TreatmentUpdate 207 - CATIE · TreatmentUpdate 207 — Vol. 27 No. 2 Page 3 Results Among...

I HEPATITIS C VIRUS

A. About some terms – SVR12 vs. SVR24

After a person has successfully completed treatment for hepatitis C virus (HCV), there is a period when HCV viral load in the blood is undetectable. If this period of undetectability lasts for 12 consecutive weeks after the cessation of treatment, it is called a sustained virological response (written as SVR12). This period usually then leads to a further 12 consecutive weeks of undetectable HCV, for a total of 24 weeks of undetectability since treatment cessation (written as SVR24). Historically, a person is considered cured when they have achieved SVR24.

In clinical trialsFor much of the past decade, SVR24 was considered the main result (or endpoint) of clinical trials that sought to cure participants of HCV, particularly when treatment consisted of just peginterferon + ribavirin. However, in recent clinical trials with emerging and powerful combinations of all-oral anti-HCV drugs, regulatory authorities have told drug companies that SVR12 is sufficient to determine whether these treatments are working and whether to launch phase II or III trials with the drugs in question. That is because in the vast majority of cases in which the new and powerful all-oral regimens are used, SVR12 leads to SVR24. This helps companies move faster with the development of anti-HCV therapy. Participants are still monitored to see if they do indeed achieve SVR24 but the decision as to whether a corporation continues to develop a drug can be made faster.

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TreatmentUpdate 207Available online at

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Contents

I HEPATITIS C VIRUSA. About some terms – SVR12 vs. SVR24 1

B. SVR linked to longer survival and other benefits 2

C. Issues with emerging therapies for HCV 3

D. Simeprevir + sofosbuvir – experience in the clinic 5

E. Holkira Pak approved in Canada for genotype 1 8

F. Holkira Pak – results in genotype 1a without severe liver injury 9

G. Holkira Pak – results in genotype 1a with severe liver injury 10

H. Holkira Pak – effectiveness in people with kidney dysfunction 11

I. Holkira Pak – effectiveness in people with liver transplantation 12

II HIV AND TRANSPLANTATIONA. HIV and liver transplants in

British Columbia 13

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Vol. 27, No. 2 February 2015

TreatmentUpdate 207 — Vol. 27 No. 2

In the clinicIn the everyday world of caring for patients with HCV infection, doctors and nurses continue to assess SVR12 and SVR24, just to be sure that a person is cured. However, many doctors who have had experience with testing the new all-oral regimens of anti-HCV drugs in clinical trials generally consider their patients cured if they have achieved SVR12.

To find out more about this issue of SVR12 vs. SVR24, see “The changing role of SVR12 in clinical trials of HCV drugs” in TreatmentUpdate 198.

B. SVR linked to longer survival and other benefits

After a person is exposed to hepatitis C virus (HCV), the virus enters the blood and makes its way to the liver, where it infects cells of this vital organ. Liver cells injured as a result of HCV infection release chemical signals that alert the immune system about the invading virus. The immune system is then mobilized and tries to contain HCV but this germ becomes entrenched in the liver, leading to a state of chronic infection.

Undaunted by this setback, the immune system keeps trying to rid the liver of HCV-infected cells. These attempts by the immune system against HCV cause inflammation. The struggle between the immune system and HCV lasts for years. Over time, healthy liver cells are replaced with useless scar tissue in a process called fibrosis.

Eventually, as fibrosis spreads throughout the liver, this organ becomes increasingly dysfunctional and complications arise, including the following:

• internal bleeding• enlarged abdomen (and sometimes legs) due

to the build-up of fluid• kidney dysfunction• bacterial infections• fatigue• problems with thinking clearly and

remembering

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

Thus, screening for HCV is important. People who have this virus need swift referral to assessments of liver health and discussions with doctors and nurses about treatment options.

A note about termsAs the study discussed later in this report was done in the time before the arrival of potent all-oral therapy for HCV, SVR means 24 weeks after the cessation of therapy, written as SVR24. The point that the research teams are trying to make here is that the goal of SVR is important and so we do not write it as we have done elsewhere in this issue of TreatmentUpdate (such as SVR12 or SVR24).

Exploring clinical trialsLeading specialists who study the liver and gastrointestinal tract have been conducting research to explore the many benefits of HCV treatment and cure (SVR24). They collected health-related information from participants with and without severe HCV-related liver injury. All participants had HCV mono-infection (that is, no other co-infections) and their degree of fibrosis was confirmed with a liver biopsy.

The bulk of data used in this analysis was collected from participants who initiated interferon-based therapy between 1990 and 2003. However, additional data focusing on survival were collected up to October 2011. Participants in this analysis came from five major clinics in the following countries:

• the Netherlands• Canada• Germany• Switzerland

A total of 535 participants were monitored for between six and 11 years.

Their average profile at the start of the study was as follows:

• 70% were men and 30% were women• age – 48 years• 192 (36%) achieved an SVR24 (herein after

referred to as an SVR)


ResultsAmong participants who achieved an SVR, a small number (13) died during the study period. Over an average of 10 years of monitoring, the researchers found that 91% of participants who had achieved an SVR were still alive.

