JAC Advance Access originally published online on January 9, 2007
Journal of Antimicrobial Chemotherapy 2007 59(3):565-568; doi:10.1093/jac/dkl497
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Antiretroviral activity of pegylated interferon alfa-2a in patients co-infected with HIV/hepatitis C virus
Department of Infectious Diseases, University of Turin, Amedeo di Savoia Hospital, Corso Svizzera 164, Turin, Italy
* Corresponding author. Tel: +39-011-4393980; Fax: +39-011-4393882; E-mail: diego.agui{at}libero.it
Received 12 September 2006; returned 29 October 2006; revised 9 November 2006; accepted 13 November 2006
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Abstract |
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Objectives: To evaluate the early anti-HIV activity of pegylated interferon (PEG-IFN) alfa-2a and ribavirin in HIV/hepatitis C virus (HCV) co-infected patients not receiving antiretroviral therapy.
Patients and methods: In 19 patients with baseline plasma HIV load (HIV-RNA) >1000 copies/mL treated with PEG-IFN alfa-2a and ribavirin, HIV-RNA and T-cell subsets were measured at baseline and 2, 4 and 12 weeks after initiation of anti-HCV therapy.
Results: We observed a significant HIV-RNA decrease (>1 log10 copies/mL) through week 12 of anti-HCV treatment. The magnitude of HIV-RNA decline was associated with baseline HIV-RNA, CD4 count and PEG-IFN weight-adjusted dose.
Conclusions: A significant early anti-HIV activity of PEG-IFN alfa-2a was observed. Such an effect warrants further clinical evaluation in the management of co-infected patients.
Keywords: anti-HIV activity , interferons , anti-HCV therapy
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Introduction |
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Widespread use of highly active antiretroviral therapy (HAART) and the consequent increase in life expectancy of HIV-positive individuals has led to the emergence of hepatitis C virus (HCV) related liver disease as a major cause of morbidity and mortality in HIV/HCV co-infected patients.1 The association of pegylated interferon (PEG-IFN) and ribavirin was found to significantly improve the cure rate of HCV infection in HIV/HCV co-infected patients in large clinical trials.2–4 However, only limited data on the anti-HIV activity of such combinations have been reported, with few reports suggesting some degree of antiretroviral activity of interferon.5,6 The aim of our study was to evaluate the magnitude as well as the factors influencing the early anti-HIV activity of the combination of PEG-IFN alfa-2a and ribavirin in HIV/HCV co-infected patients.
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Patients and methods |
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At our department, 36 co-infected patients were consecutively placed on anti-HCV treatment in the first and second trimester of 2005. Of this case-series, 19 patients treated with PEG-IFN alfa-2a (180 µg/week) and ribavirin (10.6 mg/kg per day), without concomitant HAART and with baseline HIV-RNA above 1000 copies/mL, were prospectively evaluated. HIV-RNA and T-cell subsets were measured at baseline and 2, 4 and 12 weeks after initiation of anti-HCV therapy. Informed consent was obtained from patients for the use of clinical data. Parametric test and univariate linear regression analysis were used as appropriate. Statistical significance was established when P< 0.05. All values are expressed as medians (interquartile range).
