – SVR12 vs. SVR24

A. About some terms – SVR12 vs. SVR24 1 After a person has successfully completed treatment
for hepatitis C virus (HCV), there is a period when
B. SVR linked to longer survival and 2 HCV viral load in the blood is undetectable. If this
other benefits period of undetectability lasts for 12 consecutive
weeks after the cessation of treatment, it is called
C. Issues with emerging therapies 3 a sustained virological response (written as SVR12).
for HCV This period usually then leads to a further 12
consecutive weeks of undetectable HCV, for a total
D. Simeprevir + sofosbuvir – experience of 24 weeks of undetectability since treatment
cessation (written as SVR24). Historically, a person
in the clinic 5 is considered cured when they have achieved SVR24.

E. Holkira Pak approved in Canada 8 In clinical trials
for genotype 1
For much of the past decade, SVR24 was considered
F. Holkira Pak – results in genotype 1a the main result (or endpoint) of clinical trials that
sought to cure participants of HCV, particularly
without severe liver injury 9 when treatment consisted of just peginterferon +
ribavirin. However, in recent clinical trials with
G. Holkira Pak – results in genotype 1a emerging and powerful combinations of all-
oral anti-HCV drugs, regulatory authorities have
with severe liver injury 10 told drug companies that SVR12 is sufficient to
determine whether these treatments are working
H. Holkira Pak – effectiveness in people and whether to launch phase II or III trials with
the drugs in question. That is because in the vast
with kidney dysfunction 11 majority of cases in which the new and powerful
all-oral regimens are used, SVR12 leads to SVR24.
I. Holkira Pak – effectiveness in people This helps companies move faster with the
development of anti-HCV therapy. Participants
with liver transplantation 12 are still monitored to see if they do indeed achieve
SVR24 but the decision as to whether a corporation
II  HIV AND TRANSPLANTATION continues to develop a drug can be made faster.

A. HIV and liver transplants in 13
British Columbia

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Page 2 TreatmentUpdate 207 — Vol. 27 No. 2 Thus, screening for HCV is important. People who
have this virus need swift referral to assessments
In the clinic of liver health and discussions with doctors and
nurses about treatment options.
In the everyday world of caring for patients with
HCV infection, doctors and nurses continue to A note about terms
assess SVR12 and SVR24, just to be sure that a person
is cured. However, many doctors who have had As the study discussed later in this report was done
experience with testing the new all-oral regimens of in the time before the arrival of potent all-oral
anti-HCV drugs in clinical trials generally consider therapy for HCV, SVR means 24 weeks after the
their patients cured if they have achieved SVR12. cessation of therapy, written as SVR24. The point
that the research teams are trying to make here is
To find out more about this issue of SVR12 vs. SVR24, that the goal of SVR is important and so we do not
see “The changing role of SVR12 in clinical trials of write it as we have done elsewhere in this issue of
HCV drugs” in TreatmentUpdate 198. TreatmentUpdate (such as SVR12 or SVR24).

B. SVR linked to longer survival and Exploring clinical trials
other benefits
Leading specialists who study the liver and
After a person is exposed to hepatitis C virus (HCV), gastrointestinal tract have been conducting
the virus enters the blood and makes its way to the research to explore the many benefits of HCV
liver, where it infects cells of this vital organ. Liver treatment and cure (SVR24). They collected health-
cells injured as a result of HCV infection release related information from participants with and
chemical signals that alert the immune system without severe HCV-related liver injury. All
about the invading virus. The immune system is participants had HCV mono-infection (that is, no
then mobilized and tries to contain HCV but this other co-infections) and their degree of fibrosis was
germ becomes entrenched in the liver, leading to a confirmed with a liver biopsy.
state of chronic infection.
The bulk of data used in this analysis was collected
Undaunted by this setback, the immune system from participants who initiated interferon-based
keeps trying to rid the liver of HCV-infected cells. therapy between 1990 and 2003. However, additional
These attempts by the immune system against data focusing on survival were collected up to
HCV cause inflammation. The struggle between October 2011. Participants in this analysis came
the immune system and HCV lasts for years. Over from five major clinics in the following countries:
time, healthy liver cells are replaced with useless
scar tissue in a process called fibrosis. • the Netherlands
• Canada
Eventually, as fibrosis spreads throughout the liver, • Germany
this organ becomes increasingly dysfunctional and • Switzerland
complications arise, including the following:
A total of 535 participants were monitored for
• internal bleeding between six and 11 years.
• enlarged abdomen (and sometimes legs) due
Their average profile at the start of the study was
to the build-up of fluid as follows:
• kidney dysfunction
• bacterial infections • 70% were men and 30% were women
• fatigue • age – 48 years
• problems with thinking clearly and • 192 (36%) achieved an SVR24 (herein after

remembering referred to as an SVR)

Infection with HCV also raises the risk for
developing liver cancer.

Results TreatmentUpdate 207 — Vol. 27 No. 2 Page 3

Among participants who achieved an SVR, a small this risk is reduced compared to people whose
number (13) died during the study period. Over an HCV treatment did not result in an SVR.
average of 10 years of monitoring, the researchers
found that 91% of participants who had achieved Bear in mind
an SVR were still alive.
The present multinational study is based on
In contrast, about 100 participants who did not looking back in time at medical records. Such
achieve an SVR died. Over an average of 10 years of a retrospective study could have unmeasured
monitoring, 74% of people who did not achieve an factors that could have inadvertently biased the
SVR were still alive. interpretation of the data. However, the researchers
focused on a few simple factors and survival, and
Comparisons their conclusions are reasonable and make sense.

