Treatment of Chronic Hepatitis B With Tenofovir At The University Teaching Hospital Campus of Lome (Togo)

Chronic hepatitis caused by the hepatitis B virus (HBV) affects a high number of people and it was a major cause of mortality and morbidity. It is estimated that approximately 240 million people get chronic infection of hepatitis B virus ¹. Chronic viral hepatitis is a serious but underestimated global public health problem ². Diagnosis and management remain complex and many countries lack the human resources and medical infrastructure to provide treatment. New drugs are now available to treat or to stop the spread of the hepatitis B virus infection, but most people with chronic viral hepatitis are unaware of their infection and do not receive appropriate treatment ³. Up to one third of the chronic viral hepatitis carriers will die of liver cirrhosis or liver cancer if they are not well diagnosed and directed to the appropriate units. Togo is a country located in areas of high endemicity of HBV ⁴. with high prevalence of chronic HBV-related diseases (43.24%) ⁵. Despite this fact the country lacks infrastructures and sufficient resources to combate chronic hepatitis B. The new drugs including tenofovir (TDF) are only actually available in our country for 2 years and the cost of treatment is still at the expense of the patient. We, therefore find this study important, to study the clinical, biological and evolutionary features of mono infected patients with HBV treated with TDF in our department.

This is a descriptive prospective study of patients in the department of hepatology and gastroenterology at the teaching hospital campus of Lomé, from february 2012 to july 2015 and treated with TDF for an indefinite period. The only available dose of TDF was administered at a daily dose of 300 mg in the country and is also used for HBV and HIV co-infection. The inclusion criteria were: active chronic HBV (HBsAg positive for more than 6 months, high intermittent or persistent aminotransferases, HBV DNA ≥ 2000 IU / ml for the HBeAg negative or ≥ 20 000 IU / ml for HBeAg positive and necro-inflammation or moderate to severe fibrosis), the absence of HCV, HDV, or HIV co-infection and treatment with tenofovir. We included in this study, patients with a family history of hepatocellular carcinoma and patients with HBV-related cirrhosis. Patients with HDV, HCV or HIV coinfection, inactive chronic carriers of HBV, HBV carriers not treated or treated with another molecule have been excluded. The following parameters were also studied: demographic (age, sex), clinical, biochemical (aminotransferases), serum (HBsAg, total anti-HBc, HBeAg, anti-HBe), virological (DNA of HBV by quantitative PCR). All patients went through abdominal ultrasonography in search of signs of portal hypertension, cirrhosis or hepatocellular carcinoma (HCC). At the level of cirrhosis patients had an upper digestive endoscopy for signs of portal hypertension and determination of alpha fetoprotein in search of hepatocellular carcinoma. The detection of HBsAg was performed according to ELISA sandwich method; as well as the HBeAg, the anti-HBe and the anti-HCV. The DNA of the HBV was measured by the COBAS Ampli Prep technique / HBV COBAS Taq Man Version 2.0 of Roche (Meylan, France) with a positive threshold of 20 IU / ml (linearity from 20 IU / ml to 170.000.000IU / ml). Hepatic fibrosis was assessed by the non-invasive method of the Fibrotest-Actitest. The data were analyzed by SPP 21.0 software.

During the period of this study 4410 patients have consulted in our department, including 819 cases of viral hepatitis (18.6%). There were 702 cases of hepatitis B (15.9%) and 117 cases of hepatitis C (2.65%). Among patients with HBV, 75 were put under treatment with TDF (10.68%). The mean age of patients was 33.01±9.81 years old with extremes of 15 and 57 years old. There was male predominance (68%) with a sex ratio of 1.9. The mean age of women was 29 years old against 32.1years old in men (p = 0.058). There was predominance (53.3%) of the age group of ^{30313233343536373839404142434445}; very few of our patients were insured (8%) (Table1).

Clinically, the circumstances of discovery were essentially during blood donation (65.3%), etiologic assessment of cirrhosis (18.7%) and a routine checkup (14.7%). Clinical examination was normal in most of the cases (86.7%), apart from hepatomegaly (9.3%) and jaundice (4%). Livercheckup had enabled to notice: ALT 72.87±19.4 IU/l, AST 58.88±83.1 IU/l, ALP 190.51±116.5 IU/l, GGT 66.53±68.4 IU/l, albumin 43.54±5.1 g/l, prothrombin 54.76±10.7%, the level of alpha fetoprotein 1.11± 1 ng/ml. The HBeAg was negative in 89.3% of cases; the average DNA was 7.56 ±8.01 log10 IU/ml. Abdominal CT scan was performed in all patients and we found hepatomegaly (18.67%), splenomegaly (10.67%), a dilation of the portal vein(4%), and an ascites (5.3%). The assessment of fibrosis and activity was based on the fibrotest-actitest and had helped to find a fibrosis higher or equal to 2 in 12 cases (16%) and an activity higher or equal to 2 in 9 cases (12%). We got a fibrosis F4 in 4 cases (5.33%). The gastroscopy performed in 9 patients had revealed 3 cases (4%) of esophageal varices of which 3 of grade 2 and a case (1.33%) of grade 3.

