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News Briefs
by Enid Vázquez
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Subjects:
Drug Guide
clarification
New dose for Invirase and Fortovase
Crixivan label changes
New Viramune warning
Another One Bites the Dust: T-1249
Vaccine fails again
For Shame, Part 2
New rapid HIV test
The winner: Sustiva/Combivir
News
Briefs from 11th Annual Retrovirus Conference
Genetics
affect Sustiva side effects
Disparities workshop at Vanderbilt
Viramune resistance after labor
Prevention for sex partners
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Drug Guide
clarification
Viracept is approved for three times
a day dosing. However, the newer twice-a-day dosing is preferred
by most patients and should have been depicted in the drug photo
at the top of our page. Our apologies.
New dose for Invirase
and Fortovase
It’s official: you shouldn’t
take Invirase without Norvir. The U.S. Food and Drug Administration
(FDA) in December approved a change to Invirase’s label—its
dose is now 1,000 mg with 100 mg of Norvir both twice a day
(five 200 mg capsules plus one 100 mg capsule). The two drugs
are each protease inhibitors. Invirase is poorly absorbed without
a mini-dose of Norvir.
Fortovase is a better absorbed (about
four times as much) version of Invirase. Fortovase can still
be given as the only protease inhibitor in a combination—but
not really recommended by most HIV doctors without another protease
inhibitor (PI). The change to Invirase’s label makes official
the often-used dosing of 1,000 mg plus 100 mg of Norvir twice
a day. Combining a protease inhibitor with a mini-dose of Norvir
(between 100 and 400 mg) usually helps cut down the number of
pills people need to take, lower the risk of side effects and
make the drug more effective. The FDA notes that Fortovase by
itself remains an option “for patients who are unable to
tolerate ritonavir [Norvir].” Norvir can make you sick
to your stomach, as they say. Lots of gastrointestinal side
effects.
Crixivan label
changes
The FDA in January approved changes
to the package insert for Crixivan (indinavir), one of the HIV
protease inhibitor drugs. The changes add new forms of possible
kidney damage to watch out for (tubulointerstitial nephritis
with medullary calcification and cortical atrophy in people
with asymptomatic severe leukocyturia, or excess white blood
cells in their urine). The FDA says discontinuation of Crixivan
should be considered in people with this type of leukocyturia.
The FDA also added the following wording,
“Immune reconstitution syndrome has been reported in patients
treated with combination antiretroviral therapy (CART), including
Crixivan. During the initial phase of treatment, patients responding
to antiretroviral therapy whose immune system responds to CART
may develop an inflammatory response to indolent or residual
opportunistic infections (such as MAI, CMV, PCP, or TB), which
may necessitate further evaluation and treatment.” This
may be seen with other anti-HIV medicines, but Crixivan’s
label has been changed to reflect its documented cases.
The FDA notes that both Crixivan and
one of newest protease inhibitors on the market, Reyataz (atazanavir),
are associated with indirect (unconjugated) hyperbilirubinemia.
While they have not been studied in combination, taking Crixivan
with Reyataz is not recommended. Unconjugated hyperbilirubinemia
is not associated with disease the way conjugated hyperbilirubinemia
is, but it can cause yellowing of the skin and eyes. That’s
the reason why the manufacturer of Reyataz has already recommended
that the two drugs not be taken together.
Lastly, the FDA added “increased
cholesterol” to the list of possible side effects in the
section on Marketing Experience (what’s been reported since
the drug was approved and put in the pharmacy).
New Viramune
warning
The FDA in February updated the black
box warning for Viramune (nevirapine). It now cautions that
women with CD4 cell counts above 250, including pregnant women,
have a 12-fold greater risk of serious liver side effects, and
that these have sometimes been fatal. Liver events present the
greatest risk of fatality if they occur in the first six weeks
of treatment, and are often associated with rash. However, manufacturer
Boehringer Ingelheim advises doctors to closely monitor patients
for the first 18 weeks of therapy. Even when treatment is discontinued,
in some instances hepatic injury has continued to progress.
