Hepatitis B: The view from West Africa

The Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study began in 2011 in The Gambia, Sénégal and Nigeria. The study aims to reduce the risk of hepatocellular carcinoma (HCC) in West Africa through the suppression of the Hepatitis B virus (HBV). The biological samples collected allow for the detection of novel liver cancer biomarkers in the hope of improving the diagnostic ability of early disease states. The PROLIFICA platform hopes to improve cancer diagnostics whilst simultaneously providing the training, skills and infrastructure necessary to develop the quality of liver cancer care in West Africa

Population-based interventions to reduce the public health burden related with hepatitis B virus infection in the gambia, west Africa.

In The Gambia, West Africa, the prevalence of chronic hepatitis B virus (HBV) infection in adults exceeds eight percent and hepatocellular carcinoma (HCC) has been the most frequent type of malignancy. Two population-based intervention studies to control HBV infection, namely, GHIS (Gambia Hepatitis Intervention Study) and PROLIFICA (Prevention of Liver Fibrosis and Cancer in Africa), are discussed. The GHIS started in 1986 as a nation-wide trial of the HBV vaccine to evaluate the effectiveness of infant HBV vaccination in preventing HCC in adulthood. The vaccine was progressively introduced into the Expanded Program of Immunization (EPI) of The Gambia over four years in a phased manner, called the "stepped-wedge" design. This was because instantaneous universal vaccination in the country was impossible for logistic and financial reasons. However, this design also allowed the study to have an unvaccinated control group which consisted of the newborns of the areas where HBV vaccine has not yet been incorporated in the EPI. To assess the outcome, a national cancer registry was founded and all HCC patients in this birth cohort are linked with the vaccine trial database. The study is still ongoing to answer whether the HBV vaccine in infancy prevent HCC in adulthood in The Gambia. Although the universal HBV vaccination since 1990 has been successful in reducing the prevalence of chronic HBV infection in young Gambians, the number of HCC cases may not decline over the next decades as people infected prior to the immunization program are likely to continue to develop the diseases. To reduce the HCC incidence through community-based screening of HBV infection and provision of antiviral therapy, the PROLIFICA project started in 2011. Study hypothesis and design of these two studies, GHIS and PROLIFICA, are further discussed

Acceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study

Background Despite the introduction of immunisation for hepatitis B virus (HBV) in the 1990s, HBV-related morbidity and mortality remain high in sub-Saharan Africa. Identifi cation and treatment of asymptomatic people with chronic HBV infection should reduce the disease burden. We therefore assessed the feasibility of a screen-and-treat programme for HBV infection in The Gambia, west Africa, and estimated the proportion of HBV-infected people who had signifi cant liver disease in need of treatment. Methods Between Dec 7, 2011, and Jan 24, 2014, individuals living in randomly selected communities in western Gambia were off ered hepatitis B surface antigen (HBsAg) screening via a point-of-care test. The test was also off ered to potential blood donors attending the central hospital in the capital, Banjul. HBsAg-positive individuals were invited for a comprehensive liver assessment and were off ered treatment according to international guidelines. We defi ned linkage to care as visiting the liver clinic at least once. Eligibility for treatment was judged in accordance with the 2012 European Association for the Study of the Liver guidelines. Findings HBsAg screening was accepted by 5980 (weighted estimate 68·9%, 95% CI 65·0–72·4) of 8170 adults from 27 rural and 27 urban communities and 5559 (81·4%, 80·4–82·3) of 6832 blood donors. HBsAg was detected in 495 (8·8%, 7·9–9·7) individuals in communities and 721 (13·0%, 12·1–13·9) blood donors. Prevalence was higher in men (239 [10·5%, 8·9–12·1] of 2328 men vs 256 [7·6%, 6·5–8·7] of 3652 women; p=0·004) and middle-aged participants. Linkage to care was high in the communities, with 402 (81·3%) of 495 HBsAg-positive individuals attending the clinic. However, only 300 (41·6%) of 721 HBsAg-positive people screened at the blood bank linked into care. Of those who attended the clinic, 18 (4·4%, 2·5–7·7) patients from the communities and 29 (9·7%, 6·8–13·6) from the blood bank were eligible for treatment. Male sex was strongly associated with treatment eligibility (odds ratio 4·35, 1·50–12·58; p=0·007). Interpretation HBV infection remains highly prevalent in The Gambia. The high coverage of community-based screening, good linkage into care, and the small proportion of HBsAg carriers who need treatment suggest that largescale screening and treatment programmes are feasible in sub-Saharan Africa

