Treatment of Hepatitis C with Pegylated Interferon Alpha-2 a and Ribavirin : Experience from Benin

Background: Viral hepatitis C (HCV) is common in Benin. Untreated, it can be complicated by cirrhosis and hepatocarcinoma, which are sources of death. The objectives of this work were twofold: 1) to evaluate the effectiveness and safety of treatment with classic dual interferon pegylated alpha-2a (IFN) and ribavirin therapy in Benin, and 2) to present problems related to financial accessibility to this treatment. Methods: This was a cross-sectional, descriptive and analytical study, with a retrospective collection of data from November 1, 2010 to December 31, 2015 and prospective collection from January 1, 2016 to July 31, 2016 (7 months). We included all patients treated with IFN + ribavirin for hepatitis C at CNHU/HKM. Sustained virological response (SVR) was defined as undetectable viral load C 6 months after stopping treatment. Safety was appreciated by the search for clinical and hematological adverse effects. Results: One hundred and six patients were followed for HCV, of whom 58 (54.7%) undergoing treatment (26 under standard dual therapy and 32 under direct-acting antivirals). Of the 26 patients underconventional dual therapy, 12 (46.1%) were genotype 1, 13 (50%) genotype 2 and one (3.9%) genotype 4. In conventional dual therapy, SVR was achieved in 15 (57.7%) patients, including the genotype 4 patient, 4 out of 12 (33.3%) genotype 1 patients, and 10 out of 13 (76.9%) for genotype 2 patients. The most common side effects with this treatment were severe asthenia (23 cases), flu-like symptoms (22 cases), weight loss (21 cases) and neutropenia (22 cases), anemia and thrombocytopenia (20 of 26 cases). The overall cost of treatment per patient was 11,800,624 FCFA for genotypes 1 and 4; and How to cite this paper: Kpossou, A.R., Séhonou, J., Adjigbé, G.M.G., Vignon, R.K., Alassan, K.S. and Kodjoh, N. (2018) Treatment of Hepatitis C with Pegylated Interferon Alpha-2a and Ribavirin: Experience from Benin. Open Journal of Gastroenterology, 8, 275-283. https://doi.org/10.4236/ojgas.2018.88030 Received: June 25, 2018 Accepted: August 5, 2018 Published: August 8, 2018 Copyright © 2018 by authors and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/


Introduction
Viral hepatitis is defined as any diffuse inflammatory process of the liver due to viruses with dominant hepatic tropism [1].There are five types of viruses: A, B, C, D and E. But only some of them can cause chronic hepatitis.These are mainly hepatitis B and C viruses that will therefore be the subject of therapeutic drug management.Hepatitis E virus can also give chronic forms but only in immunocompromised individuals.
The World Health Organization (WHO) estimated in 2015 to 71 million, the number of chronic carriers of the hepatitis C virus (HCV) worldwide [2].Nearly 63% of those infected before the age of 40 progress to chronic infection with a 5% incidence of cirrhosis in 20 years and an annual mortality from chronic liver failure of 3.7% after the onset of cirrhosis [3] [4].HCV infection is a major public health problem in developing countries.WHO estimates that in some countries, such as Egypt and Cameroon, its prevalence would be 10% to 15%.In Benin, it is estimated at 4.12% in blood donors [5].The chronic forms of hepatitis B and C are most often the cause of death by their complications which are cirrhosis and hepatocellular carcinoma.But, effective treatments are available to avoid the occurrence of these complications and to obtain healing.
Although treatment for viral hepatitis C (VHC) has been around for many years and is widely used in developed countries, the high cost of pharmaceuticals (pegylated interferon and ribavirin) and pre-, per-, and post-treatment assessment has long been a brake on its implementation in developing countries, including Benin.Since 2010, a subsidy granted by the State allowed to begin in Benin a therapeutic management of the VHC.Two treatment regimens are available: traditional dual therapy (interferon + ribavirin) used since 2010 and direct-acting antivirals (DAAs) since the end of 2015.
No previous study has addressed the treatment of hepatitis C in Benin.The objectives of this study were to evaluate the effectiveness of the treatment by conventional dual therapy of patients with VHC in Benin as well as the tolerance and the cost of this treatment.

