Genotype 2 or 3-Impact of Obesity on the Bioavailability of Peginterferon-α2a and Ribavirin

Impact of Obesity on the Bioavailability of Peginterferon-α2a and Ribavirin and Treatment Outcome for Chronic Hepatitis C Genotype 2 or 3

Åsa Alsiö¹, Karolina Rembeck¹, Galia Askarieh¹, Peer Brehm Christensen², Martti Färkkilä³, Nina Langeland⁴, Mads Rauning Buhl⁵, Court Pedersen², Kristine Mørch⁴, Bart L. Haagmans⁶, Salmir Nasic⁷, Johan Westin¹, Kristoffer Hellstrand¹, Gunnar Norkrans¹, Martin Lagging^1*

1 Department of Infectious Diseases/Virology, Institute of Biomedicine, University of Gothenburg, Gothenburg, Sweden, 2 Department of Infectious Diseases, University of Southern Denmark, Odense, Denmark, 3 Department of Gastroenterology, Helsinki University, Helsinki, Finland, 4 Department of Medicine, Haukeland University Hospital and Institute of Medicine, University of Bergen, Bergen, Norway, 5 Department of Infectious Diseases, Aarhus University, Aarhus, Denmark, 6 Department of Virology, Erasmus MC, Rotterdam, The Netherlands, 7 Department of Research and Development/Statistics, Skaraborg Hospital, Skövde, Sweden

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Abstract
Background and Aims

Having a body mass index above or equal to 30 kg/m² in conjunction with chronic hepatitis C virus infection is associated with non-responsiveness to treatment with interferon and ribavirin, but details regarding the mechanisms whereby obesity reduces the efficacy of therapy remain unclear.

Methods

This study evaluated impact of obesity on outcome as well as interferon and ribavirin concentrations following standard-of-care fixed dosing with peginterferon-α2a 180 µg once weekly and ribavirin 800 mg daily among 303 HCV genotype 2/3-infected patients enrolled in the per-protocol analysis of a recently completed phase III trial (NORDynamIC).

Results

Patients with BMI ≥30 kg/m² showed poorer outcome following 24 weeks of therapy (SVR 62% vs. 89% for BMI ≥30 vs. <30; P = 0.006) along with significantly higher steatosis grade (P = 0.002), HOMA-IR (P<0.0001), triglyceride levels (P = 0.0002), and baseline viral load (P = 0.028). Obesity was also significantly associated with lower plasma interferon concentrations on days 3, 7, and 29 (P = 0.02, P = 0.0017, and P<0.0001, respectively) and lower plasma ribavirin concentrations day 29 (P = 0.025), and lower concentration of interferon in turn was associated with a poorer first phase reduction in HCV RNA (P<0.0001). In multivariate analysis, ribavirin concentrations week 12, interferon concentrations day 29, and baseline HCV RNA levels were independent predictors of achieving SVR among patients treated for 24 weeks (n = 140).

Conclusions

Reduced bioavailability of interferon and ribavirin along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic hepatitis C.

Citation: Alsiö Å, Rembeck K, Askarieh G, Christensen PB, Färkkilä M, et al. (2012) Impact of Obesity on the Bioavailability of Peginterferon-α2a and Ribavirin and Treatment Outcome for Chronic Hepatitis C Genotype 2 or 3. PLoS ONE 7(5): e37521. doi:10.1371/journal.pone.0037521
Editor: Maureen J. Donlin, Saint Louis University, United States of America

Received: February 10, 2012; Accepted: April 20, 2012; Published: May 24, 2012
Copyright: © 2012 Alsiö et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Funding: This work was supported by the Swedish Society of Medicine, The Swedish Medical Research Council, Cancerfonden, The Torsten and Ragnar Söderberg Foundation, The Swedish Society of Microbiology, and ALF (Avtal om Läkarutbildning och Forskning) Funds at the Sahlgrenska University Hospital. Unrestricted grants from Roche affiliates in the Nordic region also supported this study. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: The authors have read the journal's policy and have the following conflicts: Unrestricted grants from Roche affiliates in the Nordic region also supported this study. This does not alter the authors’ adherence to all the PLoS ONE policies on sharing data and materials.
* E-mail: martin.lagging@medfak.gu.se

Discussion Only

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In spite of the pending introduction of direct antiviral agents (DAA) in routine clinical practice for HCV genotype 1, few of the currently available DAAs are active against genotype 2 or 3. Thus interferon-α and ribavirin are likely to retain pivotal roles in the management of chronic HCV genotype 2/3 infection, and a fixed dose of 800 mg/day ribavirin in conjunction with fixed 180 µg dosing of peginterferon-α2a [6] or weight-adjusted dosing of peginterferon-α2b [22] currently is the standard of care for these viral genotypes. In this setting, the main finding in the present study was that higher BMI was associated with significantly lower concentrations of ribavirin and interferon as well as poorer outcome following fixed dosing of ribavirin and peginterferon-α2a, that lower plasma concentrations of interferon were associated with a poorer first phase reduction in HCV RNA, and that both ribavirin and interferon concentrations along with baseline viral load were independent predictors of SVR.

