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HIV/Hepatitis C
Coinfection
Management and Treatment of
Hepatitis C Virus Infection in HIV-Infected Adults:
Recommendations from the Veterans Affairs Hepatitis C
Resource Center Program and National Hepatitis C Program
Office
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Introduction
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Coinfection with human
immunodeficiency virus (HIV) and hepatitis C virus
(HCV) is of concern in U.S. veterans. Nearly 40% of
HIV-infected veterans on highly active
antiretroviral therapy (HAART) are coinfected with
HCV(1)
compared to the approximately 25% of HIV-infected
patients who are coinfected with HCV in the United
States, nationally.(2)
The prevalence, however, varies considerably among
risk groups. The majority (nearly 100%) of
HIV-infected hemophiliacs in the United States are
HCV-infected(3),
compared to a range of 50-90% of HIV-infected
injection drug users(4),
and about 2-14% who acquired HIV via sexual
contact.(5,
6)
Liver disease has become a
significant cause of death in men and women with HIV
in the era of HAART(7-9),
as a result of the decline in mortality due to AIDS
and AIDS-related illnesses. In U.S.veterans with
HIV, HCV seropositivity is associated with an
increased risk of death(1)
and among HIV/HCV-coinfected veterans seen at the
Houston VA Medical Center, liver disease accounted
for 47% of deaths. HIV itself may also accelerate
the progression of HCV-related liver disease.(10)
With the recent advances in
therapy for HCV, it is becoming increasingly
important that all patients infected with HCV be
considered for treatment, including those who are
also coinfected with HIV. The response rate and
safety of HCV therapy in HIV/HCV-coinfected
individuals are now well established in several
clinical trials, which show improved response rates
using pegylated formulations of interferon plus
ribavirin when compared to standard interferon plus
ribavirin.(11-13)
However, the long-term benefits of HCV therapy in
the HIV/HCV-coinfected patient including
improvements in survival and quality of life have
yet to be demonstrated.
In addition, it is important to
recognize other considerations when deciding whether
or not to initiate HCV treatment in the coinfected
population. One study found that only one-third of
HIV/HCV-coinfected patients are eligible for HCV
treatment.(14)
This proportion was not different from patients with
HCV infection only. The major barriers to HCV
treatment in HIV/HCV-coinfected patients identified
in this study included nonadherence to medical
visits, active psychiatric disease, ongoing drug or
alcohol use in the preceding 6 months, decompensated
liver disease, advanced HIV disease, and medical
comorbidities.(14)
A recent multicenter VA study (Cleveland, Houston,
Manhattan)(15)
found that of 300 HIV/HCV-coinfected patients, 30%
reported current alcohol consumption but only 29% of
those who drank reported that they had been advised
to stop drinking. Similarly, 16% of the 300 patients
reported current illicit drug use; only 12.5% of
those who used drugs reported that their doctors
were concerned about such drug use. These results
suggest that counseling for HIV/HCV-coinfected
patients regarding substance abuse can be improved.
In addition, the majority of HIV-infected patients
identified their HIV provider as their primary care
provider, suggesting that recommendations for the
management and treatment of HCV in
HIV/HCV-coinfected patients should be directed to
HIV providers.
The following recommendations (Table
1) emphasize management and treatment issues
specific for the HIV/HCV-coinfected patient.
Recommendations are graded according to those used
by the American Association for the Study of Liver
Disease (AASLD) practice guidelines for the
diagnosis, management, and treatment of hepatitis
C.(16)
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| I |
Randomized, controlled trials |
| II-1
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Controlled trials without
randomization |
| II-2
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Cohort
or case-control analytic studies
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| II-3 |
Multiple Time-series, dramatic
uncontrolled experiments |
| III
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Opinions of respected authorities,
descriptive epidemiology |
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Progression of HCV and HIV in the HIV/HCV-Coinfected
Patient
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Progression of HCV Disease in
HIV/HCV-Coinfected Patients
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Establishing the diagnosis
of HCV infection in the HIV- infected
patient is of primary importance. Studies
find that HIV infection is associated with
an increased risk of severe liver disease in
patients also infected with HCV, and HIV/HCV
coinfection may lead to a more rapid
progression of liver fibrosis than in those
with HCV infection alone.(17-23)
A meta-analysis of eight separate studies
investigating the role of HIV on liver
disease in HCV-infected patients found that
HIV/HCV-coinfected patients had
approximately two times the risk of
cirrhosis diagnosed on liver biopsy and
approximately six times the risk of
decompensated liver disease (severe liver
disease accompanied by clinical conditions
including ascites, varices, or
encephalopathy) when compared to
HCV-monoinfected patients.(24)
In one of the eight studies, a median
fibrosis progression rate (calculated by the
fibrosis score divided by the duration of
HCV infection) was found to be greater in
HIV/HCV-coinfected patients when compared to
HCV-monoinfected patients.(18)
Because the use of HAART
is an integral part of the care of the
HIV-infected patient, the impact of HAART
itself on HCV liver disease is being
studied. There are several possible
interactions between HAART and the severity
of liver disease, both beneficial and
detrimental. Potential detrimental
interactions between HAART and HCV include
hepatotoxic effects of HAART. Several
studies show that hepatotoxicity as a result
of antiretroviral medications may be
worsened in the presence of concomitant HCV
infection.(25-27)
Potential beneficial
interactions between HAART and HCV include a
slowing of HCV-related liver disease in
patients on HAART. Data exist suggesting
that the long-term use of protease inhibitor
containing HAART regimens may have a
beneficial impact on HCV-related liver
disease independent of CD4 response.(28)
In addition, immune reconstitution with
HAART might improve: (i) the natural history
of HCV-related liver disease in the long
term or (ii) the response to HCV treatment.
