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Responsive to Treatment, Elusive to Detection: HCV Genotypes 5 and 6

As novel direct-acting antiviral therapies consistently yield SVR12 rates around or above 90% in such challenging populations as those with genotype 3 HCV or HIV coinfection, the clinical community is investigating deeper into the epidemiology of HCV. That search has moved toward genotypes 5 and 6 disease.

The main obstacle with these two genotypes is that they are endemic to areas of the developing world that are not usually centers for academic research, according to Eric M. Yoshida, MD, MHSc, professor of Medicine at the University of British Columbia and the head of the Division of Gastroenterology at Vancouver General Hospital. “From an epidemiological perspective, genotype 5 is endemic in Africa, especially South Africa, and genotype 6 in Asia,” he said.

Jordan J. Feld, MD, MPH, a hepatologist at Toronto General Hospital and scientist at the McLaughlin-Rotman Centre for Global Health at the University of Toronto, agreed. “The challenge is in terms of epidemiology,” he said. “There is nothing that makes genotype 5 and 6 particularly difficult to treat. We just don’t have large enough studies to lead to approval because they are relatively rare in most regions of the world, so it has been hard to include patients with these genotypes in clinical studies.”

Jordan J. Feld

The good news, according to most experts, is that novel therapies have been as effective in these two genotypes as they have been in others. “Clinically, these patients are no different to treat than patients with genotype 1, 2 or 3 HCV infection,” Yoshida said. “They respond to therapy with a pangenotypic NS5A and NS5B inhibitor antiviral combination very well, and in terms of clinical liver disease, they are also no different than the other genotypes.”

Despite positive outcomes, misdiagnosis of genotype 5 or 6 patients is common among Western clinicians who don’t treat many patients with these genotypes. In addition, because of ongoing questions about treatment, approvals in developed countries and the developing world have lagged. HCV Next spoke with several experts about these and other issues surrounding genotype 5 and 6 HCV.

Finding These Infections

Dan and Lim published a report on trends in various genotypes around the world. They noted that genotype 6 is found in Indochina and that approvals of DAA therapies in Asia are far behind those in the West. They suggest that DAA therapies will be used more widely in Asian countries by 2019, but that, in the meantime, peginterferon and ribavirin remains the go-to regimen. They added that screening and linkage to care are the biggest barriers for this group of patients with genotype 6 disease.

“The difficulty is accessing interferon-free therapy for these patients,” Yoshida said. “I don’t believe that there is a licensed indication for genotype 5 and 6.”

Nguyen and Nguyen also found that genotype 6 is common in Southeast Asia and the surrounding regions. “Most data on DAAs to date have been derived from clinical trials conducted in Western countries, where HCV-6 is rare,” they wrote. “The standard of care for patients with HCV-6 is still pegylated interferon and ribavirin.”

“The number of patients in Canada and the United States with genotype 5 and 6 infection is very small compared to genotype 1, 2 and 3,” Yoshida said. “At my center, we only see a small number compared with the large numbers of patients with those other genotypes. Because of this, it is difficult for anyone to claim to have a large body of personal experience.”

Feld reported similar concerns. “For us in most Western countries, we just don’t see that many of these patients,” he said. “One important point is that sometimes when these patients are seen, they’re missed. This is particularly true for genotype 6, which is [frequently] typed as genotype 1 with some commercially available genotyping assays. In someone from Southeast Asia with genotype 1 infection, the question of whether this could be genotype 6 should at least be raised.” All of this can be frustrating because, as Yoshida reports, SVR12 rates in genotype 5 and 6 patients are usually 90% or higher with many novel regimens.

Sofosbuvir-Based Therapies

In the ELECTRON-2 study, for instance, in which sofosbuvir/ledipasvir (Harvoni, Gilead Sciences) was assigned for 12 weeks in 25 treatment-naive or previously treated patients with genotype 6 disease, the SVR12 rate in this cohort was 96%. Harvoni received supplemental new drug application approval from the FDA based on these findings.

Bourlière and colleagues investigated the fixed-dose combination of sofosbuvir and ledipasvir in a group of patients that included those with genotypes 5 and 6 disease. Although patients with genotype 3 responded less than optimally, encouraging results were reported for genotypes 5 and 6.

“For both genotype 5 and 6, sofosbuvir and ledipasivir would, in my opinion, be effective,” Yoshida said. “This is based on small studies and small numbers of reported patients, but I do not see any reason why these patients would not respond.”

Eric M. Yoshida

Lai and colleagues highlighted the prevalence of genotypes 1b and 6a disease in Hong Kong. They aimed to evaluate sofosbuvir and ribavirin in a cohort of 31 treatment-naive patients in an open-label study. There were 11 patients with genotype 6 disease included in the analysis. From the overall cohort, 10 patients were treated for 12 weeks, 11 for 16 weeks and 10 for 24 weeks. SVR12 served as the primary endpoint.

