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HIV Treatment Series
II - Part three of four
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sponsored in part by
an unrestricted grant from
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| Hepatitis
C Co-Infection Review
by Daniel Raymond
Chronic infection with the hepatitis
C virus (HCV) has become a major concern for people living with
HIV (PLWH). In the United States, over 200,000 people—an
estimated 25% of all PLWH—also have hepatitis C. The majority
of HIV/HCV co-infected persons acquired both viruses from injection
drug use with contaminated equipment. While the course of hepatitis
C infection varies widely, research indicates that HIV can accelerate
the course of hepatitis C, leading to more rapid progression
of liver disease and increasing HCV viral loads. Hepatitis C
treatment does not work as well in HIV-positive people, and
people with hepatitis C can have more trouble tolerating antiretrovirals
for HIV, which can be hard on the liver (hepatotoxic). In recent
years, end-stage liver disease from hepatitis C has become a
leading cause of death for people living with HIV. This article
will review recent research on hepatitis C and HIV co-infection,
with a focus on new data on hepatitis C treatment for PLWH.
How hepatitis C works
The hepatitis C virus infects the liver,
the organ responsible for storing, filtering, and metabolizing
chemicals that pass through the body, including nutrients from
food, drugs, and medications. Most people who acquire HCV develop
chronic infection, though about 30% can clear the virus spontaneously
within a few months after being infected. Hepatitis C is thought
to damage the liver by triggering immune responses that attempt
to kill infected liver cells. As cells die, the liver responds
by producing fibers to seal up the damaged areas, a process
called fibrosis. This allows the liver to regenerate while preventing
further damage.
With chronic hepatitis C infection,
the liver often fails to maintain the balance between damage
and regeneration. The immune system tries to keep hepatitis
C in check, but this requires the on-going destruction of potentially
infected liver cells. Over time, fibrous tissue can build up,
leading to cirrhosis, or scarring of the liver. Many people
have well-compensated cirrhosis, where the liver can still function
in spite of significant scarring. Some people progress to decompensated
cirrhosis, a life-threatening conditioning that occurs when
the accumulation of scar tissue interferes with the proper functioning
of the liver, ultimately leading to liver failure. People with
cirrhosis are also at risk of developing liver cancer, also
called hepatocellular carcinoma, which is potentially fatal.
The good news is that for people with
hepatitis C, liver damage is typically a very slow process,
occurring over decades. Some people never develop any significant
liver damage, and the majority does not progress to cirrhosis.
However, several studies have documented more rapid fibrosis
progression in people co-infected with hepatitis C and HIV.
It is unclear why co-infected people experience more rapid and
severe liver disease, though people with low CD4 T-cell counts
are at highest risk of cirrhosis and end-stage liver disease.
HIV may impair the immune system’s ability to respond effectively
to hepatitis C, particularly in people with low CD4 T-cell counts.
The result is the worst of both worlds—higher hepatitis
C viral loads and more liver damage. Some people hope that successful
highly active antiretroviral therapy (HAART) might offset HIV’s
effect on fibrosis progression, while others worry that HIV
medications may worsen liver disease due to hepatotoxicity.
Available research has been inconclusive or shown little effect
of HAART on fibrosis, positive or negative. Some HIV medications—particularly
Viramune (nevirapine) and full-dose Norvir (ritonavir) are more
likely to be hepatotoxic, particularly in people co-infected
with hepatitis C, and require careful monitoring.
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These studies suggest
that earlier assessments of fibrosis in co-infected people
may have been overly pessimistic.
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| Update
on fibrosis
Despite this grim outlook, two recent reports from Johns Hopkins
University, presented at the 11th Conference on Retroviruses
and Opportunistic Infections (CROI) in February, offer some
good news for people co-infected with hepatitis C and HIV. Both
studies used liver biopsies, the most accurate test for liver
damage. The liver biopsy is a procedure that uses a long needle
to take a small sample of liver tissue that can be examined
for signs of fibrosis and inflammation. One study looked at
a random selection of 115 co-infected patients in a clinical
cohort. Only 17% had cirrhosis, and 43% showed no fibrosis.
A second study looked at fibrosis progression in 116 injection
drug users with chronic hepatitis C who had received two liver
biopsies, averaging four years apart. Over half of the people
in the study showed little or no fibrosis, and only 6% had cirrhosis.
Fibrosis progression was fairly slow overall. Though 28% of
the study group was co-infected with HIV, HIV status did not
influence the rate of fibrosis progression. Together, these
studies suggest that earlier assessments of fibrosis in co-infected
people may have been overly pessimistic.
In the Johns Hopkins studies, elevated liver enzyme levels (ALTs,
for alanine aminotransferase, or ASTs, for aspartate aminotransferase)
were associated with greater risk of fibrosis progression and/or
serious fibrosis. Another report from Italian researchers supports
these results, finding that 75% of co-infected persons with
persistently normal ALT levels had little or no fibrosis, while
those with elevated ALTs tended to have more serious fibrosis.
