The Disclosure Policy of Projects In Knowledge requires that faculty participating in a CME activity disclose to the audience: any significant relationship they may have with a pharmaceutical or medical equipment company, product, or service that may be mentioned as part of their presentation; any relationship with the commercial supporter of this activity; if discussion includes 1) therapies that are unapproved for use or are investigational; 2) ongoing research; or 3) preliminary data. Faculty will disclose such discussion.

For complete prescribing information on the products discussed during this CME activity, please see your current Physicians’ Desk Reference (PDR).

Nezam H. Afdhal, MD, has received grant/research support from Bristol-Myers Squibb Company, Cooley Pharmaceuticals, Idenix Pharmaceuticals Inc, Idun Pharmaceuticals, Inc, InterMune Inc, Isis Pharmaceuticals, Inc, Ortho Biotech Products, LP, Prometheus Laboratories, Inc, Schering-Plough Corporation, United Therapeutics, and Valeant Pharmaceuticals International; is a consultant for EchoSens, Gilead Sciences, Inc, Idenix Pharmaceuticals Inc, Isis Pharmaceuticals, Inc, Ortho Biotech Products, LP, Prometheus Laboratories, Inc, Schering-Plough Corporation, and Valeant Pharmaceuticals International; and is on the speakers bureau of Gilead Sciences, Inc, Ortho Biotech Products, LP, and Schering-Plough Corporation.

Steven L. Flamm, MD, has received grant/research support from InterMune Inc, Roche Pharmaceuticals, and Schering-Plough Corporation; and is on the speakers bureau of Roche Pharmaceuticals and Schering-Plough Corporation.

John G. McHutchison, MD, FRACP, has received grant/research support from Akros Pharma Inc, Amgen Inc, Bayer Pharmaceuticals, Biomedicines, Bristol-Myers Squibb Company, Cytel Corporation, Fujisawa Healthcare, Inc, Gen-Probe, Gilead Sciences, Inc, Idun Pharmaceuticals, Isis Pharmaceuticals, Inc, Ortho Diagnostic Systems, Inc, Prometheus Laboratories, Ribozyme Pharmaceuticals, Inc, Roche Pharmaceuticals, Schering-Plough Corporation, SciClone Pharmaceuticals, Triangle Pharmaceuticals Inc, and Vertex Pharmaceuticals, Inc; is a consultant for Amgen Inc, Anadys Pharmaceuticals, Inc, Centocor, Inc, GlaxoSmithKline, InterMune Inc, Isis Pharmaceuticals, Inc, National Genetics Institute Inc, Novartis Pharmaceuticals Corporation, Pfizer Inc, Prometheus Laboratories, Ribozyme Pharmaceuticals, Inc, and Schering-Plough Corporation; and is on the speakers bureau of InterMune Inc, Roche Pharmaceuticals, and Schering-Plough Corporation.

Peer Reviewer has received grant/research support from Roche Pharmaceuticals, Valeant Pharmaceuticals International, and Wyeth Pharmaceuticals; is on the speakers bureau of Gilead Sciences, Inc, and Roche Pharmaceuticals; is a consultant for Amgen Inc (ad hoc) and Roche Pharmaceuticals; and has received honoraria from Amgen Inc, Gilead Sciences, Inc, and Roche Pharmaceuticals.

There may be discussion of unlabeled/unapproved uses of drugs or devices in this activity.

The opinions expressed in this activity are those of the faculty and do not necessarily reflect those of Projects In Knowledge.

This CME activity is provided by Projects In Knowledge solely as an educational service. Specific patient care decisions are the responsibility of the physician caring for the patient.

This independent CME activity is supported by an educational grant from
Schering-Plough Corporation.

African Americans have up to a three-fold higher rate of HCV infection compared with Caucasians.¹ Risk factors for infection are the same in African Americans as in the general population, but this subpopulation tends to have unique viral characteristics, including a higher prevalence of genotype 1 infection (>95%) and a lower rate of viral load decline with interferon monotherapy.^{2, 3}

Until recently, African Americans have been underrepresented in clinical trials despite the higher rate of infection. Data that are available, however, demonstrate overall lower response rates. Several retrospective studies noted that African Americans have lower rates of response to anti-HCV treatment, unrelated to compliance or disease severity.^2-5 Prospective studies by Muir et al and Jeffers et al confirmed a significantly lower rate of sustained virologic response (SVR) (19% and 26%, respectively) among African Americans receiving standard courses of peginterferon/ribavirin combination therapy compared with Caucasians (39% and 52%, respectively), regardless of genotype.^{6, 7}

Findings from the WIN-R (Weight-Based Dosing of PEG-INTRON and REBETOL) trial, reported by Ira Jacobson, MD, show that weight-based dosing of ribavirin offers a significant advantage in the treatment of African Americans infected with genotype 1 compared with fixed dosing of ribavirin.⁸ WIN-R is a large prospective trial with more than 200 centers throughout the United States to study weight-based versus standard fixed dosing of ribavirin.

Approximately 5000 treatment-naive patients were randomized into two study arms: 1) peginterferon alfa-2b 1.5 �g/kg QW plus ribavirin 800 mg/d, and 2) peginterferon alfa-2b 1.5 �g/kg QW plus weight-based ribavirin (Table 1).⁸ There were no significant patient demographic differences between the two arms, although notably, mean patient weights in each arm were heavier than in pivotal registration trials of peginterferon alfa-2a and alfa-2b plus ribavirin combination therapy, and 30% had stage F3 to F4 fibrosis. Patients infected with genotype 1 were treated for 48 weeks, whereas patients infected with genotype 2 or 3 were treated for either 24 or 48 weeks. SVR was determined at the end of a 24-week posttreatment phase. Growth factors were also permitted, according to strict criteria, for hematologic adverse effects.

Jacobson reported the findings from a subset of 387 African Americans infected with genotype 1 who had received at least one dose of drug. Of those weighing ≥65 kg (n = 362), 188 received standard fixed dosing and 174 received weight-based dosing of ribavirin. Of these 362 patients, those who received weight-based dosing of ribavirin achieved end-of-treatment response (ETR) and SVR at approximately twice the rate of those who received fixed dosing of ribavirin (ETR: 29% and 16%
[P = .006], respectively; SVR: 21% versus 10% [P = .004], respectively) (Figure 1).⁸ Among all 387 patients, including the 25 patients weighing <65 kg, the SVR rates for the weight-based and fixed-dose groups were 19% and 11%, respectively (Figure 2).⁸ Patients with high baseline viral loads (>600,000 copies/mL) achieved higher SVRs with weight-based dosing compared with fixed dosing: 17% versus 7%, respectively. As patient weight increased, standard dosing declined in efficacy, while weight-based dosing increased in efficacy. Response rates could not be associated with adherence, as this community-based study design did not gather adherence data.

