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Co-infection with hepatitis
C virus (HCV) has become a significant concern for an estimated
16% to 25% of HIV-positive Americans. Although results from
two pivotal studies on the efficacy of pegylated interferon
and ribavirin for treatment of hepatitis C in co-infected
people are not yet available (results from the Adult AIDS
Clinical Trials Group’s 5071 are expected later this year,
and Roche’s APRICOT will conclude in 2004), this year’s Conference
on Retroviruses and Opportunistic Infections (CROI) offered
information on HIV/HCV epidemiology, natural history, diagnostics,
treatment strategies, side effect management, drug interactions
and liver transplantation in HIV-positive people.
This information is essential,
yet several other important concerns revolve around co-infection.
To address some of these issues and introduce their draft
Research & Policy Recommendations for Hepatitis C Virus
(HCV)/HIV Co-infection (http://www.aidsinfonyc.org/tag/comp/hcvhivresearch.html),
the Treatment Action Group hosted a roundtable discussion
on the opening day of CROI. Panelists included Dan Church,
the Massachusetts Hepatitis C Coordinator, Donald Grove, the
Director of Operations at Harm Reduction Coalition, Dr. Lisa
Hirschhorn, the Director of HIV Medical Care and Research
at Dimock Community Health Center, Jules Levin, the Executive
Director of NATAP (National AIDS Treatment Advocacy Project)
and Dr. Kenneth E. Sherman, the Director of Hepatology and
Liver Transplant Section at Cincinnati College of Medicine.
They discussed a range of issues affecting people with hepatitis
C and HIV/HCV co-infection: the lack of state and federally
funded programming for HCV prevention and education, questions
about sexual transmission of HCV, the expense of, and limited
access to, HCV treatment, barriers to care and treatment for
active drug users and prisoners, the absence of treatment
guidelines for co-infected individuals and other aspects of
treatment, research and policy. Despite these crucial questions,
Dr. Sherman provided an optimistic perspective of the current
state of affairs, reminding us of breakthroughs in hepatitis
C research and treatment, from the identification of the hepatitis
C virus in 1989 to the current pegylated interferon-based
regimens which have greatly improved hepatitis C treatment
outcomes for HCV-monoinfected individuals.
Epidemiology and Natural
History
In the United States, an
estimated 16% to 25% of people with HIV are also co-infected
with hepatitis C; rates of co-infection are higher among those
with a history of injection drug use (IDU). A closer look
at HCV prevalence and co-infection prevalence among 557 current
and former injection and non-injection drug users in New York
City found that 89% (204/229) of the HIV-positive study volunteers
had antibodies to hepatitis C, indicating an exposure to the
virus. To confirm or rule out current, active hepatitis C
infections, HCV RNA (viral load) testing was performed on
those with antibodies to HCV (unlike HIV, a person can have
antibodies to hepatitis C without harboring the virus). Three-quarters
of the HCV-antibody positive group (170/229) had detectable
HCV RNA, indicating the presence of chronic HCV infection.
HIV-positive people were more likely to have detectable HCV
RNA, as were males and people with a history of IDU.
Hepatitis C is a smaller
virus than HIV; larger amounts of it are usually present in
infected blood. Because hepatitis C viral loads are often
high, and there’s so much actual virus in a small amount of
blood, hepatitis C is very easily transmitted from injection
drug use with shared, unsterilized equipment—much more so
than HIV. Many co-infected injection drug users already had
hepatitis C before contracting HIV. In the pre-HAART (highly
active antiretroviral therapy, for HIV) era, there were a
few instances of rapid HCV disease progression in individuals
who were infected with HIV and HCV at the same time, or had
an underlying HIV infection when they acquired HCV. Coming
at this question from the other side, a group of researchers
examined the influence of hepatitis C viral load on HIV progression
in a group of injection drug users who had hepatitis C before
becoming infected with HIV. They found no association with
the amount of HCV RNA in a person’s blood prior to HIV infection
and CD4 T-cells decreases, progression to AIDS or AIDS-related
death.