In contrast, about 100 participants who did not achieve an SVR died. Over an average of 10 years of monitoring, 74% of people who did not achieve an SVR were still alive.

ComparisonsThe 10-year survival figure of 91% of participants with an SVR was not significantly different from the survival rates of HCV-negative Dutch people of the same age and gender over the same period of time. Thus, even for people with severe liver injury, getting an SVR can lead to broadly similar rates of survival as HCV-negative people.

As mentioned earlier, among people who did not achieve an SVR after treatment, 100 deaths occurred, resulting in a 74% survival rate. This rate of survival is significantly worse than that of the average HCV-negative Dutch person of the same age and gender during the same calendar period.

Other benefitsThe researchers stated that those people who developed an SVR were likely to experience the following:

• decreased inflammation in the liver• some degree of healing with healthy liver

tissue being formed• reduced risk for liver dysfunction• reduced risk for liver cancer

As well, the researchers stated that as a result of successful treatment (SVR) patients would also experience the following:

• reduced risk for diabetes• reduced risk for severe kidney injury• reduced risk for heart attack

The researchers also stated that although people with severe liver injury (cirrhosis) can obtain an SVR with treatment, they are still at risk for the subsequent development of liver cancer. However,

this risk is reduced compared to people whose HCV treatment did not result in an SVR.

Bear in mindThe present multinational study is based on looking back in time at medical records. Such a retrospective study could have unmeasured factors that could have inadvertently biased the interpretation of the data. However, the researchers focused on a few simple factors and survival, and their conclusions are reasonable and make sense.

Although data from HCV-negative people were only used from the Netherlands, survival estimates for this group are broadly similar across high-income countries, including Canada.

For the futureIn the coming years, as more powerful and interferon-free regimens become licensed and subsidized by regional authorities, a similar analysis needs to be done with such regimens. Such analyses should also review the long-term results among people co-infected with HIV and HCV.

REFERENCE:van der Meer AJ, Wedemeyer H, Feld JJ, et al. Life expectancy in patients with chronic HCV infection and cirrhosis compared with a general population. JAMA. 2014 Nov 12;312(18):1927-8.

C. Issues with emerging therapies for HCV

For much of the past decade in Canada and other high-income countries, the mainstay of hepatitis C treatment has been a combination of the following two drugs:

• a long-acting form of interferon-alpha called peginterferon

• ribavirin

Peginterferon works by activating genes in a cell that then produce many antiviral substances. In general, it is difficult for hepatitis C virus (HCV) to counteract the action of these genes. This is why peginterferon has, until very recently, been the backbone of HCV treatment.


Ribavirin is a nucleoside analogue and has activity against a broad range of viruses, at least in laboratory experiments with cells. Exactly how ribavirin works against HCV-infected cells is not clear.

The debut of DAAsAs mentioned earlier, the historical mainstays of HCV treatment were drugs that affected HCV indirectly. However, in 2011 the first licensed direct-acting antivirals (DAAs) for HCV became available:

• boceprevir• telaprevir

These two drugs belong to a class called protease inhibitors. Boceprevir and telaprevir were taken orally but needed to be used with interferon and ribavirin. Furthermore, regimens containing either of these DAAs were largely only effective against one strain of HCV—genotype 1. Both regimens were associated with side effects, had to be taken for prolonged periods and their effectiveness was not very high—if patients completed their course of therapy, recovery rates ranged from 60% to 75%.

Fortunately, today more DAAs are being approved and can be used without interferon. What’s more, therapy with newer DAAs is generally shorter (12 to 24 weeks) compared to regimens several years ago.

In this issue of TreatmentUpdate, we largely focus on several combinations of agents including these:

• sofosbuvir (Sovaldi) with ribavirin and/or peginterferon

• simeprevir (Galexos, Olysio) with sofosbuvir• Holkira Pak (nick-named the “3D” regimen)

made by AbbVie.

In the next issue of TreatmentUpdate (issue 208) we will have detailed information about another exciting HCV therapy called Harvoni (sofosbuvir + ledipasvir) that is made by Gilead Sciences.

Access delayedIn Canada and other high-income countries, most people cannot afford to pay for the high cost of treating and managing catastrophic illnesses such as HIV, HCV and cancer. In response to this situation, regional health authorities have

established formularies—lists of drugs that are subsidized by the state.

Until a drug is listed on the formulary, most patients cannot get access to it, though some companies may have very limited compassionate access programs for people with HCV. Some patients may also be able to access these drugs because they have private health insurance.

The formularies negotiate with pharmaceutical companies about the cost of their drugs. This back and forth between the formularies and companies takes time. The cost of the new DAAs will be high and it is not clear when they will be on every formulary.

The high cost of the new regimens may mean that access to the new DAAs will be delayed and rationed. Formularies can put restrictions on who can get their listed medicines. For instance, it is possible that some formularies may insist that there be conditions on access—this may include issues such as the stage of liver injury, such that only the healthiest patients (who generally have the highest rates of recovery) or the sickest (whose need for medicines is greatest) get treatment. Alternatively, if a good bargain is struck by formularies, there may be few or no restrictions on the use of new HCV therapies.

