Dr. John C Rwegasha.FRCP(Lond),MSc, Muhimbili National Hospital Dar es Salaam Tanzania 15/09/2018 1
No disclosures. 15/09/2018 2
Sub-Saharan Africa (SSA) has a high burden of morbidity and mortality resulting from chronic hepatitis B virus (HBV) infections. Despite the availability of safe, effective and increasingly inexpensive antiviral treatments, screening, care, and treatment services for chronic HBV is not generally available in Sub Saharan Africa (SSA). This demonstration project will implement and evaluate a low-cost strategy following the World Health Organization (WHO) Guidelines published in March 2015for care and treatment of persons infected with chronic HBV and may serve as a model for HBV care and treatment in SSA and other resource-limited settings. 15/09/2018 3
Program Goal Implement and evaluate the feasibility of a care and treatment model for persons infected with chronic hepatitis B virus in resource-limited settings. Main Objectives Objective 1: To implement a model care and treatment program, including clinical evaluation and initiation of oral antiviral treatment, for persons with chronic HBV infection by clinicians in Zanzibar and in Dar es Salaam, United Republic of Tanzania. Use WHO Guideline for HBV to institute regular follow-up of persons with HBV infection and select appropriate candidates for treatment. 15/09/2018 4
Objective 2: To evaluate the feasibility and acceptability of the care model (for patients, clinicians, and institutions) to advance chronic HBV care and treatment in low-resource settings Objective 3: To evaluate the impact of the care model on proximal disease outcomes (e.g., reduced hepatic necroinflammation and viral load, decrease incidence of liver related complications of HBV). Objective 4: To increase the capacity of health professionals in Zanzibar and Dar es Salaam to independently provide clinical management of persons with chronic HBV infection including increasing laboratory capacity to test for HBV sero markers and HBV DNA. 15/09/2018 5
Sub-Aims of the Evaluation Develop a training manual for clinicians and nurses in the care and treatment of patients with chronic HBV infection. Develop educational materials for patients with chronic HBV infection and evaluate in a real world setting. Establish HBV management and treatment strategies for areas with limited resources and evaluate these strategies over a 5-year period. Implement and provide evaluation of WHO Guidelines for Care and Treatment of Persons with Chronic HBV Infection, published in2015. Observe the incidence of hepatocellular carcinoma and end stage liver disease in persons who meet treatment criteria compared to rates available from this region of Africa. Observe the rates of HBeAg and HBsAg clearance in treated patients compared to those who do not meet WHO treatment criteria. 15/09/2018 6
Program recruitment strategy: Blood donors who test positive for HBV infection (HBsAg+) and test negative for HIV and HCV at NBTS Centers in Zanzibar and Dar es Salaam will be referred to clinics established at Mnazi Mmoja Hospital (Zanzibar) and Muhimbili National Hospital (Dar-es Salaam) for assessment, care and treatment of their HBV infection. The majority of participants will come from Blood banks since routine screening is not conducted anywhere else; however, clinicians may also choose to refer from other areas (i.e. hospital inpatient, clinics, etc.). Pregnant women who test positive in hospital or outpatient clinics will also be invited to participate. In addition, household and sexual contacts of HBsAg-positive persons will be offered screening and patients may accrue from this public health task. Individuals that test HBsAg+ will be contacted by a staff member within 4 weeks to be invited to participate in the program, and those wishing to participate will be given informed consent by a trained staff member. 15/09/2018 7
