Wahid Doss

Historical epidemiology of hepatitis C virus (HCV) in selected countries

Chronic infection with hepatitis C virus (HCV) is a leading indicator for liver disease. New treatment options are becoming available, and there is a need to characterize the epidemiology and disease burden of HCV. Data for prevalence, viremia, genotype, diagnosis and treatment were obtained through literature searches and expert consensus for 16 countries. For some countries, data from centralized registries were used to estimate diagnosis and treatment rates. Data for the number of liver transplants and the proportion attributable to HCV were obtained from centralized databases. Viremic prevalence estimates varied widely between countries, ranging from 0.3% in Austria, England and Germany to 8.5% in Egypt. The largest viremic populations were in Egypt, with 6 358 000 cases in 2008 and Brazil with 2 106 000 cases in 2007. The age distribution of cases differed between countries. In most countries, prevalence rates were higher among males, reflecting higher rates of injection drug use. Diagnosis, treatment and transplant levels also differed considerably between countries. Reliable estimates characterizing HCV‐infected populations are critical for addressing HCV‐related morbidity and mortality. There is a need to quantify the burden of chronic HCV infection at the national level.

Strategies to manage hepatitis C virus (HCV) disease burden

The number of hepatitis C virus (HCV) infections is projected to decline while those with advanced liver disease will increase. A modeling approach was used to forecast two treatment scenarios: (i) the impact of increased treatment efficacy while keeping the number of treated patients constant and (ii) increasing efficacy and treatment rate. This analysis suggests that successful diagnosis and treatment of a small proportion of patients can contribute significantly to the reduction of disease burden in the countries studied. The largest reduction in HCV‐related morbidity and mortality occurs when increased treatment is combined with higher efficacy therapies, generally in combination with increased diagnosis. With a treatment rate of approximately 10%, this analysis suggests it is possible to achieve elimination of HCV (defined as a >90% decline in total infections by 2030). However, for most countries presented, this will require a 3–5 fold increase in diagnosis and/or treatment. Thus, building the public health and clinical provider capacity for improved diagnosis and treatment will be critical.

Sofosbuvir plus ribavirin for treating Egyptian patients with hepatitis C genotype 4

BACKGROUND & AIMS Egypt has the highest prevalence of chronic hepatitis C virus (HCV) infection in the world, and more than 90% of patients are infected with genotype 4 virus. We evaluated the efficacy and safety of the HCV polymerase inhibitor sofosbuvir in combination with ribavirin in HCV genotype 4 patients in Egypt. METHODS Treatment-naïve or treatment-experienced patients with genotype 4 HCV infection (n=103) were randomly assigned to receive either 12 or 24 weeks of sofosbuvir 400 mg and ribavirin 1000-1200 mg daily. Randomization was stratified by prior treatment experience and by presence or absence of cirrhosis. The primary endpoint was the percentage of patients with HCV RNA <25 IU/ml 12 weeks after therapy (SVR12). RESULTS Among all patients, 52% had received prior HCV treatment and 17% had cirrhosis at baseline. SVR12 rates were 90% (46/51) with 24 weeks and 77% (40/52) with 12 weeks of sofosbuvir and ribavirin therapy. Patients with cirrhosis at baseline had lower rates of SVR12 (63% 12 weeks, 78% 24 weeks) than those without cirrhosis (80% 12 weeks, 93% 24 weeks). The most common adverse events were fatigue, headache, insomnia, and anemia. Two patients experienced serious adverse events (cerebral ischemia, dyspnea). No adverse events resulted in treatment discontinuation. CONCLUSION Sofosbuvir plus ribavirin for 12 or 24 weeks is effective in treating both treatment-naïve and treatment-experienced Egyptian patients with genotype 4 HCV.

Towards realistic estimates of HCV incidence in Egypt

Accurate incidence estimates are essential for quantifying hepatitis C virus (HCV) epidemic dynamics and monitoring the effectiveness of public health programmes, as well as for predicting future burden of disease and planning patient care. In Egypt, the country with the largest HCV epidemic worldwide, two modelling studies have estimated age‐specific incidence rates that, applied to the age pyramid, would correspond to more than 500 000 Egyptians getting infected annually. This is in contrast to figures of the Egyptian Ministry of Health and Population that estimates new infections to be approximately 100 000 per year. We performed new analyses of nationwide data to examine the modelling assumptions that led to these estimates. Thus, we found that the key assumption of these models of a stationary epidemic is invalid. We propose an alternate approach to estimating incidence based on analysing cohort data; we find that the number of annual new infections is <150 000.