Clinical trials and realityThe new all-oral DAA regimens being developed by AbbVie and Gilead generally have very high success rates—ranging from 95% to 100%—depending on the sub-populations being tested, at least in clinical trials. However, in the real world outside of a clinical trial, doctors have come to expect that medicines may not perform as well for many conditions. Perhaps this happens because patient populations in clinical trials are usually highly selected and do not always reflect the diversity of illness that occurs in the real world. In general, clinical trials usually do not enroll the sickest and hardest-to-treat patients.

RetreatmentThe cost of initial treatment with DAAs is relatively expensive. What happens if a new regimen fails to cure the patient? Arguably, given the potency of the new DAAs such cases should not be common,


particularly among patients who have never been previously treated. However, in cases of treatment failure will the state agree to pay for another course of a different but equally expensive DAA-based therapy? Will insurance companies also agree to pay for retreatment if an initial regimen of DAAs fails? Cases of reinfection may occur if successfully treated people are again exposed to HCV—how will the state deal with this issue given the high cost of therapy? These are just some of the issues that could become controversial in an era of enforced austerity.

Cost and accessThese issues of rationing are sufficient reason why people with HCV and organizations that serve them need to monitor what formularies are doing in order to understand how these organizations arrive at decisions that can impact the health and survival of the population.

For the futureAlthough new, powerful regimens are being licensed by regulatory authorities, it is not clear which medicines will become available on formularies early in 2015 and much work remains to be done.

REFERENCES:1. Pollack A. AbbVie deal heralds changed landscape for hepatitis drugs. 22 December 2014. New York Times. Available at: http://tinyurl.com/ppesz7h [registration or subscription may be required].

2. Jerzyk E. Rhode Island Medicaid limits supply of hepatitis C drug due to cost. The Brown Daily Herald. 4 December 2014. Available at: http://tinyurl.com/o7xxtse

3. Langreth R. More medicine goes off limits in drug-price showdown. Bloomberg News. 25 November 2014. Available at: http://www.bloomberg.com/news/articles/2014-11-25/more-medicine-goes-off-limits-in-drug-price-showdown

4. John M and Hirschler B. France pegs Gilead hepatitis C drug at “lowest price in Europe.” Reuters. 20 November 2014. Available at: http://tinyurl.com/oj4n4gw

5. Pierson B. Gilead sued over “exorbitant” hepatitis C drug prices. Reuters. 10 December 2014. Available at: http://tinyurl.com/l43koty

D. Simeprevir + sofosbuvir – experience in the clinic

Leading hepatitis C virus (HCV) researchers in Canada, Germany, New Zealand and the U.S. have formed a research group called HCV Target. The purpose of Target is to conduct observational studies of emerging therapies for HCV. Data are captured from medical records from HCV clinics in the participating countries and placed in a shared database.

Target has enrolled 2,330 participants, most of whom (96%) have decided to collaborate with their doctor to initiate HCV therapy. Among participants who have agreed to start therapy, 93% have already begun to take medicines.

Participants were distributed among the following regimens:

• sofosbuvir + peginterferon + ribavirin – 338 people

• sofosbuvir + ribavirin – 667 people• sofosbuvir + simeprevir – 784 people• sofosbuvir + simeprevir + ribavirin –

228 people

The average profile of participants before they started taking these medications was as follows:

• 64% men, 36% women• age – 58 years; 19% were older than

65 years old• never previously treated – 48%• among those who were previously treated,

18% had tried a regimen based on a protease inhibitor such as boceprevir or telaprevir

• presence of cirrhosis – 48%• presence of liver cancer – 10%• had a liver transplant – 11%• co-infected with HIV – 2%

Most participants had one of the following strains, or genotypes, of HCV: genotype 1, 2 or 3.

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.


Sofosbuvir + peginterferon + ribavirin in genotype 1Participants generally responded well to this therapy. Four weeks after the course of treatment ended the results were as follows:

• 85% of participants continue to have undetectable HCV in their blood (this is called SVR4)

• 13% who were initially able to suppress HCV had the virus again become detectable

Among the remaining patients, the regimen was never able to suppress HCV and one participant stopped attending the clinic.

Another way to look at the response to therapy is to assess results by the degree of pre-existing liver injury. Four weeks after treatment cessation, undetectable HCV viral loads (SVR4) were distributed as follows:

• no severe liver injury (cirrhosis) – 90% had an undetectable HCV viral load

• cirrhosis present – 70% had an undetectable HCV viral load

Sofosbuvir + ribavirin in genotype 2Four weeks after therapy ended the results were as follows:

• 90% continue to have undetectable HCV viral load (SVR4)

• 8% were initially able to suppress HCV but their viral load is now detectable

In most of the remaining participants the regimen was not sufficiently powerful. Two additional participants stopped attending their clinic.

The results of viral load based on cirrhosis status were as follows:

• no cirrhosis – 91% had a suppressed viral load• cirrhosis – 88% had a suppressed viral load

Sofosbuvir + simeprevir with or without ribavirin in genotype 1Four weeks after the cessation of therapy the results were as follows:

• 89% continue to have undetectable HCV viral load (SVR4)

• 9% initially suppressed HCV but it later became detectable

The distribution of suppressed viral loads by cirrhosis status was as follows:

• no cirrhosis – 92% had an undetectable viral load

• cirrhosis – 87% had an undetectable viral load

Among participants who had cirrhosis and symptoms of severe liver injury, 75% had undetectable viral load four weeks after the cessation of therapy (SVR4).