Individuals experiencing an allergy to Viramune should “discontinue…treatment
and seek medical evaluation immediately” and Viramune “should
not be restarted in these patients,” the company adds.
Some experts recommend that liver function be monitored at least
once a month.
Another One Bites
the Dust: T-1249
Anticipating the need for patients who
may develop resistance to T-20 (Fuzeon), Trimeris and its Swiss
partner, Roche, worked on another fusion inhibitor, T-1249.
Because T-1249’s activity site was more broad than Fuzeon’s,
it held the potential of helping those individuals who may develop
resistance to Fuzeon. Additionally, T-1249 was expected to be
administered once daily, less than the twice-a-day injections
needed for Fuzeon.
However, Trimeris recently announced
that development of T-1249 has been discontinued. Once-daily
injections of T-1249 may not have been optimum. Also, Trimeris
and Roche felt that as other competitive compounds are already
undergoing clinical trials by other pharmaceutical companies,
by the time T-1249 would get into the marketplace, better options
may beat 1249’s development. Trimeris and Roche also announced
that they’ve signed “a further research agreement
to discover, develop and commercialize the next generation of
HIV fusion inhibitors.”
For patients who need further options
to combat resistance to current treatments, the news may not
all be bad. Schering Plough presented a preliminary study of
their entry inhibitor SCH-D at the Conference on Retroviruses
and Opportunistic Infections in February. Patients who took
three different oral doses of SCH D, twice daily, demonstrated
good suppression of HIV. A larger clinical trial is expected
to begin this spring. Bristol-Myers Squibb also has a drug candidate
in this class that can also reach market in the next three to
four years.—Daniel S. Berger,
MD
Vaccine fails
again
The AIDSVax trial in Thailand reported
in November 2003 that the HIV vaccine was safe, but it was not
effective in stopping new transmissions. Results from the first
AIDSVax trial reported early last year were the same (see May/June
2003). AIDSVax was the first preventive HIV vaccine tested
in large studies.
Of 2,546 participants, half were given
the vaccine and half were given placebo (fake drug). There were
the same number of infections in both groups, 106 in the vaccinated
people and 105 in the placebo group. (There were 5,400 people
in the first trial.) There are also therapeutic trials with
other vaccines which are given to people already living with
HIV, in the hopes of preventing disease. It was hoped that if
vaccinated people did become infected, AIDSVax would slow the
progression of HIV disease, but this did not happen.
In a press release, International AIDS
Vaccine Initiative (IAVI) president and CEO Dr. Seth Berkley
noted that, “Although AIDSVax was found not to work, the
trials themselves were a success. VaxGen demonstrated that it
is possible to conduct large-scale trials of AIDS vaccines in
both industrialized and developing countries.” VaxGen reported
that more than 90% of the volunteers, all injection drug users,
completed the three-year study.
For Shame, Part
2
The former San Francisco city health
commissioner who had been fined $5 million for lying to an ex-lover
about having HIV had his case thrown out in a higher court in
December. A Superior Court judge in that city determined that
Ronald Hill was not guilty of intentionally infecting others
with HIV, as required for prosecution in the state of California.
Two men had told a grand jury that they were infected by Hill,
and that Hill told them he didn’t have HIV. Hill had supposedly
claimed he had poor health due to cancer. One of the men, Thomas
Listor, was quoted by the San Francisco Chronicle as saying,
“It’s a law that is not working—and we need to
change that.” Here in Illinois we have a law called “disclosure.”
You tell someone you have HIV and they decide whether or not
to take their chances. It’s not perfect, but California
may want to consider something better than what it has now.
Intentionally infect? Get real.
New rapid HIV
test
The U.S. Food and Drug Administration
(FDA) in December approved the Uni-Gold Recombigen HIV rapid
test. Results from either plasma, serum or whole blood are available
in 10 minutes, but the test is only available in places with
clinical laboratory professionals and a quality assurance program
(like a hospital or some walk-in clinics). (OraQuick, a rapid
HIV test already on the market, can only be used on whole blood.)