Another group looked at the
trends in HIV-related hospitalizations by diagnosis in 1996,
1998 and 2000, finding that hospitalizations for liver-related
complications rose significantly, while hospital admissions
for opportunistic infections have decreased dramatically.
More than 327,000 hospitalizations from 12 states were separated
into four groups: opportunistic illnesses, complications from
injection drug use, liver-related complications and other
causes. Between 1996 and 2000, hospital admissions for opportunistic
infections decreased from 41% to 29%. The number of hospital
admissions for complications from injection drug use remained
fairly stable, and the hospitalizations for liver-related
complications grew from 13% to 18%.
Many studies have found that
HIV accelerates hepatitis C disease progression. A direct
look at liver biopsies from 492 co-infected people with elevated
liver enzymes discovered more advanced liver disease than
that found in people with a similar estimated duration of
HCV monoinfection. Three factors were associated with more
severe liver fibrosis: being infected with hepatitis C for
more than 15 years, heavy alcohol consumption and being over
20 years old when infected with HCV. More than half of the
study participants had never used antiretroviral therapy.
While a number of other studies
have identified end-stage liver disease as a leading cause
of death for people with HIV, new data from the Veteran’s
Aging Cohort Study found that the risk of death from HIV alone
before 1996 was higher than the risk of death from co-infection
after 1996. In this cohort, the risk of death from HCV mono-
or co-infection has increased since 1996, while the risk of
death from HIV has decreased during the same period. It appears
that the gains in survival from HAART have offset the increased
risk of mortality from co-infection in this group, although
co-infected people had a higher risk of death than those with
HCV alone. However, a longer follow-up period is needed to
truly assess the impact of co-infection and HAART on survival
in this group.
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Many co-infected people are
wondering how HAART will affect the liver. A study of 33 co-infected
individuals starting their first HAART regimen examined immunologic
responses and liver disease progression after 12 months of
antiretroviral therapy. Immune response was defined as either
an increase of 100 or more CD4 T-cells or a doubled CD4 T-cell
count after 12 months of HAART. Liver biopsies were performed
on 25 participants at study entry and 12 months after starting
antiretroviral treatment. Liver disease progression was defined
by an increase of at least two points on the Knodell score
and more than one point on the Metavir score over 12 months
(the Knodell and Metavir systems are used to determine both
the amount of disease activity [grade] and the amount of liver
damage [stage]). Although this study did not find a relationship
between immunologic response to HAART and liver disease progression,
it did observe a significant relationship between elevated
liver enzymes and liver disease progression; 80% of the five
individuals with liver enzyme elevations (defined as five
times above the upper limit of normal) also had liver disease
progression. According to the study investigators, elevations
in liver enzymes were caused by alcohol intake in two persons,
by hepatitis C in two persons and by antiretrovirals (Fortovase,
Norvir, Ziagen and Zerit) in one person. The study concluded
with recommendations for frequent monitoring of liver enzymes
and reducing or eliminating alcohol intake while on HAART.
Longer and larger studies are needed to provide us with more
information on the effect of HAART on liver histology.
An analysis of the data from
41,262 HIV-positive male veterans in care found higher rates
of diabetes mellitus in those with HIV/HCV co-infection than
those with HIV alone; 19.7% of co-infected individuals were
diagnosed with diabetes, as compared with 14.8% of those with
HIV alone. As a comparison, the rate of diabetes in the general
population is 6.2%, and the rate of diabetes among all veterans
in care is 11.83%. The prevalence of diabetes increased among
co-infected individuals over 40 years of age, Black and Hispanic
males and individuals with an alcohol-related diagnosis. Data
on family history and body mass index, two predictors of diabetes,
were not available. Information on protease inhibitor use
in this cohort was not available. Diabetes is more prevalent
among individuals taking PI-based regimens; the link with
protease inhibitors, diabetes and co-infection needs further
investigation. The authors concluded with a recommendation
to screen co-infected veterans for diabetes so that they may
benefit from early diagnosis and intervention.