The distribution of undetectable viral loads by HCV genotype was as follows:

• genotype 1a – 86%• genotype 1b – 95%

Simeprevir + sofosbuvir with or without ribavirin for genotype 1 and prior treatment failure with a protease inhibitorAfter treatment cessation the results were as follows:

• 81% had a suppressed viral load (SVR4)• 19% of participants relapsed and viral load

was detectable

Among participants with and without cirrhosis the results were as follows:

• no cirrhosis – 85% achieved SVR4• cirrhosis – 79% achieved SVR4

Analyses suggest that the addition of ribavirin to a regimen of simeprevir + sofosbuvir was of marginal benefit regardless of the following characteristics 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 preliminary until SVR12 results become available.

Watch for thisLater in 2015, results from a large study called Optimist will become available. For this study, researchers tested the combination of simeprevir + sofosbuvir.

Relationship between SVR4 and SVR12 in TargetA limited proportion of participants in Target have sufficient data collected so that researchers can report their SVR12 results. Not surprisingly, what has become clear to the researchers is that anyone who did not have an SRV4 also did not have an SVR12.

Of greater interest is the proportion of participants who had an SVR4 who maintained a suppressed viral load to the 12th week after therapy had ceased (SVR12). We caution readers that so far only very limited SVR12 data have been made available from Target for the following three regimens:

Simeprevir + sofosbuvir with or without ribavirin in genotype 1• 97% (143) of participants who had an SVR4

also achieved an SVR12

Sofosbuvir + peginterferon + ribavirin in genotype 1• 94% (51) of participants who had an SVR4 also

achieved an SVR12

Sofosbuvir + ribavirin in genotype 2• 98% (57) of participants who had an SVR4 also

achieved an SVR12

These analyses suggest that SVR4 is an important preliminary result and appears to be highly predictive of who will achieve an SVR12. As a result, there is likely to be more focus on SVR4 both in clinical trials and in the clinic in the future.

Side effects and complicationsAdverse effect is the term used for describing a symptom and/or abnormal lab result and complication that occurs during a clinical trial. This term encompasses at least the following scenarios:

• medication-related side effects• complications that may be due to the disease

process being studied (for example, an effect of chronic HCV infection) that may have nothing to do with the study drugs

• accidents (these may also be unrelated to the study drugs)

In Target, participants who received peginterferon were more likely to report symptoms of a flu-like illness as well as depression, difficulty falling asleep, rash and fatigue. Such symptoms are common with exposure to peginterferon.

In general, the regimen with the fewest side effects was the combination of simeprevir + sofosbuvir.

Rates of the following side effects with each of the other regimens appear below.

Simeprevir + sofosbuvir• fatigue – 25%• nausea – 12%• difficulty falling asleep – 9%• itchy skin – 8%• irritability – 3%• depression – 2%• anemia – 1%

Simeprevir + sofosbuvir + ribavirin• fatigue – 38%• anemia – 30%• difficulty falling asleep – 18%• nausea – 17%• itchy skin – 14%• irritability – 8%• depression – 7%

Sofosbuvir + peginterferon + ribavirin• fatigue – 42%• anemia – 28%• nausea – 22%• difficulty falling asleep – 16%• irritability – 16%• depression – 10%• itchy skin – 9%


Sofosbuvir + ribavirin• fatigue – 38%• anemia – 21%• nausea – 17%• difficulty falling asleep – 14%• depression – 11%• itchy skin – 8%• irritability – 7%

Serious adverse events were distributed by regimen as follows:

• simeprevir + sofosbuvir – 5% of participants• simeprevir + sofosbuvir + ribavirin –

8% of participants• sofosbuvir + peginterferon + ribavirin –

3% of participants• sofosbuvir + ribavirin – 8% of participants

A total of 12 patients died; nine of the 12 deaths were among people with cirrhosis. Here are the causes of death distributed by regimen:

• simeprevir + sofosbuvir – one case each of stroke, kidney failure, pneumonia and shock; two cases of liver failure

• simeprevir + sofosbuvir + ribavirin – one case each of unknown cause and suicide

• sofosbuvir + peginterferon + ribavirin – one case of severe bacterial infection leading to blood poisoning

• sofosbuvir + ribavirin – one case of multi-organ failure; two cases of heart attacks

Key pointsAccording to the interim data from Target:

• All regimens are broadly effective.• There were low rates of treatment failure.• There were low rates of treatment

discontinuation.• There were fewer side effects from all-oral

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.

REFERENCE:Jensen DM, O’Leary JG, Pockros PJ, et al. Safety and efficacy of sofosbuvir-containing regimens for hepatitis C: Real-world experience in a diverse, longitudinal observational cohort. Program and abstracts of The Liver Meeting, 7-11 November 2014, Boston, Ma. Abstract 45.

