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Update from DDW: Part 2
Alan Franciscus, Editor-in-Chief
Part 2 will focus on information presented on hepatitis
C and veterans at the DDW 2004 Conference.
HCV Therapy for African Americans
Liz Highleyman
The rate of hepatitis C among
African Americans is estimated to be 2-3 times higher than
the rate among whites. Several recent studies have examined
the manifestations of hepatitis C in different racial/ethnic
groups, as well as differences in response to HCV therapy.
HealthWise: Herbs and Hepatitis C: Part3
Lucinda K. Porter, RN, CCRC
The first installment of this three-part series presented
an overview on the subject of herbs and hepatitis C virus
(HCV) infection. Last month's column suggested guidelines
and tools that can be used for making informed choices about
the use of herbs. This month's column focuses on a few herbs
that may be helpful or problematic for those with liver disease.
A list of resources has been provided at the end of this article
for those who want more information about herbs.
Stay informed on the latest news
..click here to register for email alerts
Update
from DDW: Part 2
Alan Franciscus, Editor-in-Chief
Part 2 will focus on information presented on hepatitis
C and veterans at the DDW 2004 Conference.
It is estimated that 5 to 10% of the veteran
population is infected with hepatitis C (HCV). In many ways
the Veterans Administration health care system has been at
the forefront of research, screening, treatment and disease
management. As the veteran population with HCV ages, HCV disease
progression will increase proportionately. This increase in
disease progression among veterans will have a dramatic impact
on the future burden of care in the VA health care system.
HCV Prevalence
Among Veterans
It is well known that the veteran population has a higher
prevalence of HCV than the general population. J. Dominitz
and colleagues conducted a study of 3863 randomly selected
patients at 20 VA Medical Centers to estimate the prevalence
HCV antibodies among veterans. Of the original 3863 patients,
only 1288 were included in the study. The remaining patients
refused to participate, could not be contacted or could not
have blood drawn.
The authors reported a 4% HCV prevalence rate in their study,
but, after controlling for many factors, estimated that 5.4%
of the general veteran population in the United States is
infected with hepatitis C. Sixty-three percent of all patients
and 100% of those positive for HCV reported blood transfusions,
intravenous drug use, drug snorting, tattoos, incarceration,
or more than 15 sexual partners, which is consistent with
risk factors found in the general population. The authors
stated that "the VA system should start to prepare for
the increasing burden of care since HCV positive patients
will progress on to more serious disease progression over
time."
HCV Screening
and Referral
In a study to determine the effectiveness of screening and
referral in a large urban Veterans Medical Center, H. Groom
and colleagues conducted a retrospective review of all patients
tested for hepatitis C from 1/1/00 through 12/31/01. Six hundred
and eighty-one patients were identified of whom 670 received
confirmatory HCV RNA (viral load) testing. Seventy-eight percent
(520 patients) tested positive for HCV RNA and 22% (150 patients)
tested negative.
Of the 520 patients that tested HCV RNA positive, 83% (430
patients) were referred to specialty care in the hepatitis
C clinic. The remaining 17% (90 patients) were neither referred
nor scheduled. Eighty-nine percent of the patients (382 patients)
referred to a specialty clinic attended at least one appointment;
eleven percent (48 patients) did not attend any referral appointments.
The authors found that the average time between diagnosis
and scheduled appointment was 63 days, with 21% of patients
having had a scheduled follow-up more than 6 months after
diagnosis. A total of 33% (124 patients) of these patients
received interferon drug-based therapy over 3.5 years during
the study follow-up. Of the original 124 patients, 109 patients
completed therapy and 39.4% (36) patients in the group achieved
a sustained virological response (SVR).
In an effort to increase the number of patients seeking medical
care, the authors recommended that patient referrals after
screening should be increased and the waiting time between
screening and clinic appointment should be reduced. The authors
also stated that improvements in clinical care and treatment
options are needed.
Access to Care
Why do many so patients fail to access medical care when effective
therapeutic options exist? This is a question that Eric W.
