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HCV Genotype 4: A Global Challenge

Issue: May 2015

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A number of recent studies demonstrated that, when treated with direct-acting antivirals, there were comparable response rates in patients with hepatitis C virus genotype 4 as those reported for other genotypes. That is, upward of 95%. However, experts remain confounded by a host of obstacles that stand in the way of marginalizing — or eradicating — hepatitis C virus genotype 4.

The first is that genotype 4 disease affects very few North Americans but accounts for the majority of the burden in the Mediterranean and Middle East region, particularly in Egypt, the country with the highest prevalence of HCV. Because U.S.-based pharmaceutical companies have led the way in developing HCV drugs, they have not gathered sufficient numbers of patients to show definitive efficacy rates in this patient group. Moreover, creating intervention strategies in two hemispheres will require a coordinated international public health effort and must account for immigration patterns among those moving west to east and east to west.

Within the Mideast and African regions, wealthy countries like Saudi Arabia and the United Arab Emirates may have the resources to eliminate genotype 4 entirely, whereas more economically challenged states like Egypt or those in West Africa may be left at the mercy of high prices in the current marketplace.

Tarek Hassanein

For Tarek Hassanein, MD, professor of medicine at the School of Medicine at the University of California, San Diego, director of Southern California Liver Centers and director of Southern California Research Center, the current debate hinges on the FDA. He told HCV Next that genotype 4 disease responds to two-drug combinations like sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) and three-drug combinations like ombitasvir/paritaprevir/ritonavir with dasabuvir (Viekira Pak, AbbVie), but that those formulations are mostly left sidelined because they lack FDA approval for genotypes outside genotype 1.

“The FDA runs the show,” Hassanein said. “When they set the rules, the companies follow. Insurance companies tell me they can’t approve the use of these drugs, even though we know they work.”

In short, although many clinicians would consider off-label use of sofosbuvir/ledipasvir and ombitasvir/paritaprevir/ritonavir with dasabuvir in genotype 4 patients, this approach is cost-prohibitive for most of the estimated 20 million people worldwide with this disease.

But despite these concerns, preliminary findings indicate that genotype 4 could be manageable with current therapies.

SYNERGY, PEARL-I

In the SYNERGY trial, researchers assessed 21 patients with HCV genotype 4 from Washington, D.C. However, the majority of patients came from Cameroon, Egypt and Ethiopia originally. Patients were treated with 12 weeks of sofosbuvir/ledipasvir.

The overall sustained virologic response rate at 12 weeks was 95%. Treatment history or fibrosis status did not affect outcomes. The researchers observed normalized alanine aminotransferase in 75% of the cohort after 4 weeks of treatment. The adverse event profile was consistent with what is normally reported for this regimen.

“This is the first report of an interferon and ribavirin free therapy for patients with HCV GT4. Interim data suggests that this single-pill combination therapy may be an effective regimen for this patient population,” the researchers concluded.

Findings from the open-label phase 2 PEARL-I study of ombitasvir/paritaprevir/ritonavir with ribavirin demonstrated 100% SVR12 rates in 42 treatment-naive patients and 49 previous treatment failures with peginterferon and ribavirin who received the three-drug regimen plus ribavirin.

Among 44 treatment-naive patients who received ombitasvir/paritaprevir/ritonavir, but without ribavirin, 90.9% achieved SVR12.

No patients discontinued treatment due to adverse events, and the regimens were generally well tolerated. No virologic failures were reported.

Sanaa Kamal, MD, professor of medicine in the department of gastroenterology, hepatology and infectious diseases at the Ain Shams Faculty of Medicine in Cairo, put these findings in perspective. “Exciting news,” she said. “However, such results must be interpreted cautiously. Let’s look at the numbers. In SYNERGY and PEARL-1, only 21 and 86 [genotype 4] patients were enrolled. Thus, the conclusions derived from such studies may require careful consideration of the assumptions and inferences, given the small sample size.”

She added, “Currently, several trials are being conducted in Egypt to investigate the outcome of various DAA combinations on patients with chronic HCV genotype 4 to optimize therapies with high sustained virologic response, reasonable treatment period and minimal adverse events. Cost-effectiveness is an important issue given the huge numbers of patients treated. The results of such trials are important to standardize therapy of HCV genotype 4.”

Eric M. Yoshida, MD, professor of medicine and head of the division of gastroenterology of the University of British Columbia and the Vancouver General Hospital, painted a slightly different picture. “The numbers are small, but there is no reason why you can’t generalize to a larger population,” he said.