Methods
This study took place in the University Clinic of Hepato-gastroenterology of CNHU-HKM in Cotonou.This was a cross-sectional study, retrospective from November 1, 2010 to December 31, 2015 (62 months) and prospective from January 1, 2016 to July 31, 2016 (7 months).Systematic and exhaustive recruitment was carried out in all the patients followed in the department for chronic hepatitis C during the period and placed on conventional dual therapy.
The conventional dual therapy included pegylated interferon alpha-2a 180 μg/week subcutaneously plus ribavirin 800 to 1200 mg/day per os.Patient consent was obtained prior to inclusion in the study.Among them, were selected those in whom a therapeutic response was evaluable (treatment completed with a viral load carried out 6 months after the end of treatment).Sustained viral response (SVR) was defined as undetectable viral load C 6 months after the end of treatment.The biochemical response was based on normalization of aminotransferases.Safety was assessed by looking for clinical and biological side effects (patients were reviewed every 2 weeks the first month and then once a month).The data was collected on a survey card.This collection was done in part through a direct interview with socio-demographic variables (age, sex, occupation, religion, marital status, level of education, monthly income) and clinical variables (history and comorbidities).The collection was done also by consultation of the medical files allowing to note variables: clinical (the general state based on the index of performance status according to the World Organization of the Health (WHO), the mode of discovery, the main clinical signs) and paraclinical (initial viral HCV load, initial aminotransferases levels, genotype for HCV, liver biopsy puncture results or non-invasive liver fibrosis tests, abdominal ultrasound findings); therapeutics (treatment-related side effects classified by WHO toxicity grade and evolution data i.e.SVR, biochemical response, relapse or death).For statistical analysis, the data was recorded with the EPI Data 3.1 software and analyzed in the EPI Info 3.5.1 software.For frequency comparison, the Chi 2 (x 2 ) test was used.A p < 0.05 was considered as evidence of a statistically significant difference.

Characteristic of the Studied Population
A total of 1,764 patients had been received for consultation in the department during the study period.Among them, 106 patients (6%) had hepatitis C, including 5 cases of co-infection with hepatitis B virus and 1 case of co-infection with HIV.Of the 106 patients followed for hepatitis C, 52.8% (56 patients) were genotype 2, 46.2% (49 patients) genotype 1 and 0.9% (1 patient) genotype 4.
Among them, 58 patients (54.7%) were treated for VHC (including 27 genotype 1 patients, 46.6%, 30 genotype 2 or 51.7% and one genotype 4 or 1.7%).Of the 58 patients treated, 26 were treated with conventional dual therapy and 32 with DAAs.The results for patients on AAD are the subject of another article.
Regarding patients under conventional dual therapy, their age ranged between 32 and 76 years with an average age of 57.53 ± 10.78 years.The most represented age group was 55 years and over.There were 16 men and 10 women with a sex ratio of 1.6.The majority of the treated patients were civil servants and especially senior managers (11 patients i.e. 42.3%) and middle-grade managers (7 patients i.e. 26.9%).The majority of patients (16 patients or 61.5%) had a monthly income above 200,000 FCFA; with extremes ranging from 95,000 to 1,700,000 FCFA.
The discovery of HCV was most often made during routine screening (10 patients or 40%).About 57.7% (15 out of 26) had clinical symptoms.This symptomatology was marked by digestive manifestations (in 7 cases) dominated by abdominal pain especially of the right hypochondrium (3 cases) and constipation (2 cases).Most extradigestive manifestations were marked by physical asthenia (4 cases).HCV was often not accompanied by repercussions on the general condition (performans status according to the WHO to 0 in 22 cases i.e. 84.6%).No case treated with dual therapy had co-infection with either HBV or HIV.The main comorbidities were hypertension and obesity (11 cases, or 42.3% for each).It should be noted that 9 out of 26 patients (34.6%) had cirrhosis (defined by F4 Fibrotest fibrosis or hepatic biopsy puncture, or an APRI score ≥ 2); of which 6 of genotype 1 and 3 of genotype 2.

Effectiveness of Treatment
Twenty-six patients were treated with interferon alpha + ribavirin, during 48 weeks for the 12 genotype 1 and genotype 4 patients, and during 24 weeks for the 13 genotype 2 patients.SVR was obtained altogether in 15 patients, i.e. 57.7%.According to the genotype, SVR was obtained in 4 out of 12 patients of genotype 1 (33.3%) and in 10 out of 13 patients of genotype 2 (76.9%) with a statistically significant difference (p = 0.02, OR = 0.11, 95% CI = 0.02 -0.81).Thus, SVR was better for genotype 2 than for genotype 1.Note that among patients who did not respond, three of genotype 1 and two of genotype 2 had discontinued treatment for intolerance.
The only patient with genotype 4 had an SVR and a biochemical response at 6 months post-treatment.
In treated patients, none developed cirrhosis or hepatocarcinoma during treatment.There was only one case of death.The cause of death was hepatocarcinoma 80 weeks after stopping dual therapy because of severe neutropenia and thrombocytopenia.