Audio Commentary 

As expected, anemia (Hgb < 11 g/mL) was more common in the weight-based group (47%) than in with the fixed-dose group (29%). Consequently, ribavirin dose reductions and erythropoietin use were more common in the weight-based group. Within the weight-based group, however, anemia did not increase with greater ribavirin doses. Discontinuations for adverse events were equivalent for both groups: 18% for the weight-based group and 17% for the fixed-dose group.

Jacobson concluded that weight-based dosing of ribavirin is superior to fixed dosing in African Americans. Safety concerns do not rise as the ribavirin dose increases, as patients receiving ribavirin 1400 mg/d had no more adverse events than patients receiving a lesser dose. Completion of the entire WIN-R database is expected by mid-2005, with numerous observational results emerging.

Although response rates were higher in the African American patients who received weight-based dosing of ribavirin, the response rates were still inferior to the known response rates in Caucasians. Mechanisms for a lower response in African Americans need to be elucidated and thus is currently the focus of a large NIH sponsored study called the VIRAHEP-C study.

Carroll M. Leevy, MD, reported findings from a single-center, open-label trial of interferon alfacon-1 (consensus interferon or CIFN) plus ribavirin in peginterferon/ribavirin nonresponders.⁹ Consensus interferon is a genetically engineered molecule that has demonstrated greater biologic potency compared with the naturally occurring interferon alfas, such as interferon alfa-2a or alfa-2b.

The 137 patients enrolled in the study were separated into treatment groups according to race: African American, n = 45; Caucasian, n = 92. The groups were matched for genotype, viral load at baseline, viral load after peginterferon alfa-2b/ribavirin therapy but before consensus interferon, age, and gender. All patients failed to achieve early virologic response (EVR) after 12 weeks with peginterferon alfa-2b 1.5 �g/kg QW plus ribavirin 1000 to 1200 mg/d and were started immediately, with no washout period, on consensus interferon 15 �g/d plus ribavirin 1000 to 1200 mg/d for 12 weeks, with the frequency of consensus interferon reduced to thrice weekly for an additional 36 weeks.

Audio Commentary 

At weeks 12, 24, and 48, African-American patients achieved a lesser virologic response compared with Caucasians (Figure 3).⁹ This lesser response continued through to the end of the 24-week follow-up period, at which time 27% of African Americans had achieved SVR compared with 41% of Caucasians (P = .09), a difference that was statistically insignificant. The only time period with a statistically significant difference between the response of African Americans and Caucasians was at week 12, when 13% of African Americans were HCV RNA negative compared with 28% of Caucasians (P = .04).

Therapy was well tolerated. Hematologic adverse events were treated with growth factors according to study protocol. Sixteen percent of patients required granulocyte colony-stimulating factor due to absolute neutrophil count <750 cells/mL. Fifteen percent of patients required either dose reduction or a drug holiday during the treatment period, but all patients completed the trial. Adherent patients were preselected by enrolling only patients with 80/80/80 adherence during the 12 weeks of peginterferon/ribavirin therapy.

These study findings demonstrate that African Americans who failed to achieve EVR on previous peginterferon/ribavirin therapy had a clinically significant rate of response following therapy with CIFN/ribavirin. Although African Americans had a trend toward lesser virologic response compared with Caucasians, this difference was statistically insignificant after week 12. A randomized, controlled trial of consensus interferon plus ribavirin in a larger sample of African Americans is now warranted.

For patients who have not achieved a virologic response to therapy, maintenance therapy is a potential strategy to achieve histologic benefit, thereby potentially preventing fibrosis progression. In a prospective 2-year study, Shiffman et al treated patients with low doses of standard interferon monotherapy and noted an improvement in inflammation and a trend toward less fibrosis in the subgroup of patients who had viral load reductions.¹⁰

Three ongoing studies are evaluating lower doses of peginterferon monotherapy given over 2 to 4 years to evaluate the effect of maintenance therapy: HALT-C (Hepatitis C Antiviral Long-Term Treatment Against Cirrhosis), sponsored by the National Institutes of Health; COPILOT (Colchicine versus PegIntron Long-Term), sponsored by Schering-Plough Corporation, and EPIC-3 (Evaluation of PegIntron in Control of Hepatitis C Cirrhosis), also sponsored by Schering-Plough Corporation.

COPILOT is a multicenter, randomized, controlled, 4-year study of colchicine versus low-dose peginterferon alfa-2b aimed at determining if such a strategy can delay or prevent progression of liver disease in patients with advanced HCV fibrotic disease (Ishak >3) who have failed prior interferon-based therapy. Nezam H. Afdhal, MD, reported results of the planned 2-year interim analysis of the primary clinical endpoints.¹¹ These endpoints include death, liver failure with sustained Child-Pugh-Turcotte (CPT) score increase >2 points, variceal bleeding, and hepatocellular carcinoma (HCC) or liver transplant. Endpoints were analyzed using Kaplan-Meier survival curves (intention-to-treat).

A total of 534 patients are enrolled in the study to date and have been randomized to receive either colchicine 0.6 mg BID or peginterferon alfa-2b 0.5 mg/kg QW. Both groups were well matched for age, gender, ethnicity, disease duration, prior therapy, genotype, cirrhosis, and disease severity. Prior to randomization, patients were stratified only according to presence or absence of cirrhosis. Liver biopsy, ultrasound, and endoscopy were performed at baseline and at week 96, the time of interim analysis. Monitoring was performed throughout the study, with clinical evaluation at 12-week intervals and ultrasound at 24-week intervals. A total of 68 patients (peginterferon 26; colchicine 42) have reached a clinically verified endpoint, with endpoints more common in the colchicine group (Table 2).¹¹

Audio Commentary 

The superiority of peginterferon compared with colchicine in terms of event-free survival was highly statistically significant (P = .007) (Figure 4).¹¹ This advantage remained when event-free survival was analyzed according to stratification for cirrhosis (P = .007) and for portal hypertension (P < .01). For patients without portal hypertension, the event rate for those who received colchicine was approximately 6% compared with 7% in those who received peginterferon. These rates are statistically equivalent. In contrast, for patients with portal hypertension, differences in event rates between the treatment groups were statistically significant: 27% in those who received colchicine compared with 11% in those who received peginterferon.