Program Clinical Protocol Consenting patients will receive a physical examination focused on detecting signs of liver disease (e.g. ascites, spider angioma, splenomegaly in persons without malaria, esophageal varices, hepatic encephalopathy). Laboratory testing including HBV markers (HBsAg, HBeAg, anti-hbeag, HBV DNA), HCV, and HIV and additional laboratory testing including ALT, AST, bilirubin, albumin, platelet count, prothrombin time, INR, alpha fetoprotein, and AST to platelet ratio index (APRI score). Testing for renal function (BUN, creatinine, serum phosphorous, egfr, and urine protein) will also be done at the initial visit to ensure that Tenofovir (TDF) can be used safely in persons who meet treatment criteria. Patients will be tested for quantitative HBV DNA at CPL -MNH to facilitate the correlation of HBV DNA levels with serologic markers of HBV infection, liver enzymes and liver function tests. 15/09/2018 8
WHO eligibility criteria for HBV treatment based on the WHO Guidelines: Clinical evidence of compensated or decompensated cirrhosis (or fibrosis based on APRI score >1.5 or FB4 Criteria). Persons without cirrhosis over 30 years of age who have persistently elevated ALT on at least 2 occasions 6 months apart and have HBV DNA level of >20,000 IU/ml. Persons who meet eligibility criteria will be offered oral TDF therapy, receive counseling about HBV infection, including suggested lifestyle modifications and interventions to prevent transmission and improve liver health, and be provided regular follow-up schedule. Persons who do not initially meet treatment criteria will receive counseling and given scheduled follow-up visits for evaluations over the program period. 15/09/2018 9
Clinicians at participating hospitals will receive training from Program investigators on diagnosis, evaluation and management (including physical examination for liver disease/laboratory assessment), and clinical management of persons with chronic HBV infection. Enrolled participants who meet WHO treatment criteria will be counseled on appropriate use of medications, including proper administration and potential side effects, and dispensed a sufficient quantity of TDF to cover them between scheduled visits. They will be provided with contact information for clinic staff for any questions or concerns that arise between visits. The program duration will be 5 years and continue through 2020; at the end of the program, TDF will continue to be available indefinitely for enrolled patients at Mnazi Mmoja and Muhimbili clinical centers. 15/09/2018 10
FLOWCHART: Chronic HBV Management at Hepatology Clinic - MNH Blood Donor > 18 Tests HBsAg+ at NTBS Center Donor also tested HIV+? No Donor also tested HCV+? YES YES Counsel/ Refer to HIV/AIDS Tx Center (usual protocol) Counseling (usual protocol) No Counsel/ Refer to HBV Clinic Patient consents to testing and management? No Counsel (ETOH, PRN Return, etc ) YES Physical Exam Stigmata of cirrhosis Labs: HBeAg, anti-hbe, HBV DNA, ALT, AST, Bilirubin, BUN, Creatinine, PT, APTT, CBC & platelets, egfr, Calculated APRI, Phosphorous, Urine Protein, AFP Counseling: Appointment for Follow-up visit in 1 month 15/09/2018 11
FLOWCHART: Chronic HBV Management at Hepatology Clinic - MNH No First Follow-up Clinic Visit after Baseline Evaluation and Labs ALT > 2x ULN and HBV DNA > 20,000 IU/mL OR PE Revealed Stigmata of cirrhosis OR APRI > 1.5 and HBV DNA > 2,000 IU/mL Education & Counseling 6 Month F/U Visit YES Initiate TDF 300 mg QD Renal Function WNL YES No Consult Medical Seniors & Schedule F/U Education & Counseling Medication Supply 6 Month F/U Visit HBV DNA (viral load). AFP Elevated? YES Consult Medical Seniors & Address F/U 15/09/2018 12
