Damian McNamara

November 22, 2016

LAS VEGAS — Rapid advances in the treatment of hepatitis C have clinicians seeing outcomes they never thought possible, and experts are optimistic that more complex and challenging patients will respond to therapy.

However, treatment choice can be tricky. And caveats are emerging, including reports that direct-acting antivirals used for the treatment of hepatitis C might increase the risk for hepatitis B reactivation and liver cancer in some patients.

But the big picture is one of clinical success. "We know that 95% to 100% of patients treated for hepatitis C can be cured. It's pretty amazing," said Tram Tran, MD, from the Cedars–Sinai Medical Center and the University of California at Los Angeles.

Dr Tran is one of several experts who provided an update on treatment regimens, genotypes, and evidence at the recent American College of Gastroenterology 2016 Annual Scientific Meeting.

 
Unlike most viruses, this is a virus we can cure.
 

"Unlike most viruses, this is a virus we can cure," said Stanley Cohen, MD, from University Hospitals Cleveland Medical Center, whose presentation looked at the latest options for the treatment of genotype 1.

"The key is to keep screening, especially the baby-boomer generation," Dr Cohen explained. Baby boomers should have at least one hepatitis C test, he said, citing an emergency department study that showed high rates of unrecognized disease in patients born from 1946 to 1965, as reported by Medscape Medical News.

Expanding Therapeutic Options

For patients with genotype 1 hepatitis C, which is the most common form in the United States, cure rates are high with recommended treatment combinations, Dr Tran said. The sustained virologic response cure rate in this cohort of patients is greater than 90%, "so I think for genotype 1, we have it in the bag," she said.

The goals of therapy include a sustained virologic response 12 weeks after the end of treatment (SVR12), although some clinicians monitor patients out to 24 weeks.

 
I'd like to say that liver experts are smart, but we've jumped on the HIV model.
 

More than 99% of patients who achieve a sustained virologic response will remain negative. "I'd like to say that liver experts are smart, but we've jumped on the HIV model," Dr Cohen quipped.

A meta-analysis of 34,563 patients — reported at the American Association for the Study of Liver Diseases meeting in 2014 (abstract 44) — showed that the attainment of a sustained virologic response almost completely eliminated the need for liver transplantation.

One thing that concerns clinicians is Model for End-Stage Liver Disease (MELD) purgatory, said Fred Poordad, MD, from the Texas Liver Institute in San Antonio, whose presentation looked at the complicated hepatitis C patient. MELD purgatory happens when sick patients get better and their MELD scores improve, which can reduce the chance of organ transplantation, but their quality of life is not significantly better.

The treatment regimens for genotype 1 that are approved by the US Food and Drug Administration (FDA) are very effective, Dr Cohen said.

However, it "depends a bit on whether or not you have cirrhosis," he added. Historically, regimens that included ribavirin — which is associated with adverse effects — were common. "Ribavirin is not dead yet. It still has a role, especially in difficult-to-treat patients," Dr Cohen pointed out.

"So which drug regimen combination do we use?" he asked. All regimens in the registration trials of treatment-naïve patients with genotype 1 are above 90%, and many approach 100%, he reported. In addition, about 95% of treatment-experienced genotype 1 patients typically achieve a sustained virologic response.

"In some cases, 8 weeks can be as effective as 12 weeks, which is cost-saving and worth considering," Dr Cohen added.

"We have other genotypes in the bag as well," said Dr Tran. In June, the FDA approved the pangenotypic combination of sofosbuvir and velpatasvir (Epclusa, Gilead Sciences) for genotypes 1 to 6, as reported by Medscape Medical News. "Genotypes 2, 4, 5, and 6 seem to have excellent overall sustained virologic response," she reported.

But "it is also very important for us to successfully cure genotype 3 patients," she explained. In the past few years, sustained virologic response rates were not always high in this cohort of patients, but with the new pangenotype combination, they are. However, some cirrhotic patients with genotype 3 hepatitis C might need ribavirin as well, she said.

Therapies in development could make a clinical difference. "We have several regimens in the pipeline that could further our ability to treat genotypes 2 and 3," said Joseph Lim, MD, from the Yale University School of Medicine in New Haven, Connecticut, whose presentation focused on genotypes 2 and 3.

Staying Up to Date

 
Don't try to memorize the 28 regimens.
 

As treatment combinations continue to be approved by the FDA, it can be difficult to stay informed.

"What I want is for the average GI, infectious disease, or primary care doctor to keep up. Don't try to memorize the 28 regimens," Dr Cohen told Medscape Medical News. Instead, he recommends that physicians consult the guidelines issued by the American Association for the Study of Liver Diseases and the Infectious Disease Society of America, which are continuously updated.

These guidelines "change weekly or monthly as new information comes out," Dr Cohen explained. "It's a living, breathing, online guideline."

The link between direct-acting antiviral therapies and the reactivation of hepatitis B or the increase in the risk for liver cancer "is very controversial," said Dr Tran. "I would say it's relatively early in our understanding of this potential phenomenon."

Hepatitis B Reactivation and Liver Cancer Risk

Dr Tran said she has seen more reactivation of hepatitis B in the past year or so.

"If you are a clinician treating a patient for hepatitis C, you need to make sure you check them for hepatitis B," she explained. When direct-acting antivirals drive an immediate drop in the hepatitis C virus, it can cause hepatitis B to flare. "The FDA has seen 24 case reports in which, as soon as the hepatitis C goes down, the hepatitis B virus goes up," she explained. In some cases, this can cause severe viremia.

