Clinical Science: Concise Communication
Pegylated interferon alpha 2b and ribavirin in HIV/hepatitis C virus-co-infected non-responders and relapsers to IFN-based therapy
Myers, Robert Pa,c; Benhamou, Yvesa; Bochet, Mariea; Thibault, Vincentb; Mehri, Delphinea; Poynard, Thierrya
From the aService d'Hépato-Gastroentérologie and bLaboratoire de Virologie, Groupe Hospitalier Pitié-Salpêtrière, Paris, France; and cLiver Unit, University of Calgary, Calgary, Alberta, Canada.
See also pp. 1, 59, 67, 121, 131
Correspondence and reprint requests to Dr Robert P. Myers, G126, 3350 Hospital Drive NW, Calgary, AB, Canada T2N 4N1.
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Received: 16 May 2003; revised: 3 June 2003; accepted: 24 June 2003.
Background: Pegylated interferon alfa (PEG-IFN-α) and ribavirin is the most effective available treatment for chronic hepatitis C virus (HCV) infection. Its role in HIV/HCV-co-infected patients who have failed IFN-based therapy is unclear.
Objective: The aim of this study was to determine the safety and efficacy of this therapy in HIV/HCV-co-infected non-responders and relapsers.
Design: An open-label cohort study of 32 non-responders and relapsers to IFN (with or without ribavirin). Patients were treated for 48 weeks with PEG-IFN-α2b and ribavirin.
Main outcome measure: A sustained virological response (SVR) defined as a negative HCV-RNA level 24 weeks after the end of treatment.
Results: The mean age of the patients was 40 years; 78% were men, 67% had genotype 1, and 36% had bridging fibrosis or cirrhosis. The majority had a CD4 cell count greater than 200 cells/μl (97%) and an undetectable HIV-RNA level (81%). Fifteen patients (47%) withdrew because of adverse events, predominantly neuropsychiatric. In an intention-to-treat analysis, a SVR was observed in five patients (16%); 9% with genotype 1 versus 29% with genotype 3 and 33% with genotype 4 (P = NS). Additional, but statistically non-significant, univariate predictors of response were lower serum HCV-RNA (P = 0.07) and higher alanine aminotransferase levels (P = 0.055) at baseline. No patient with bridging fibrosis or cirrhosis responded. Treatment had a minimal impact on HIV parameters.
Conclusion: PEG-IFN-α2b and ribavirin is a potentially useful therapy in HIV/HCV-co-infected patients who have failed standard IFN-based regimens. Strategies to improve adherence are vital so as to maximize long-term response rates.
In patients with chronic hepatitis C virus (HCV) infection, HIV co-infection is associated with accelerated fibrosis progression and possibly an increased risk of liver-related complications [1,2]. Consequently, the development of safe and effective anti-HCV treatments for use in co-infected patients is essential. Although data are limited, IFN and ribavirin combination therapy leads to a sustained virological response (SVR) in 19–40% of this population [3–5]. The majority of patients (non-responders and relapsers) thus require additional treatment options. In the HIV-negative population, pegylated interferon alpha (PEG-IFN-α) and ribavirin is the most effective therapy available. An SVR has been reported in 54–61% of treatment-naive patients [6–8] and 10–20% of non-responders [9,10]. Data regarding the feasibility of this therapy in HIV/HCV-co-infected patients are sparse and are limited to treatment-naive patients [11–14]. No previous reports have examined PEG-IFN retreatment in co-infected patients who have failed standard IFN-based regimens.
The objectives of this open-label study were to evaluate the safety and efficacy of PEG-IFN-α2b and ribavirin in HIV/HCV-co-infected patients with a previous non-response or relapse to IFN-based therapy.
