by Roberta Villa

Table of contents

  1. What are the current treatments available for HepC and how did we get there?
  2. How is the efficacy of anti HCV drugs measured? Is this outcome reliable?
  3. How effective are the new HCV drugs in trial and in the real world?
  4. What drives the choice of treatment?
  5. Could widespread use of new drugs lead to emergence of resistant strains?
  6. Do new drugs have side effects?
  7. Does co-infection with HIV change the management of hepatitis C?
  8. Who determines dosage and duration of treatments?
  9. Who should be tested?
  10. Who should be treated?
  11. Is eradication of HepC the actual goal? 
  12. How much do these new drugs cost?
  13. How is (and could) Hepatitis C be treated and managed in low and middle resources countries?

1. What are the current treatments available for HepC and how did we get there?

In the span of just a couple years, approval of new treatments for hepatitis C has given real hope to patients, particularly those who have experienced the severe side effects of older regimens, without achieving treatment success.

HCV drug development timeline

The first treatment for Hepatitis C was approved in the nineties. It was a manufactured version of interferons, proteins naturally produced in the body that enhance the immune system’s response to viral infection. Interferon-alfa (IFN-α) treatment required subcutaneous injections three to five times per week.

In 2001, two modified forms of interferon were introduced (PEGylated interferons: PegIFN-α2a and PegIFN-α2b). These modified interferons circulated in the body for a longer period of time before being cleared by the kidneys, so injections were only needed once a week.

A drug combination that included PEGylated interferon-α later became the standard of care for hepatitis C. Ribavirin was administered with PEGylated interferon-α to enhance its effects, but despite this improvement, still less than half of patients benefitted from treatment. Genotype 1, the most common strain of Hepatitis C in higher income countries, was particularly unresponsive to these drugs. The treatment regimen required ingestion of several capsules of ribavirin per day and one injection per week of PEGylated interferon for 48 weeks. Many people abandoned therapy prematurely because of intolerable side effects such as flu-like symptoms, including fever and weakness. Anemia was also common and often severe. Some patients reported that their treatment had a significant impact on mood, leading to feelings of depression (See Figure 1).

These treatments improved the patient’s natural response against HCV, but did not target the virus itself. Efficacy was low, while side effects were significant.

A cure against HCV genotype 1, the most common strain of HCV in high income countries, remained elusive. Drug companies saw a large and potentially profitable market so they steered funds and resources towards this branch of research. Publicly funded research was also aggressively investigating viral hepatitis C during this period.

These efforts led to the development of a new class of drugs – the direct-acting antivirals (DAAs). This class of drug does not affect the patient’s immune system, but attacks the virus itself, blocking one or more steps of its life-cycle. The precise mechanism of the different DAAs will be explored in section 2.

In 2011, the protease inhibitors were the first DAAs to be introduced, named for their ability to inhibit viral protein synthesis. Boceprevir and telaprevir, both given orally in combination with PEGylated interferon-α and ribavirin, improved cure rates (the percentage of people cured)― up to 75% for genotype 1, but they also produced additional side effects to those already present with previous treatments and increased the overall burden of side effects proportionately (see Figure 1).

Another research breakthrough led to the development of new HCV DAAs that could inhibit viral replication. Their first passage from clinical trials to the real world was a disappointment, however; despite good results in initial trials, these treatments proved to be less effective and more toxic (even fatal) when used in the field.

The turning point was in 2014. A new class of direct acting antivirals (DAA) was released on the market. Sofosbuvir was very effective on genotype 1 and produced successful results in a great majority of patients. Administered in combination with PEGylated interferon and ribavirin, Sofosbuvir tablets produced a cure rate of over 90 % of patients with hepatitis C genotype 1, 2, 3 and 4. In addition, the new treatment was much shorter (usually 12-24 weeks), simple to take, and very well tolerated.

In the months that followed, other DAA drugs and DAA drug combinations with comparable dramatic success rates were approved (see table 1). Indeed, it had become clear that by combining more than one drug, each acting on a different aspect of the virus life cycle, the highly mutable Hepatitis C virus could be stopped, and its resistance to treatment prevented (see section 2 for a discussion on how drug combinations successfully provide a high barrier to resistance).

