Abstract
Background
Direct-acting antivirals (DAAs) have revolutionized treatment for HCV. Compared to interferon-based therapies, DAAs achieve higher rates of sustained virologic response, with more tolerable side effects. Nonetheless, interferon-based therapies have the potential to cause weight loss, and literature documenting the impact of DAAs on weight is limited. Appetite suppression may occur with chronic HCV. It is plausible that DAAs may indirectly cause weight gain given their ability to cause rapid virologic suppression, leading to improved hepatic function.
Methods
A retrospective chart review identified 220 patients who initiated DAA therapy between 1 February 2019, and 29 February 2020. Patients 18 years and older who completed therapy with a DAA were included in the study if they had a documented initial weight (weight on the day therapy was initiated) and final weight (weight 12 weeks after therapy completion). Change in weight was assessed as the primary outcome. Comorbidities with the potential to impact weight were assessed as confounders.
Results
Multiple variables were analyzed and baseline BMI was the only factor that influenced a change in weight (P = 0.016). Patients with a higher BMI at baseline experienced statistically significant weight gain. Weight was increased by 0.14 kg per unit of BMI (95% CI: 0.026, 0.25). Patient demographics relating to age and gender, progression of cirrhosis and concurrent comorbidities had no statistically significant impact on change in weight.
Conclusion
Weight changes after treatment with a DAA may be related to the individual’s weight prior to treatment.
Introduction
On a global spectrum, hepatitis C virus (HCV) impacts the lives of 71 million individuals. Its genetic diversity and prevalence vary by region, with the most common genotypes as genotypes 1, 3 and 4 [1]. HCV may manifest as an acute infection with the potential to develop into a chronic infection. Chronic, unresolved HCV has many consequences including cirrhosis, liver failure and hepatocellular carcinoma. In some instances, the progression may result in fatality. As a primary cause of liver cancer, treatment of HCV is imperative. Viral replication can be disrupted with the use of direct-acting antivirals (DAAs) and the use of DAAs has led to curative responses in patients with HCV [1].
Compared to their predecessor, DAAs have revolutionized the treatment of HCV and widely diminished the use of interferon-alpha (INF-α) and ribavirin. DAAs are preferred due to their tolerable side effect profile, shorter duration of therapy and high rates of sustained virologic response at 12 weeks (SVR12); greater than 95% independent of genotype [2]. The most commonly reported side effects of DAAs include fatigue, itching and dizziness [3]. Conversely the use of INF-α as monotherapy or in combination with ribavirin often resulted in negative adverse reactions that led to therapy discontinuation and suboptimal outcomes [4].
However, historic treatments for HCV have been known to induce weight loss as a side effect [5]. To an extent, the weight loss properties of INF-α may be viewed as advantageous depending on the patient’s baseline weight and body habitus. As it relates to DAAs, current literature does not adequately document their impact on weight. A prospective cohort study by Schlevogt et al. determined that DAA use was associated with weight gain in 44% of patients during long-term follow-up (48 weeks). The prevalence of weight gain was more profound in patients less than 60 years of age [5]. Similarly, a prospective cohort study by Do et al. determined that patients had a statistically significant weight gain after the use of a DAA [6]. This correlation was also linked to a younger age. Additionally, the occurrence of weight gain was more profound in patients who achieved SVR12, had cirrhosis, moderate alcohol consumption, or were overweight or obese [6].
Independently, HCV impacts glucose metabolism resulting in increased insulin resistance which may later progress to type 2 diabetes mellitus [5]. Its effect on the liver; alters lipid replication pathways leading to dyslipidemia and hepatic steatosis [5]. The disease process can also cause appetite suppression and weight loss [6,7]. It is plausible that DAAs may indirectly cause weight gain given their ability to cause rapid virologic suppression leading to improvements in hepatic function. To better understand the relationship between DAAs and their impact on weight, this study aimed to determine if a change in weight occurred after a patient completed therapy with DAA. Understanding the relationship between weight and DAAs will allow for tailored patient counselling prior to therapy and following therapy completion.
Methods
Trial design and data source
A retrospective, single-centre, chart review was conducted within JPS Health Network. Internal data were extracted from electronic medical records between 1 February 2019 and 29 February 2020. Available data included demographic characteristics, weight, height, body mass index (BMI), DAA regimen, duration of therapy, HCV genotype, presence of cirrhosis and fibrosis stage. Data extracted also noted if patients had any of the following comorbidities: diabetes mellitus, hyperlipidemia, hypertension, hypothyroidism, chronic hepatitis B (HBV) and human immunodeficiency virus (HIV). Because of the retrospective nature of this study, the informed consent of participants was waived. The protocol for this study was approved by the North Texas Regional Institutional Review Board. This study was not funded by an external source. All authors willingly contributed to the completion of this manuscript, attest compliance to the protocol and affirm the accuracy of the data reported.
