Efficacy of Pegylated Interferon-alpha-2a in Chronic Hepatitis Delta: Experience from a Tertiary Care Hospital in Karachi

INTRODUCTION

The hepatitis delta virus (HDV) is unique in being a defective single-stranded RNA virus, which is dependent upon hepatitis B surface antigen (HBsAg) to use its envelope and thus enters the body of patients already infected with the hepatitis B virus (HBV). Nearly half a century since its recognition, there has not been much success in its treatment.¹ The lack of success in this area of high importance is multifold and may be attributed to various factors such as low prevalence in comparison to its counterparts, namely, the HBV and hepatitis C virus (HCV), along with a much more difficult population. Additionally, the adverse side effects may contribute to treatment adherence.² There are an estimated 10–20 million patients of coinfection of hepatitis D among an already huge number of 240 million individuals suffering from CHB. The seropositivity for HDV antibodies in Pakistani HBsAg-positive individuals is approximately 16.6%.^3,4 Among the HBV/HDV co-infected patients there is an accelerated rate of cirrhosis. Hepatitis delta virus causes more rapid rates of disease progression and early cirrhosis with a high incidence of hepatocellular carcinoma (HCC, 70–90%).⁵

Since its inception, pegylated interferon (PEG-IFN) is potentially the only viable therapeutic option for patients infected with chronic hepatitis D (CHD). It stems from the conventional interferon (IFN) therapy which was discontinued due to very limited efficacy.⁶ In comparison to Standard IFN therapy, the pegylated form was found to be superior, efficacious, and associated with better sustained virological response (SVR) in these patients and might improve the outcome of patients with HDV.⁷ Bulevirtide (hepatocyte entry inhibitor) and lonafarnib (farnesyl transferase inhibitor) are on the horizon as new HDV treatment options.⁸ While INF-lambda is showing promising results both as mono and as a combination therapy.⁹

The response to PEG-IFN therapy is variable. Various studies have assessed varying dosages and durations of treatment for anti-hepatitis D virus (anti-HDV) therapy, utilizing both standard and PEG-IFN. However, most of these studies exhibit shortcomings in their selection processes, inadequate sample sizes, restricted data availability, or design-related deficiencies. Most of these studies have selection flaws, incomplete data, or design flaws. These studies evaluated various aspects of HDV therapy in terms of variation in dose and treatment duration however most of them had shortcomings in one aspect or the other.^10–15 The response rate to HDV with standard or PEG-IFN has been on a scale of 18–41%. Nevertheless, the local studies exhibit a significant degree of antiquity and deficiency in statistical relevance.⁷ Several studies have shown a fixed treatment duration of 12 months for the treatment of CHD.^10–15 Prolonging treatment duration more than this is not associated with a favorable outcome yet at the cost of unwanted and at times significant side effects. As some patients with HBV/HDV coinfection had cirrhosis since the start of treatment, prolonging the duration can lead to decompensation of their disease.

The present investigation endeavors to assess the therapeutic efficacy and adverse effects of PEG-IFN-alfa-2a administered to CHD patients for a 12-month treatment. This research aims to provide seminal insights that may serve as a foundation for future studies on a larger scale.

MATERIALS AND METHODS

Patients who received treatment for CHD with PEG-IFN therapy for CHD at the Department of Gastroenterology and Hepatology, Jinnah Postgraduate Medical Center, Pakistan, from July 2020 to October 2022 were prospectively enrolled. An ethical review was sought before the conduction of the study. All participants gave informed consent.

RESULTS

A total of 207 patients whose HCV-PCR was positive were initially inducted. Twenty patients were excluded [decompensated cirrhosis, n = 15; HCC, n = 02; and thrombocytopenia, n = 03 (platelet count <70 × 10⁹/L)] while 187 patients were found eligible to receive PEG-IFN-alfa-2a therapy. During the follow-up period of 48 weeks, 20 patients dropped out (incomplete follow-up period), 18 patients stopped therapy due to side effects, and 1 patient died (due to hepatic failure) before completing the study duration. A total of 148 patients completed the 48-week course of treatment and were considered for final analysis (Fig. 1).