E. Holkira Pak approved in Canada for genotype 1

Holkira Pak is the brand name for the suite of AbbVie drugs licensed in Canada and the U.S. for the treatment of hepatitis c virus (HCV) genotype 1. Holkira Pak consists of the following medicines:

• paritaprevir (formerly ABT-450) – 150 mg• ritonavir – 100 mg• ombitasvir (formerly ABT-267) – 25 mg• dasabuvir (formerly ABT-333) – 250 mg

Paritaprevir + ritonavir + ombitasvir are taken once daily. All three drugs are inside one pill. Two of these pills are taken in the morning.

Dasabuvir is taken in a separate pill, once in the morning and once in the evening.

All pills in Holkira Pak should be taken with food.

These medicines—paritaprevir + ombitasvir + dasabuvir—work against HCV-infected cells in three different ways.

Ritonavir, the other medicine inside Holkira Pak, does not work against HCV. The purpose of ritonavir is to boost the level of paritaprevir in the blood so that once-daily dosing is possible.

In some cases AbbVie also recommends the use of the broad-spectrum antiviral agent ribavirin. The combinations recommended by AbbVie are as follows:

• genotype 1a without cirrhosis – Holkira Pak + ribavirin for 12 weeks

• genotype 1b without cirrhosis – Holkira Pak for 12 weeks

• genotype 1a or 1b with cirrhosis – Holkira Pak + ribavirin for 12 weeks


• genotype 1a and 1b or genotype 1 with unknown subtype – Holkira Pak + ribavirin for 12 weeks

• genotype 1a with cirrhosis and previous poor response to interferon + ribavirin – Holkira Pak + ribavirin for 24 weeks

In the EU and U.S.The AbbVie drugs are also licensed in the U.S., where they are known as Viekira Pak. In the EU the AbbVie drugs have also been licensed and will be called Viekirax (paritaprevir + ritonavir + ombitasvir) and Exviera (dasabuvir).

Formulary accessAfter a drug is licensed in Canada, it can often take between six and 12 months before it is approved for placement on formularies (publicly subsidized lists of medicines). Canada’s provinces and territories as well as private and public health plans have formularies. AbbVie will be negotiating with Canada’s provinces and territories about listing Holkira Pak on their formularies.

In this issueIn TreatmentUpdate 207 we present some research findings on Holkira Pak from clinical trials that demonstrate its power and safety.

F. Holkira Pak – results in genotype 1a without severe liver injury

Nearly 3,000 people with hepatitis C virus (HCV) genotype 1 have received Holkira Pak in clinical trials. Among participants with the subtype of this strain called genotype 1b, rates of cure (SVR12) are relatively high, about 99%. Genotype 1b responds relatively well to the new and powerful anti-HCV drugs such as Holkira Pak and Harvoni. Past experience with boceprevir and telaprevir suggests that strains of genotype 1a are harder to treat. We now focus on clinical trial results from participants with genotype 1a who were treated with Holkira Pak with and without ribavirin. These results, particularly among participants who received ribavirin are very promising.

Focus on 1aIn four phase III trials (code-named Sapphire-1, Sapphire-2, Pearl-4 and Turquoise-2) researchers recruited 1,058 participants with genotype 1a who were distributed as follows:

• no prior exposure to anti-HCV therapy – 70% (744 people)

• a history of HCV therapy – 30% (314 people)

One-quarter of all genotype 1a participants had severe liver injury (cirrhosis).

Results—1a without cirrhosisOverall results after 12 weeks of therapy were as follows:

• Holkira Pak – 90% had SVR12• Holkira Pak + ribavirin – 96% had SVR12

Among participants with no prior exposure to treatment:

• Holkira Pak – 90% had SVR12• Holkira Pak + ribavirin – 96% had SVR12

Researchers divided participants with a history of treatment into the following three groups based on their prior response to peginterferon + ribavirin:

• relapse – initially suppressed HCV while on treatment but viral load became detectable once treatment ceased

• partial response – had a significant decline in viral load while on treatment but viral load never became undetectable

• null response – no significant decline in viral load occurred while on treatment

Here are the responses of these three groups to treatment with AbbVie’s direct-acting antivirals (DAAs):

• prior relapse – 94% had SVR12• prior partial response – 100% had SVR12• prior null response – 95% had SVR12


The risk of treatment failureResearchers found that the risk of treatment failure with Holkira Pak among genotype 1a participants was associated with the following factors:

• being obese• not using the broad-spectrum antiviral

drug ribavirin

Side effects and complicationsSevere or serious side effects or complications were uncommon and were distributed as follows:

• Holkira Pak alone – 2%• Holkira Pak + ribavirin – 5%

Side effects that were sufficiently bothersome, causing participants to prematurely leave the study, were distributed as follows:

• Holkira Pak alone – 2 people• Holkira Pak + ribavirin – 3 people

Ribavirin commonly causes temporary reductions in the number of red blood cells. In 7% of cases where ribavirin was used, doctors had to reduce the dose to minimize this problem.

REFERENCE:Everson GT, Dusheiko G, Coakley E, et al. Integrated efficacy analysis of four phase 3 studies in HCV genotype 1a-infected patients treated with ABT-450/r/ombitasvir and dasabuvir with or without ribavirin. Program and abstracts of The Liver Meeting, 7-11 November 2014, Boston, MA. Abstract 83.