Study patients
Patients were screened for enrolment in the study by chart review. The study included patients ages 18 years or older with a documented diagnosis of chronic HCV; who completed the intended duration of treatment with DAA. Patients who were lost to follow-up or who did not attend their appointment to assess SVR12 post completion of treatment were also excluded from the study.
Direct-acting antiviral regimens
Current guideline recommendations by the American Association for the Study of Liver Diseases (AASLD) denote DAA-based therapy as the sole treatment for HCV [8]. AASLD guidelines further specify preferred agents for treatment-naïve and treatment-experienced patients. Patient-specific factors such as insurance coverage or lack thereof and the ability to adhere to particular dosing regimens should also be considered when selecting therapy. Additionally, HCV genotype further influences the selection of DAA therapy. Clinical guidelines and shared decision-making between the patient and their provider were utilized to determine the most appropriate DAA and duration of therapy for each patient.
This study assessed the five different DAA regimens that are currently on the market. Patients who received treatment with a sofosbuvir-based regimen either received sofosbuvir/velpatasvir, sofosbuvir/ledipasvir or sofosbuvir/velpatasvir/voxilaprevir. Patients who received treatment with a non–sofosbuvir-based regimen were treated with glecaprevir/pibrentasvir or elbasvir/grazoprevir. Patients receiving DAA in conjunction with ribavirin were assessed with the intention to treat analysis. Because there is no alternative treatment to DAAs, it was not possible to create a control group, containing patients who were treated with other therapies. Patients receiving a sofosbuvir-based regimen were therefore compared to patients receiving a non–sofosbuvir-based regimen.
Study outcomes
The purpose of this study was to determine the impact of DAA on weight in patients being treated for HCV. Change in weight from baseline was the primary outcome of this study. The completed chart review identified the patient’s initial and final weights. Initial weight was defined as the patient’s weight on the day DAA therapy was initiated. Their final weight was determined 12 weeks post-therapy completion. If the weight was not documented on that exact day, the closest measurement within 30 days was used. Since the DAA regimen a patient received was based on patient-specific factors, change in weight with respect to the DAA regimen was assessed as a secondary outcome. Additionally, comorbid conditions may influence an individual’s weight. The following comorbidities including diabetes mellitus, hyperlipidemia, hypertension and hypothyroidism were assessed as potential confounding factors. Co-infection with chronic HBV or HIV may influence metabolic changes and were also assessed as confounding factors.
Statistical analysis
Descriptive statistics were used to assess patient demographics, baseline characteristics and DAA treatment regimen. A stepwise approach was used to analyze confounding factors. First, univariate pre-filtering was used to determine which variables were marginally significant with a P-value of ≤0.2. Factors that were considered significant were included in the full model and analyzed using a multivariate regression. Backward stepwise regression was then used to construct parsimonious models. Where appropriate, non-parametric data was assessed using the Wilcoxon–Mann–Whitney U test. For variables with less than five data points, Fisher’s exact test was used. Alternatively, for variables with more than five data points, a chi-square analysis was completed. Statistical significance for these tests was determined by a P-value of <0.05. The results of this study were analyzed using SAS® 9.4 statistical software (SAS Institute Inc. Cary, NC, USA).
Results
Patient characteristics
Distribution of demographics, comorbidities, fibrosis stage, and by direct-acting antiviral regimen.
Note: There were 26 patients on sofosbuvir/velpatasvir, 13 on sofosbuvir/ledipasvir and 5 on sofosbuvir/velpatasvir/voxilaprevir.
aWilcoxon–Mann–Whitney U test was performed.
bChi square was performed.
cFisher’s exact test was performed.
This flowchart outlines the process used to determine eligible study participants.
Baseline characteristics between patients receiving a sofosbuvir-based regimen and a non–sofosbuvir-based regimen were relatively similar with the exception of comorbidities. The percentage of patients with diabetes was greater in those receiving a sofosbuvir-based regimen, while there was a greater number of patients with hyperlipidemia receiving a non–sofosbuvir-based regimen. Cirrhosis status also differed between the two groups. There was a greater proportion of non-cirrhotic patients receiving a non–sofosbuvir-based regimen (77.9%). Supplementary Table 1 compares patient demographics for those who were excluded from the study due to missing weights to those who met the inclusion criteria. Minimal differences were seen between these two groups. Patients who were excluded were slightly older in age and had less patients with advanced fibrosis.
Change in body weight
Full model assessing direct-acting regimen on change in weight, kg.
Reduced model assessing direct-acting antiviral regimen on change in weight, kg.
Discussion
In this retrospective analysis, 122 participants completed treatment for HCV with a DAA. DAA regimens were classified as sofosbuvir-based regimens or non–sofosbuvir-based regimens. This study aimed to determine if the use of DAA caused changes in weight. Twelve weeks after completing therapy, weight was reassessed and the use of a sofosbuvir-based regimen did not result in a clinically significant change in weight when compared to non–sofosbuvir-based regimens. Additionally, initial BMI was a confounding factor that also precipitated weight change; particularly in patients with higher BMIs at baseline.