However, some people with normal liver enzyme levels do have
cirrhosis, which can only be determined through liver biopsy.
Because biopsies are invasive procedures that can be painful
and carry a small risk of complications, several researchers
are looking for ways to gauge fibrosis and cirrhosis through
blood tests. So far, results from various types of blood tests
have not been as accurate at fibrosis, though another Johns
Hopkins poster at CROI described a combination of tests that
could identify a substantial proportion of co-infected people
with minimal liver damage, reducing the need for biopsy.
Hepatitis C treatment
Liver biopsies provide crucial information for people considering
hepatitis C treatment. People with minimal fibrosis may choose
to defer treatment and get a follow-up biopsy in another 2–3
years. However, HCV treatment is recommended for people with
moderate to severe fibrosis or compensated cirrhosis. Treatment
is not indicated for people with decompensated cirrhosis, where
damage to the liver has compromised its ability to function.
Decompensated cirrhosis generally requires a liver transplant.
Treatment for hepatitis C consists of a combination of two drugs,
pegylated interferon and ribavirin. Pegylated interferon is
a synthetic form of interferon alpha, an antiviral molecule
naturally produced by the body. Pegylated interferon is taken
once a week by injection. The FDA has approved two forms of
pegylated interferon: Pegasys, made by Roche, and Peg-Intron,
marketed by Schering-Plough. Ribavirin is a nucleoside analogue
(like AZT and Epivir) that comes in pill form, taken orally
twice a day. Both drugs can have serious side effects, including
flu-like symptoms, fatigue and anemia, and depression and insomnia.
A substantial number of people have to reduce their doses of
pegylated interferon and/or ribavirin at least temporarily due
to side effects, and some people cannot tolerate a full course
of therapy and discontinue treatment early. A small but worrisome
number of suicides have been reported among people undergoing
hepatitis C treatment. People with histories of drug use may
have particular difficulty dealing with the side effects of
treatment, putting them at risk of relapse to addiction.
The goal of hepatitis C treatment is total clearance of HCV,
with an undetectable hepatitis C viral load. People maintaining
an undetectable viral load six months after the end of treatment
are called sustained virologic responders. Studies in people
with hepatitis C alone show that the vast majority of people
who experience a sustained virologic response (SVR) remain undetectable
after several years of follow-up. Many people that clear hepatitis
C during treatment relapse on or after therapy, with their viral
load rebounding to detectable levels, and do not achieve an
SVR. Even people who do not achieve an SVR may benefit from
hepatitis C treatment; some people who do not clear HCV experience
improvements in the condition of their liver, which may reduce
long-term risk of end-stage liver disease. |
Three large clinical
trials reported their final results at the 11th CROI, and
this data will shape treatment for the foreseeable future.
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main determinant of treatment success is hepatitis C genotype,
or strain of HCV. At least six HCV genotypes exist; genotype
1 is most common in the United States, followed by genotypes
2 and 3. Genotype 1 is the hardest to clear. In hepatitis C
monoinfection (HIV-negitive), those with genotype 1 are treated
for a full year, and treatment results in an SVR in about half
of people receiving therapy. In contrast, people with genotype
2 or 3 require a shorter duration of treatment, typically 6
months. In people with hepatitis C alone, those with genotype
2 or 3 respond very well to HCV treatment, and the majority—over
80%—achieve a sustained virologic response. Studies in
people infected with hepatitis C alone (HCV monoinfection) show
that for all genotypes, if their HCV viral load does not drop
100-fold or become undetectable by the end of 12 weeks of hepatitis
C treatment, they will not achieve an SVR.
The latest studies
Until recently, most information about
HCV treatment has come from studies of people with hepatitis
C monoinfection. The FDA approved combination therapy with Pegasys
or Peg-Intron and ribavirin without any substantive data on
the safety and efficacy of these treatments in co-infected people.
The tolerability of these drugs in people with HIV was a central
concern. For instance, interferon reduces the CD4 T-cell count
during treatment, though levels return to baseline after therapy.
Ribavirin can induce anemia, a condition already common in people
living with HIV, especially among those taking AZT-containing
regimens (including Combivir and Trizivir). Moreover, rates
of depression run high among PLWH, and the majority of co-infected
persons have histories of drug use, indicating that management
of mental health and substance abuse would be vital. Finally,
preliminary studies suggested that co-infected people may be
less likely to achieve an SVR on hepatitis C treatment, especially
since their hepatitis C viral loads tend to be higher than people
with HCV alone; studies in HCV monoinfection show that people
with lower hepatitis C viral loads respond better to treatment.
All of these issues raise thorny questions about the relative
risks and benefits of HCV treatment for co-infected people,
who have a higher risk of progressing to liver disease.
Three large clinical trials examining
the efficacy and safety of hepatitis C treatment in co-infected
people reported their final results at the 11th CROI, and this
data will shape treatment decisions for the foreseeable future.
All three studies compared pegylated interferon/ribavirin to
the previous standard of care, combination therapy with standard
interferon (requiring three injections per week, compared to
once a week for the longer-acting pegylated versions) and ribavirin.