COPILOT is one of the first prospective studies of a large group of select patients in which the true annual event rate was evaluated. Distribution of events shows a 50% reduction in the liver-related event rate (on-treatment analysis) with peginterferon compared with colchicine (P = .004) (Table 3).¹¹ Peginterferon was also superior to colchicine in reducing all intention-to-treat events, including patients with portal hypertension.

Safety profiles of peginterferon and colchicine were similar. Importantly, there was no difference between the groups in terms of rate of infection or neutropenia. Of the complete enrollment group, 38 patients have discontinued treatment due to adverse effects (colchicine 15; peginterferon 23) and 83 patients have failed to comply with the treatment protocol. The incidence of depression was the same in the two groups. Intolerance of peginterferon was typically due to common interferon-related symptoms, such as fatigue.

Data from this interim analysis suggest that peginterferon is superior to colchicine as maintenance therapy over an initial 2 years. Long-term studies will be necessary to determine if this benefit can extend up to and beyond 4 years and whether either treatment can prevent HCC or slow fibrosis progression.

Audio Commentary 

Despite recent advances in the treatment of HCV infection, approximately 50% of patients treated with peginterferon/ribavirin will not achieve SVR. This high rate of nonresponse, coupled with the projected slow pace of new HCV drug development over the next decade, results in a large pool of nonresponders that is only expected to increase.

Currently there are limited options available for these patients. In nonresponders to standard interferon/ribavirin, retreatment with peginterferon/ribavirin has produced SVR in only 6% to 12% of patients.^12-18 Higher SVRs (27%) have been reported recently by Kaiser et al in nonresponders to peginterferon/ribavirin treated with a high-dose consensus interferon/ribavirin induction regimen.¹⁹ Continued study of effective and tolerable methods of treatment is clearly needed for this population.

Thierry Poynard, MD, presented 12-week virologic response data from the EPIC-3 trial, a large, prospective, controlled trial having two objectives.²⁰ The first objective is to determine the efficacy of peginterferon alfa-2b and weight-based ribavirin in the retreatment of nonresponders to interferon/ribavirin. The second objective, which applies to patients who do not have a virologic response to retreatment, is to determine the efficacy of low-dose peginterferon alfa-2b monotherapy compared with no treatment in delaying the progression of hepatic fibrosis or in preventing end-stage liver disease in cirrhotics. This retrospective review of 12-week HCV RNA viral load data from EPIC-3 was prompted by the recent release of encouraging data from the lead-in phase of the HALT-C study by Shiffman et al, which showed a virologic response of 28% at week 20 followed by a 12% SVR in prior nonresponders to interferon/ribavirin re-treated with peginterferon alfa-2a/ribavirin.¹⁶

According to the EPIC-3 study design, nonresponders or relapsers to prior interferon/ribavirin were re-treated with peginterferon alfa-2b 1.5 �g/kg QW plus weight-based ribavirin 800 to 1400 mg/d for 48 weeks. HCV RNA testing was performed at week 12. Poynard reported data on the first 1435 patients with available 12-week HCV RNA.²⁰ Eighty-four percent were infected with genotype 1 and 89% had steatosis.

For all genotypes, 65% of patients achieved a ≥2-log decline in HCV RNA from baseline at week 12 and 40% achieved undetectable HCV RNA. Patients infected with genotypes 2 and 3 had greater rates of virologic response at week 12 compared with patients infected with genotype 1 (Figure 5).²⁰ Similarly, patients with prior relapse achieved higher rates of virologic response at week 12 compared with nonresponders (Figure 6).²⁰ When data were re-evaluated by baseline viral load, body mass index, or fibrosis stage, there were no significant differences in 12-week response.

Audio Commentary 

These findings indicate an unexpectedly high 12-week response among prior nonresponders re-treated with peginterferon alfa-2b/ribavirin. Final conclusions require SVR data following completion of 48 weeks of therapy and 24 weeks of follow-up.

Past studies have linked SVR to adequate dosing of both peginterferon and ribavirin.^16,21,22 Using the complete database from the HALT-C trial, Shiffman et al studied the impact of dosing of both peginterferon alfa-2a and ribavirin, independently, in a large sample of 1145 nonresponders to prior therapy.²³ Findings were presented in a poster session.

All patients were enrolled in the lead-in phase of the HALT-C trial and were nonresponders to prior interferon or interferon/ribavirin therapy. Of the 1145 patients, 934 were infected with genotype 1. The regimen and target dose for all patients was peginterferon alfa-2b 180 �g QW and ribavirin 1000 to 1200 mg/d. Growth factors were not utilized. Actual doses were recorded as a percentage of the target.

In the first 20 weeks of therapy, patients who received >80% of the target dose of peginterferon alfa-2a and >80% of the target dose of ribavirin achieved an SVR of 17% (Table 4).²³ Dose reduction of ribavirin to <60% of the target dose affected SVR only when the dose of peginterferon was reduced to <80% of the target dose. Dose reduction of peginterferon to <60% of the target dose lowered the SVR to 8% when ribavirin was maintained at <80% of the target dose. Discontinuing ribavirin during the first 20 weeks had a dramatic effect on SVR, with no patient who discontinued ribavirin in this time period achieving SVR.

Audio Commentary 

These findings differ from previous studies on the importance of the dosing of ribavirin and/or peginterferon.^16,21,22 Further study of optimal target doses, particularly of ribavirin, and the impact of adherence to both drugs is needed.

Efforts are ongoing to find early and efficient ways to predict response so as to limit the cost of treatment and the risk of adverse effects in patients who are not likely to respond. A poster session by Feld et al presented a hepatic gene expression profile that may theoretically be a useful tool in predicting response to interferon-based therapy.²⁴

Audio Commentary 

More than 120 treatment-naive patients were enrolled in this gene expression study.²⁴ Gene expression profiling was performed using a microarray assay on percutaneous needle liver biopsies prior to initiation of peginterferon/ribavirin therapy. All patients then received peginterferon alfa-2a/2b 80 �g QW plus ribavirin 800 to 1200 mg/d for 24 weeks (genotypes 2/3) or 48 weeks (genotype 1).

Gene expression profiles of the first 15 nonresponders and 16 responders were compared with 20 normal controls. The nonresponders and responders were found to have significant differences in 18 genes. Of these, further analysis identified eight interferon-sensitive genes that were significantly upregulated in nonresponders. This eight-gene profile accurately predicted response status in 30/31 patients (ie, relapsers or nonresponders versus responders), even in patients infected with genotype 1 (n = 23). The predictive ability of the profile was verified by unsupervised hierarchical clustering, principal components analysis, and linear discriminants analysis.