FLOWCHART: Chronic HBV Management at Hepatology Clinic - MNH Pt taking TDF: F/U Visits q 6 months Pt not taking TDF: F/U Visits q 12 months Physical Exam: Attention to stigmata of cirrhosis Labs: HBsAg, HBeAg, anti-hbe, ALT, AST, Bilirubin, BUN, Creatinine, PT, APTT, CBC & platelets, egfr, Calculated APRI, Phosphorous, Urine Protein, AFP. Note: HBV DNA will be re-tested for HBV DNA annualy Physical Exam: Attention to stigmata of cirrhosis* Labs: HBsAg, HBV DNA * *, HBeAg, anti- Hbe, ALT, AST, Bilirubin, PT, APTT, CBC & platelets, APRI, AFP. * * * Education & Counseling Dispense TDF x 6 months 6 Month F/U Visit Renal Function Normal? No AFP Elevated? YES Education & Counseling 12 Month F/U Visit Note: Treatment may be stopped for patients who are HBeAg- positive and seroconvert to HBeAg-negative and for those who are anti-hbepositive with normal ALT for at least 12 months Consult Medical Seniors Contact for early RTC if indicated * If physical exam findings indicate cirrhosis consult medical director, may consider initiating TDF 300 mg QD * * * If ALT > 2x ULN or APRI >1.5, Patient will be contacted for earlier Follow Up visit, renal function testing, and initiation of TDF 300 mg QD * * If HBV DNA between 2,000 and 20,000 IU/mL with normal or minimal elevation of 15/09/2018 ALT need HBV DNA at each 13 visit
Anticipated enrollment. 40 HBV mono infected patients to be recruited monthly. 2,400 patients to be recruited over period of 5years. 1750 patients to be enrolled. Estimates of eligible patients for treatment. 10%-15% of 1750 of up to 200 over period of 5 years. 15/09/2018 14
The programmatic outcomes will include: The proportion of enrollment vs. recruitment. Adherence to follow-up. Proportion of the cohorts who meet WHO criteria for treatment. Adherence to medications. Drop-out rates. Adherence by providers to WHO Guidelines for HBV. Feasibility prospects of care and treatment program. 15/09/2018 15
Clinical endpoints: The proportion of patients meeting WHO criteria for treatment. The proportion of patients losing active viral markers: (comparing those on treatment to those not meeting treatment criteria). Proportion who normalize their liver function indices. Proportion of HBV DNA un detected, HBeAg and HBsAg sero conversion. Proportion who develop HCC and /or ESLD. 15/09/2018 16
Muhimbili National Hospital, Dar es Salaam Large public teaching hospital with Gastroenterology,Endoscopy, Ultrasound/CT/MRI, HBV DNA PCR Lab capacity. Target enrollment 350 / year Trained 10 physicians, 7 field assistance, 3 laboratory technician, 2 pharmacists, and 1 data manager. Mnazi Mmoja Hospital, Zanzibar Public hospital for Zanzibar; primary care and internal medicine providers Ultrasound/CT Lacks endoscopy and HBV DNA capacity. Target enrollment 150 / year. Trained 2 physicians, 2 nurses, 1 laboratory technician, 1 pharmacist, and 1 data manager. 15/09/2018 17
1200 1000 944 1052 800 600 400 535 629 200 0 108 94 123 REGISTERED ENROLLED TREATMENT ELIGIBLE 133 117 10 9 126 TREATMENT RECEIVED MUHIMBILI MNAZI MMOJA TOTAL 15/09/2018 18
Achievable Two clinics of excellence established to provide HBV care and treatment following WHO guidelines. Successful recruitment and enrollment is on-going. Challenges: Fluctuating costs of laboratory supplies; reagents for HBV DNA and HBV serology testing. Demand for HBV care and treatment is much higher than capacity to care for all the patients with HBV. Patients previously taking Truvada. Significant number of patients presenting to clinics with advanced disease (Decompensated liver cirrhosis and Hepatocellular carcinoma). 15/09/2018 19
Next steps Continue recruitment and enrollment Monitor and evaluate adherence to protocol at two clinics of excellence Evaluate the feasibility and sustainability of continuing such a program in low resource settings. Analyze data to evaluate impact of program on improvement of patient with chronic HBV mono infection. 15/09/2018 20
CDC Foundation. Gilead Sciences. Program staff and Participants. 15/09/2018 21
1.WHO Hepatitis B Fact Sheet: http://www.who.int/en/news-room/fact-sheets/detail/hepatitis-b. 2.WHO. 2015.Guidelines for the prevention, care and treatment of persons with chronic hepatitis B infection. http://www.who.int/hepatitis/publications/hepatitis-b-guidelines/en/ 3.Barth RE, et al.2012.international J of Infectious Diseases. 15/09/2018 22