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Breaking the 12-Week Barrier: The Search for Shorter Treatment Duration in HCV Therapy

Issue: March 2015

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Despite vastly improved sustained virologic response rates with 12 weeks of newer therapies, researchers have continuously worked for shorter, still effective treatment windows, believing that a cure obtained in 4 or 6 weeks would lighten the load of adherence and cost placed on patients with hepatitis C virus.

The clinical community and the FDA have arrived at 12 weeks as the optimal treatment duration for most novel direct-acting antiviral regimens in most uncomplicated populations with HCV. More difficult patients, namely those with decompensated cirrhosis and those with cirrhosis who are already treatment-experienced, should be treated for 24 weeks. And although 12-week SVR rates of greater than 95% are considerably better than the rates reported for 48 weeks of interferon-based therapy (not to mention the crippling adverse events), researchers have continued to investigate shorter courses of combination DAAs. But it remains to be seen whether 4 or 6 or 8 weeks of treatment will be as effective, cost-effective or durable.

A key element to the discussion is whether real-world outcomes will match those seen in clinical trials. Adherence issues have long been problematic for HCV populations, including injection drug users. Although novel oral therapies are mostly user-friendly, primary care providers and other non-HCV experts may be treating the disease for the first time. The resulting miscommunication and misinformation could also cause a drop-off in SVR12 rates.

Then there is the matter of cost. Treating patients for 8 or 6 weeks can reduce the price tag for a round of therapy, but not if patients relapse or experience burdensome downstream complications. Moreover, with so many new patients flooding the system in a resource-limited environment, there is some debate about whether time and money should be spent on studies looking at shorter regimens. Data sets for 8-week, 6-week and even 4-week courses have raised as many questions as answers.

A solution may lie in more potent drug combinations. The addition of a fourth or fifth agent may eradicate the disease after a brief period of intervention, but whether this approach is worth investigating is also up for debate.

James N. Cooper

HCV Next spoke to a number of experts, including James N. Cooper, MD, professor of life sciences and director of medical research development at George Mason University in Virginia, about these topics. “In general, all of us — clinicians, patients and even pharma — would like to have a shorter period of treatment,” he said. “But it is a matter of collecting data and doing analysis to determine whether 8 or 6 weeks of therapy will be effective. We just can’t say for certain right now. There is still work to be done.”

Rationale for Studying Duration

Most experts appreciate the complexity of the arguments for and against using research dollars and resources toward investigating shorter treatment courses. In a perfect world, fast-acting, durable therapies are most attractive. However, given the obstacle of limited resources, the clinical community must make choices every step of the way.

“Testing has to be the primary focus right now,” James Levin, MD, of the Dean Medical Center in Madison, Wis., said. “There are many people in the baby boomer generation who don’t know they have the disease and need to be identified. Once identified, linkage into care for treatment is mandatory. Once this is accomplished, then we can focus on shortening duration.”

James Levin

Prevalence rates are increasing because of the accumulation of patients being tested in the baby boomer group, but also in groups such as injection drug users, according to Cooper. “What is more troubling is that a lot of people don’t even know that they are infected,” he said. “If we don’t test people, going out 20 or 30 years, the mortality rates could be extremely high, and the cost burden of taking care of patients with end-stage disease or who require transplantation is going to be high.”

For Levin, it comes back to adherence. “It is important to reduce treatment duration as much as possible because of adherence,” he said. “The longer someone is on therapy, the less likely they are to remain adherent.”

Real-World Results

The issue of adherence is the centerpiece of the discussion about how novel DAA therapies will perform in the real world. The move from clinical trials to clinical practice can often lead to some reduction in efficacy for any drug or combination, but whether reducing the duration from 12 or 24 weeks will help or hurt that outcome is up for some consideration.

“Shorter duration will definitely be a plus when it comes to adherence and compliance,” Ziad Younes, MD, medical director and director of clinical research at Gastro One in Memphis, Tenn., said in an interview. “The longer the duration the more likely there is a possibility for intercurrent illnesses and patient forgetfulness.”

