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The Evolution of Special Populations in HCV

New therapies are redefining the category of difficult-to-treat patients

Issue: October 2014

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As treatment options for hepatitis C virus infection have improved in recent years, specific groups of patients who were traditionally considered difficult to treat are no longer presenting the clinical challenges they once did.

Examples of these difficult-to-treat, special populations in HCV include patients with compensated and decompensated cirrhosis, HIV/HCV coinfection, advanced renal failure, those who have undergone liver transplantation and those who are immunosuppressed for reasons other than transplantation, according to Thomas Reiberger, MD, associate professor, division of gastroenterology and hepatology, Medical University of Vienna, Austria. The reasons they were considered special are myriad, including poor responses to therapy, high risk for serious adverse events and potential drug-drug interactions with essential co-medication. However, whether any of these patient populations could still be considered special is under discussion, largely because of advances in direct-acting antiviral therapies.

“The promising virological response rates with novel interferon-free combinations of DAAs have ushered in a new era in the treatment of HCV-infected patients,” Reiberger told HCV Next. “Response rates of close to 100% in various trials have been observed even in patient populations that have traditionally been considered as difficult-to-treat and/or difficult-to-cure.”

Robert S. Brown

Robert S. Brown Jr., MD, MPH, Frank Cardile professor of medicine and medical director of the transplantation initiative at Columbia University College of Physicians and Surgeons in New York, said special populations are becoming easier to treat. “The difference in response rates between so-called ‘special’ and ‘standard’ populations is getting smaller and smaller. When we eliminate interferon completely from HCV treatment regimens, the number of patients in these special populations who cannot be treated will become even smaller,” he told HCV Next.

“The term ‘special population’ is one that we created largely because of inadequate immunological response to interferon. Certain populations will simply not have a response to that drug,” Fred Poordad, MD, said in an interview. “But novel DAA therapies don’t work on that immunological response. They have leveled the playing field, and all but eliminated many of what we used to call special populations,” said Poordad, who is vice president of academic and clinical affairs at The Texas Liver Institute and clinical professor of medicine at the University of Texas Health Science Center, San Antonio.

Despite recent advances in treatment and care, HCV Next Editorial Board member Nancy S. Reau, MD, associate professor of medicine at the University of Chicago, said the clinical community should not simply shelve the notion of special populations. “The response rates are better,” she said. “But that does not mean that special populations no longer exist.”

Clinical challenges in some of these groups remain. HCV Next spoke with a cross section of experts to redefine the shifting borders of special populations in HCV.

The Effect of Novel DAAs

The influence of novel DAAs is noteworthy because the drugs eliminate the HCV infection with few adverse effects, but also because they do not come with the same complications associated with interferon-based treatments.

“Interferon is no longer an essential component of novel HCV treatment regimens,” Reiberger told HCV Next. “Thus, various severe adverse events, especially in cirrhotic patients, that could trigger hepatic decompensation can be avoided. Also, the use of very specific and targeted inhibitors of HCV-specific enzymes with high antiviral efficacy, as compared with the first-generation DAAs, seem to be associated with no, or almost no, off-target effects while achieving effective suppression of HCV replication in most patients,” he said.

Such outcomes are cause for optimism, according to Brown.

“We were at 70% [sustained virologic response] with telaprevir and boceprevir, which caused decompensation, even in patients who were compensated. That was just 3 years ago. I don’t think anyone anticipated that things were going to move as quickly as they did.

“The idea of testing drugs in decompensated cirrhotics is amazing; it is amazing that we are even at a point where we can talk about it. We are at a point where 90% SVR is not good enough. Ten years ago, 54% SVR would have been good enough,” Brown said.

Nancy S. Reau

The issue now becomes one of HCV treatment duration in traditional populations. As more data accumulate on which patients can receive shorter durations of therapy, the rules for 8 weeks vs. 12 weeks may not apply to cirrhotics and coinfected patients with HCV, according to Brown.

“We may need a longer treatment duration for some of these populations,” Reau said. However, she recommended caution when dealing with prolonged treatment duration. “Cure is our main priority. Although some populations may need up to 24 weeks of therapy with the next all-oral regimens, future therapies are expected to become increasingly shorter. Investigational regimens requiring more than 12 weeks will not be viable in this climate.”