This eight-gene profile warrants further study as a signature marker to predict response status. In addition, the identified genes may suggest future novel mechanistic targets for anti-HCV therapies.

Standard treatment of HCV is combination therapy with peginterferon (alfa-2a or alfa-2b) plus ribavirin. The efficacy and safety of both peginterferon products were established in their respective phase 3 pivotal registration trials.^22,25 A comparison of each product's labeling reveals differences not only in chemical composition of the polyethylene glycol (PEG) moiety (size, structure, and site of attachment) but also in pharmacokinetic properties.^26,27 These differences may translate to differences in viral kinetic profiles between the products, which in turn could translate to differences in rapid viral clearance and EVR, particularly in difficult-to-treat patients with genotype 1 infection and high viral load. Until now the two products have not been compared in any head-to-head clinical trial.

The COMPARE trial, a randomized, double-blind, parallel-group trial, studied the effects of these chemical and pharmacokinetic differences on expression of interferon-stimulated genes (ISGs) and initial viral load reduction. ISGs are a significant focus because they are the mediators of interferon's antiviral effect within the cell and are of particular importance during the first kinetic phase of viral elimination.^28-30 An advantage of the prolonged exposure conferred by the addition of the large PEG moiety is that there is greater opportunity for the interferon to interact with ISGs.

A total of 36 treatment-naive patients with genotype 1 infection were randomized to receive peginterferon alfa-2a 1.5 �g/kg QW or peginterferon alfa-2a 180 �g QW monotherapy for 4 weeks, with the addition of ribavirin 13 mg/kg/d for an additional 4 weeks.³¹ Peginterferon products were administered at weekly clinic visits. Pharmacodynamic studies consisted of HCV RNA testing along with measurements of ISG messenger RNA levels for the ISGs protein kinase (PKR) and 2',5'-oligoadenylate synthetase (2'5'-OAS). Pharmacokinetic studies consisted of serum peginterferon trough concentrations.

Audio Commentary 

At weeks 1 and 4, the serum trough concentrations of peginterferon alfa-2a were 16 and 25 times greater, respectively, compared with peginterferon alfa-2b. This increased concentration did not translate into greater antiviral efficacy, however, in that peginterferon alfa-2b demonstrated a significantly greater mean area under the curve (AUC) (ie, cumulative) viral load reduction compared with peginterferon alfa-2a at both weeks 1 and 4 (Figure 7).³¹ In addition, the mean maximum log₁₀ viral load reduction at weeks 1 and 4 was also significantly greater for peginterferon alfa-2b compared with peginterferon alfa-2a (Figure 8).³¹ Weight to exposure ratio was equal across weights for patients receiving peginterferon alfa-2b and higher in lighter patients compared with heavier patients in those receiving peginterferon alfa-2a.

Upregulation of ISGs (PKR and 2'5'-OAS) was also significantly higher in patients receiving peginterferon alfa-2b (Figure 9) and was associated with virologic response (P < .01 for PKR and
P = .034 for 2'5'-OAS).³¹ Finally, 77% of patients receiving peginterferon alfa-2b achieved virologic response (>2-log decline in HCV RNA) at week 8 compared with 44% of patients receiving peginterferon alfa-2a. The mean of individual change from baseline in absolute neutrophil count was significantly lower in the peginterferon alfa-2b group compared with the peginterferon alfa-2a group. Four patients discontinued treatment in the peginterferon alfa-2b group (3, thrombocytopenia; 1, anemia) compared with 2 patients in the peginterferon alfa-2a group (1, erythema multiforme; 1, thrombocytopenia).

Further studies are needed on the relationship between early viral load decline, interferon alfa response gene upregulation, and the clinical outcome of viral clearance.

Di Bisceglie et al presented a poster that outlined preliminary data of a randomized multicenter trial comparing viral load reductions of the two peginterferon products in combination with ribavirin in the treatment of patients infected with HCV genotype 1.³² Patients were randomized 1:1 into two treatment arms: peginterferon alfa-2a 180 �g QW or peginterferon alfa-2b 1.5 �g/kg QW, both in combination with weight-based ribavirin (1000-1400 mg/d) for a total of 12 weeks. At the end of week 12, patients would continue therapy for a total of 48 weeks. As of September 1, 2004, 107 had completed at least 4 weeks of treatment.

The primary endpoint was a change from baseline in serum HCV RNA at week 12. Early virologic response was defined as undetectable HCV RNA or ≥2-log decline in HCV RNA from baseline. The peginterferon products were also administered at weekly clinic visits. Also at these visits, blood was drawn for serum HCV RNA and serum trough interferon concentrations, as well as concentrations of protein (IFN) moieties.³²

The poster reported results of 28 of the 107 patients who completed 4 weeks of treatment for whom drug trough concentration levels have been determined. In all patients receiving peginterferon alfa-2a, trough concentrations were above the limit of quantitation (LOQ) at weeks 3 and 4 (250 pg/mL). In contrast, trough concentrations were below LOQ in 9 of 14 patients receiving peginterferon alfa-2b. The trough serum concentration levels of the IFN moieties of peginterferon alfa-2a and alfa-2b were 9670 � 449 pg/mL and 256 � 140 pg/mL, respectively.³²

The poster also reported results of 88 patients (44 in each group) who completed 8 weeks of therapy and for whom HCV RNA levels have been determined. Despite the differences in trough concentration between the two peginterferon products through week 4, the decline in HCV RNA levels through week 6 was the same in the two groups. By week 8, mean serum levels of HCV RNA decreased by 3.22 � 0.24 log₁₀ IU/mL in patients treated with peginterferon alfa-2a/ribavirin and by 2.65 � 0.27 log₁₀ IU/mL in patients treated with peginterferon alfa-2b/ribavirin.³² The cumulative HCV RNA decline over time, as measured by AUC, was 15.8 � 1.47 HCV RNA (IU) log₁₀/wk/mL for peginterferon alfa-2a/ribavirin and 14.3 �1.65 HCV RNA (IU) log₁₀/wk/mL for peginterferon alfa-2b/ribavirin.³²

At week 1, 6/54 patients receiving peginterferon alfa-2b had achieved virologic response compared with 4/53 patients receiving peginterferon alfa-2a. At week 4, 50% (22/53 in each group) of patients in both peginterferon groups had achieved virologic response. By week 8, seven additional patients receiving peginterferon alfa-2a had achieved virologic response (total, 29/44), whereas the number for those treated with peginterferon alfa-2b remained the same (total, 22/44).³²

Audio Commentary 

Although final results of the 12-week data are pending, these data suggest differences between the two peginterferon products in terms of pharmacokinetics and viral clearance in patients with HCV genotype 1 infection. Further studies are needed.

