Abstract
Background
Although Egypt was the country with the highest prevalence of hepatitis C in the world, the availability of sofosbuvir based therapies enabled Egypt to be the first country to eliminate hepatitis C and cure more than 4 million chronically infected patients.
Purpose
This is a small tribute to John Martin.
Methodology and conclusion
Here I present a summary of the HCV problem in Egypt, and how we, through Gilead's Access program under his leadership, were able to eliminate the disease.
Background
Till 2008, Egypt had the highest burden of hepatitis C virus (HCV) infection, where about 15% of the population between the ages of 15 and 59 were seropositive and 10% chronically infected (around 6 million persons viremic) [1], with HCV-genotype 4 the main genotype [2]. HCV transmission was ongoing, and incidence rates in 2010 had been estimated at 2.4 per 1000 person years (close to 165,000 new infections annually at the time) [3].
To address the problem of HCV infection in Egypt, the Ministry of Health (MoH) in 2006 established the National Committee for the Control of Viral Hepatitis (NCCVH): a volunteer board of experts (hepatologists/gastroenterologists, infectious disease specialists and epidemiologists) to set the necessary plans for management of viral hepatitis in the country [4]. The NCCVH was mandated to obtain quality data on HCV prevalence and transmission (it included HCV serology and viremia in the 2008 and 2015 DHS surveys), set treatment guidelines, decide on medications, negotiate prices, and set prevention and infection control recommendations. All NCCVH’s recommendations and guidelines were adopted by the MoH, obliging to all MoH hospitals and centers all over the country, and the recommendations and guidelines became accepted and adopted by all insurers.
During the interferon (IFN) treatment era, the NCCVH established specialized IFN treatment centers, where initially patients were managed by trained hepatologists and gastroenterologists experienced in IFN therapy and its complications. This started with one center in 2007 and reached 26 centers by 2014.
Before the advent of direct acting anti-viral agents (DAAs), sustained virologic response (SVR) rates for patients treated with pegylated interferon (PEG) and ribavirin (RBV) therapy decreased with increasing fibrosis scores. Real-life data showed response rates of 41.5% for patients without bridging fibrosis or cirrhosis on liver biopsy versus 27% for those who had bridging fibrosis or cirrhosis [5]. PEG-RBV therapy was associated with several predictors of response/non-response, including baseline viral load [6], IL-28B genotype [7], ethnicity, weight, and insulin resistance [8]. In addition, side effects of PEG-IFN and RBV were a major problem, and the list of contraindications for HCV therapy was long including decompensated cirrhosis [9]. With the low SVR rate of patients with cirrhosis treated with PEG-RBV, the national treatment program in Egypt had decided to limit treatment on the expense of the state to patients with biopsy proven F2-F3 fibrosis. Patients with no or F1 fibrosis were deferred to be treated when better treatment options became available, and patients with cirrhosis were not treated. With a liver biopsy mandatory to decide on patient selection for therapy, we were performing more than 80,000 liver biopsies annually, and treating 50,000 patients with PEG-RBV, with many patients preferring not to come forward for treatment because of the mandatory liver biopsy, because of the side effects of therapy, and because of the low response rate. Hence, alternative treatments were needed.
The introduction of boceprevir [10] and telaprevir [11] as the first directly acting protease inhibitors for treatment of HCV-genotype-1 announced the beginning a new era in the management of HCV infection. However, they were not effective in HCV-genotype-4-infected patients. Nevertheless, they heralded the development of other classes of DAAs, many of which proved to be effective for genotype 4.
The John Martin and Gilead impact
The discovery of the nucleotide polymerase inhibitor sofosbuvir (SOF) (initially PSI-7977) by Pharmasset (later to be acquired by Gilead Sciences in 2011 for US$ 11 billion) [12] heralded a new era for the treatment of chronic hepatitis C and especially HCV-genotype-4 [13].
Favorable results of the use of sofosbuvir in patients infected with HCV-genotype-4 started to appear from the US in a study that included patients of Egyptian origin living in the US [14], and then from trials conducted in Egypt [15]. The efficacy of using SOF with PEG-RBV or with RBV in HCV-genotype-4 was established, and its introduction into the national treatment program in Egypt became a necessity.
