The end of 2014 brought exciting new advancements in hepatitis C virus (HCV) treatment, with the approval of Gilead Sciences’ Harvoni (ledipasvir/sofosbuvir) and AbbVie’s Viekira Pak (ombitasvir/paritaprevir/ritonavir; dasabuvir), each of which boasts higher success rates over previously approved treatments, and neither of which requires interferon. But the addition of these regimens to the hep C arsenal hasn’t done much for the estimated 30 percent of HCV-positive Americans who have genotypes 2 through 6 of the virus, since the U.S. Food and Drug Administration (FDA) only approved these new regimens to treat genotype 1. So what are the choices for people who have these genotypes, and what new drugs for them are on the horizon?

Keep in mind that ribavirin is an unfortunate downside to most of the currently available regimens for non-genotype 1’s. The drug can cause anemia, fatigue and birth defects. Additionally, some of the regimens still call for interferon, which can cause miserable, flu-like side effects. Drugs about to emerge from the pipeline will all do away with interferon, and most of them should jettison ribavirin as well.

Genotype 2
The American Association for the Study of Liver Diseases (AASLD) recommends 12 weeks of Gilead’s Sovaldi (sofosbuvir) plus ribavirin, and 16 weeks if someone with genotype 2 has cirrhosis. According to James Burton, MD, medical director of liver transplantation at the University of Colorado Hospital in Aurora, people with genotype 2 who have little or no fibrosis likely have a greater than 90 percent chance of a cure from the 12-week treatment.

“As long as somebody’s able to tolerate the regimen,” says Andrew H. Talal, MD, MPH, a professor of medicine and hepatologist at State University of New York at Buffalo, “I think it is reasonable to go ahead with [Sovaldi] and ribavirin.”

Genotype 3
Whereas genotype 1 used to be the most difficult to treat, genotype 3 has grabbed that dubious distinction since Gilead’s Sovaldi and Harvoni came along. Consequently, the AASLD recommends a full 24 weeks of Sovaldi and ribavirin for genotype 3. Or, as an alternative, the same regimen can be taken with interferon for just 12 weeks. Exchanging treatment time for interferon is not necessarily an equal tradeoff, however, because of interferon’s side effects.

For those being treated for the first time, 24 weeks of Sovaldi and ribavirin has a cure rate of about 92 to 94 percent, while the chance of being cured for those who have failed a previous treatment is in the 80 percent ballpark, and for those with cirrhosis the chance is around 60 percent. In the event of a viral relapse after treatment with Sovaldi and ribavirin, research suggests that the Sovaldi-ribavirin-interferon regimen offers a cure range in the 80 percent ballpark.

Twelve weeks of Harvoni plus ribavirin might be another option for genotype 3—recent research has shown very high cure rates among people with genotype 3 who are new to treatment as well as people who have been treated before. Getting insurance to cover the therapy will likely be difficult since the FDA hasn’t approved Harvoni for this genotype.

Daniel Fierer, MD, an associate professor of medicine and an infectious disease specialist at Mount Sinai Hospital in New York City, says that people with genotype 3 and minimal liver damage may want to wait for the next generation of hep C drugs called NS5A inhibitors to hit the market.

Genotype 4
Although the FDA has not approved Harvoni or Viekira Pak for the treatment of genotype 4, the AASLD recommends one of three options: 12 weeks of Harvoni; 12 weeks of Viekira Pak (without the dasabuvir component) plus ribavirin; or 24 weeks of Sovaldi and ribavirin. As an alternative, there is Janssen’s Olysio (simeprevir) plus Sovaldi, with or without ribavirin, for 12 weeks, or Sovaldi plus ribavirin and interferon for 12 weeks.

If you’re angling for Harvoni or Viekira Pak, the tricky thing will be reimbursement without the FDA’s stamp of approval, since neither therapy is approved for this genotype. According to Burton, your doctor’s office would have to appeal to your insurance company, which he’s successfully done with a couple of patients he put on Harvoni so far. When it comes to waiting for more effective drugs, he says that Harvoni, with its cure rate in the mid-90 percent range, is likely to be as good as they get. If you are looking to be treated soon, the main reason to stall would be to wait for a more hospitable insurance environment.

Genotype 5
Twelve weeks of Sovaldi, ribavirin and interferon is recommended, with an alternative of interferon and ribavirin for 48 weeks. Genotype 5 is rare in the United States, and none of the drugs that have come out in the last two years is approved to treat it.

Genotype 6
Like genotype 5, genotype 6 is rare in the United States, and none of the current crop of direct-acting antivirals has been approved for its use. The AASLD recommends 12 weeks of Harvoni, and, as an alternative, Sovaldi, ribavirin and interferon for 12 weeks.

To wait or not to wait?
“If someone has no fibrosis and has had hepatitis C for a long time, it’s hard to make the case that they need treatment right now,” says Burton.

Indeed, the most urgent need for treatment lies with those who have advanced fibrosis or cirrhosis. Unfortunately, cure rates with current therapies may be lower if someone has cirrhosis.

Over the next year or so, it’s likely that new drug regimens will be approved with specific indications for those with genotypes other than 1, allowing for higher cure rates in many cases, as well as more tolerable regimens. Additionally, an FDA indication will hopefully allow for greater ease in gaining insurance coverage. This is not to say, however, that the reimbursement experience will be a breeze, considering how insurers, both public and private, have been dragging their feet when it comes to paying for highly expensive hep C treatments.

Perhaps the biggest upcoming hep C regimen is Gilead’s fixed-dose combination tablet of Sovaldi and the NS5A inhibitor GS-5816. Gilead is conducting four Phase III studies of this regimen among people with all genotypes of hep C, and is expected to file an application for approval sometime this year. Phase II studies offer cure rates in the mid-90 percent range across genotypes.

Although the timing is unclear, the FDA will likely approve Bristol-Myers Squibb’s (BMS) NS5A inhibitor daclatasvir in combination with Sovaldi for genotype 3. BMS initially filed for approval of the NS5A inhibitor daclatasvir with the company’s NS3/4A protease inhibitor asunaprevir for genotype 1b, but withdrew the application for the latter drug when it became apparent that the cure rates for the pair fell below today’s standards. BMS is working with the FDA to gain approval of daclatasvir in combination with other therapies, setting its sights on genotype 3s as well as those coinfected with HIV and people who are awaiting or have had a liver transplant. The company intends to resubmit its application to the FDA soon. In the recent Phase III ALLY-3 trial, 12 weeks of Sovaldi and daclatasvir among people with genotype 3 cured 90 percent of those treated for the first time and 86 percent of those who had been treated before.

Additionally, Merck has a host of Phase III trials running of its fixed-dose combination tablet of the NS3/4A protease inhibitor grazoprevir and the NS5A inhibitor elbasvir, testing the regimen with all genotypes (although people with genotypes 2, 3 and 5 are underrepresented when compared with genotypes 1, 4 and 6). The company intends to file for FDA approval during the first half of the year.