The 10-year survival figure of 91% of participants Although data from HCV-negative people were
with an SVR was not significantly different from only used from the Netherlands, survival estimates
the survival rates of HCV-negative Dutch people of for this group are broadly similar across high-
the same age and gender over the same period of income countries, including Canada.
time. Thus, even for people with severe liver injury,
getting an SVR can lead to broadly similar rates of For the future
survival as HCV-negative people.
In the coming years, as more powerful and
As mentioned earlier, among people who did interferon-free regimens become licensed and
not achieve an SVR after treatment, 100 deaths subsidized by regional authorities, a similar
occurred, resulting in a 74% survival rate. This rate analysis needs to be done with such regimens. Such
of survival is significantly worse than that of the analyses should also review the long-term results
average HCV-negative Dutch person of the same among people co-infected with HIV and HCV.
age and gender during the same calendar period.
REFERENCE:
Other benefits
van der Meer AJ, Wedemeyer H, Feld JJ, et al. Life expectancy
The researchers stated that those people who in patients with chronic HCV infection and cirrhosis
developed an SVR were likely to experience compared with a general population. JAMA. 2014 Nov
the following: 12;312(18):1927-8.

• decreased inflammation in the liver C. Issues with emerging therapies
• some degree of healing with healthy liver for HCV

tissue being formed For much of the past decade in Canada and other
• reduced risk for liver dysfunction high-income countries, the mainstay of hepatitis C
• reduced risk for liver cancer treatment has been a combination of the following
two drugs:
As well, the researchers stated that as a result of
successful treatment (SVR) patients would also • a long-acting form of interferon-alpha called
experience the following: peginterferon

• reduced risk for diabetes • ribavirin
• reduced risk for severe kidney injury
• reduced risk for heart attack Peginterferon works by activating genes in a cell
that then produce many antiviral substances. In
The researchers also stated that although people general, it is difficult for hepatitis C virus (HCV)
with severe liver injury (cirrhosis) can obtain an to counteract the action of these genes. This is why
SVR with treatment, they are still at risk for the peginterferon has, until very recently, been the
subsequent development of liver cancer. However, backbone of HCV treatment.

Page 4 TreatmentUpdate 207 — Vol. 27 No. 2 established formularies—lists of drugs that are
subsidized by the state.
Ribavirin is a nucleoside analogue and has activity
against a broad range of viruses, at least in laboratory Until a drug is listed on the formulary, most patients
experiments with cells. Exactly how ribavirin works cannot get access to it, though some companies may
against HCV-infected cells is not clear. have very limited compassionate access programs
for people with HCV. Some patients may also be
The debut of DAAs able to access these drugs because they have private
health insurance.
As mentioned earlier, the historical mainstays of
HCV treatment were drugs that affected HCV The formularies negotiate with pharmaceutical
indirectly. However, in 2011 the first licensed direct- companies about the cost of their drugs. This
acting antivirals (DAAs) for HCV became available: back and forth between the formularies and
companies takes time. The cost of the new DAAs
• boceprevir will be high and it is not clear when they will be
• telaprevir on every formulary.

These two drugs belong to a class called protease The high cost of the new regimens may mean
inhibitors. Boceprevir and telaprevir were taken that access to the new DAAs will be delayed and
orally but needed to be used with interferon and rationed. Formularies can put restrictions on who
ribavirin. Furthermore, regimens containing either can get their listed medicines. For instance, it is
of these DAAs were largely only effective against possible that some formularies may insist that there
one strain of HCV—genotype 1. Both regimens be conditions on access—this may include issues
were associated with side effects, had to be taken such as the stage of liver injury, such that only the
for prolonged periods and their effectiveness was healthiest patients (who generally have the highest
not very high—if patients completed their course rates of recovery) or the sickest (whose need for
of therapy, recovery rates ranged from 60% to 75%. medicines is greatest) get treatment. Alternatively,
if a good bargain is struck by formularies, there
Fortunately, today more DAAs are being approved may be few or no restrictions on the use of new
and can be used without interferon. What’s more, HCV therapies.
therapy with newer DAAs is generally shorter (12 to
24 weeks) compared to regimens several years ago. Clinical trials and reality

In this issue of TreatmentUpdate, we largely focus The new all-oral DAA regimens being developed by
on several combinations of agents including these: AbbVie and Gilead generally have very high success
rates—ranging from 95% to 100%—depending
• sofosbuvir (Sovaldi) with ribavirin and/or on the sub-populations being tested, at least in
peginterferon clinical trials. However, in the real world outside
of a clinical trial, doctors have come to expect
• simeprevir (Galexos, Olysio) with sofosbuvir that medicines may not perform as well for many
• Holkira Pak (nick-named the “3D” regimen) conditions. Perhaps this happens because patient
populations in clinical trials are usually highly
made by AbbVie. selected and do not always reflect the diversity of
illness that occurs in the real world. In general,
In the next issue of TreatmentUpdate (issue 208) clinical trials usually do not enroll the sickest and
we will have detailed information about another hardest-to-treat patients.
exciting HCV therapy called Harvoni (sofosbuvir +
ledipasvir) that is made by Gilead Sciences. Retreatment