Creatinine was stable in all patients, and no cases of kidney failure were reported as tenofovir side effect.

The clinical and virologic outcome was marked by an undetectable viral load (DNA-HBV˂10 IU/l) in 89.3% of the patients after 1 year of treatment.

This prospective study is the first to show the results of chronic hepatitis B treatment in Togo. Our methodology is similar to the one of Kissi and al in west Africa⁶ and that of Nwokediuko and al⁷ in Asia. Our sample was made of 75 patients with chronic hepatitis B and cirrhosis. This remark is frequent in our practice where most of patients did not know they are hepatitis B virus carriers or they consulted late at the stage of cirrhosis.

The mean age of patients was 33.01±9.8 years old which clearly shows that the population is young even younger than other studies from West Africa ^{6, 8}. The mean age is higher in Europe than 45 years old ^{9, 10}. This result can be explained by the fact that the contamination of HBV in Africa is most often occurred through mother to child transmission and during childhood. There was male predominance (68%) as in majority of studies in Africa ^{6, 8}, Europe and in Asia ^{10, 11, 12}. The circumstances of HBV discovery varied and were mainly dominated by blood donation and cirrhosis. These results show that, the research of HBV in routine in our context is not systematic, which explains the fact that the diagnosis is made at the stage of complication (cirrhosis) or during a free checkup like blood donation. The systematic research of HBV in routine could help to reduce cases of dangerous complications like cirrhosis or hepatocellular carcinoma. The majority (89.3%) of our patients was HBeAg negative as in most of European studies ^{13, 14}. This high prevalence of the negative HBeAg is the current world wide trend ¹⁵ apart from Asia where there is still high prevalences of HBeAg positive ¹². The indication of the HBV treatment according to World Health Organization is based on the ALT rate higher than the normal, the DNA of HBV and the severity of the liver disease based on the METAVIR score, APRI score or FIB4, the fibroscan or fribotest-actitest ¹⁶. In our study we focused on ALT dosages, the HBV DNA and the fibrotest-actitest. The ALT of our patients was 72.87±19.4 IU/l. This result is comparable to the African data⁶, but much less than the European and Asian data ¹² where we had respectively found 110 IU/l and 155.4IU / l. The average DNA in our study was 7.56 ±8.01 log10 IU/ml. This rate is comparable to that of Kissi and al⁶ who found 7.4±7.7log10 IU/ml, however it is much higher than the one of Sang Kyung Jun and al ¹² who found 4.9±2.3 log10 IU/ml in Kore.

The assessment of the severity of the disease in our context was based on the clinic in the search of signs of cirrhosis decompensation as jaundice and ascites in 4% respectively. These data were confirmed by abdominal CT scan. The fibrosis was evaluated by a non-invasive test (fibrotest - actitest) as suggested by the majority of the recommendations ¹⁸. This test had enabled to find a significant fibrosis in approximately 21.33% of cases and/or a significant activity in 12% of cases. Actually, it has been revealed that most of chronic HBV carriers with HBeAg negative were often discovered late at a stage of liver disease ¹⁰. Based on clinical arguments, ultrasonography, endoscopic and non-invasive fibrosis test, we found in our study 5.3% of patients at the stage of cirrhosis before treatment. In Turkey ⁹ a study had found 3.7% of cirrhotic patients whereas another study in Korean ¹¹ found 51% before the TDF treatment.

All our patients were naïve to anti-viral treatment. It is said that the anti-viral long-term treatment enables a regression of histological lesions ¹⁰. Treatment with TDF is efficient in monotherapy in naïve patients ¹⁹ as the results of our study indicated with 89.3% of patient who had an undetectable viral load after one year treatment.

The TDF is the first treatment of HBV in our country but the cost of this treatment is still entirely at the expense of the patient.TDF had enabled to find out an undetectable viral load in 58.6% of negative HBeAg patients after a year of treatment. Improving patient care could also include reducing the cost of treatment and implementing treatment in all regions of the country.