Negotiations with Gilead started in 2013 and took several months, including legal consultations on both sides and developing an “anti-diversion plan” if the drug was to be priced in Egypt at a lower price than in other countries. This aimed to prevent diverting the drug to other markets at the lower price in Egypt. By March 2014, negotiations on administrative and legal issues had reached the final stages, and the final price was to be decided.
In a meeting in Cairo with the Gilead Access Program management in March 2014, we were hoping to reach a price that was affordable to the national treatment program. The Access Program management team indicated that they had decided a three-tier global pricing system for SOF depending on a country’s per-capita gross domestic product (GDP), with Egypt categorized as a middle-income country (with the price set for middle-income countries being US$ 5000 for one bottle of 28 tablets or a 4-week supply). We demonstrated the magnitude of the HCV problem in Egypt and that regarding HCV infection and prevalence, Egypt should be categorized as the most deserving country of the lowest price: the magnitude of our HCV problem was much higher than that of all low-income countries. In addition, the set-up of the Egyptian national treatment program infrastructure as a tightly supervised system preventing diversion of medication outside the treatment centers or to other countries, and the availability of outcome data in a national database helped convince them that the drug will only be given to Egyptian patients on the expense of the state according to tight guidelines and that all treatment outcomes will be known and recorded. They deliberated privately for a few minutes then came back with the price of US$ 300 for a bottle of 28 pills or 4-week supply (a reduction from US$ 28,000 in the US market), which was the price set for low-income countries in sub-Saharan Africa. What was impressive is that the Access Program negotiating team and management were empowered to take on-the-spot decisions that involved several hundred million US dollars without having to go back to company management [16]. This price and agreement set the stage for the largest treatment program in the world, and the elimination of hepatitis C from the country with the highest disease burden.
The memorandum of understanding was signed with the minister of health, and the first supply of sofosbuvir was a batch of 50,000 bottles to be available for patients in September.
What made the treatment program in Egypt more affordable is that Gilead set no limitations on introduction of other DAAs to the program or their registration in Egypt. The Gilead deal set the bar for the cost of introducing other DAAs to Egypt. Similar negotiations with the other DAA manufacturers resulted in equivalent reduction of prices of their medications for the national program: simeprevir and daclatasvir at US$ 250 for a month’s supply each, paritaprevir-ombitasvir at US$ 300 for a month’s supply and sofosbuvir-ledipasvir for the equivalent of US$ 400 for a month’s supply. The prices were set in local currency equivalent, and with the devaluation of local currency in 2016–2017, the prices in US$ decreased by 50%.
Gilead also agreed to forgo IP protection for sofosbuvir which allowed the MoH in 2016 to grant several local pharmaceutical companies approvals to manufacture SOF, DCV, and SOF-LDV. In addition, Gilead provided voluntary licensing to two local pharmaceutical companies to produce sofosbuvir at prices equivalent to the locally produced generics. The cost of a 12-week treatment with SOF+DCV for the national program came down from US$ 900 to less than US$ 300 in 2016, and to less than US$ 100 in 2018.
The DAA treatment program
The National DAA treatment program started in October 2014 [17]. More than 700,000 patients with known diagnosis (>200,000 IFN treatment failures and 300,000 deferred treatment for presence of cirrhosis or no fibrosis, and a few hundred thousand who had opted not to receive interferon because of the adverse events and low efficacy) were waiting eagerly for the start of the DAA treatment program. The administrative problem and lining up these patients to be evaluated and start treatment was enormous and needed novel solutions.
The NCCVH set up a web-based registration and appointment management system, where patients would go online, register their names, national ID number and residence and they would be assigned an appointment at the first time available in the closest center to their residence. Daily workload and appointments were set according to each center’s capacity. Patients would receive the appointment online and by text messages to their mobile phones. On the first day of the launch of the portal, 103,000 patients registered to receive treatment, by the end of the first month more than 500,000 had registered and by the end of November 2016 around 1,500,000 patients had registered and received appointments through the web-based system.