However, the body's improved immune response
and thus ability to control HCV-infected
hepatocytes may also acutely lead to adverse
consequences in the liver. Liver
decompensation and acute hepatitis have been
reported in HIV/HCV-coinfected patients
shortly after initiating antiretroviral
therapy.(29,
30) |
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Progression of HIV Disease in
HIV/HCV-Coinfected Patients
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While HIV infection and
its therapy may affect the progression of
HCV-related liver disease, HCV infection
conversely may affect the progression of HIV
disease. Two large European cohort studies
show that after the initiation of potent
antiretroviral therapy in HIV-infected
patients, CD4 cell recovery was impaired in
HIV/HCV-coinfected patients when compared to
patients infected with HIV alone.
HIV/HCV-coinfected patients also
demonstrated more rapid progression to
clinical AIDS or death, compared to patients
infected with HIV alone.(31,
32) The impaired recovery of CD4 cells
in HIV/HCV-coinfected patients was also
demonstrated in another study of patients
initiating HAART as part of clinical
trials.(33)
However, in patients enrolled in other large
cohort studies in the United States, Europe,
and Asia, there was no difference in CD4
cell recovery, progression to clinical AIDS
or death between HIV/HCV-coinfected patients
and HIV-monoinfected patients.(34-37)
Further studies are clearly needed to
understand the role of HCV on HIV disease
progression.
However, HIV infection
does appear to have an adverse effect on the
progression of HCV disease. Because of the
more rapid progression of HCV-related liver
disease in HIV/HCV-coinfected patients,
treatment of HCV should be strongly
considered in this population, as well as
institution of measures that may prevent the
progression of liver disease, including
hepatitis A and hepatitis B vaccination if
not immune, and alcohol counseling. |
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Diagnosis and Testing of HCV in HIV Patients
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Several national guidelines
including those from the U.S. Public Health Service
and the Infectious Diseases Society of America
recommend that all HIV patients be tested for HCV.(38,
39)
Determination of antibodies to HCV
is performed using an enzyme immunoassay test (EIA).
A third generation EIA is recommended, as it has a
sensitivity of greater than 99% in high-risk
populations. A positive antibody to HCV (anti-HCV)
should be followed up with testing for HCV RNA using
a sensitive HCV RNA assay to determine chronic HCV
infection.
The qualitative HCV RNA polymerase
chain reaction (PCR) assay has a lower limit of
detection for HCV of approximately 50 IU/mL, and is
reported as "positive" if the test detects more than
50 IU/mL of HCV in the blood; "negative" if less
than 50 IU/mL. The qualitative assay is used to
determine if any HCV RNA, even low-level viremia, is
present. The quantitative HCV RNA assay determines
an absolute number of circulating HCV in the serum,
also referred as the "HCV viral load." Most
FDA-approved quantitative HCV RNA assays have a
lower limit of detection that is higher than the
qualitative HCV RNA PCR assay.(16)
The most cost-effective and pragmatic strategy is to
perform the quantitative HCV RNA assay to
simultaneously confirm chronic HCV infection and
determine the pre-HCV treatment HCV viral load. If
the quantitative HCV RNA assay reveals an
undetectable HCV viral load, then the qualitative
HCV RNA PCR assay can be performed.
It is important to recognize that
a patient may have a negative HCV EIA and still have
HCV infection. There are two clinical settings in
which this may occur: (i) Acute infection: After
acute exposure to HCV, there is a "window period" of
approximately 30-150 days before anti-HCV is
detectable. The window period of HCV seroconversion
may be prolonged in the setting of concurrent
HIV/HCV seroconversion. However, HCV viremia may be
detectable within 7-21 days after acute HCV
infection. Therefore, if a patient is assessed
during the "window period," the patient may be
anti-HCV negative but HCV RNA positive. Serial
testing of anti-HCV and HCV RNA is recommended to
see if HCV infection spontaneously resolves (loss of
HCV RNA without treatment) or persists. HCV therapy
in this acute setting should be considered, as some
data in HCV-monoinfected patients suggest high rates
of HCV RNA clearance after HCV treatment.(40,
41) (ii) Severe immunosuppression due to HIV or
chronic dialysis: False negative HCV EIA results
have been reported in about 6% of HIV patients using
the second generation anti-HCV EIA test.(42,
43) In one study, 6 of 110 HIV-infected patients
with a negative anti-HCV were HCV viremic and the
median CD4 count was 36 cells/mm3
compared to 235 cells/mm3 in the 259
HIV-infected patients that had a positive anti-HCV.
Another study found that 20 of 100 HIV-infected
patients with a negative anti-HCV were HCV viremic
and the mean CD4 count was 225 cells/mm3
compared to 392 cells/mm3 in the 30
HIV-infected patients that had a positive anti-HCV.
The results from these studies suggest that
HIV-induced immunocompromise can lead to a false
negative anti-HCV result. Because the range of CD4
counts in the HIV/HCV-coinfected patients with a
false negative anti-HCV result in the two studies
were so different, it is difficult to suggest a
specific CD4 cutoff level whereby all HIV patients
with negative anti-HCV should have HCV RNA testing
performed. However, in an HIV-infected patient with
unexplained liver disease or elevations in liver
enzymes and a negative HCV EIA, the HCV RNA
qualitative PCR assay should be performed.
Finally, once the diagnosis of
chronic HCV infection has been made using these
above strategies and techniques, providers should
complete the process with the following:
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Patient
notification of test results with
appropriate posttest counseling. Counseling
regarding modes of transmission of HCV
including parenteral and sexual
transmission. |
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Education
regarding potential interactions between
viral hepatitis and other factors such as
alcohol, high doses of acetaminophen, or
alternative therapies. |
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Evaluation
for potential treatment of HCV. |
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Vaccination
for hepatitis A virus (HAV) and hepatitis B
virus (HAB), if seronegative. |
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Consideration of hepatocellular carcinoma
screening in patients with clinical or
histologic evidence of cirrhosis.
