Five-year results of a treatment program for chronic hepatitis B in Ethiopia.

BACKGROUND: In sub-Saharan Africa, less than 1% of treatment-eligible chronic hepatitis B (CHB) patients receive antiviral therapy. Experiences from local CHB programs are needed to inform treatment guidelines and policies on the continent. Here, we present 5-year results from one of the first large-scale CHB treatment programs in sub-Saharan Africa. METHODS: Adults with CHB were enrolled in a pilot treatment program in Addis Ababa, Ethiopia, in 2015. Liver enzymes, viral markers, and transient elastography were assessed at baseline and thereafter at 6-month intervals. Tenofovir disoproxil fumarate was initiated based on the European Association for the Study of the Liver (EASL) criteria, with some modifications. Survival analysis was performed using the Kaplan-Meier method. RESULTS: In total, 1303 patients were included in the program, of whom 291 (22.3%) started antiviral therapy within the initial 5 years of follow-up. Among patients on treatment, estimated 5-year hepatocellular carcinoma-free survival was 99.0% in patients without cirrhosis at baseline, compared to 88.8% in patients with compensated cirrhosis, and 54.2% in patients with decompensated cirrhosis (p < 0.001). The risk of death was significantly higher in patients with decompensated cirrhosis at baseline (adjusted hazard ratio 44.6, 95% confidence interval 6.1-328.1) and in patients older than 40 years (adjusted hazard ratio 3.7, 95% confidence interval 1.6-8.5). Liver stiffness declined significantly after treatment initiation; the median change from baseline after 1, 3, and 5 years of treatment was - 4.0 kPa, - 5.2 kPa, and - 5.6 kPa, respectively. CONCLUSIONS: This pilot program demonstrates the long-term benefits of CHB therapy in a resource-limited setting. The high mortality in patients with cirrhosis underscores the need for earlier detection of CHB and timely initiation of antiviral treatment in sub-Saharan Africa. TRIAL REGISTRATION: The study was registered at ClinicalTrials.gov (NCT02344498) on January 26, 2015.

Renal Safety of Long-term Tenofovir Disoproxil Fumarate Treatment in Patients With Chronic Hepatitis B.

Background: Data on renal safety of tenofovir disoproxil fumarate (TDF) treatment among individuals with chronic hepatitis B (CHB) are inconsistent. The current study aimed to assess the effect of long-term TDF treatment on renal outcomes in adult patients with CHB. Methods: From a CHB cohort in Ethiopia, we included 233 patients treated with TDF and 126 untreated controls. Levels of creatinine and creatinine clearance over time were described in patients with and without TDF treatment. Linear mixed effects models with a treatment × time interaction were used to investigate the effect of TDF on creatinine and creatinine clearance. In treated patients only, change in creatinine and creatinine clearance was estimated separately in the first year as compared with subsequent years via linear mixed effects models. Results: Median follow-up in the treated group was 51 months (IQR, 27-72), and 75% of patients were male (median age, 33 years; IQR, 26-40). Median follow-up in the untreated group was 69 months (IQR, 66-72), and 48% of participants were male (median age, 33 years; IQR, 27-41). We found no change in creatinine over time in TDF-treated patients as compared with a slight increase in untreated patients (P interaction = .003). There was a decrease in creatinine clearance over time in both groups, which was stronger in patients without TDF treatment (P interaction = .007). In TDF-treated patients, changes in creatinine and creatinine clearance occurred mainly within the first 12 months after treatment initiation. Conclusions: This study showed no evidence of long-term renal toxicity of TDF treatment in patients with CHB.

Mother-to-Child Transmission of Hepatitis B Virus in Ethiopia.