Patients were evaluated for treatment in centers managed by the NCCVH or the national Health Insurance Organization (HIO) where they had a clinical examination, blood counts, biochemical tests, viral load test, and an abdominal ultrasound. Initially, the supply was limited to 50,000 patients in the first three months. At that time, we had to prioritize treatment to patients with advanced fibrosis/cirrhosis and decided to limit treatment to patients with F2-F4 fibrosis provided that patients with cirrhosis were compensated. We initially mandated a liver-stiffness measurement by Fibroscan to evaluate fibrosis and select patients for treatment. With the initial huge flow of patients and the limited availability of Fibroscan machines in the country, patients had to wait several weeks for a Fibroscan appointment (and in some areas several months), and it became apparent that this was a major bottle neck in the program. We changed the fibrosis evaluation method to use FIB-4 as a measure to evaluate fibrosis, where patients with FIB-4 values >3.25 were considered to have cirrhosis, and patients with FIB-4 <1.45 were considered not to have significant fibrosis and were deferred till availability of more medications.
Treatment-naive patients without cirrhosis were treated with SOF-PEG-RBV for 12 weeks, and previous PEG-RBV treatment failures and patients with cirrhosis were treated with SOF-RBV for 24 weeks. Treatment protocols were sequentially modified to accommodate availability of new medications and to adapt to administrative difficulties as they appeared. Several changes were made during the first 18 months of the program, to include more patients, to change treatment regimens according to results, and to include newer drugs as they became available. Cost was always a factor in the decision-making process, while selecting regimens suitable to the unique situation of HCV-GT-4 in the Egyptian population was crucial [18]. To ease patient flow, the number of treatment centers were increased and reached more than 150 evaluation and treatment centers managed by both the NCCVH and the National Health Insurance Organization. By mid 2016, with the availability of more supply of medication and more treatment centers, all patients were evaluated and started treatment within the same week of registering on the portal.
Sofosbuvir remained the only available DAA in Egypt till March 2015. During this time, more than 150,000 patients had started treatment. Simeprevir was registered and became available in March 2015, and 12 weeks of SOF-SMV combination replaced SOF-PEG-RBV for patients without cirrhosis, and SOF-RBV for 24 weeks remained the treatment for patients with cirrhosis till daclatasvir (DCV) became registered and available. At that time, the cost of DCV was much less than SMV, and the available supply of SMV was reserved for patients with renal impairment to be treated with SMV-DCV.
After treating more than 400,000 in 2015, and with the availability of locally produced generic sofosbuvir and DCV in early 2016, medication supply allowed ending prioritization and treating all patients with HCV irrespective of the presence or absence of fibrosis and its stage. FIB-4 remained the method for evaluating fibrosis, and the treatment guidelines were simplified to allow task-shifting to general gastroenterologists and internal medicine specialists. Patients were categorized as “easy to treat” (treatment-naive patients without cirrhosis), who were treated with SOFD-CV for 12 weeks, and “difficult to treat” (previous treatment failures or patients with FIB-4 >3.25), who were treated with SOF-DCV-RBV for 12 weeks (or SOF-DCV for 24 weeks if they were RBV intolerant).
Almost all patients were treated with different combinations of SOF-containing regimens (only a small minority (3%) with paritaprevir-ritonavir-ombitasvir (PrO), which was reserved mostly for patients with renal impairment). All DAA treatment failures were re-treated with an SOF-containing regimen (SOF-SMV-DCV or SOF-PrO with or without RBV). The real life sustained virologic response rates for treatment with SOF-containing regiments were 94% with SOF-PEG-RBV, 83% with SOF-RBV, 97% with SOF-SMV, and 98.5% with SOF-DCV [19].
By 2018, more than 2 million patients had started treatment. These were almost all those who were living with the diagnosis. The program started losing momentum, and the number of patients registering for treatment monthly decreased to less than 10,000 patients, much less than the necessary number to sustain the elimination targets which necessitated treating at least 350,000 patients per year [20].
Screening program
The availability of large supply of sofosbuvir and the lower prices reached in early 2018 (less than US$ 100 for a 12-week supply of SOF-DCV), allowed adopting a national screening program to screen all adults in the country who had not been treated for HCV previously, and treating all those who proved viremic in the shortest time possible [21]. Preparation for the national screening program started in July 2018, and it took three months for preparation, supplier negotiations, procurement, and training the screening teams. The screening method was changed to a rapid diagnostic test for HCV antibody, with immediate results at a low cost of US$ 0.56 per test. Seropositive patients were electronically linked to the nearest evaluation center where they had a clinical examination, lab tests, a PCR test for HCV-RNA (at a negotiated low cost of < US$ 5 per test), and an ultrasound examination. Viremic patients received 12 weeks SOF-DCV with or without RBV. The details of the screening program have been previously reported [21]. Over 7 months, of a target population of 62.5 million, 49.6 million persons were screened for HCV antibodies, 2.4 million seropositive persons were identified, and 1.6 million viremic patients were identified and treated, with SVR rates higher than 98%.