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Recommendations:
- All HIV patients should be tested for
antibodies to HCV (III).
- HCV RNA testing should be performed in:
- the HIV patient with a positive anti-HCV
test to determine chronic HCV infection
(III).
- the HIV patient with unexplained liver
disease and a negative anti-HCV test,
particularly in those with HIV-associated
immune compromise (III).
- the HIV patient with suspected acute HCV
infection (III).
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Assessment of the HIV/HCV-Coinfected Patient prior
to Initiating Anti-HCV Therapy
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All HIV patients with confirmed,
chronic HCV infection should be evaluated for HCV
treatment since: (i) HCV treatment can lead to a
sustained virologic response (SVR), defined as an
undetectable HCV RNA 6 months after discontinuing
therapy; and (ii) HCV treatment may slow the
progression of hepatic fibrosis and/or delay the
onset of clinical consequences of decompensated
cirrhosis.
Each patient needs a careful
individualized assessment to determine the relative
risks and benefits of beginning therapy immediately
versus deferring treatment to a later date versus
foregoing treatment. This decision in the
HIV/HCV-coinfected patient is even more complex than
in those with HCV infection alone, since response
rates are lower, the risk of potential toxicities is
higher and treatment is potentially complicated by
drug interactions between ribavirin and
antiretroviral medications.
Key aspects of the evaluation
prior to beginning HCV therapy in the
HIV/HCV-coinfected patient are summarized in this
section. The pre-HCV treatment evaluation for the
HIV/HCV-coinfected patient is similar to that for
the HCV-monoinfected patient, but additional factors
in the medical history relating to HIV must be
considered.
Table 2 summarizes the pre-HCV treatment
assessment and issues specific to the HIV patient
are shown in italics. Contraindications for HCV
therapy are also similar for HIV/HCV-coinfected and
HCV-monoinfected patients and can be found in
Table 3.
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Necessary |
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Medical history, including the
determination of complications of
liver disease, significant
extrahepatic disease, and symptoms
associated with chronic HCV, which
may reduce quality of life.
HIV-associated opportunistic
infections and malignancies must
also be assessed. |
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Psychiatric history, including the
determination of past or ongoing
psychiatric and substance use
disorders, previous and current
treatments and response |
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Screening for depression and alcohol
use** |
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Biochemical markers of liver injury
and assessment of hepatic synthetic
function (serum ALT, serum albumin,
serum total bilirubin and direct
bilirubin, prothrombin time). |
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Hemoglobin, hematocrit, total white
cell count with differential, and
platelet count |
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Creatinine |
| TSH
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| Serum
glucose or HgbA1C in diabetics |
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Pregnancy test (necessary for women
of child-bearing potential) |
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Anti-HAV total |
| Serum
HBsAg, anti-HBc (total), anti-HBs
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| HIV
serology; absolute CD4 count,
CD4%, and HIV RNA measurement |
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Quantitative HCV RNA measurement by
PCR or bDNA |
| HCV
genotype |
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Electrocardiogram in patients with
preexisting cardiac disease |
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Highly Recommended |
| Liver
biopsy to stage the severity of
liver disease
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Fundoscopic exams for patients at
risk for retinal disease, eg, those
with severe immunosuppression
(CD4<100), diabetes, and/or
hypertension |
| Serum
ferritin |
| Urine
toxicology screen for opiates,
cocaine, and amphetamines |
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Life-determining extrahepatic
disease (eg, end-stage AIDS,
malignancy, unstable angina, severe
COPD) |
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Clinically decompensated liver
disease** |
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Uncontrolled autoimmune disorders
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Pregnancy or planned pregnancy in a
patient or the patient's sexual
partner or unwilling to use adequate
birth control |
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Documented serious nonadherence to
prior medical treatment or the
failure to complete HCV disease
evaluation appointments and
procedures |
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Inability to self-administer
parenteral medication or to arrange
appropriate administration of
parenteral medication |
| Severe
uncontrolled psychiatric disease,
particularly depression with current
suicidal risk |
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Ongoing injection drug use |
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Ongoing alcohol abuse***
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Assessment of Liver Disease Severity
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Candidates for HCV
treatment should have evidence of
HCV-associated liver disease, yet
demonstrate preserved hepatic synthetic
function as indicated by a normal or near
normal serum albumin, direct serum bilirubin,
and prothrombin time. Cirrhotic
HIV/HCV-coinfected patients on HAART appear
to be at increased risk for the development
of hepatic decompensation compared to
patients not receiving HAART.(44)
The pharmaceutical package insert for
pegylated interferon alfa-2a lists hepatic
decompensation with Child-Pugh score >=6 in
cirrhotic HIV/HCV-coinfected patients as a
contraindication for starting or continuing
pegylated interferon alfa-2a. While
biochemical markers of liver function should
be obtained, histologic evidence of liver
damage on liver biopsy is the best method to
assess liver disease severity, regardless of
transaminase levels, especially in the
patient coinfected with HIV/HCV. Patients
with cirrhosis should also undergo screening
for hepatocellular carcinoma.
Liver Function Tests.