G. Holkira Pak – results in genotype 1a with severe liver injury

AbbVie researchers analysed data from participants who took the following regimens:

• Holkira Pak + ribavirin for 12 weeks – 142 participants

• Holkira Pak + ribavirin for 24 weeks – 121 participants

ResultsOverall results were as follows:

• Holkira Pak + ribavirin for 12 weeks – 89% had SVR12

• Holkira Pak + ribavirin for 24 weeks – 95% had SVR12

Here are the results among sub-groups of participants:

No previous treatment• Holkira Pak + ribavirin for 12 weeks – 92%

had SVR12• Holkira Pak + ribavirin for 24 weeks – 95%

had SVR12

Researchers divided participants with a history of treatment into the following three groups based on their prior response:

• relapse – initially suppressed HCV while on treatment but viral load became detectable once treatment ceased

• partial response – had a significant decline in viral load while on treatment but viral load never became undetectable

• null response – no significant decline in viral load occurred while on treatment

Here are the responses of these three groups to treatment with AbbVie’s DAAs + ribavirin:

Relapse• Holkira Pak + ribavirin for 12 weeks – 93%


had SVR12

Partial response• Holkira Pak + ribavirin for 12 weeks – 100%


had SVR12

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


had SVR12


Complications and side effectsIn general, during clinical trials Holkira Pak was well tolerated and side effects were usually mild.

Common side effects of Holkira Pak without ribavirin included the following:

• fatigue• headache

Among participants who took a combination of Holkira Pak and ribavirin, common side effects included the following:

• fatigue• headache• nausea• itchy skin• difficulty falling asleep

Severe adverse events were distributed as follows:

• Holkira Pak + ribavirin for 12 weeks – 9% of participants


Serious adverse events were distributed as follows:



Unfortunately, we do not yet have the details about severe and serious adverse effects.

The proportions of participants that required a reduction in the dose of ribavirin were as follows:



REFERENCES:1. Everson GT, Dusheiko G, Coakley E, et al. Integrated efficacy analysis of four phase 3 studies in HCV genotype 1a-infected patients treated with ABT-450/r/ombitasvir and dasabuvir with or without ribavirin. Program and abstracts of The Liver Meeting, 7-11 November 2014, Boston, MA. Abstract 83.

2. AbbVie. Holkira PAK: ombitasvir/paritaprevir/ritonavir film-coated tablets (12.5/75/50 mg) and dasabuvir (as dasabuvir sodium monohydrate) film-coated tablets (250 mg). Product Monograph. 22 December, 2014.

H. Holkira Pak – effectiveness in people with kidney dysfunction

People with chronic hepatitis C virus (HCV) infection can also develop kidney injury and dysfunction. Historically, people with HCV who also have kidney dysfunction have not responded well to combination therapy with peginterferon and ribavirin.

Prior to testing Holkira Pak in HCV-positive people with kidney dysfunction, AbbVie conducted a study to assess the safety of the following two regimens in HCV-negative people:

• Holkira Pak (sometimes called the 3D regimen)

• a so-called 2D regimen consisting of paritaprevir, ritonavir and ombitasvir

Participants received one of the above two regimens for seven consecutive days.

Twenty-four participants with the following degrees of kidney dysfunction were recruited:

• normal kidney function – 6 people• mild kidney dysfunction – 6 people• moderate kidney dysfunction – 6 people• severe kidney dysfunction – 6 people

Participants were in their sixties, and there were 21 men and 3 women.

Technicians performed extensive laboratory analyses of blood and urine samples during the study.

ResultsIn general, levels of the direct-acting antivirals (DAAs) were between 20% and 50% higher in blood samples from participants with kidney dysfunction compared to participants with normal kidney function. Also, levels of ritonavir in the blood of people with kidney dysfunction were between 42% and 114% higher. Despite this,


according to the research team, these differences were not “clinically relevant.”

No new or unexpected safety issues emerged and no side effects were judged to be serious.

One participant reported a moderate degree of nausea, muscle pain and vomiting. Another developed severe nausea and/or vomiting. And a third participant developed mild diarrhea.

AbbVie plans to pursue studies of its drugs in people with chronic HCV infection who also have kidney dysfunction.

REFERENCE:Khatri A, Dutta S, Marbury TC, et al. The pharmacokinetics and safety of the direct acting antiviral regimen of ABT-450/r, ombitasvir with/without dasabuvir in subjects with mild, moderate and severe renal impairment compared to subjects with normal renal function. Program and abstracts of The Liver Meeting, 7-11 November 2014, Boston, MA. Abstract 238.

I. Holkira Pak – effectiveness in people with liver transplantation

In cases of severe liver injury due to hepatitis C virus (HCV) infection, doctors may refer patients to a transplant centre. However, in cases where patients are transplanted with a healthy liver, HCV generally recurs after this procedure. Furthermore, the transplanted liver may become injured because of the recurrence of HCV.

In an ongoing phase II clinical trial called Coral-1, researchers are assessing the safety and effectiveness of Holkira Pak + ribavirin in participants who have received a liver transplant and who also have HCV infection. So far 34 participants have been recruited and have taken Holkira Pak + ribavirin. Participants are supposed to take these drugs for 24 weeks. After this period, they will be monitored for an additional 48 weeks.

