TREATMENT OF HEPATITIS C IN SPECIAL POPULATIONS
Overview
A breakthrough in the treatment of chronic hepatitis C virus (HCV)
occurred with the development of pegylated interferon (PEG-IFN), which,
in combination with ribavirin, markedly increases sustained viral
response (SVR), as confirmed by 3 recent landmark studies. These
studies, however, have become increasingly recognized as not
representative of several vulnerable populations affected by HCV. This
newsletter focuses on HCV treatment in the following groups: patients
co-infected with HIV and HCV, patients co-infected with chronic
hepatitis B virus (HBV) and HCV, patients with end-stage renal disease
(ESRD), African Americans and other ethnic minority populations, and
liver transplant recipients with recurrent HCV.
HIV-HCV co-infection
Between 30% and 50% of patients with HIV are co-infected with HCV,
which accelerates liver fibrosis. Consequently, decompensated cirrhosis
from HCV has become one of the most common causes of death in this
population, particularly because these patients are surviving longer
since the introduction of protease inhibitors. In patients with low CD4
counts, treatment with anti-HIV medications is the priority in order to
prevent the complications of HIV. Most studies of this population have
required a stable anti-HIV regimen with a CD4 count of at least 100-200
cells/mm3. Four pivotal studies are briefly reviewed.
In the APRICOT study, Torriani et al
randomized 868 subjects co-infected with HIV and HCV (who had not
previously been treated with interferon [IFN] or ribavirin) to receive
one of the following 3 regimens: (1) PEG-IFN alfa-2a (180 mcg/wk) plus
ribavirin (800 mg/d), (2) PEG-IFN alfa-2a plus placebo, or (3) IFN
alfa-2a (3 MU 3 times/wk) plus ribavirin. Patients were treated for 48
weeks. The primary endpoint was SVR, defined as a serum HCV RNA level
less than 50 IU/mL at the end of 72 weeks of follow-up. SVR was
significantly higher among the recipients of PEG-IFN alfa-2a plus
ribavirin than among those assigned to IFN alfa-2a plus ribavirin (40%
vs 12%, P <.001) or PEG-IFN alfa-2a plus placebo (40% vs 20%,
P <.001). Among subjects infected with HCV genotype 1, SVR rates
were 29% with PEG-IFN alfa-2a plus ribavirin, 14% with PEG-IFN alfa-2a
plus placebo, and 7% with IFN alfa-2a plus ribavirin. Corresponding
rates among subjects infected with HCV genotype 2 or 3 were 62%, 36%,
and 20%. Neutropenia and thrombocytopenia were more common among
subjects treated with regimens that contained PEG-IFN alfa-2a, and
anemia was more common among subjects treated with regimens containing
ribavirin. In conclusion, PEG-IFN alfa-2a plus ribavirin was
significantly more effective than the other combinations.
In the ACTG A5071 study, Chung et al conducted a multicenter, randomized
trial in which 66 subjects were assigned to 180 mcg/wk of PEG-IFN alfa-2a
for 48 weeks and 67 subjects were assigned to 6 MU of IFN alfa-2a 3 times/wk
for 12 weeks, followed by 3 MU 3 times/wk for 36 weeks. Both groups received
ribavirin according to a dose-escalation schedule. This study showed that
the combination of PEG-IFN and ribavirin was associated with a significantly
higher SVR rate (HCV RNA level <50 IU/mL 24 weeks after completing therapy)
than the IFN and ribavirin combination (27% vs 12%, P = .03). In
the group administered PEG-IFN and ribavirin, only 14% of subjects with HCV
genotype 1 infection achieved SVR, compared with 73% of subjects with an HCV
genotype other than 1 (P <.001). A key finding from the study was
histologic improvement in 35% of subjects with no virologic response who
underwent liver biopsy, suggesting that the effects of the IFN and ribavirin
combination on hepatic histology may be independent of its antiviral
activity and that the combination may have a possible role for maintenance
therapy in selected patients. In conclusion, PEG-IFN and ribavirin are
superior to standard IFN and ribavirin and may also provide clinical benefit
in the absence of virologic clearance.