There were 96 (65%) males. Their mean age was 26 ± 8.3 years. Nearly half of the patients were aged 30 years or below (n = 68, 46%). Other demographic characteristics are shown in Table 1. Laboratory parameters such as complete blood count and LFT were compared at three different time points: Baseline, 24 weeks, and 48 weeks. It was noted that hemoglobin (p < 0.001), platelets (p = 0.013), alanine aminotransaminase (ALT, p < 0.001), aspartate aminotransferase (AST, p < 0.001), ALP (p < 0.001), and total bilirubin (p < 0.001) showed significant within-group median differences (Table 2).

Response to the therapy was observed at 24 weeks and 48 weeks. The virological response rate was 40.5 and 32.4% at weeks 24 and 48, respectively. Partial response was seen in 24% at weeks 24 and 48. The treatment failure rate was 36 and 44% at weeks 24 and 48, respectively (Fig. 2).

A total of 29 out of 60 (48.3%) patients who had a negative PCR at week 24 remained negative at week 48, while others relapsed; 16 out of 35 (45.7%) patients who had partial response upon week 24 became PCR negative upon week 48. Three out of 53 (6%) patients who had treatment failure at week 24 achieved ETR whereas 10 (19%) out of these nonresponders achieved partial response at week 48 (Table 3). Treatment responses at week 24 and week 48 were not found to be significantly associated with each other (p = 0.128).

Laboratory parameters of weeks 0, 24, and 48 were compared with treatment response at 48 weeks. It was found that baseline platelets (p = 0.009), ALT (p = 0.029), AST (p = 0.02), and ALP (p = 0.004) at week 0 showed significant median differences for treatment response at week 48 (Table 4). Similarly, platelets (p = 0.016) and ALP (p = 0.043) at week 24, and hemoglobin (p = 0.028), WBC (p = 0.006), and platelets (p = 0.028) at 48 weeks showed significant median differences for treatment response at week 48.

For risk factor analysis using a multivariate model, a partial response was merged with a complete response and compared with the treatment failure group. The GEE model was run to assess the effect of laboratory parameters on therapy response. The multivariate model was adjusted for variables with a p-value below 0.250 in the univariate model. It revealed that an increase in hemoglobin (OR = 0.84, 95% CI = 0.73–0.98; p = 0.024) and WBC (OR = 0.84, 95% CI = 0.72–0.99, p-value = 0.034) with time was associated with lower risk of treatment failure. Whereas with an increase in total bilirubin (OR = 1.31, 95% CI = 1.01–1.68, p = 0.045), patients were more likely to have treatment failure (Table 5).

DISCUSSION

Hepatitis delta virus along with HBV poses a significant health threat, accelerating liver cirrhosis progression and increasing morbidity and mortality.¹⁸ Our study highlights the demographic composition of HDV patients in Pakistan, with a substantial proportion under the age of 30. This finding, along with only 32% response rate to PEG-IFN in our study, underscores the urgency for effective therapeutic interventions in this younger demographic.

Our analysis revealed that over half of the patients were below 30 years old, corroborating the findings of Mumtaz et al. who showed a 16.6% prevalence of HDV infection and most of them belong to the same age group as ours.¹⁹ To worsen the existing situation, more than half of them live in urban areas where education, access to knowledge, and healthcare facilities are suboptimal. As discussed in the study by Abbas Z et al., nearly two decades ago also observed a preponderance of HDV infection in young adults.⁷

The standard 48-week PEG-IFN therapy achieved a 32.4% treatment success rate in our study, slightly lower than the 42% reported by Abbas Z et al.⁷ However, international literature has documented success rates as high as 82%, with these studies primarily treating HDV subspecific genotypes and incorporating oral agents alongside PEG-IFN. Additionally, some studies employed smaller sample sizes, potentially affecting the accuracy of efficacy determinations.^20–22