Reiberger called on the HCV research community to build on previous study results involving interferon-free DAA regimens. In addition, data on pharmacokinetics are limited and additional toxicity might occur in patients with severe renal impairment or on renal-replacement therapy, and the antiviral efficacy of novel DAA regimens must be assessed in these groups. Moreover, other research has identified certain patient characteristics associated with lower response rates to certain DAAs, such as previous treatment failure, IL28B non-CC genotype, HCV RNA levels >800,000 IU/mL and male gender, he said.

“There will always be patients on the margins who do not respond to the new therapies as well as other patients, and that is an important point to talk about,” Brown said.

Patients with Cirrhosis

Recent data indicate that patients with cirrhosis may be one of the last special populations with a truly lower response rate to HCV therapies.

“HCV patients with cirrhosis are the ones most in need of antiviral therapy. However, traditionally, SVR rates were discouraging and severe adverse events attributed to antiviral therapy were frequent,” Reiberger said.

Thomas Reiberger

New DAAs have changed the game in that regard. Reiberger provided an overview of relevant data on DAA combinations in HCV patients with cirrhosis (see Table).

“However, in many trials using novel interferon-free DAA combinations, patients with advanced fibrosis (stage F3) and cirrhosis (stage F4) have been lumped together when reporting SVR rates for cirrhotic patients. In addition, when cirrhosis is diagnosed by liver biopsy or transient elastography, further assessment must be used to more precisely define the stage of cirrhosis,” he said. Such assessment might include abdominal ultrasound, upper GI endoscopy and measurement of portal pressure, he said. Measuring liver stiffness could also be useful for stratifying these patients, according to Reiberger. “Patients with F4 cirrhosis can show liver stiffness values from 12 kPa up to 75 kPa, clearly indicating different stages within histological F4 cirrhosis. This approach would allow distinguishing patients with HCV cirrhosis that can be easily treated with interferon-free DAA combinations from patients in whom data are limited and who still represent a special population,” he said.

Experts interviewed by HCV Next noted that patients with well-compensated cirrhosis should no longer be in the special-population category, but decompensated cirrhosis still presents a treatment challenge.

“Although SVR is associated with favorable outcome in patients with cirrhosis and even regression to less-advanced stages of fibrosis after SVR, some patients still remain at risk for complications, particularly hepatocellular carcinoma,” Reiberger said. “In my opinion, HCV patients with decompensated cirrhosis, as indicated by portal hypertension, impaired synthetic function, ascites or hepatic encephalopathy, should still be regarded as a special HCV population in whom data on SVR rates to interferon-free DAA combinations are limited.”

The clinical community awaits data from the SOLAR studies, which include HCV patients with decompensated cirrhosis on the transplant waiting list (SOLAR-1) or after transplantation (SOLAR-2) who are being treated with the sofosbuvir/ledipasvir (Gilead) combination with or without ribavirin.

“We may see that decompensated cirrhotics can be treated with new therapies. But questions about how the drugs are metabolized, whether they are active in decompensated cirrhotics and how they get to the virus are still unanswered. With these potent drugs, we can make patients negative for HCV, but the question is whether they will stay negative,” Brown said in an interview.

The challenge of decompensation, specifically portal hypertension, is one that the research community is still trying to tackle. There are little to no data on portal hypertension, according to Brown. “Decompensated cirrhotics will probably remain the most difficult group because most studies have either excluded them specifically or excluded them de facto by not including patients with abnormal bilirubin, albumin or other markers of cirrhosis,” he said.

Reau put the issue into clinical perspective. “We will still need to monitor cirrhotics for hepatocellular carcinoma after they attain SVR,” she said.

“Even if response rates appear to be almost similar to those observed in nonspecial HCV populations, these patients will always represent a particular subset of patients that should ideally be treated in specialized centers, just given their higher likelihood of severe complications related to their comorbidities or severity of liver disease,” Reiberger said.

