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2006 19: 37Journal of Pharmacy Practice
Kelly McNelis

Management of Hepatitis C Infection in the HIV-Infected Patient



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10.1177/0897190005284096MCNELISHEPATITIS C INFECTION IN HIV

Management of Hepatitis C Infection
in the HIV-Infected Patient

Kelly McNelis, BS, PharmD

Morbidity and mortality associated with HIV infection have
rapidly decreased with the introduction of highly active
antiretroviral therapy. Of recent concern is the increase of un-
usual opportunistic infections, particularly hepatitis C virus
in this population. Because of the shared route of transmis-
sion, a significant number of HIV-infected patients are also
coinfected with hepatitis C virus. HIV infection has been

demonstrated to increase the rate of hepatitis C virus disease
progression. New data on the use of pegylated interferon plus
ribavirin indicate that while cure of hepatitis C virus in the
coinfected patient is a clinical challenge, it is possible. Ag-
gressive management of anemia, drug-induced depression,
and drug interactions increase the opportunity for clinical
response and positive patient outcomes.

KEY WORDS: Pegylated interferon, ribavirin, hepatitis C virus, liver biopsy, fibrosis.

IN THE UNITED STATES, highly active anti-retroviral therapy (HAART) has led to a significant
decrease in HIV- and AIDS-related morbidity and mor-
tality.1,2 HAART has also decreased morbidity and mor-
tality from common opportunistic infections experi-
enced by this patient population.3,4 Because of the
shared routes of transmission, hepatitis C virus (HCV)
coinfection in HIV-infected individuals has emerged as
a significant and somewhat common opportunistic in-
fection. HCV can be transmitted from intravenous drug
use (IVDU), from mother to infant, via needle-stick in-
jury, or through unprotected sexual contact. HCV has
become the most important cause of chronic liver dis-
ease and ultimately death from cirrhosis and
hepatocellular carcinoma.5,6 In the United States, the
number of HIV and HCV coinfected persons is esti-
mated to be 150 000 to 300 000.3,6 In HIV-infected pa-
tients with a history of IVDU, several studies have doc-
umented a 50% to 90% coinfection rate.7-9 The
management of HCV in the setting of HIV is compli-
cated but safe and in most cases well tolerated. Newer
data on the use of combination therapy with pegylated
interferon and ribavirin in coinfected patients indi-
cates improved outcomes. Pharmacists as members of
HIV and HCV treatment teams can positively affect
patient care.

EPIDEMIOLOGY

HCV is a single-stranded RNA virus of the
Flaviviridae family, within the Hepacivirus genus. The

virus was discovered in 1989 and has since been recog-
nized as a significant cause of hepatocellular
carcinoma, chronic hepatitis, and liver fibrosis.10 There
are approximately 50 subtypes but only 6 genotypes. In
the United States, genotype 1 is most commonly seen,
accounting for approximately 70% to 75% of all infec-
tions. Genotype 1 also has the lowest response rate to
treatment. Genotypes 2, 3, and, to a lesser extent 4, 5,
and 6, account for the remaining number of cases.4,6 Be-
cause genotypes 2 and 3 respond more favorably to
treatment, genotyping patients before treatment is ex-
tremely important. In the United States, approximately
2% of the general population or about 2.7 million peo-
ple are HCV infected.11,12 The efficiency of transmitting
HCV varies depending on the route of transmission.
Heterosexual transmission of HIV is more common
than is the transmission of HCV. Sexual transmission of
HCV, while uncommon, may be increased in the setting
of HIV/HCV coinfection.13 HCV is approximately 10

To whom correspondence should be addressed: Kelly McNelis, BS,
PharmD, Christiana Care Health Services–Wilmington Hospital
Annex, HIV Community Program Room 221, PO Box 1668,
Wilmington, DE 19899-1668; e-mail: [email protected]

Kelly McNelis, BS, PharmD, clinical pharmacy specialist–HIV
Community Program, Christiana Care Health Services, Wilmington
Hospital Annex, Wilmington, Delaware.

JOURNAL OF PHARMACY PRACTICE 2006. 19;1:37–52
© 2006 Sage Publications
DOI: 10.1177/0897190005284096

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Page 8

HIV RNA levels changed minimally through week 24
of treatment, and no clinical progression to AIDS was
seen during this trial. All values returned to baseline 24
weeks after stopping therapy.

Although adherence to HCV treatment regimen was
not measured during this trial, it is an important mea-
sure that should be reviewed as a factor influencing
SVR. Dose escalation of ribavirin in this study design
was done to decrease hematologic toxicity and retain
participants. ACTG 5071 documented a 12% prema-
ture discontinuation rate despite incorporating this
strategy into the trial.