Our findings also demonstrated that half of the treatment-responsive patients at 24 weeks lost their response at week 48, while nearly half of the partial responders at 24 weeks cleared their virus by week 48. Interestingly, only 5.7% of nonresponders at 24 weeks ultimately achieved viral clearance at the end of treatment. This suggests that early treatment response, whether partial or complete, increases the likelihood of response at the end of treatment. On the contrary, a lack of response at 24 weeks predicts a low probability of treatment success. Some studies suggested HDV RNA at 24 weeks can predict the response to the treatment, giving a clue that if the treatment continuation would be beneficial or not.^21,23

The AST elevation could be attributed to the drug-induced effect of PEG-IFN. Conversely, alkaline phosphatase and bilirubin levels improved over the treatment course, potentially reflecting fibrosis improvement. However, this needs to be substantiated by longitudinal follow-up of these values along with other liver fibrosis parameters (FIB-4, FibroScan) during and after therapy.

A novel finding from our study is the association between treatment response and an increase in hemoglobin and WBC count. Patients with increase in hemoglobin and WBC counts had an increased likelihood of treatment response, while those with increase in total bilirubin were more prone to treatment failure. These findings, previously unreported in the literature, warrant further exploration to determine their potential utility in treatment response prediction.

Despite the less promising treatment outcomes compared to chronic hepatitis C, PEG-IFN therapy remains a viable option for CHD patients, particularly in resource-limited settings like Pakistan. The younger age of our patient population and the potential years of life saved through treatment underscores the importance of continued efforts to optimize CHD management. Further studies investigating hemoglobin and WBC count as treatment response predictors are warranted. While PEG-IFN therapy exhibits limitations, the development of newer, more effective therapies for CHD is eagerly anticipated.

Although our study encompasses a larger patient cohort than any other from our region, further research involving a broader patient population is necessary. Additionally, separate analyses of patients with and without cirrhosis would provide valuable insights into the differential therapeutic responses and adverse effects of PEG-IFN in these subgroups. A larger cohort would also enable us to determine the significance of the response-predicting variables identified in our study and explore the feasibility of developing a pretreatment predictive score.

CONCLUSION

It is noted that PEG-IFN therapy remains as a viable treatment among patients with CHD, despite its limitations. The urgent need for effective alternative therapies for CHD patients is evident.

REFERENCES

1. Rizzetto M, Canese MG, Aricò S, et al. Immunofluorescence detection of new antigen-antibody system (delta/anti-delta) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 1977;18(12):997–1003. DOI: 10.1136/gut.18.12.997.

2. Abbas Z, Khan MA, Salih M, et al. Interferon alpha for chronic hepatitis D. Cochrane Database Syst Rev 2011;2011(12):CD006002. DOI: 10.1002/14651858.CD006002.pub2.

3. Abbas Z, Qadeer MA, Mandviwalla HA, et al. The severity of hepatitis D in young adults of age 18–25 Years. Cureus 2020;12(10):e10855. DOI: 10.7759/cureus.10855.

4. Abbas Z. Hepatitis D in Pakistan. J Coll Physicians Surg Pak 2012;22(9):547–548. PMID: 22980605.

5. Wranke A, Borzacov LMP, Parana R, et al. Clinical and virological heterogeneity of hepatitis delta in different regions world-wide: The Hepatitis Delta International Network (HDIN). Liver Int 2018;38(5):842–850. DOI: 10.1111/liv.13604.

6. Abbas Z, Abbas M. Management of hepatitis delta: Need for novel therapeutic options. World J Gastroenterol 2015;21(32):9461–9465. DOI: 10.3748/wjg.v21.i32.9461.