Twelve weeks post completion of therapy was the specified time point used to determine final weight. This time point was used with the knowledge that sustained virologic response would be assessed 12 weeks after treatment end date in patients who completed therapy. At the time that sustained virologic response was assessed, final weight was also assessed. The 12 weeks post completion of therapy time point does not take into account variations in treatment duration. Treatment duration varied with respect to patient-specific factors and the DAA used. In some instances patients were treated for up to 24 weeks. A greater duration of therapy may allow for more opportunity for external and confounding factors to influence weight gain. In the study by Schlevogt et al. weight was assessed at the end of treatment, 24 weeks and 48 weeks post treatment. In hindsight assessing weight at the end of treatment would minimize the time allowed for confounding factors to impact weight. Although longer time periods may result in more opportunities for external factors to cause weight fluctuations, long time periods may be useful in differentiating between acute and chronic weight changes secondary to DAA.
The prospective study by Do et al. assessed 11,469 patients who completed therapy with a DAA. Weight gain occurred in 52.6% of participants and excessive weight gain (≥4.5 kg) occurred in 19.8% of participants. Weight gain and excessive weight gain were more common in those who achieved SVR. Other positive predictors of weight gain included younger age, advanced fibrosis, cirrhosis and whether participants were overweight or obese at treatment initiation. The results of this study are comparable in that, BMI, as a surrogate marker for weight, was a positive predictor of weight gain. Furthermore, patients with higher weights at baseline are more likely to experience weight gain at the completion of therapy. This study further affirms that initial BMI is a confounding factor that resulted in an increased post-treatment weight. Schvelgot et al. concluded that DAA therapy is associated with weight gain. Of the 76 participants assessed at the 48 follow-up week appointments, 44% of participants experienced an increase in weight. However, the only positive predictor of weight gain was age ≤60 years.
Unlike the aforementioned studies, our study did not find an association between age and weight gain. Consistent with the results of Do et al., baseline BMI was a positive predictor of weight gain and was more pronounced in patients who were overweight or obese. Also consistent with previous studies, there was no relationship between weight and the use of a DAA regimen containing sofosbuvir or not containing sofosbuvir. This study also supports that the type of DAA regimen used is not strongly associated with changes in weight.
Per AASLD HCV treatment guidelines, genotype testing can be bypassed when a pan-genotypic DAAs is used. As all patients may not receive genotype testing upon therapy initiation, this recommendation may bias the use of sofosbuvir/velpatasvir and glecaprevir/pibrentasvir; pan-genotypic agents that can be used in treatment-naïve patients [8]. In this study, these agents were the most commonly used. Glecaprevir/pibrentasvir, a non–sofosbuvir-based regimen, superseded all other agents. Sofosbuvir/velpatasvir was the second most common. Aside from their structural components, notable differences between these agents include their dosing regimen and duration of therapy. It is possible that glecaprevir/pibrentasvir was used in greater frequency due patients preferring the shortest treatment duration. Because of the prevalent use of pan-genotypic agents, the results of this study may be more applicable to sofosbuvir/velpatasvir and glecaprevir/pibrentasvir.
An individual’s weight is multifactorial and a congregate of many characteristics. Fluctuations can be impacted by parameters such as diet, weight and medications [9]. In this study, diabetes mellitus, hyperlipidemia, hypertension, hypothyroidism, chronic HBV and HIV were comorbidities assessed as confounding factors that influence weight. In this study, none were identified as factors that precipitated a change in weight. The assessment of comorbidities was not all-inclusive. In retrospect, the presence of ascites, heart failure, malnutrition secondary to chronic alcohol use and baseline medications are additional covariates that could have been assessed amongst many others. Ultimately, it may not be feasible to truly assess every factor that impacts weight.
Conclusion
Literature documenting the effects of DAAs on weight is limited. However, previous studies show evidence of weight gain after completing treatment for HCV with a DAA. This study determined that individuals with a higher BMI at baseline, particularly those deemed overweight or obese, experienced more weight gain following treatment with a DAA. Ambiguity still surrounds the mechanism by which DAAs impact weight. Baseline BMI may impact the degree of weight gain patients experience. Further studies should be conducted to better explain the correlation between use of DAAs and weight gain post treatment.
Supplemental Material
Supplemental Material - Understanding the effect of direct-acting antiviral therapy on weight in patients with chronic hepatitis C
Supplemental Material for Understanding the effect of direct-acting antiviral therapy on weight in patients with chronic hepatitis C by Chinyere L Nkwocha, Pamela S Carter, Somer Blair, James M Blackwell and Esther O Fasanmi in Antiviral Therapy
Footnotes
Acknowledgements
The authors are grateful to the following individuals for their contributions and assistance in data collection and review of this manuscript: Jorge Sanchez, MPH, MBA, Claire Rodrigues, PharmD, BCACP, W. Cheng Yuet, PharmD, BCACP, CDCES.
Declaration of conflicting interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.
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References
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