Diagnostics
Currently, liver biopsy is
the only way to truly assess the grade and stage of liver
disease, and biopsy results are used to evaluate the need
for hepatitis C treatment. The search for less invasive, less
painful and less expensive substitutes for biopsy is an important
concern for co-infected people, clinicians, researchers and
payers. The data from five hepatitis C treatment trials—including
demographics, liver biopsy results, HIV status and other clinical
information were examined. Mean alanine aminotransferase (ALT)
levels were higher in co-infected individuals with no fibrosis,
mild to serious fibrosis and cirrhosis than in those with
HCV monoinfection. Mean ALT level did increase with fibrosis
progression; in persons with mild or no fibrosis, the mean
ALT level was 96.8; the mean ALT rose to 120.9 in individuals
with fibrosis and to 137.9 in those with severe fibrosis or
cirrhosis. However, ALT levels appeared to have limited predictive
value for determining liver histology, and the search for
biopsy substitutes continues.
Treatment Strategies
Data from pivotal studies
of pegylated interferon and ribavirin have indicated that
a sustained virologic response (SVR, undetectable HCV RNA
six months after finishing a course of hepatitis C treatment)
is extremely unlikely for individuals who don’t have either
undetectable HCV RNA or a 2-log drop in HCV RNA after 12 weeks
of treatment. Because the side effects of interferon and ribavirin
may be quite severe, especially among co-infected people,
an early evaluation of the probability of achieving an SVR
spares those who are unlikely to achieve a sustained virologic
response from continuing HCV treatment. A group of researchers
examined the applicability of this “early stopping rule” to
conifected individuals using ribavirin with pegylated or standard
interferon, finding a negative predictive value of 100% at
week 12. However, a high rate of relapse was observed in individuals
with early virologic responses (EVR) at 12 weeks; while 52/89
(58%) had a 12 week EVR, only 29 of those 52 (56%) achieved
a sustained virologic response. High relapse rates were observed
in those with genotypes 2 and 3, who received six months of
treatment as compared with the year of treatment given to
individuals with genotypes 1 and 4. Although six months of
treatment appears to be adequate for individuals with HCV
alone, co-infected people with genotypes 2 and 3 may want
to consider a year of treatment.
The efficacy of two dosing
strategies of standard interferon with ribavirin was evaluated
in 180 co-infected people. One group was given interferon
daily, while the other received three doses of interferon
per week. The discontinuation rate was high, and the rate
of sustained virologic response was low in both arms. The
once-daily arm had fewer dropouts and a higher rate of SVR
by on-treatment (those who finished the study, and those with
no data missing) as well as intent-to-treat analysis (discontinuations
and missing data were considered as treatment failures). The
on-treatment analysis found SVR among 42.9% of those in the
daily interferon arm and 28% in the thrice-weekly arm. When
the more strict intent-to-treat analysis was used, the SVR
rates dropped to 9.3% of those receiving daily interferon
and 4.3% in the thrice-weekly arm. Hopefully, higher rates
of SVR will be achieved with pegylated interferons, mirroring
the improvement in treatment outcomes seen with pegylated
interferons in HCV monoinfection.
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Side Effect Management
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Many side effects have been
associated with hepatitis C treatment. Occular problems, such
as blocked blood supply to the retina, retinal hemorrhages,
and cotton wool spots are known side effects of interferon
alfa. Optic neuropathy, which may result in color blindness
or complete loss of vision, is a rarer side effect of interferon
alfa. New information about screening for, and incidence of,
ophthalmologic disorders during treatment with pegylated interferon
was also presented at the 10th CROI. A study of 18 co-infected
people who were treated for hepatitis C with pegylated interferon
alfa-2b (Schering’s Peg-Intron) and ribavirin found a 39%
incidence of different ocular pathologies (cataracts in one
or both eyes and cotton wool spots) among study participants.
Eye exams were done at baseline and at least every three months.