In October, the FDA issued a boxed warning on all direct-acting antivirals because two patients required liver transplant or died because of hepatitis B reactivation, Dr Tran said.

In addition, "you need to make sure you follow patients for liver cancer, especially if they have any significant degree of fibrosis and certainly if they have a history of liver cancer," she explained.

These two risk factors for the recurrence of aggressive liver cancer emerged in a recent report of 344 cirrhotic patients treated with direct-acting antiviral therapies and followed for 6 months (J Hepatol. 2016;65:727-733). The researchers reported a sustained virologic response rate of 91.0%, but also detected liver cancer in 7.6% of the cohort, 28.0% of whom had been previously treated for liver cancer.

In a recent study, the incidence of hepatocellular carcinoma after a sustained virologic response was still "relatively high," at 0.33% per person-year risk (Hepatology. 2016;64:130-137).

At the International Liver Congress earlier this year, there was a "lot of press on stage 3 and 4 patients showing up with liver cancer 2 to 3 months post-treatment, so it's something to keep an eye on," Dr Cohen said.

Other Clinical Challenges

One of the challenges that clinicians have overcome is decompensated cirrhosis. "Just a couple of years ago, we could not treat these patients — interferon made decompensation worse — but we can treat them today," Dr Lim said.

Resistance is still an issue, though. Many of the approximately 5% of patients who fail therapy do so because of differences at baseline. "Previous therapy matters. If there was previous failure of protease inhibitors, there are multiple options for retreatment," said Dr Poordad. However, "if there is previous failure of any NS5A, the recommendation is to wait for new therapies, which should be here in the next year." Today's failures related to resistance will be successfully treated tomorrow, he pointed out.

 
There will be rescue therapies coming very soon.
 

For patients requiring salvage therapy, triple-therapy regimens with direct-acting antivirals look promising in phase 2 studies. Most physicians have one or two patients in their clinic who fail to respond. "I'm optimistic," said Dr Tran. "Whether it's a three-drug combination or a very potent two-drug combination, there will be rescue therapies coming very soon."

Renal disease is also an issue. About 8% of dialysis patients in the United States have hepatitis C; in some pockets of the world, that rate is closer to 40% to 50%, Dr Poordad said. Unfortunately, one of the most common drugs, sofosbuvir, is not renal-friendly. However, the combination of elbasvir and grazoprevir for 12 weeks showed efficacy in a recent study (Lancet. 2015;386:1537-1545). "Even patients on dialysis, who are usually quite sick, can tolerate [this combination] with excellent SVR," said Dr Poordad.

For patients with cirrhosis and portal hypertension, interferon-free treatments can be effective. A recent study showed no increase in 104 patients with portal hypertension induced by hepatitis C, and 63% experienced a reduction in hypertension (J Hepatol. 2016;65:692-699). "The earlier we catch them in the clinical development of portal hypertension, the better the chance of being able to reduce hypertension and all the complications," Dr Tran said.

After orthotopic liver transplantation, the key is "to treat all patients as quickly as you can. Don't wait until they progress to cirrhosis, then you get a lower SVR," Dr Poordad explained. In such cases, outcomes can be similar for patients with and without cirrhosis, provided the patient has not decompensated, he added.

A member of the audience asked whether patients with compensated cirrhosis who are treated with direct-acting antivirals can become decompensated.

"That has been observed, but the natural history of decompensation is 4% to 7% per year," Dr Poordad reported. "We're still trying to figure out if the DAA regimens themselves contribute. We need to remain open-minded because we still don't know everything about these medications."

Another member of the audience asked how to follow patients after treatment.

"I think the answer is variable," Dr Cohen responded. "I personally check hepatitis C virus RNA at 1, 3, and 6 months post-therapy."

"I also check at 1, 3, and 6 months," said Dr Lim. "If they have stage 0 to 2, I will do a FibroScan [transient elastography exam, EchoSens Corp.] and consider discharge from practice. If they have stage 3 or 4, I keep them long-term. For someone with more advance disease at baseline, longer-term monitoring is warranted," he added.

"I agree," said Dr Poordad. "The FDA does accept SVR12. But in the long-term studies, we see 1% relapse rates between weeks 12 and 24, so we should bring them back at 24 weeks for a check."

Promising Future

An ultrarapid virologic response is another potential advance, Dr Tran said. In a recent study, 18 of 26 patients with hepatitis C tested negative on day 2 of their antiviral regimen (Lancet Gastroenterol Hepatol. 2016:1:97-104). However, the study population consisted of Asian patients with genotype 1a disease, "so I'm not sure this will pan out for most patients."

The present is "pretty great," Dr Tran said. "All genotypes can be cured at high rates, although some may still need more ribavirin, including the cirrhotic and previously treated patients."

"The future is extremely positive. We see data for retreatment strategies coming for patients who relapse," she added. In addition, shorter therapies might be possible for all patients. "I think 8 weeks of treatment for all patients has strong potential. We will continue to push boundaries."

"When I first started, cure rates were 16% on interferon," Dr Cohen said. "We are now at a point we should almost be able to eradicate hepatitis C."

Dr Tran reports financial relationships with AbbVie, Bristol-Myers Squibb, Gilead Sciences, and Merck. Dr Cohen reports financial relationships with AbbVie, Bristol-Myers Squibb, and Gilead. Dr Poordad reports financial relationships with AbbVie, Bristol-Myers Squibb, Gilead, Janssen, Merck, and Salix. Dr Lim reports financial relationships with Bristol-Myers Squibb and Gilead.

American College of Gastroenterology (ACG) 2016 Annual Scientific Meeting. Presented October 17 and 19, 2016.

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