HIV/HCV Coinfection

A number of data sets demonstrated the difficulties in treating patients coinfected with HIV and HCV. In a study from 2010, Ananthakrishnan and colleagues reviewed outcomes for 474,843 discharges with HCV monoinfection, 206,758 with HIV monoinfection and 56,304 with HCV/HIV coinfection. Coinfected patients experienced higher mortality rates than those with HCV monoinfection (OR=1.41; 95% CI, 1.2-1.65), but not higher than those reported for patients with HIV monoinfection. Cirrhosis or complications arising from cirrhosis yielded a nearly fourfold increase in mortality risk in patients with HIV compared with those monoinfected with HCV (OR=3.96; 95% CI, 3.29-4.79). Patients with HCV/HIV were hospitalized at a rate of 23.5% vs. 14.8% for those with HCV and 19.9% for those with HIV monoinfection (P<.001).

But novel DAA therapies are rapidly changing the game.

Sulkowski and colleagues conducted the PHOTON-1 study, which involved patients with HCV/HIV coinfection. Sofosbuvir (Sovaldi, Gilead Sciences) and ribavirin for 12 weeks was associated with an 88% SVR12 rate in patients with genotype 2 infection and 67% in genotype 3 infection. Twenty-four weeks of sofosbuvir and ribavirin was associated with 76% SVR12 in treatment-naive patients with genotype 1 infection. Those rates were 92% for treatment-experienced patients with genotype 2 and 94% for treatment-experienced patients with genotype 3.

“The combination of sofosbuvir and ribavirin for 12 weeks is not sufficient for HIV/HCV genotype 3,” Reiberger said. “This combination for 24 weeks is not sufficient for HIV/HCV genotype 1. However, when ribavirin is replaced by another second-generation DAA, the efficacy will likely be improved while the toxicity of ribavirin can be avoided.”

With this in mind, studies such as the one presented by Osinusi and colleagues at the recent European Association for the Study of the Liver’s International Liver Congress are of great interest to the clinical community. A fixed-dose combination of sofosbuvir and ledipasvir for 12 weeks in patients with HIV and HCV genotype 1 infection was associated with an SVR12 rate of 100% in 10 patients with no concomitant ART. The SVR4 rate among patients receiving concomitant ART was also 100% (22/22).

“This will most likely be the standard of care for HIV/HCV genotype 1, particularly when effective in patients with advanced cirrhosis as well,” Reiberger said. “Activity for other genotypes is very likely, but has to be shown for HIV coinfection.”

In the C-Worthy study, Sulkowski and colleagues investigated the compounds MK-5172 plus MK-8742 (Merck) with or without ribavirin for noncirrhotic patients with HIV and HCV genotype 1 infection. The SVR4 rate was 97% (28/29) with ribavirin and 90% without ribavirin (26/29).

As more results such as these emerge, the onus then will be on the FDA to determine which combinations should move most rapidly toward approval.

For patients with HIV and HCV, the term “special population” has two meanings, according to Brown. One is the question whether coinfected patients respond differently and the other has to do with how they are regulated, he said.

Norah A. Terrault

“The special population designation by the FDA will still be important. Academia and the pharmaceutical industry are required to do necessary studies in these patients to find safety and efficacy data because they have the most rapidly progressive disease,” Brown said.

Norah A. Terrault, MD, MPH, professor of medicine and surgery and director of the Viral Hepatitis Center at University of California, San Francisco, built on this point. “Drug-drug interactions can be a challenge in managing HCV/HIV coinfected patients. We are going to encounter patients who are stable on an HIV regimen that has not yet been studied with a specific HCV drug combination,” she said.

For example, according to Terrault, sofosbuvir and ledipasvir have been studied with some, but not all, of the HIV mainstays. “We are going to have to switch them to a regimen that has been studied, or treat off-label, which always raises fears about an interaction,” Terrault said. “I hope that the companies that are developing these drugs are keeping these issues in mind.”

Transplantation, Previous Nonresponders

Another area lacking data is patients who have undergone liver transplantation, according to Reau. HCV infection frequently persists after transplantation. These patients traditionally experienced high rates of transplant failure in addition to poor outcomes with conventional dual therapy and early generation protease inhibitors.

