Just a few years ago the standard treatment for hepatitis C virus (HCV) infection in Canada and other high-income countries was a combination of long-lasting interferon (called peginterferon) and the nucleoside analogue (nuke) ribavirin. Both drugs have tolerability issues. Interferon can cause muscle aches, bone pains, fatigue, irritability, anxiety and depression. Ribavirin can cause severe fatigue, itchy skin and can affect the health of the bone marrow. Furthermore, treatment with these drugs usually cured only about 50% of people infected with HCV alone. Rates of recovery among people co-infected with HCV and HIV were much lower.
Both interferon and ribavirin attack HCV indirectly and also help the immune system in its effort to overcome this virus.
About 10 years ago, researchers with the pharmaceutical company Boehringer-Ingelheim in Quebec discovered and began to develop a novel therapy for HCV. This drug was given the interim designation BILN 2061. It could reduce levels of HCV in the blood and worked by interfering with an enzyme needed by HCV-infected cells, called NS3 protease. In other words, this drug was the first HCV protease inhibitor to enter clinical trials. However, while initial results with BILN 2061 were promising, development of this drug was halted due to cardiac toxicity in animals and the worry that the same side effect could occur in people. BILN 2061 was an example of a drug that attacked HCV directly. Such designer drugs are called Direct Acting Agents (DAAs).
Since that time, particularly in the past three years, progress in HCV drug development has moved rapidly. The first wave of HCV protease inhibitors approved in high-income countries were meant to be used as part of the following regimens:
These protease inhibitors, when used as part of combination therapy, generally increased recovery rates to between 65% and 75%. However, they were mainly designed to treat one strain (or genotype) of HCV called genotype 1 (GT1). Moreover, the protease inhibitors had to be taken several times a day, and telaprevir had to be taken with fat. In some cases, prolonged therapy was required. These drugs also had side effects and drug interactions, some of which could be dangerous. A major weakness of both drugs is that their effectiveness relied heavily upon interferon and ribavirin.
In December 2013, two new HCV drugs were licensed for use in Canada:
Sofosbuvir has to be used in combination with ribavirin, and sometimes both ribavirin and peginterferon, depending on the genotype of HCV that is being targeted. Simeprevir has to be used with both peginterferon and ribavirin. Both simepevir and sofosbuvir can be taken once daily without food requirements. Courses of treatment will vary between 12 and 24 weeks, depending on factors such as the strain of HCV and the combination of drugs used. Cure rates can reach between 75% and 100%.
In just four years, that is enormous progress: from 48 weeks down to 12 weeks of therapy and very high rates of recovery.
Both sofosbuvir and simeprevir are being tested in clinical trials in combination with each other and with other drugs, in many cases without the addition of ribavirin or interferon.
Other leading contenders are combinations of drugs being developed by pharmaceutical companies Abbvie and Bristol-Myers Squibb. Thus, perhaps three years from now, it is possible that the choice for initial treatment of HCV, particularly the most common strains found in high-income countries, will be interferon-free regimens. Moreover, newer combinations of DAAs may be even more potent, achieving cure rates of 99% or greater.
Five years from now there may still be a role for peginterferon, though this will probably be restricted to cases where first- and second-line therapies have failed.
Many potential users of HCV treatment have concerns about interferon; this is reasonable because of the potential side effects previously mentioned. But as interferon becomes less necessary, another element of HCV treatment regimens comes under scrutiny -- ribavirin. Historically, exposure to this drug is generally linked to anemia and fatigue. As more powerful DAAs emerge, more researchers are comparing ribavirin-containing and ribavirin-free regimens. In general, these emerging DAAs have few side effects compared to interferon- and ribavirin-based regimens. Furthermore, as interferon is gradually being supplanted in regimens with new DAAs, it is becoming clear that ribavirin causes a wide range of unpleasant side effects. Hopefully, future regimens will be sufficiently potent to exclude ribavirin.
A further indicator of progress is that scientists at the U.S. National Institutes of Health (NIH) recently announced preliminary results from an experimental combination of drugs that suggested only six consecutive weeks of therapy may be needed to cure some cases of HCV, provided the combination of DAAs was sufficiently potent. As we mentioned, the results are still preliminary and relatively small numbers of participants were enrolled but this direction suggests a promising trend. Dutch virologist Charles Boucher, PhD, has suggested that even shorter regimens -- just four weeks -- be tested for their effectiveness.
The field of HCV therapy promises to be exciting for many years as doctors working with available regimens try to answer at least the following questions:
As each year passes, it seems that more is being demanded of emerging HCV regimens.
For the majority of people with HCV infection, therapy is expensive. Most HCV-positive people in high-income countries are able to access therapy either because they have private insurance coverage or they can have therapy subsidized by regional authorities. The listed prices for DAAs are not trivial and so regional health authorities need to negotiate a reasonable discount from manufacturers, as they have done for therapies for cancer, HIV and other catastrophic illnesses. In the absence of a large discount, it is likely that rationing of HCV therapy may become necessary. If a large discount from manufacturers is obtained, health authorities can then begin to plan campaigns where the offer of HCV testing is made followed by counselling and swift referral for HCV treatment in cases where infection has been confirmed.
In this issue of TreatmentUpdate, we cover leading combinations of HCV drugs mainly used for the treatment of HCV mono-infection. However, as more powerful anti-HCV drugs are developed and licensed, leading hepatologists, gastroenterologists and infectious disease specialists increasingly think it is likely that the same combinations used by HCV mono-infected people can be used by people co-infected with HCV and HIV.
Here are some links to important background information about HCV drugs and their effectiveness:
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