Torriani and colleagues,43 with the AIDS Pegasys
Ribavirin International Coinfection Trial (APRICOT)
study group, compared 3 regimens: peginterferon alfa-
2a and ribavirin, peginterferon alfa-2a and placebo,
and interferon alfa-2a and ribavirin. The clinical end
point of this trial was an HCV RNA <50 IU/mL 72
weeks after starting therapy (SVR), 48 weeks on ther-
apy, and at 24 weeks of follow-up. Patients were strati-
fied by HCV genotype, presence of cirrhosis, baseline
ALT divided by the upper limit of normal (ALT quo-
tient), geographic region, CD4 cell count <200 or �200
cells/mm3, antiretroviral therapy, and histologic activ-
ity index score. This score was calculated based on
liver biopsy findings to stage hepatic inflammation and
fibrosis. All patients received liver biopsies in this trial.
Virologic response was defined as an HCV RNA <50
IU/mL at the end of study follow-up and was measured
at weeks 4, 12, 24, 36, and 48 of treatment and at weeks
12 and 24 during the study follow-up period. The over-
all SVR, regardless of HCV genotype, was dramatically
different in the peginterferon and ribavirin group ver-
sus interferon and ribavirin or peginterferon and pla-
cebo: 40%, 12%, and 20%, respectively (P < .001). In
genotype 1, the SVR rates were 29% for peginterferon
and ribavirin, 14% for peginterferon and placebo, and
7% for interferon and ribavirin. As expected, those
with HCV genotypes 2/3 had significantly better re-
sponse rates than did participants with genotype 1
(62% vs 29% achieved SVR, respectively). As with the
ACTG 5071 trial, mean CD4 cell counts decreased in all
groups and CD4 percentages increased, with little to no
change in HIV RNA levels. The APRICOT trial had 10
AIDS-defining events distributed evenly between the 3
study groups.

The impressive size of this trial provides significant
results. It is interesting to note that the peginterferon
and placebo group had better SVR rates than the inter-
feron and ribavirin group did, which may be important
in cases in which patients may not be able to tolerate
ribavirin, although the current standard of care is
peginterferon and ribavirin combination therapy. It is

important to note for all of the clinical trials reviewed
here that higher doses of ribavirin in HCV-
monoinfected patients, 1000 to 1200 mg/d, demon-
strated improved SVR.44 Consideration should be given
to comparing SVR rates of this study and ACTG 5071.
The latter trial had lower SVR rates, with a particularly
large difference between those with genotype 1 infec-
tion. It is difficult to compare these trials, but perhaps
the stepped ribavirin-dosing approach used by Chung
and colleagues42 negatively affected SVR outcomes.

Laguno and colleagues,45 for the Barcelona Study
Group, compared peginterferon alfa-2b plus ribavirin
with interferon alfa-2b plus ribavirin for the treatment
of HCV in coinfected patients. The primary clinical
end point of the trial was the number of patients with
undetectable HCV PCR at 48 and 72 weeks (<500 cop-
ies/ml). If patients were not undetectable at 24 weeks,
they were considered treatment failures and therapy
was discontinued. Secondary clinical end points in-
cluded EVR at 48 weeks, sustained biochemical re-
sponse (SBR) defined as normal ALT levels at the end
of 24 weeks, and relapses in patients who had EVR but
did not maintain SVR. Patients were divided into 1 of 2
treatment arms. Peginterferon was dosed at 100 �g for
patients weighing less than 75 kg and 150 �g for pa-
tients weighing more than 75 kg. The ribavirin dosing
was weight based and is reviewed in Table 1. Patients
who received interferon received 3 million units sub-
cutaneously 3 times a week with weight-based
ribavirin. HCV RNA was measured at weeks 4, 24, 36,
48 (end of therapy), 60, and 72. Liver biopsy was per-
formed on all patients prior to randomization and was
graded by one pathologist at the institution. Most of the
study participants were men on antiretroviral therapy
who had a previous history of IVDU. Sixty-three per-
cent of the study population was genotype 1 or 4. Pa-
tients who were genotype 2 or 3 received 24 weeks of
therapy if their HCV RNA was <800000 IU/mL at base-
line. Dose adjustments could be made in peginterferon,
interferon, or ribavirin based on adverse events as an
attempt to keep patients in the study and on medica-
tion. Overall, 34% of all participants achieved an SVR,
44% in the peginterferon group versus 21% in the in-
terferon group (P = .17). Of those with genotype 1 or 4,
24% had SVR at 48 weeks versus 50% of those with ge-
notype 2 or 3, regardless of treatment group. Patients
with lower baseline HCV PCR, genotype 2 or 3, and a
lower degree of fibrosis had increased rates of SVR.45

CD4 count, not percentage or HIV RNA, decreased
slightly in study participants. In short, therapy was
well tolerated, and the peginterferon plus ribavirin
group had statistically significant increased rates of
SVR when compared to interferon plus ribavirin in all

JOURNAL OF PHARMACY PRACTICE 2006(19.1) • 43

HEPATITIS C INFECTION IN HIV

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study participants. The authors recognized that 20% of
patients obtaining SVR had increased ALT levels at the
end of the study, noting that SBR is not a good marker of
virologic response to treatment and should not be used
as such.