In the HIV/HCV-coinfected patient, abnormal
transaminase levels and hepatic synthetic
function studies may also be the result of
antiretroviral drug-associated toxicity
and/or opportunistic infections, making
interpretation of liver enzyme elevations
more problematic than for patients with HCV
infection alone. In general,causes of
abnormal liver function can be broadly
classified as hepatic (with elevated serum
transaminase levels but normal or near
normal serum bilirubin and alkaline
phosphatase) and cholestatic (with abnormal
alkaline phosphatase and/or serum bilirubin,
but only minor changes in serum transaminase
levels). In HIV/HCV-coinfected patients, the
likelihood of specific pathogens or disease
processes causing these patterns of liver
injury depends in part on the severity of
immune compromise.
Table 4 lists possible pathogens or
diseases of the liver that are usually but
not always seen in the CD4 ranges listed.
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Predominantly cholestatic |
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Drug Toxicity |
Fungal Infection |
Cytomegalovirus |
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Tuberculosis |
Candidiasis |
Mycobacterium avium
complex (MAC) |
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Kaposi's sarcoma |
Coccidioidomycosis |
Microsporidia |
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Lymphoma |
Histoplasmosis |
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Cholelithiasis |
Cryptococcosis |
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Acalculous cholecystitis |
Blastomycosis |
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Bacterial abscess |
Cryptosporidia |
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AIDS cholangiopathy |
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Bacillary angiomatosis and
peliosis due to
bartonella infection
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Predominantly
hepatocellular |
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Drug toxicity |
Pneumocystis carinii |
Cytomegalovirus |
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Steatosis |
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Viral hepatitis |
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Herpes simplex virus |
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Liver Biopsy. Liver
biopsy is the best method for quantifying
the severity of liver injury. The degree of
liver injury is measured by the stage of
liver fibrosis and the grade of
necroinflammation, which has been shown to
determine the rapidity of fibrosis
progression.(45)
The serum ALT level is not a sensitive
marker of HCV-associated liver disease and
most HIV/HCV-coinfected patients have some
degree of fibrosis, whether or not their
serum ALT values are elevated.(46,
47)
The stage of fibrosis is
an important factor that should be
considered in the decision of whether or not
to initiate therapy. In patients without
contraindications to HCV therapy who
demonstrate histological evidence of
fibrosis (more than portal fibrosis to those
with cirrhosis, ie, stages 2-4) and/or
significant inflammatory activity, HCV
antiviral therapy should be initiated. In
patients with no fibrosis (stage 0) or who
lack evidence of inflammation on liver
biopsy (grade 0), HCV antiviral therapy can
be deferred. However, recent data show that
over 25% of 51 HIV/HCV-coinfected patients
seen in an urban clinic with no or minimal
fibrosis demonstrated a greater than
two-stage fibrosis progression over an
approximately 3-yr interval.(48)
In patients with genotype 2 or 3 HCV
infection, which is generally associated
with higher response rates, HCV treatment
should be considered even in the presence of
no or minimal fibrosis since the chances of
eradicating HCV are very good. In
HIV/HCV-coinfected patients with genotype 1
HCV infection, some data suggest that those
with a low HCV viral load <800,000 IU/mL may
have higher response rates than those with
HCV viral load >800,000 IU/mL.(44)
A routine liver biopsy
should be performed in all
HIV/HCV-coinfected patients who are able to
undergo biopsy regardless of genotype,
because the information obtained on biopsy
may: (i) focus screening for hepatocellular
carcinoma in patients found to have grade 3
or higher fibrosis and (ii) provide
information that guides management of HCV
infection prior to the initiation of HCV
therapy, but also during HCV therapy. The
stage of fibrosis on liver biopsy may
influence the decision of whether or not to
continue HCV therapy if complications or
adverse drug effects should arise during
treatment. Patients in whom therapy is
deferred, for reasons including minimal
histological liver disease,
contraindications to treatment, or the
patient not being ready to start therapy or
waiting for the development of newer HCV
therapies, a repeat liver biopsy should be
performed at an interval of 3 yr (49)
to assess for the rate of disease
progression and reassess the need for
treatment. |
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Additional Laboratory Testing
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Complete Blood Count (CBC).
Patients should have a CBC performed as part
of the pretreatment assessment since adverse
reactions of combination HCV treatment
include anemia, neutropenia, and
thrombocytopenia. Prior to initiating HCV
treatment, a platelet count >70 k/mm3,
an absolute neutrophil count >1.5 k/mm3,
and a hemoglobin >=12 g/dL for men, and >=11
g/dL for women are desirable. In the
HIV/HCV-coinfected patient, there is a
higher incidence of anemia and neutropenia
than in the HCV-monoinfected patient, as a
result of marrow suppression from HIV and
other comorbid conditions or medications
associated with HIV disease. Therefore, if
possible, providers should consider first
treating any other conditions and/or
changing medications such as zidovudine that
may contribute to bone marrow suppression
prior to initiating HCV therapy. Patients
who continue to have values below these
cutoffs may still be considered for therapy,
but may require HCV treatment dose
reductions and/or the addition of growth
factors (eg,erythropoietin,
granulocyte-colony stimulating factor [G-CSF])
in order to be able to tolerate doses
necessary for achieving treatment benefit.
At this time, however, there is an absence
of data supporting the preemptive use of
growth factors in this patient population.
Renal Function. A
creatinine should be performed as part of
the pretreatment assessment. A creatinine
clearance of less than 50 mL/min is given as
a contraindication to the use of ribavirin
in the pharmaceutical package insert.
Generally, a creatinine <=1.5 mg/dL is
desirable.
HCV RNA Quantitative
Assay.
Table 5 shows the available assays for
quantification of HCV RNA in serum and the
dynamic range (ie, the lower limit and upper
limit of detection) for each assay.
Quantification of HCV RNA or the "HCV viral
load" is useful in several ways. First, the
pretreatment HCV viral load is one of the
predictors of response to HCV treatment. The
likelihood of achieving an SVR is greater in
patients with a pretreatment HCV RNA level
of less than 800,000 IU/mL than in those
with levels greater than 800,000 IU/mL.