Access delayed The cost of initial treatment with DAAs is relatively
expensive. What happens if a new regimen fails to
In Canada and other high-income countries, most cure the patient? Arguably, given the potency of
people cannot afford to pay for the high cost of the new DAAs such cases should not be common,
treating and managing catastrophic illnesses
such as HIV, HCV and cancer. In response to
this situation, regional health authorities have

particularly among patients who have never been TreatmentUpdate 207 — Vol. 27 No. 2 Page 5
previously treated. However, in cases of treatment
failure will the state agree to pay for another course D. Simeprevir + sofosbuvir – experience
of a different but equally expensive DAA-based in the clinic
therapy? Will insurance companies also agree to
pay for retreatment if an initial regimen of DAAs Leading hepatitis C virus (HCV) researchers in
fails? Cases of reinfection may occur if successfully Canada, Germany, New Zealand and the U.S.
treated people are again exposed to HCV—how have formed a research group called HCV Target.
will the state deal with this issue given the high The purpose of Target is to conduct observational
cost of therapy? These are just some of the issues studies of emerging therapies for HCV. Data are
that could become controversial in an era of captured from medical records from HCV clinics
enforced austerity. in the participating countries and placed in a
shared database.
Cost and access
Target has enrolled 2,330 participants, most of
These issues of rationing are sufficient reason why whom (96%) have decided to collaborate with their
people with HCV and organizations that serve doctor to initiate HCV therapy. Among participants
them need to monitor what formularies are doing who have agreed to start therapy, 93% have already
in order to understand how these organizations begun to take medicines.
arrive at decisions that can impact the health and
survival of the population. Participants were distributed among the following
regimens:
For the future
• sofosbuvir + peginterferon + ribavirin –
Although new, powerful regimens are being 338 people
licensed by regulatory authorities, it is not clear
which medicines will become available on • sofosbuvir + ribavirin – 667 people
formularies early in 2015 and much work remains • sofosbuvir + simeprevir – 784 people
to be done. • sofosbuvir + simeprevir + ribavirin –

REFERENCES: 228 people

1. Pollack A. AbbVie deal heralds changed landscape for The average profile of participants before they
hepatitis drugs. 22 December 2014. New York Times. Available started taking these medications was as follows:
at: http://tinyurl.com/ppesz7h [registration or subscription
may be required]. • 64% men, 36% women
• age – 58 years; 19% were older than
2. Jerzyk E. Rhode Island Medicaid limits supply of hepatitis
C drug due to cost. The Brown Daily Herald. 4 December 2014. 65 years old
Available at: http://tinyurl.com/o7xxtse • never previously treated – 48%
• among those who were previously treated,
3. Langreth R. More medicine goes off limits in drug-price
showdown. Bloomberg News. 25 November 2014. Available at: 18% had tried a regimen based on a protease
http://www.bloomberg.com/news/articles/2014-11-25/more- inhibitor such as boceprevir or telaprevir
medicine-goes-off-limits-in-drug-price-showdown • presence of cirrhosis – 48%
• presence of liver cancer – 10%
4. John M and Hirschler B. France pegs Gilead hepatitis C • had a liver transplant – 11%
drug at “lowest price in Europe.” Reuters. 20 November 2014. • co-infected with HIV – 2%
Available at: http://tinyurl.com/oj4n4gw
Most participants had one of the following strains,
5. Pierson B. Gilead sued over “exorbitant” hepatitis or genotypes, of HCV: genotype 1, 2 or 3.
C drug prices. Reuters. 10 December 2014. Available at:
http://tinyurl.com/l43koty Target is an ongoing collaboration and not all
results are available, so we are presenting the
preliminary results. Note that due to rounding,
percentages may not total 100.

Page 6 TreatmentUpdate 207 — Vol. 27 No. 2 Sofosbuvir + simeprevir with or without
ribavirin in genotype 1
Sofosbuvir + peginterferon + ribavirin Four weeks after the cessation of therapy the results
in genotype 1 were as follows:
Participants generally responded well to this
therapy. Four weeks after the course of treatment • 89% continue to have undetectable HCV viral
ended the results were as follows: load (SVR4)

• 85% of participants continue to have • 9% initially suppressed HCV but it later
undetectable HCV in their blood (this is became detectable
called SVR4)
The distribution of suppressed viral loads by
• 13% who were initially able to suppress HCV cirrhosis status was as follows:
had the virus again become detectable
• no cirrhosis – 92% had an undetectable
Among the remaining patients, the regimen was viral load
never able to suppress HCV and one participant
stopped attending the clinic. • cirrhosis – 87% had an undetectable viral load

Another way to look at the response to therapy Among participants who had cirrhosis and
is to assess results by the degree of pre-existing symptoms of severe liver injury, 75% had
liver injury. Four weeks after treatment cessation, undetectable viral load four weeks after the
undetectable HCV viral loads (SVR4) were cessation of therapy (SVR4).
distributed as follows:
The distribution of undetectable viral loads by
• no severe liver injury (cirrhosis) – 90% had an HCV genotype was as follows:
undetectable HCV viral load
• genotype 1a – 86%
• cirrhosis present – 70% had an undetectable • genotype 1b – 95%
HCV viral load
Simeprevir + sofosbuvir with or without
Sofosbuvir + ribavirin in genotype 2 ribavirin for genotype 1 and prior treatment
Four weeks after therapy ended the results were failure with a protease inhibitor
as follows: After treatment cessation the results were as follows:

• 90% continue to have undetectable HCV viral • 81% had a suppressed viral load (SVR4)
load (SVR4) • 19% of participants relapsed and viral load

• 8% were initially able to suppress HCV but was detectable
their viral load is now detectable
Among participants with and without cirrhosis the
In most of the remaining participants the regimen results were as follows:
was not sufficiently powerful. Two additional
participants stopped attending their clinic. • no cirrhosis – 85% achieved SVR4
• cirrhosis – 79% achieved SVR4
The results of viral load based on cirrhosis status
were as follows: Analyses suggest that the addition of ribavirin to a
regimen of simeprevir + sofosbuvir was of marginal
• no cirrhosis – 91% had a suppressed viral load benefit regardless of the following characteristics
• cirrhosis – 88% had a suppressed viral load or features:

• degree of liver injury
• symptoms of liver injury
• genotype
• history (or not) of treatment
• prior treatment failure with triple therapy

Readers should treat these results from Target as TreatmentUpdate 207 — Vol. 27 No. 2 Page 7
preliminary until SVR12 results become available.
Side effects and complications
Watch for this
Adverse effect is the term used for describing
Later in 2015, results from a large study called a symptom and/or abnormal lab result and
Optimist will become available. For this study, complication that occurs during a clinical trial. This
researchers tested the combination of simeprevir term encompasses at least the following scenarios:
+ sofosbuvir.
• medication-related side effects
Relationship between SVR4 and SVR12 • complications that may be due to the disease
in Target
process being studied (for example, an effect
A limited proportion of participants in Target of chronic HCV infection) that may have
have sufficient data collected so that researchers nothing to do with the study drugs
can report their SVR12 results. Not surprisingly, • accidents (these may also be unrelated to the
what has become clear to the researchers is that study drugs)
anyone who did not have an SRV4 also did not have
an SVR12. In Target, participants who received peginterferon
were more likely to report symptoms of a flu-like
Of greater interest is the proportion of participants illness as well as depression, difficulty falling asleep,
who had an SVR4 who maintained a suppressed rash and fatigue. Such symptoms are common with
viral load to the 12th week after therapy had ceased exposure to peginterferon.
(SVR12). We caution readers that so far only very
limited SVR12 data have been made available from In general, the regimen with the fewest side effects
Target for the following three regimens: was the combination of simeprevir + sofosbuvir.

Simeprevir + sofosbuvir with or without Rates of the following side effects with each of the
ribavirin in genotype 1 other regimens appear below.
• 97% (143) of participants who had an SVR4
Simeprevir + sofosbuvir
also achieved an SVR12 • fatigue – 25%
• nausea – 12%
Sofosbuvir + peginterferon + ribavirin • difficulty falling asleep – 9%
in genotype 1 • itchy skin – 8%
• 94% (51) of participants who had an SVR4 also • irritability – 3%
• depression – 2%
achieved an SVR12 • anemia – 1%

Sofosbuvir + ribavirin in genotype 2 Simeprevir + sofosbuvir + ribavirin
• 98% (57) of participants who had an SVR4 also • fatigue – 38%
• anemia – 30%
achieved an SVR12 • difficulty falling asleep – 18%
• nausea – 17%
These analyses suggest that SVR4 is an important • itchy skin – 14%
preliminary result and appears to be highly • irritability – 8%
predictive of who will achieve an SVR12. As a result, • depression – 7%
there is likely to be more focus on SVR4 both in
clinical trials and in the clinic in the future. Sofosbuvir + peginterferon + ribavirin
• fatigue – 42%
• anemia – 28%
• nausea – 22%
• difficulty falling asleep – 16%
• irritability – 16%
• depression – 10%
• itchy skin – 9%

Page 8 TreatmentUpdate 207 — Vol. 27 No. 2 REFERENCE:

Sofosbuvir + ribavirin Jensen DM, O’Leary JG, Pockros PJ, et al. Safety and efficacy
• fatigue – 38% of sofosbuvir-containing regimens for hepatitis C: Real-world
• anemia – 21% experience in a diverse, longitudinal observational cohort.
• nausea – 17% Program and abstracts of The Liver Meeting, 7-11 November
• difficulty falling asleep – 14% 2014, Boston, Ma. Abstract 45.
• depression – 11%
• itchy skin – 8% E. Holkira Pak approved in Canada for
• irritability – 7% genotype 1

Serious adverse events were distributed by regimen Holkira Pak is the brand name for the suite of
as follows: AbbVie drugs licensed in Canada and the U.S. for
the treatment of hepatitis c virus (HCV) genotype
• simeprevir + sofosbuvir – 5% of participants 1. Holkira Pak consists of the following medicines:
• simeprevir + sofosbuvir + ribavirin –
• paritaprevir (formerly ABT-450) – 150 mg
8% of participants • ritonavir – 100 mg
• sofosbuvir + peginterferon + ribavirin – • ombitasvir (formerly ABT-267) – 25 mg
• dasabuvir (formerly ABT-333) – 250 mg
3% of participants
• sofosbuvir + ribavirin – 8% of participants Paritaprevir + ritonavir + ombitasvir are taken once
daily. All three drugs are inside one pill. Two of
A total of 12 patients died; nine of the 12 deaths these pills are taken in the morning.
were among people with cirrhosis. Here are the
causes of death distributed by regimen: Dasabuvir is taken in a separate pill, once in the
morning and once in the evening.
• simeprevir + sofosbuvir – one case each of
stroke, kidney failure, pneumonia and shock; All pills in Holkira Pak should be taken with food.
two cases of liver failure
These medicines—paritaprevir + ombitasvir +
• simeprevir + sofosbuvir + ribavirin – one case dasabuvir—work against HCV-infected cells in
each of unknown cause and suicide three different ways.