Results showed that Uni-Gold Recombigen HIV was able to correctly
detect 100% of HIV-positive results (sensitivity) and more than
99.7% of the negative results (specificity). As usual with an
HIV test, positive results require a confirmatory test. Cost
is approximately $10 per test.
The winner: Sustiva/Combivir
If you’re starting HIV therapy
for the first time, Sustiva and Combivir may be the way to go.
So reports the National Institutes of Health (NIH). In a press
release the NIH reported that, “Until now, it has been
unclear which sequences of antiretroviral regimens provide the
greatest benefit to patients previously untreated,” according
to Gregory K. Robbins, M.D., of Massachusetts General Hospital
and Harvard Medical School, and lead author of one of the two
papers on this study.
In a complicated trial with six combinations
of HIV drugs in 620 study participants, NIH found that starting
out with Sustiva/Combivir was the most effective over the longest
period of time. Moreover, it was successful longer even when
given as a second regimen, compared to other combinations people
were switched to (see “Starting Therapy”
table).
After one year (48 weeks), Sustiva/Combivir
therapy failed for 10% of the people taking it. This compared
to 30–40% failure with the other regimens: Sustiva/Zerit/Videx;
Viracept/Zerit/Videx; and Viracept/Combivir. (Combivir is a
combination of two HIV drugs in one—AZT, brand name Retrovir,
and Epivir).
What the researchers were most interested
in was the sequence of drug combinations. It’s well-known
that HIV therapies stop working after a while and the people
taking them have to go on a new drug combination (if that’s
what they decide they want to, or should, do). Here researchers
found that treatment success on a second regimen was greater
for people starting with Sustiva/Combivir than with any of the
other combinations studied.
The study also looked to see if a couple
of four-drug combinations were more potent than the three-drug
combos (Sustiva/Viracept/Combivir and Sustiva/Viracept/Videx/Zerit).
They weren’t, but they did delay time to a second regimen
and the development of drug resistance compared to all the triple
therapies except one—Sustiva/Combivir. Interestingly, the
four-drug combos did not cause more side effects than did the
three-drug regimens.
However, any group starting with Videx/Zerit
did experience more toxicity. These toxicities included two
serious ones associated with the drugs: peripheral neuropathy,
a neurological disorder resulting from damage to the peripheral
nerves, and inflammation to the pancreas, among other problems.
NIH notes that, “Based in part on the results of this study,
leading researchers now recommend that anti-HIV treatment should
not begin with regimens that contain both ddI and d4T [Videx
and Zerit].”
There are many other strong combinations
that can be taken, but nearly all are taken with either Retrovir,
Combivir, or Zerit. Remember, Sustiva must be avoided by women
who hope to become pregnant. It also has a wide range of neural-psychiatric
side effects. However, many people find it extremely tolerable.
Epivir has probably the least amount of side effects of any
HIV drug, but Retrovir is known for fatigue, headaches and anemia.
Sustiva/Combivir has long been one of the most popular triple
combinations used for first time therapy. This study confirms
the value of that choice.
The findings were reported in the December
11 issue of The New England Journal of Medicine. See
www.niaid.nih.gov. |
| Starting
Therapy—ACTG 384 |
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Three-drug combinations |
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First regimen |
Second regimen
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Sustiva + Combivir
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Viracept +
Videx + Zerit |
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Sustiva + Videx + Zerit |
Viracept +
Combivir |
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Viracept + Videx + Zerit |
Sustiva +
Combivir |
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Viracept + Combivir |
Sustiva +
Videx + Zerit |
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Four-drug combinations |
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First regimen |
Second regimen
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Sustiva + Viracept + Combivir |
None |
| Sustiva +
Viracept + Videx + Zerit |
None
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News Briefs
from 11th Annual Retrovirus Conference
The following items were among several
hundred presented at the 11th Annual Retrovirus Conference,
held in February in San Francisco. For more information on
these and other news, visit the conference website at www.retroconference.org.