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Results |
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Thirteen (68.4%) patients were HAART-naive, while 6 had stopped HAART from 1 week to 3.5 years previously (median wash-out of 4 months). Reasons for stopping HAART were immunovirological stability with high nadir CD4 count and patients' unwillingness to take concomitantly both antiretroviral and anti-HCV therapies. Fourteen (73.7%) were male; median weight was 70 kg (59–75), age was 39 years (36–42), and weight-adjusted dose of interferon was 2.57 µg/kg (2.40–3.05). At baseline, HIV-RNA in log10 copies/mL was 4.30 (4.04–4.69), number and percentage of CD4 count were 469 cells/mm3 (408–560) and 29.9% (22.8–34.3), respectively, and CD4/CD8 ratio was 0.6 (0.4–0.85) (Table 1). Naive subjects showed a higher baseline percentage of CD4 count [31% (23.8–36.1) versus 22.8% (18.2–26.3), P = 0.044] and a higher baseline CD4/CD8 ratio (0.8 (0.4–0.9) versus 0.45 (0.3–0.6), P = 0.041) as compared with experienced subjects. Median (range) HIV-RNA decline was –1.46 (2.75; –0.22), –1.43 (–2.84; 0.21), and –1.07 (–2.46; 0.62) log10 copies/mL at 2, 4 and 12 weeks, respectively (Figure 1). At these time points, viral suppression, defined as HIV-RNA below 50 and 400 copies/mL, was achieved by 1 (5.3%), 3 (15.8%) and 0 subjects, and by 4 (21.1%), 6 (31.6%) and 2 (10.5%) subjects, respectively. At week 2, HIV-RNA decrease was shown to correlate with HIV-RNA value at baseline (the higher the baseline value the higher the magnitude of decrease, R = 0.607, P = 0.006), baseline number and percentage of CD4 count (R = 0.475, P = 0.04; and R = 0.489, P = 0.034), and baseline CD4/CD8 ratio (R = 0.475, P = 0.04). No association was found between HIV-RNA decrease and the mentioned factors at weeks 4 and 12.
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Finally, subjects with higher weight-adjusted PEG-IFN alfa-2a dose showed a greater HIV-RNA decrease at week 2 (R = 0.495, P = 0.031) and week 4 (R = 0.614, P = 0.005).
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Discussion |
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To our knowledge, this study is the first to clinically characterize the early antiretroviral activity of PEG-IFN alfa-2a and ribavirin. An anti-HIV in vitro effect of interferon and of PEG-IFN alfa had been previously suggested.7 In some clinical studies with PEG-IFN alfa (investigated as an antiretroviral drug), some degree of HIV-RNA decrease has been reported.8–10 Most studies were pilot investigations, conducted on few subjects. Moreover, only naive HIV-positive patients with low HIV-RNA values at baseline,10 or under stable partially effective HAART8 were studied, thus making it difficult to evaluate the full anti-HIV activity of PEG-IFN. These studies used the alfa-2b formulation of PEG-IFN. Similarly, the large trials of PEG-IFN alfa and ribavirin for the treatment of chronic HCV infection in HIV-positive persons,2–4 enrolled patients either receiving HAART or with rather favourable virological profile at baseline. This makes it difficult to characterize the effect of anti-HCV treatment on HIV replication. As an example, among published data, in a nested study of the APRICOT trial11 an HIV-RNA decrease of about 1 log10 copies/mL was shown, but data were drawn from only two patients with detectable HIV-RNA at baseline. Moreover, these subjects were enrolled in two different arms of the study (PEG-IFN alfa-2a plus ribavirin and IFN alfa-2a plus ribavirin) and one of them was concomitantly receiving HAART.
In our study, a marked early anti-HIV activity of the PEG-IFN alfa-2a and ribavirin association was found. This effect is likely to be attributable to PEG-IFN alfa-2a, since no antiretroviral activity has been attributed to ribavirin in vivo.12 HIV-RNA decline appeared to be significant through week 12. The magnitude of such effect at weeks 2 and 4 (–1.46 and –1.43 log10 copies/mL, respectively) was impressive, being substantially equivalent to the viral decay seen with some antiretroviral drugs given as monotherapy, e.g. tipranavir/ritonavir.13 Moreover, the correlation of viral decay with baseline HIV-RNA value, and the median viral load decrease of 1.87 log10 copies/mL at week 4 seen in the four patients with baseline HIV-RNA >50 000 copies/mL seems to clearly describe a significant antiretroviral effect of PEG-IFN in these patients.
It is noteworthy that a similar HIV-RNA decrease at 4 weeks (–1.31 log10 copies/mL) was found by Hatzakis et al.9 in the course of monotherapy with PEG-IFN alfa-2b in a Phase I study. However, twice the standard PEG-IFN alfa-2b dosage was used to achieve this goal.
The relationship found in our study between magnitude of HIV-RNA decrease and the immunological status of the patients, indicated by baseline number and percentage of CD4 count, suggests an immune-mediated anti-HIV effect of PEG-IFN alfa-2a.