RESTORE & DAUPHINE

Moreno and colleagues conducted the single-arm RESTORE trial to evaluate efficacy and safety outcomes associated with simeprevir (Olysio, Janssen) administered with pegylated interferon alfa-2a/ribavirin in a cohort of 107 patients with chronic HCV genotype 4 disease. SVR12 was reported in 65.4% of the group. The rate was 82.9% among treatment-naive patients, whereas 86.4% of prior relapsers, 60% of prior partial responders and 40% of prior null responders reached SVR12. Twenty-four weeks of therapy yielded SVR12 rates of 93.5% of treatment-naive patients and 95% of those who had previously relapsed.

“Efficacy and safety of simeprevir 150 mg twice a day for 12 weeks with [pegylated interferon and ribavirin] in treatment-naive or experienced patients with chronic HCV [genotype 4] infection were in line with previous reports for HCV [genotype 1] infection,” the researchers concluded.

Everson and colleagues studied ritonavir-boosted danoprevir (Array BioPharma) with or without PEG-IFN and ribavirin for 12 or 24 weeks in a cohort of patients with genotype 4 disease. SVR rates at 24 weeks after the end of treatment were 100% in three of the danoprevir-containing arms and 87.5% in the other danoprevir arm. Although the response rate was 66.7% among patients receiving only PEG-IFN and ribavirin, the researchers concluded that the combination of danoprevir with pegylated interferon and ribavirin may be efficacious in genotype 4 disease.

Eric M. Yoshida

“We have seen again and again that these are miraculous treatments with few side effects,” Yoshida said. “I would expect similar results in any cohort of genotype 4 patients.”

Dealing with Egypt

No conversation about HCV genotype 4 is complete without discussion of the burden of disease in Egypt.

“In a country with the highest incidence and prevalence of HCV in the world where GENOTYPE 4 is the predominant genotype, the real-life situation is quite different from the standardized conditions of clinical trials,” Kamal said. “Given the subclinical presentation of acute HCV and absence of well-conducted nationwide surveillance and screening programs, many HCV cases are recognized in an advanced stage with cirrhosis. Although the interferon-free therapies seem promising, it is hard to tell how the vast majority of such a population will respond to therapy.”

Compliance may be an issue with novel therapies, given that many of them are self-administered oral formulations, according to Kamal. She added that comorbidities and coinfections are frequent in Egypt and influence therapy responses.

Hassanein built on this point. “We are dealing not only with the virus but with the disease state of the liver,” he said. “The comorbidities patients experience differ from one country to the next. Here in the United States, we might see more fatty liver and alcohol-induced liver disease. In Egypt, we see schistosomiasis and associated fibrosis. Even when we cure the HCV, we are left with the underlying liver disease.”

It is for this reason that Hassanein recommends treating patients with F2 or F3 fibrosis, and not waiting for patients to decompensate. “Cirrhotics in Egypt are not undergoing transplants,” he said. “So even if you cure the virus, people still succumb to consequences of advanced liver disease.”

But the difficulties do not stop in the clinic. “Currently, Egypt is facing enormous political, societal and economic challenges,” Kamal said. “Thus, rationing and prioritizing treatment is inevitable. However, this approach needs transparency and strict control to avoid disparities.”

Tracking Global Burden

More troublesome is the fact that the disease burden of genotype 4 in Egypt may extend beyond the Egyptian border. “Currently, genotype 4 represents 20% to 25% of HCV infections worldwide and is spreading beyond its strongholds in Africa and the Middle East toward Europe through migration and population movement. Thus, such a genotype deserves more trials and investigations,” Kamal said.

Sanaa Kamal

Ruane and colleagues investigated 60 treatment-naive and experienced patients of Egyptian ancestry living in the United States. Eligible participants with genotype 4 infection underwent 12 or 24 weeks of therapy with sofosbuvir (Sovaldi, Gilead Sciences) plus weight-based ribavirin.

There were 32 patients in the treatment-experienced arm, of whom 63% were prior nonresponders.

In the treatment-naive group, all 14 patients treated for 24 weeks and 79% of those treated for 12 weeks reached SVR12. Among treatment-experienced patients, 87% of those treated for 24 weeks and 59% of those treated for 12 weeks achieved SVR12.

So, despite increasing numbers of Egyptian nationals living abroad, it seems likely that they will be able to be cured.

The burden is not limited to Egyptians, according to Hassanein. “We see genotype 4 in Mexican Hispanics,” he said. “It is difficult to figure out where they got the infection. There are pockets of genotype 4 all around the world that might be related to immigration patterns.”

Similar uncertainties and disparities exist even within the Middle East, according to Kamal. “There are more cases of genotype 4 HCV in the Kingdom of Saudi Arabia compared to Kuwait and the United Arab Emirates, where HCV is not really prevalent,” she said. “HCV cases are declining in the Gulf states.”