High viral load and positive hepatitis B e-antigen (HBeAg) results are risk factors for mother-to-child transmission (MTCT) of hepatitis B virus (HBV). In sub-Saharan Africa, little is known about the distribution of these risk factors, as well as early childhood HBV transmission. In this study, Ethiopian women aged 18-45 years with chronic hepatitis B were assessed for the presence of HBeAg and high viral load. Their children below 4 years of age were invited for assessment of viral markers, defining active HBV infection as a positive hepatitis B s-antigen (HBsAg) and/or detectable HBV DNA. In total, 61 of 428 HBV-infected women (14.3%) had a positive HBeAg result and/or a high viral load. Of note, 26 of 49 women (53.1%) with viral load above 200,000 IU/mL were HBeAg negative. Among 89 children born of HBV-infected mothers (median age 20 months), 9 (10.1%) had evidence of active HBV infection. In conclusion, one in seven women with chronic hepatitis B had risk factors for MTCT, and HBeAg was a poor predictor of high viral load. One in ten children born of HBV-infected women acquired HBV-infection despite completing their scheduled HBV vaccination at 6, 10 and 14 weeks of age.

Validity of a point-of-care viral load test for hepatitis B in a low-income setting.

The recent launch of the first point-of-care Xpert® hepatitis B virus (HBV) viral load kit from Cepheid could help to scale up treatment for chronic hepatitis B (CHB) in resource-limited settings. This study aimed to assess the performance of the Xpert kit under field conditions in Ethiopia. One-hundred-and-thirty CHB patients with viral loads ranging from <1 log10 to>7 log10 IU/mL were randomly sampled. The viral load was assessed with both the Xpert and the gold standard Abbott RealTime HBV Viral Load assay in each patient. There was a high correlation between the viral loads assessed by Xpert and Abbott (r = 0.948, p < 0.001). The Bland-Altman plot showed a small bias between the two assays, with an on average 0.23 log10 IU/mL higher viral load result of the Xpert kit; 4 samples differed by>1 log10 IU/mL. Using the treatment threshold of 2000 IU/mL in both tests, Xpert had a sensitivity of 94 %, specificity of 71 %, positive predictive value of 70 %, and negative predictive value of 95 %. In conclusion, the Xpert kit demonstrated good validity for the measurement of HBV viral load in a real-life setting.

Predictors of mortality in patients under treatment for chronic hepatitis B in Ethiopia: a prospective cohort study.

BACKGROUND: Antiviral treatment for chronic hepatitis B (CHB) is largely unavailable in sub-Saharan Africa; hence, little is known about the prognosis after initiating treatment in African CHB patients. In this study we aimed to assess predictors of mortality in one of the largest CHB cohorts in sub-Saharan Africa. METHODS: Two-hundred-and-seventy-six CHB patients who started treatment with tenofovir disoproxil fumarate at a public hospital in Ethiopia between March 18, 2015, and August 1, 2017, were included in this analysis. Patients were followed up until October 1, 2017, and deaths were ascertained through hospital records and telephone interview with relatives. Decompensated cirrhosis was defined as current or past evidence of ascites, either by clinical examination or by ultrasonography. Cox proportional hazard models were used to identify independent predictors of mortality. RESULTS: Thirty-five patients (12.7%) died during follow-up, 33 of whom had decompensated cirrhosis at recruitment. The median duration from start of treatment to death was 110 days (interquartile range 26-276). The estimated survival was 90.3, 88.2 and 86.3% at 6, 12 and 24 months of follow-up, respectively. Independent predictors of mortality were decompensated cirrhosis (adjusted hazard ratio [AHR] 23.68; 95% CI 3.23-173.48; p = 0.002), body mass index < 18.5 kg/m2 (AHR 3.65; 95% CI 1.73-7.72; p = 0.001) and older age (per 1-year increment; AHR 1.06; 95% CI 1.02-1.10; p = 0.007). CONCLUSIONS: Decompensated cirrhosis, low body mass index and older age were independent predictors of mortality. Improved access to antiviral treatment and earlier initiation of therapy could improve the survival of African CHB patients. TRIAL REGISTRATION: NCT02344498 ( ClinicalTrials.gov identifier). Registered 16 January 2015.