All patients had reached HCV RNA < LLOQ by the fourth week of treatment and remained that way at the end of treatment. SVR12 rates were 100% in both the 12- and 16-week groups, while those treated for 24 weeks reached a 90% response rate. The one patient who did not achieve SVR12 had genotype 1 disease.

The regimen was generally well tolerated by all patients, including those with genotype 6a HCV.

“Sofosbuvir is clearly highly active against both of these genotypes,” Feld said. “When you combine it with a second drug, it seems to be highly effective.”

He noted, however, that there may be difficulty in treating patients who have renal disease or who have another contraindication to sofosbuvir. “It would be helpful to have non-sofosbuvir-based regimens for genotypes 5 and 6 so we have a few more options, but I don’t think [not having them] will prove to be an Achilles’ heel of treatment,” he said.

Velpatasvir-Based Regimens

The good news is that encouraging data for alternate treatments continues to roll in. In the double blind, placebo-controlled phase 3 ASTRAL-1 study, Feld and colleagues investigated a once-daily, fixed-dose combination of sofosbuvir (Sovaldi, Gilead) 400 mg and velpatasvir (Gilead) 25 mg in a cohort that included patients with genotypes 5 and 6 HCV. Due to low numbers, all patients with genotype 5 disease received active study drug. The analysis, presented at AASLD 2015, included 624 patients, with 6% genotype 5 (n = 35) and 7% genotype 6 (n = 41).

“In the end, there were actually more patients with genotype 6 than genotype 5,” Feld said. “We didn’t randomize patients with genotype 5 infection because the placebo was only to assess safety, not efficacy. We had no reason to think that safety would vary by genotype and we wanted to make sure we had enough genotype 5 patients in the active treatment arm to assess efficacy. Fortunately, we ended up with reasonable numbers for both genotypes 5 and 6.”

The overall SVR12 rate for patients on active study drug was 99% (95% CI, 98->99). The serious adverse event rate was 2%.

Treatment-naive and experienced patients, along with those with compensated cirrhosis, responded favorably.

“Although the numbers with genotypes 5 and 6 were not huge, there were no virological failures in any of patients with these infections. All those with genotype 6 were cured and with the exception of one patient who was lost to follow-up, all of those with genotype 5 achieved SVR as well,” Feld said.

In other research, Everson and colleagues also looked at a sofosbuvir/velpatasvir regimen in a randomized phase 2 open-label study with or without ribavirin in a randomized fashion, this time in a cohort of treatment-naive, non-cirrhotic patients. Part A of the study included 377 participants who were treated for 12 weeks.

Among 23 patients with genotypes 2, 4, 5 and 6 HCV who received 25 mg velpatasvir, the SVR12 rate was 96%. For 22 patients with those same genotypes who were treated with 100 mg velpatasvir, the SVR12 rate was 95%. The researchers noted that the numbers for these genotypes were small.

Douglas T. Dieterich

Douglas T. Dieterich, MD, of Mount Sinai School of Medicine in New York and an HCV Next Editorial Board member, weighed in on the use of velpatasvir in genotypes 5 and 6 in an interview with HCV Next. “We have seen good response rates with this upcoming drug,” he said.

Interferon Not Obsolete

Most experts agree that treating all patients with DAAs is optimal, but remains something of a luxury. The reality is that interferon-based regimens remain in active use in other parts of the world.

Cai and colleagues suggested that uncertainty remains regarding the optimal treatment of genotype 6. They conducted an open-label, randomized controlled trial comparing 24 and 48 weeks of peginterferon/ribavirin in a cohort of 210 treatment-naive, non-cirrhotic patients in southern China. Eligible participants were those with genotype 6a who had reached HCV RNA negativity by week 4 of the study.

In the intention-to-treat analysis, 90.8% of patients treated for 24 weeks and 88.2% of those treated for 48 weeks reached SVR. In the per-protocol analysis, 95.7% of those in the 24-week group and 97% of those in the 48-week arm reached SVR. Anemia was higher in the 48-week group, 46.1% vs. 28.9% (P = .03). However, the rest of the adverse event profile was comparable for the two study arms.

The researchers concluded that 24 weeks of peginterferon and ribavirin was non-inferior to 48 weeks.

While fewer weeks of treatment is a positive for patients, “in light of the ASTRAL-1 results, sofosbuvir and velpatasvir may be the [up-and-coming] combination of choice for these patients if the drug combination gets a license for this indication,” Yoshida said. “In this day and age, I do not feel that treating any patient, including genotype 5 and 6 patients, with a peginterferon and ribavirin combination is appropriate.”

Raising Awareness

As for diagnosing genotype 6, Feld suggested physicians engage in “clinical caution.”