Cost-eff ectiveness of community-based screening and treatment for chronic hepatitis B in The Gambia: an economic modelling analysis

Background Despite the high burden of hepatitis B virus (HBV) infection in sub-Saharan Africa, absence of widespread screening and poor access to treatment leads to most people remaining undiagnosed until later stages of disease when prognosis is poor and treatment options are limited. We examined the cost-eff ectiveness of community-based screening and early treatment with antiviral therapy for HBV in The Gambia. Methods In this economic evaluation, we combined a decision tree with a Markov state transition model to compare a screen and treat intervention consisting of adult community-based screening using a hepatitis B surface antigen (HBsAg) rapid test and subsequent HBV antiviral therapy versus current practice, in which there is an absence of publicly provided screening or treatment for HBV. We used data from the PROLIFICA study to parameterise epidemiological, primary screening, and cost information, and other model parameter inputs were obtained from a literature search. Outcome measures were cost per disability-adjusted life-year (DALY) averted; cost per life-year saved; and cost per quality-adjusted life-year (QALY) gained. We calculated the incremental cost-eff ectiveness ratios (ICERs) between current practice and the screen and treat intervention. Costs were assessed from a health provider perspective. Costs (expressed in 2013 US$) and health outcomes were discounted at 3 Findings In The Gambia, where the prevalence of HBsAg is 8·8 treatment for HBV has an incremental cost-eff ectiveness ratio (ICER) of$540 per DALY averted, $645 per life-year saved, and$511 per QALY gained, compared with current practice. These ICERs are in line with willingness-to-pay levels of one times the country’s gross domestic product per capita ($487) per DALY averted, and remain robust over a wide range of epidemiological and cost parameter inputs. Interpretation Adult community-based screening and treatment for HBV in The Gambia is likely to be a cost-eff ective intervention. Higher cost-eff ectiveness might be achievable with targeted facility-based screening, price reductions of drugs and diagnostics, and integration of HBV screening with other public health interventions

Development of a simple score based on HBeAg and ALT for selecting patients for HBV treatment in Africa.

BACKGROUND & AIMS: To eliminate hepatitis B virus (HBV) infection, it is essential to scale up antiviral treatment through decentralized services. However, access to the conventional tools to assess treatment eligibility (liver biopsy/Fibroscan®/HBV DNA) is limited and not affordable in resource-limited countries. We developed and validated a simple score to easily identify patients in need of HBV treatment in Africa. METHODS: As a reference, we used treatment eligibility determined by the European Association for the Study of the Liver based on alanine aminotransferase (ALT), liver histology and/or Fibroscan and HBV DNA. We derived a score indicating treatment eligibility by a stepwise logistic regression using a cohort of chronic HBV infection in The Gambia (n = 804). We subsequently validated the score in an external cohort of HBV-infected Africans from Senegal, Burkina Faso, and Europe (n = 327). RESULTS: Out of several parameters, two remained in the final model, namely HBV e antigen (HBeAg) and ALT level, constituting a simple score (treatment eligibility in Africa for the hepatitis B virus: TREAT-B). The score demonstrated a high area under the receiver operating characteristic curve (0.85, 95% CI 0.79-0.91) in the validation set. The score of 2 and above (HBeAg-positive and ALT ≥20 U/L or HBeAg-negative and ALT ≥40 U/L) had a sensitivity and specificity for treatment eligibility of 85% and 77%, respectively. The sensitivity and specificity of the World Health Organization criteria based on the aspartate aminotransferase-to-platelet ratio index (APRI) and ALT were 90% and 40%, respectively. CONCLUSIONS: A simple score based on HBeAg and ALT had a high diagnostic accuracy for the selection of patients for HBV treatment. This score could be useful in African settings. LAY SUMMARY: Limited access to the diagnostic tools used to assess treatment eligibility (liver biopsy/Fibroscan/hepatitis B virus DNA) has been an obstacle to the scale up of hepatitis B treatment programs in low- and middle-income countries. Using the data from African patients with chronic HBV infection, we developed and validated a new simple diagnostic score for treatment eligibility, which only consists of hepatitis B virus e antigen and alanine aminotransferase level. The diagnostic accuracy of the score for selecting patients for HBV treatment was high and could be useful in African settings