The WHO guidelines for chronic hepatitis B fail to detect half of the patients in need of treatment in Ethiopia.

BACKGROUND & AIMS: In 2015, the World Health Organization (WHO) issued guidelines for the management of chronic hepatitis B (CHB) in low- and middle-income countries, but little is known about the applicability of the WHO treatment criteria in sub-Saharan Africa. The aim of this study was to evaluate the diagnostic performance of the WHO guidelines in a large CHB cohort in Ethiopia. METHODS: Treatment-naïve adults who attended a public CHB clinic in Addis Ababa were included in this analysis. All patients underwent a standardized evaluation at recruitment, including blood tests and transient elastography (Fibroscan®). A Fibroscan result >7.9 kPa was used to define significant fibrosis and >9.9 kPa to define cirrhosis. Treatment eligibility was assessed using the most recent guidelines from the European Association for the Study of the Liver (EASL) as the 'gold standard'. RESULTS: Out of 1,190 patients with CHB, 300 (25.2%) were eligible for treatment based on the EASL 2017 guidelines and 182 (15.3%) based on the WHO 2015 guidelines. The sensitivity and specificity of the WHO criteria were 49.0 and 96.1%, respectively. Most patients (94 of 182; 51.6%) who fulfilled the WHO criteria had decompensated cirrhosis and might have a dismal prognosis even with therapy. Only 41 of 115 patients (35.7%) with compensated cirrhosis, who are likely to benefit the most from therapy, were eligible for treatment based on the WHO criteria. CONCLUSIONS: The WHO guidelines for CHB failed to detect half of the patients in need of treatment in Ethiopia, implying the need for a revision of the WHO treatment criteria. LAY SUMMARY: Antiviral therapy prevents disease progression and death in patients with chronic hepatitis B (CHB), but the identification of patients in need of treatment is a challenge in low- and middle-income countries. The World Health Organization (WHO) has suggested treatment eligibility criteria for use in such settings, but in our study the WHO criteria detected less than half of those in need of therapy in a large Ethiopian cohort of 1,190 patients with CHB. Our findings suggest that the WHO criteria might be unsuitable in sub-Saharan Africa. TRIAL REGISTRATION NUMBER: NCT02344498 (ClinicalTrials.gov identifier). Registered 16 January 2015.

Treatment of chronic hepatitis B in sub-Saharan Africa: 1-year results of a pilot program in Ethiopia.

BACKGROUND: The World Health Organization has set an ambitious goal of eliminating viral hepatitis as a major public health threat by 2030. However, in sub-Saharan Africa, antiviral treatment of chronic hepatitis B (CHB) is virtually unavailable. Herein, we present the 1-year results of a pilot CHB treatment program in Ethiopia. METHODS: At a public hospital in Addis Ababa, CHB patients were treated with tenofovir disoproxil fumarate based on simplified eligibility criteria. Baseline assessment included liver function tests, viral markers, and transient elastography (Fibroscan). Changes in laboratory markers were analyzed using Wilcoxon signed-rank tests. Adherence to therapy was measured by pharmacy refill data. RESULTS: Out of 1303 patients, 328 (25.2%) fulfilled the treatment criteria and 254 (19.5%) had started tenofovir disoproxil fumarate therapy prior to September 1, 2016. Of the patients who started therapy, 30 (11.8%) died within the first year of follow-up (28 of whom had decompensated cirrhosis), 9 (3.5%) self-stopped treatment, 7 (2.8%) were lost to follow-up, and 4 (1.6%) were transferred out. In patients who completed 12 months of treatment, the median Fibroscan value declined from 12.8 to 10.4 kPa (p < 0.001), 172 of 202 (85.1%) patients with available pharmacy refill data had taken ≥ 95% of their tablets, and 161 of 189 (85.2%) patients with viral load results had suppressed viremia. Virologic failure (≥ 69 IU/mL) at 12 months was associated with high baseline HBV viral load (> 1,000,000 IU/mL; adjusted OR 2.41; 95% CI 1.04-5.55) and suboptimal adherence (< 95%; adjusted OR 3.43, 95% CI 1.33-8.88). CONCLUSIONS: This pilot program demonstrated that antiviral therapy of CHB can be realized in Ethiopia with good clinical and virologic response. Early mortality was high in patients with decompensated cirrhosis, underscoring the need for earlier detection of hepatitis B virus infection and timely initiation of treatment, prior to the development of irreversible complications, in sub-Saharan Africa. TRIAL REGISTRATION: NCT02344498 (ClinicalTrials.gov identifier). Registered 16 January 2015.