Another advancement between late 2014 and early 2015, was the discovery that interferon-free regimens (sometimes even without ribavirin) can be equally effective, showing that it may be possible to circumvent the worst treatment side effects that continued to hinder treatment and compliance in some patients.

Figure 1

BeAware BOX 1The development of the new DAA drugs caused a major shift in the hepatitis C treatment landscape –they could be used to treat every patient with the disease. However getting access to them would prove difficult. Their prohibitive price has meant that they are beyond the reach of a majority of patients, especially in low and middle income countries.

All over the world, patient associations, doctors and health authorities are advocating for industries to drop these prices in order to treat as many patients as possible, as was done for HIV/AIDS drugs.

This has shifted the focus of the hepatitis C problem from a medical issue to one of public policy. Political, economic, and ethical issues surrounding access to care and who pays the costs of medical research, drug development and marketing, are at the forefront of this rapidly evolving health issue.

Table 1


According to their mechanism of action, the new DAAs drugs can be classified into 4 classes:

1. the first class, NS3-4A protease inhibitors, block the production of viral proteins (i.e. simeprevir, paritaprevir)

All the other three classes block the production of viral genes (RNA). These include:

2. Nucleotide analogues that inhibit the enzyme (NS5B polymerase) needed for viral replication (i.e. sofosbuvir);

3. Non-nucleotide analogues that inhibit the same enzyme (NS5B polymerase) needed for viral replication but with a different mechanism (i.e. dasabuvir);

4. NS5A inhibitors block both the replication and the assembly of the virus (i.e. ledipasvir, daclatasvir, ombitasvir,..)

As of July 2015, the approved treatments available for treating Hep C are summarized in the following table:

Table 2b_revised_smaller


BeAwareBOX 2

Many other new molecules and combinations are currently under investigation in order to simplify the treatment and tackle the few patients resistant to the current available drugs.

2. How is the efficacy of anti HCV drugs measured? Is the currently used outcome reliable?

The best way to assess the efficacy of anti HCV drugs as well as of any other treatment would be through well designed randomized, placebo controlled trials – possibly independent from industry – that would measure the effect of drugs on the progression of liver disease and on the risk of illness/morbidity and mortality. These would prove that the new drugs not only cure infection, but can prevent more advanced liver disease and deaths that happen decades later in people with chronic infection.

However disease progression of chronic hepatitis C is very slow. Conditions like cirrhosis and liver cancer take decades to develop and these clinical outcomes must be measured 20-30 years after the time of treatment. These types of trials would be very costly. Furthermore, a relatively small proportion of patients develop a severe disease (15-30% of patients with chronic hepatitis develop cirrhosis and 3-17% of patients with cirrhosis develop liver cancer), so large numbers of participants would need to be included in these trials to reach statistical significance. There are also ethical considerations, regarding the use of a placebo control group in this case!

A surrogate outcome is therefore used in these situations. This is a measure that does not directly assess the important outcome (ie.: reducing severe liver disease and death), but is believed to reflect the important outcome. The measure used here is the continued absence of hepatitis C virus in blood for 6 months which is referred to as a sustained virologic response (SVR)).

The reliability of this outcome has been questioned by some experts because it is not clear whether the virus might “hide” in certain cellular compartments and body tissues while the bloodstream is clear of virus. Several studies conducted in the past with older therapies showed however that a sustained response usually corresponds to 1) a lack of virus in other body tissues -indeed, the idea that the virus could hide in so called “sanctuaries”, i.e. other tissues, as HIV does, has never been proven and 2) less liver related illness/morbidity and mortality compared with people without a sustained response.

3. How effective are the new HCV drugs in clinical trials and in the real world?

Indeed, recent clinical trials on the new drugs for HCV, the DAAs, are reporting 85-100% cure rates across genotypes, with the precise level of effectiveness depending on the genotype and drug combination. However, it is important to note that these drugs are still under investigation, and we do not yet have much data on what the results will be in the field– Real life is always messier in terms of treatment safety and efficacy. Below are the issues that must be considered when interpreting clinical trial results.

