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Global View: Egypt in Focus

In many parts of the world today, the fast-moving clinical environment that is HCV is a reason for hope. However, certain countries and regions still face more significant obstacles than others in dealing with the disease. It is with this in mind that HCV Next is undertaking the Global View Series, a three-part investigation of HCV in places that face unique and appreciable hurdles. In this installment, we look at Egypt.

By most metrics, Egypt has the most overwhelming epidemic of HCV of any country in the world. The overall prevalence rate is estimated to be 15% — a staggering number — with as many as 500,000 new infections each year. Prevalence among pregnant women may also approach 15% by some estimates, which ensures that a significant proportion of the population is at risk even before birth. Infection rates among other high-risk groups such as individuals on dialysis or those who have received transfusions can climb well over 50%. Moreover, Egyptians living outside of the country, particularly in the U.S., are confronted with a whole different set of concerns as they attempt to manage their infection.

Clinically speaking, Gamal Shiha, MD, professor of internal medicine and head of the Liver and GI Unit in the Faculty of Medicine at Mansoura University in Egypt, noted that genotype 4 disease comprises more than 90% of the patient population in Egypt. Although early results indicate that novel direct-acting antivirals will be effective even in this challenging genotype, there is uncertainty about the future of these therapies in the country. It remains to be seen whether the headline-grabbing deal the Egyptian government made with Gilead for the price of sofosbuvir (Sovaldi, Gilead Sciences) will happen again with other compounds and combinations, and exactly how effective those combinations will be. Cost is a factor. The sheer numbers are a factor. Targeting modes of transmission is a factor.

Let’s Make a Deal

No conversation of HCV in Egypt can begin without a discussion of the landmark deal struck with Gilead. Imam Waked, MD, professor of medicine in the hepatology department at the National Liver Institute in Egypt, laid out the details in an interview with HCV Next.

“We reached a price of $300 per box, compared to the then price of $28,000 per box in the U.S.,” he said. “This price was to provide the drug to patients treated on the expense of the Ministry of Health and Health Insurance Organization in their specialized hospitals and clinics, with a different price — $2,000 per box — for general pharmacies for cash paying patients. This is working out fine, better than anticipated. Gilead has been very cooperative with the supply, and the chain is going very smoothly in most places.”

“This was a breakthrough, which makes it possible to deliver the therapy with a reasonable cost,” Shiha added.

Patients who can tolerate interferon receive sofosbuvir with peginterferon and ribavirin for 12 weeks, while those who cannot take interferon receive sofosbuvir plus ribavirin for 24 weeks. “Currently, 66% are taking sofosbuvir and ribavirin without interferon,” Waked said.

Egyptians living abroad are guaranteed the same rights to free treatment or treatment at the discounted prices as those in the country, according to Waked. However, they must come to Egypt for treatment to receive the discounted rate or else pay local prices where they live. “The cost is much higher in other Arab countries and Europe,” Waked said. “To receive the Gilead or Johnson & Johnson products, they have to come every month for the refill. Otherwise, they can use the generic sofosbuvir and take the full treatment supply with them.”

Staggering Numbers

Once the plan took shape, Waked said that the next obstacle was prioritizing patients for treatment. “The Ministry of Health’s National Committee for Control of Viral Hepatitis decided to start treating patients who had advanced fibrosis/cirrhosis — F3 and compensated F4 — and created a web portal where patients registered to be evaluated for treatment,” he said.

When news of the deal broke, 1.1 million Egyptians registered to be evaluated for treatment. Of nearly 350,000 patients treated with interferon over the last 5 years, approximately 200,000 did not respond, according to Waked.

“The main challenge currently is the overwhelming numbers,” Waked said. He explained that patients in the program who are eligible for free treatment are being evaluated, treated and followed up in 30 centers spread geographically around the country, but that the numbers are beyond the capacity of the centers.

“Patients are currently waiting a few months for their appointment, and then a month or two for the approval for free treatment,” he said. “We need to speed up the process, so that patients can have access to treatment faster, hopefully within a week or two at most, and we need to increase the number and personnel of the treatment centers.”

“The bureaucracy and the time lag between asking for therapy and getting it are the biggest obstacles,” Shiha said.

Despite these obstacles, nearly 350,000 patients have been evaluated, of whom 150,000 have been selected for treatment in 2015. Therapy has been initiated in 120,000 of those patients. “Initially, starting in October 2014, we were including 2,000 patients a month, and now we are including 10,000 to 12,000 new patients a month,” Waked said. “We are increasing treatment centers, and are hoping to reach 15,000 new patients a month before year end. Our plan is to treat at least 350,000 patients a year.”

“The numbers who have reached 3 months after the end of therapy for sofosbuvir, peginterferon and ribavirin treatment are still small, but are increasing, and we are currently analyzing our [sustained virologic response] rates for these patients,” Waked said. As expected, response rates are well above 90%. “We will have more data over the next few months, and our first 10,000 patients’ results will be available by September.”

