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The Challenge of Genotype 3

Once plagued by longer therapy and poorer results, clinicians see hope on the horizon.

Issue: September 2014

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For many clinicians, genotype 3 now presents the greatest challenge in the treatment and management of patients with hepatitis C virus.

In a recent paper published in the Journal of Viral Hepatology, HCV Next Editorial Board member Nezam H. Afdhal, MD, and Elliot B. Tapper, MD, from Beth Israel Deaconess Medical Center, called genotype 3 “potentially the most difficult-to-treat genotype and an area of intense research for new drug development.”

Genotype 3 is estimated to affect 54.3 million people and is the second most common worldwide behind genotype 1 (83.4 million), according to a report by Messina and colleagues published in Hepatology in July.

Special characteristics of genotype 3, including a more rapid development of liver disease, increased rates of steatosis and a disproportionately higher risk for hepatocellular carcinoma, present unique challenges for the clinical community that cares for patients with HCV.

“Genotype 3 is associated with progressive disease, and drug development has long been targeted on genotype 1 disease,” Eric J. Lawitz, MD, vice president of scientific and research development at The Texas Liver Institute and clinical professor of medicine at University of Texas Health Science Center, told HCV Next.

Difficult to Treat

Genotype 3 differs from other HCV genotypes in a number of ways.

Samuel S. Lee

“While the cause and effect is not completely clear, these patients tend to have risk profiles that make them more difficult to treat. They have resistant disease, are older, have more advanced fibrosis and tend to be a little more obese,” Samuel S. Lee, MD, professor of medicine at University of Calgary, Canada, told HCV Next.

According to Catherine Stedman, MD, clinicians have “traditionally focused on host factors such as age at infection, gender, alcohol consumption, BMI and coinfection as factors that alter rates of liver fibrosis progression in hepatitis C.” However, “emerging data suggest that viral genotype may also influence the natural course of hepatitis C,” Stedman, specialist gastroenterologist and hepatologist at Christchurch Hospital and clinical senior lecturer at University of Otago, New Zealand, said in an interview.

Aggressive Liver Damage

The clinical community is largely in agreement that the more aggressive nature of genotype 3 lies in the damage it causes to the liver.

“In early studies, HCV genotype was not recognized as an independent predictor of fibrosis progression, evolution to cirrhosis or decompensation of liver disease. The more aggressive natural history of genotype 3 was not appreciated because most of the studies included relatively few patients with genotype 3 infection and lacked statistical power,” said Gregory T. Everson, MD, professor of medicine and director of hepatology at the University of Colorado Denver School of Medicine. “We now recognize that genotype 3 may be the most aggressive HCV genotype.”

In a recent analysis, Kanwal and colleagues aimed to determine the effect of genotype 3 on cirrhosis and HCC risk using data from a large US Veterans Affairs cohort of 110,484 patients with active HCV infection (8,337 with genotype 3). Compared with genotype 1, patients with genotype 3 were 31% more likely to develop cirrhosis (adjusted HR=1.31; 95% CI, 1.22-1.39) and 80% more likely to develop HCC (adjusted HR=1.8; 95% CI, 1.61-2.03). The researchers noted that the association between these increased risks and genotype 3 is independent of factors, including age, diabetes, BMI or antiviral therapy.

“Currently, the most challenging area is the treatment of treatment-experienced patients with genotype 3 who have established cirrhosis and also those with decompensated liver disease,” Stedman said.

Beyond cirrhosis and cancer risk lies the prevalence of steatosis in patients with genotype 3.

In a Journal of Hepatology study, Rubbia-Brandt and colleagues assessed steatosis rates in certain patient populations with HCV and found that steatosis was most common in patients with genotype 3. Other research by Kumar and colleagues found that hepatic steatosis was present in 62% of a cohort of 34 patients with genotype 3. Although sustained virologic response was associated with a significant decrease in steatosis (P<.001), no change in steatosis was reported among patients who failed to achieve SVR. Further, SVR was identified as the only variable that predicted improvement in steatosis in this study. “These data provide strong support for a direct causal association between HCV genotype 3 and hepatic steatosis,” Kumar and colleagues concluded.

It is not known why genotype 3 has the propensity to develop histologic steatosis that is virologically mediated, according to Lawitz. “It may be a biologic marker for an increased risk of developing more rapid progressive disease, but we do not yet know enough about the mechanism,” he said. This is virologic fat, and not metabolic fat, in the liver of patients with genotype 3; this steatosis is different than that observed in nonalcoholic steatohepatitis, according to Lawitz. “The virologic steatosis in these patients may be a signal for those at risk for a more progressive disease course; however, why this is commonly seen in genotype 3 but no other genotype is a topic for future research. It is plausible that this steatosis is an observable marker for patients at risk for a more rapid progression,” he said.

