JAC Advance Access published online on June 21, 2008
Journal of Antimicrobial Chemotherapy, doi:10.1093/jac/dkn262
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Original research |
Efficacy of pegylated interferon and ribavirin for retreatment of chronic HCV infection in HIV co-infected patients failing a previous standard interferon-based regimen
1 Infectious Diseases Department, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain 2 Infectious Diseases Unit, Hospital Universitario de Valme, Sevilla, Spain 3 Infectious Diseases Unit, Hospital Universitario Virgen Macarena, Sevilla, Spain 4 Internal Medicine Department, Hospital Torrecárdenas, Almería, Spain 5 Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Puerta del Mar, Cádiz, Spain 6 Infectious Diseases Department, Hospital Universitario Virgen del Rocío, Sevilla, Spain 7 Infectious Diseases Unit, Internal Medicine Department, Hospital Universitario Virgen de la Victoria, Málaga, Spain 8 Infectious Diseases Unit, Hospital Universitario Reina Sofía, Córdoba, Spain 9 Internal Medicine Department, Hospital Juan Ramón Jiménez, Huelva, Spain 10 Liver Unit, Department of Medicine, Hospital Universitari Vall d'Hebron, Universitat Autònoma de Barcelona, Spain
* Corresponding author. Tel: +34-630150090; Fax: +34-934282762; E-mail: mcrespo{at}vhebron.net
Received 28 February 2008; returned 25 March 2008; revised 24 April 2008; accepted 3 June 2008
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Abstract |
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Background: Combination of pegylated interferon (Peg-IFN) and ribavirin is the standard treatment for HCV infection in HIV co-infected patients. However, data available on the efficacy of this therapy in co-infected patients who failed a former interferon-based regimen are limited.
Methods: We analysed the efficacy and safety of the Peg-IFN alfa-2a or alfa-2b plus ribavirin combination in a multicentre observational cohort study including 54 HCV/HIV co-infected patients who had failed to respond to or relapsed on interferon-based treatment. The primary efficacy endpoint was the proportion of patients who achieved a sustained virological response (SVR), defined as HCV RNA <50 IU/mL 24 weeks after completion of therapy.
Results: By intention-to-treat analysis, 30% of the patients achieved an SVR. Viral eradication by genotype was 18.9% (7/37) genotype 1; 57.1% (8/14) genotype 3 and 33.3% (1/3) genotype 4. The only independent predictor of SVR was genotype 3 (odds ratio: 5.3; 95% confidence interval: 1.4–19.8). Fourteen (38%) patients with genotype 1 had undetectable viral load at week 48 of treatment. Nevertheless, 50% of them relapsed during the follow-up period. Severe adverse events or progression of HIV infection did not occur during the study; however, 39% of the patients required Peg-IFN dose reduction because of intolerance or haematological toxicity.
Conclusions: Combined Peg-IFN and ribavirin achieved a substantial rate of SVR in HCV/HIV co-infected patients who failed a prior standard interferon-based regimen. The decision to retreat any co-infected patient should be individual-based. More aggressive strategies may be necessary to avoid the high relapse rate observed among patients with genotype 1.
Key Words: HCV non-responders , HCV retreatment strategies , HIV co-infection
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Introduction |
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In randomized trials, 27% to 55% of HCV/HIV co-infected patients treated with pegylated interferon (Peg-IFN) alfa-2a or alfa-2b plus ribavirin achieved a sustained viral response (SVR).1–5 However, data are scarce regarding the efficacy of this combination for treating HCV/HIV co-infected patients who failed interferon-based therapy,6,7 and currently, no specific recommendations are available concerning retreatment of these patients.8
Here, we analyse the efficacy and safety of Peg-IFN alfa-2a or Peg-IFN alfa-2b plus ribavirin in a cohort of HCV/HIV co-infected patients who failed to respond to or relapsed on interferon-based therapy.
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Methods |
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Patient selection and treatment
From October 2001 to September 2006, 54 HCV/HIV co-infected patients, who had failed to respond to or relapsed on 24 weeks or more of interferon-based therapy, started treatment with Peg-IFN alfa-2a (180 µg/weekly; Pegasys, Roche, Basel, Switzerland) or Peg-IFN alfa-2b (1.5 µg/kg/weekly; PegIntron, Schering-Plough, Kenilworth, NJ, USA) at the discretion of the treating physician, plus ribavirin (<65 kg, 800 mg/day; 65–85 kg, 1000 mg/day; >85 kg, 1200 mg/day) in eight tertiary care centres in Spain and were analysed retrospectively. Additional criteria for study inclusion were: age, 18–60 years; HCV RNA, >1000 IU/mL, CD4+ T cell count, 
100 cells/mm3 and serum HIV RNA, <50 copies/mL for patients under highly active antiretroviral therapy. The main exclusion criteria were active drug or alcohol abuse, decompensated cirrhosis, serum creatinine 1.5 times the upper normal limit, haemoglobin <11 g/dL in women or <12 g/dL in men, neutrophil count <1500/mm3, platelet count <50 000/mm3 or a major psychiatric illness. The study protocol was approved by the Ethics Committee of the coordinating centre. All patients provided informed consent for participation.