Second, quantification of HCV RNA prior to
therapy also allows measurement of changes
in HCV RNA on treatment.
An early virologic
response (EVR) is defined as either a loss
of HCV RNA measured by qualitative PCR-based
assays and/or a two-log reduction in
quantified levels of HCV RNA 12 wk into a
course of HCV treatment. Measurement of an
EVR is most valuable in predicting who will
not achieve an SVR, an observation that
appears to be true for HCV-monoinfected as
well as HIV/HCV-coinfected patients.(12,
50) Patients who do not have an EVR will
rarely clear virus with further therapy. To
allow for consistent comparisons in HCV RNA
levels, the same HCV RNA quantitative assay
should be used throughout the course of
therapy in a given patient. However, to
better allow for comparisons between the
various HCV RNA assays, they have been
standardized to international units/mL (IU/mL).
Finally, when monitoring HCV treatment
response, it is important that an absolute
HCV RNA number is reported, because of the
prognostic importance of measuring an EVR.
In situations where the HCVRNA level is
reported as above the range of detection of
the assay, specimens may need to be retested
in the laboratory using a dilutional
technique that will allow the reporting of
an absolute HCV RNA number.
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AMPLICOR HCV Monitor V2.0
(Roche molecular systems) |
0.9 |
Manual competitive reverse
transcriptase PCR (rtPCR) |
600-500,000 |
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COBAS AMPLICOR HCV Monitor
V2.0 (Roche molecular
systems) |
2.7 |
Semi-automated
competitive rtPCR |
600-500,000 |
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Versant HCV RNA 3.0
quantitative assay (Bayer
diagnostics) |
5.2 |
Semi-automated 'branched
DNA' assay |
615-7,690,000 |
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LCx HCV RNA quantitative
assay (Abbot diagnostics)
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3.8 |
Semi-automated competitive
rtPCR |
25-2,630,000 |
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SuperQuant (National
Genetics Institute) |
3.4 |
Semi-automated competitive
rtPCR |
30-1,470,000
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HCV Genotype.
Patients should have pretreatment testing
for HCV genotype. The infecting genotype is
an important predictor of SVR rates, with
genotypes 1 and 4 associated with lower
response rates than genotypes 2 and 3. This
test does not need to be repeated after the
initial pretreatment test for HCV genotype.
Hepatitis B Testing.
Patients should be tested for hepatitis B
surface antigen (HBsAg), hepatitis B core
antibody (anti-HBcore (total)), and
hepatitis B surface antibody (anti-HBs) to
evaluate need for hepatitis B immunization
and the possibility of concurrent infection
with HBV. It is important to properly
interpret the different patterns in HBV
testing and understand the implication of
these results. First, a negative test to all
three HBV markers indicates that the patient
has never been exposed to HBV and should now
be vaccinated against HBV. Response rates to
HBV vaccination are lower in
immunocompromised patients with HIV
infection than in patients with an intact
immune system. Studies performed early in
the course of vaccine development revealed
that only one-third of HIV-infected patients
developed protective immunity to
vaccination.(51,
52) Despite these findings, all HIV
patients should receive a series of HBV
vaccinations (at 0, 1, and 6 months), and
follow-up testing for anti-HBs after
completion of the series will determine
whether seroconversion has occurred. The
likelihood of seroconversion in vaccine-nonresponders
following repeat immunization is low.
Second, a positive HBsAg may indicate acute
infection or more likely chronic carrier
status and should be further evaluated
through HBeAg testing and HBV DNA levels.
Third, a positive anti-HBc and anti-HBs
indicate natural immunity and no additional
follow-up is needed. Fourth, a positive
anti-HBc alone (with a negative anti-HBs and
negative HBsAg) also likely indicates
natural immunity, although this pattern can
also indicate low-level HBV replication
(detectable HBV DNA by PCR-based methods),
particularly in patients with HIV
infection.(53,
54) There is no consensus as to whether
patients with positive anti-HBc alone will
benefit from HBV vaccination. Finally, a
positive anti-HBs alone generally indicates
vaccine-induced immunity.
Hepatitis A Testing.
Antibodies to hepatitis A virus (anti-HAV)
should be measured. A positive anti-HAV (ie,anti-HAV,
total or HAV IgG) indicates immunity and no
additional follow-up is needed. It is not
possible to determine whether the immunity
is due to prior vaccination or prior
infection. A negative anti-HAV, total
indicates no prior history of infection and
the patient should be vaccinated against
HAV. One small study demonstrated a more
fulminant course of hepatitis A in patients
infected with HCV compared to those with
HBV, supporting HAV vaccination in all
patients with HCV infection.(55)
Fasting Blood Glucose
Level. Because interferon can cause
hyperglycemia, patients with impaired
glucose tolerance (fasting glucose between
110 and 125 mg/dL) should be monitored
closely and those with diabetes (fasting
glucose >125 mg/dL on more than one
occasion) should be controlled. In addition,
certain protease inhibitors such as
indinavir may also be associated with
hyperglycemia and insulin resistance. HIV
patients on these antiretroviral agents
should be monitored. |
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Assessment of Mental Health
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A careful evaluation of
the HIV/HCV-coinfected patient for
psychiatric disease is critical when
considering initiation of HCV treatment.
There is no evidence that the incidence of
psychiatric comorbidity is higher in the
HIV/HCV-coinfected patient compared to the
HCV-monoinfected patient. Similar to the
HCV-monoinfected patient, the pretreatment
assessment of psychiatric disorders and
substance use should be carefully weighed
before beginning treatment. Validated
screening instruments for depression and
alcohol use are available and may be useful
in identifying patients who should receive
treatment for depression and alcohol use
prior to initiation of HCV therapy. They
also provide a baseline assessment, should
changes occur during treatment for HCV.