Treatment was not discontinued in individuals with evidence
of mild retinopathy (less than five cotton wool spots in the
back of either eyeball); if an individual had more than ten
cotton wool spots in the back of either eyeball and any other
signs of ocular problems, treatment was discontinued. One
individual had a 50% loss in color vision, which was evidence
of optic neuropathy. Treatment was discontinued and the problem
resolved completely 10 weeks later. Currently, there are no
guidelines for performing ophthalmologic evaluations during
treatment with pegylated interferon; vigilant surveillance
during treatment with standard and pegylated interferons,
including color vision testing, will decrease the risk of
permanent ocular damage.
Drug Interactions
The FDA’s Adverse Event Reporting
system (AERS, Med Watch) has received information on several
cases of apparent mitochondrial toxicity among HIV/HCV co-infected
individuals who took ribavirin with nucleoside reverse transciptase
inhibitors (NRTIs). A search of the AERS by a group from the
FDA and the University of Cincinnati found 85 unduplicated
reports of adverse events among individuals who were taking
ribavirin with NRTIs. A cluster of events suggestive of mitochondrial
toxicity were reported in 31 of 85 cases. The reported events
included pancreatitis and increased lipase (18), lactic acidosis/increased
lactate (17), increases in liver function tests (8), hepatic
steatosis (fatty liver) (5), hepatic failure (3), increased
CK (1) and neuropathy (1). Of the 31 individuals with suspected
mitochondrial toxicity, 27 were receiving Videx (and 20/27
also received Zerit). Five of the individuals with events
suggestive of mitochondrial toxicity died from complications
of lactic acidosis; all five had received Videx. From this
data, the combination of Videx and ribavirin was associated
with a 5-fold increase in the risk of side effects suggesting
mitochondrial toxicity as compared with the use of ribavirin
with other nucleoside reverse transcriptase inhibitors. In
September 2002, the FDA began including a precaution that
co-administration of ribavirin and Videx is not recommended
because ribavirin increases exposure of Videx’s active metabolite
(ddI-triphosphate), which may cause or worsen ddI-related
clinical toxicities, including pancreatitis, symptomatic hyperlactatemia/lactic
acidosis, and peripheral neuropathy.
Liver Transplantation
Before HAART, transplantation
in HIV-positive people was turned down because of poor survival;
since the advent of HAART, a small number of HIV-positive
people have undergone liver transplants. A follow-up of 23
HIV-positive liver transplant recipients found that their
post-transplant survival rates at 12, 24 and 36 months were
similar to those of HIV-negative organ recipients of comparable
age and race. Survival at 12, 24 and 36 months was 90.9%,
75.9% and 75.9% for HIV-positive recipients vs. 86.6%, 82.3%
and 79.2% for HIV-negative recipients. Although pre-transplant
CD4 count, HIV RNA level and ability to tolerate HAART did
not influence transplant outcomes, post-transplant survival
was poorer among those who were unable to tolerate HAART after
transplantation, individuals with post-transplant CD4 T-cells
counts under 200 and HIV viral load above 400 copies/ml.
Although hepatitis C was
associated with poorer post-transplant survival, there was
no difference in survival between co-infected transplant recipients
and those with HIV alone.
Tracy Swan has been involved
with HIV-related work since 1990. She is currently working
on the updated Hepatitis/HIV HCV Report from Treatment Action
Group (TAG), and lives in New York City. She can be reached
at tracyswan9@aol.com.
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Morphine and Hepatitis
C Replication
One study looked at the effects
of morphine on HCV replication, using a replicon system. Because
hepatitis C doesn’t replicate in cells outside of the human
body, researchers use replicons (synthetic RNA sequences containing
pieces of the HCV genome) to study what HCV does inside of
cells. Although hepatitis C replicons can copy themselves,
they cannot infect new cells.
Although morphine enhanced
expression of HCV RNA in the replicon system, these results
may not apply to the more complex environment of the human
body; a replicon is not the hepatitis C virus itself, and
a replicon system is not the human body. The effects of morphine
on a replicon are not equal to the effects of morphine on
the human body.
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