Genetics affect
Sustiva side effects
Researchers from the AIDS Clinical Trials
Group (ACTG) found a correlation between genetics and nervous
system syndroms side effects in people taking Sustiva. The association
was seen in the very first four weeks of therapy, but disappeared
out to six months time despite the continued high blood levels
of Sustiva. The ACTG analysis found that a particular genetic
marker caused people to clear the drug out of their body more
slowly. This led to higher blood levels of the drug—three
times greater than the average area under the curve (AUC)—with
a higher rate of central nervous syndroms.
Nevertheless, the researchers said that
long-term toxicity remains to be determined. The people taking
Sustiva noted their side effects through a questionnaire taken
regularly throughout a sub-study of ACTG 5095.
The genetic marker, found on the CYP2B6
liver enzyme, was more common in African Americans than in Caucasians.
(CYP enzymes process drugs in the liver.) The form of the gene
associated with the highest Sustiva levels was present in 20%
of African Americans but only 3% of Caucasians. Either group,
however (as well as Latinos) can have the CYP2B6 G516T polymorphism
marker, and with it, greater side effects. There was a lot of
overlap. Some of the African American participants had lower
Sustiva concentrations, and some of the Caucasians had higher
concentrations. Of the few Latinos in the sub-study, the one
who was homozygous for TT at position 516 had the highest Sustiva
blood levels. There were 157 persons on Sustiva included in
the genetic analysis, 57% of them Caucasian, 32% African American
and 10% Latino. No gender difference was found.
After adjusting for weight there was
still an association with decreased Sustiva clearance. Analysis
of DNA from a separate group of individuals, including about
100 Caucasians and 100 African Americans, confirmed that the
G516T polymorphism is much more common in African Americans
than in Caucasians. Previous research, including an ACTG study
presented at CROI, found higher blood levels of Sustiva on average
in African Americans than in Caucasians.
The researchers said their findings
raise several questions, including whether the same genetic
markers also affect Viramune, an HIV antiviral in the same drug
class as Sustiva; the effect on viral load, T-cell count and
HIV drug resistance; and the effect on different ethnic and
racial groups around the world. They noted that their findings
need to be confirmed.
Of special interest is the fact that
due to results from previously published data, no one expected
these findings. Presenter Dr. David Haas of Vanderbilt University
gave credit to Dr. Edward Acosta of the University of Alabama
for the idea leading to this analysis (as well as to the people
who carried it out). Said Dr. Haas, “I think we’re
just hitting the tip of the iceberg on all this. It’s very
complicated.”
Disparities
workshop at Vanderbilt
Dr. Haas invited the audience to attend
the 2004 Workshop on Disparities and the HIV Epidemic November
18–19. The national meeting will present up-to-date information
about racial, ethnic and gender disparities that affect clinical
practice, including disparities in the epidemiology, pathogenesis,
and treatment/vaccine responses of HIV and other pathogens (such
as hepatitis C virus and M. tuberculosis) and current research
on biological and genetic mechanisms that may underlie these
disparities (such as pharmacogenomics and host factors involved
in HIV replication). For more information, contact R. Renae
Speck, Ph.D. at renae.speck@vanderbilt.edu or (615) 322-6126.
Viramune resistance
after labor
Viramune very effectively cuts the rate
of HIV transmission from mothers to infants, but even a single
dose given to a woman at the time of labor has been shown to
cause drug resistance. Researchers looked for drug resistance
in women who recently gave birth and whether it had any effect
on their HIV therapy later on.
They looked at women in a study conducted
in Thailand. That study found that HIV transmission to infants
was further cut—by 80%—when one dose of Viramune was
added to on-going Retrovir (AZT).