Dieperink and colleagues sought to answer with specific focus
groups in order to develop strategies that would encourage
veterans to seek medical care. The authors conducted seven
focus groups consisting of patients that were actively in
HCV care (2 groups) and patients that did not attend any specialty
care appointments (5 groups). The patient characteristics
were similar in both groups.
The researchers identified several factors that influence
barriers to seeking care, including the lack of patient knowledge
regarding HCV care, disease progression and treatment. In
addition, the authors found that social stigma was an important
factor that prevented patients from seeking medical care.
The authors recommended several strategies for improving access
to care including flexibility of appointment scheduling, support
group availability, and the interest and knowledge of the
staff. Additional recommendations included: peer resources
to enhance knowledge regarding asymptomatic disease versus
active disease; resources that target family and friends to
decrease stigma; and decreases in the time from diagnosis
to first appointment, which will improve the connection between
patient education and test results.
Treatment
A. Anantharaju and colleagues released data from a study conducted
at an urban VA hospital on the effectiveness of pegylated
interferon plus ribavirin combination therapy in veterans
with hepatitis C.
This study followed 246 male HCV patients who started pegylated
interferon (Peg-Intron and Pegasys) plus ribavirin therapy
between May 2001 and April 2004. The pegylated interferons
were given at the recommended dose; ribavirin was given at
a dose of 11 mg/kg. Pretreatment liver biopsies and genotype
tests were obtained. Growth factors were used as needed for
cytopenias.
Of the 246 patients who began therapy, 168 patients completed
therapy and 141 patients were available for the 24-week post
follow up evaluation. The overall sustained virological response
(SVR) was 31.2%. A total of 61.3% patients reported side effects—anemia
(30.5%), psychiatric disturbances (19.1%), thrombocytopenia
(5.1%), neutropoenia (7.1%), and hypothyroidism (8.5%). Approximately
20% stopped therapy due to side effects. The authors concluded
that the SVR among veterans is higher when compared to standard
interferon and ribavirin, but lower than the large pegylated
interferon plus ribavirin clinical registration trials.
The authors also released data on another study examining
the use of pegylated interferon plus ribavirin in veterans
with compensated cirrhosis. In this study 55 patients were
enrolled of whom 31 completed 48 weeks of therapy. The overall
SVR was 11.8%. Reported side effects included: anemia (28.9%),
psychiatric disturbances (22.2%), thrombocytopenia (15.6%),
neutropenia (11.1%), and hypothyroidism (8.5%). Approximately
20% of the patients did not complete therapy due to side effects.
The authors concluded that treatment with pegylated interferon
and ribavirin showed a poor response rate in veterans with
compensated cirrhosis compared to HCV patients treated in
the general population.
Treatment Related
Depression among Veterans
E. Paredez and colleagues presented data on a study to identify
trends of psychiatric side effects in patients with a history
of significant psychiatric disorders compared to patients
without psychiatric disorders.
The study analyzed data from all patients (total of 40 patients)
with hepatitis C who finished HCV treatment at the Albuquerque
Veterans Administration Medical Center between January 2002
and September 2003. Information, including clinical and psychiatric
data in addition to the CES-D scale (Center for Epidemiologic
Studies - Depression), was collected at baseline, week 2,
4, 8, 12 and every 6 weeks thereafter. Data collected included
the increase in psychiatric medications, completion of planned
HCV therapy and sustained virological response rates. The
researchers found that more than half of the veterans with
or without a psychiatric diagnosis required an addition or
increase in psychiatric medication while receiving interferon-based
therapy, but that patients with psychiatric diagnoses did
not have a worsening of their depression. The authors stated
that this may be due to timely interventions and adjustment
of their psychiatric medication during treatment. More importantly
the authors found that the treatment response rates and the
rate of patients that completed therapy were similar between
the two groups.