In terms of the ability to
predict adherence to HCV treatment prior to
HCV treatment initiation, a useful marker
may be how well the patient adheres to his
or her HIV medications.
Recommendations:
- Consider HCV treatment in all
HIV/HCV-coinfected patients (III).
- Provide education about the pros and
cons of HCV treatment in the presence of
HIV/HCV coinfection (III).
- Regardless of ALT level and HCV
genotype, perform a liver biopsy (if no
contraindications to liver biopsy exist)
prior to initiating therapy in order to
determine the extent of HCV-related
liver disease and the presence of other
causes of liver disease (III).
- Consider the decision to treat the
HIV/HCV-coinfected patient on an
individual basis including information
on the severity of liver disease,
genotype, viral quantification, and
state of any comorbid conditions (III).
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HIV-Specific Assessment Prior to Initiating HCV
Therapy
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This section highlights
HIV-specific issues including optimizing HIV control
and minimizing hepatotoxic side effects of HIV drugs
to successfully treat HCV in the HIV/HCV-coinfected
patient eligible for treatment. However, the risks
and benefits of changing HIV drug regimens must be
carefully assessed on a case-by-case basis. If
options for switching HIV treatment to a less
hepatotoxic regimen are limited due to significant
HIV resistance, for example, the decision to
initiate treatment for HCV should be reassessed. If
possible, HIV regimens should be stable and no
further changes in the antiretroviral regimen
anticipated when initiating HCV therapy.
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CD4
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Early studies in
HIV/HCV-coinfected patients, which were
small in sample size demonstrated lower SVR
rates among patients with lower CD4 counts.
However, recent data from two multicenter
randomized clinical trials (12,
13) suggest that baseline CD4 at the
time of HCV treatment initiation does not
adversely affect response rates. Patients
were included into these two trials if they
had a baseline CD4 count more than 100
cells/mm3. Therefore, no safety
or efficacy data are available for the use
of pegylated interferon in
HIV/HCV-coinfected individuals with CD4
below 100 cells/mm3.
In one trial (13),
among those randomized to the pegylated
interferon plus ribavirin arm, the rate of
SVR was higher in the 17 patients with CD4
cell count below 200 cells/mm3
when compared to the entire 289 individuals
in the pegylated interferon plus ribavirin
arm (47% vs 40%).These data should be
interpreted with caution, because of the
small numbers of individuals with a CD4 cell
count below 200 cells/mm3 in this
trial. This trial also did not demonstrate
an increased rate of AIDS defining events in
patients with a CD4 cell count below 200
cells/mm3. The second trial (12)
did not find any relationship between the
baseline CD4 and the SVR to pegylated
interferon and ribavirin. |
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Hepatotoxicity
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Drug-induced
hepatotoxicity, especially as a result of
the use of certain antiretroviral
medications is a common problem in HIV.
Therefore, all medications, particularly
antiretroviral medications must be reviewed,
and patients on medications with potential
hepatotoxic side-effects should be followed
closely. In patients who are ready to start
antiretroviral medications, consideration
should be used to minimize the initiation of
drugs with potential hepatotoxic
side-effects. Current FDA approved
antiretroviral medications fall into four
classes of drugs: the nucleoside reverse
transcriptase inhibitors (NRTI), the
nonnucleoside reverse transcriptase
inhibitors (NNRTI),the protease inhibitors
(PI), and the fusion inhibitors (FI). As
mentioned above, certain drugs within the
NRTI class have been associated with lactic
acidosis.
Among the NNRTIs,
nevirapine has most often been associated
with hepatotoxicity in HIV-infected
patients, particularly within the first few
weeks after starting therapy.(61-63)
The mechanism is believed to be an acute
hypersensitivity reaction. Recent data
suggest that nevirapine-induced
hepatotoxicity may be more common in those
with HIV/HCV coinfection and especially
those with more advanced histologic liver
disease.(64)
Women and HIV-infected patients with higher
CD4 counts also may be at increased risk for
nevirapine-induced hepatotoxicity. The other
commonly prescribed NNRTI, efavirenz has
also been associated with increased
hepatotoxicity, which may also be more
common in the HIV/HCV-coinfected patient
with more advanced histologic liver
disease.(64)
Among the PIs, the
incidence of severe hepatotoxicity in
patients taking full doses of ritonavir
(1,200 mg/day) was greater than that in
patients prescribed nucleoside regimens or
prescribed other protease inhibitor
containing regimens including indinavir,
nelfinavir, or saquinavir.(65)
Ritonavir given in doses of 400 mg twice a
day in conjunction with saquinavir also at
400 mg twice a day resulted in a similar
incidence of hepatotoxicity as full doses of
ritonavir. This study, however, did not show
that severe hepatotoxicity in HIV-infected
patients taking ritonavir was increased in
the presence of chronic HCV.
Ritonavir used at lower
doses in conjunction with other PIs has
become the standard of care in HIV.
Ritonavir is a potent inhibitor of
cytochrome P-450 3A4 metabolism and is used
to increase the bioavailability of other PIs
including indinavir, lopinavir, saquinavir,
amprenavir, and atazanavir, thereby allowing
for lower doses of these drugs.