BeAwareBOX 3

The 5-15% matter

Finally, even a small percentage, such as the 5-15% of patients that will not respond to treatment or experience a relapse, can represent a very large absolute number of patients that could fail treatment when it comes to treating millions of people all over the world.

If we anticipate that 10 per cent of patients will not experience success with the new drugs, then 15 million people in the world will not be cured with treatment. So we can say that the great majority of patients today in theory could be cured, but not all of them. Issues with resistance will also arise in this patient population, because treatment failure will represent selection of drug-resistant viruses, and alternate second-line treatment choices will be limited.

Table 3_revisedFINAL_smaller


4. What drives the choice of treatment?

The choice of treatment for chronic hepatitis C is driven by many factors linked to:

  • the virus genotype (and sometimes subtype)
  • the stage of liver disease (especially the presence of cirrhosis)
  • patient’s clinical history (such as being treated before/having undergone a treatment failure)
  • The patient’s genetic characteristics (for example which ethnic group they are part of) can have an impact on the efficacy of older drugs. A variant of gene IL28B – a gene involved in the immune response to HCV. There are three IL28B subtypes – CC, CT, TT. If a person has the CC variant of the gene, the individual is not only more likely to clear the virus without treatment during the acute phase, if a chronic infection does develop it is 3 times likely that PegIFN and Ribavirin will cure infection.

In addition, the presence of a Q80K genetic variant that develops in certain strains of HCV makes the virus less susceptible to simeprevir.

Possible co-infections (i.e. with Hepatitis BVirus and/or HIV) do not influence therapeutic approaches with the new drugs, but still need to be considered in all those settings where the latest treatments are not available.

Finally, the most relevant, often critical, factor in the choice of treatment in most parts of the world is currently the access to the new drugs.

This issue will be dealt with in a following section.

The European Association for the Study of the Liver (EASL 2015), as well as the American Association for the Study of Liver Diseases (AASLD) and the Infectious Diseases Society of America (IDSA) rely on clinical aspects to formulate treatment recommendations. These recommendations identify the best approved treatment options (either in Europe or in the USA) for each patient based on current scientific evidence.

On this basis, without considering economic issues, the EASL 2015 guidelines recommend interferon-free regimens as the best option, when available, in all HCV infected patients because of their effectiveness, ease of use, and tolerability.

Where new drugs are not available, either PegIFNα+ ribavirin or triple combination with telaprevir or boceprevir (protease inhibitors) remain acceptable in selected patients likely to respond, at least until new drugs become available and affordable.

The choice of treatment is mainly based on HCV genotype, HCV subtype and viral load. Also to be considered is whether the patient has cirrhosis, or has been treated previously with other drugs.

Different options, unless otherwise indicated, are equally effective, so that doctors can choose what is best and economically feasible for each patient, according to the reimbursement conditions in their own country.


Table 4B copy


5. Could widespread use of the new drugs lead to emergence of resistant strains?

Since the hepatitis C virus can change or mutate, some strains naturally acquire genetic characteristics that make them resistant to one treatment or another. When an antiviral drug is given, it blocks replication in all sensitive viruses. Those viruses that are resistant are able to proliferate in that patient. The patient does not respond to treatment anymore and the disease grows. To avoid this, a combination of drugs that affect different aspects of HCV viral replication have always been given together, for a duration that is sufficient to eliminate the infection.

Despite this, some patients still become resistant to treatment and other options have to be found. The best strategy for these cases is still under investigation.

6. Do new drugs have side effects?
The new drugs against hepatitis C, the so-called “second-generation DAAs”, are very well tolerated by patients and cause fewer, and much less severe, side effects than the previous treatments. Patients who were previously treated with earlier generations of medications report a significant difference.