The Evaluation and Use of Antidepressants
in Veterans
J. Nelligan and colleagues examined the use of antidepressants
for treatment of interferon-induced depression. Four hundred-seventy-eight
veterans were enrolled in the study and completed a Beck Depression
Inventory-II (BDI-II) test as part of their initial HCV specialty
clinic appointment. It was found that, of the 478 veterans
enrolled in the study, (31.5%) were taking a psychotropic
medication prescribed for depression, anxiety, sleep difficulty,
pain, psychotic symptoms, etc. One hundred-thirty-two (27.6%)
were taking an antidepressant (mostly SSRIs); 96 patients
(20.1%) were taking opioid pain medications and 32 patients
(6.7%) were taking other types of pain medication.
According to the completed BDI-II scores, it was found that
about 1/3 of the patients had moderate to severe depression
of whom 72 (56%) patients were not taking an antidepressant.
Furthermore, 57 (44%) patients continued to experience moderate
to severe depression despite taking antidepressants. The 260
veterans who were not prescribed antidepressants at the beginning
of the trial scored lower (less depression) than those veterans
(119) taking an antidepressant (14.2 vs. 19.1, p<.0001).
The authors noted that depression was common in this sample
group and recommended routine screening for psychiatric illness
to facilitate the treatment of depression, which should decrease
treatment related side effects, allowing the patient to stay
on HCV therapy, thereby increasing treatment response.
Back to top
HCV
Therapy for African Americans
Liz Highleyman
The rate of hepatitis C among
African Americans is estimated to be 2-3 times higher than
the rate among whites. Several recent studies have examined
the manifestations of hepatitis C in different racial/ethnic
groups, as well as differences in response to HCV therapy.
Various retrospective studies have
suggested that blacks do not respond as well as whites to
interferon-based therapy. But not all studies have reached
this conclusion. For example, Richard Sterling and colleagues
reported in the May 2004 issue of the American Journal
of Gastroenterology that in a retrospective analysis
of 59 Virginia prison inmates, blacks and whites with genotype
1 HCV treated with standard interferon plus ribavirin achieved
similar sustained virological response (SVR) rates (29% vs
33%). The authors concluded that—at least in a correctional
setting where directly observed therapy ensures excellent
adherence—blacks respond about as well as whites.
Most past HCV treatment research has included relatively small
numbers of African Americans. Recently, however, two prospective
studies designed to include adequate representation of blacks
also concluded that people of African descent do not respond
as well as whites.
In the June 2004 issue of Hepatology, Lennox Jeffers
and colleagues reported on an open-label study of 78 blacks
and 28 non-Hispanic whites, all with genotype 1, receiving
HCV treatment for the first time. The characteristics of the
two groups were generally similar, but the black group included
more men and the black participants were slightly older, somewhat
heavier, and slightly more likely to have high viral loads.
After 48 weeks of therapy with Pegasys plus ribavirin, 26%
of blacks and 39% of whites achieved SVR in an intent-to-treat
analysis. This is the highest response rate yet seen in a
black population. In a multivariate analysis, black race,
age less than 40, lower viral load, and lower baseline ALT
levels were significantly associated with SVR.
Side effects were more common in whites, and more whites discontinued
therapy due to adverse events. However, about twice as many
blacks had their Pegasys dose reduced due to neutropenia (a
low level of neutrophils, a type of immune system white blood
cell). Because healthy blacks naturally have lower neutrophil
levels than healthy whites, neutropenia is a greater concern
for black patients. However, studies suggest that neutropenia
does not increase the risk of serious infections in blacks
being treated for HCV. Paired pre- and post-treatment biopsies
revealed that more than 90% in both groups showed improved
or stabilized fibrosis progression. Overall, 25% of black
subjects showed evidence of improvement, including 22% of
patients who did not achieve SVR.