According to Stedman, the excess fat may result from a direct viral effect that is independent of other predisposing conditions such as overweight, obesity or alcohol use. “Hepatic steatosis may underlie the accelerated fibrosis observed in genotype 3 infection,” she said. “Other changes in lipoprotein metabolism are also observed in people with genotype 3, such as hypocholesterolemia. The exact cause of the lipid abnormalities and steatosis is not clear; however, they are almost certainly caused by the virus as successful treatment of hepatitis C reverses steatosis and hypocholesterolemia in these people.”

Catherine Stedman

Certain mechanisms responsible for hepatic steatosis are common to all HCV genotypes, including increased rates of lipogenesis, decreased fatty acid oxidation and reduced lipoprotein export, according to Everson. “Genotype 3 not only amplifies these derangements but further augments steatosis via more profound changes in many additional lipid pathways. It would seem that genotype 3, the oldest subtype in the HCV genotype spectrum, has evolved complex processes to survive chronically within its host,” he said.

In their editorial, Tapper and Afdhal suggested that a direct correlation exists between genotype 3 viral load and grade of steatosis. “The clinical significance of this is manifest most starkly by the finding that when comparing [patients with genotype 3 vs. patients without genotype 3] and controlling for other variables, histological steatosis is associated with progression of fibrosis, mainly in [genotype 3],” they wrote. “Treating the virus fortunately reverses this effect. First shown in a group of patients treated mainly with interferon-alfa monotherapy, those with [genotype 1] experienced no change in hepatic steatosis after treatment, irrespective of the treatment response. Conversely, amongst those with [genotype 3] infection, SVR significantly reduced steatosis but not amongst those without SVR. This effect was later confirmed in large-scale randomized trials.”

Around the World

Of the 54.3 million cases of HCV genotype 3 infection worldwide, as reported by Messina and colleagues based on 90% of the world population, three-quarters occur in South Asia. Other data suggest that genotype 3 can also be found in up to 30% of cases in European countries such as Greece, Poland and the Netherlands.

“The global dissemination of genotype 3 is likely due to the association of subtype 3a with injection drug use and to the population migration from countries where subtype 3a is dominant, such as India and Pakistan,” Messina and colleagues wrote.

In contrast, genotype 1, the most common genotype in the world, is more dominant in the United States, Australia and Western Europe.

Lee said, in Canada, where he cares for patients with HCV, most patients with genotype 3 are immigrants from Pakistan and India. “The vast majority of HCV patients in many South Asian regions have genotype 3 infection,” he noted. Medical injections in certain places in South Asia and other parts of the world are still not sterilized properly, according to Lee. “A doctor’s office in those regions may still be a prime mode of HCV transmission,” he said.

Treatment Challenges

Beyond liver complications, genotype 3 presents ongoing challenges in terms of effective therapies. Genotype 3 has been associated with longer treatment and poorer results. In particular, early direct-acting antiviral therapies have failed to achieve strong SVR rates in this patient population.

Despite traditionally placing genotypes 2 and 3 in the same group when making a decision about treatment dose or duration, Javier Ampuero, MD, Manuel Romero-Gómez, MD, and K. Rajender Reddy, MD, suggest not grouping the two together for analyses of SVR or therapeutic strategies. “More recently, genotype 2, unlike genotype 3, has been found to be sensitive to various direct-acting antivirals, thus resulting in differences in SVR rates. Given the recent approval of the DAAs … and with new imminent therapies, it is important that we recognize that genotype 3 is now the more difficult genotype to treat,” they wrote in Alimentary Pharmacology and Therapeutics.

“Sofosbuvir has significant efficacy in the treatment of HCV genotype 3 and represents a major advance in successful treatment,” Stedman said.

The current recommendation for treating patients with genotype 3 is sofosbuvir (Sovaldi, Gilead) plus ribavirin. The American Association for the Study of Liver Diseases/Infectious Disease Society of America/International Antiviral Society-USA Recommendations for Testing, Managing and Treating Hepatitis C suggest 12 weeks of sofosbuvir and weight-based ribavirin for patients with genotype 2 and 24 weeks of sofosbuvir and ribavirin for patients with genotype 3 (12 weeks if interferon-eligible).

