[Viva] Fwd: CATIE News - Canadian study explores the possible effect of abacavir on liver health in co-infection
Tami Starlight
tamistarlight at gmail.com
Fri Oct 2 00:49:09 PDT 2015
for your information
CATIE News - Bite-sized HIV and hepatitis C news bulletins
CATIE News - Canadian study explores the possible effect of abacavir on
liver health in co-infection
Due to shared routes of infection, co-infection with HIV and hepatitis C
virus (HCV) is relatively common. Chronic infection with HCV injures the
liver and causes this vital organ to eventually become dysfunctional.
Serious complications can arise from chronic HCV infection, including death.
Studies have found that co-infected people who take potent combination
anti-HIV therapy (commonly called ART) to reduce the amount of HIV in their
blood to very low levels can generally slow the pace of HCV-related liver
injury.
Long-term studies of modern ART are needed to assess the safety of these
medicines in co-infected people. To determine the potential impact of ART
on the rate of progress of liver injury, researchers with the Canadian
Co-infection Cohort <http://www.cocostudy.ca/> (CCC) study analysed
health-related information from more than 300 participants collected in
their database. The researchers found that some ART regimens containing the
anti-HIV drugs abacavir and 3TC (both drugs are co-formulated and sold in
one pill called Kivexa in Canada and the European Union, and Epzicom in the
United States) were associated with an increase in blood tests suggestive
of accelerated liver injury. The researchers suspect that abacavir may be
the drug responsible. The implications of this finding are discussed later
in this *CATIE News* bulletin but first some background information.
About the CCC
As of October 2015, the CCC study has recruited 1,498 participants from 18
sites across Canada: 72% men, 27% women and 1% transgender people. All
participants have both HIV and HCV and are regularly monitored by
researchers.
Co-infection, HCV and assessment of liver injury
Chronic HCV infection causes inflammation in the liver as the immune system
tries to rid this organ of HCV. The inflammation resulting from the
struggle between the immune system and HCV injures the liver. Over time,
this causes healthy liver cells to be replaced with useless scar tissue. If
HCV infection is left untreated the liver degrades, resulting in liver
dysfunction, reduced quality of life, serious complications, infections and
death. Chronic HCV infection increases the risk for the development of
liver cancer.
There are many factors that can speed up the pace of scarring in the liver.
One such factor is inflammation. HIV infection causes a great deal of
inflammation that degrades many organs, including the liver. ART
significantly reduces the amount of HIV in the blood. As HIV levels fall so
does HIV-related inflammation. As a result, in cases of HIV-HCV
co-infection, ART also can slow down the pace of liver injury. Treatment
for HCV infection is also important.
Historically, assessment of liver health and the extent of scarring in this
organ have relied on a liver biopsy, the removal of a tiny piece of the
liver for analysis. However, in the past decade an alternative method of
assessing the liver has been developed. Using a specialized ultrasound scan
called Fibroscan, doctors can now get a generally reliable idea of the
extent of scarring within the liver. Also, over the past decade doctors
have found that when used in an equation some blood test results can, in
many cases, let doctors know if scarring in the liver has become worse. The
equation is called the AST to platelet ratio index (APRI) and the result is
called an APRI score. Increasing values for APRI are highly suggestive of
serious liver injury. APRI requires a blood test to measure the levels of
the liver enzyme AST and the platelet count.
Study details
Researchers with the CCC combed through their database and selected
participants who were taking as part of their regimens one of the following
classes of HIV medicines: a protease inhibitor or non-nuke.
Examples of protease inhibitors include the following:
- atazanavir (Reyataz)
- darunavir (Prezista and in Prezcobix)
- ritonavir (Norvir and in Kaletra)
- lopinavir + ritonavir (Kaletra)
Examples of non-nukes include the following:
- efavirenz (Sustiva, Stocrin and in Atripla)
- etravirine (Intelence)
- nevirapine (Viramune)
- rilpivirine (Edurant and in Complera)
In addition, researchers also took note of which nucleoside analogues
(commonly called nukes) participants were using. Usually they were the
following combinations:
- tenofovir + FTC (sold as Truvada and found in Atripla and Complera)
- abacavir + 3TC (sold as Kivexa and found in Triumeq and Trizivir)
The researchers found 314 participants who were taking only the nukes
listed above with either a protease inhibitor or a non-nuke.
To reduce the potential for bias when analysing their results, the
researchers took into account many factors that could have affected their
results, including the following:
- age
- gender
- length of time infected with HCV
- whether or not participants injected street drugs
- CD4+ count
- whether or not HIV viral load was less than 50 copies/ml
The researchers also took into account the fact that the vast majority of
participants who used a non-nuke were taking Atripla (efavirenz + tenofovir
+ FTC).
Researchers then matched the data from each participant taking a protease
inhibitor-based regimen with data from another co-infected person taking a
non-nuke-based regimen, and vice versa.
Using all of these data, researchers created a mathematical model to
explore links to an accelerated pace of liver disease.
Results abacavir + 3TC
When researchers took into account the length of time that participants
were taking nukes, they found that “the rates of change in APRI scores
appeared to be driven by [the use of abacavir + 3TC].” On average, the
researchers found that among people who took abacavir + 3TC and at least
one protease inhibitor, APRI scores increased by 16% over five years. When
abacavir + 3TC was used with a non-nuke, APRI scores increased by an
average of 11% over five years. These increases were statistically
significant; that is, not likely due to chance alone.
tenofovir + FTC
Among participants who used tenofovir + FTC and a protease inhibitor, APRI
scores increased by 8% over five years. In participants who used these
drugs with a non-nuke, APRI scores increased by an average of 3% over five
years. These changes in APRI scores among participants who used tenofovir +
FTC were not statistically significant.