Ziad Younes

William Sievert, MD, of Monash University and Monash Health in Melbourne, Australia, discussed the issue in practical terms. “The only way to cure the infection will be to take the medication,” he said. “Health care providers and consumers will need to understand the dosing regimens well and how important it will be to adhere to them.”

Levin added that beyond patient failure to remember to take their pills, pharmacies may not carry enough of the product or have it available in a timely fashion when next prescription is due. “These logistical complications happen not infrequently,” he said. “They can have a damaging effect on response.”

Early data indicate that, when compared with clinical trial results, a real-world reduction in SVR12 may not be seen with many of the new combinations, according to Sievert. “Many of the new DAA regimens are so effective that the number of conditions in the past that constituted difficult to treat groups will no longer be relevant,” he said. “However, patients with cirrhosis will remain an important group in relation to indications for therapy and treatment success. The risk for hepatocellular carcinoma is likely to remain even after cure of HCV infection and long-term surveillance will be important.”

William Sievert

For Cooper, it is a matter of comparison with interferon and ribavirin. “Those of us who have treated patients with the original regimens know how difficult it could be,” he said. “Just a handful of patients would make it through therapy. What we have now, even at 12 weeks, is an incredible change in the way we treat.”

More Drugs vs. Longer Duration

The compliance issue is intertwined with the debate about whether more drug classes could be the magic bullet to shorten treatment duration, according to Levin. “If you want to shorten the duration, you are going to need to hit at least three different enzymes and stop replication,” he said. “That just rocks the virus so it shuts replication completely down.”

Sievert outlined the necessary targets for the research community to investigate. “In addition to viral proteins — NS3/4 protease, NS5A replication complex, NS5B polymerase — there are other viral targets such as inhibitors of viral entry as well as host targets such as cyclophilins and microRNAs,” he said. “Further development of novel drugs and regimens will be beneficial for patients who fail current DAA therapy. Combination therapy aimed at multiple viral and host targets could lead to effective and short duration therapy in the future. If such regimens were safe, well tolerated and affordable, that would be an important step in achieving global HCV eradication.”

Conventional wisdom, however, suggests that more drugs may mean more pills, which could have negative consequences. “If you have to take four different pills multiple times a day, you get co-pay and adherence issues,” Levin said. “When you come up with a multidrug combination, you have to do the most you can to minimize the pill burden.”

Cooper agreed, and offered a solution. “One way to deal with this is to go to directly administered therapy, where they come to the clinic once a day to get their pill,” he said.

For Bradley Freilich, MD, director of the Kansas City Research Institute and the Liver and Pancreas Institute of Kansas City, drug-drug interactions will remain a challenge for the research community. “While there are few side effects with newer drugs, we still have issues with drug interactions when multiple drugs are used and the continued use of ribavirin in some regimens requires closer monitoring.”

C-SWIFT

The latest data set in the duration discussion is the phase 2, open-label C-SWIFT study, conducted by Lawitz and colleagues. This was the first study to investigate 4 weeks of therapy.

Patients were treated with fixed-dose triple-therapy regimen that included grazoprevir (Merck & Co.), elbasvir (Merck & Co.) and sofosbuvir (Sovaldi, Gilead) in a small cohort of treatment-naive patients with genotype 1 infection and without cirrhosis.

Results indicated that 12 of 31 patients treated for 4 weeks (38.7%) achieved SVR12. That percentage increased to 86.7% when patients were treated for 6 weeks.

“The data from C-SWIFT were disappointing when it comes to the 4-week treatment arm,” Younes said. “It tells us that we may not be ready for 4 weeks with agents we have or that 4 weeks of therapy may require a four-drug regimen.” Some have also suggested that there may simply be a floor in terms of treatment duration below which one cannot go and still achieve optimal rates of SVR.