In the meantime, studies like the one conducted by Shelbaya and colleagues deal with the financial impact of various treatment approaches in Egypt. They used disease severity at baseline as a key factor in creating the model for intervention strategy. They modeled outcomes for treating 8% of the patient population (450,000 viremic cases per year) vs. treating 5% or 1%. Results indicated that the disease burden would be reduced from 5.5 million patients to 2.5 million to 1 million cases in the 1%, 5% and 8% treatment rate models, respectively. By 2030, liver-associated mortality would decrease from 41,000 to 24,000 to 14,000 in the 1%, 5% and 8% scenarios, respectively.

In the first year of treating 8% of patients, the cost would be $1.3 billion. However, that figure would be reduced to $580 million by 2030 with continued treatment of 8% of patients.

The researchers concluded that treating this proportion of patients would be costly in short-term, but manageable by 2030 as the number of patients decreased.

However, vertical transmission is a problem that must be dealt with if HCV is to be eradicated in Egypt. Benova and colleagues estimated vertical transmission rates using data from the 2008 birth cohort. Results demonstrated that between 3,080 and 5,167 vertical transmissions occurred in that year. Vertical transmission may account for as many as half of incident HCV infections among children younger than 5 years. “The absolute number of vertical transmissions and the young age at infection highlight a public health concern,” they concluded.

The Future of Other DAAs

The only other DAA that is currently available is simeprevir (Olysio, Janssen), at the negotiated price of $250 per box, according to Waked. “We are starting to use 12 weeks of simeprevir and sofosbuvir with or without ribavirin for 12 weeks in the program,” he said, explaining that this will replace 24 weeks of sofosbuvir and ribavirin, as the 12-week regimen is cheaper and of shorter duration. “Only a few thousand patients have started simeprevir-sofosbuvir. Widespread use started in June. We are anticipating including 5,000 to 8,000 patients a month.”

Ledipasvir/sofosbuvir (Harvoni, Gilead Sciences) and the 2D regimen (25 mg of ombitasvir, 150 mg of paritaprevir and 100 mg of ritonavir every day for 12 weeks) are in the registration process, according to Shiha. “They are expected to be on the market before the end of this year,” he said. Waked said the Ministry of Health recently came to an agreement with the both manufacturers for a price of $400 for 1 month’s supply.

Daclatasvir (Daklinza, Bristol-Myers Squibb) is in the final process of registration and may be available within months at a price of $170 for 1 month’s supply, according to Waked.

“They are all negotiating preferential price with the Ministry of Health,” Waked said.

Genotype 4 Disease

Much has been written about the prevalence and challenges of genotype 4 disease in Egypt, including an earlier piece in HCV Next. There is hope in the clinical community that genotype 4 can be controlled as well as other genotypes.

“Response rates in genotype 4 will be as good as those we’ve seen in genotype 1 patients, and we are hoping for an 85% or above real-life SVR results,” Waked said.

However, studies of genotype 4 are ongoing. Elrazek and colleagues mined data for 1,018 patients with genotype 4 disease in Egypt. They evaluated patients for cirrhosis and esophageal varices. The cohort was more than 60% men. Patients with cirrhosis comprised 62.4% of the cohort, while 47.4% of those with cirrhosis demonstrated degrees of large esophageal varices. Esophageal wall thickness greater than 6.5 mm as measured by conventional ultrasound independently predicted esophageal varices, according to the results.

“Egyptians with HCV-4 infection are at a higher risk to develop cirrhotic liver and esophageal varices,” the researchers concluded. “Data mining, a new analytic technique in [the] medical field, shed light in this study on the clinical importance of esophageal wall thickness as a useful predictor for risky esophageal varices using decision tree algorithm.”

“Patients with advanced or decompensated cirrhosis — child B and C — is one of our biggest unmet needs,” Waked said.

Risk Factors

It is no secret that the Egyptian government’s comprehensive effort to deal with schistosomiasis in the latter half of the 20th century lies at the root of the HCV epidemic in the country. However, researchers continue to investigate the myriad ways in which Egyptians acquire the infection.

Metwally and colleagues aimed to investigate behaviors among Egyptians that put them at risk for HCV. Data for January 2011 through January 2012 underwent analysis. Univariable results indicated that invasive medical procedures carried the most significant association with HCV infection, followed by wound stitches, illiteracy and marriage. Women who delivered babies at home with a traditional birth attendant were at a nearly threefold risk for HCV compared with those who delivered at a hospital. Veiled women who shared scarf pins with someone in their household also were at risk. Shaving at barbershops carried a two fold risk for men. Sharing a loofah for personal cleaning and sharing toothpaste among family members also were associated with increased HCV incidence.

“Increasing risk of HCV infection in Egypt reinforces the need for strict implementation of effective HCV prevention programs according to the prevailing risk behaviors,” the researchers concluded.

Similarly, Mohsen and colleagues reviewed surveillance data for 2002 through 2012 to determine risk factors for HCV acquisition. Hospital admission carried a fourfold risk (OR = 4.2; 95% CI, 1.7-10.5) for acute HCV infection among non-drug users. Along the same lines, admission to a surgery unit, receipt of sutures, IV injections and IV infusions also were linked to HCV incidence.