In a second study reported in the May 27, 2004 issue of the
New England Journal of Medicine, Andrew Muir and
colleagues treated 100 black and 100 white subjects (98% in
both groups with genotype 1) with Peg-Intron plus ribavirin
for 48 weeks. The characteristics of the two groups were similar
although, here again, there were more men in the black group
and the black patients were slightly older, somewhat heavier,
and had been infected with HCV slightly longer. Although adherence
was comparable, SVR rates were considerably lower for blacks
than whites: 19% vs 52% in an intent-to-treat analysis. In
a multivariate regression analysis, only black race was significantly
associated with lower response rates.
In contrast to Jeffers’ study, side effects were similar
in both groups, as were the rates of dose reduction and treatment
discontinuation. However, in this trial 10 black patients
were initially excluded due to low neutrophil counts. A comparison
of pre- and post-treatment liver biopsies from patients who
did not achieve SVR revealed that white participants experienced
a greater reduction in histological activity and fibrosis
scores than blacks.
It is not clear why people of African descent respond less
well to HCV treatment, but there are several possible contributing
factors. Blacks are more likely than whites (about 90-95%
vs 65-75%) to have hard-to-treat genotype 1 HCV, but this
was not relevant in these two studies, which included only
or mostly individuals with this genotype. Male sex, older
age, and heavier weight are also linked to worse treatment
outcomes, but these factors were not significantly associated
with decreased SVR rates in these studies.
Jeffers and colleagues suggested that differences in the rate
of viral clearance may be due to “variations in interferon
pharmacokinetics, signal transduction pathways, or immunologic
factors.” Recent research has shown that interferon
does not produce as much HCV suppression within the first
24-48 hours in black patients. It is possible that blacks
process interferon differently in their bodies. Or, they may
respond differently to interferon. Some studies suggest that
blacks have a weaker natural interferon response to HCV, which
may explain why they are less likely to spontaneously clear
the virus and more likely to develop chronic hepatitis C.
Other possible factors include higher testosterone levels
in blacks and differences in CD4 and CD8 cell activity and
cytokine (intracellular chemical messenger) production. Another
hypothesis points to different genetic patterns of HLA molecules,
antigens on human cells that influence immune response.
While African Americans respond less well to interferon, the
news is not all discouraging. Studies also indicate that blacks
appear to suffer less HCV-related liver damage. In the June
2004 issue of Clinical Gastroenterology and Hepatology,
Kester Crosse and colleagues reported that in a retrospective
comparison, despite being older and more likely to have genotype
1, black patients had lower ALT levels and lower fibrosis
and histological activity scores than whites (7.6 vs 8.7),
indicating less liver necrosis (cell death) and inflammation.
Sterling’s team (see above) also found that
blacks had lower mean ALT levels, less piecemeal necrosis,
and lower fibrosis scores than whites, although a similar
proportion had bridging fibrosis or cirrhosis. And in a retrospective
analysis of 355 liver biopsy specimens, T.E. Wiley and colleagues
found that African Americans with HCV had lower ALT levels,
less liver inflammation, and less cirrhosis than individuals
of other racial/ethnic groups. It is not yet clear why this
is the case, but because HCV-related liver damage is largely
due to the immune system’s response rather than the
virus itself, the variations in immune activity discussed
above could help explain these differences as well.
Clearly, more research is need on the natural history of hepatitis
C and response to treatment in different racial/ethnic groups.
These studies highlight the importance of including adequate
numbers of African Americans and other non-Caucasian individuals
in clinical research. A large National Institutes of Health
trial called VIRAHEP-C is currently underway to further explore
treatment response in African Americans with chronic hepatitis
C.
Back to top
HealthWise:
Herbs and Hepatitis C—Part 3
Lucinda K. Porter, RN, CCRC
The first installment of this three-part series presented
an overview on the subject of herbs and hepatitis C virus
(HCV) infection. Last month's column suggested guidelines
and tools that can be used for making informed choices about
the use of herbs. This month's column focuses on a few herbs
that may be helpful or problematic for those with liver disease.
A list of resources has been provided at the end of this article
for those who want more information about herbs.