The last important clinical trial to be discussed is
from Carrat and colleagues for the ANRS HCO2
RIBAVIC Study Team.46,47 This study compared
peginterferon alfa-2b administered weekly plus 800
mg of ribavirin daily to 3 million IU interferon alfa-2b
administered 3 times a week plus 800 mg of ribavirin
daily for 48 weeks. As with the other trials reviewed
here, the primary clinical end point for this study was
SVR < 50 IU/mL at week 72, although HCV RNA levels
were reviewed at weeks 4, 12, 24, 48, and 72. The sec-
ondary end point for this trial was histological im-
provement determined by review of pre- and
posttreatment biopsy results. Liver tissue inflamma-
tion and fibrosis were evaluated using previously vali-
dated scoring systems.35,36 A decrease of 1 point or more
between the Metavir and/or Ishak scores pre- and
posttreatment was considered histologic improve-
ment. Patients were stratified by HCV genotype, sever-
ity of HIV infection, baseline HCV RNA, antiretroviral
history, and mode of acquiring HCV infection. All pa-
tients received liver biopsy before and after treatment.
This study included a stepwise reduction in
peginterferon and interferon as well as in ribavirin dos-
ing, with the goal of keeping patients on therapy while
decreasing the rates of adverse events. A total of 412 pa-
tients was included in data analysis with the following
clinical outcomes: 27% of patients in the peginterferon
and 20% of patients in the standard interferon group
had an SVR at week 72. If patients did not have an un-
detectable HCV RNA at week 12 in either group, 99%
to 100% of them were unable to obtain an SVR at week
72, demonstrating that early virologic response to treat-
ment is essential for SVR once therapy is completed.
Those with genotype 1 or 4 had poorer SVR rates com-
pared to those with genotypes 2, 3, or 5: 17% versus
44%, respectively. However, in genotype 1 or 4, those
who received peginterferon/ribavirin had better rates
of SVR than did those who received interferon/
ribavirin: 17% versus 8% (P = .006), respectively. The
authors did not report any CD4 cell or HIV RNA
changes during this trial. There was 1 study death that
was attributed to peginterferon and ribavirin therapy.
This patient developed decompensated cirrhosis, se-
vere thrombocytopenia, sepsis, and liver failure and
died at study week 32. In addition, it is important to
note that 11 patients receiving didanosine containing
HAART developed symptomatic mitochondrial toxic-

ity. The manufacturers of didanosine added a warning
to the prescribing information that coadministration of
didanosine and ribavirin is contraindicated.48,49 The
ribavirin dose-reduction component of this study did
not appear to keep more patients on HCV therapy. This
important clinical trial demonstrated that HCV
genotype is the most important predictor of disease
response followed by younger age and a lower HCV
RNA level.

Drug Therapy

The pegylated formulations of interferon provide a
longer half-life, easier dosing, and higher serum con-
centrations than do standard interferon prepara-
tions.48,49 The addition of polyethyleneglycol (PEG) to
interferon produces a molecule that is active against
HCV and cleared more slowly from the body.48-50 These
preparations combined with ribavirin have become the
standard of care for the HCV-monoinfected population
because of better clinical outcome data and increased
rates of SVR.6 Combination therapy with pegylated in-
terferon and ribavirin has not been FDA approved in
the coinfected population because of a lack of clinical
trial data. However, multiple interferon alfa-2b and in-
terferon alfa-2a products are FDA approved for the
treatment of HCV infection in the non-HIV-infected pa-
tient population.3

Currently, 2 pegylated interferon products are com-
mercially available in the United States. PEG-Intron,
peginterferon alfa-2b, is manufactured and marketed
by the Schering Corporation. This product is available
as a Redipen for direct reconstitution and injection and
also as a vial of powder requiring reconstitution with
sterile water. The polyethylene glycol (PEG) molecule
in PEG-Intron is covalently attached to interferon alfa-
2b. The addition of this large molecule, 12 000 d, ex-
tends the half-life of interferon. The peginterferon
product has a 10-fold greater Cmax and 50-fold greater
area under the curve (AUC) than does Schering’s stan-
dard interferon product. It is not known whether
peginterferon has any effect on drugs metabolized by
the cytochrome P450 enzyme system. Table 3 reviews
dosing and drug discontinuation guidelines.48

Roche Laboratories makes PEGASYS, peginterferon
alfa-2a. This product is marketed with COPEGUS,
ribavirin, and has a molecular weight of 20 000 d.
PEGASYS is available in an injectable solution as well
as in prefilled syringes. Maximum serum concentra-
tions of this product occur 72 to 96 hours after dosing,
and the drug clears at a significantly slower rate than

44 • JOURNAL OF PHARMACY PRACTICE 2006(19.1)

MCNELIS

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