Five-year results of chronic hepatitis B treatment program in Ethiopia | BMC Medicine

Research setting and participants

Adults (≥18 years) with CHB were recruited between February 9 and December 14, 2015, at St. Paul’s Hospital Millennium Medical College, a referral hospital in Addis Ababa, Ethiopia. CHB was defined as hepatitis B surface antigen (HBsAg) seropositivity persisting for more than 6 months. When the program was launched, there was no public sector treatment program in Ethiopia for patients who were single-infected with hepatitis B, although a small number of patients were able to import drugs from abroad or purchase them on the inconsistent “black market.” A detailed description of the study population, design, and patient assessment has been reported previously (16, 17).

Treatment decisions and follow-up procedures

There are no hepatitis B treatment guidelines in Africa; therefore, treatment eligibility criteria are based on the European Association for the Study of the Liver (EASL) guidelines published in 2012 (18) with some modifications. In this case, liver biopsy was impractical and was therefore replaced by transient elastography (Fibroscan® 402, Echosens, France). Based on previous meta-analyses and a study in West Africa (19, 20), we used Fibroscan thresholds of 7.9 kPa to define significant fibrosis and 9.9 kPa to define cirrhosis.

Two EASL criteria related to liver inflammation (Metavir ≥ A2, viral load > 2000 IU/ml, alanine aminotransferase (ALT) > 80 IU/L, viral load > 20,000 IU/ml) were combined into one: ALT > 80 IU /L Viral load > 2000 IU/ml. In addition, because African patients may be at increased risk for HCC (21) , a new eligibility criterion was added, namely a first-degree relative with HCC and an elevated viral load.

Therefore, patients who meet the following criteria are considered eligible for treatment:

1. 1)

   decompensated cirrhosis

2. 2)

   Compensated cirrhosis (confirmed by ultrasound and/or transient elastography >9.9 kPa)

3. 3)

   Marked fibrosis (transient elastography > 7.9 kPa) and viral load > 2000 IU/mL
4. 4)

   Moderate/severe liver inflammation (ALT > 80 IU/L) and viral load > 2000 IU/mL

5. 5)

   First-degree relative with HCC and viral load > 2000 IU/mL

Decompensated cirrhosis is diagnosed if there is past or present evidence of ascites (diagnosed clinically and/or sonographically), hepatic encephalopathy, esophageal variceal bleeding, or jaundice.

Patients with known or suspected HCC were not included in the study but were subject to further diagnostic workup and/or therapeutic management. Likewise, those found to be HIV-positive at baseline or during the study were excluded and transferred to local HIV treatment units.

Information on previous and current alcohol intake was obtained at baseline using a frequency/amount questionnaire. Alcohol abuse is considered as drinking > 20 grams per day for women and > 30 grams per day for men for at least 6 months.

Anti-HCV in serum was measured using an enzyme-linked immunosorbent assay (ELISA) method (Elisys Uno, HUMAN, Wiesbaden, Germany). Co-infection with hepatitis C virus (HCV) was detected at baseline, whereas hepatitis D Viral antibodies (anti-HDV detected by ELISA in plasma samples (ETI-AB-DELTAK-2, Diasorin, Italy)) and intermediate confirmed by a second anti-HDV ELISA (Dia.Pro Diagnostic Bioprobes Srl, Milan, Italy) or weak positive results. This plan cannot treat mixed HCV and HDV infections.

Hepatitis B (TDF) antiviral treatment, laboratory testing, and transient elastography were provided free of charge throughout the study period.

Follow-up of patients eligible for antiviral therapy

Eligible patients are obligated to complete adherence counseling before initiating antiviral therapy. Patients meeting the above treatment eligibility criteria received tenofovir disoproxil fumarate (TDF) (Viread®, Gilead Sciences, Inc., Foster City, CA, USA) 300 mg once daily.

After initiating antiviral therapy, patients were followed up at 2 and 4 weeks and every 3 months thereafter. Follow-up appointments focused on treatment efficacy, adverse drug reactions, compliance monitoring, and laboratory testing, including standard biochemistry (Humalyzer 3000, Human, Germany) and hematology (Huma-Count 30, Human, Germany). Human immunodeficiency virus (HIV) screening every 3 months using a World Health Organization-approved rapid diagnostic test (RDT) (HIV 1+2 Antibody Colloidal Gold (KHB), Shanghai Kehua Bioengineering Co., Ltd., China) , positive results were confirmed using HIV 1/2 STAT-PAK® RDT (Chembio Diagnostics, New York, USA).Every 6 months, HBsAg status was assessed using WHO-approved RDT (Determine™, Alere Inc., USA), followed by HBV DNA viral load testing using Abbott RealTiricee HBV test (Abbott Molecular, IL, USA) and from 2019 the Xpert HBV viral load kit (Cepheid, CA, USA). Transient elastography was performed after fasting for at least 2 hours every 6 months to assess liver fibrosis as previously described (16, 17).

