A Johns Hopkins study has proved false an established
medical practice that an antiretroviral drug widely used to
treat hepatitis B liver infections was safe to use on its
own in patients co-infected with HIV. Their findings
demonstrate that treatment with entecavir leads to
cross-resistance to other antiviral drugs used to treat the
"Our results show that entecavir is no different from
any other that has been shown to be active against HIV; it
breeds resistance rapidly, despite its ability to reduce
the amount of HIV in the body," said senior study author
and infectious disease specialist Chloe Thio.
Researchers say the findings, presented Feb. 28 at the
2007 Conference on Retroviruses and Opportunistic
Infections in Los Angeles, have serious implications for
the more than 4 million people worldwide believed to be
infected with both viral illnesses but who need to treat
their hepatitis B and are not yet on anti-HIV drugs.
Authors of the study have informed the U.S. Food and
Drug Administration of their results so that prescribing
physicians can be notified and drug labeling changed. They
also have notified Bristol-Myers Squibb, which makes and
sells entecavir under the brand name Baraclude.
"The alert should go out to co-infected people to
consult with their physicians immediately about entecavir
to see if it is the right drug to treat their hepatitis B
in the first place and to evaluate alternative therapies,"
said Thio, an associate professor of
medicine at the Johns Hopkins School of Medicine.
Thio said she has stopped prescribing entecavir as her
first option in treating hepatitis B in co-infected
patients who are not already using drugs to suppress
"The good news is that co-infected patients already on
HIV therapy can still use entecavir to treat their
hepatitis B, but the bad news is that there are now fewer
options for treating hepatitis B first," she said.
Hepatitis B infection attacks the liver and can lead to
cirrhosis, liver cancer or even death from liver
Entecavir, first marketed in March 2005, has been a
leading treatment for chronic forms of hepatitis B, which
can be fatal to almost a quarter of those infected if it is
left untreated. The drug's label information currently
states that it has no clinical effects on HIV.
According to Thio, some co-infected patients decide to
treat their hepatitis B infection first if HIV has not yet
weakened their immune system and to avoid the debilitating
side effects of anti-HIV medications.
In the Johns Hopkins study, researchers found in both
laboratory and clinical tests that within six months of
entecavir therapy, a so-called M184V mutation of HIV
develops. Thio said viruses with this mutation are known to
be resistant to lamivudine, better known as 3TC, a
medication that prevents HIV replication and "is a
cornerstone of most drug-combination therapies used to
fight the immune system disease." Because lamivudine is in
the same category of HIV therapies as another widely used
drug, emtricitabine, its effectiveness is also compromised
by entecavir, she said.
Thio began to investigate entecavir's effects on HIV
in fall 2006 after noticing reports of anti-HIV activity in
two co-infected patients, one at the Johns Hopkins Moore
Clinic, which specializes in HIV/AIDS care, and another at
a San Diego medical center. The patients (and there is now
a third case) were taking only entecavir yet showed a
tenfold decrease in the amount of HIV in their blood.
Previous studies had shown entecavir not to have any
significant effects on HIV, but those studies were based on
older tests that could not quantify the effects of HIV on
individual immune cells or detect mutations. Thio said she
believed that the recent patient cases called for a more
thorough investigation with more advanced techniques.
She and her team combined various concentrations of
entecavir with 100,000 human immune cells from a healthy
blood donor, then infected them with an HIV test virus and
measured the number of cells infected over time.
The lab test, developed at Johns Hopkins by study
co-author Robert Siliciano, a professor at Johns Hopkins
and a Howard Hughes Medical Institute investigator,
specifically tests what drugs affect HIV and can be
tailored to probe effects on any particular mutant of
Lab results showed that entecavir, in concentrations
less than a 10th of what is used in humans, cut the number
of newly infected cells in half; however, at increasing
concentrations, the drug had no greater impact on
suppressing HIV replication. HIV is a virus renowned for
its ability to change form and thus evade or develop
resistance to therapies designed to stop its action.
Similar testing with entecavir, immune cells and the
M184V form of HIV showed that the drug did not stop the
virus from infecting the cells. This provided evidence,
scientists say, that the drug specifically fostered
development of this mutation in HIV, later confirmed by
When researchers tested the blood of one of the
co-infected patients for the M184V mutation, they found
none in samples taken at the start of entecavir thereapy.
But they did find it in 61 percent of viral samples tested
after four months of therapy, and in 96 percent tested at
Other Johns Hopkins investigators involved in this
research, which was supported by funding from the National
Institutes of Health, were Moira McMahon, Benjamin Jilck,
Timothy Brennan, Lin Shen, Yan Zhou, Shridhar Bhat, Robert
Hegarty, Curtis Chong and Jun Liu. Additional assistance
from the Naval Medical Center in San Diego was provided by
More than 1.2 million Americans are infected with
hepatitis B. A vaccine against the virus has been available
in the United States since 1982, but an estimated 60,000
new infections occurred in the United States in 2004 alone.
Hepatitis B is transmitted by contact with blood and other
body fluids of an infected person through sexual
activities, injection drug use, sharing of personal care
items or direct contact.