HCV Treatment
and Herbs
There is virtually no research on the safety of herbs and
supplements co-administered with pegylated interferon/ribavirin
therapy. Because of this, it is common for patients to abstain
from milk thistle and herb use while undergoing antiviral
therapy. Even commonly used botanicals need to be used with
caution. Quite a few herbs can alter laboratory results. Some
herbs and supplements can hinder the ability of the blood
to clot. For instance, ginger is widely used to relieve nausea.
However, patients with gallstones should talk to their healthcare
provider prior to using ginger. Additionally, ginger has an
anticlotting action and should not be taken if you have reduced
blood clotting ability. Interferon therapy and/or cirrhosis
can also interfere with blood clotting, so there may be an
increased risk if some herbs are used simultaneously under
these conditions. Other commonly used herbs, such as chamomile
and St. John's Wort carry a warning of potential drug interactions.
The rule of thumb is to be informed and talk to your healthcare
provider prior to using any botanical product.
Milk Thistle
Milk thistle, (Silybum marianum), is the most commonly
used herb for liver problems. A frequently asked question
regarding chronic HCV infection concerns the use of this herb.
If you are considering taking a milk thistle product, talk
to your doctor and find out if it is compatible with other
drugs or supplements you are taking. Verify that the supplement
is not contraindicated for any other condition you may have
(see “A Warning about Milk Thistle and Drug Interactions”
below). Do not use milk thistle if you have decompensated
cirrhosis.
Medical consultants for the Consumers Union recommended the
following in the April 2001 issue of Consumer Reports
On Health:
• Patients should not use milk thistle to replace a
conventional treatment for viral hepatitis;
• Patients should not take milk thistle while on a conventional
treatment for viral hepatitis;
• Milk thistle is probably safe and no one should be
discouraged from taking it if there are no other options;
• Choose a brand that contains silibin and phosphotidyl
choline, which may be better absorbed.
There is insufficient research to establish a suggested daily
dose of milk thistle. Typical dosages are in the range of
140-420 mg in divided doses, 2-3 times a day, of 70-80% silymarin.
See the section "Suggested
Guidelines for Herbal Use" in part 2 of this
series for more information on choosing milk thistle and other
herbal products.
A Warning About
Milk Thistle and Drug Interactions
Raman Venkataramanan and colleagues1 at the University
of Pittsburg reported observations about silymarin, a compound
found in milk thistle. In short, this report raised concerns
that silymarin may impair the metabolism of certain drugs
when taken together. Further, the potential exists for increased
toxicity of co-administered drugs in the presence of silymarin.
The medication levels of the following may increase if taken
by people who are also using milk thistle. The source for
this list is the Community AIDS Treatment Information Exchange
(CATIE). It is not meant to be complete.
• protease inhibitors
• non-nucleoside analogues
• methadone
• heart drugs - Tambocor (flecainide), Rythmol (propafenone)
• antibiotics - erythromycin, rifampin
• anti-seizure drugs - carbamazepine (Tegretol)
• antidepressants - St. John's wort, Zyban/Wellbutrin
(bupropion), Paxil (paroxetine), Prozac (fluoxetine), Luvox
(fluvoxetine), Serzone (nefazodone), Zoloft (sertraline),
Effexor (venlafaxine)
• antifungals - itraconazole (Sporanox), ketoconazole
(Nizoral)
• gastrointestinal motility agents - Prepulsid (Cisapride)
• ergot drugs - Ergonovine, Ergomar (ergotamine)
• anti-psychotics - Clozaril (clozapine), Orap (pimozide)
• sedatives/sleeping pills - Ambien (zolpidem), Halcion
(triazolam), Versed (midazolam)
• lipid-lowering drugs (statins) - Lescol (fluvastatin),
Mevacor (lovastatin), Pravachol (pravastatin) and Zocor (simvastatin),
Baycol (ceriva-statin)
• transplant drugs - cyclosporine (Neoral, Sandimmune),
ProGraf (tacrolimus)
Milk thistle also has the potential to lower levels of the
following drugs:
• anti-parasite drugs - Mepron (atovaquone)
• sedatives/sleeping pills - Ativan (lorazepam)
• hormones - estrogen
Some Herbs Associated
with Liver Toxicity
This list is primarily liver specific and by no means exhaustive.