However, the association between HIV-RNA decline through week 4 and weight-adjusted PEG-IFN dosage also suggest a dose-dependent anti-HIV activity of the latter. Therefore, a multifactorial mechanism of such antiretroviral activity could be proposed.
Furthermore, median HIV-RNA decrease at week 12 showed a limited rebound as compared with previous time points, suggesting a tendency to viral adaptation, but it remained more than 1 log10 copies/mL as compared with baseline. No hypotheses have been proposed about the virological or immunological mechanism of this adaptation. Our data point to the need for further evaluation of the current restrictions for introducing anti-HCV treatment in HAART-naive HIV-infected patients.1 Strong anti-HIV activity of PEG-IFN alfa-2a during the first trimester could allow good HIV replication control, and consequent safe HAART deferral also in those with high baseline HIV-RNA value. In a similar way, PEG-IFN alfa-2a antiretroviral activity might allow temporary discontinuation of HAART in patients with high CD4 count undergoing anti-HCV therapy, avoiding problems of toxicity or adherence related to the co-administration of the two treatments. Finally, such an antiretroviral effect deserves to be explored not only over the whole course of anti-HCV treatment, but also as a complementary therapeutic weapon for anti-HIV salvage therapy, since resistance selected by conventional antiretrovirals is unlikely to have any impact on PEG-IFN alfa-2a activity on HIV.
Based on these findings we believe that the marked antiretroviral activity of PEG-IFN alfa-2a shown in our study warrants further clinical evaluation.
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None to declare.
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1 Alberti A, Nathan C, Simon C, et al. (2005) Short statement of the first European consensus conference on the treatment of chronic hepatitis B and C in HIV co-infected patients. J Hepatol 42:615–24.[CrossRef][Web of Science][Medline]
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Chung RT, Andersen J, Volberding P, et al. (2004) Peginterferon alfa-2a plus ribavirin versus interferon alfa-2a plus ribavirin for chronic hepatitis C in HIV-coinfected persons. N Engl J Med 351:451–9.
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5 Wensing A, Cohen Stuart JWT, Sprenger H, et al. Is interferon-alpha the solution for HIV-infected patients who have failed on HAART? Abstracts of the 39th Interscience Conference on Antimicrobial Agents and Chemotherapy1999San Francisco, CA, USA(American Society for Microbiology, Washington, DC, USA) pp. 538 Abstract 2208.
6 Hatzakis A, Gargalianos P, Kiosses V, et al. (2001) Low-dose IFN-alpha monotherapy in treatment-naive individuals with HIV-1 infection: evidence of potent suppression of viral replication. J Interferon Cytokine Res 21:861–9.[CrossRef][Web of Science][Medline]
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9 Hatzakis A, Laughlin M, Gargalianos P, et al. (2000) Safety, tolerability and antiviral pharmacodynamics of pegylated interferon-alpha-2b in HIV-1 infection: a phase I study. Abstracts of the Fifth International Congress on Drug Therapy in HIV Infection2000Glasgow, UKAIDS 14:Suppl 4, pp. S18 Abstract P6.
10 Schugt I, Kreuter A, Schlottmann R, et al. Pegylated interferon alfa-2b: a new therapeutic option in the treatment of early-stage HIV infection. Abstracts of the 10th Conference on Retroviruses and Opportunistic Infections2003(Foundation for Retrovirology and Human Health, Alexandria, VA, USA) pp. 78 Abstract 59.
11 Torriani FJ, Ribeiro RM, Gilbert TL, et al. (2003) Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) dynamics during HCV treatment in HCV/HIV coinfection. J Infect Dis 188:1498–507.[CrossRef][Web of Science][Medline]
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13 McCallister S, Valdez H, Curry K, et al. (2004) A 14-day dose–response study of the efficacy, safety, and pharmacokinetics of the nonpeptidic protease inhibitor tipranavir in treatment-naive HIV-1-infected patients. J Acquired Immune Defic Syndr 35:376–82.
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