| GMCarter 2005-11-23, 10:49 am |
| On 23 Nov 2005 05:19:33 -0800, "DavidT" <david199@volcanomail.com>
wrote:
>Yes, it may be a class effect, but I think Pfizer are keeping their
>fingers crossed.
From Natap:
NATAP http://natap.org/
_______________________________________________
Is Liver Toxicity a CCR5 Antagonist Class Effect?
2NN & Hepatoxicity; D.A.D. study & liver related death; Liver toxicity
& HIV, Italian study
A Report from the 10th European AIDS Conference (EACS), November
17-20, 2005, Dublin
Mark Mascolini (markmascolini@earthlink.net)
No one knows the answer to the question posed in this review's title.
But an unscheduled addendum to an add-on talk in the EACS side effects
session raised that grisly possibility.
The add-on talk came from Glaxo's Helen Steel, who explained in
exacting detail why the company dismantled the development machine
behind aplaviroc, Glaxo's CCR5 antagonist. The unscheduled addendum
came from a Pfizer spokesman in the audience, prodded to the
microphone by HIV and liver expert Stefan Mauss of Düsseldorf. Mauss
asked for anyone from Pfizer to comment on swirling reports that
serious liver toxicity had struck someone taking maraviroc.
A fellow from Pfizer read this prepared statement:
“Over a thousand patients have been enrolled in the maraviroc
program to date. Pfizer has very recently become aware of a single
case of hepatotoxicity in a patient receiving maraviroc. As the
patient was also simultaneously receiving several drugs which have
reported hepatic toxicities, the causality is unclear.
“Pfizer is still gathering more information regarding this patient
and has called an additional review by the independent Data Safety
Monitoring Board (DSMB) of the maraviroc program. While this review is
awaited we are providing all patients, investigators, ethics
committees and regulatory authorities with currently available
information. We will comment further when we receive feedback from the
DSMB and regulatory authorities.�
The Pfizer spokesman declined to take questions.
Those who haven't been following the CCR5 antagonist saga should know
the background for this unwelcome bomblet. Clinical trials of Pfizer's
maraviroc, Glaxo's aplaviroc, and Schering's vicriviroc had been
sailing along with few ill winds of late. Most concern focused on two
questions:
o Would drugs that smother the CCR5 coreceptor on CD4 cells prod
the protean virus to shift coreceptor allegiance and start hooking
onto CXCR4, the coreceptor that arises in about half of people with
late-stage HIV infection?
o Would virus resistant to one CCR5 antagonist prove
cross-resistant to the others?
HIV's vexing capacity to do the right thing for itself and the wrong
thing for patients suggests the answers could be yes, though evidence
of “coreceptor switching� has been sparse in the limited clinical
trials to date.
Then Glaxo put a chill on warm hopes for aplaviroc when severe
hepatotoxicity arose in a few antiretroviral-naive people taking the
drug. The company promptly shut down that trial and looked hard for
sick liver signals in treatment-experienced people taking aplaviroc.
Glaxo found exactly what everyone hoped it wouldn't-the same kind of
liver toxicity in experienced people taking aplaviroc with other
antiretrovirals for salvage.
What sunk aplaviroc
Why would a bare handful of liver problems-four, as it turned
out-bring a megabucks clinical trial juggernaut to a clanging halt?
Because, Glaxo's Steel explained, liver experts figure that the
specific type of toxicity they saw will kill 10% to 50% of those who
have it.
No one in the Glaxo trials died, and the toxicity always resolved when
they stopped aplaviroc. When researchers rechallenged one of these
people with aplaviroc and Combivir (AZT/3TC), signals of hepatic
distress arose again.
All four people had elevated alanine aminotransferase (ALT)-sometimes
sky-high ALT-plus simultaneously soaring bilirubins. The FDA lists an
ALT more than 3 times the upper limit of normal (ULN) plus total
bilirubin more than 1.5 times ULN as a “cause for concern.�
The trial enrollee who alerted Glaxo to the liver threat had an ALT 70
times ULN and a bilirubin 5 times ULN after taking aplaviroc and
Combivir for 59 days. He did not have HBV or HCV coinfection and
started the trial with a normal ALT, aspartate aminotransferase (AST),
and bilirubin. Nothing else in his medical history suggested why his
ALT might suddenly spike to nosebleed heights. Liver biopsy showed a
chronic inflammatory infiltrate “consistent with drug-induced
hepatotoxicity.�
Scouring the central lab database on aplaviroc for similar cases,
Glaxo found three it could attribute to the CCR5 antagonist, including
one with an ALT 24 times ULN, one with an ALT 12 times ULN, and one
with an ALT and AST 9 times ULN.