One study also compared pegylated interferon/ribavirin to pegylated
interferon alone. All showed that pegylated interferon/ribavirin
was superior, though SVR rates were lower than those seen in
HCV monoinfection studies.
APRICOT (AIDS Pegasys-Ribavirin International
Co-infection Trial): An international trial of 860 co-infected
persons (289 receiving 180 µg of Pegasys once a week and
800 mg of ribavirin daily). About 60% had HCV genotype 1. Median
CD4 T-cell count was about 530, and 85% were receiving antiretroviral
therapy, with 60% having undetectable HIV viral loads. About
60% had a history of injection drug use.
ACTG 5071: A U.S. study conducted by
the Adult AIDS Clinical Trials Group of 133 co-infected persons
(66 receiving 180 µg of Pegasys once a week with daily
ribavirin). Ribavirin was initially dosed at 600 mg/day, with
the ribavirin dose increasing every four weeks by 200 mg to
a maximum 1000 mg/day as tolerated. About 77% had HCV genotype
1. Median CD4 T-cell counts ranged from 444–492, and about
86% were receiving antiretroviral therapy, with 60% having undetectable
HIV viral loads.
RIBAVIC (ANRS HC02): A French study
conducted by the Agence nationale de recherches sur le sida
of 412 co-infected persons (205 receiving 1.5 µg/kg of
Peg-Intron once a week and 800 mg of ribavirin daily). About
60% had HCV genotype 1. Median CD4 T-cell count ranged from
501–527, and about 83% were receiving antiretroviral therapy,
with 66% having HIV viral loads below 400. About 79% had a history
of injection drug use.
Results of these studies for participants
in the pegylated interferon/ribavirin arms appear below, with
discontinuation rates for adverse events (side effects and lab
abnormalities, see table below).
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The next major question for co-infection
research is whether extending the duration of treatment
can improve sustained virologic response (SVR) rates.
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The highest SVR in co-infected people
with genotype 1 was seen in APRICOT—about twice as high
as rates in the other studies. Both APRICOT and ACTG 5071 had
fairly high SVR rates for people with genotype 2 or 3. RIBAVIC
had the highest rate of premature treatment discontinuations
for adverse events. While it can be difficult and misleading
to compare results across studies, due to differences between
protocols and patient populations, several reasons for the disparate
results have been proposed:
- The APRICOT participants may have been
healthier (less advanced liver disease) than those in the
other studies, and had a lower proportion of people with
a history of injection drug use—thus representing a
best-case scenario. ACTG 5071 had a higher proportion of
African Americans (about 33%), who are less likely to achieve
an SVR.
- ACTG 5071 may have started people
on too low a dose of ribavirin. Evidence from HCV monoinfection
studies indicate that higher doses of ribavirin increase
the chances of achieving an SVR; in HCV monoinfection, people
receive 1,000-1,200 mg of ribavirin daily with Pegasys.
Increasingly, EPO (epoetin alfa, a red cell growth factor)
is used to reverse or prevent ribavirin-induced anemia,
allowing people to maintain optimal doses of ribavirin during
HCV treatment.
- While Pegasys and Peg-Intron work
similarly, they have different pharmacokinetic properties—Pegasys
appears to have a longer half-life. These differences may
influence their efficacy and safety profiles.
Further analyses of these studies are
on-going, in an attempt to clarify factors that influence treatment
response. The next major question for co-infection research
is whether extending the duration of treatment can improve sustained
virologic response (SVR) rates. APRICOT treated people with
genotypes 2 and 3 for 48 weeks, rather than the standard 24
weeks used in HCV monoinfection, and found that virtually no
people relapsed. Some doctors have already begun extending treatment
for people with genotype 1. Further research is also underway
investigating whether long-term maintenance therapy with a half-dose
of pegylated interferon can improve or stabilize the condition
of the liver in people who do not achieve an SVR.
In the meantime, co-infected people
now have more information for making hepatitis C treatment decisions.
Beyond treatment, PLWH should make sure that they have been
successfully vaccinated for the hepatitis A and hepatitis B
viruses. Other strategies for liver health include reducing
or eliminating alcohol, careful monitoring of liver enzyme levels
when starting new medications, good nutrition, and reducing
stress. These factors can help to protect your liver until better
hepatitis C medications become available, hopefully in the next
four or five years.
Daniel Raymond is Hepatitis C Policy Analyst
for the Harm Reduction Coalition, in New York City. Special
thanks to Tracy Swan for her comments and suggestions.
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Study (regimen):
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Genotype 1 SVR:
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Genotype 2/3 SVR:
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Discontinuations (adverse events):
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| APRICOT (Pegasys/RBV) |
29% |
62% |
15% |
| ACTG 5071 (Pegasys/RBV) |
14% |
73% |
12% |
| RIBAVIC (Peg-Intron/RBV) |
15% |
44% |
31% |
| RBV = ribavirin |
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