The lower bioavailability of peginterferon noted in our study corroborates the findings reported by Lam et al. (among 11 HCV infected patients, 6 obese and 5 non-obese) who reported a non-significant trend towards lower interferon concentrations and higher baseline viral load following a single dose of 10 mIU of unpegylated interferon-α2b without the addition of ribavirin among obese patients. Interestingly in contrast to the present study, no difference in the first phase decline in HCV RNA was noted though the sample size was small [15].

The finding in the present study that patients with BMI ≥30 kg/m² had significantly lower concentrations of ribavirin following fixed dosing of 800 mg ribavirin/day is not surprising, and may substantiate the report by Pattullo et al. that weight based dosing of ribavirin may negate the influence of BMI and weight on outcome [23]. However, this latter study had only a limited number of patients infected with genotypes 2 (n = 22) or 3 (n = 31), and a substantial proportion of patients received weight based dosing of peginterferon-α2b. Fried et al. noted that among difficult-to-cure (i.e. body weight >85 kg and viral load >800,000 IU/mL) HCV genotype 1 infected patients higher fixed doses of both ribavirin (1600 mg daily) and peginterferon-α2a (270 µg/week) improved viral kinetics and SVR rates as compared to lower doses of ribavirin (1200 mg daily) and peginterferon-α2a (180 µg/week) [24]. This is in contrast to the PROGRESS study where no benefit was noted from giving 1400/1600 mg ribavirin daily as compared to 1200 mg in an intention-to-treat analysis among difficult-to-treat (i.e. body weight ≥85 kg and viral load ≥400,000 IU/mL) HCV genotype 1 infected patients [25]. It should be noted, however, that 42% of these patients had a BMI below 30 kg/m², and no subset analysis restricted to patients with BMI ≥30 kg/m² has yet been reported. Additionally in a per-protocol analysis restricted to patients with at least 80% exposure to the planned ribavirin dose, numerically higher SVR rates were obtained with intensified regimens suggesting that such strategies may be successful if tolerated [25].

Similarly it may be hypothesized that patients with BMI ≥30 kg/m² may benefit from increased dosing of interferon, which is substantiated by the abovementioned study by Fried et al. [24]. However, in the PROGRESS study no significant differences in SVR were noted in patients weighing ≥85 kg receiving a 12-week induction regime of 360 µg peginterferon-α2a weekly as compared to standard dosing in an intention-to-treat analysis [25]. However, when the analysis was restricted to patients tolerating at least 80% of the planned interferon dosing, numerically higher SVR rates were achieved with intensified regimens reiterating the importance of adherence [25]. Additionally the potential benefit of exposure to higher doses of interferon beyond 12 weeks of therapy was not investigated in this latter study. Similarly, in the IDEAL study, no significant difference in SVR was noted among patients with higher weight regardless whether they received weight based dosing of peginterferon-α2b or a fixed 180 µg dosing of peginterferon-α2a although a non-significant trend towards slightly higher SVR rates was noted in patients weighing between 105 and 125 kg who received weight based dosing of interferon (44.9%, 42.1%, and 38.9% for peginterferon-α2b 1.0 and 1.5 µg/kg body weight and 180 µg peginterferon-α2a respectively) [26]. However, it should be noted that in this weight class patients treated with peginterferon-α2b received 1400 mg ribavirin daily as opposed to 1200 mg daily for patients treated with peginterferon-α2a, and thus lower ribavirin dosing may have contributed to the lower numerical SVR rates noted following fixed interferon dosing.

In addition to differences in bioavailability of interferon and ribavirin, we also noted that patients with higher BMI had higher baseline viral load, more pronounced steatosis, in addition to features of the metabolic syndrome as previously reported, e.g. higher systolic and diastolic blood pressure, higher HOMA-IR, and higher baseline triglyceride levels. Although weight reduction among obese HCV patients is known to normalize many aspects of the metabolic syndrome as well as liver histology [27], [28] and thus is likely to have a beneficial impact on combination therapy for HCV, this cannot be addressed in the present study. Similarly whether increased treatment duration beyond 24 weeks for patients with BMI ≥30 kg/m² would improve outcome is outside the scope of this study. Since replication, assembly and release of HCV occurs in close proximity to intracellular lipid droplets [29], the finding of a higher baseline viral load among obese patients, hypothetically, may be secondary to the elevated pre-treatment plasma triglyceride levels or to more advanced steatosis.

In conclusion, higher BMI is associated with lower bioavailability of both peginterferon and ribavirin, which subsequently along with higher baseline viral load are dominant risk factors for treatment failure in obese patients with chronic HCV genotypes 2 and 3 infection.

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