7. Abbas Z, Memon MS, Mithani H, et al. Treatment of chronic hepatitis D patients with pegylated interferon: A real-world experience. Antivir Ther 2014;19(5):463–468. DOI: 10.3851/IMP2728.

8. Deterding K, Wedemeyer H. Beyond pegylated interferon-alpha: New treatments for hepatitis delta. AIDS Rev 2019;21(3):126–134. DOI: 10.24875/AIDSRev.19000080.

9. Etzion O, Hamid S, Lurie Y, et al. Treatment of chronic hepatitis D with peginterferon lambda-the phase 2 LIMT-1 clinical trial. Hepatology 2023;77(6):2093–2103. DOI: 10.1097/HEP.0000000000000309.

10. Alavian SM, Tabatabaei SV, Behnava B, et al. Standard and pegylated interferon therapy of HDV infection: A systematic review and meta-analysis. J Res Med Sci 2012;17(10):967–974. PMID: 23825999.

11. Rizzetto M. Treatment of chronic delta hepatitis. Hepat Mon 2011;11(9):701–702. DOI: 10.5812/kowsar.1735143X.759.

12. Rizzetto M, Smedile A. Pegylated interferon therapy of chronic hepatitis D: In need of revision. Hepatology 2015;61(4):1109–1111. DOI: 10.1002/hep.27585.

13. Niro GA, Ciancio A, Gaeta GB, et al. Pegylated interferon alpha-2b as monotherapy or in combination with ribavirin in chronic hepatitis delta. Hepatology 2006;44(3):713–720. DOI: 10.1002/hep.21296.

14. Saracco G, Rizzetto M. A practical guide to the use of interferons in the management of hepatitis virus infections. Drugs 1997;53(1):74–85. DOI: 10.2165/00003495-199753010-00005.

15. Garripoli A, Di Marco V, Cozzolongo R, et al. Ribavirin treatment for chronic hepatitis D: a pilot study. Liver 1994;14(3):154–157. DOI: 10.1111/j.1600-0676.1994.tb00065.x.

16. Da BL. Clinical trials in hepatitis D virus: Measuring success. Hepatology 2023;77(6):2147–2157. DOI: 10.1002/hep.32732.

17. Lok AS, Negro F, Asselah T, et al. Endpoints and new options for treatment of chronic hepatitis D. Hepatology 2021;74(6):3479–3485. DOI: 10.1002/hep.32082.

18. Alfaiate D, Clément S, Gomes D, et al. Chronic hepatitis D and hepatocellular carcinoma: A systematic review and meta-analysis of observational studies. J Hepatol 2020;73(3):533–539. DOI: 10.1016/j.jhep.2020.02.030.

19. Mumtaz K, Hamid SS, Adil S, et al. Epidemiology and clinical pattern of hepatitis delta virus infection in Pakistan. J Gastroenterol Hepatol 2005;20(10):1503–1507. DOI: 10.1111/j.1440-1746.2005.03857.x.

20. Anastasiou OE, Yurdaydin C, Maasoumy B, et al. A transient early HBV-DNA increase during PEG-IFNα therapy of hepatitis D indicates loss of infected cells and is associated with HDV-RNA and HBsAg reduction. J Viral Hepat 2021;28(2):410–419. DOI: 10.1111/jvh.13439.

21. Yurdaydin C. Treatment of chronic delta hepatitis. Semin Liver Dis 2012;32(3):237–244. DOI: 10.1055/s-0032-1323629.

22. Keskin O, Yurdaydin C. Letter to the editor: Interferon is not an optimal treatment for chronic hepatitis delta but needs “fair treatment” by us. Hepatology 2012;74(2):1127. DOI: 10.1002/hep.31501.

23. Erhardt A, Gerlich W, Starke C, et al. Treatment of chronic hepatitis delta with pegylated interferon-alpha2b. Liver Int 2006;26(7):805–810. DOI: 10.1111/j.1478-3231.2006.01279.x.