The gamma-glutamyl transpeptidase to platelet ratio (GPR) predicts significant liver fibrosis and cirrhosis in patients with chronic HBV infection in West Africa.

BACKGROUND: Simple and inexpensive non-invasive fibrosis tests are highly needed but have been poorly studied in sub-Saharan Africa. METHODS: Using liver histology as a gold standard, we developed a novel index using routine laboratory tests to predict significant fibrosis in patients with chronic HBV infection in The Gambia, West Africa. We prospectively assessed the diagnostic accuracy of the novel index, Fibroscan, aspartate transaminase-to-platelet ratio index (APRI), and Fib-4 in Gambian patients with CHB (training set) and also in French and Senegalese CHB cohorts (validation sets). RESULTS: Of 135 consecutive treatment-naïve patients with CHB who had liver biopsy, 39% had significant fibrosis (Metavir fibrosis stage ≥F2) and 15% had cirrhosis (F4). In multivariable analysis, gamma-glutamyl transpeptidase (GGT) and platelet count were independent predictors of significant fibrosis. Consequently, GGT-to-platelet ratio (GPR) was developed. In The Gambia, the area under the receiver operating characteristic curve (AUROC) of the GPR was significantly higher than that of APRI and Fib-4 to predict ≥F2, ≥F3 and F4. In Senegal, the AUROC of GPR was significantly better than Fib-4 and APRI for ≥F2 (0.73, 95% CI 0.59 to 0.86) and better than Fib-4 and Fibroscan for ≥F3 (0.93, 0.87 to 0.99). In France, the AUROC of GPR to diagnose ≥F2 (0.72, 95% CI 0.59 to 0.85) and F4 (0.87, 0.76 to 0.98) was equivalent to that of APRI and Fib-4. CONCLUSIONS: The GPR is a more accurate routine laboratory marker than APRI and Fib-4 to stage liver fibrosis in patients with CHB in West Africa. The GPR represents a simple and inexpensive alternative to liver biopsy and Fibroscan in sub-Saharan Africa

Acceptability and feasibility of a screen-and-treat programme for hepatitis B virus infection in The Gambia: the Prevention of Liver Fibrosis and Cancer in Africa (PROLIFICA) study.