• sofosbuvir + peginterferon + ribavirin – one Ritonavir, the other medicine inside Holkira
case of severe bacterial infection leading to Pak, does not work against HCV. The purpose of
blood poisoning ritonavir is to boost the level of paritaprevir in the
blood so that once-daily dosing is possible.
• sofosbuvir + ribavirin – one case of multi-
organ failure; two cases of heart attacks In some cases AbbVie also recommends the use
of the broad-spectrum antiviral agent ribavirin.
Key points The combinations recommended by AbbVie are
as follows:
According to the interim data from Target:
• genotype 1a without cirrhosis – Holkira Pak +
• All regimens are broadly effective. ribavirin for 12 weeks
• There were low rates of treatment failure.
• There were low rates of treatment • genotype 1b without cirrhosis – Holkira Pak
for 12 weeks
discontinuation.
• There were fewer side effects from all-oral • genotype 1a or 1b with cirrhosis – Holkira Pak
+ ribavirin for 12 weeks
regimens than there are with interferon-
containing regimens.
• Side effects were lowest with the simeprevir
+ sofosbuvir regimen, as it did not contain
interferon or ribavirin.

• genotype 1a and 1b or genotype 1 with TreatmentUpdate 207 — Vol. 27 No. 2 Page 9
unknown subtype – Holkira Pak + ribavirin
for 12 weeks Focus on 1a
In four phase III trials (code-named Sapphire-1,
• genotype 1a with cirrhosis and previous poor Sapphire-2, Pearl-4 and Turquoise-2) researchers
response to interferon + ribavirin – Holkira recruited 1,058 participants with genotype 1a who
Pak + ribavirin for 24 weeks were distributed as follows:

In the EU and U.S. • no prior exposure to anti-HCV therapy – 70%
(744 people)
The AbbVie drugs are also licensed in the U.S.,
where they are known as Viekira Pak. In the EU • a history of HCV therapy – 30% (314 people)
the AbbVie drugs have also been licensed and
will be called Viekirax (paritaprevir + ritonavir + One-quarter of all genotype 1a participants had
ombitasvir) and Exviera (dasabuvir). severe liver injury (cirrhosis).

Formulary access Results—1a without cirrhosis
Overall results after 12 weeks of therapy were
After a drug is licensed in Canada, it can often take as follows:
between six and 12 months before it is approved for
placement on formularies (publicly subsidized lists • Holkira Pak – 90% had SVR12
of medicines). Canada’s provinces and territories • Holkira Pak + ribavirin – 96% had SVR12
as well as private and public health plans have
formularies. AbbVie will be negotiating with Among participants with no prior exposure to
Canada’s provinces and territories about listing treatment:
Holkira Pak on their formularies.
• Holkira Pak – 90% had SVR12
In this issue • Holkira Pak + ribavirin – 96% had SVR12

In TreatmentUpdate 207 we present some research Researchers divided participants with a history of
findings on Holkira Pak from clinical trials that treatment into the following three groups based on
demonstrate its power and safety. their prior response to peginterferon + ribavirin:

F. Holkira Pak – results in genotype 1a • relapse – initially suppressed HCV while on
without severe liver injury treatment but viral load became detectable
once treatment ceased
Nearly 3,000 people with hepatitis C virus (HCV)
genotype 1 have received Holkira Pak in clinical • partial response – had a significant decline in
trials. Among participants with the subtype of this viral load while on treatment but viral load
strain called genotype 1b, rates of cure (SVR12) are never became undetectable
relatively high, about 99%. Genotype 1b responds
relatively well to the new and powerful anti-HCV • null response – no significant decline in viral
drugs such as Holkira Pak and Harvoni. Past load occurred while on treatment
experience with boceprevir and telaprevir suggests
that strains of genotype 1a are harder to treat. We Here are the responses of these three groups
now focus on clinical trial results from participants to treatment with AbbVie’s direct-acting
with genotype 1a who were treated with Holkira antivirals (DAAs):
Pak with and without ribavirin. These results,
particularly among participants who received • prior relapse – 94% had SVR12
ribavirin are very promising. • prior partial response – 100% had SVR12
• prior null response – 95% had SVR12

Page 10 TreatmentUpdate 207 — Vol. 27 No. 2 Results
Overall results were as follows:
The risk of treatment failure
Researchers found that the risk of treatment failure • Holkira Pak + ribavirin for 12 weeks – 89%
with Holkira Pak among genotype 1a participants had SVR12
was associated with the following factors:
• Holkira Pak + ribavirin for 24 weeks – 95%
• being obese had SVR12
• not using the broad-spectrum antiviral
Here are the results among sub-groups of
drug ribavirin participants:

Side effects and complications No previous treatment
Severe or serious side effects or complications were • Holkira Pak + ribavirin for 12 weeks – 92%
uncommon and were distributed as follows:
had SVR12
• Holkira Pak alone – 2% • Holkira Pak + ribavirin for 24 weeks – 95%
• Holkira Pak + ribavirin – 5%
had SVR12
Side effects that were sufficiently bothersome,
causing participants to prematurely leave the study, Researchers divided participants with a history of
were distributed as follows: treatment into the following three groups based on
their prior response:
• Holkira Pak alone – 2 people
• Holkira Pak + ribavirin – 3 people • relapse – initially suppressed HCV while on
treatment but viral load became detectable
Ribavirin commonly causes temporary reductions once treatment ceased
in the number of red blood cells. In 7% of cases
where ribavirin was used, doctors had to reduce the • partial response – had a significant decline in
dose to minimize this problem. viral load while on treatment but viral load
never became undetectable
REFERENCE:
• null response – no significant decline in viral
Everson GT, Dusheiko G, Coakley E, et al. Integrated efficacy load occurred while on treatment
analysis of four phase 3 studies in HCV genotype 1a-infected
patients treated with ABT-450/r/ombitasvir and dasabuvir Here are the responses of these three groups to
with or without ribavirin. Program and abstracts of The Liver treatment with AbbVie’s DAAs + ribavirin:
Meeting, 7-11 November 2014, Boston, MA. Abstract 83.
Relapse
G. Holkira Pak – results in genotype 1a • Holkira Pak + ribavirin for 12 weeks – 93%
with severe liver injury
had SVR12
AbbVie researchers analysed data from participants • Holkira Pak + ribavirin for 24 weeks – 100%
who took the following regimens:
had SVR12
• Holkira Pak + ribavirin for 12 weeks –
142 participants Partial response
• Holkira Pak + ribavirin for 12 weeks – 100%
• Holkira Pak + ribavirin for 24 weeks –
121 participants had SVR12
• Holkira Pak + ribavirin for 24 weeks – 100%

had SVR12

Null response
• Holkira Pak + ribavirin for 12 weeks – 80%

had SVR12
• Holkira Pak + ribavirin for 24 weeks – 93%

had SVR12

Complications and side effects TreatmentUpdate 207 — Vol. 27 No. 2 Page 11
In general, during clinical trials Holkira Pak was
well tolerated and side effects were usually mild. 2. AbbVie. Holkira PAK: ombitasvir/paritaprevir/ritonavir
film-coated tablets (12.5/75/50 mg) and dasabuvir (as dasabuvir
Common side effects of Holkira Pak without sodium monohydrate) film-coated tablets (250 mg). Product
ribavirin included the following: Monograph. 22 December, 2014.

• fatigue H. Holkira Pak – effectiveness in
• headache people with kidney dysfunction

Among participants who took a combination of People with chronic hepatitis C virus (HCV)
Holkira Pak and ribavirin, common side effects infection can also develop kidney injury and
included the following: dysfunction. Historically, people with HCV who
also have kidney dysfunction have not responded
• fatigue well to combination therapy with peginterferon
• headache and ribavirin.
• nausea
• itchy skin Prior to testing Holkira Pak in HCV-positive people
• difficulty falling asleep with kidney dysfunction, AbbVie conducted a study
to assess the safety of the following two regimens in
Severe adverse events were distributed as follows: HCV-negative people:

• Holkira Pak + ribavirin for 12 weeks – • Holkira Pak (sometimes called the
9% of participants 3D regimen)

• Holkira Pak + ribavirin for 24 weeks – • a so-called 2D regimen consisting of
9% of participants paritaprevir, ritonavir and ombitasvir

Serious adverse events were distributed as follows: Participants received one of the above two regimens
for seven consecutive days.
• Holkira Pak + ribavirin for 12 weeks –
7% of participants Twenty-four participants with the following
degrees of kidney dysfunction were recruited:
• Holkira Pak + ribavirin for 24 weeks –
4% of participants • normal kidney function – 6 people
• mild kidney dysfunction – 6 people
Unfortunately, we do not yet have the details about • moderate kidney dysfunction – 6 people
severe and serious adverse effects. • severe kidney dysfunction – 6 people

The proportions of participants that required a Participants were in their sixties, and there were 21
reduction in the dose of ribavirin were as follows: men and 3 women.

• Holkira Pak + ribavirin for 12 weeks – Technicians performed extensive laboratory
7% of participants analyses of blood and urine samples during
the study.
• Holkira Pak + ribavirin for 24 weeks –
7% of participants Results

REFERENCES: In general, levels of the direct-acting antivirals
(DAAs) were between 20% and 50% higher in
1. Everson GT, Dusheiko G, Coakley E, et al. Integrated efficacy blood samples from participants with kidney
analysis of four phase 3 studies in HCV genotype 1a-infected dysfunction compared to participants with
patients treated with ABT-450/r/ombitasvir and dasabuvir normal kidney function. Also, levels of ritonavir
with or without ribavirin. Program and abstracts of The Liver in the blood of people with kidney dysfunction
Meeting, 7-11 November 2014, Boston, MA. Abstract 83. were between 42% and 114% higher. Despite this,

Page 12 TreatmentUpdate 207 — Vol. 27 No. 2 The average profile of participants recruited so far
is as follows:
according to the research team, these differences
were not “clinically relevant.” • 80% men, 20% women
• age – 60 years
No new or unexpected safety issues emerged and • time since transplant – at least three years
no side effects were judged to be serious. • HCV subtypes – 85% had genotype 1a and the

One participant reported a moderate degree remainder had genotype 1b
of nausea, muscle pain and vomiting. Another • HCV viral load – 4 million IU/ml
developed severe nausea and/or vomiting. And a • most participants had a mild-to-moderate
third participant developed mild diarrhea.
degree of liver injury
AbbVie plans to pursue studies of its drugs in • liver enzyme levels in the blood were
people with chronic HCV infection who also have
kidney dysfunction. generally elevated