Audio Commentary 

The standard anti-HCV treatment algorithm in treatment-naive patients calls for a quantitative HCV RNA assay at baseline, followed by another at week 12.³³ A ≥2-log drop in HCV RNA or undetectable HCV RNA at week 12 indicates EVR and is predictive of SVR.^25,34 Up to this time point, the algorithm is the same for all patients, regardless of genotype. The duration of treatment after this point for patients who achieve EVR, however, is different depending on genotype. Patients infected with genotypes 2 and 3 are typically treated for an additional 12 weeks (a total of 24 weeks). In contrast, patients infected with genotypes 1, 4, 5, and 6 are typically treated for an additional 36 weeks (a total of 48 weeks). Irrespective of genotype, treatment is typically discontinued in patients who do not achieve EVR unless it is continued for histologic benefit alone.

Olav Dalgard, MD, presented findings from a nonrandomized multicenter trial that studied the duration of treatment in 122 treatment-naive patients infected with genotypes 2 and 3.³⁵ All patients received peginterferon alfa-2b 1.5 �g/kg QW plus ribavirin 800 to 1400 mg/d based on body weight. HCV RNA viral loads were measured at weeks 4 and 8. Patients with undetectable HCV RNA at both time points discontinued treatment at week 14. Patients with detectable HCV RNA at either of these time points continued to receive treatment for a total of 24 weeks. SVR was determined at 6 months posttreatment.

Of the 122 patients, 78% (95/122) had undetectable HCV RNA at weeks 4 and 8 and so received only 14 weeks of treatment. SVR was achieved in 90% (85/95) of this group. In contrast, of the 27 patients with detectable HCV RNA at weeks 4/8 who continued treatment for 24 weeks, only 56% (15/27) achieved SVR. Predictors of SVR, by logistic regression analysis, were absence of bridging fibrosis/cirrhosis and adherence.

Based on these findings, Dalgard et al concluded that 14 weeks is a sufficient duration of therapy for patients infected with genotypes 2 and 3 with undetectable HCV RNA at week 8. A large randomized controlled trial to address this question is planned.

Audio Commentary 

Prolonged treatment as a means to increase SVR in patients who do not rapidly clear HCV RNA was the subject of a study reported by Jose Sanchez-Tapias, MD.³⁶ A total of 510 treatment-naive patients received peginterferon alfa-2a 180 �g QW plus ribavirin 800 mg/d for 4 weeks. Those with undetectable HCV RNA at week 4 (n = 184) continued therapy for a total of 24 or 48 weeks, depending on genotype. Those with detectable HCV RNA (n = 326) at week 4 were randomized 1:1 to continue on therapy for a total of either 48 or 72 weeks, with a 24-week follow-up period for both groups.

The SVR rate with 72 weeks of therapy was significantly higher compared with 48 weeks of therapy, the difference being greater in patients infected with genotype 1 (Figure 10).³⁶ In addition, the relapse rate was significantly lower in the 72-week group than in the 48-week group (Figure 11).³⁶

Adverse effects, including serious adverse effects, were similar for both the 72- and the 48-week groups. Treatment discontinuation was rare in the initial phase of the study, but progressed to 8% in patients receiving the standard duration of therapy and 36% in patients receiving prolonged therapy. In each group, approximately half of the decisions to discontinue were made by the patient: 4.8% in the 48-week group compared with 18% in the 72-week group.

Audio Commentary 

These findings suggest that longer treatment duration may increase SVR rates in patients who do not achieve rapid viral clearance at week 4 with peginterferon alfa-2a plus ribavirin at a lower than standard dose of the latter. Extension to 72 weeks does not increase the incidence or severity of adverse effects, but does increase the rate of patient-led discontinuations. Further study is warranted, particularly using a higher dose of ribavirin similar to that of the approved peginterferon alfa-2a/ribavirin combination.

Prolonged treatment for patients infected with genotype 1 was studied as a means to prevent the relatively higher rate of relapse seen in this population. Thomas Berg, MD, presented findings that suggest 72 weeks of therapy, rather than the standard 48 weeks, may produce a significant reduction in the relapse rate in genotype-1-infected patients with a late virologic response (HCV RNA positive at week 12 and negative at week 24).³⁷

This study was a retrospective review of results from a German multicenter trial reported at last year's AASLD meeting.³⁸ In this trial, 453 treatment-naive genotype-1-infected patients received peginterferon alfa-2a 180 �g QW plus ribavirin 800 mg/d but were randomized to a treatment duration of either 48 or 72 weeks.

The relapse rate was found to be similar between both groups: 26% in the 48-week group compared with 19% in the 72-week group (P = .09). When the data were analyzed according to virologic response, however, late virologic responders in the 72-week group had a significantly lower rate of relapse than late responders in the 48-week group (Table 5).³⁷ There was no statistical difference between the two groups among early virologic responders. When the data were analyzed according to viral load at week 12, only patients with low-level viremia (50 to 5000 IU/mL) were found to benefit from extended treatment.³⁷ In contrast to relapse rates, SVR rates (75% to 80%) showed no difference between the 48- and 72-week groups based on early virologic response.

As in the study by Sanchez-Tapias et al, this study used a lower than standard dose of ribavirin in combination with peginterferon alfa-2a. Genotype-1-infected patients treated with this regimen who are HCV RNA negative at week 12 achieve a high rate of SVR- 75% to 80%-whether treated for 48 or 72 weeks. Patients who are late responders, however, have a significantly reduced rate of relapse with treatment prolonged to 72 weeks compared with 48 weeks.

Audio Commentary 

Published studies indicate that 25% to 30% of HIV-infected individuals (an estimated 10 million worldwide) are coinfected with HCV.^39-41 HCV and HIV infection each have an adverse effect on the other. HCV infection affects the progression of HIV disease and the response to antiretroviral therapy (ART).⁴² Likewise, the natural history timeline of HCV infection is compressed in coinfected patients, who experience more rapid development of fibrosis, end-stage liver disease, HCC, and death.

Three recent studies have evaluated the safety and efficacy of peginterferon/ribavirin therapy in coinfected patients: ACTG (AIDS Clinical Trials Group) A5071,⁴³ ANRS HC02-RIBAVIC,⁴⁴ and APRICOT (AIDS Pegasys Ribavirin International Coinfection Trial).⁴⁵ Published data to date show response rates in genotype 1 infection that are about half those observed in HCV-monoinfected patients. Response rates in genotype 2/3 infection are better, but still less in HIV/HCV-coinfected patients compared with HCV-monoinfected patients.

