[Viva] Fwd: CATIE News - Drug interaction warning for hepatitis C: serious side effects when using telaprevir and bosentan

Thu Feb 14 17:31:09 PST 2013

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    CATIE News - Bite-sized HIV/AIDS news bulletins
       CATIE News - Drug interaction warning for hepatitis C: serious side
effects when using telaprevir and bosentan

Higher-than-normal pressure in the arteries that supply the lungs with
oxygen-rich blood—a condition called pulmonary arterial hypertension
(PAH)—can occur in a small proportion of HIV-positive people. If left
untreated, PAH can lead to serious consequences.
 Hepatitis C treatment

The current standard of care for people infected with a hepatitis C virus
strain called genotype 1 in Canada and other high-income countries is one
of the following combinations:

   - boceprevir (Victrelis) + ribavirin + a long-lasting form of interferon
   called peg-interferon
   - telaprevir (Incivek) + ribavirin + peg-interferon

 Both telaprevir and boceprevir are processed by enzymes in the liver, as
are many other drugs, including some used for the treatment of HIV
infection.

Multiple medicines that are processed by the same liver enzymes have the
potential to interact, influencing the speed at which each medicine is
broken down. Such interactions have the potential to do the following:

   - Slow the breakdown of a drug. This can raise the concentration of
   drug(s) in the blood beyond safe levels, leading to new side effects or
   worsening pre-existing side effects.
   - Speed up the breakdown of a drug. This can lower the concentration of
   drug(s) in the blood to a point where it is only partially effective or not
   effective at all. For people with viral infections, this may lead to
   serious problems. When drug concentrations are low for a prolonged period,
   virus-infected cells can survive and evolve to better resist therapy. This
   can cause treatment failure and can reduce future treatment options.

 This is why consulting with a knowledgeable pharmacist is an important
part of care for people with HIV, HCV, TB and other chronic infections.
 An unexpected result

A medical team in Paris, France, has reported an unexpected and disturbing
drug interaction between a drug used to treat PAH—bosentan (Tracleer)—and
the HCV drug telaprevir. The interaction led to serious side effects.
 Case details

A 58-year-old man infected with HIV, HCV and hepatitis B virus (HBV) sought
emergency care. On examining him, the hospital found he had the following
symptoms:

   - severe confusion
   - blurred vision
   - dizziness
   - lower-than-normal blood pressure
   - difficulty maintaining his balance
   - difficulty walking

 Seventeen days earlier he had begun treatment for HCV, as he had severe
liver damage from this viral infection. At the time of his hospitalization
he was taking the following medicines:

   - *HCV* treatment: telaprevir 750 mg three times daily + ribavirin 600
   mg twice daily + peg-interferon 180 mcg once weekly
   - *HIV* treatment: raltegravir (Isentress) 400 mg twice daily + Truvada
   (containing 200 mg FTC and 300 mg tenofovir) once daily
   - *PAH*: bosentan 125 mg twice daily

 The man had been HIV positive for several decades; his viral load was less
than 400 copies/ml and his CD4+ count was 500 cells.

Blood tests done at the time of hospitalization revealed that levels of the
liver enzymes ALT (alanine aminotransferase) and AST (aspartate
aminotransferase) in his blood were elevated, suggestive of liver injury.
As a result of these and other test results, as well as his symptoms,
doctors stopped treatment of his HCV and PAH. Two days later, the man’s
neurological symptoms cleared. Five days after interrupting his HCV
therapy, levels of his liver enzymes returned to normal.
 Drug levels

Further analyses of the man’s initial blood samples found that the
concentration of bosentan was four-fold greater than was expected. Levels
of HIV drugs were within their normal ranges, as was the concentration of
telaprevir. Interferon and ribavirin were not likely to have caused the
interaction.

Once he recovered from bosentan toxicity, doctors resumed his HCV therapy
and levels of this virus in his blood swiftly fell. Furthermore, no new
interactions occurred.

To treat his PAH, doctors prescribed a new drug, ambrisentan (Volibris).
They chose this drug because, based on available information from
pharmacologists, it was unlikely to interact with telaprevir. Indeed, after
he started taking this drug, no side effects emerged.
 Bosentan and other drugs

The problem of drug interactions associated with bosentan has been found in
a clinical trial with HIV-negative volunteers who took the HIV medicine
lopinavir-ritonavir (in Kaletra) and bosentan. In that study, levels of
bosentan in the blood rose five-fold greater than usual. Side effects
reported were headache; no increase in liver enzymes was detected. Bear in
mind that in the study volunteers were *not* co-infected and only received
bosentan for four days. The research team that did this study with Kaletra
expects that a similar increase in bosentan levels in the blood could occur
with other common combinations of protease inhibitors such as
darunavir-ritonavir or atazanavir-ritonavir.
 For the future

The report from the Parisian medical team is a reminder to healthcare
professionals and patients that drug-drug interactions do happen. Over the
next five years, more therapies will be licensed for the treatment of HCV
infection. While there is urgency to get potent, tolerable and
interferon-free therapies for HCV, it is important to remember that with
emerging and relatively new therapies, every possible drug interaction has
not been studied and unexpected ones can occur. Vigilance is always
necessary when taking multiple medications for different conditions,
particularly understudied combinations of drugs.
 Reporting side effects

It is important to report side effects (also called adverse effects) to
regulatory authorities.
 In Canada

Health Canada has instructions and links for reporting suspected adverse
effects via mail, Internet and telephone here:

http://www.hc-sc.gc.ca/dhp-mps/medeff/report-declaration/index-eng.php#a1
 In the U.S.

The Food and Drug Administration (FDA) has links and instructions as to how
to report suspected adverse events via the Internet or telephone here:

http://www.fda.gov/Safety/MedWatch/HowToReport/ucm085568.htm

*Resources*

Understanding pulmonary
hypertension<http://www.catie.ca/en/treatmentupdate/treatmentupdate-192/side-effects-and-complications/understanding-pulmonary-arterial->

Pulmonary arterial hypertension and
HIV<http://www.catie.ca/en/treatmentupdate/treatmentupdate-192/side-effects-and-complications/pulmonary-arterial-hypertension-a>

hepcinfo.ca <http://www.hepcinfo.ca/> – CATIE’s hepatitis C website

*—Sean R. Hosein*

REFERENCES:

   1. Lê MP, Gervais A, Le Beller C, et al. Serious neuropsychiatric
   adverse effects in a hepatitis C virus/hepatitis B virus/HIV-coinfected
   patient receiving bosentan and telaprevir. *Journal of Antimicrobial
   Chemotherapy*. 2013; *in press.*
   2. Dingemanse J, van Giersbergen PL, Patat A, et al. Mutual
   pharmacokinetic interactions between bosentan and lopinavir/ritonavir in
   healthy participants. *Antiviral Therapy*. 2010;15(2):157-63.

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