Which Hepatitis C Treatment to Start

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Are All Treatments Created Equal?

The last five years have seen a flurry of drug approvals for new and highly effective hepatitis C (HCV) medications that don't require peginterferon and ribavirin (Rebetol) for most patients. These approvals have come at an almost breakneck pace. For example, simeprevir (Olysio), one of the first new direct-acting antivirals (DAAs), has fallen out of favor less than four years after its approval.

In a major milestone, recent approvals of the two-drug combination sofosbuvir/velpatasvir (Epclusa) and the three-drug combo sofosbuvir/velpatasvir/voxilaprevir (Vosevi) mean the addition of new drugs that can treat all six HCV genotypes.

In addition to new treatments, new side effects have recently become apparent. In 2016, the U.S. Food and Drug Administration (FDA) warned that all DAAs carry the risk of reactivating hepatitis B, after two patients died and 24 cases of reactivation were reported. Physicians are now advised to screen for hepatitis B, and patients are urged to watch for side effects.

Considering the variety of treatments now available, what's the best DAA for each patient? Even with sofosbuvir/velpatasvir/voxilaprevir on the market, picking the right drug will depend on each patient's medical history, level of liver damage, coinfections and, to some extent, insurance coverage.

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Rapid-Fire Approvals and a "Living Document" Guidance Document

The two medical associations responsible for crafting HCV treatment guidelines are the American Association for the Study of Liver Disease (AASLD) and the Infectious Disease Society of America (IDSA). Together, these associations have crafted what they call a "living document," which is posted online and updated continually to reflect the rapidly changing treatment landscape. Still, as of August 2017, some newer drugs such as sofosbuvir/velpatasvir/voxilaprevir had not been incorporated into the document.

Yet, despite the rapid-fire approvals, almost all of the prior guidance holds true. For example, the guidelines recommend treatment for all HCV-infected people, except in extreme circumstances such as terminal illness. In addition, the guidelines no longer recommend daily sofosbuvir (Sovaldi) with ribavirin or pegylated interferon (even in combination) due to the plethora of better alternatives now available.

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Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi): Pan-Genotypic and Salvage Therapy

The newest player in the DAA market is sofosbuvir/velpatasvir/voxilaprevir, a triple-drug regimen that was approved to treat all patients with HCV genotypes 1-6 and without cirrhosis or with only minor cirrhosis. In addition, the drug is the first to be approved to treat patients who have previously failed treatment with an NS5A inhibitor.

Sofosbuvir/velpatasvir/voxilaprevir is essentially a new-and-improved version of the two-drug combo sofosbuvir/velpatasvir. Both are made by Gilead, which also makes earlier blockbusters sofosbuvir and sofosbuvir/ledipasvir (Harvoni). Gilead has made waves for its high price tags, famously pricing sofosbuvir at $1,000 per pill. At $74,760 for a 12-week course of treatment, sofosbuvir/velpatasvir/voxilaprevir isn't significantly more discounted than prior regimens from Gilead. Ultimately, a prescription for sofosbuvir/velpatasvir/voxilaprevir may come down to the preferred status of Gilead's drug in the eyes of each patient's insurance plan.

Sofosbuvir/velpatasvir/voxilaprevir is likely to be a good option (both medically and financially) for tough-to-treat patients who have previously failed treatment with an NS5A inhibitor.

Image credit: Gilead Sciences, Inc.

Sofosbuvir/Velpatasvir (Epclusa): The Precursor to Sofosbuvir/Velpatasvir/Voxilaprevir (Vosevi)

Sofosbuvir/velpatasvir (Epclusa), approved in June 2016, is a two-drug combination of Gilead's backbone "nuc" sofosbuvir and the pan-genotypic NS5A inhibitor velpatasvir. It was the first single-pill regimen that could treat all six genotypes. Previously, patients with tough-to-treat genotypes, such as genotype 3, were given a combination of Gilead's sofosbuvir and Bristol-Myers Squibb's daclatasvir (Daklinza), another pan-genotypic NS5A.

Now, the recent approval adds a third drug, voxilaprevir, to Gilead's pill. This is the first single pill not only to treat all six genotypes but also to work in patients who have previously failed treatment with an NS5A.

Guidelines recommend that patients who fail treatment should be tested for treatment resistance. As of August 2017, the treatment guidelines had not yet incorporated sofosbuvir/velpatasvir/voxilaprevir. Currently, the guidelines suggest that patients without detected NS5A resistance-associated substitutions should be retreated with sofosbuvir/ledipasvir or with sofosbuvir/velpatasvir, both with ribavirin, for 24 weeks. For patients with detected resistance, the guidelines recommend retreatment with sofosbuvir and simeprevir -- and ribavirin -- for 24 weeks. This guidance is specific to patients with genotype 1, the most common one in the United States.

Image credit: Gilead Sciences, Inc.

AbbVie's Trio: Ombitasvir/Paritaprevir/Dasabuvir (Viekira Pak)

Since 2014, the pharmaceutical company AbbVie has sold its three-drug combination ombitasvir/paritaprevir/dasabuvir (Viekira Pak), plus ritonavir, which boosts blood levels of paritaprevir. The combination of pills is approved to treat patients with genotype 1 infection, the most common genotype in the United States.

A second formulation, ombitasvir/paritaprevir/ritonavir (Technivie), is essentially the same, but omits dasabuvir. It is recommended as a preferred treatment for genotype 4 patients with compensated cirrhosis. However, in October 2015, both pill combos took a hit when the FDA warned that they can cause liver damage in patients with severe liver disease or damage classified as Child-Pugh class B or C.

Image credit: AbbVie Inc.

Late to the Party: Merck's Elbasvir/Grazoprevir (Zepatier)

On Jan. 28, 2016, the FDA approved elbasvir/grazoprevir (Zepatier) with or without ribavirin for the treatment of chronic hepatitis C genotypes 1 and 4 infections in adult patients. The two-drug combination comprises an NS5A inhibitor (elbasvir) and an NS3/4A protease inhibitor (grazoprevir).

Although it is not pan-genotypic, elbasvir/grazoprevir can be used to treat patients with end-stage kidney disease and people who are on dialysis -- a special population that is not well met by other regimens. The drug was approved to treat patients with mild to moderate cirrhosis, but it is not recommended for patients with severe liver impairment.

Image credit: Merck & Co., Inc.

Newcomers: Glecaprevir/Pibrentasvir (Mavyret) and Daclatasvir/Asunaprevir/Beclabuvir

Two new drugs coming down the pipeline promise to address the small remaining areas of unmet need. AbbVie's two-drug combination glecaprevir/pibrentasvir (Mavyret) is a pan genotypic regimen that also has data to support its use in people with chronic kidney disease. The FDA approved this drug in early August 2017, providing a new option for patients with chronic kidney disease and any genotype.

A second experimental regimen, Bristol-Myers Squibb's daclatasvir/asunaprevir/beclabuvir, is currently in Phase III trials. The drug combo, which includes the approved NS5A daclatasvir, is being tested in patients with chronic hepatitis C infection, genotypes 1, 4 and 6.

Image credit: AbbVie Inc.