However, she suggested that the clinical community remains uncertain about the origin of genotype 4 in Saudi Arabia. “Some speculate that this genotype was introduced with foreign manpower who moved and inhabited the Kingdom in the ’50s and ’60s of the last century,” Kamal said. “The huge number of pilgrims has been suggested as a source. For the last few decades, the Kingdom adopted and implemented a strict strategy of conducting obligatory HCV screening for all foreign workers and employees. The marked improvement in health systems and hygienic measures significantly reduced the overall prevalence of HCV.”

Moving south, Kamal noted that the actual status and prevalence of genotype 4 in Africa is not clear due to a paucity of studies on the continent. “Some studies showed that this genotype is prevalent in some African countries,” she said. “Well-designed studies are crucially needed to undercover the magnitude of the problem in such countries, taking into consideration that it is a complicated situation. African countries already have huge public health problems such as HIV, malaria and other helminthic and viral infections. Ebola is still ravaging. Thus, serious coinfections are expected.”

Yoshida agreed. “Compared to genotypes 1, 2 and 3 in Canada, genotype 4 is a small proportion in North America,” he said. “The major concern, though, is that genotype 4 patients often end up needing a liver transplant.”

Money and Resources

Many of these clinical issues exist because the price of direct-acting antiviral agent therapies remains out of reach for many patients. “The big question is how to set priorities in countries with limited resources and huge public health challenges,” Kamal said. “We have to decide whether to secure expensive HCV therapies or provide basic health needs. The realistic and more logical approach is to enhance health infrastructure and investigate preventive strategies like HCV vaccine research.”

Hassanein agrees, but prefers efforts should concentrate on infection control in hospitals and outpatient clinics, while enforcing the standard health precautions as established in the developed countries around the world.

But wealth and health infrastructure vary from country to country, particularly within the Mideast region.

“As is well known, Egypt has negotiated a price to treat the millions of patients there,” Hassanein said. “Countries like Dubai, Kuwait and Qatar are not getting this discount, but it may not matter. One of these small, rich Arab countries will be most likely to eliminate genotype 4 HCV because they have small numbers of patients and the resources to cure them.”

But there remain issues within the countries that have the resources to quell the disease, according to Hassanein. “The plan in some of these Arab countries is to only treat the native population and not provide therapy for ex-pats,” he said.

Cost issues are also variable in the developed world, as well. Hassanein noted that the price of sofosbuvir is lower in Japan than it is in most places in Europe.

“Most Canadians are not very wealthy,” Yoshida added. “Right now, the system is not picking up the tab for these drugs. Only wealthy Canadians can afford them.”

All of this leaves the clinical community with some good news and some bad news.

“A lot of companies know how to hit the virus now,” Hassanein said. “We are seeing activity in drug development outside of the U.S. market. This could lead to lower development costs and lower pricing at the end.”

Kamal tempered this enthusiasm. “The medical insurance system is still deficient,” she said. “Therefore, governments need to look into sponsorship of treatment campaigns” for those in need.

For Hassanein, a critical piece of the puzzle for treatment of genotype 4 in the U.S. is the FDA. “The FDA can always mandate that clinical trials should include X, Y and Z,” he said. “We have a lot of patients with genotype 6 disease in our practice, but no one wants to treat them because the FDA didn’t include them. These patients are at a disadvantage. The same is true for genotype 4.”

Moving Forward

Investigators and clinicians continue to push forward for solutions to the various challenges presented by HCV genotype 4. Asselah and colleagues explored a potential association between interleukin-28B polymorphism and treatment responses in 164 patients with chronic HCV genotype 4. They compared IL-28B polymorphisms for 78 patients with Metavir F0-F1 and those for 82 patients with F2-F4 fibrosis.

After treatment with pegylated interferon and ribavirin, results indicated improved treatment response in the C allele of single nucleotide polymorphism rs12979860 (P = .0008). Patients with genotype CC experienced a treatment response of 81.8%, whereas those with CT responded at 46.5% and those with TT responded at 29.4% when using Interferon-based therapies.

Disease severity and rs12979860 appeared to be unrelated.

“Analysis of IL28B genotype might be used to guide treatment for these patients,” the researchers concluded.

Whether this information is used in drug development, vaccine development or both, remains to be seen. But such studies will push the body of knowledge forward and hopefully lead to improved outcomes.

For Hassanein, the issue is fairly simple. “In genotype 4 HCV,” he said. “You can treat with a protease inhibitor and an NS5A or with the combination of sofosbuvir and any other DAA.”

Yoshida echoed this point, but with qualifications. “For genotype 4, the future is bright if patients can get access to treatments,” he said. “But that’s a big if.”

He added that despite low toxicities, there may be small clinical challenges to account for when using novel DAAs. “Because they are coformulated, you can’t dose reduce,” he said. “For most patients it will be OK, but there may be difficulties for those dependent on dialysis.”

Kamal encouraged the HCV community not to rest easy. “We know that these therapies work, but there are still challenges and roadblocks ahead,” she said. – by Rob Volansky