However, it cannot be said that this issue has been completely overcome. Many regimens still require interferons and/or ribavirin because of the characteristics of the virus and the stage of liver disease. The side effects of these drugs (anemia, low white cell count, headache, fatigue, skin rashes and so on) must be considered by all the patients for whom interferon and ribavirin-free treatment cannot be prescribed.

The risk of adverse events may always be considered an acceptable alternative to liver failure or cancer in patients with advanced liver disease. However for those without concurrent liver disease the risks associated with treatment may be less acceptable, as only a fraction of them will go on to develop serious consequences.

Moreover, safety data on new treatments are still limited, since post-marketing surveillance (i.e. the recording of any registered side effect when a drug is on the shelves) for most of these drugs has just begun. Post-marketing surveillance is always important, but even more so for new drugs such as these, which were approved very rapidly because of their ability to cure infection and save lives.

In the clinical trials, the rate of serious adverse events (resulting in persistent disability, hospital admission, or death) was very low (0,5-3%) . Such a small percentage, could still represent a significant absolute number of cases if millions of people are treated. Of the estimated 150 million people in world who are infected chronic HCV, this percentage of adverse events would represent 750, 000 to 4.5 million people affected.

Treating hundreds of thousands people could also reveal rare side effects unlikely to be detected in trials with fewer participants.

Moreover, the safety profile of these drugs needs to be evaluated in unselected patients, who can have other concurrent diseases, genetic characteristics, be of different ages and ethnic groups.

The main cause for concern at the moment is the risk of drug interactions. This kind of side effect can more easily emerge when treatment is given in the real world, where patients can have other diseases for which they take medications not considered during clinical trials.

An example of this is the recent FDA advisory about amiodarone, a drug used to treat the irregular beating of the heart (arrhythmias). When taken with simeprevir and other antivirals, severe (even fatal) bradycardia has been reported prompting the US FDA to published an alert against the concomitant use of these two medications.

7) Does co-infection with HIV change the management of hepatitis C?

There is a significant amount of stigma associated with HIV and HCV. Both are infectious diseases which in and of itself is sufficient to lead to stigma and discrimination, especially if the diseases and their methods of transmission are not well understood by the general public. Further, in certain countries the incidence of these viruses is highest among intravenous drug users.

Co-infection with HIV does not have an impact on the success rate of the new direct antivirals. However co-infected patients still require more attention because they have a higher risk of drug-drug interactions and their impaired immune systems could let the disease progress more quickly and aggressively.

8. Who determines dosage and duration of treatments?

Optimal dosage and length of anti HCV treatments have been established in clinical trials. The recommended dosage is a set parameter, not to be changed. However, the degree of “aggressiveness” of a drug therapy can be changed by altering: 1) the number of drugs in the combination and 2) the length of treatment. “Overtreatment” may be advisable in real life settings for patients who are more difficult to cure. However, under-treatment without supporting evidence could lead to the emergence of dangerous resistant strains.

9. Who should be tested?

Since the vast majority of people are unaware of their condition because they are asymptomatic or experiencing symptoms too generic to arouse suspicion, patients must first be identified before addressing treatment issues. This can be done by screening.

There are controversial policy issues surrounding the ethics of screening, particularly if a country does not have the resources to treat the number of individuals that are expected to be identified. This is discussed at length in the public policy module.

Some countries recommend screening people with risk factors such as current or previous injection drug users or those who received blood transfusions prior to implementing safe screening strategies. Other countries recommend screening high risk groups, such as those born between 1945-1965 ― a generation that was more exposed to infection before the virus was identified.

As the risk of being infected is higher in these groups, the probability of finding patients with asymptomatic liver disease who would benefit from treatment is higher as well.

Encouraging everybody to get tested, would increase the number of infected people identified. Many of these individuals may have been well for decades (and maybe would have died of other causes before even knowing they were infected by HCV), but they are now suddenly told that they have a disease. Since transmission of HCV is not so easy in everyday life, and common hygienic habits are enough to avoid it, this revelation is unlikely to improve prevention measures markedly. However studies show that people diagnosed with HCV express relief in knowing about their disease as they feel more in control of avoiding infecting those they love. In addition, individuals who become aware of their infection can take measures to help limit further damage to their liver. There are many life style changes that an infected patient can adopt, such as no longer consuming alcohol.