REFERENCE: Results
A total of 33 out of 34 (97%) participants achieved
Khatri A, Dutta S, Marbury TC, et al. The pharmacokinetics an SVR12 and the same proportion achieved an
and safety of the direct acting antiviral regimen of ABT-450/r, SVR24.
ombitasvir with/without dasabuvir in subjects with mild,
moderate and severe renal impairment compared to subjects In one participant HCV viral load was suppressed
with normal renal function. Program and abstracts of The during therapy but rose three days after the cessation
Liver Meeting, 7-11 November 2014, Boston, MA. Abstract 238. of treatment. Analyses of this participant’s blood
found that during the study there was HCV that
I. Holkira Pak – effectiveness in was resistant to several of the drugs in Holkira Pak.
people with liver transplantation
Complications and side effects
In cases of severe liver injury due to hepatitis C Common side effects included the following:
virus (HCV) infection, doctors may refer patients
to a transplant centre. However, in cases where • fatigue – 50%
patients are transplanted with a healthy liver, HCV • headache – 44%
generally recurs after this procedure. Furthermore, • anemia – 29%
the transplanted liver may become injured because • diarrhea – 27%
of the recurrence of HCV. • difficulty falling asleep – 27%
• nausea – 24%
In an ongoing phase II clinical trial called Coral-1,
researchers are assessing the safety and effectiveness Complications and side effects were serious in only
of Holkira Pak + ribavirin in participants who two participants, as follows:
have received a liver transplant and who also have
HCV infection. So far 34 participants have been • One participant had low blood pressure and
recruited and have taken Holkira Pak + ribavirin. rapid heart beats associated with the use of
Participants are supposed to take these drugs for 24 the drug tamsulosin (Flomax, used for the
weeks. After this period, they will be monitored for treatment of enlarged prostate glands).
an additional 48 weeks.
• Another participant developed pain due to the
AbbVie recommends the following doses of build-up of fluid in the legs. This participant
transplant medicines be used in people who are had diabetes and had also encountered the
taking Holkira Pak: pain and fluid issues prior to starting Holkira
Pak.
• tacrolimus (Prograf) – 0.5 mg once weekly or
0.2 mg every other day In general, abnormal lab test results were
uncommon.
• cyclosporine (Neoral, Sandimmune) – 1/5 of
the daily dose that was used prior to initiating
therapy with Holkira Pak

Two participants developed very elevated levels TreatmentUpdate 207 — Vol. 27 No. 2 Page 13
of the waste product bilirubin in their blood.
However, this problem occurred once and then II  HIV AND TRANSPLANTATION
resolved without any intervention.
A. HIV and liver transplants in
Anemia British Columbia

Ribavirin can cause temporary anemia. Most Thanks to the widespread availability of
participants (55%) had mild or moderate degrees antiretroviral therapy (commonly referred to as
of anemia. Only one person developed anemia that ART or HAART) in Canada and other high-income
was considered serious by the study team. countries, researchers increasingly expect that some
young adults who are infected with HIV today and
Five participants with anemia received the bone who are diagnosed and begin treatment shortly
marrow stimulant EPO (erythropoietin). This drug thereafter will likely live into their eighties.
stimulates the bone marrow to produce more red
blood cells. Some people with HIV infection may experience
liver injury because of co-infection with hepatitis
No participants died. B and/or C viruses. In some cases of severe liver
injury, a liver transplant may become necessary.
No participants developed any immunological
problems with their transplanted liver while Doctors in Vancouver, British Columbia, have
taking Holkira Pak + ribavirin. Concentrations of had experience performing a limited series of
transplant medicines were not very different before liver transplants in HIV-positive people. So far, all
and during exposure to Holkira Pak. four patients who received liver transplants have
recovered from surgery and are doing well.
The high rate of recovery from HCV infection
and the lack of immunological complications are Many steps
remarkable, as historically this population has been
difficult to treat. Organ transplantation involves complex processes
and procedures, ranging from screening and
For the future interaction with a multidisciplinary team
(including a psychologist and social worker to
AbbVie is extending the study to enroll people assess a patient’s suitability for transplantation) to
who have greater severity of liver injury. In monitoring and counselling through surgery and
these future participants, researchers plan to care. There are infections after surgery that need
assess the effectiveness of Holkira Pak with and treatment and also the long-term use of transplant
without ribavirin. medicines that require complex monitoring and
dose adjustment. All of these many steps require
REFERENCE: frequent medical care.

Mantry P, Kwo PY, Coakley E, et al. High sustained A change in transplantation assessment
virologic response rates in liver transplant recipients with
recurrent HCV genotype 1 infection receiving ABT-450/r/ Until relatively recently, despite a clear medical
ombitasvir+dasabuvir plus ribavirin. Program and abstracts need for organ transplantation, such procedures
of The Liver Meeting, 7-11 November 2014, Boston, MA. were rarely carried out for HIV-positive people
Abstract 198. because of a number of concerns, including the
short life span of patients and fear of the transplant
team becoming infected with HIV either during
surgery or via needle-stick injury. However, thanks
to the educational and advocacy efforts of patients,
infectious disease specialists and policy planners,
HIV-positive people can now be considered
for organ transplantation in B.C., Ontario and

Page 14 TreatmentUpdate 207 — Vol. 27 No. 2 Common co-existing health conditions among
referred patients included the following:
elsewhere. Furthermore, concerns about the safety
of the transplant team in B.C. were resolved after • anxiety and/or depression
the first surgery for a co-infected person when • inherited bleeding disorders
the transplantation team deployed universal
precautions against HIV infection and no one Common causes of liver disease included infection
became inadvertently infected. with hepatitis-causing viruses.