Physical examination and laboratory tests were performed at least at treatment weeks 4, 12, 24, 36 and 48, and 8 and 24 weeks post-treatment. Stepwise reductions of 200 mg of ribavirin, to a minimum of 600 mg/day, reductions by 45 µg/week of peginterferon alfa-2a and reductions of peginterferon alfa-2b to 1.0, 0.75 and 0.5 µg/kg/weekly were allowed to manage adverse events.
Serum HCV RNA was detected using a qualitative PCR test with a detection limit of 50 IU/mL (Cobas Amplicor HCV v2.0; Roche Molecular Systems, Branchburg, NJ, USA) at 24 week intervals. A quantitative PCR test (Monitor HCV Test v2.0, Roche Diagnostics, sensitivity 600 IU/mL) was used to assess HCV RNA at baseline and at week 12 of treatment. Patients with HCV RNA <50 IU/mL at week 24 completed 48 weeks of treatment; otherwise, they were considered non-responders and discontinued treatment. The primary outcome was SVR, defined as undetectable HCV RNA 24 weeks after the end of treatment. A secondary analysis identified pre-treatment variables associated with SVR.
Virological response rates were calculated on an intention-to-treat (ITT) basis (incomplete data = failure). The Mann–Whitney U-test was used to compare continuous variables, and the 
2 or Fisher's exact test was used to compare categorical variables. Logistic regression analysis was conducted to assess the effect of pre-treatment variables on the likelihood of achieving an SVR. The following covariates were analysed: sex, age, weight, genotype (3 versus 1/4), pre-treatment HCV RNA both as a continuous and a categorical variable (<800 000 versus 800 000 IU/mL), fibrosis stage (cirrhosis versus no cirrhosis), ribavirin dose (mg/kg), previous regimen (interferon versus interferon plus ribavirin), former virological response (no response versus relapse), alanine aminotransferase and 
-glutamyl transpeptidase. Data were analysed using SPSS, version 12.0 for Windows (SPSS Inc., Chicago, IL, USA).
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Results |
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Demographic and clinical characteristics of the 54 patients analysed are summarized in Table 1. Two-thirds of the patients had a high HCV viral load, 67% of them had HCV genotype 1 and over a third of 41 patients who underwent liver biopsy had cirrhosis. Approximately three-quarters of the patients had been treated with interferon plus ribavirin, and 65% were former non-responders.
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Tolerance and safety
Treatment was prematurely withdrawn because of intolerance (n = 2) or thrombocytopenia (n = 1) in 3 patients and was stopped in 22 additional cases because of no virological response at week 12 (HCV RNA drop <2 log; n = 5) or detectable viral load at week 24 (n = 17). Peg-IFN dose reduction was required in 21 patients (38.9%) at a median of 2.6 months of treatment [interquartile range (IQR), 1.6–3.4 months], mainly because of neuropsychiatric adverse events (n = 7), moderate-to-severe flu-like syndrome (n = 7) and/or haematological toxicity (n = 5). Ribavirin dose was decreased in eight patients (14.8%) because of anaemia. Erythropoietin was used in four cases. No Grade 4 or mitochondrial toxicity-associated clinical events were observed. Neither HIV virological failure nor onset of opportunistic infections occurred during the study.
Overall, at the end of treatment ITT analysis, 46.3% of the patients (25/54) were HCV RNA-negative (Figure 1). Corresponding figures by genotype were: genotype 1/4, 37.5% (15/40) and genotype 3, 71.4% (10/14). Among the 25 end-of-treatment responders, 9 (36%) relapsed (2 with genotype 3 and 7 with genotype 1). Therefore, 16 patients (29.6%; 95% CI: 18.0–43.6) achieved an SVR. Rates of SVR according to HCV genotype were as follows: genotype 1/4, 20% (8/40; 95% CI: 9.1–35.6); genotype 3, 57.1% (8/14; 95% CI: 28.9–82.3) and genotype 4, 1 of 3 patients. Lastly, none of the 21 patients without an early virological response and continuing treatment for at least 24 weeks cleared the virus.