1. 1.Lozano R, Naghavi M, Foreman K, Lim S, Shibuya K. (1990) Aboyans V and al.(2012) Global and regional mortality from 235 causes of death for 20 age groups in. 380(9859), 2095-128.
   PubMed·Search at Google Scholar

1. 2.OMS. (2003) Progrès réalisés sur la voie de la vaccination des enfants contre l’hépatite B. REH,78, 366-370 Document WHO/HSE/PED/HIP/GHP 2012-1.
   Search at Google Scholar

1. 3.Hadziyannis S J. (2011) Natural history of chronic hepatitis B in Euro-Mediterranean and African Countries. , Journal of 55(1), 183-191.
   View article·PubMed·Search at Google Scholar

1. 4.Bouglouga O, Bagny A, Djibril M A, Lawson-ananisoh L M.Aspects épidémiologiques, diagnostiques et évolutifs de la cirrhose hépatique dans le service d’hépato-gastroentérologie du. , CHU Campus de Lomé.(2012) J. Rech. Sci. Univ. Lomé 14(2), 1-7.
   Search at Google Scholar

1. 5.Djibril M A, Mba K B, Bagnyn A, Kaaga Y L, Gueant J L et al. (2008) Profil etiologique des hépatopathies cytolytiques au CHU Campus de Lomé. , J. Rech. Sci. Univ. Lomé 10(2), 45-48.
   View article·Search at Google Scholar

1. 6.Kissi-anzouan-kakou Y H, Doffou S A, Diallo D, Bangoura D A, Adehoumi Y. (2016) . Traitement of chronic hepatitis B with Tenofovir disoproxil fumarate in Ivory coast. Open journal of gastroenterology,6 39-45.
   View article·Search at Google Scholar

1. 7.S C Nwokediuko. (2011) Chronic Hepatitis B: Management Challenges. in Resource-Poor Countries.HepatitisMonthly,11 786-793.
   PubMed·Search at Google Scholar

1. 8.Sombié R, Sangaré L, Guingané A, Tiendrébéogo A, Kaboré D et al. (2015) Traitement de l’hépatite B chronique par les analogues de nucléos(t)ides.Journal Africain d’Hépato-Gastroentérologie,9. 114-118.
   Search at Google Scholar

1. 9.Örmeci N, Özbaş B, Güner R, Özkan H, Yalçi A et al.and al.(2015) Tenofovir-Best Hope for Treatment of Chronic Hepatitis. , B Infection?The Turkish Journal of Gastroenterology,26 322-327.
   View article·PubMed·Search at Google Scholar

1. 10.Papachrysosa N, Hytirogloub P, Papalavrentiosa L, Sinakosa E, Kouvelisa L. (2015) . Antiviral Therapy Leads to Histological Improvement of HBe Ag-Negative Chronic Hepatitis B Patients.AnnalsofGastroenterology,28 372-376.
   Search at Google Scholar

1. 11.Ahn S S, Chon Y E, Kim B K, Kim S U, Kim D Y.. Ahn SH and al.(2014) Tenofovir Disoproxil Fumarate Monotherapy for Nucleos(t)ide-Naive Chronic Hepatitis B Patients in Korea: Data from the Clinical Practice Setting in a Single Center Cohort.ClinicalandMolecularHepatology,20 261-266.
   View article·Search at Google Scholar

1. 12.Jung S K, Kim K-Y. (2015) Ha SY,Lee HK,Kim YD,Lee. , B 21-41.
   PubMed·Search at Google Scholar

1. 13.Assi D R, Tenore S B, Pinho J R, Lewis D S, Ferreira P R. (2015) Caracteristics of an outpatient chronic hepatitis B virus infection cohort. 13(2), 189-95.
   PubMed·Search at Google Scholar

1. 14.Gomez R R, Guardiola A A, Gomez Moreno AZ, Garcia Vela A, Gomez Hernando C et al. (2013) Characteristics of patients with chronic hepatitis B virus infection. Analysis of a series of 474 patients. , Gastroenterol 36(4), 243-53.
   PubMed·Search at Google Scholar

1. 15.Wu D L, Xu G H, Lu S M, Ma B L, Miao N Z et al. (2012) Age versus clinical virological characteristics in chronic hepatitis B virus infection :a case series study in China. , Eur J Gastroenterol Hepatol 24(4), 406-13.
   View article·Search at Google Scholar

1. 16.Liaw Y F, Sung J J, Chow W C, Farrell G, Lee C Z et al. (2004) Lamivudine for patients with chronic hepatitis B and advanced liver disease NEnglJ. , Med 351, 1521-1531.
   View article·PubMed·Search at Google Scholar

1. 17.Marcellin P, Zoulim F, Hezode C, Causse X, Roche B et al. (2016) . Effectiveness and Safety of Tenofovir Disoproxil Fumarate in Chronic Hepatitis B: A 3-Year, Prospective, Real-World Study in France.DigDisSci 61, 3072-3083.
   View article·PubMed·Search at Google Scholar

1. 18. (2015) World Health Organisation.
   View article·Search at Google Scholar

1. 19.Choi M S, Sinn D H, Kim S-A, Lee Y S, Choi W et al. (2012) The Clinical and Laboratory Characteristics of Patients with Chronic Hepatitis B Using Current or Past Antiviral Therapy in Korea: A Multi-Center, Nation-Wide. , Cross-Sectional Epidemiologic Study.Gut 6-241.
   View article·PubMed·Search at Google Scholar