Levin saw its place in this debate: “This was a proof-of-concept trial, which is absolutely necessary in the research process,” he said. “This was a great study that needed to be done, even if it proved that 4 weeks is not enough right now.”

Such studies help determine which patients need longer therapy and which patients may benefit from a shorter course, according to Cooper, while further studies may help identify which patients can attain SVR with ultra-short treatment durations. “Studies like C-SWIFT help us define clinical predictors of outcomes,” he said.

There may be hope in the rapid mechanism of action of DAA therapies, according to Levin. “We know these combinations suppress the virus quickly, sometimes down to thousands of copies within hours,” he said. “Various companies are moving forward with different combinations. We may not have seen the end of 4-week regimens.”

This sentiment was echoed by Freilich. “Just because the results from Lawitz and colleagues were suboptimal doesn’t mean that we will never see effective 4 to 6 week regimens,” he said. “It is certainly possible that others will follow over the next 2 to 3 years.”

When discussing C-SWIFT, Sievert questioned the role of adherence. “A concern with truncated regimens is that they may be relatively unforgiving in terms of adherence,” he said. “With 12- or 24-week regimens, missing a tablet or two may not compromise your chance of cure, but ultra-short regimens may require strict adherence.”

8-week Results

The debate continues about C-SWIFT and the future of 4-week regimens, but the outcomes have been less ambiguous in trials involving 8 weeks of therapy.

Kowdley and colleagues treated 647 treatment-naive patients with genotype 1 disease and without cirrhosis.

SVR12 rates were 94% (95% CI, 90-97) among patients treated with ledipasvir/sofosbuvir (Harvoni, Gilead) for 8 weeks, 93% (95% CI, 89-96) for those treated for 8 weeks with ledipasvir/sofosbuvir plus ribavirin, and 95% (95% CI, 92 to 98) for patients who received 12 weeks of lepipasvir/sofosbuvir without ribavirin. However, relapse rates were 5% with 8 weeks of treatment without ribavirin, and 1% in those treated for 12 weeks. A post-hoc analysis revealed that baseline viral load was a critical determinant of the comparative SVR rates between 8 and 12 weeks of therapy.

Eight weeks of ledipasvir/sofosbuvir yielded 1% higher SVR12 than 12 weeks of ledipasvir/sofosbuvir (97.5% CI, −4 to 6), whereas 8 weeks with ribavirin led to an SVR12 rate that was 1% lower than the non-ribavirin group (95% CI, −6 to 4). Adverse events were slightly more common in the ribavirin group. More than 60% of the patients had HCV RNA less than 6 million IU/ml.

In the ELECTRON 2 study, Gane and colleagues investigated 8 weeks of therapy with sofosbuvir-containing regimens along with pangenotypic NS5A inhibitor GS-5816 (Gilead).

Regimens included sofosbuvir plus GS-5816 25 mg with or without ribavirin, and sofosbuvir plus GS-5816 100 mg with or without ribavirin. Eligible participants were treatment-naive with genotype 3 disease and without cirrhosis.

SVR12 rates were 100% among 27 patients in the 25-mg, non-ribavirin arm; 88% among 24 patients in the 25-mg regimen ribavirin arm; 96% among 27 patients in the 100-mg non-ribavirin arm; and 100% among 26 patients in the 100-mg ribavirin arm.

Tran and colleagues treated patients with daily sofosbuvir 400 mg in addition to GS-5816 25 mg with or without ribavirin, or GS-5816 100 mg with or without ribavirin. Results were reported for patients with genotype 1 disease. SVR12 rates for the 25-mg cohort were 87% without ribavirin and 83% with ribavirin. For the 100-mg group, SVR12 rates were 90% in the non-ribavirin arm and 81% in the ribavirin arm.

Tran also reported findings for patients with genotype 2 disease. Pretreatment for NS5A resistance-associated variants were associated with poorer response rates than those without pretreatment for NS5A RAVs, according to Tran. She suggested that the duration of treatment may have been insufficient in this patient population.