Although only four of 308 aplaviroc trial enrollees met the criterion
of simultaneous high ALT and bilirubin, that was four too many. Glaxo
had no choice but to pull the plug on aplaviroc.
What's up with maraviroc?
Pfizer says it wants to alert trial participants and investigators to
the single liver toxicity case it found before disseminating the
findings publicly. NATAP will report full details as soon as they
become available.
That even one such case arose came as a rude surprise since DSMBs for
maraviroc trials had just finished a hair-splitting scrutiny of
ongoing trials and found nothing that encouraged them even to tinker
with the trial protocols.
Liver readings did jog out of line in 5 of 12 healthy volunteers
taking maraviroc for 8 days with tipranavir/ritonavir in a
pharmacokinetic study [1]. Pfizer planned this study to address the
concern that inhibitors or inducers cytochrome P450 (CYP) enzymes-the
enzymes responsible for metabolizing so many drugs-affect maraviroc
concentrations.
Pfizer has already decided to halve maraviroc's dose when giving it
with puissant inhibitors of CYP3A4 like ritonavir. But tipranavir is a
CYP3A4 inducer. So Pfizer wanted to know how standard-dose
tipranavir/ritonavir (500/200 mg twice daily) might affect 150 mg of
maraviroc (the half dose) twice daily.
Pfizer's Samantha Abel and colleagues gave the volunteers that dose of
maraviroc with either placebo or tipranavir/ritonavir for 8 days.
Later the volunteers switched to the regimen they hadn't already
tried.
Tipranavir/ritonavir did not change maraviroc levels enough to merit a
dose adjustment. But these healthy volunteers had more side effects
when taking maraviroc with the protease inhibitors (PIs) than when
taking it with placebo.
Most notably, 5 of 12 people taking maraviroc with the PIs had
elevated ALT or AST after 8 days of dosing. Four of these transaminase
jumps rated as grade 1 or 2 elevations, and one ranked as a more
serious grade 3 change. No one in the trial had simultaneous surges in
bilirubin-the cofactor that killed aplaviroc.
All transaminase elevations vanished spontaneously when people stopped
maraviroc and the PIs. Tipranavir/ritonavir can certainly pummel the
liver in people with HIV, and liver toxicity did not arise with
maraviroc plus placebo. So this study cannot pin the liver enzyme
blips on maraviroc.
Still, no one can be happy about the unpropitious proportion of ALT or
AST leaps in these healthy people, 42% Grade 1 or 2 “events� may
not seem troubling, but these healthy people took maraviroc and
tipranavir/ritonavir for only 8 days. In the red-alert case from the
aplaviroc trial, liver enzymes looked just fine for 58 days.
Even if maraviroc didn't stir up liver enzymes all by itself-as
aplaviroc did-a drug that compounds liver toxicity from other
antiretrovirals would have a more limited salvage role or-at a
minimum-would require tight monitoring.
So far Schering has reported no liver toxicity with its CCR5
antagonist, vicriviroc. But the company shuttered a trial in
previously untreated people when vicriviroc plus Combivir trailed
efavirenz plus Combivir in slowing HIV replication [2].
At an October IAPAC meeting in Amsterdam, Joep Lange from the Academic
Medical Center noted that AZT spurred emergence of CXCR4-favoring HIV
in monotherapy trials. Whether drugs with that trait are the best
partners for CCR5 antagonists remains unexplored. Schering plans to
keep testing vicriviroc in treatment-naive people with a partner other
than Combivir.
Will hepatotoxicity prove to be a CCR5 antagonist class effect? The
optimist would say toxic class effects are the exception rather than
the rule. Nucleosides differ considerably in how mess up mitochondria;
efavirenz does not induce the acute liver toxicity seen with
nevirapine; and PIs differ in how they affect lipid levels and glucose
control. The pessimist would say don't rule anything out until you
have lots of data from lots of people.