Patients and treatment
Between September 2000 and June 2001, 32 HIV/HCV-co-infected patients who had failed 12 weeks or more of IFN therapy (≥ 3 million units three times weekly alone or with ribavirin) initiated treatment with PEG-IFN-α2b and ribavirin (Pegetron; Schering Corp., Kenilworth, NJ, USA) in our tertiary care Liver Unit. All were HCV-RNA positive by polymerase chain reaction assay with a compatible liver biopsy (median 12 months before treatment; range 0.7–67). Exclusion criteria included decompensated cirrhosis, ongoing substance abuse, active psychiatric conditions, a white blood cell count less than 2000 cells/μl, haemoglobin less than 100 g/l, and platelets less than 50 000/μl. All patients consented to treatment and the use of data for research purposes.
Dosages of PEG-IFN-α2b and ribavirin were based on the discretion of the treating physician and patient tolerance. All physicians were experienced in the management of chronic hepatitis C and were actively involved in randomized trials of this therapy. Target doses were: PEG-IFN-α2b (1.5 μg/kg a week) and ribavirin (weight ≤ 75 kg, 1000 mg/day; > 75 kg, 1200 mg/day). Patients were treated for 48 weeks and followed for 24 weeks. Treatment was discontinued in patients with a persistently positive HCV-RNA level at 24 weeks.
Patients were assessed at weeks 4, 12, 24, 36, and 48; and 24 weeks after treatment. A CD4 cell count (direct immunofluorescence) and plasma HIV-RNA load (Amplicor HIV Monitor; Roche Diagnostics, Neuilly-sur-Seine, France; sensitivity 2.3 log10 copies/ml) were performed every 12 weeks. The serum HCV-RNA level was detected using a qualitative polymerase chain reaction assay (Cobas Amplicor HCV Monitor v2.0; Roche Diagnostics; sensitivity 50 IU/ml) at 24-week intervals. Quantification in baseline samples was performed using a branched DNA signal amplification assay (Quantiplex HCV RNA v2.0; Chiron, Emeryville, CA, USA), and HCV genotype using the Inno-LiPA line-probe assay (Innogenetics, Ghent, Belgium). Liver biopsies were analysed according to the METAVIR classification ; post-treatment biopsies were not requested.
The primary outcome was SVR, defined as an undetectable HCV-RNA level 24 weeks after the end of treatment. Data were analysed according to the intention-to-treat principle (NCSS 2001; NCSS, Kaysville, UT, USA). Continuous variables were compared using t-tests and Mann–Whitney tests, and categorical variables using Fisher's exact tests. Two-sided tests were used for all comparisons; a P-value of 0.05 or less was considered significant. Multivariate analyses were not performed because of the small sample size.
The baseline characteristics of the study population are outlined in Table 1. Two patients (6%) were non-responders to IFN monotherapy, and 30 patients (94%) had failed combination therapy with ribavirin (non-responders n = 24; relapsers n = 6). The HCV genotypes were 1 (67%), 3 (22%), and 4 (9%). Twelve patients (38%) had bridging fibrosis or cirrhosis. One patient was hepatitis B surface antigen positive, but remained hepatitis B e antigen negative and hepatitis B virus DNA negative (HBV Monitor MWP assay; Roche Diagnostics) throughout the study. The mean baseline alanine aminotransferase (ALT) level was 103 ± 66 IU/l; three patients (9%) had normal ALT. All except two patients (94%) were on antiretroviral therapy. The mean CD4 cell count was 478 ± 208 cells/μl and 26 patients (81%) had undetectable HIV-RNA levels.
The dosages of PEG-IFN-α2b and ribavirin are outlined in Table 2. Eleven patients (34%) discontinued therapy at 24 weeks because of persistently positive HCV-RNA levels. At the end of treatment, six patients (19%) had undetectable HCV-RNA levels. Five (16%) had an SVR; all were biochemical responders. An SVR was observed in 50% (1/2) of the interferon non-responders, and 13% (3/24) and 17% (1/6) of the non-responders and relapsers to combination therapy, respectively (P = NS).