For drug users, multiple sexual relations (OR = 4; 95% CI, 1.1-14.7), IV drug use (OR = 3.9; 95% CI, 1.2-13) and shaving at barbershops (OR = 8.7; 95% CI, 2.4-31.4) were the most significant risk factors for HCV. Illiteracy and marriage were significantly associated with HCV among drug users and non-drug users alike.

Jonathan Fenkel, MD, director of the Jefferson Hepatitis C Center and associate medical director of liver transplantation at Thomas Jefferson University Hospital, noted that the large Coptic Christian population in Egypt is at risk due to the tattoos they receive as part of their faith. “Unlike in other places, injection drug use is not the primary risk factor for HCV in Egypt,” he said. “The attempt to control bilharzia is most significant, but we also see a lot of Coptic Christians at risk.”

Away from Egypt

Fenkel has done considerable work with patients in the Philadelphia region, as has Sandra Khalil, PE, MBA, president and founder of CrossLink Medical Resources. Both suggested that complications pertaining to access to care are the most significant obstacles faced by Egyptians with HCV living in Philadelphia. It would not be unreasonable to assume that those living in other parts of the U.S. face similar challenges.

“We see a lot of care coordination and transportation issues,” Khalil said. “But it is more than that. They don’t understand the insurance system. There is difficulty paying for doctor’s visits. They are getting some help from assistance programs, but now they are waiting for confirmation to come through, and they don’t understand why they’re waiting. Until recently, with the approval of the new drug, they didn’t understand the discussion with their doctor on whether to treat now as opposed to treat later due to waiting for FDA approval. They don’t understand the FDA approval system and why it takes so long. This is a common struggle among immigrants.”

Fenkel, through Khalil, has tried to work with the two main Coptic Christian churches in the Philadelphia region. “The older generation often doesn’t speak English, which of course makes it difficult for them,” he said. “They have little access to public health, so the church itself may be a place where health care could be delivered for hepatitis C. We hope to apply for a grant to help this community have better access to hepatitis C diagnostic testing and linkage to treatment.”

Another problem, according to Fenkel, is connecting the community to the proper care.

“Many of the first generation Egyptian immigrants lack financial stability and this may lead to more problems with access to specialists, as there are logistical considerations with regard to transportation, copays, and diagnostic testing,” Fenkel said.

Khalil agreed. “Money is usually a factor,” she said. “If there was a way to get doctors’ visits and diagnostics paid for, we’d do it, but many of them are concerned about paying for it and won’t engage.”

Khalil added that there are more clinical challenges, as well, and highlighted the two-step screening process as an example of how one complication can build on another. “Part of the education is to notify them that a positive antibody result means they need another test to confirm an active virus,” she said. “However, we also tell them that they might have had a prior case that had been treated, and therefore it is not necessarily an active virus. When we translate that, it immediately sets off a denial. They might deny it because they think they don’t have the disease, or maybe it is because they don’t have the money.”

The good news is that there are people like Khalil and Fenkel working to educate patients and minimize the obstacles faced by Egyptians living in the U.S. “If people want the help, we are ready to help them,” Khalil said.

• References:
• Shelbaya A, et al. Abstract #P1265. Presented at: International Liver Congress; April 22-26, 2015; Vienna.
• Mohsen A, et al. Trop Med Int Health. 2015;doi:10.1111/tmi.12410.
• Metwally A, et al. Iran J Public Health. 2014;43:1385-1394.
• Kamal SM, et al. Aliment Pharmacol Ther. 2015 doi:10.1111/apt.13261.
• Elrazek A, et al. Medicine (Baltimore). 2014;doi:10.1097/MD.0000000000000204.
• Doss W, et al. J Hepatol. 2015;doi:10.1016/j.jhep.2015.04.023.
• Benova L, et al. Hepatology. 2015;doi:10.1002/hep.27596.

• For more information:
• Jonathan Fenkel, MD, can be reached at 132 S. 10th St., Suite 480, Philadelphia, PA 19107; email: Jonathan.Fenkel@jefferson.edu.
• Sandra Khalil, PE, MBA, can be reached at P.O. Box 202, West Point, PA 19486; email: sck5000@gmail.com.
• Gamal Shiha, MD, can be reached at Mansoura–Sherbin-Damietta highway, Dakahliah, Egypt; email: g_shiha@hotmail.com.
• Imam Waked, MD, can be reached at the National Liver Institute, Menoufia University, Gamal Abdel Nasser, Menoufia University, Shebin El Kom, Menoufia, Egypt; email: imam@waked.org.

Disclosures: Fenkel reports associations with Abbvie, Bristol-Myers Squibb, Gilead and Janssen. Khalil reports no relevant financial disclosures. Shiha reports no relevant financial disclosures. Waked reports being a speaker, investigator and/or being on the advisory board for Abbvie, Bristol-Myers Squibb, Gilead Sciences, Janssen, Merck and Roche.