10. Who should be treated?

Now that effective and tolerable treatments are available, many patients’ associations, doctors and experts worldwide feel that all the people infected with HCV should be treated, irrespective of the state of their liver or of the cost of treatment.

From a clinical point of view, the goal of treatment is to cure HCV patients of infection to prevent hepatic cirrhosis, or halt cirrhosis before the liver is too damaged to function, known as decompensated cirrhosis. Other long terms effects include liver cancer, and even severe health issues in other parts of the body – including autoimmune conditions and nephropathies, and death.

In patients with advanced fibrosis and cirrhosis, the cure reduces the risk of decompensation and cancer. When a patient already has decompensated cirrhosis, the treatment can reduce the need for a liver transplantation. However, it should be noted that the impact on middle-to long term survival in these patients is still unknown.

According to the 2015 EASL guidelines, all patients with chronic liver disease due to HCV should be considered for treatment, with priorities associated to the severity of their condition.

Treatment with an interferon-free regimen is urgent in patients with decompensated cirrhosis and should be prioritized in patients with significant fibrosis or cirrhosis, i.e. with F3 to F4 score on the METAVIR scale of liver disease severity.

In patients with no damage or mild disease the treatment can be either deferred or considered in particular cases of severity (HBV or HIV coinfection, significant extra-hepatic manifestations, debilitating fatigue) or when the risk of transmitting HCV to others is high.

Indications for treatment of chronic hepatitis C in 2015: Who should be treated and when?

Table 5



Modified from EASL Recommendations on Treatment of Hepatitis C 2015

11. Is eradication of hepatitis C the actual goal?

Despite the availability of very effective treatments, complete eradication of hepatitis C from the world is not a realistic goal without a vaccine. A much more realistic goal is control of the disease, which can be achieved at least in high income countries, through prevention, diagnosis, a good healthcare system and access to drugs.

12. How much do these new drugs cost?

Negotiations between countries and pharmaceutical companies vary from one country to another. As a result, their price is different from drug to drug and from country to country.
In the US, when sofosbuvir was introduced, each pill cost about 1000 dollars US, for a total price of 80.000-90.000 dollars for a cycle of 12 weeks.

In Europe different health systems have negotiated different prices, in some circumstances up to half the US price. In Italy, for example, a price/volume system of payment has been established, with the cost of drugs going down the more patients are treated.

In low income countries firms have agreed on a cheaper price. In Egypt a whole cycle of sofosbuvir costs about 500 US dollars. In India, Gilead (the company that owns sofosbuvir) has allowed 11 generic firms to produce the drug at low prices and sell it to about 90 developing countries, with a list of clauses to avoid illicit marketing towards middle and high-income countries.

13. How is (and could) Hepatitis C be treated and managed in low and middle resources countries?

The challenge of Hepatitis C in low and middle income countries is not only about the price of drugs. There are other hurdles to face, such as traditional habits that hinder prevention and facilitate the transmission of the disease, the cost and difficulties of screening and the lack of medical resources. Hepatologists, for example, are very rare in Africa, but infectious disease specialists knowledgeable in liver diseases could be recruited. The network of institutions, facilities and staff built up to address HIV in many low and middle income countries could be now exploited to deal with HCV as well.

When an effective treatment to control AIDS was developed, it seemed costs would be prohibitive for low income countries. Instead, today, thanks to the efforts of governments, industry and non- governmental organizations, most patients who are diagnosed in the world can have access to treatment.

The same result can hopefully be achieved for hepatitis C.


Ghany MG, Strader DB, Thomas DL, Seeff LB; American Association for the Study of Liver Diseases. Diagnosis, management, and treatment of hepatitis C: an update. Hepatology. 2009;49:1335-74. I can’t get access to this – but that is the original reference which should be checked out.

R Koretz et al. Is widespread screening for hepatitis C justified? BMJ 2015; 350:g7809