“If you have someone from Southeast Asia, think about genotype 6, even if the genotyping assay reports genotype 1,” he said. “This is due to overlapping sequences between genotype 6 and genotype 1 in key regions used by some of the commercial genotyping assays. This can occasionally result in a genotype 6 sample coming back reported as genotype 1. If genotyping is done by direct sequencing, there is no issue, so if you suspect 6 [in a patient from Southeast Asia, for instance] and the result comes back as 1, you may consider re-genotyping using another assay or, ideally, sequencing to be sure.”

Feld suggested that once truly pan-genotypic therapies are available, this will be less important. “But for now, it’s important to be sure of the genotype so you don’t use the wrong therapy for the wrong patient and you don’t end up with a surprise non-response,” he said, and noted that regimens such as ombitasvir/paritaprevir/ritonavir/dasabuvir (Viekira Pak, AbbVie) are currently only approved for use in genotype 1. “You would not want to unwittingly give this regimen to a patient with a genotype 6 infection. For regimens like ledipasvir/sofosbuvir that are approved for both genotypes 1 and 6, it is less of an issue, but in general, being certain of the genotype is still a good idea before embarking on therapy.”

In addition, Yoshida suggested that HCV genotype 5 and 6 patients do not always have the typical risk factors for HCV that are found in patients from North America. Lack of information about HCV and these risk factors at both the clinical and patient level is an additional concern not only in the developing world, but also in Western countries, as well. Aho-Glele and colleagues recently investigated two case patients with genotype 5a disease from the dialysis unit of a hospital in France. They concluded that nosocomial infection was the cause of HCV in the second patient, with transmission most likely occurring via the hands of health care workers. “This investigation also underlines the need to periodically evaluate prevention and control practices,” they wrote.

No matter how HCV infection is transmitted, “there is less awareness that patients who immigrated from [endemic] geographic [areas] are at risk [for HCV 5 and 6],” Yoshida said. “Therefore, on the primary care front lines, the need for screening may not be perceived to be necessary. I also add that North Americans who have resided in these geographic areas for an extended period could also be at risk and should consider getting tested for HCV.”

• References:
• Aho-Glele LS, et al. Infect Control Hosp Epidemiol. 2015;Oct 29:1-6. [Epub ahead of print]
• Bourlière M, et al. Expert Rev Gastroenterol Hepatol. 2015;10.1586/17474124.2015.1111757.
• Cai Q, et al. PLoS One. 2015;10.1371/journal.pone.0140853.
• Dan YY and Lim SG. Gastroenterol Clin North Am. 2015;10.1016/j.gtc.2015.07.007.
• Everson GT, et al. Ann Intern Med. 2015;10.7326/M15-1000.
• Feld JJ, et al. N Engl J Med. 2015;10.1056/NEJMoa1512610.
• Gane E, et al. High Efficacy of LDV/SOF Regimens for 12 Weeks for Patients with HCV Genotype 3 or 6 Infection. Abstract LB-11. Presented at the 65th Annual Meeting of the American Association for the Study of Liver diseases; Nov. 7-11, 2014; Boston, USA.
• Lai CL, et al. Aliment Pharmacol Ther. 2015;10.1111/apt.13429.
• Nguyen NH and Nguyen MH. Gastroenterol Clin North Am. 2015;10.1016/j.gtc.2015.07.010.

• For more information:
• Douglas T. Dieterich, MD, can be reached at: Icahn School of Medicine at Mount Sinai, Annenberg 21-42, New York, NY, 10029; email: douglas.dieterich@mountsinai.org.
• Jordan J. Feld, MD, MPH, can be reached at Toronto Western Hospital Liver Centre Sandra Rotman Centre for Global Health, University of Toronto, Toronto, ON M5R 0A3 Canada; email: Jordan.Feld@uhn.ca.
• Eric M. Yoshida, MD, MHSc, can be reached at the Division of Gastroenterology, Vancouver General Hospital, Diamond Health Care Centre, 5th Floor, 2775 Laurel St., Vancouver, BC, V5Z 1M9, Canada; email: Eric.Yoshida@vch.ca.

Disclosures: Dieterich reports associations with Achillion, Boehringer Ingelheim, Gilead, Idenix Pharmaceuticals, Janssen, Merck and Vertex. Feld reports receiving support for research and/or honoraria for scientific consulting for AbbVie, Abbott, Bristol-Myers Squibb, Gilead, Janssen, Merck, Theravance and Trek. Yoshida reports being an investigator of clinical trials sponsored by AbbVie, Boehringer Ingleheim, Gilead, Hoffman-LaRoche, Janssen, Merck and Vertex; and receiving honoraria for lectures from AbbVie, Boehringer Ingleheim, Gilead, Hoffman-LaRoche, Merck and Vertex.