No trials have compared PEG-IFN alfa-2a plus ribavirin with PEG-IFN
alfa-2b plus ribavirin in patients co-infected with HIV and HCV.
However, in a 2004 Spanish randomized study comparing PEG-IFN alfa-2b
(100-150 mcg/wk) plus ribavirin (800-1200 mg/d) with IFN alfa-2b (3 MU 3
times/wk) plus ribavirin (800-1200 mg/d) in 95 patients, Laguno
and colleagues reported significantly better SVRs with the pegylated
combination (44% vs 21%, P = 0.017). The multicenter,
randomized RIBAVIC study by Carrat et al also supported
the use of PEG-IFN alfa-2b plus ribavirin versus IFN alfa-2b plus
ribavirin, as SVR was greater in the former group (27% vs 20%, P
= 0.047). Interestingly, this difference between treatments was found in
patients with HCV genotype 1 or 4 (17% for PEG-IFN vs 6% for standard
IFN, P = .006) but not in patients with HCV genotype 2, 3, or 5
(44% for PEG-IFN vs 43% for standard IFN, P = .88).
These 4 studies have established PEG-IFN and ribavirin as the treatment
of choice for patients co-infected with HIV and HCV and also have identified
poor prognostic indices for HCV eradication, including high baseline HCV
RNA, low ribavirin dose, high frequency of dose reductions, defects in the
cellular immune response, and drug interactions. For example, ribavirin
leads to increased intracellular didanosine accumulation; an alternative
agent should be considered before starting therapy.
HBV-HCV co-infection
Despite the high prevalence of HBV and HCV worldwide, this form of
co-infection remains uncommon in the United States, particularly in the
absence of HIV infection. Unfortunately, optimal treatment regimens have
not been established. Four studies on this topic are worth mentioning.
Guptan et al treated 14 co-infected patients
with 6 MU IFN alfa 3 times/wk for 6 months and reported undetectable HBV
DNA in 71% of patients and undetectable HCV RNA in 29% of patients.
However, this small study was not randomized and 7 patients had
comorbidities that may have influenced treatment outcome. In 2001, Villa
et al randomized 30 co-infected patients to 6 MU IFN alfa versus 9 MU
IFN alfa 3 times/wk for 6 months. All patients were HBV surface
antigen–positive and HCV RNA–positive and underwent pretreatment and
posttreatment biopsies. The authors reported that a high dose of
standard IFN could clear HBV and HCV in 31% of patients versus none in
the lower-dose group. Furthermore, improved histologic scores were noted
in 29% of the higher-dose group versus none in the other group,
suggesting a new role for high-dose IFN.
Liu et al used standard IFN and ribavirin. They discovered that SVR was
achieved at rates comparable with patients with HCV alone, and they reported
that up to 21% of patients lost HBV surface antigen. Given the increasing
efficacy of PEG-IFN over standard IFN, these investigators are currently
conducting a multicenter study using PEG-IFN and ribavirin in patients
co-infected with HBV and HCV. Recently, Chuang et al
performed a case-control study of 126 patients (42 cases, 84 controls) to
investigate the effectiveness of IFN-alfa and ribavirin. The authors
reported that SVR to HCV was similar between cases and controls. However,
HCV responders had significantly higher rates of HBV DNA resurgence than HCV
nonresponders during and after treatment, which suggests reciprocal viral
interference between HCV and HBV after therapy.
End-stage renal disease
Patients with ESRD and HCV have higher liver-related mortality rates
than those without HCV. In turn, renal transplant recipients infected
with HCV have higher liver-related death rates compared to renal
transplant patients negative for HCV. HCV treatment in these patients is
problematic because ribavirin is contraindicated, IFN monotherapy is not
as effective as combination therapy, and IFN doses frequently have to be
reduced. However, as IFN is contraindicated after kidney or kidney-liver
transplantation, eradication of HCV should be attempted prior to organ
transplantation.