During the same time, a simultaneous screening program screened teenagers (between the ages of 12 and 18) in middle and high schools. They were screened in their schools if their parents signed a consent agreeing that their child be tested for HCV and treated if infected. Although screening was carried out in schools, to prevent stigmatization, the results were not known to the students or the school staff and were mailed to the parents, with an appointment in a health-insurance clinic for positive children to be evaluated and treated away from their schools. Of a target of 12 million teenagers, 7 million participated in screening, and 20,000 (0.3%) seropositive children were identified and evaluated. The SVR rate for treated children was 100%. This was the first teenage screening and treatment program for hepatitis C anywhere.
National outcome
With SOF-based therapy, Egypt managed to treat more than 4 million patients with hepatitis C with SVR rates above 95% [22]. We estimate that the current viremic prevalence has decreased from 6% of the population in 2015 (5 million patients) to less than 0.5% of the population in 2021 (less than 500,000 patients). Egypt has diagnosed more than 90% of the HCV-infected population, treated more than 90%, and cured more than 95%, thus achieving, through SOF-based treatments, all the WHO elimination targets. The benefit will continue over the years to come. A modeling study (in press) predicts that the SOF-based treatment program since 2014 and the national screening campaign in 2018–2019 will result in preventing 250,000 new infections between 2014 and 2030, averting more than 1 million DALYs, preventing close to 250,000 HCV-related mortalities and more than 150,000 new cases of HCC.
The incidence of HCV infection in the high prevalence area in the Nile Delta was previously estimated to be 6.1/1000 person years in 2005 [23] and 2.4/1000 person years in 2010 [3]. A study in 2018 (estimating the impact of the treatment program before the national screening campaign) found the incidence rate to be 0.37/1000 person years in the same geographical area, an overall 84.6% reduction in incidence [24]. The national screening and treatment campaign of 2018–2019 with identifying and treating 1.6 million more patients is projected to have decreased the incidence further to 0.07/1000 person years, or close to 7000 new cases a year, down from an estimated 150,000 new cases a year before the start of the SOF-based DAA program or more than 95% reduction in incidence.
John Martin and Gilead had a great impact on the HCV problem in Egypt. Through the availability and affordability of sofosbuvir, Egypt has been able to cure more than 4 million patients chronically infected with hepatitis C. The prevalence of viremic infection in the country decreased from 6% (5 million patients) in 2015 to an estimated 0.4% (400,000–500,000 patients) in 2021. The economic impact of the treatment program is also enormous. Despite the large cost of the treatment program since 2014 and the cost of the screening and treatment program in 2018–2019, the economic return is huge. At a cost of US$ 350 million for treatment between 2014 and 2018, and US$ 207 million for the screening and treatment campaign in 2018–2019, the total economic gain in both direct and indirect costs is calculated to be more than US$ 7 billion between 2020 and 2030, or each US dollar spent in the program will result in an economic gain of more than US$ 11 over the following 10 years.
John Martin in person
John Martin was very pleasant and personable. We met several times in Europe and in the US, and he came to Cairo for the 2015 “Hepatology on the Nile” meeting (Figure 1). He did not exhibit any appearances of luxury or of being the chairman of one of the most profitable multi-billion-dollar pharmaceutical companies at the time. He was a very modest and down-to-earth person. He did not go around in a luxury limo or with an entourage of companions or use a tour operator or tour guide. He went around town and to the museum and the pyramids with his partner unaccompanied in a regular taxi (which are mostly old run-down cars that many would find inappropriate). His and Gilead’s participation in allowing for the cure and elimination of hepatitis C in Egypt will always be remembered. John Martin during a visit to Egypt in 2015, with the Minister of Health (at the time) HE Professor Adel Adawy and Professor Wahid Doss, the chairman of the NCCVH, in an interview for national television.