Researchers looked for HIV drug resistance
in blood samples 10 days after the women gave birth. In a random
sample of 90 women, 18% had at least one HIV genetic mutation
associated with resistance to Viramune (expected to decrease
the drug’s effectiveness). Three months after giving birth,
80% of the 66 women with at least one mutation and 87% of the
112 women who received a single dose of Viramune had less than
400 viral load, compared to 88% of the 41 women who did not
receive Viramune. Six months after giving birth, those figures
were 68% of 50 women, 80% of 90 women and 85% of 27 women, respectively
(presumably the missing numbers are for women who had dropped
out of the study or did not reach the study time point when
the analysis was conducted). This was not statistically different,
although there was a trend to a statistical significant difference.
However, there was a large statistical
difference when looking at women who started HIV therapy immediately
after labor or those who waited six months. Women who waited
did much better on therapy. For the women who received a single
dose of Viramune and started therapy six months after birth,
77% of the women with mutations and 91% of the women without
mutations had less than 400 viral load. This compared to 58%
and 69%, respectively, of the women who started therapy earlier.
The researchers said that while single-dose
Viramune may reduce the effectiveness of a woman’s HIV
therapy later on, there was still a large number of women in
this group who achieved an effective response against the virus
with therapy. The difference in when to start therapy gives
hope to finding effective strategies for reducing transmission
to infants while not compromising future therapy for either
mother or infant. They noted that HIV resistance to Viramune
may last a long time and may re-emerge when the patient is once
again exposed to Viramune or another non-nucleoside analog.
Prevention
for sex partners
University of California, San Francisco
researchers updated their previous report on the use of HIV
drugs to prevent infection in sexual partners. In that report
they found that drug therapy did not cause people to become
lax about safe sex. Although the study was not designed to study
efficacy, they did report that there were no new infections
within 6 months of starting PEP. This time, however, they were
presented some information that causes a more cautious interpretation.
At 12 weeks after starting PEP, there
were seven infections out of 700 people. Those seven persons
had high-risk sexual activity before and after receiving therapy
and there was never virus available from the potential source
of infection, making it impossible to know if these infections
resulted from another exposure or from the failure of PEP to
prevent infection . These type of cases will make the effectiveness
of prevention therapy difficult to determine. (You could remove
this sentence Infection may occur as much as six months after
exposure, so it can be hard to determine which exposure led
to infection.)
Post-exposure prophylaxis (PEP for short—prophylaxis
means “prevention”) was given within 72 hours of a
sexual or needle-sharing exposure. PEP consisted of either Combivir,
Zerit plus Epivir or Zerit plus Videx (a combination that is
no longer recommended in U.S. treatment guidelines). Treatment
was given for 28 days. People exposed to a partner who had a
detectable viral load while on antiretroviral therapy were also
offered a protease inhibitor drug in addition to two of the
drugs listed above. Risks reduction and adherence counseling
were also provided. The researchers noted that for needlestick
injuries in healthcare, the use of AZT (Retrovir) for a month
was known to cut the transmission of HIV by 81%.
All seven of the men who seroconverted
had had unprotected anal receptive intercourse (four of them
with partners who they knew had had HIV; the others were at
risk for HIV) within 72 hours before PEP, compared to half of
the people who did not seroconvert. All also had additional
high risk behaviors in the 6 months prior to starting PEP. Three
of the seven also had unprotected anal receptive sex within
months after PEP and at least one may have already been HIV-infected
at the time of PEP although his antibody test was negative.
The seroconverters started PEP at a
mean of 45.5 hours compared to 32.5 hours among those who did
not seroconvert, but this was only a trend towards statistical
significance. One of them reported fair adherence to the medications
while two reported poor adherence—the drugs can be very
hard to take. The poster presentation noted that, “Most
importantly, primary prevention efforts must be reinforced to
reduce both occupational and non-occupational HIV exposures.”
Lead researcher Dr. Michelle Rolland
said, “I have always been very cautious in letting people
know that this is an unproven strategy. The immune system of
the mucosa [in sexual contact] is different from what the virus
will confront in a needlestick injury. Given all the related
data in the occupational, mother-to-child transmission and animal
studies I suspect there must be at least partial effectiveness
of PEP after non-occupational exposures, but we don’t know
that for sure.” |
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