HCV treatment in patients with ESRD has been addressed in
several small studies, but 2 meta-analyses of predominantly uncontrolled
studies have drawn important conclusions. Fabrizi et al identified 14
clinical trials of which only 2 were controlled studies. SVR and dropout
rates were 37% and 17%, respectively. The most frequent adverse effects
requiring interruption of treatment were flulike symptoms (17%),
neurologic symptoms (21%), and gastrointestinal symptoms (18%). The
overall weighted estimate for SVR in patients with HCV genotype 1 was
30.6%. In the subgroup of clinical trials (n = 5) with standard IFN
administration (3 MU 3 times/wk), SVR was 39%. In the second
meta-analysis, Russo et al analyzed 11 trials and
reported an SVR of 33% with 3 MU and an SVR of 26% in patients with
genotype 1. Of 152 patients in 8 studies treated with IFN monotherapy,
45 patients (29.6%) discontinued therapy because of side effects.
In conclusion, tolerance to initial IFN monotherapy was lower in
patients on dialysis than in nonuremic patients, although more than one
third of patients with ESRD have been successfully treated with IFN. Further
studies using PEG-IFN, with and without ribavirin, are in process to define
the optimal antiviral regimen for such patients.
African Americans and other minority populations
Several small studies have reported a lower response rate to IFN alfa
among black patients with HCV than whites with HCV, although the
etiology remains to be elucidated. Three important studies are reviewed.
Muir et al treated 100 black patients and 100
non-Hispanic white patients with HCV with PEG-IFN alfa-2b and ribavirin
for 48 weeks. The groups had similar proportions of patients with
genotype 1. SVR rates were higher among non-Hispanic white subjects than
among black subjects (52% vs 19%, P <.001). Multivariate
analyses examining sociodemographic and clinical characteristics found
that race was the only variable significantly associated with the
difference in response rates.
Jeffers et al treated 78 African Americans
with HCV genotype 1 with PEG-IFN alfa-2a (180 mcg/wk) and ribavirin
(1000-1200 mg/d) for 48 weeks and reported an SVR of only 26% compared
to 39% in 28 treated whites. Interestingly, 25% of black responders
demonstrated improved histologic scores in their posttreatment biopsy.
Hepburn et al recently analyzed data from 661 patients from 2
multicenter trials to determine predictors of successful viral
eradication and the role of ethnicity. After performing multiple
logistic regression analyses adjusted for factors known to affect
outcome such as genotype, the authors reported that, in comparison with
white patients, Asians were more likely to respond to treatment, whereas
Hispanics and African Americans were less likely to respond.
Liver transplant recipients with recurrent HCV
Recurrent HCV infection can lead to cirrhosis in 30% of patients
within 5 years of transplantation and is emerging as the most common
cause of retransplantation in the United States. Since 1996, several
small noncontrolled studies evaluating IFN-based therapies for recurrent
HCV infection have reported disappointing results. This was confirmed by
a recent landmark study by Samuel et al who randomized subjects to
receive either no treatment or therapy with IFN alfa-2b (3 MU 3
times/wk) plus ribavirin (1000-1200 mg/d) for 1 year. SVR was only 21%,
and no significant histologic improvement was noted. Forty-three percent
of patients also discontinued therapy because of adverse events. Despite
the low SVR reported by Samuel and others, Narayanan Menon et al and
Mukherjee et al identified a subgroup of patients who
demonstrated improved fibrosis scores despite failure to eradicate the
virus, suggesting a role for maintenance therapy in some patients.
Although PEG-IFN and ribavirin are the current treatment of choice, the
management of this disease remains severely limited by a paucity of
randomized, controlled trials or cost-effective analyses.
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