AbbVie recommends the following doses of transplant medicines be used in people who are taking Holkira Pak:

• tacrolimus (Prograf) – 0.5 mg once weekly or 0.2 mg every other day

• cyclosporine (Neoral, Sandimmune) – 1/5 of the daily dose that was used prior to initiating therapy with Holkira Pak

The average profile of participants recruited so far is as follows:

• 80% men, 20% women• age – 60 years• time since transplant – at least three years• HCV subtypes – 85% had genotype 1a and the

remainder had genotype 1b• HCV viral load – 4 million IU/ml• most participants had a mild-to-moderate

degree of liver injury• liver enzyme levels in the blood were

generally elevated

ResultsA total of 33 out of 34 (97%) participants achieved an SVR12 and the same proportion achieved an SVR24.

In one participant HCV viral load was suppressed during therapy but rose three days after the cessation of treatment. Analyses of this participant’s blood found that during the study there was HCV that was resistant to several of the drugs in Holkira Pak.

Complications and side effectsCommon side effects included the following:

• fatigue – 50%• headache – 44%• anemia – 29%• diarrhea – 27%• difficulty falling asleep – 27%• nausea – 24%

Complications and side effects were serious in only two participants, as follows:

• One participant had low blood pressure and rapid heart beats associated with the use of the drug tamsulosin (Flomax, used for the treatment of enlarged prostate glands).

• Another participant developed pain due to the build-up of fluid in the legs. This participant had diabetes and had also encountered the pain and fluid issues prior to starting Holkira Pak.

In general, abnormal lab test results were uncommon.


Two participants developed very elevated levels of the waste product bilirubin in their blood. However, this problem occurred once and then resolved without any intervention.

AnemiaRibavirin can cause temporary anemia. Most participants (55%) had mild or moderate degrees of anemia. Only one person developed anemia that was considered serious by the study team.

Five participants with anemia received the bone marrow stimulant EPO (erythropoietin). This drug stimulates the bone marrow to produce more red blood cells.

No participants died.

No participants developed any immunological problems with their transplanted liver while taking Holkira Pak + ribavirin. Concentrations of transplant medicines were not very different before and during exposure to Holkira Pak.

The high rate of recovery from HCV infection and the lack of immunological complications are remarkable, as historically this population has been difficult to treat.

For the futureAbbVie is extending the study to enroll people who have greater severity of liver injury. In these future participants, researchers plan to assess the effectiveness of Holkira Pak with and without ribavirin.

REFERENCE:Mantry P, Kwo PY, Coakley E, et al. High sustained virologic response rates in liver transplant recipients with recurrent HCV genotype 1 infection receiving ABT-450/r/ombitasvir+dasabuvir plus ribavirin. Program and abstracts of The Liver Meeting, 7-11 November 2014, Boston, MA. Abstract 198.

II HIV AND TRANSPLANTATION

A. HIV and liver transplants in British Columbia

Thanks to the widespread availability of antiretroviral therapy (commonly referred to as ART or HAART) in Canada and other high-income countries, researchers increasingly expect that some young adults who are infected with HIV today and who are diagnosed and begin treatment shortly thereafter will likely live into their eighties.

Some people with HIV infection may experience liver injury because of co-infection with hepatitis B and/or C viruses. In some cases of severe liver injury, a liver transplant may become necessary.

Doctors in Vancouver, British Columbia, have had experience performing a limited series of liver transplants in HIV-positive people. So far, all four patients who received liver transplants have recovered from surgery and are doing well.

Many stepsOrgan transplantation involves complex processes and procedures, ranging from screening and interaction with a multidisciplinary team (including a psychologist and social worker to assess a patient’s suitability for transplantation) to monitoring and counselling through surgery and care. There are infections after surgery that need treatment and also the long-term use of transplant medicines that require complex monitoring and dose adjustment. All of these many steps require frequent medical care.

A change in transplantation assessmentUntil relatively recently, despite a clear medical need for organ transplantation, such procedures were rarely carried out for HIV-positive people 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


elsewhere. Furthermore, concerns about the safety of the transplant team in B.C. were resolved after the first surgery for a co-infected person when the transplantation team deployed universal precautions against HIV infection and no one became inadvertently infected.

The experience in VancouverDoctors in Vancouver—including infectious disease specialists and transplant surgeons—reviewed the medical charts of 28 HIV-positive people whose doctors referred them to the B.C. transplant program for evaluation for a possible liver transplant.

After referral by their doctor for screening for an organ transplant, the transplant team’s social worker and psychologist interview and counsel candidate patients. Additional staff from the transplant team, including nurses and surgeons, also meet and get to know the patient.

After a candidate patient has been favourably assessed for a transplant, he or she is placed on the waiting list. HIV-positive people (like HIV-negative people) have to be successfully assessed and meet the following general criteria for transplantation:

• no active infections (such as those that can cause life-threatening infections)

• no cancer• no active substance use• HIV-positive people should be on ART and

under the care of an HIV specialist• HIV viral load should be under the level of

detection (commonly called “undetectable”)• HIV-positive people should have at least 150

CD4+ cells/mm3

The patientsOverall, the transplant program received referrals 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.