Peginterferon/ribavirin produces significantly higher SVR rates compared with interferon/ribavirin in HIV/HCV coinfected patients according to final results from ANRS HC02-RIBAVIC, a large French prospective, multicenter, randomized trial presented in a poster by Stanislas et al.⁴⁶ The aim of this trial was to compare the efficacy and tolerability of pegylated versus standard interferon in combination with ribavirin for the treatment of HCV infection in HIV/HCV-coinfected patients. A total of 416 patients were enrolled. All had HIV-1 RNA < 1 log₁₀ over the preceding 3 months and were treatment-naive for anti-HCV therapy, and were either stable on ART or not receiving ART. Both demographically matched groups were randomized to receive either peginterferon alfa-2b 1.5 �g/kg QW plus ribavirin 800 mg/d or standard interferon alfa-2b 3 MU TIW plus ribavirin 800 mg/d. Both groups received treatment for 48 weeks and were followed for an additional 24 weeks. The primary endpoint was SVR at week 72. Secondary endpoints included safety and tolerability markers.

Audio Commentary 

In intention-to-treat analysis, patients taking peginterferon/ribavirin achieved a higher SVR compared with those taking interferon/ribavirin: 27% versus 20%, P = .03. SVR varied with genotype
(Figure 12),⁴⁶ but not with baseline Metavir score or the adjusted ribavirin dose. Pretreatment factors associated with response included genotypes other than 1 or 4 (overall response [OR] = 5.9), no concomitant protease-inhibitor therapy (OR = 2.0), age < 40 years (OR = 1.9), and elevated alanine aminotransferase activity (>3 times the upper limit of normal; OR = 1.8). The 12-week rule for EVR held true in this study: Presence of EVR at week 12 predicted SVR with 87% positive predictive value, and absence of EVR had a 99% negative predictive value.

Safety profiles were similar in both study groups, with serious side effects occurring in 35% and 34% of patients receiving peginterferon/ribavirin and interferon/ribavirin, respectively (P = .73). Mitochondrial toxicity occurred most often in patients receiving ART regimens containing didanosine (OR for ddI = 45). The incidence of mitochondrial toxicity was 0 in patients not receiving concomitant ART, 200.2 per 1000 patient years in patients receiving didanosine-containing ART, and 47.5 per 1000 patient years in all patients.

Final results from this study confirm the superiority of peginterferon/ribavirin compared with standard interferon/ribavirin in the treatment of HCV in HIV/HCV coinfected patients.

The impact of anti-HCV treatment on histologic outcome, in addition to virologic outcome, is as important in the coinfected population as it is in other populations. SVR rates from APRICOT were previously reported by Torriani et al: 62% for genotypes 2/3 and 29% for genotype 1.45 Lissen et al reported on the histologic outcome of HIV/HCV coinfected patients receiving peginterferon/ribavirin in this large trial, as well as the correlation between histologic and virologic response in those patients where paired biopsies were available.⁴⁷

A total of 860 coinfected patients with stable HIV disease and untreated HCV infection were randomized into three treatment groups: 1) interferon alfa-2a 3 MU TIW plus ribavirin 800 mg/d; 2) peginterferon alfa-2a 180 �g QW plus placebo; and 3) peginterferon alfa-2a 180 �g QW plus ribavirin 800 mg/d. After 48 weeks of treatment, patients were followed for an additional 24 weeks, at which time SVR was determined. A positive histologic response was defined as a ≥2-point reduction in the Ishak-modified Histologic Activity Index (HAI) in patients with paired biopsies taken ≤15 months prior to treatment and ≥56 days after treatment. All biopsies were scored by unblinded pathologists at each site. There was no difference in baseline HAI scores between the three treatment groups.

Patients in the peginterferon/ribavirin group had a significantly greater reduction in HAI, and a higher percentage of patients achieving histologic response, compared with patients in the other two groups (Figure 13).⁴⁷ In all three groups, patients who achieved SVR were more likely to achieve histologic response compared with those who did not achieve SVR (69% versus 43% for patients in the peginterferon alfa-2a/ribavirin group who did and did not achieve SVR, respectively).

Findings from the study demonstrate that peginterferon/ribavirin produces a higher rate of histologic response than standard interferon alone or in combination with ribavirin. Among all treatment groups, the majority of patients who achieved SVR also achieved histologic response, and approximately one-third of patients who did not achieve SVR still achieved histologic response-similar to previous observations in the HCV mono-infected population.

Audio Comentary 

Approximately 15% to 40% of acutely infected HCV patients spontaneously clear the virus and do not develop chronic infection.⁴⁸ Studies indicate that individuals who mount and sustain an effective T-lymphocyte response to acute HCV infection are more likely to clear the virus and avoid progression to chronic infection.^49,50

Although there are no approved therapies for treating acute hepatitis C infection, Jaeckel et al previously reported that treatment with interferon alfa during the acute stage may prevent chronic infection.⁵¹ Questions have been raised, however, regarding the effect of interferon alfa on HCV-specific T-cell responses in acute HCV in terms of the kinetics, strength, specificity, and persistence of response, as well as the correlation with treatment outcome.

Wiegand et al studied the T-cell response in eight HLA-A2+ patients with acute HCV infection who were treated for 24 weeks with peginterferon alfa-2b 1.5 �g/kg QW.⁵² Peripheral blood mononuclear cells were collected from these patients before, during, and after therapy, and were cryopreserved for interferon-gamma-ELISPOT assays, proliferation assays, and flow-cytometry
(HLA-A2-restricted tetramers). Of these eight patients, four achieved SVR, one experienced relapse (HCV RNA negative at ETR but became positive during follow-up period), one experienced breakthrough infection (HCV RNA negative during therapy but became positive prior to ETR), and two achieved ETR with SVR results pending.

Although the magnitude of T-cell responses prior to therapy varied among the patients, only the patient who experienced breakthrough infection had no detectable HCV-specific T-cells prior to therapy. In all patients, both HCV-specific CD4+ and CD8+ cells were boostered immediately after the start of therapy but declined after week 4. In four patients, HCV-specific T-cells became undetectable. The two patients who achieved SVR had only a weak T-cell response during all phases of testing. Thus, a successful treatment outcome could not be predicted on the basis of T-cell response before or during therapy.

Audio Commentary 

Additional findings that warrant further study include the lack of restoration of HCV-specific cellular immunity following successful therapy and the alteration of the general T-cell pools by interferon.