Lopinavir/ritonavir is the recommended PI
for initial PI-based HAART regimens in
recent guidelines for the treatment of HIV
infection.(66)
Recent studies (67-69)
investigating the effect of
lopinavir/ritonavir (where ritonavir is
administered at a total dose of 200 mg/day)
on hepatotoxic events find an increased
incidence in HIV/HCV-coinfected patients
compared to HIV-infected patients. One study
compared liver function tests collected from
eight clinical trials of lopinavir/ritonavir
through 48 wk.(69)
In this study, higher rates of grade 3 or
higher elevations (>5 x the upper limit of
normal) in AST or ALT were observed in
HIV/HCV-coinfected patients compared to
HIV-monoinfected patients. However, patients
with baseline transaminases more than three
times the upper limit of normal were
excluded and, therefore, the impact of HCV
coinfection may be underestimated.
The incidence of liver
enzyme elevations following the initiation
of a variety of PI-based regimens with or
without low-dose ritonavir was recently
studied.(26)
In multivariate analyses, HCV infection as
well as the use of PI regimens containing
indinavir with or without ritonavir and
saquinavir/ritonavir (where the ritonavir
dose was 800 mg/day) was associated with a
twofold greater risk of hepatotoxicity when
compared to regimens containing nelfinavir.
The addition of low-dose ritonavir to
indinavir, however, did not increase the
risk of hepatotoxicity. The incidence of
severe hepatotoxicity was also compared in
those with HIV/HCV coinfection and those
with HIV infection only for each PI with and
without ritonavir. A higher incidence of
severe hepatotoxicity was identified in
HIV/HCV-coinfected patients who were taking
nelfinavir when compared to HIV-monoinfected
patients and in those taking
saquinavir/ritonavir. The incidence of
severe hepatotoxicity appeared increased in
HIV/HCV-coinfected patients taking
lopinavir/ritonavir (200 mg/day) but was not
statistically significant. There was no
difference among HIV/HCV-coinfected and
HIV-monoinfected patients taking
indinavir/ritonavir (200 or 400 mg/day).
A comparative study
between lopinavir/ritonavir and nelfinavir
in one trial of antiretroviral naïve
HIV/HCV-coinfected patients found a lower
incidence of grade 3+ AST and ALT elevations
in the patients randomized to
lopinavir/ritonavir arm compared to patients
randomized to the nelfinavir arm over a
60-wk period.(69)
No patients in either arm discontinued
therapy due to hepatotoxicity. Isolated
hyperbilirubinemia has also been associated
with the use of the PIs, indinavir, and
atazanavir in HIV-monoinfected patients.
Other medications used in
the management of HIV-infected patients may
also result in abnormal liver enzymes (Table
6).
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Clarithromycin |
Atazanavir |
|
Dapsone |
Clarithromycin |
|
Delaviridine |
Dapsone |
|
Didanosine (ddI) |
Indinavir |
|
Dideoxycytidine (ddC) |
Ketoconazole |
|
Efavirenz |
Rifabutin |
|
Fluconazole |
Rifampin |
|
Isoniazid |
Trimethoprim-sulfamethoxazole |
|
Itraconazole |
|
|
Lopinavir/ritonavir |
|
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Nelfinavir |
|
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Nevirapine |
|
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Pentamidine |
|
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Ritonavir |
|
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Saquinavir |
|
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Stavudine (d4T) |
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Trimethoprim-sulfamethoxazole
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Voriconazole |
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Zidovudine |
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Other HIV and HCV Drug Interactions
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Providers should be aware
of other effects of HIV therapies in the
patient with HIV/HCV coinfection. For
example zidovudine causes bone marrow
suppression that may aggravate the hemolytic
anemia observed with ribavirin. In vitro
data have shown that ribavirin inhibits the
phosphorylation of zidovudine, stavudine,
lamivudine, and zalcitabine (ddC),
potentially impairing the HIV antiviral
activity of these drugs. However, clinical
studies have failed to demonstrate an
adverse effect of ribavirin at 800 mg/day on
intracellular phosphorylation and/or plasma
pharmacokinetics of zidovudine, lamivudine,
or stavudine in HIV/HCV-coinfected
patients.(70)
Trimethoprim/sulfamethoxazole that is
commonly used for prophylaxis against
pneumocystis carinii pneumonia when CD4
counts fall below 200, can also
independently cause cytopenias including
anemia, thrombocytopenia, and neutropenia.
Recommendations:
- Prior to initiating HCV therapy,
antiretroviral therapy should be
optimized in the HIV/HCV-coinfected
patient by:
- ensuring that the patient is on
a stable regimen with maximal CD4
benefit (III).
- avoiding ddI (III).
- considering a discontinuation of
zidovudine because of the risk of
synergistic myelosuppression (III).
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HCV Treatment Response Rates in the
HIV/HCV-Coinfected Patient
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Definition of HCV Treatment Endpoints
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Treatment endpoints for
HCV are the same for HCV-monoinfected
patients and HIV/HCV-coinfected patients. An
undetectable HCV RNA level or a 2-log
reduction in HCV RNA levels at 12 wk is
referred to as an EVR. An undetectable HCV
RNA at the end of therapy is referred to as
an end-of-treatment response (ETR) and an
undetectable HCV RNA 6 months after therapy
is referred to as SVR. Because failure to
achieve an EVR has been shown to predict
strongly an inability to achieve an SVR in
both HCV-monoinfected and HIV/HCV-coinfected
patients, discontinuation of therapy should
be considered at 12 wk in the absence of an
EVR.(71,
72)
Therefore, in the patient
with an undetectable HCV RNA level at 12 wk
or an EVR, follow-up HCV RNA levels should
be drawn again at the end of treatment. In
those with an ETR, a follow-up HCV RNA level
should be drawn 6 months after the end of
treatment. |
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HCV Treatment Responses in the
HIV/HCV-Coinfected Patient
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Three recent studies (11-13)
show that in HIV/HCV-coinfected patients,
the combination of pegylated interferon plus
ribavirin is superior to the combination of
standard interferon alfa plus ribavirin. In
the AIDS Clinical Trials Group (ACTG) 5071
Study (12),
133 HIV/HCV-coinfected adults were
randomized to receive either standard
interferon alfa-2a subcutaneously at 3
million international units (MIU) three
times a week (tiw) or pegylated interferon
alfa-2a (40 kD) subcutaneously at 180 µg/wk,
each combined with increasing doses of
ribavirin escalated from 600 to 1,000 mg
daily. Overall (genotype 1 and genotype
non-1 combined) results at both 48 wk (ETR)
and 72 wk (SVR) (24 wk after discontinuation
of therapy) show that HCV RNA was
undetectable in a higher percentage of
persons in the pegylated interferon arm when
compared to the standard interferon arm (Table
7). Twelve percent of patients in both
arms discontinued treatment.