Pellicelli and colleagues investigated sofosbuvir and daclatasvir 60 mg/day (Bristol-Myers Squibb) with or without ribavirin in 12 transplant recipients with severe recurrent HCV-related disease. Eleven patients were treated for at least 4 weeks, whereas seven others received more than 12 weeks of treatment. There were three deaths in the overall cohort, and four more patients experienced severe adverse events that the researchers deemed unrelated to the therapies under investigation. Week-4 results indicated undetectable serum HCV RNA levels in 82% of the 11 patients remaining in the cohort. By week 12, seven of seven patients achieved this outcome. Week-12 results also indicated significant improvements in serumbilirubin and Child-Pugh score compared with those reported at baseline (P=.02).

“Sofosbuvir and daclatasvir combination is a highly effective antiviral treatment in [liver transplantation] recipients with severe recurrent hepatitis C and has no interactions with immunosuppressants,” the researchers concluded. “However, despite improved liver function in survivors, deaths and severe disease complications occur frequently in this very sick population. These data strongly support that this potent combination must be initiated before the onset of cholestasis or decompensation.”

“We may never have great clinical trial numbers for post-transplant populations,” Reau said. “But we still have to know how to take care of them. It may not be wise to approve an HCV agent only for that population, but we absolutely need to understand the efficacy and drug interactions with our available treatments.”

Poordad cited data from Kwo and colleagues that demonstrated 96% SVR in a cohort of noncirrhotic, post-transplant patients with ABT-450 boosted by ritonavir, ombitasvir, dasabuvir and ribavirin (AbbVie). “We have every reason to believe that forthcoming results will be similar,” he said.

Fred Poordad

“One caveat in terms of treating this group is that there are some drug-drug interactions that we need to be mindful of,” Terrault said, noting that cyclosporine may present difficulties with the sofosbuvir/simeprevir combination. “This may also be an issue for the ritonavir-boosted AbbVie regimen. That said, most transplant physicians are comfortable managing these drug-drug interactions in the transplant setting.”

Additionally, patients who have previously failed other therapies should also be investigated as thoroughly as possible.

“The prior nonresponders are an evolving group,” Reau said. “I don’t think we need to worry too much about prior pegylated interferon/ribavirin failures, as efficacy with the next wave of therapy appears the same in these individuals as those who are naive to treatment. However, you have to look at prior DAA failures. Some of these populations will be more complicated than others.”

In another study conducted by Osinusi and colleagues, sofosbuvir and ledipasvir were assigned in pretreatment of HCV genotype 1 in a cohort of 12 patients who previously failed on sofosbuvir and ribavirin. All 12 patients achieved SVR12, according to the results.

Reau said caution is warranted when interpreting data sets such as these. A patient who failed with a sofosbuvir/ribavirin regimen may be different from someone who failed sofosbuvir/ledipasvir or the AbbVie three-drug combination, according to Reau.

Despite optimism about other populations, Poordad said treatment failures are “clearly the unknown.” He added, “we simply don’t have any data, and we don’t yet know what to do with them. We will have to wait for those studies.”

Moving Forward

Reau called on regulatory agencies to keep pace with the evolving borders of special populations.

“With the guidelines, it is not so much who to treat, because almost everybody will benefit from viral eradication,” she said. “The question is how to prioritize urgency. Most special populations are prioritized because of higher risk for cirrhosis, decompensation or liver cancer. They should be treated with more urgency than someone who has minimal fibrosis. This does not mean we should not treat those with mild disease. Once there is capacity to treat everyone, treatment should not be limited. Recommendations need to account for these nuances.”

Overall, for Reiberger, “special HCV populations still exist.” These patients remain at high risk for liver-related complications and mortality just due to severity of their underlying liver disease, he said.

Terrault acknowledged the clinical community that will not have the full spectrum of HCV therapies to use in some patient populations. “We can get to the desired endpoint, but we may be limited in the pathways to get us there,” she said.

For Brown, there is a mixture of impatience and optimism in the clinical community right now. “It is good that we have become so impatient with these DAA therapies, and that it is going so well for so many patients, but we have to be cognizant of the fact that we have come a long way in a really short period of time,” he said. “Once you see 90% SVR, you want to see 95%, then you want to see 100%.”

The ultimate goal is to cure HCV, period, according to Brown. “The only way to achieve that goal is to have both a close to 100% cure rate and to treat every patient,” he said. “If we fail to achieve those two things, we will never get a cure.” — by Rob Volansky