Approximately
40% of people living with HIV are co-infected with hepatitis C (HCV). At
least twice that rate (80%) has been found among injection drug users and
people with hemophilia. Compared to HIV and hepatitis B, HCV is not easily
transmitted sexually, but, because of its higher rate of replication, it is
much more easily transmitted blood-to-blood. HIV produces billions of new
virons (virus particles) each day, while HCV produces trillions daily.
An
accelerated rate of HCV progression occurs in people co-infected with both
viruses compared to those living with HCV alone. One European study of 547
patients with HCV showed that among the 431 who were HIV-, the average time
to development of cirrhosis (nonfunctioning scar tissue) was 23.2 years; for
the 116 HIV+ individuals, the average time to cirrhosis was 6.9 years.
Co-infected individuals also run an increased risk of developing liver
cancer and liver decomposition. Many co-infected individuals are surviving
HIV only to die due to HCV complications. These complications are the
leading reasons for liver transplants. Fortunately, new information is
emerging to better understand and treat HIV/HCV co-infection and to increase
survival.
Research
from UCSF indicates that when an individual with HIV has a CD4 rate <200
cells/ml, HCV is able to mutate more easily. It gets around the defenses of
the weakened immune system and evolves new quasi-species (variants) that can
survive and multiply, leading to further disease progression. Other research
shows that older age and greater consumption of alcohol also lead to
increased fibrosis (early scarring which can lead to cirrhosis) in
co-infected individuals.
Progress
has been made at U. of Pittsburgh regarding liver transplants in a few
co-infected individuals. These people were far along in their HCV disease,
but early enough in HIV progression to survive both the surgery and the
immune suppressing drugs needed for recovery. Securing funding for this work
is due in large part to the work of community activists.
Only a
year ago, researchers were debating which disease to treat first—HIV or
HCV. People with HIV have higher HCV viral loads than those with HCV alone.
Most research suggests that HCV does not affect HIV viral loads or CD4
counts. The consensus is growing that, other things being equal, it is best
to get HIV stabilized first, then treat HCV if serious liver disease is
seen.
Some HIV
medications such as protease inhibitors (PIs), most notably ritonavir and,
to a lesser extent, indinavir, are toxic to the liver. Co-infected
individuals tend to be more sensitive to this toxicity. Most research shows
that co-infected individuals see increased liver enzyme levels for up to
several months after beginning HIV treatment. Most can ride it out and
tolerate a regimen containing one of the less hepatotoxic PIs. There is
evidence that people using a PI tend to slow the rate of liver fibrosis. The
reason for this bonus has not yet been explained. If another combination is
needed, different non-protease containing combinations can be used, using
current HIV treatment guidelines and always looking for combinations likely
to be easiest on the liver.
The only
way doctors can tell the extent of liver disease is by liver biopsy.
Unlike common blood tests for HIV, common HCV blood tests such as
viral load and liver enzyme levels (ALT, AST) do not correlate with disease
progression. A liver biopsy is
an outpatient procedure. The doctor inserts a needle to take a tiny sample
of liver tissue to look at. It is actually easier and less painful than it
sounds. If the patient does not have any liver inflammation or fibrosis, and
all liver enzymes are in normal ranges, just monitoring your status and
waiting for better treatments is one viable option to discuss with your
doctor.
Studies
have examined the response of co-infected individuals to interferon therapy,
an immune system modulator, that is the most common treatment for HCV.
Interferon is usually self-injected under the skin three times a week.
Results have universally shown that getting a “sustained response”
(maintenance of HCV viral load below the level of detection 6 months after
treatment has ended) is more difficult for co-infected people than for
singly HCV infected individuals. CD4 counts can drop significantly during
interferon therapy, so this treatment is not recommended for individuals
with CD4 counts below 200. Other co-factors that challenge response to
treatment include increased age, increased alcohol use, higher baseline
viral load, genotype 1a or 1b (the most common variants of HCV in the US),
being male, and being African American. We do not know why African-Americans
respond more poorly to HCV treatments than other ethnic groups. Higher doses
of interferon and/or daily dosing increase sustained response rates, but
usually no more than 28% of those studied with genotypes 1a or 1b. Results
are somewhat better for other genotypes.