BACKGROUND: Despite the introduction of immunisation for hepatitis B virus (HBV) in the 1990s, HBV-related morbidity and mortality remain high in sub-Saharan Africa. Identification and treatment of asymptomatic people with chronic HBV infection should reduce the disease burden. We therefore assessed the feasibility of a screen-and-treat programme for HBV infection in The Gambia, west Africa, and estimated the proportion of HBV-infected people who had significant liver disease in need of treatment. METHODS: Between Dec 7, 2011, and Jan 24, 2014, individuals living in randomly selected communities in western Gambia were offered hepatitis B surface antigen (HBsAg) screening via a point-of-care test. The test was also offered to potential blood donors attending the central hospital in the capital, Banjul. HBsAg-positive individuals were invited for a comprehensive liver assessment and were offered treatment according to international guidelines. We defined linkage to care as visiting the liver clinic at least once. Eligibility for treatment was judged in accordance with the 2012 European Association for the Study of the Liver guidelines. FINDINGS: HBsAg screening was accepted by 5980 (weighted estimate 68·9%, 95% CI 65·0-72·4) of 8170 adults from 27 rural and 27 urban communities and 5559 (81·4%, 80·4-82·3) of 6832 blood donors. HBsAg was detected in 495 (8·8%, 7·9-9·7) individuals in communities and 721 (13·0%, 12·1-13·9) blood donors. Prevalence was higher in men (239 [10·5%, 8·9-12·1] of 2328 men vs 256 [7·6%, 6·5-8·7] of 3652 women; p=0·004) and middle-aged participants. Linkage to care was high in the communities, with 402 (81·3%) of 495 HBsAg-positive individuals attending the clinic. However, only 300 (41·6%) of 721 HBsAg-positive people screened at the blood bank linked into care. Of those who attended the clinic, 18 (4·4%, 2·5-7·7) patients from the communities and 29 (9·7%, 6·8-13·6) from the blood bank were eligible for treatment. Male sex was strongly associated with treatment eligibility (odds ratio 4·35, 1·50-12·58; p=0·007). INTERPRETATION: HBV infection remains highly prevalent in The Gambia. The high coverage of community-based screening, good linkage into care, and the small proportion of HBsAg carriers who need treatment suggest that large-scale screening and treatment programmes are feasible in sub-Saharan Africa. FUNDING: European Commission (FP7)

Clinical characteristics and outcomes of patients with cirrhosis and hepatocellular carcinoma in The Gambia, west Africa: a prospective cohort study.

BACKGROUND: Chronic liver disease is a major cause of premature death in sub-Saharan Africa. Efficacy of antiviral therapy among patients with hepatitis B virus (HBV)-related cirrhosis is not well established in Africa. We described the clinical characteristics and outcomes of patients with cirrhosis and hepatocellular carcinoma in The Gambia and assessed the impact of tenofovir disoproxil fumarate (TDF) on survival of HBV-infected patients with cirrhosis. METHODS: In this prospective cohort study, we followed up adults who were consecutively diagnosed with cirrhosis or hepatocellular carcinoma between 2012 and 2015 in The Gambia, west Africa. Patients with chronic HBV infection and cirrhosis, without hepatocellular carcinoma, were offered TDF. Primary outcome was overall survival. To determine the effect of TDF on survival, we performed a Cox proportional hazard regression model with inverse probability of treatment weighting (IPTW) based on propensity score. FINDINGS: Of 529 patients enrolled in this study, 336 patients (252 with hepatocellular carcinoma and 84 with cirrhosis) were analysed. Patients were predominantly male (253 [75%] men and 83 [25%] women), with a median age of 42 years (IQR 33-55). 276 (84%) of 327 of patients with data were positive for HBV biomarkers, 31 (10%) of 311 were positive for hepatitis C virus antibodies, and 22 (10%) of 223 were positive for hepatitis D virus antibodies. 64% of patients with hepatocellular carcinoma had multifocal tumour, with a median size of 7·5 cm (IQR 5·4-10·8). 173 patients with hepatocellular carcinoma and 70 patients with cirrhosis were included in the survival analysis. Median survival was 1·5 months (95% CI 1·1-2·0) in patients with hepatocellular carcinoma and 17·1 months (11·2-24·0) in patients with cirrhosis (log-rank p<0·0001). In patients with hepatocellular carcinoma, ascites (hazard ratio [HR] 1·78, 95% CI 1·21-2·60), partial or complete portal thrombosis (HR 2·61, 1·58-4·30), and platelet count (HR 1·80, 1·19-2·70) were independent predictive factors of mortality at baseline. In HBV-infected patients with cirrhosis, median turnaround time between cirrhosis diagnosis and TDF initiation was 4·9 months (IQR 3·2-7·3). In IPTW analysis, TDF treatment was associated with improved survival in patients with HBV-related cirrhosis (adjusted HR 0·14, 0·06-0·34; p<0·0001). INTERPRETATION: These results highlight poor survival of patients with cirrhosis or hepatocellular carcinoma as well as the effectiveness of TDF in reducing the premature mortality of patients with cirrhosis and HBV infection. Interventions for early diagnosis and treatment of cirrhosis as well as screening programmes for hepatocellular carcinoma are urgently required in Africa. FUNDING: European Commission and Medical Research Council UK. TRANSLATION: For the French translation of the abstract see Supplementary Materials section