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Predictors of SVR
The chance of obtaining an SVR was higher among patients with genotype 3 (P = 0.016) and in previous relapsers (47.4%; 9/19) versus non-responders (20%; 7/35) (P = 0.035). A trend for a better response was observed in patients previously treated with interferon alone (6/14; 42.9%) versus those failing the interferon plus ribavirin combination (10/40; 25%) (P = 0.308). No differences were found between patients with cirrhosis (32%; 8/25) and those with less advanced fibrosis (25%; 4/16) (P = 0.734), or between patients with CD4+ cell count 350 cells/mm3 (30%; 12/40) and those with CD4+ cell count <350 cells/mm3 (27.3%; 3/1) (P = 0.860). By logistic regression analysis, the probability of eradicating the infection was 5-fold higher among patients with HCV genotype 3 than in those bearing genotype 1/4 [adjusted odds ratio (aOR): 5.33; 95% CI: 1.44–19.8]. A trend towards a greater response was observed among relapsers in comparison with former non-responders (aOR: 2.72; 95% CI: 0.74–9.98).
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Discussion |
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In our study, almost 30% of the HCV/HIV co-infected patients who had failed a previous interferon-based regimen obtained an SVR after retreatment with peginterferon plus a weight-adjusted dose of ribavirin. However, it should be noted that this overall rate was mainly driven by the high virological response rate among patients with genotype 3 (57%), whereas only 19% of the patients with genotype 1 eradicated the infection.
Similar low response rates to retreatment among non-responders to a previous interferon-based therapy have been reported from several trials in HCV-mono-infected patients9–12 and from two short observational cohort studies in HCV/HIV co-infected patients.6,7 These data underscore the idea that careful patient selection should remain the mainstay of retreatment.
Apart from the retrospective nature of the analysis, the main limitation of our study is the limited sample size. However, our data might be clinically useful with regard to decision-making and optimizing the cost-effectiveness of retreatment. The likelihood of obtaining an SVR was 5-fold higher in patients with genotype 3. Also, the chance of eradicating HCV infection was higher, although not statistically significant, in former relapsers. Conversely, the most unfavourable subsets of patients were those with genotype 1 or 4 and true non-responders to the former regimen. In keeping with previous reports in HCV-mono-infected and HCV/HIV co-infected patients,6,7 36% (9/25) of our patients with undetectable viral load at the end of the treatment relapsed. Indeed, the relapse rate peaked at 50% (7/14) among HCV genotype 1 patients.
In our study, patients were considered non-responders and stopped therapy if the viral load remained detectable at treatment week 24. However, none of the patients showing a viral drop of <2 log at week 12 of treatment cleared the virus, which suggests that virological response at week 12 may also be useful for the early identification of non-response to retreatment. Nevertheless, the utility of the 2 log stopping rule during retreatment requires further investigation.11
Lastly, no severe adverse events were observed in our study. Premature withdrawal of treatment was required in only three patients (5.6%). Furthermore, as concerns HIV infection, neither virological failure nor opportunistic infections occurred. However, almost 40% of the patients required reduction of the Peg-IFN dose because of intolerance or haematological toxicity. Although we did not find a correlation between dose reduction and HCV clearance, recently reported data have shown that a more than 20% reduction in the cumulative Peg-IFN dose during the first 20 weeks of therapy has a huge impact on SVR.12 Accordingly, strategies aiming to improve adherence and avoid dose reductions may reduce the risk of virological relapse in these patients.
In summary, 30% of the HCV/HIV co-infected patients who had failed previous treatment with interferon-based therapy achieved an SVR under retreatment with Peg-IFN plus a weight-adjusted ribavirin dose. Accurate selection of patients may further improve the response rate. Our data suggest that more aggressive strategies should be explored to reduce the high relapse rate observed among patients with HCV genotype 1.
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Funding |
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This study was supported in part by grants from Red Temática Cooperativa de Investigación en SIDA (Red de grupos 173) from the FISS, Centro de Investigación Biomédica en Red en Enfermedades Hepáticas y Digestivas (Ciberehd, 06/040028), Consejería de Salud Junta de Andalucía (Reference: 0017/07) and Instituto de Salud Carlos III (ISCIII-RETIC RD06/006).
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Transparency declarations |
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None to declare.
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Footnotes |
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Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (Ciberehd). 
Grupo para el Estudio de las Hepatitis Víricas de la Sociedad Andaluza de Enfermedades Infecciosas (SAEI).
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Acknowledgements |
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We acknowledge Ciberehd, funded by the Instituto de Salud Carlos III. We thank Celine Cavallo for English language editing.
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References |
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