The experience in Vancouver Of the 28 referrals, 23 returned for assessments at the
Transplant Program. Of these, five were considered
Doctors in Vancouver—including infectious suitable for transplantation. These five patients had
disease specialists and transplant surgeons— the following pre-transplantation complications
reviewed the medical charts of 28 HIV-positive and/or co-infections:
people whose doctors referred them to the B.C.
transplant program for evaluation for a possible • severe liver injury caused by the immune
liver transplant. system attacking the liver (autoimmune
hepatitis)
After referral by their doctor for screening for
an organ transplant, the transplant team’s social • a liver that had become very fatty and injured
worker and psychologist interview and counsel from excess deposits of fat
candidate patients. Additional staff from the
transplant team, including nurses and surgeons, • hepatitis B virus and delta infections
also meet and get to know the patient. • hepatitis C virus

After a candidate patient has been favourably One patient died while on the transplant waiting
assessed for a transplant, he or she is placed on the list (this patient was from another province).
waiting list. HIV-positive people (like HIV-negative
people) have to be successfully assessed and meet The vast majority of the 23 assessed patients were
the following general criteria for transplantation: not placed on the waiting list because the transplant
team deemed their liver disease as “stable.”
• no active infections (such as those that can
cause life-threatening infections) Focus on the four patients

• no cancer Patient 1 received a liver transplant at 59 years
• no active substance use old because of autoimmune hepatitis. According
• HIV-positive people should be on ART and to the doctors, he has been medically stable for
more than six years after his transplant. His HIV
under the care of an HIV specialist is well controlled. His initial immunosuppression
• HIV viral load should be under the level of (affected by transplantation drugs) consisted of the
following medicines:
detection (commonly called “undetectable”)
• HIV-positive people should have at least 150 • tacrolimus (Prograf)
• mycophenolate mofetil (CellCept)
CD4+ cells/mm3 • gradually increased doses of corticosteroids

The patients He developed kidney injury while taking
tacrolimus but has since recovered and now uses
Overall, the transplant program received referrals CellCept. His transplanted liver is healthy.
for 28 HIV-positive patients. Their average age
was 47 years; 74% percent were male and 25%
were women.

Most patients referred to this program were from
B.C., although doctors stated that “some were from
other Canadian provinces and one was from the
U.S.” All patients had chronic liver disease.

Patient 2 received a liver transplant at age 55 because TreatmentUpdate 207 — Vol. 27 No. 2 Page 15
of a fatty liver. Three years after transplantation,
his HIV is well controlled with the following • psychologist
three drugs: • social worker

• a fixed-dose formulation of abacavir + 3TC The study authors made the following statement:
(Kivexa)
“Patients were selected for transplantation based
• raltegravir (Isentress) on [the presence of severely worsening liver
disease]. There is absolutely no bias against the
He was given the same three transplant drugs as HIV-infected individual; in fact, we have been
Patient 1. There have been no interactions between their advocates.”
his transplant medicines and HIV treatment. His
new liver is healthy. The B.C. doctors added that “…our three long-term
transplant patients are the longest surviving HIV-
Patient 3 received a liver transplant at age 49 because positive transplant recipients in Canada and were
of HCV co-infection. He also received the same the second, third and fourth HIV-infected patients
trio of transplant medicines as the other patients. to receive liver transplants in this country.”
However, three months after transplantation, HCV
infection recurred. As a result, doctors performed The doctors found that the care and treatment
additional blood tests and he underwent a of co-infected patients was challenging.
liver biopsy. However, they note that there are clearly some
patients who experience good long-term health
Two years after transplantation, the levels of the after transplantation.
waste product bilirubin in his blood were elevated
but his levels of liver enzymes in the blood Building on success
(suggestive of liver inflammation) had decreased.
The B.C. doctors are hopeful that their positive and
Two years and three months after his liver transplant, successful experience will encourage doctors in
the patient suddenly developed fluid build-up in other parts of Canada so that organ transplantation
his abdomen, suggestive of ongoing liver injury for HIV-positive people will become more common.
and inflammation. Doctors are planning to treat
him with an interferon-free regimen of HCV drugs REFERENCE:
in the future.
Tan-Tam C, Liao P, Montaner JS, et al. HIV and liver
Patient 4 was co-infected with hepatitis B and transplantation: The British Columbia experience, 2004 to
hepatitis delta viruses. In addition, he developed 2013. The Canadian Journal of Infectious Diseases & Medical
liver cancer. Immediately after transplantation Microbiology. 2014 May;25(3):159-62.
he developed several complications, including
bleeding and kidney injury. As a result he required
prolonged hospitalization and rehabilitation.
However, his overall health is now stable and
tests have not detected hepatitis viruses in his
blood samples.

Factors for success

The B.C. doctors said that the main reasons for
their patients’ generally successful course and
survival after transplant were the presence of the
following members on the transplant team:

• transplant surgeons
• specialists in transplant medicine
• specialists in HIV medicine

Page 16 TreatmentUpdate 207 — Vol. 27 No. 2

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