Ombitasvir, paritaprevir, and ritonavir plus ribavirin for chronic hepatitis C virus genotype 4 infection in Egyptian patients with or without compensated cirrhosis (AGATE-II): a multicentre, phase 3, partly randomised open-label trial

BACKGROUND In Egypt, chronic hepatitis C virus (HCV) infection occurs in around 10% of the population (about 8 million individuals), and is a leading cause of liver cirrhosis, hepatocellular carcinoma, and mortality. Although HCV genotype 4 constitutes about 20% of HCV infections worldwide, the prevalence in Egypt is more than 90%. We assessed the efficacy and safety of the two direct-acting antiviral drugs ombitasvir, an NS5A inhibitor, and paritaprevir, an NS3/4A protease inhibitor dosed with ritonavir, plus ribavirin in treatment of chronic HCV infection in Egypt. METHODS AGATE-II was a phase 3, open-label, partly randomised trial in patients with chronic HCV genotype 4 infection recruited from five academic and hepatology centres in Egypt. Patients were HCV treatment-naive or treatment-experienced with interferon-based regimens. Eligible patients were aged 18 years or older, and had been chronically infected with HCV genotype 4 for at least 6 months with a plasma HCV RNA concentration of more than 1000 IU/mL at screening. Patients without cirrhosis were assigned to receive 12 weeks of 25 mg ombitasvir, 150 mg paritaprevir, and 100 mg ritonavir orally once daily plus weight-based ribavirin. Patients with compensated cirrhosis were randomly assigned (1:1) to receive the same treatment for either 12 weeks or 24 weeks. Randomisation was stratified by previous pegylated interferon and ribavirin treatment experience using a web-based interactive response technology system and computer-generated schedules prepared by personnel from the funders statistics department. Investigators were masked to randomisation schedules and were informed of each patients assigned treatment by the interactive response technology system immediately after allocation. The primary endpoint was the proportion of patients with a sustained virological response (HCV RNA <15 IU/mL) 12 weeks after the last dose of study drug (SVR12). All patients who received at least one dose of study drugs were included in the primary and safety analysis. This study is registered with ClinicalTrials.gov, number NCT02247401. FINDINGS Between Nov 4, 2014, and March 16, 2015, we screened 182 patients with HCV infection, of whom 160 were eligible for inclusion; 100 patients were assessed as not having cirrhosis and were given 12 weeks of treatment, and 60 patients assessed as having cirrhosis were randomly assigned to the 12-week treatment group (n=31) or the 24-week treatment group (n=29). 94 (94%; 95% CI 88-97) of 100 patients in the without cirrhosis group, 30 (97%; 84-99) of 31 patients in the cirrhosis 12-week treatment group, and 27 (93%; 78-98) of 29 patients in the cirrhosis 24-week treatment group achieved SVR12. The most common adverse events in patients without cirrhosis were headache (41 [41%]) and fatigue (35 [35%]). Fatigue occurred in nine (29%) patients in the cirrhosis 12-week treatment group and 11 (38%) patients in the cirrhosis 24-week treatment group, and headache occurred in nine (29%) patients in the cirrhosis 12-week treatment group and in 10 (35%) patients in the cirrhosis 24-week treatment group. Adverse events were predominantly mild or moderate in severity, and laboratory abnormalities were not clinically meaningful. No patients discontinued treatment because of an adverse event. One serious adverse event in the group without cirrhosis was attributed to study drugs by the investigators; the patient had deep venous thrombosis. INTERPRETATION Ombitasvir, paritaprevir, and ritonavir plus ribavirin for 12 weeks achieved SVR12 in a high proportion of patients and was well tolerated in Egyptian patients with HCV genotype 4 infection with or without compensated cirrhosis. Extension of treatment to 24 weeks in patients with cirrhosis did not improve the proportion of patients achieving SVR12. A shorter duration regimen could be useful to address the significant burden of HCV genotype 4 infection in patients with compensated cirrhosis. FUNDING AbbVie.

Sofosbuvir‐based treatment regimens: real life results of 14 409 chronic HCV genotype 4 patients in Egypt

Chronic hepatitis C virus infection is one of the most important health problems in Egypt. The Ministry of Healths National Treatment Programme introduced sofosbuvir‐based therapy in October 2014.