Liver toxicity of unknown origin associated with HIV-infection
Assaults on the liver are bad enough when you know their cause. But
research from Spain and Italy suggests severe liver disease with no
known origin besets about 1 in 200 people with HIV [3]. Some EACS
attendees questioned the study's methods.
Ivana Maida (University of Sassari, Italy) and colleagues in Madrid
and Seville combed records of 3200 people with HIV infection, defining
liver disease of unknown origin as persistently high ALT or AST
without replicative HBV or HCV infection or another known cause of
liver problems. Seventeen people (0.5%) met that definition, while the
rate in the general population lies below 0.01%. To flush out possible
contributors to the condition, Maida matched these 17 people to
HIV-infected controls on the basis of age, gender, and CD4 count.
Fourteen people with unexplained transaminase spurts (82%) were men,
and 13 men picked up HIV from sex with other men. The 17 people with a
high ALT or AST had a median age of 42 years and had HIV infection for
a median of 15 years. The most common potentially hepatotoxic drugs on
their charts were nevirapine, ddI, and d4T.
Nine of the 17 people had portal hypertension, 6 had portal
thrombosis, 5 had gastrointestinal bleeding, and 2 had hepatic
encephalopathy. No one died. Liver biopsy or the noninvasive Fibroscan
rated fibrosis advanced (Metavir score F3 or F4) in 7 cohort members.
People with liver toxicity differed from the controls without it in
having less antiretroviral experience (4.53 versus 6.88 years, P =
0.02) but more ddI experience (47 versus 25 months, P = 0.009). Cases
and controls did not differ in length of treatment with d4T or
nevirapine, or in any other variable measured.
Multivariate analysis singled out a solitary factor that independently
raised the risk of unexplained liver problems: Taking ddI upped the
odds 1.04 times for every month of treatment.
Maida noted that the analysis cannot rule out other explanations of
liver upsets in this population. Most of those affected, she
explained, were gay men, and gay men have higher rates of
pylephlebitis (inflammation or thrombosis of the liver's portal vein)
than do other people with HIV.
Stefan Mauss raised the concern that excluding people with
nonalcoholic steatohepatitis and hepatic steatosis from the analysis
may have made it impossible to spot correlations between
antiretroviral therapy and a compromised liver. Another attendee
questioned the fibrosis finding, arguing that research has not
validated Fibroscan in people with HIV and the test may be accurate
only in those with advanced fibrosis.
High 2NN liver toxicity rates with
once-daily nevirapine tied to Thai site
After-the-fact analysis of data from the 2NN trial [4] showed that the
high rates of liver toxicity seen with once-daily nevirapine could be
traced largely to the single Thai site in this international study
[5]. At other sites rates of symptomatic and asymptomatic liver
toxicity did not vary significantly when researchers compared people
taking once-daily nevirapine, twice-daily nevirapine, or
efavirenz-after accounting for pretreatment CD4 count-in this
randomized trial of people starting antiretroviral therapy.
Boehringer Ingelheim's Jonathan Leith and colleagues defined
asymptomatic liver toxicity as an ALT or AST at least 5 times ULN
without symptoms of clinical hepatitis.
In the overall 2NN population, rates of symptomatic and asymptomatic
liver toxicity were highest with once-daily nevirapine, lower with
twice-daily nevirapine, and lowest with efavirenz (Table). The
analysis excluded 2NN's nevirapine-plus-efavirenz arm.
Rates of liver toxicity in 2NN by trial site and entry CD4 count
When Leith divided results between Thai and non-Thai trial sites,
rates of symptomatic and asymptomatic liver toxicity were higher with
once- or twice-daily nevirapine than with efavirenz in both Thai and
non-Thai groups (Table). But when Leith looked only at non-Thai trial
participants who began nevirapine at currently recommended CD4 counts
(below 250 cells/µL for women and below 400 cells/µL for men),
toxicity differences between the three arms disappeared.