Hepatitis delta virus infection in a large cohort of chronic hepatitis B patients in Ethiopia.

BACKGROUND & AIMS: Hepatitis D virus (HDV) infection is associated with a more severe outcome in patients with chronic hepatitis B (CHB); however, little is known about the presence of HDV in sub-Saharan Africa. We aimed to determine the prevalence of HDV infection, as well as its clinical, biological and virological characteristics, in a large CHB cohort in Ethiopia. METHODS: In total, 1267 HIV-negative CHB patients at St. Paul's Hospital Millennium Medical College in Addis Ababa were screened for anti-HDV antibodies using ELISA assays. Confirmed positive samples were further tested for HDV RNA using a consensus commercial real-time RT-PCR assay. HDV genotypes were also determined for RNA-positive samples by nucleotide sequencing followed by phylogenetic analyses. Demographical, clinical and biological data from patients were recorded and compared based on HDV RNA results. RESULTS: Most patients (n = 748, 59.0%) were men, and the median age was 31 years (interquartile range 26-40). Anti-HDV antibodies were detected in 19 individuals (1.5%), 12 of whom were HDV RNA-positive with a viral load ranging from <2 to >8 log 10 IU/mL. All strains were genotype 1. HDV RNA-positive patients were more likely to have significant liver fibrosis (63.6% vs 24.7%, P = .007) and cirrhosis (45.5% vs 16.4%, P = .024). CONCLUSIONS: HDV infection is rare in Ethiopia but is associated with more advanced liver fibrosis.

Early experiences from one of the first treatment programs for chronic hepatitis B in sub-Saharan Africa.

BACKGROUND: Treatment for chronic hepatitis B (CHB) is virtually absent in sub-Saharan Africa. Here we present early experiences from a pilot program for treatment of CHB in Ethiopia. METHODS: Adults (≥18 years) with CHB were included in a cohort study at St. Paul's Hospital Millennium Medical College, Addis Ababa, from February 2015. The baseline assessment included liver function tests, viral markers and transient elastography (Fibroscan 402, Echosense, France). Logistic regression models were used to identify predictors of fibrosis. Tenofovir disoproxil fumarate (TDF) was initiated based on the European Association for the Study of the Liver (EASL) criteria, with some modifications. The initial 300 patients underwent a more comprehensive evaluation and are presented here. RESULTS: One-hundred-and-thirty-eight patients (46.0%) were women and median age was 30 years (interquartile range 26-40). Co-infections were rare: four patients (1.3%) were anti-HCV positive, 11 (3.7%) were anti-HDV positive, whereas 5 (1.7%) had HIV-infection. The majority were hepatitis B e-antigen (HBeAg) negative (n = 262; 90.7%) and had a normal (≤40 U/L) alanine aminotransferase (ALT) (n = 245; 83.1%). Of 268 patients with a valid Fibroscan result, 79 (29.5%) had significant fibrosis (>7.9 kPa). Independent predictors of fibrosis were male sex, age > 35 years and viral load >20,000 IU/ml. In total, 74 patients (24.7%) started TDF therapy, of whom 46 (62.2%) had cirrhosis. CONCLUSIONS: The majority were HBeAg negative and had normal ALT. However, one quarter of the patients were in need of antiviral treatment, underscoring the need to scale up CHB treatment on the African continent. TRIAL REGISTRATION: NCT02344498 ( ClinicalTrials.gov identifier). Registered 16 January 2015.