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n = 67 |
n = 66 |
|
ETR (Overall) |
12% |
41%* |
|
Genotype 1 |
6% |
29% |
|
Non-genotype 1 |
33% |
80% |
|
SVR (Overall) |
12% |
27%** |
|
Genotype 1 |
6% |
14% |
|
Non-Genotype 1 |
33% |
73% |
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In the AIDS PEGASYS
Ribavirin International Coinfection Trial
(APRICOT) (13),
860 HIV/HCV-coinfected adults were
randomized to one of three treatment arms:
(i) standard interferon alfa-2a at 3 MIU tiw
plus ribavirin at 800 mg/day, (ii) pegylated
interferon alfa-2a (40 kD) at 180 µg/wk plus
ribavirin 800 mg/day, or (iii) pegylated
interferon alfa-2a (40 kD) at µg/wk plus
placebo. Overall (genotype 1 and genotype
non-1 combined) results at both 48 wk (ETR)
and 72 wk (SVR) also demonstrate the
superiority of pegylated interferon plus
ribavirin when compared to standard
interferon plus ribavirin (Table
8). Surprisingly, both the ETR rate and
the SVR rate in the pegylated interferon
plus placebo arm was higher than those on
combination therapy with standard interferon
plus ribavirin. The treatment
discontinuation rate was higher in the
standard interferon plus ribavirin group
than the pegylated interferon plus placebo
arm and the pegylated interferon plus
ribavirin arm (39% vs 31% vs 25%,
respectively), which may explain the lower
than expected response rate in the standard
interferon plus ribavirin. Response rates
were derived from all patients who initiated
therapy regardless of whether or not they
later discontinued therapy. Interestingly,
pegylated interferon resulted in a 0.9 log
decrease in HIV RNA levels.
Finally, in the French
RIBAVIC study (11),
412 patients were randomized to either
pegylated interferon alfa-2b (12kD) at 1.5
µg/kg per week combined with ribavirin 800
mg/day or standard interferon alfa-2b at 3
MIU tiw combined with ribavirin 800 mg/day,
the SVR rates in the pegylated interferon
arm was also superior to the standard
interferon arm (Table
9). The overall ETR was reported in the
pegylated interferon arm.
All three studies showed
that combination therapy with pegylated
interferon (alfa-2a or alfa-2b) plus
ribavirin is superior to combination therapy
with standard interferon plus ribavirin. The
SVR rates from these studies are lower than
those reported in HCV-monoinfected patients,
particularly for those with genotype 1
infection. The SVR rates for genotype 2, 3
infection after 48 wk of therapy are
comparable to those reported in genotype 2,
3 HCV-monoinfected patients after 24 wk of
therapy.
The SVR rates reported in
the combination pegylated interferon plus
ribavirin arm in the three studies performed
in HIV/HCV-coinfected patients also vary.
Several factors may account for the lower
overall SVR rates in the ACTG 5071 trial and
the RIBAVIC Study. In the ACTG 5071 trial,
the initial starting dose of ribavirin was
lower than the other two studies at a total
dose of 600 mg/day. Studies in
HCV-monoinfected patients increasingly
demonstrate that ribavirin at higher doses
initially are important and may prevent
relapse.(73)
Interestingly, in the ACTG 5071 trial, the
overall ETR was 41% for the pegylated
interferon plus ribavirin arm and 12% for
the standard interferon plus ribavirin arm.
However, 24 wk after the discontinuation of
therapy, the overall SVR rate in the
pegylated plus ribavirin arm had fallen to
27%. In addition, about 33% of the patients
in the ACTG 5071 trial were African
American, a population that has consistently
across many trials been shown to be
resistant to HCV therapy.(74)
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| |
n = 285 |
n = 286 |
n = 289 |
|
ETR (Overall) |
14% |
33% |
49% |
|
Genotype 1 |
8% |
21% |
38% |
|
Non-Genotype 1 |
27% |
57% |
64% |
|
SVR (Overall) |
12% |
20%* |
40%** |
|
Genotype 1 |
7% |
14% |
29% |
|
Non-Genotype 1 |
20% |
36% |
62% |
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In the RIBAVIC trial,
treatment discontinuation occurred in 42% of
the patients overall, divided equally
between both arms. Severe side effects
occurred in 31% of patients. The results
reported are based on an intent-to-treat
analysis. When including those who completed
treatment, the overall sustained virologic
rates were 36% in the pegylated interferon
plus ribavirin arm and 28% in the standard
interferon plus ribavirin alone arm. In this
study, 80% of the patients had a history of
injection drug use (IDU) and 40% had
bridging fibrosis or cirrhosis--higher than
in the ACTG 5071 trial and the APRICOT
Study. Thus differences in response to
pegylated interferon plus ribavirin therapy
between trials appear to be multifactorial,
and a function not only of differences in
study design but also in differences in
characteristics of the population under
investigation. |
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