Predictors of sustained virological response
An SVR was observed in 9% of patients with genotype 1 (2/22) versus 29% with genotype 3 (2/7; P = 0.24) and 33% with genotype 4 (1/3; P = 0.33 and P = 1.00 versus genotypes 1 and 3, respectively). Patients with an SVR tended to have lower baseline serum HCV-RNA levels (5.32 ± 0.93 versus 6.16 ± 0.79 log10 IU/ml; P = 0.07), and higher ALT levels (139 ± 37 versus 96 ± 68 IU/l; P = 0.055) and CD4 cell counts (580 ± 172 versus 460 ± 211 cells/μl; P = 0.17) than non-responders. No patient with bridging fibrosis or cirrhosis responded (P = 0.13 versus mild fibrosis). Age, sex, body weight, and HIV-RNA load did not predict a response to treatment (P = NS).
Ribavirin dosages did not differ between groups; however, responders received lower initial and maximum dosages of PEG-IFN-α2b (P = 0.06 and P = 0.009, respectively). No sustained responder received an initial PEG-IFN-α2b dosage greater than 1.0 μg/kg a week versus 17 out of 27 non-responders (63%; P = 0.01). Maximum dosages exceeded this threshold in 21 out of 27 non-responders (78%) versus only one out of five sustained responders (20%; P = 0.02). This inverse dose–response relationship was not attributable to differences in treatment discontinuation, dosage reduction, duration of therapy, or ALT levels during treatment (data not shown). However, patients with genotype 3 received lower dosages of PEG-IFN-α2b. The mean maximum dosages (in μg/kg a week) were: genotype 1, 1.23 ± 0.22; genotype 3, 1.05 ± 0.26 (P = 0.06 versus genotype 1); and genotype 4, 1.32 ± 0.28 (P = 0.41 and P = 0.09 versus genotypes 1 and 3, respectively).
PEG-IFN-α2b and ribavirin were poorly tolerated; 15 patients (47%) withdrew prematurely. Their characteristics and antiretroviral regimens did not differ from those who completed therapy (n = 17) except for lower baseline haemoglobin concentrations (139 ± 16 versus 150 ± 16 g/l; P = 0.07). Psychiatric complications were the most common reason for discontinuation (n = 6; 19%). Three patients withdrew because of depression (one requiring hospitalization), two for agitation and delirium, and one because of anxiety. Two patients stopped treatment because of haematological toxicity (neutropenia, 550/μl; and thrombocytopenia, 25 000/μl). Additional reasons included hepatocellular carcinoma (n = 1), and non-specific symptoms including fatigue, insomnia, and weight loss (n = 6). No deaths or mitochondrial toxicity were observed.
A dosage reduction of PEG-IFN-α2b was required in five patients (16%: neutropenia, n = 3, 9%; anaemia, n = 2, 6%). Ribavirin dosages were reduced in four patients (13%), all for anaemia. Platelet counts less than 50 000/μl were observed in three patients (9%); neutrophils less than 500/μl in one patient (3%); and haemoglobin less than 100 g/l in two patients (6%).
Impact on HIV parameters
Antiretroviral regimens were modified in six patients (19%) as a result of an increase in HIV replication or a decrease in the CD4 cell count (n = 4), anaemia (n = 1), and diarrhoea (n = 1). Twenty-five patients (78%) had a reduction in the absolute CD4 cell count of 50 cells/μl or greater (median change −135 cells/μl; range −441 to +16). However, mean counts returned to baseline by 36 weeks (P = 0.33), and the CD4 cell percentages did not change (baseline 24 ± 8% versus end of treatment 25 ± 9%; P = 0.44). Between baseline and the end of treatment, the mean HIV-RNA load (2.43 ± 0.38 versus 2.52 ± 0.57 log10 copies/ml; P = 0.18) and the proportion of patients with detectable HIV-RNA loads (19 versus 22%; P = 1.00) remained stable.
In this open-label study, PEG-IFN-α2b and ribavirin therapy led to an SVR in 16% of HIV/HCV-co-infected patients who had failed standard IFN-based regimens. Although preliminary studies in HIV-negative patients have reported similar results (10–20%) [9,10], to our knowledge, this is the first study in HIV-co-infected non-responders.