The predominance of Human Immunodeficiency Virus type 1 (HIV-1) circulating recombinant form 02 (CRF02_AG) in West Central Africa may be related to its replicative fitness

BACKGROUND: CRF02_AG is the predominant HIV strain circulating in West and West Central Africa. The aim of this study was to test whether this predominance is associated with a higher in vitro replicative fitness relative to parental subtype A and G viruses. Primary HIV-1 isolates (10 CRF02_AG, 5 subtype A and 5 subtype G) were obtained from a well-described Cameroonian cohort. Growth competition experiments were carried out at equal multiplicity of infection in activated T cells and monocyte-derived dendritic cells (MO-DC) in parallel. RESULTS: Dual infection/competition experiments in activated T cells clearly indicated that CRF02_AG isolates had a significant replication advantage over the subtype A and subtype G viruses. The higher fitness of CRF02_AG was evident for isolates from patients with CD4+ T cell counts >200 cells/μL (non-AIDS) or CD4+ T cell counts <200 cells/μL (AIDS), and was independent of the co-receptor tropism. In MO-DC cultures, CRF02_AG isolates showed a slightly but not significantly higher replication advantage compared to subtype A or G isolates. CONCLUSION: We observed a higher ex vivo replicative fitness of CRF02_AG isolates compared to subtype A and G viruses from the same geographic region and showed that this was independent of the co-receptor tropism and irrespective of high or low CD4+ T cell count. This advantage in replicative fitness may contribute to the dominant spread of CRF02_AG over A and G subtypes in West and West Central Africa

Deciphering the Complex Distribution of Human Immunodeficiency Virus Type 1 Subtypes among Different Cohorts in Northern Tanzania.

Increased understanding of the genetic diversity of HIV-1 is challenging but important in the development of an effective vaccine. We aimed to describe the distribution of HIV-1 subtypes in northern Tanzania among women enrolled in studies preparing for HIV-1 prevention trials (hospitality facility-worker cohorts), and among men and women in an open cohort demographic surveillance system (Kisesa cohort). The polymerase encompassing partial reverse transcriptase was sequenced and phylogenetic analysis performed and subtype determined. Questionnaires documented demographic data. We examined factors associated with subtype using multinomial logistic regression, adjusted for study, age, and sex. Among 140 individuals (125 women and 15 men), subtype A1 predominated (54, 39%), followed by C (46, 33%), D (25, 18%) and unique recombinant forms (URFs) (15, 11%). There was weak evidence to suggest different subtype frequencies by study (for example, 18% URFs in the Kisesa cohort versus 5-9% in the hospitality facility-worker cohorts; adjusted relative-risk ratio (aRR) = 2.35 [95% CI 0.59,9.32]; global p = 0.09). Compared to men, women were less likely to have subtype D versus A (aRR = 0.12 [95% CI 0.02,0.76]; global p = 0.05). There was a trend to suggest lower relative risk of subtype D compared to A with older age (aRR = 0.44 [95% CI 0.23,0.85] per 10 years; global p = 0.05). We observed multiple subtypes, confirming the complex genetic diversity of HIV-1 strains circulating in northern Tanzania, and found some differences between cohorts and by age and sex. This has important implications for vaccine design and development, providing opportunity to determine vaccine efficacy in diverse HIV-1 strains