Bear in mind
1. The report from the CCC is likely the first to explore the rate of
fibrosis in HIV-HCV co-infected people and how some ART regimens interact
with the pace of liver injury. The findings are interesting and suggest a
possible cautionary signal with abacavir (researchers suspect that this
drug could be affecting the livers of some participants). The study had
several strengths, including its prospective nature and, in a broad sense,
was representative of the co-infection population accessing care in Canada
because of its inclusion of women, Aboriginal people and people who
injected street drugs.
The results of the study are relevant to co-infection studies in the modern
era, as none of the participants had taken nukes notorious for their
general toxicity (so-called “d-drugs”), such as the following:
- ddC (Hivid)
- d4T (stavudine, Zerit)
- ddI (didanosine, Videx)
2. The CCC research team should be lauded for exploring the issue of liver
fibrosis and co-infection. Although the researchers took great pains to
reduce the possibility that some factor(s) might have inadvertently biased
(or confounded) their conclusion(s), such a possibility can never truly be
ruled out. This arises because the study’s design is that of a cohort
study—essentially an observational study. Such studies are good at finding
associations between a drug and an event, but they are unable to prove
that, in this case, abacavir accelerated liver fibrosis when used with a
protease inhibitor. Furthermore, the researchers generously acknowledge
that it is also possible that exposure to protease inhibitors themselves
may have accelerated the pace of liver injury in their study.
Unfortunately, the CCC does not have the statistical power to discern the
impact of protease inhibitors on the pace of liver injury. A much larger
study is needed to explore this potential effect of protease inhibitors.
3. Potential sources of bias
There may be several sources of potential bias in this study. The
researchers mentioned that protease inhibitors “are often favoured for
persons with poor adherence in order to lower risks of [HIV developing
resistance to treatment].” Confounding is possible because the researchers
stated that “if more [users of protease inhibitors] had unstable lives”
this could have impaired their ability to take ART exactly as directed and
exposed participants “to potential risk factors for liver injury such as
alcohol use and uncontrolled [HIV] replication.”
4. Why suspect abacavir?
Abacavir is broken down, or metabolized, by the liver. It is possible that
during the process of breaking down abacavir highly reactive molecules are
released with the potential to cause toxicity. However, abacavir is a
widely prescribed drug. Regulatory agencies consider it a generally safe
and effective part of ART regimens when it is used according to treatment
guidelines. In the past decade, there appear to have been only three cases
of abacavir-associated liver injury reported in biomedical journals. In all
three cases, participants had been taking nevirapine for some time without
any problems. Note that nevirapine use is associated with an increased risk
for liver injury. At any rate, published reports of abacavir-associated
liver injury seem to be exceedingly rare.
The other drug commonly used with abacavir is 3TC, and doctors consider
this to be quite safe.
5. Next steps
Cohort or observational studies are a good first step to explore an idea or
theory. If an association is found in a study of an observational design,
then it needs to be studied and understood, both at the laboratory level
with cells, viruses and drugs and also in a study of a more robust
statistical design. A more robust study will be expensive, and in an era of
enforced austerity such a study may not be possible or may take many years
of fundraising and would be time-consuming for all concerned. Thus, no
simple answers as to the potential role of abacavir in accelerating liver
injury will become available anytime soon.
In the meantime, the CCC team has *not* suggested that co-infected people
avoid abacavir. They have found a signal of *potential* concern, but it
requires verification in at least another study.
The CCC study is funded by the Canadian HIV Trials Network, CIHR and Fonds
de recherche du Québec (FRSQ).
*Acknowledgement*
We thank Marina Klein MD MSc and Laurence Brunet PhD, McGill University,
for their expert review and helpful assistance with this article.
*Resources*
- Hepatitis C <http://www.catie.ca/en/hepatitis-c> – CATIE’s hepatitis C
information
- Living with HIV and Hepatitis C Co-infection
<http://www.catie.ca/en/practical-guides/hiv-and-hepatitis-co-infection>
– CATIE
- Canadian Co-Infection Cohort <http://www.cocostudy.ca/>
- The CTN <http://www.hivnet.ubc.ca/home/> – CIHR Canadian HIV Trials
Network
- Canadian Institutes of Health Research
<http://www.cihr-irsc.gc.ca/e/193.html> (CIHR)
- Fonds de recherche du Québec <http://www.frq.gouv.qc.ca/en/> (FRSQ)
*—Sean R. Hosein*
REFERENCES:
1. Brunet L, Moodie EE, Young J, et al. Progression of liver fibrosis
and modern combination antiretroviral therapy regimens in HIV-hepatitis C
co-infected persons. *Clinical Infectious Diseases*. 2015; *in press*.
2. Di Filippo E, Ripamonti D, Rizzi M. Abacavir-induced liver toxicity
in an HIV-infected patient. *AIDS*. 2014 Feb 20;28(4):613.
3. Soni S, Churchill DR, Gilleece Y. Abacavir-induced hepatotoxicity: a
report of two cases*. AIDS*. 2008 Nov 30;22(18):2557-8.
4. Grilo NM, Charneira C, Pereira SA, et al. Bioactivation to an
aldehyde metabolite—possible role in the onset of toxicity induced by the
anti-HIV drug abacavir. *Toxicology Letters*. 2014 Jan 30;224(3):416-23.
5. Banasch M, Frank J, Serova K, et al. Impact of antiretroviral
treatment on (13) C-methionine metabolism as a marker of hepatic
mitochondrial function: a longitudinal study. *HIV Medicine*. 2011
Jan;12(1):40-5.
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