Several patient and treatment-related characteristics appeared to be predictive of an SVR, although they were not statistically significant possibly because of the small sample size. As previously reported [6–10,13], patients with genotype 1 tended to have a lower rate of response (9%) than those with non-1 genotypes (29–33%). In addition, lower baseline serum HCV-RNA levels, higher ALT levels, and the absence of advanced fibrosis were favourable (but non-significant) predictors of response. No patient with bridging fibrosis or cirrhosis responded. Although viral eradication appears to be unlikely in this subgroup, maintenance therapy requires investigation . As previously reported [4,17], responders tended to have higher baseline CD4 lymphocyte counts (all > 350 cells/μl), although confounding with advanced fibrosis must be considered . A negative relationship was observed between SVR and the PEG-IFN-α2b dosage. Treatment discontinuations, reductions and duration, and ALT levels on therapy (a potential impetus for dosage increases) did not differ according to the PEG-IFN-α2b dosage (less than versus 1.0 μg/kg or greater a week). However, patients with genotype 3 received lower dosages of PEG-IFN-α2b, possibly because the treating physicians considered this a more easily treated subgroup.
PEG-IFN-α2b and ribavirin were poorly tolerated; nearly 50% withdrew because of adverse events. This rate exceeds that in the HIV-negative population (10–14%) [6,7] and preliminary reports in naive, co-infected patients (15–30%) [12–14]. Neuropsychiatric and non-specific complaints (e.g. fatigue) accounted for two-thirds of the discontinuations. The thresholds at which these complications should precipitate treatment withdrawal are difficult to define, and are partly related to patient motivation. Many withdrawing patients were biochemical non-responders, and considered this factor in electing to discontinue treatment. Moreover, it is possible that dosage reduction, which was relatively infrequent in this study (≈ 15%) [6,7], may have been a more appropriate strategy in some patients. Nineteen per cent withdrew because of psychiatric complications (mainly depression). The majority was successfully managed by PEG-IFN-α2b discontinuation and antidepressants, although a few required hospitalization. As a psychiatric history is common in HIV-infected patients , this problem warrants special attention. In our unit, an experienced psychiatrist routinely evaluates at-risk individuals before therapy. The apparently poor success of this approach suggests that other strategies, including prophylactic antidepressants  and improved risk assessment tools , require further evaluation.
Concerns have been raised regarding in-vitro drug–drug interactions between ribavirin and nucleoside analogues with the potential for in-vivo anti-HIV antagonism [21,22], or the potentiation of the anti-HIV activity of didanosine and the precipitation of mitochondrial toxicity [13,23,24]. In this study, no significant effects on HIV parameters or cases of mitochondrial toxicity were observed, although lactate concentrations were not monitored. Although larger confirmatory studies are clearly required, these data suggest that PEG-IFN-α and ribavirin can be used safely in combination with antiretroviral agents.
This study was limited by a small sample size and the absence of a standardized dosing protocol; drug regimens were based on the discretion of experienced physicians. Although perhaps limiting the generalizability of the results, this approach permitted liberal treatment criteria. In fact, one-fourth of this cohort would have been excluded from randomized trials as a result of cytopenia [6,7,12]. In addition, the approach of titrating doses upwards led to acceptable rates of haematological toxicity, despite frequently low baseline values. Moreover, although higher-dose therapy may have increased the rate of SVR, the reverse cannot be ruled out; that is, lower response rates as a result of reduced adherence to higher-dose treatment. Finally, the similarity of these results to those of preliminary reports in HIV-negative non-responders and relapsers [9,10] indirectly supports the conservative approach used in this study.
In conclusion, this study demonstrates that PEG-IFN-α2b and ribavirin is a potentially useful therapy in HIV/HCV-co-infected patients who have failed standard IFN-based regimens. Strategies to improve the tolerability of this therapy (e.g. the use of growth factors) are needed so as to maximize adherence, and hopefully, long-term response rates.
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