The goal of successful anti-HCV therapy for all patients is the driving force behind these trials, which were presented at the 55th Annual Meeting of the AASLD, as well as the driving force behind the clinician's efforts to stay apprised of the latest research and expert recommendations. Researchers and practicing clinicians alike must be aware of current challenges to successful therapy and how these challenges are potentially addressed by the findings and conclusions of ongoing and completed clinical trials.

1. Alter MJ, Kruszon-Moran D, Nainan OV, et al. The prevalence of hepatitis C virus infection in the United States, 1988 through 1994. N Engl J Med. 1999;341:556-562.
2. McHutchison JG, Poynard T, Pianko S, et al. The impact of interferon plus ribavirin on response to therapy in black patients with chronic hepatitis C. The International Hepatitis Interventional Therapy Group. Gastroenterology. 2000;119:1317-1323.
3. Reddy KR, Hoofnagle JH, Tong MJ, et al. Racial differences in responses to therapy with interferon in chronic hepatitis C. Consensus Interferon Study Group. Hepatology. 1999;30:787-793.
4. De Maria N, Colantoni A, Idilman R, Friedlander L, Harig J, Van Thiel DH. Impaired response to high-dose interferon treatment in African-Americans with chronic hepatitis C. Hepatogastroenterology. 2002;49:788-792.
5. Kinzie JL, Naylor PH, Nathani MG, et al. African Americans with genotype 1 treated with interferon for chronic hepatitis C have a lower end of treatment response than Caucasians. J Viral Hepat. 2001;8:264-269.
6. Muir AJ, Bornstein JD, Killenberg PG. Peginterferon alfa-2b and ribavirin for the treatment of chronic hepatitis C in blacks and non-Hispanic whites. N Engl J Med. 2004;350:2265-2271.
7. Jeffers LJ, Cassidy W, Howell CD, Hu S, Reddy KR. Peginterferon alfa-2a (40 kd) and ribavirin for black American patients with chronic HCV genotype 1. Hepatology. 2004;39:1702-1708.
8. Jacobson I, Brown R, McCone J, et al. Weight based ribavirin dosing improves virologic response in HCV-infected genotype 1 African-Americans (AA) compared to flat dose ribavirin with peginterferon alfa-2b combination therapy. Abstract 125. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
9. Leevy C, Chalmers C, Blatt LM, et al. Comparison of African American and non African American patient end of treatment response for PEG-IFN alpha 2 + weight-based ribavirin nonresponders retreated with IFN alfacon-1 + weight-based ribavirin. Abstract 172. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
10. Shiffman ML, Hofmann CM, Contos MJ, et al. A randomized, controlled trial of maintenance interferon therapy for patients with chronic hepatitis C virus and persistent viremia. Gastroenterology. 1999;117:1164-1172.
11. Afdhal N, Freilich B, Levine R, et al. Colchicine versus PEG-INTRON Long Term (COPILOT) Trial: interim analysis of clinical outcomes at year 2. Abstract 171. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
12. Gross JB, Therneau TM, Johnson SM, Kwo PY, Afdhal NH, Flamm S. The RENEW trial: a national, multicenter study of high-dose peginterferon alfa-2b plus ribavirin for non-responders with hepatitis C. Abstract 321. Presented at: Digestive Disease Week 2003; May 15-20, 2003; New Orleans, La.
13. Jacobson IM, Ahmed F, Russo MW, et al. Pegylated interferon alfa-2b plus ribavirin in patients with chronic hepatitis C: a trial in prior nonresponders to interferon monotherapy or combination therapy and in combination therapy relapsers: final results. Abstract 504. Presented at: Digestive Disease Week 2003; May 15-20, 2003; New Orleans, La.
14. Lawitz EJ, Gala NS, Becker S, et al. Pegylated interferon alfa 2b and ribavirin for hepatitis C patients who were nonresponders to previous therapy. Abstract 1293. Presented at: Digestive Disease Week 2003; May 15-20, 2003; New Orleans, La.
15. Selim K, Hyun C, Jensen J, et al. Histological improvement in patients with pegylated interferon alpha-2b plus ribavirin who were previously non-responders to Rebetron [abstract 217]. Presented at: Digestive Disease Week 2003; May 15-20, 2003; New Orleans, La.
16. Shiffman ML, Di Bisceglie AM, Lindsay KL, et al. Peginterferon alfa-2a and ribavirin in patients with chronic hepatitis C who have failed prior treatment. Gastroenterology. 2004;126:1015-1023.
17. Sulkowski M, Rothstein K, Stein L, Godofsky E, Goodman R, Dieterich D. PEG-interferon a-2b plus ribavirin for treatment of patients with chronic hepatitis C who have previously failed to achieve a sustained virologic response following interferon alfa or interferon a-2b plus ribavirin therapy. Abstract T1292. Presented at: Digestive Disease Week 2003; May 15-20, 2003; New Orleans, La.
18. Teuber G, Kallinowski B, Niederau C, et al. Retreatment with pegylated interferon-alpha2b plus ribavirin in patients with chronic hepatitis C not responding to a previous antiviral treatment with standard interferons combined with ribavirin. Abstract 1216. Presented at: Digestive Disease Week 2003; May 15-20, 2003; New Orleans, La.
19. Kaiser S, Mass H, Gregor M. Successful retreatment of peginterferon nonresponder patients with chronic hepatitis C with high dose consensus interferon induction therapy. Abstract 106346. Presented at: Digestive Disease Week 2004; May 15-20, 2004; New Orleans, La.
20. Poynard T, Schiff E, Becker S, et al. High early viral response (EVR) with PEG-INTRON/REBETOL (PR) weight based dosing (WBD) in previous interferon/ribavirin HCV treatment failures; early results of the EPIC3 trial. Abstract 170. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
21. McHutchison JG, Manns M, Patel K, et al. Adherence to combination therapy enhances sustained response in genotype-1-infected patients with chronic hepatitis C. Gastroenterology. 2002;123:1061-1069.
22. Manns MP, McHutchison JG, Gordon SC, et al. Peginterferon alfa-2b plus ribavirin compared with interferon alfa-2b plus ribavirin for initial treatment of chronic hepatitis C: a randomised trial. Lancet. 2001;358:958-965.
23. Shiffman ML, Morgan TR, Ghany MG, Wright EC. The impact of peginterferon (PEGIFN) and ribavirin (RBV) dosing on sustained virologic response (SVR) in patients with chronic hepatitis C virus (HCV) undergoing retreatment in the HALT-C trial. Abstract 349. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