Are non-invasive fibrosis markers for chronic hepatitis B reliable in sub-Saharan Africa?

BACKGROUND: In the absence of liver biopsy, the World Health Organization recommends non-invasive tests, such as aspartate aminotransferase to platelet ratio index and FIB-4, to assess liver fibrosis in patients with chronic hepatitis B. However, these tests are not well validated in sub-Saharan Africa. Recently, a new marker, gamma-glutamyl transpeptidase to platelet ratio, was found to be more accurate in an African setting, but this needs confirmation in other cohorts. METHODS: A treatment program for chronic hepatitis B was initiated in Addis Ababa, Ethiopia, in 2015. Non-invasive tests were compared with transient elastography (Fibroscan 402, Echosense, France) using the following thresholds: no fibrosis (≤7.9 kPa), significant fibrosis (>7.9 kPa) and cirrhosis (>11.7 kPa). The diagnostic accuracy was estimated by calculating the area under the receiver operating characteristics curve. RESULTS: Of 582 treatment-naïve patients, 141 (24.2%) had significant fibrosis and 90 (15.5%) had cirrhosis. The area under the receiver operating characteristics curve of aspartate aminotransferase to platelet ratio index, FIB-4 and gamma-glutamyl transpeptidase to platelet ratio was high both to diagnose significant fibrosis (0.79 [95% CI 0.75-0.84], 0.79 [95% CI 0.75-0.84], 0.80 [95% CI 0.75-0.85]) and cirrhosis (0.86 [95% CI 0.81-0.91], 0.86 [95% CI 0.81-0.91], 0.87 [95% CI 0.82-0.91]). The specificity was high for all tests (94%-100%); however, the sensitivity was poor both to detect fibrosis (10%-45%) and cirrhosis (10%-36%). CONCLUSIONS: Aspartate aminotransferase to platelet ratio index, FIB-4 and gamma-glutamyl transpeptidase to platelet ratio had good diagnostic properties to detect liver fibrosis and cirrhosis in patients with chronic hepatitis B in East Africa. However, the sensitivity was low, and only 10% of patients with cirrhosis were detected using aspartate aminotransferase to platelet ratio index at the World Health Organization recommended threshold.

Dry Blood Spots a Reliable Method for Measurement of Hepatitis B Viral Load in Resource-Limited Settings.

BACKGROUND & AIMS: Hepatitis B virus (HBV) quantification is essential in the management of chronic hepatitis B, both to determine treatment eligibility and in the monitoring of treatment effect. This test, however, is rarely available in resource-limited settings due to high costs and stringent requirements for shipment and storage of plasma. Dried Blood Spots (DBS) can be a convenient alternative to plasma, but its use for HBV monitoring has not been investigated under real-life conditions in Africa. METHODS: The performance of DBS in HBV quantification was investigated using a modified commercial test (Abbott RealTime HBV assay). Paired DBS and plasma samples were collected from an HBV positive cohort in Addis Ababa, Ethiopia. DBS were stored at ambient temperature for 4-39 days before shipment to the laboratory. RESULTS: Twenty-six paired samples were selected covering the total range of quantification, from 2.14 log IU/ml to >7 log IU/ml. HBV was detected in 21 of 21 (100%) DBS from patients with a corresponding plasma viral load above 2.70 log IU/ml. The mean difference between plasma and DBS was 0.59 log IU/ml, and the correlation was strong (R2 = 0.92). In stability studies there was no significant change in DBS viral load after storage at room temperature for up to 12 weeks. CONCLUSIONS: This study suggests that DBS can be a feasible and reliable alternative to plasma for quantification of HBV in resource-limited settings. DBS can expand access to antiviral treatment for patients in low- and middle-income countries.