The substances on this list are referred to in their oral
form only.
• Blue-green Algae
• Borage (Borago officianalis)
• Bupleurum
• Chaparral (Larrea tridentata)
• Comfrey (Symphytum officinale and S.
uplandicum)
• Dong Quai (Angelica polymorpha)
• Germander (Teucrium chamaedrys)
• Jin Bu Huan (Lycopodium serratum)
• Kava
• Mistletoe (Phoradendron leucarpum and Viscum
album)
• Pennyroyal (Mentha pulegium)
• Sassafras (Sassafras albidum)
• Shark Cartilage
• Skullcap (Scutellaria lateriflora)
• Valerian
Warning: Bupleurum
is a popular herb used in a variety of traditional Chinese
and Japanese medicine mixtures for liver conditions. At least
16 deaths have been reported in Japan in HCV patients being
treated simultaneously with alpha interferon and Xiao Chai
Hu Tang (Minor Bupleurum).
Ephedra
Although not specifically associated with liver toxicity,
products containing ephedrine alkaloids (ephedra) should be
avoided. Reports of heart attacks, strokes, seizures, psychosis,
and death have been linked to the use of ephedrine alkaloids.
The FDA has banned the sale of dietary supplements containing
ephedrine alkaloids, including ephedra and Ma Huang.
Final Words
Herbs have been part of the healing arts for centuries. Clearly
more research needs to be conducted in this area in order
to better understand and incorporate the use of botanical
products into current health practices. In the meantime, make
informed decisions regarding your health. Your future depends
on it.
References
1Venkataramanan R, Ramachandran V, Komoroski BJ,
et al. Milk thistle, a herbal supplement, decreases the activity
of CYP3A4 and uridine diphosphoglucuronosyl transferase in
human hepatocyte cultures. Drug Metabolism and Disposition
2000;28(11):1270-1273.
Resources:
Books
•The American Pharmaceutical Association Practical
Guide to Natural Medicines, by Andrea Peirce
•The ABC Clinical Guide to Herbs, edited by
Mark Blumenthal, et al at the American Botanical Council
•ConsumerLab.com's Guide to Buying Vitamins &
Supplements: What's Really in the Bottle, by Tod Cooperman,
M.D., William Obermeyer, Ph.D., Denise Webb, R.D., Ph.D.
•The Green Pharmacy, by James A. Duke
•Herbs of Choice, by James E. Robbers and Varro E. Tyler
•PDR for Herbal Medicines, published by the
Medical Economics Company
•Tyler's Honest Herbal: A Sensible Guide to the
Use of Herbs and Related Remedies, by Stephen Foster
and Varro E. Tyler, Ph.D.
Organisations
•American Botanical Council - 512-926-4900,
www.herbalgram.org
•American Herbal Products Association www.ahpa.org
•ConsumerLab.com www.consumerlab.com
•FDA Dietary Supplement website - http://vm.cfsan.fda.gov/~dms/supplmnt.html
•HerbMed - www.herbmed.org
•Memorial Sloan-Kettering Cancer Center www.mskcc.org/aboutherbs
•National Center for Complementary and Alternative Medicine
- 888-644-6226, http://nccam.nih.gov
•National Institutes of Health Clincal Trial Information
www.clinicaltrials.gov
•National Sanitation Foundation (NSF International)
www.nsf.org
•The United States Pharmacopeia - 800-822-8772, www.usp.org
•UC Berkeley Wellness Letter www.wellnessletter.com
©July 2004 Lucinda Porter,
RN and the Hepatitis C Support Project / HCV Advocate www.hcvadvocate.org
- All Rights Reserved.
Reprint is granted and encouraged with credit to the author
and to the Hepatitis C Support Project
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