National treatment programme of hepatitis C in Egypt: Hepatitis C virus model of care

Hepatitis C virus (HCV) infection is a major health problem in Egypt as the nation bears the highest prevalence rate worldwide. This necessitated establishing a novel model of care (MOC) to contain the epidemic, deliver patient care and ensure global treatment access. In this review, we describe the process of development of the Egyptian model and future strategies for sustainability. Although the magnitude of the HCV problem was known for many years, the HCV MOC only came into being in 2006 with the establishment of the National Committee for Control of Viral Hepatitis (NCCVH) to set up and implement a national control strategy for the disease and other causes of viral hepatitis. The strategy outlines best practices for patient care delivery by applying a set of service principles through identified clinical streams and patient flow continuums. The Egyptian national viral hepatitis treatment programme is considered one of the most successful and effective public health programmes. To date, more than one million patients were evaluated and more than 850 000 received treatment under the umbrella of the programme since 2006. The NCCVH has been successful in establishing a strong infrastructure for controlling viral hepatitis in Egypt. It established a nationwide network of digitally connected viral hepatitis‐specialized treatment centres covering the country map to enhance treatment access. Practice guidelines suiting local circumstances were issued and regularly updated and are applied in all affiliated centres. This review illustrates the model and the successful Egyptian experience. It sets an exemplar for states, organizations and policy‐makers setting up programmes for care and management of people with hepatitis C.

Effect of preventive and curative interventions on hepatitis C virus transmission in Egypt (ANRS 1211): a modelling study

BACKGROUND Most hepatitis C virus (HCV) transmission in Egypt is related to medical injections and procedures. To control the spread of HCV, the Egyptian Ministry of Health initiated awareness and education campaigns, strengthened infection control in health-care facilities, and subsidised anti-HCV treatment. We aimed to investigate the effect of these interventions on the spread of HCV by mathematical modelling. METHODS We developed a mathematical model of HCV transmission in Zawyat Razin, a typical rural community. Our model assumes that each individual has two distinct types of medical procedures: injections and more invasive medical procedures. To quantify the severity of the spread of HCV, we used the notion of the basic reproduction number R0, a standard threshold parameter signalling whether transmission of an infectious disease is self-sustained and maintains an epidemic. If R0 is greater than 1, HCV is self-sustained; if R0 is 1 or less, HCV transmission is not self-sustained. We investigated whether heterogeneity in the rate of injection or invasive medical procedures is the determinant factor for HCV transmission and whether most iatrogenic transmission is caused by a small group of individuals who receive health-care interventions frequently. We then assessed whether interventions targeted at this group could reduce the spread of HCV. FINDINGS The R0 of the spread of HCV without treatment was 3·54 (95% CI 1·28-6·18), suggesting a self-sustained spread. Furthermore, the present national treatment programme only decreased R0 from 3·54 to 3·03 (95% CI 1·10-5·25). Individuals with high rates of medical injections seem to be responsible for the spread of HCV in Egypt; the R0 of the spread of HCV without treatment would be 0·64 (95% CI 0·41-0·93) if everybody followed the average behaviour. The effect of treatment on HCV transmission is greatly enhanced if treatment is provided a mean of 2·5 years (95% CI 0·1-9·2) after chronic infection and with drug regimens with more than 80% efficacy. With these treatment parameters, preventive and curative interventions targeting individuals with high rates of medical injections might decrease R0 below 1 for treatment coverage lower than 5%. INTERPRETATION Targeting preventive and curative interventions to individuals with high rates of medical injections in Egypt would result in a greater reduction the spread of HCV than would untargeted allocation. Such an approach might prove beneficial in other resource-limited countries with health-care-driven epidemics. FUNDING Agence Nationale de Recherche sur le SIDA et les Hépatites Virales (ANRS 1211), ANR grant Labex Integrative Biology of Emerging Infectious Diseases.

Effectiveness and Cost-effectiveness of Immediate Versus Delayed Treatment of Hepatitis C Virus–Infected Patients in a Country With Limited Resources: The Case of Egypt

BACKGROUND Because of logistical and economic issues, in Egypt, as in other resource-limited settings, decision makers should determine for which patients hepatitis C virus (HCV) treatment should be prioritized. We assessed the effectiveness and cost-effectiveness of different treatment initiation strategies. METHODS Using a Markov model, we simulated HCV disease in chronically infected patients in Egypt, to compare lifetime costs, quality-adjusted life expectancy (QALE), and the incremental cost-effectiveness ratio (ICER) of different treatment initiation strategies. RESULTS Immediate treatment of patients at stages F1/F2/F3 was less expensive and more effective than delaying treatment until more severe stages or not providing treatment (in patients diagnosed at F1: QALE = 18.32 years if treatment at F1 vs 18.22 if treatment at F2). Treatment of F4 patients was more effective than no treatment at all (QALE = 10.33 years vs 8.77 years) and was cost-effective (ICER =

MxA expression as marker for assessing the therapeutic response in HCV genotype 4 Egyptian patients.

1915/quality-adjusted life-year [QALY]). When considering that affordable triple therapies, including new direct-acting antivirals, will be available starting in 2016, delaying treatment until stage F2, then treating all patients regardless of their disease stage after 2016, was found to be cost-effective (ICER =