Tolerance of Treatment
The most common side effects were physical asthenia (23 out of 26), flu-like symptoms (22 out of 26), weight loss (21 out of 26), and neutropenia (22 out of 26), thrombocytopenia and anemia (20 cases out of 26 respectively).These results are summarized in Table 1.Neutropenia was grade 0 in 2 cases, grade 2 in 4 cases, grade 3 in 6 cases, and grade 4 in 10 cases.Thrombocytopenia was grade 0 in 9 cases, grade 1 in 5 cases, grade 2 in 3 cases, and grade 3 in 3 cases.
Anemia was grade 0 in 1 case, grade 1 in 14 cases, grade 2 in 3 cases, grade 3 in 1 case and grade 4 in 1 case.
Treatment was discontinued due to severe anemia, thrombocytopenia and neutropenia side effects in 3 genotype 1 and 2 genotype 2 patients.
The management of adverse events occurring with interferon + ribavirin

Cost of Treatment
The cost of the pre-therapeutic assessment in the patients to be treated was

Discussion
The percentage of patients treated was 54.7%.This rate is relatively low as it is currently recommended to treat all patients with chronic hepatitis C [6] [7].This low rate is due to the fact that only patients with at least moderate fibrosis (F > 1) were selected for treatment.This limitation of access to treatment is explained by a prioritization for economic reasons.In terms of treatment efficacy, in our study, the overall SVR was 57.7%.This result is similar to the 56% reported in a multicentric study by Fried MW et al. [8].In genotype 1 patients treated with conventional dual therapy, SVR was 33.3%.This value is lower than those reported by most authors.In different studies around the world, the proportion of genotype 1 HCV-infected patients achieving SVR in conventional dual therapy was 40% in North America and 50% in Western Europe [9] [10].
According to studies by Fried [15].In studies in America and Western Europe, the SVR for genotype 2 was 80% [10].According to studies by Fried MW et al. [8], Hadziyannis SJ et al. [9] and Manns M et al. [11], it was 76% for naïve patients of genotype 2. The value found in our study is lower than the 100% mentioned by Farley JD et al. [13].It is also higher than those of 58.8% and 60% respectively found by Maru et al. [12] and Chew et al. [14].For genotype 4, we had only one genotype 4 patient treated with pegylated interferon + ribavirin for 48 weeks in whom SVR was obtained.
Concerning the predictive factors of response under the classic bitherapy, those especially mentioned are the genotype and the existence or not of a  The main limitation of this work is the small number of patients treated with the conventional dual therapy, explaining the low power of the study.

Conclusion
The treatment of HCV with IFN + ribavirin in Benin is effective especially for genotype 2. But its adverse effects are manifold and its cost is high.The switch to direct-acting antivirals (more effective, better tolerated and less expensive) was

and 4 .
These costs are very high for the standard of living of our population.This is why Benin health authorities have fully covered this cost of products and monitoring under treatment.However, the patient must be able to have performed the pre-therapeutic assessment to access this care.Hope is placed in reducing the costs of generic direct-acting antivirals, in improving the national technical platform (molecular biology, ultrasonic pulse elastometry).This will allow to treat a larger number of patients.Benin could hope to reach the thresholds set by the WHO for the management of viral hepatitis: The Global Strategy for the Health Sector against Viral Hepatitis, developed by WHO, aims to detect 90% and treat 80% of people with HBV and HCV by 2030 [2].

Table 1 .
Distribution of adverse effects under conventional dual therapy.
MW et al. (2002 in North Carolina, USA) and Manns M et al. (2001 in Hanover, Germany), it ranged from 42% to 46% for naive genotype 1 patients [8] [11].Maru et al. (2008 in New Haven, Connecticut (USA)) also found 43.1% for genotype 1 [12].Our SVR for genotype 1 is close to the 31.8% reported by Farley JD et al. in 2005 in Canada [13] and better than the 18% of SVR reported by Chew KW et al. in 2009 in San Francisco, California, USA [14]; but these two studies were done in a prison population.For genotype 2, in our study, SVR for conventional dual therapy was 76.9%.This value is similar to that found by McHutchison JG et al. (2009 in the USA) which was 80% [17]lly, with regard to the cost of treatment, the cost of the pre-treatment assessment in the patients to be treated was estimated at 498,176 FCFA or 851.88 USD and was largely supported by the patient.This cost compared to that of the guaranteed minimum wage which is 40,000 FCFA or 68.40 USD is very high.It is 30 times the average per capita expenditure on health in Benin during the same period (37.21USD)[17].This has been a brake on the therapeutic management of patients with HCV in Benin, explaining partly the low rate of treated patients.Similarly, for pegylated interferon and ribavirin patients, the cost of treatment and follow-up ranged from 7,835,048 FCFA i.e. 13,397.93USD for genotype 2 patients to 11,800,624 FCFA i.e. 20,179.07USD for genotype 1