Combination
treatments using interferon with ribavirin in co-infected people are being
looked at. Ribavirin seems to make interferon work better. Early reports
last November from a small ongoing study by Dr. Douglas Dieterich at NYU
showed that, after 12 weeks of treatment, 50% of the individuals taking the
combination had undetectable HCV viral loads compared with only 9% of the
interferon monotherapy group. Laboratory research early on indicated that
ribavirin might interfere with zidovudine (AZT) or stavudine (D4T). This has
not been a problem with people using these HIV treatments in this study, but
more analysis is needed. Half of the participants on the combination
developed hemolytic anemia (low red blood cell count), a side effect of
ribavirin. Co-infected people tend to be more susceptible to this effect.
Either they need other expensive treatments such as Procrit or Epogen (erythropoetin)
for the condition or they need the ribavirin dose reduced. Some studies from
singly infected individuals indicate that 600-800mg/day of ribavirin (as
opposed to the common 1000-1200mg/day) may actually be equally effective and
less toxic.
Dr. Bennet Cecil, a clinician and
hepatitis researcher with the VA and Hepatitis Treatment Centers, Inc., in
Louisville, KY, makes the following comments regarding co-infection
treatment and cirrhosis in his experience:
”
If a patient has a platelet count below 150,000 or a prolonged prothrombin
time they may have cirrhosis. These are simple blood tests that indicate the
amount of damage each patient has. They are not perfect but they are very
good and I use them every day treating hundreds of hepatitis C patients. I
usually start with 600 mg of ribavirin each day and all of my patients do
daily interferon because it has fewer side effects (1.5 MU on Intron is
easier than 3 MU). Frail patients and cirrhotics usually start with 500,000
units daily of Intron or Roferon. I treat decompensated cirrhotics
successfully with low titrated doses of interferon and ribavirin. “
Studies
are also underway in co-infected people using pegylated interferons. The two
versions being studied (Pegasys from Roche, Peg-Intron from Schering-Plough)
are designed to be long acting interferons that only have to be injected
once a week and, ideally, maintain an even blood level of interferon in the
body. Studies are looking at using these drugs +/- ribavirin. These drugs
should be available later this year. Most research with them has been done
to date in individuals infected with HCV alone. Schering has released little
data on their drug yet. Roche has released study results that show Pegasys
monotherapy resulted in a 36% sustained response rate vs. 3% for standard
interferon. A small Pegasys + ribavirin study in Europe showed an 80%
sustained response rate. This is the highest rate shown in any HCV study to
date. This looks promising for co-infected individuals as well.
Investigations
are underway with a variety of other drugs. Ribozymes are natural enzymes
that can be synthesized to selectively inhibit disease-causing proteins by
interfering with RNA production. These are being investigated for use in HIV
and HCV. Several pharmaceutical companies are also targeting other enzymes
important in the life cycle of HCV (protease, helicase, and polymerase) for
development of inhibiting drugs.
The
goals of HCV treatment are now changing as well.
Even if treatments that use interferon do not achieve complete viral
suppression or eradication, such treatment should not be labeled a
“failure” as these treatments often slow and sometimes reverse the
development of fibrosis. The liver is an amazing organ with the ability to
regenerate itself unlike other organs of the body. Dr Thierry Poynard, a
leading hepatitis researcher, says:
“The
true goal of therapy is to reduce the rate of liver fibrosis
progression—this may be accomplished even without reducing the HCV viral
load—some patients who have a virologic response to treatment even have
regression of fibrosis. The fibrosis progression rate is for HCV what the CD4 count is for HIV
infection"
A health care provider
who knows HIV really well doesn’t necessarily know HCV. And vice versa!
It is important for co-infected individuals to have doctors with
expertise in each disease and urge them to talk to each other to coordinate
their medical care.
Research
in co-infection is slower than for either HIV or HCV alone, as drug
companies look to make sure their new treatments work in the least
complicated populations first. Patient and treatment advocates need to urge
healthcare providers, public health officials, and local drug company
representatives to work for more clinical studies and access to treatments
for people living with HIV/HCV co-infection.