“The main focus is cure of HCV infection, which is achievable in a high proportion of patients with 12 weeks of therapy,” Sievert said. “Recent studies show that 8 weeks’ therapy with a potent regimen is also effective. Some individuals may require a longer duration of therapy, depending on factors such as genotype or cirrhosis. Shorter duration therapy is desirable, as adherence may be easier for those who are treated; however, shorter duration should not come at the price of lower cure rates.”

SYNERGY: 6 weeks

In the SYNERGY trial, Kohli and colleagues investigated the fixed dose formulation of ledipasvir/sofosbuvir for 12 weeks or combined with GS-9669 (Gilead) or GS-9451 (Gilead) for 6 weeks. SVR12 rates were 100% among patients in the ledipasvir/sofosbuvir-only arm, 95% in the GS-9669 and 100% in the GS-9451 arm. No serious adverse events occurred as a result of the study drugs. The researchers noted that alanine aminotransferase normalization occurred by day 14 in 90% of the patients receiving ledipasvir/sofosbuvir alone, 100% of those receiving GS-9669 and 95% of those receiving GS-9541.

Younes discussed the Kohli and Kowdley papers together. “These sets of data are the most relevant I have seen regarding shorter duration,” Younes said. “The data from the SYNERGY trial were most impressive and hopefully will be replicated soon.”

“Some currently available regimens achieve high cure rates in 8 weeks and more are in development,” Sievert added. “Six weeks is feasible but has been studied in only small numbers of patients.”

For Levin, the SYNERGY trial was an “aha moment,” particularly for patients without cirrhosis. “We saw where more potent combinations could be beneficial,” he said.

Cost

“It is hard to predict how shorter duration will affect cost,” Younes said. “The best determinant for cost is not the cost of a single regimen but the cost of a cure. My bias is that shorter regimens will be cheaper, even if they involve a larger number of agents.”

Many experts, including Freilich, predict that competition will eventually drive drug costs down. “A number of companies are jockeying for price securing,” he said.

“We have already seen lower prices in some countries following negotiation with the pharmaceutical industry, and this is certainly a good thing for patients,” Sievert said. There is hope that such negotiations will continue to move forward in the United States.

Express Scripts will be handling the AbbVie drugs, whereas CVS has stayed with Gilead despite the high price tag of sofosbuvir. “As Bristol-Myers Squibb, Janssen, Merck and other companies enter the field, we will see an improvement in the economics,” Cooper said. “They won’t drop to the price of statins, but they will be cheaper than they are now.”

But Cooper noted that the issue is bigger than duration or even the price of the drugs.

“About 40% of people on transplant lists are HCV patients,” he said. “This is a huge projected burden on the health care system. If you can pull more HCV patients from the liver transplant waiting list, it will help.”

For Further Consideration

Freilich suggested that many of the drug companies currently making therapies are investigating pangenotypic compounds that may change the game again, once available. “More sophisticated drugs could make things easier for clinicians,” he said.

Clinicians need all the help they can get, according to Levin. For every HCV expert treating large numbers of patients, there are dozens of community-based practitioners and even methadone clinic physicians attempting to administer these potent combinations to unreliable patient populations. “When we prescribe these drugs, I tell them how and when to take their pills,” he said. “Then our nurse tells them. The pharmacist tells them. We drive the message home that the most likely way they are likely to fail is if they fail to take their medications. Not all practices have the capacity to do this. These things factor into your discussion of treatment duration.”

Cooper suggested that improved methods of evaluating fibrosis and cirrhosis may also play a role in the approach to treatment duration. “The amount of scarring impacts how well the drug will penetrate into the HCV-infected cells,” he said. At the moment, there is a certain degree of guessing when it comes to assessing liver damage.

“To a certain extent, we don’t know what we don’t know,” Cooper said. “We are still early in the process of clinical treatment with these combinations.” – by Rob Volansky