Common co-existing health conditions among referred patients included the following:

• anxiety and/or depression• inherited bleeding disorders

Common causes of liver disease included infection with hepatitis-causing viruses.

Of the 28 referrals, 23 returned for assessments at the Transplant Program. Of these, five were considered suitable for transplantation. These five patients had the following pre-transplantation complications and/or co-infections:

• severe liver injury caused by the immune system attacking the liver (autoimmune hepatitis)

• a liver that had become very fatty and injured from excess deposits of fat

• hepatitis B virus and delta infections• hepatitis C virus

One patient died while on the transplant waiting list (this patient was from another province).

The vast majority of the 23 assessed patients were not placed on the waiting list because the transplant team deemed their liver disease as “stable.”

Focus on the four patientsPatient 1 received a liver transplant at 59 years old because of autoimmune hepatitis. According to the doctors, he has been medically stable for more than six years after his transplant. His HIV is well controlled. His initial immunosuppression (affected by transplantation drugs) consisted of the following medicines:

• tacrolimus (Prograf)• mycophenolate mofetil (CellCept)• gradually increased doses of corticosteroids

He developed kidney injury while taking tacrolimus but has since recovered and now uses CellCept. His transplanted liver is healthy.


Patient 2 received a liver transplant at age 55 because of a fatty liver. Three years after transplantation, his HIV is well controlled with the following three drugs:

• a fixed-dose formulation of abacavir + 3TC (Kivexa)

• raltegravir (Isentress)

He was given the same three transplant drugs as Patient 1. There have been no interactions between his transplant medicines and HIV treatment. His new liver is healthy.

Patient 3 received a liver transplant at age 49 because of HCV co-infection. He also received the same trio of transplant medicines as the other patients. However, three months after transplantation, HCV infection recurred. As a result, doctors performed additional blood tests and he underwent a liver biopsy.

Two years after transplantation, the levels of the waste product bilirubin in his blood were elevated but his levels of liver enzymes in the blood (suggestive of liver inflammation) had decreased.

Two years and three months after his liver transplant, the patient suddenly developed fluid build-up in his abdomen, suggestive of ongoing liver injury and inflammation. Doctors are planning to treat him with an interferon-free regimen of HCV drugs in the future.

Patient 4 was co-infected with hepatitis B and hepatitis delta viruses. In addition, he developed liver cancer. Immediately after transplantation 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 successThe 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

• psychologist• social worker

The study authors made the following statement:

“Patients were selected for transplantation based on [the presence of severely worsening liver disease]. There is absolutely no bias against the HIV-infected individual; in fact, we have been their advocates.”

The B.C. doctors added that “…our three long-term transplant patients are the longest surviving HIV-positive transplant recipients in Canada and were the second, third and fourth HIV-infected patients to receive liver transplants in this country.”

The doctors found that the care and treatment of co-infected patients was challenging. However, they note that there are clearly some patients who experience good long-term health after transplantation.

Building on successThe B.C. doctors are hopeful that their positive and successful experience will encourage doctors in other parts of Canada so that organ transplantation for HIV-positive people will become more common.

REFERENCE:Tan-Tam C, Liao P, Montaner JS, et al. HIV and liver transplantation: The British Columbia experience, 2004 to 2013. The Canadian Journal of Infectious Diseases & Medical Microbiology. 2014 May;25(3):159-62.


DisclaimerDecisions about particular medical treatments should always be made in consultation with a qualified medical practitioner knowledgeable about HIV- and hepatitis C-related illness and the treatments in question.CATIE provides information resources to help people living with HIV and/or hepatitis C who wish to manage their own health care in partnership with their care providers. Information accessed through or published or provided by CATIE, however, is not to be considered medical advice. We do not recommend or advocate particular treatments and we urge users to consult as broad a range of sources as possible. We strongly urge users to consult with a qualified medical practitioner prior to undertaking any decision, use or action of a medical nature.CATIE endeavours to provide the most up-to-date and accurate information at the time of publication. However, information changes and users are encouraged to ensure they have the most current information. Users relying solely on this information do so entirely at their own risk. Neither CATIE nor any of its partners or funders, nor any of their employees, directors, officers or volunteers may be held liable for damages of any kind that may result from the use or misuse of any such information. Any opinions expressed herein or in any article or publication accessed or published or provided by CATIE may not reflect the policies or opinions of CATIE or any partners or funders.

Permission to ReproduceThis document is copyrighted. It may be reprinted and distributed in its entirety for non-commercial purposes without prior permission, but permission must be obtained to edit its content. The following credit must appear on any reprint: This information was provided by CATIE (Canadian AIDS Treatment Information Exchange). For more information, contact CATIE at 1.800.263.1638 or [email protected]

CreditsWriter Sean HoseinEditor RonniLyn Pustil

© CATIE, Vol. 27, No. 2 February 2015

ISSN 1181-7186 (print)ISSN 1927-8918 (online)CATIE Ordering Centre Catalogue Number ATI-60226E(Aussi disponible en français, ATI-60226F)

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