Follow-up of patients not suitable for antiviral treatment

For patients who do not meet treatment criteria, hematology and biochemistry testing will be performed every 3 months for the first year and every 6 months thereafter. HBsAg status and HBV DNA viral load testing were performed every 6 months for the first year and annually thereafter. Transient elastography was performed every 6 months. If patients met treatment criteria during follow-up, antiviral therapy was initiated after mandatory compliance counseling and anti-HIV testing.

seroconversion

If the HBsAg rapid test results were negative during follow-up, confirmatory HBsAg and anti-HBs ELISA tests (Elisys Uno, HUMAN, Wiesbaden, Germany) were performed locally. If true seroconversion occurs during treatment (ie, HBsAg negative and anti-HBs positive), treatment is discontinued after a consolidation period of at least 3 months.

compliance

Assessment of treatment compliance was based on pill counts, and compliance was calculated by dividing the total number of pills dispensed minus the remaining pills brought to the visit by the total number of days since the last visit. At the first visit, patients took TDF 300 mg tablets for 30 days, and for the remaining visits, they received the tablets for 90 days. Some patients who lived far from the clinic took the pills for 180 days.

Diagnosis of liver cancer

As part of the scientific evaluation of the program, patients starting treatment underwent liver ultrasound at baseline and annually thereafter. More frequent monitoring of patients with cirrhosis is not possible due to travel distance and expense. If liver lesions are detected, further evaluation is performed using alpha-fetoprotein and radiology (computed tomography or magnetic resonance imaging). The diagnosis of HCC was based on the EASL guidelines (22).

statistical methods

Calculate the serum aspartate aminotransferase (AST) to platelet ratio index (APRI) using the following formula: (AST (IU/L)/AST upper limit of normal)/platelet count (10⁹/L) × 100. HBV viral load < 69 IU/mL 被认为是病毒抑制，而 > 1000 IU/mL is considered treatment failure (7, 13). When analyzing annual viral load trends, we accepted viral load measurements for plus/minus 3 months in the first year and minus 6/plus 3 months for subsequent years. HBsAg loss was defined as HBsAg negativity in two consecutive samples at least 3 months apart without subsequent serum reversal.

Categorical variables are summarized as frequencies, while continuous variables are expressed as median and interquartile range (IQR).Comparisons between groups were performed using the Pearson chi-square test and Mann–Whitney for categorical variables. or Tests of continuous variables. Changes in ALT, viral load, and transient elastography levels over time were compared using the Wilcoxon signed-rank test.

The Kaplan-Meier method was used to estimate HCC-free survival, with differences between groups assessed using the log-rank test. Cox proportional hazards regression models were used to study factors associated with HCC-free survival time and calculate hazard ratios. Univariate Cox regression analysis was performed on the following baseline variables: sex, age, ALT level, HBV DNA viral load, hepatitis B e antigen (HBeAg), transient elastography, and cirrhosis status. Continuous variables were categorized by clinically relevant thresholds. Multicollinearity was assessed using the Spearman correlation coefficient (r

), with a cutoff value of 0.7.baseline variables pValues ​​below 0.2 in the univariate analysis were included in the multivariable model using the forward stepwise method. Patients who died were right-censored at the date of death, and patients who developed HCC were right-censored at the date of transfer to palliative care, assuming that their life expectancy would be short (21). Patients alive at last contact were right-censored on September 1, 2021.

Statistical analyzes were performed in SPSS version 29.0 (SPSS Inc., Chicago, IL, USA).arrive p-Values ​​< 0.05 were considered significant throughout the study.this Strengthen reporting on epidemiological observational studiesFollow the (STROBE) declaration guidelines (23).

ethics

The study was approved by the Ethiopian National Research Ethics Review Committee (NRERC, reference number: 3.10/829/07) and the Regional Committee on Medical and Health Research Ethics (REK Sør-Øst, reference number: 2014). /1146) in Norway. The study was conducted in accordance with the Declaration of Helsinki (24). All patients gave written consent to participate in the study.