The Boehringer researchers did not speculate on whether the higher
nevirapine toxicity seen in the single Thai center might be explained
by some genetic difference between Thais and other study participants
or whether the Thai site differed from others in recording or
reporting hepatotoxicity. Leith and colleagues point out that other
trials with a once-daily nevirapine arm charted lower ALTs and ASTs
than those recorded in 2NN and did not see the high rates of
asymptomatic liver toxicity reported from Thailand [6-9]. The FDA has
not licensed nevirapine for once-daily use.
Antiretrovirals not a factor in D:A:D liver deaths
Longer experience with antiretroviral therapy did not raise the risk
of liver-related death in the multicohort D:A:D study, but lower CD4
counts did make death from liver disease more likely [10]. Rainer
Weber (University Hospital, Zurich) and D:A:D coworkers caution,
though, that antiretrovirals' salutary (beneficial) effect on CD4
tallies could mask a detrimental antiretroviral impact on the liver.
Tracing causes of death in 1248 D:A:D participants (5.3%), Weber found
that AIDS explained the largest proportion of deaths (31%) from 2000
through February 2004, followed by liver failure (15%), heart disease
(9%) and non-AIDS malignancies (9%).
Among people who died from liver disease, Weber traced 76% of the
deaths to viral hepatitis (66% HCV and 17% HBV), 9% to hepatocellular
carcinoma, and 14% to alcohol abuse.
Univariate analysis of liver death risk factors did not link
cumulative antiretroviral duration-up to 7 years' worth-to
liver-related death. Multivariate analysis tied five variables to a
higher risk of liver-related death at the following relative rates
(and 95% confidence intervals):
o Older age: 1.3 (1.2 to 1.4) per 5 years older
o HIV transmission group: 2.0 (1.2 to 3.4) for injecting drug use
versus homosexual infection
o Lower CD4 count: 1.23 (1.17 to 1.29) per halving of the latest
CD4 count (P < 0.0001)
o HCV infection: 6.7 (3.9 to 11.2)
o HBV antigen positive: 3.7 (2.4 to 5.9)
In an attempt to uncover any negative antiretroviral impact on liver
mortality, in future analyses D:A:D number crunchers will weigh years
of antiretroviral therapy and risk of liver-related death after
adjusting for the latest CD4 count.
Mark Mascolini writes about HIV infection
(markmascolini@earthlink.net).
References
1. Abel S, Taylor-Worth R, Ridgway C, et al. Effect of boosted
tipranavir on the pharmacokinetics of maraviroc (UK 427,857) in
healthy volunteers. 10th European AIDS Conference. November 17-20,
2005. Dublin. Abstract LBPE4.3/15.
2. Schering-Plough. Schering-Plough discontinues phase II study of
vicriviroc in treatment-naive HIV patients, continues phase II study
in treatment-experienced HIV patients. October 27, 2005.
http://www.aegis.org/news/pr/2005/PR051044.html
3. Maida I, Nuñez M, Rios MJ, et al. Severe liver disease of unknown
origin in HIV-infected patients. 10th European AIDS Conference.
November 17-20, 2005. Dublin. Abstract PS5/5.
4. van Leth F, Phanuphak P, Ruxrungtham K, et al. Comparison of
first-line antiretroviral therapy with regimens including nevirapine,
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open-label trial, the 2NN Study. Lancet 2004;363:1253-1263.
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within the 2NN study: controlling for ethnicity and CD4+ count at
initiation of nevirapine therapy. 10th European AIDS Conference.
November 17-20, 2005. Dublin. Abstract PE9.6/2.
6. van Leeuwen R, Katlama C, Murphy RL, et al. A randomized trial to
study first-line combination therapy with or without a protease
inhibitor in HIV-1-infected patients. AIDS 2003;17:987-999.
7. Garcia F, Knobel H, Sambeat MA, et al. Comparison of twice-daily
stavudine plus once- or twice-daily didanosine and nevirapine in early
stages of HIV infection: the scan study. AIDS 2000;14:2485-2494.
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didanosine and stavudine combination therapy in antiretroviral-naive
HIV-1-infected adults. Antivir Ther 2000;5:267-272.
9. Negredo E, Molto J, Munoz-Moreno JA, et al. Safety and efficacy of
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antiretroviral approach. Antivir Ther 2004;9:335-342.
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among HIV-infected persons: data from the D:A:D study. 10th European
AIDS Conference. November 17-20, 2005. Dublin. Abstract PE18.4/7.
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