Approval of this nucleotide analog NS5B polymerase inhibitor in patients with genotype 3 was based on trials including FISSION, FUSION, POSITRON and VALENCE. Results of the VALENCE trial were presented at The Liver Meeting 2013 and later published in The New England Journal of Medicine. Zeuzem and colleagues reported that the criterion for SVR after treatment with sofosbuvir and ribavirin for 12 weeks was met in 93% of patients with genotype 2 infection and in 85% of patients with genotype 3 infection after 24 weeks of treatment. Response rates were 91% and 68% for patients with genotype 3 without and with cirrhosis, respectively. “Notably, the majority of these patients had failed prior therapy, and sofosbuvir was able to produce a sustained virologic response,” principal investigator Stefan Zeuzem, MD, professor of medicine and chief of the department of medicine, Goethe University Hospital, Frankfurt, Germany, stated in a press release.

In regions where sofosbuvir is unavailable, pegylated interferon and ribavirin continue to be the current standard of care for patients with genotype

Future Options Studied

Sofosbuvir may be one answer to improve the treatment of patients with genotype 3, but other DAAs and combinations are also showing activity.

“Other regimens, mainly using various combinations of NS5B polymerase inhibitors, NS5A inhibitors and protease inhibitors, are under development and may ultimately find use in the treatment of genotype 3,” Everson said.

The FDA is expected to make a decision about the approval of the interferon-free combination of sofosbuvir and the NS5A inhibitor ledipasvir (Gilead) in patients with genotype 1 by October. In genotype 3, data from the ongoing ELECTRON-2 study presented at the 49th Annual Meeting of the European Association for the Study of the Liver in April showed SVR at 12 weeks after therapy in all of the treatment-naive patients with genotype 3 studied who were assigned fixed-combination sofosbuvir and ledipasvir with ribavirin; the SVR rate was 64% without ribavirin. “This combination may require a 24-week duration or addition of ribavirin for optimum activity against genotype 3, especially for treatment-experienced patients with cirrhosis,” Everson said.

Another NS5A inhibitor, daclatasvir (Bristol-Myers Squibb), has demonstrated antiviral activity across all HCV genotypes, including genotype 3. Everson cited data from Sulkowski and colleagues, who investigated sofosbuvir and daclatasvir for 24 weeks. Results indicated an 89% SVR. “Further studies are ongoing with this regimen,” he said.

Other NS5A inhibitors being studied for genotype 3 include MK-8742 (Merck) and GS-5816 (Gilead). Everson and colleagues presented data at EASL 2014 showing that GS-5816 may have increased potency against genotype 3, he said. Phase 2 results demonstrated that GS-5816 with sofosbuvir without interferon or ribavirin yielded SVR in 25 of 27 patients with genotype 3, according to Everson.

“Looking forward, combination of pan-genotypic direct antivirals are likely to shorten courses and provide the expected high rates of sustained viral response in genotype 3 as we have achieved in genotype 1,” Lawitz said.

Eric J. Lawitz

The nucleoside polymerase inhibitor mericitabine and the cyclophilin inhibitor alisporivir are also under investigation for the treatment of genotype 3 infection.

Moreover, the clinical community may be well served to look at basic science for clues to treating genotype 3.

Firdaus and colleagues reported in PLoS One that genetic polymorphisms near the interleukin 28B gene have led to clearance of HCV in some patients. They aimed to determine the effect of rs12979860 and rs8099917, interleukin 28B single nucleotide polymorphisms (SNPs), on patient populations. Data indicated a significant association between rs12979860 and SVR in patients with genotype 3 infection. Additionally, the researchers determined that favorable CC/TT allele at rs12979860 and rs8099917 was predominant at both alleles. “CC, TT the two favorable markers at SNPs rs12979860 and rs8099917 are strongly associated with sustained virological response in genotype 3-infected populations,” the researchers concluded. “This information will aid clinicians to effectively design response based treatment regimen.”

In another study, Eslam and colleagues investigated SNPs near the interferon lambda 3, or IFNL3, region in light of associations with SVR in genotype 1 infection. Results of a logistic regression analysis indicated that rs12979860 CC and rs8099917 TT independently predicted SVR.

Rapidly Changing Environment

The experts HCV Next interviewed said they remain hopeful for the treatment of genotype 3 infection.

“The good news is that we are realizing that genotype 3 is different and difficult and leads to more progressive disease associations,” Lawitz said. “More attention is being focused on genotype 3, particularly in the development of pan-genotypic direct antivirals that are equally effective in genotype 3 as they are in the other HCV genotypes.”

However, Lawitz noted that treatments “need to continue to be improved and optimized.”

“The patient with HCV genotype 3 infection has ample reason to be optimistic,” Everson said. — by Rob Volansky