24. Feld J, Chen L, Borozan I, et al. A hepatic gene expression profile that discriminates responders and nonresponders in treatment of chronic hepatitis C viral infection. Abstract 626. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
25. Fried MW, Shiffman ML, Reddy KR, et al. Peginterferon alfa-2a plus ribavirin for chronic hepatitis C virus infection. N Engl J Med. 2002;347:975-982.
26. PEG-Intron™ (pegylated interferon alfa-2b). Product Information. Kenilworth, NJ: Schering Corporation; 2003.
27. PEGASYS™ (peginterferon alfa-2a). Product Information. Nutley, NJ: Hoffmann-La Roche Inc; 2003.
28. Goodbourn S, Didcock L, Randall RE. Interferons: cell signalling, immune modulation, antiviral response and virus countermeasures. J Gen Virol. 2000;81:2341-2364.
29. Katze MG, He Y, Gale M, Jr. Viruses and interferon: a fight for supremacy. Nat Rev Immunol. 2002;2:675-687.
30. Neumann AU, Lam NP, Dahari H, et al. Hepatitis C viral dynamics in vivo and the antiviral efficacy of interferon-alpha therapy. Science. 1998;282:103-107.
31. Silva M, Poo-Ramirez JL, Wagner F, Jackson M, Laughlin M. Comparison of peginterferon-alfa2a and peginterferon-alfa2b pharmacokinetics and pharmacodynamics in COMPARE, a randomized, prospective, blinded trial. Abstract 68. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
32. Di Bisceglie AM, Rustgi VK, Thuluvath P, et al. Pharmacokinetics and pharmacodynamics of pegylated interferon alfa-2a or alfa-2b with ribavirin in treatment naive patients with genotype 1 chronic hepatitis C. Abstract LB 18. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
33. National Institutes of Health Consensus Development Conference Statement. Management of Hepatitis C: 2002. Baltimore, Md: National Institutes of Health; August 26, 2002. Available at: http://consensus.nih.gov.
34. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38:645-652.
35. Dalgard O, Bjoro K, Hellum K, et al. Short (14 weeks) treatment with pegylated interferon alpha-2b and ribavirin in patients with hepatitis C genotype 2/3 virus infection and early virological response. Abstract 197. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
36. Sanchez-Tapias JM, Diago M, Escartin P, et al. Longer treatment duration with peginterferon alfa-2a (40 KD) (PEGASYS^®) and ribavirin (COPEGUS^®) in naive patients with chronic hepatitis C and detectable HCV RNA by week 4 of therapy: final results of the randomized multicenter TERAVIC-4 study. Abstract 126. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
37. Berg T, von Wagner M, Hinrichsen H, et al. Reduction of the relative relapse rate by prolongation of the duration of a therapy with peginterferon alfa-2a plus ribavirin in patients with genotype 1 infection up to 72 weeks. Abstract 169. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
38. Berg T, von Wagner M, Hinrichsen H, et al. Comparison of 48 or 72 weeks of treatment with peginterferon alfa-2a (40KD) (PEGASYS^®) plus ribavirin (COPEGUS^®) in treatment-naive patients with chronic hepatitis C infected with HCV genotype 1. Abstract 328. Presented at: 54th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 24-28, 2003; Boston, Mass.
39. World Health Organization. Report on the global HIV/AIDS epidemic. June 1998.
40. World Health Organization. Hepatitis C�global prevalence (update). Wkly Epidemiol Rec. 1999;74:425-427.
41. Sulkowski MS, Moore RD, Mehta SH, Chaisson RE, Thomas DL. Hepatitis C and progression of HIV disease. JAMA. 2002;288:199-206.
42. Soriano V, Sulkowski M, Bergin C, et al. Care of patients with chronic hepatitis C and HIV co-infection: recommendations from the HIV-HCV International Panel. AIDS. 2002;16:813-828.
43. Chung RT, Andersen J, Volberding P, et al. Peginterferon Alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med. 2004;351:451-459.
44. Perronne C, Carrat F, Bani-Sadr F, et al. Final results of ANRS HC02-RIBAVIC: a randomized controlled trial of pegylated-interferon-alfa-2b plus ribavirin vs interferon-alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C in HIV co-infected patients. Abstract 117LB. Presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif.
45. Torriani FJ, Rockstroh J, Rodriguez-Torres M, et al. Final results of APRICOT: a randomized, partially blinded, international trial evaluating peginterferon-alfa-2a + ribavirin vs interferon-alfa-2a + ribavirin in the treatment of HCV in HIV/HCV co-infection. Abstract 112. Presented at: 11th Conference on Retroviruses and Opportunistic Infections; February 8-11, 2004; San Francisco, Calif.
46. Stanislas P, Carrat F, Bani-Sadr F, et al. Final results of ANRS HC02-RIBAVIC: a randomized controlled trial of pegylated-interferon alfa-b2 plus ribavirin vs interferon alfa-2b plus ribavirin for the initial treatment of chronic hepatitis C in HIV co-infected patients. Abstract 351. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
47. Lissen E, Clumeck N, Sola R, et al. Histological response to peginterferon alfa-2a (40 KD) (PEGASYS^®) plus ribavirin (COPEGUS^®) in patients with HIV-HCV co-infection: results of the AIDS PEGASYS Ribavirin International Co-Infection Trial (APRICOT). Abstract 174. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.
48. National Institutes of Health Consensus Development Conference Panel statement: management of hepatitis C. Hepatology. Sep 1997;26(3 Suppl 1):2S-10S.
49. Thimme R, Oldach D, Chang KM, Steiger C, Ray SC, Chisari FV. Determinants of viral clearance and persistence during acute hepatitis C virus infection. J Exp Med. 2001;194:1395-1406.
50. Urbani S, Boni C, Uggeri J, et al. High and long-lasting frequency of circulating CD8+ T Lymphocytes is associated with control of HCV infection [abstract 1041]. Presented at: 52nd Annual Meeting of the American Association for the Study of Liver Diseases; Nov 9-13, 2001; Dallas, Tex.
51. Jaeckel E, Cornberg M, Wedemeyer H, et al. Treatment of acute hepatitis C with interferon alfa-2b. N Engl J Med. 2001;345:1452-1457.
52. Wiegand J, Aslan N, Ciner A, et al. Kinetics of HCV-specific CD4+ and CD8+ T cell responses during and after therapy with pegylated interferon-alfa-2b in patients with acute hepatitis C. Abstract 208. Presented at: 55th Annual Meeting of the American Association for the Study of Liver Disease (AASLD); October 29-November 2, 2004; Boston, Mass.